tag:blogger.com,1999:blog-70823501418271222722024-03-18T04:47:40.086-07:00DRUG SYNTHESIS INTERNATIONALMEDICINAL CHEMISTRY AT ITS BEST, Tracks information on drugs on worldwide basis by Dr Anthony Melvin Crasto, Worlddrugtracker helping millions with websites, 6 million hits on google, one lakh connections worldwide, email amcrasto@gmail.com, +91 9323115463 INDIADRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.comBlogger75125tag:blogger.com,1999:blog-7082350141827122272.post-14063907986095963812020-09-17T04:37:00.004-07:002020-09-17T04:37:29.019-07:00MOLINDONE, молиндон موليندون 吗茚酮<p> https://newdrugapprovals.org/2020/08/27/molindone-%d0%bc%d0%be%d0%bb%d0%b8%d0%bd%d0%b4%d0%be%d0%bd-%d9%85%d9%88%d9%84%d9%8a%d9%86%d8%af%d9%88%d9%86-%e5%90%97%e8%8c%9a%e9%85%ae/</p><p><br /></p><p><br /></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com21tag:blogger.com,1999:blog-7082350141827122272.post-61033488268864909472015-12-27T18:46:00.002-08:002015-12-27T18:46:52.207-08:00New Drug Approvals blog by Dr Anthony Crasto hits ten lakh views in 211 countries<div dir="ltr" style="text-align: left;" trbidi="on">
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New Drug Approvals hits ten lakh views in 211 countries<br />
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com62tag:blogger.com,1999:blog-7082350141827122272.post-18187774982804880372015-11-19T01:48:00.000-08:002015-11-19T01:51:12.309-08:00Mirogabalin<div dir="ltr" style="text-align: left;" trbidi="on">
<img alt="" data-mce-src="http://www.drugspider.com/sites/default/files/styles/structure/public/chemicalstructure/Untitled_71.png?itok=z3snEJis" src="http://www.drugspider.com/sites/default/files/styles/structure/public/chemicalstructure/Untitled_71.png?itok=z3snEJis" /><img alt="" class="" data-mce-src="http://pubchem.ncbi.nlm.nih.gov/image/img3d.cgi?cid=59509752" src="http://pubchem.ncbi.nlm.nih.gov/image/img3d.cgi?cid=59509752" height="166" width="166" /><br />
<div class="field-item even">
Mirogabalin, A-2000700, DS-5565</div>
<div class="field-item even">
1138245-13-2, C12H19NO2, 209.28</div>
<div class="field-item even">
[(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid</div>
<div class="field-item even">
2-[(1R,5S,6S)-6-(aminomethyl)-3-ethyl-6-bicyclo[3.2.0]hept-3-enyl]acetic acid</div>
<div class="field-item even">
UNII-S7LK2KDM5U</div>
<div class="field-item even">
</div>
<div class="field-item even">
<table class="field-group-format group_drugtable mce-item-table"><tbody>
<tr class=""><th class="field-label">Originator</th><td class="field-content"><div class="field field-name-field-originator field-type-taxonomy-term-reference field-label-hidden">
<div class="field-items">
<div class="field-item even">
Daiichi Sankyo</div>
</div>
</div>
</td></tr>
<tr class=""><th class="field-label">Therapeutic Claim</th><td class="field-content"><div class="field field-name-field-therapeutic-claim field-type-taxonomy-term-reference field-label-hidden">
<div class="field-items">
<div class="field-item even">
Treatment of fibromyalgia</div>
</div>
</div>
</td></tr>
</tbody></table>
Phase III clinical trials at Daiichi Sankyo for the treatment of pain associated with fibromyalgia</div>
<div class="field-item even">
<img alt="Daiichi-Sankyo Passion for Innovation. Compassion for Patients.®" data-mce-src="http://www.daiichisankyo.com/common_res/images/com_logo001.png" src="http://www.daiichisankyo.com/common_res/images/com_logo001.png" /></div>
<div class="field-item even">
</div>
<div class="field-item even">
<table class="field-group-format group_drugtable mce-item-table"><tbody>
<tr class=""><th class="field-label">Class</th><td class="field-content"><div class="field field-name-field-class field-type-taxonomy-term-reference field-label-hidden">
<div class="field-items">
<div class="field-item even">
Analgesic drugs (small molecules)</div>
</div>
</div>
</td></tr>
<tr class=""><th class="field-label">Mechanism of action</th><td class="field-content"><div class="field field-name-field-mechanism-of-action field-type-taxonomy-term-reference field-label-hidden">
<div class="field-items">
<div class="field-item even">
CACNA2D1 protein modulators</div>
</div>
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SYNTHESIS<br />
<img alt="" class="" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@525@@@254@@@jpoxmldoc01-appb-c000014.jpg" height="373" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@525@@@254@@@jpoxmldoc01-appb-c000014.jpg" width="771" /><br />
<ul class="description"><ul class="description"><ul class="description">
<li><div class="description-line">
<div class="patent-image">
<ul class="description">SEE</ul>
<ul class="description">[(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid benzenesulfonate
<li><div class="description-line-number">
</div>
<div class="description-line">
<div class="patent-image">
<a data-mce-href="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0027.png" href="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0027.png"><img alt="Figure imgb0027" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0027.png" height="164" id="ib0027" src="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0027.png" width="360" /></a></div>
</div>
</li>
</ul>
<span data-mce-style="color: #ff0000;" style="color: red;">DESIRED</span></div>
</div>
<div class="patent-image">
</div>
<div class="description-line">
<div class="patent-image">
<ul class="description">[(1S,5R,6R)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid , optical isomer of the compound
<li><div class="description-line-number">
</div>
<div class="description-line">
<div class="patent-image">
<a data-mce-href="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0023.png" href="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0023.png"><img alt="Figure imgb0023" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0023.png" height="172" id="ib0023" src="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0023.png" width="360" /></a><span data-mce-style="color: #ff0000;" style="color: red;">UNDESIRED</span></div>
</div>
</li>
</ul>
</div>
</div>
</li>
</ul>
</ul>
</ul>
<br />
<div class="field-item even">
<b>Mirogabalin</b> (<b>DS-5565</b>) is a drug developed by <a data-mce-href="https://en.wikipedia.org/wiki/Daiichi_Sankyo" href="https://en.wikipedia.org/wiki/Daiichi_Sankyo" title="Daiichi Sankyo">Daiichi Sankyo</a> and related to drugs such as <a data-mce-href="https://en.wikipedia.org/wiki/Gabapentin" href="https://en.wikipedia.org/wiki/Gabapentin" title="Gabapentin">gabapentin</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Pregabalin" href="https://en.wikipedia.org/wiki/Pregabalin" title="Pregabalin">pregabalin</a>. Similarly to these drugs, mirogabalin binds to the α<sub>2</sub>δ <a data-mce-href="https://en.wikipedia.org/wiki/Calcium_channel" href="https://en.wikipedia.org/wiki/Calcium_channel" title="Calcium channel">calcium channels</a> (<a data-mce-href="https://en.wikipedia.org/wiki/CACNA2D1" href="https://en.wikipedia.org/wiki/CACNA2D1" title="CACNA2D1">1</a> and <a data-mce-href="https://en.wikipedia.org/wiki/CACNA2D2" href="https://en.wikipedia.org/wiki/CACNA2D2" title="CACNA2D2">2</a>), but with significantly higher potency than pregabalin. It has shown promising results in Phase II <a data-mce-href="https://en.wikipedia.org/wiki/Clinical_trial" href="https://en.wikipedia.org/wiki/Clinical_trial" title="Clinical trial">clinical trials</a> for the treatment of <a data-mce-href="https://en.wikipedia.org/wiki/Complications_of_diabetes_mellitus" href="https://en.wikipedia.org/wiki/Complications_of_diabetes_mellitus" title="Complications of diabetes mellitus">diabetic</a> peripheral <a data-mce-href="https://en.wikipedia.org/wiki/Neuropathic_pain" href="https://en.wikipedia.org/wiki/Neuropathic_pain" title="Neuropathic pain">neuropathic pain</a>,<sup class="reference" id="cite_ref-1"><a data-mce-href="https://en.wikipedia.org/wiki/Mirogabalin#cite_note-1" href="https://en.wikipedia.org/wiki/Mirogabalin#cite_note-1">[1]</a></sup><sup class="reference" id="cite_ref-2"><a data-mce-href="https://en.wikipedia.org/wiki/Mirogabalin#cite_note-2" href="https://en.wikipedia.org/wiki/Mirogabalin#cite_note-2">[2]</a></sup> and is currently in Phase III trials.<br />
Mirogabalin,
a voltage-dependent calcium channel subunit alpha-2/delta-1 ligand, is
in phase III clinical trials at Daiichi Sankyo for the treatment of pain
associated with fibromyalgia. The company is also conducting phase III
clinical studies for the treatment of chronic pain and pain associated
with diabetic peripheral neuropathy.<br />
<img alt="" data-mce-src="http://chem.sis.nlm.nih.gov/chemidplus/structure/1138245-21-2" src="http://chem.sis.nlm.nih.gov/chemidplus/structure/1138245-21-2" /></div>
<h1 id="yui_3_18_1_3_1447914298079_392">
Mirogabalin besylate</h1>
<h1 id="yui_3_18_1_3_1447914298079_392">
<span id="yui_3_18_1_3_1447914298079_440">cas 1138245-21-2</span><br /> <span id="yui_3_18_1_3_1447914298079_439">UNII: 01F4FRP8YL</span></h1>
<h1>
C12-H19-N-O2.C6-H6-O3-S, 367.4635</h1>
<h4 id="infoHeader">
<i id="yui_3_18_1_3_1447914298079_480">Bicyclo(3.2.0)hept-3-ene-6-acetic acid, 6-(aminomethyl)-3-ethyl-, (1R,5S,6S)-, benzenesulfonate (1:1)</i></h4>
SEE<br />
Tert-butyl [(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetate D-mandelate.....<a data-mce-href="http://www.google.com/patents/US20140094623?cl=zh" href="http://www.google.com/patents/US20140094623?cl=zh">http://www.google.com/patents/US20140094623?cl=zh</a><br />
<h1>
<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
WO 2009041453<br />
<a data-mce-href="https://www.google.co.in/patents/EP2192109A1" href="https://www.google.co.in/patents/EP2192109A1">https://www.google.co.in/patents/EP2192109A1</a><br />
<ul class="description"><ul class="description"><ul class="description"><ul class="description">(Example
21)
[(1S,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic
acid (exemplary compound No: 8, optically active form of the compound of
Example 8)
<li><div class="description-line-number">
</div>
<div class="description-line">
<div class="patent-image">
<a data-mce-href="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0021.png" href="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0021.png"><img alt="Figure imgb0021" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0021.png" height="168" id="ib0021" src="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0021.png" width="356" /></a></div>
</div>
</li>
</ul>
</ul>
</ul>
</ul>
(21-a) Resolution of tert-butyl (±)-[(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate<br />
<ul class="description"><ul class="description"><ul class="description"><ul class="description">
<li><div class="description-line-number">
</div>
<div class="description-line">
Tert-butyl
(±)-[(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate
(230 g, 778 mmol) was resolved using Chiralpak IC (N-Hex:EtOH=98:2, 1.0
mL/min, 40°C) manufactured by Daicel Chemical Industries, Ltd. to
respectively obtain 115 g of a peak 1 (retention time: 5.2 min) and 93.7
g of a peak 2 (retention time: 6.3 min).</div>
</li>
</ul>
</ul>
</ul>
</ul>
(21-b) Tert-butyl ([(1R,5S,6S)-6-(tert-butoxycarbonylamino)methyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetate<br />
<ul class="description"><ul class="description"><ul class="description">
<li><div class="description-line-number">
</div>
<div class="description-line">
Tert-butyl
[(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate
(peak 1, 7.0 g, 23.7 mmol) was dissolved in ethanol (60 mL) and water
(21 mL). To the solution, iron powder (13.27 g, 237 mmol) and ammonium
chloride (628.1 mg, 11.9 mmol) were added, and the mixture was stirred
for 5.5 hours under heating to reflux. The mixture was allowed to cool,
then diluted with saturated saline, a saturated aqueous solution of
sodium bicarbonate, and ethyl acetate, and filtered through Celite to
remove insoluble matter. The filtrate was separated into organic and
aqueous layers. The organic layer was washed with saturated saline and
then dried over anhydrous magnesium sulfate. Then, the solvent was
distilled off under reduced pressure to obtain a pale yellow oil
substance (7.02 g). This substance was dissolved in dichloromethane (200
mL). To the solution, (Boc)<sub>2</sub>O (5.25 g, 25 mmol) and
triethylamine (5.01 g, 50 mmol) were added, and the mixture was stirred
overnight at room temperature. The solvent was distilled off under
reduced pressure, and the residue was then purified by silica gel
chromatography to obtain the title compound of interest as a pale yellow
oil substance (8.82 g, <100%). (21-c)
[(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic
acid</div>
</li>
<li><div class="description-line-number">
</div>
<div class="description-line">
A
4 N hydrochloric acid-ethyl acetate solution (100 mL) was added to
tert-butyl
(1R,5S,6S)-[6-(tert-butoxycarbonylaminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetate
(9.82 g, 23.7 mmol), and the mixture was stirred at room temperature
for 1 hour. Then, the solvent was distilled off under reduced pressure.
The residue was dissolved in dichloromethane. To the solution,
triethylamine was added dropwise, and the resulting powder was collected
by filtration, then washed with dichloromethane, and then dried to
obtain 4.02 g of a white powder. This powder was washed with ethanol and
ethyl acetate to obtain the title compound of interest as a white
powder (2.14 g, 43%).<br />
<ul class="description">(Example 31)
[(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic
acid benzenesulfonate (exemplary compound No: 8, optically active
benzenesulfonate)
<li><div class="description-line-number">
</div>
<div class="description-line">
<div class="patent-image">
<a data-mce-href="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0027.png" href="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0027.png"><img alt="Figure imgb0027" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0027.png" height="164" id="ib0027" src="https://patentimages.storage.googleapis.com/EP2192109A1/imgb0027.png" width="360" /></a></div>
</div>
</li>
<li><div class="description-line-number">
</div>
<div class="description-line">
(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic
acid (4.50 g, 20.6 mmol) was dissolved by heating in a 1 M aqueous
solution (22.7 mL) of benzenesulfonic acid monohydrate, and the solution
was then allowed to cool to room temperature. The resulting solid was
collected by filtration. The solid was washed with water (15 mL) and
then dried using a vacuum pump to obtain the compound of interest as a
colorless solid (6.45 g, 77%).</div>
</li>
</ul>
</div>
</li>
</ul>
</ul>
</ul>
<br />
<h1>
<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
JP 2010241796<br />
<h1>
<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
WO 2012169475<br />
<ul class="description">
<li><div class="description-line" id="p-0016">
</div>
</li>
<li><div class="description-line" id="p-0017">
<div class="patent-image">
<a data-mce-href="http://patentimages.storage.googleapis.com/US20140094623A1/US20140094623A1-20140403-C00002.png" href="http://patentimages.storage.googleapis.com/US20140094623A1/US20140094623A1-20140403-C00002.png"><img alt="Figure US20140094623A1-20140403-C00002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/US20140094623A1/US20140094623A1-20140403-C00002.png" src="http://patentimages.storage.googleapis.com/US20140094623A1/US20140094623A1-20140403-C00002.png" height="637" id="EMI-C00002" width="303" /></a></div>
</div>
<div class="patent-image">
<ul class="description"><ul class="description">Reference Example 1[6-Aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0102">
<div class="patent-image">
<a data-mce-href="http://patentimages.storage.googleapis.com/US20140094623A1/US20140094623A1-20140403-C00023.png" href="http://patentimages.storage.googleapis.com/US20140094623A1/US20140094623A1-20140403-C00023.png"><img alt="Figure US20140094623A1-20140403-C00023" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/US20140094623A1/US20140094623A1-20140403-C00023.png" src="http://patentimages.storage.googleapis.com/US20140094623A1/US20140094623A1-20140403-C00023.png" height="86" id="EMI-C00023" width="260" /></a></div>
</div>
</li>
</ul>
</ul>
(1-a) Ethyl 4-ethyl-3-hydroxyhept-6-enoate<br />
<ul class="description"><ul class="description">
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0103">
Sodium
hydride (>63% oil, 2.09 g, 55 mmol) was added to a solution of ethyl
3-oxohexanoate (7.91 g, 50 mmol) in tetrahydrofuran (50 mL) under ice
cooling, and the mixture was stirred in this state for 10 minutes. To
the reaction solution, n-butyllithium (1.58 M solution in hexane, 34.8
mL, 55 mmol) was added dropwise, and the mixture was further stirred for
10 minutes under ice cooling. Then, allyl bromide (4.7 mL, 55 mmol) was
added thereto, and the mixture was stirred in this state for 1 hour and
then further stirred at room temperature for 4 hours. To the reaction
solution, 1 N hydrochloric acid and a saturated aqueous solution of
ammonium chloride were added, followed by extraction with n-pentane. The
organic layer was washed with saturated saline and dried over anhydrous
magnesium sulfate, and the solvent was distilled off under reduced
pressure. The obtained residue was dissolved in ethanol (80 mL). To the
solution, sodium borohydride (1.51 g, 40 mmol) was added under ice
cooling, and the mixture was stirred in this state for 2 hours. 1 N
hydrochloric acid (50 mL) was added thereto, and the mixture was stirred
for 30 minutes. Then, saturated saline was added thereto, followed by
extraction with ethyl acetate. The organic layer was washed with
saturated saline and then dried over anhydrous magnesium sulfate, and
the solvent was distilled off under reduced pressure. The residue was
purified by silica gel column chromatography to obtain the compound of
interest as a pale yellow oil substance (3.64 g, 37%, mixture of
diastereomers).</div>
</li>
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0104">
<sup>1</sup>H-NMR (400 MHz, CDCl<sub>3</sub>):
δ ppm: 0.91 (3H, t, J=7.5 Hz), 1.28 (3H, t, J=7.2 Hz), 1.43-1.55 (2H,
m), 1.98-2.28 (2H, m), 2.45-2.48 (2H, m), 2.88-2.93 (1H, m), 4.07-4.10
(1H, m), 4.10-4.20 (2H, m), 5.01-5.09 (2H, m), 5.75-5.86 (1H, m).</div>
</li>
</ul>
</ul>
(1-b) 4-Ethyl-3-hydroxyhept-6-enoic acid<br />
<ul class="description"><ul class="description">
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0105">
Ethyl
4-ethyl-3-hydroxyhept-6-enoate (3.64 g, 18.2 mmol) was dissolved in a 2
N solution of potassium hydroxide in methanol (120 mL), and the
solution was stirred overnight at room temperature. From the reaction
solution, the solvent was distilled off under reduced pressure. To the
residue, a 1 N aqueous sodium hydroxide solution (200 mL) was then
added, followed by extraction with diethyl ether. The aqueous layer was
made acidic by the addition of concentrated hydrochloric acid under ice
cooling, followed by extraction with diethyl ether again. The organic
layer was washed with saturated saline and dried over anhydrous
magnesium sulfate. Then, the solvent was distilled off under reduced
pressure to obtain the compound of interest as a pale yellow oil
substance (3.14 g, <100%, mixture of diastereomers).</div>
</li>
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0106">
<sup>1</sup>H-NMR (400 MHz, CDCl<sub>3</sub>):
δ ppm: 0.91-0.96 (3H, m), 1.39-1.52 (3H, m), 2.01-2.28 (2H, m),
2.52-2.55 (2H, m), 4.05-4.15 (2H, m), 5.03-5.10 (2H, m), 5.74-5.86 (1H,
m).</div>
</li>
</ul>
</ul>
(1-c) Tert-butyl 3-ethylbicyclo[3.2.0]hept-3-en-6-ylideneacetate<br />
<ul class="description"><ul class="description">
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0107">
4-Ethyl-3-hydroxyhept-6-enoic
acid (3.13 g, 18.2 mmol) was dissolved in acetic anhydride (15 mL). To
the solution, potassium acetate (4.27 g, 43.6 mmol) was added, and the
mixture was stirred at room temperature for 100 minutes. The reaction
solution was heated to reflux and stirred for 3.5 hours to form
“3-ethylbicyclo[3.2.0]hept-6-en-6-one” in the reaction solution. To the
reaction solution, ice water and toluene were then added, and this
mixture was stirred overnight at room temperature. The mixture was
separated into aqueous and organic layers by the addition of saturated
saline (50 mL) and toluene (20 mL). Then, the organic layer was washed
with a 1 N aqueous sodium hydroxide solution and saturated saline in
this order, then dried over anhydrous magnesium sulfate, and filtered.
The filtrate was added to a reaction solution prepared by adding sodium
hydride (>65% oil, 761.9 mg, 20 mmol) to a solution of tert-butyl
dimethoxyphosphorylacetate (4.48 g, 20 mmol) in tetrahydrofuran (50 mL)
under ice cooling, and the mixture was further stirred for 1 hour. The
reaction solution was separated into aqueous and organic layers by the
addition of a saturated aqueous solution of ammonium chloride and
saturated saline. The aqueous layer was subjected to extraction with
ethyl acetate. The organic layers were combined, then washed with
saturated saline, and then dried over anhydrous magnesium sulfate. The
solvent was distilled off under reduced pressure, and the residue was
purified by silica gel column chromatography to obtain the compound of
interest as a pale yellow oil substance (1.32 g, 31%, E/Z mixture).</div>
</li>
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0108">
<sup>1</sup>H-NMR (400 MHz, CDCl<sub>3</sub>): δ ppm:</div>
</li>
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0109">
Major
isomer: 1.06 (3H, t, J=7.4 Hz), 1.45 (9H, s), 2.07-2.22 (3H, m),
2.59-2.70 (2H, m), 2.87-2.96 (1H, m), 3.30 (1H, ddt, J=8.6, 18.4, 2.7
Hz), 3.86-3.88 (1H, m), 5.22-5.23 (1H, m), 5.45-5.47 (1H, m).</div>
</li>
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0110">
Minor
isomer: 1.08 (3H, t, J=7.3 Hz), 1.49 (9H, s), 2.07-2.21 (3H, m),
2.43-2.47 (1H, m), 2.59-2.70 (1H, m), 2.75-2.85 (1H, m), 2.87-2.96 (1H,
m), 4.28-4.31 (1H, m), 5.35-5.38 (1H, m), 5.45-5.47 (1H, m).</div>
</li>
</ul>
</ul>
(1-d) Tert-butyl [3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate<br />
<ul class="description"><ul class="description">
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0111">
Tert-butyl
[3-ethylbicyclo[3.2.0]hept-3-en-6-ylideneacetate (1.32 g, 5.63 mmol)
was dissolved in nitromethane (7 mL). To the solution,
1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 mL, 7.3 mmol) was added, and the
mixture was heated with stirring at 50 to 60° C. for 7 hours. The
mixture was allowed to cool, and a saturated aqueous solution of
potassium dihydrogen phosphate was then added thereto, followed by
extraction with ethyl acetate. Then, the organic layer was dried over
anhydrous magnesium sulfate, and the solvent was distilled off under
reduced pressure. The residue was purified by silica gel column
chromatography to obtain the compound of interest as a colorless oil
substance (1.39 g, 84%).</div>
</li>
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0112">
<sup>1</sup>H-NMR (400 MHz, CDCl<sub>3</sub>):
δ ppm: 1.09 (3H, t, J=7.4 Hz), 1.46 (9H, s), 1.52 (1H, dd, J=7.6, 13.2
Hz), 2.06 (1H,d, 16.6 Hz), 2.14 (2H, q, J=7.4 Hz), 2.30 (1H, ddd, J=2.4,
7.6, 13.2 Hz), 2.47 (2H, s), 2.49 (1H, dd, J=7.6,16.6 Hz), 2.86 (1H,
quint, J=7.6 Hz), 3.21-3.22 (1H, m), 4.75 (1H, d, J=11.7 Hz), 4.84 (1H,
d, J=11.7 Hz), 5.27 (1H, s).</div>
</li>
</ul>
</ul>
(1-e) [6-Aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid<br />
<ul class="description">
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0113">
Tert-butyl
[3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.09 g,
4.71 mmol) was dissolved in ethanol (10 mL) and water (5 mL). To the
solution, iron powder (1.32 g, 23.5 mmol) and ammonium chloride (249.6
mg, 4.71 mmol) were added, and the mixture was stirred for 2 hours under
heating to reflux. The mixture was allowed to cool, then diluted with
saturated saline, a saturated aqueous solution of sodium bicarbonate,
and ethyl acetate, and filtered through Celite to remove insoluble
matter. The filtrate was separated into organic and aqueous layers. The
organic layer was washed with saturated saline and then dried over
anhydrous magnesium sulfate, and the solvent was then distilled off
under reduced pressure. To the residue, a 4 N solution of hydrochloric
acid in ethyl acetate (20 mL) was added, and the mixture was stirred at
room temperature for 1 hour. Then, the solvent was distilled off under
reduced pressure. The residue was suspended in dichloromethane. To the
suspension, triethylamine was added dropwise, and the resulting powder
was collected by filtration, then washed with dichloromethane, and then
dried to obtain the compound of interest as a white powder (425.1 mg,
43%).</div>
</li>
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0114">
<sup>1</sup>H-NMR (400 MHz, CD<sub>3</sub>OD):
δ ppm: 1.10 (3H, t, J=7.4 Hz), 1.48 (1H, dd, J=7.5, 12.5 Hz), 2.03-2.08
(2H, m), 2.14 (2H, q, J=7.4 Hz), 2.46 (1H, d, J=16.2 Hz), 2.46-2.53
(1H, m), 2.51 (1H, d, J=16.2 Hz), 2.85 (1H, quint, J=7.5 Hz), 3.09-3.10
(1H, m), 3.14 (1H, d, J=13.0 Hz), 3.18 (1H, d, J=13.0 Hz), 5.38 (1H, dd,
J=1.7, 3.7 Hz).</div>
</li>
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0115">
(Step of Performing Optical Resolution from Diastereomeric Mixture)</div>
</li>
</ul>
</div>
<ul class="description">Reference Example 2Tert-butyl [(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetate D-mandelate
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0116">
<div class="patent-image">
<a data-mce-href="http://patentimages.storage.googleapis.com/US20140094623A1/US20140094623A1-20140403-C00024.png" href="http://patentimages.storage.googleapis.com/US20140094623A1/US20140094623A1-20140403-C00024.png"><img alt="Figure US20140094623A1-20140403-C00024" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/US20140094623A1/US20140094623A1-20140403-C00024.png" src="http://patentimages.storage.googleapis.com/US20140094623A1/US20140094623A1-20140403-C00024.png" height="545" id="EMI-C00024" width="304" /></a></div>
</div>
</li>
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0117">
Acetonitrile
(4.7 L, 8.6 v/w) was added to tert-butyl
[6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetate (627.0 g,
net: 543.6 g, 2.05 mol, 85:15 diastereomeric mixture), and the mixture
was stirred at 40° C. To the reaction solution, D-mandelic acid (116.3
g, 0.76 mmol, 0.37 eq.) was added, and the mixture was stirred at 40° C.
for 1 hour and then allowed to cool slowly to 3° C. After stirring at
3° C. for 1 hour, the resulting crystal was collected by filtration.
Then, the crystal was dried under reduced pressure under the condition
of 40° C. to obtain tert-butyl
[(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetate
D-mandelate as a white powder (251.2 g, yield: 29.4%, 97.6% ee, 99.6%
de).</div>
</li>
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0118">
<sup>1</sup>H-NMR
(400 MHz, DMSO-d6) δ ppm: 1.04 (3H, t, J=7.6 Hz), 1.28-1.35 (1H, m),
1.39 (9H, s), 1.96-2.11 (4H, m), 2.28 (1H, d, J=15.6 Hz), 2.33 (1H, d,
J=15.6 Hz), 2.36-2.40 (1H, m), 2.72 (1H, quint, J=7.6 Hz), 3.00 (1H, d,
J=13.2 Hz), 3.03 (1H, d, J=13.2 Hz), 3.31 (1H, br s), 4.54 (1H, s),
5.21-5.23 (1H, m), 7.13-7.25 (3H, m), 7.35-7.37 (2H, m).</div>
</li>
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0119">
[α]<sub>20</sub> <sup>D </sup>−104.4° (C=0.108, MeOH).</div>
</li>
<li><div class="description-line-number">
</div>
<div class="description-line" id="p-0120">
Anal. calcd for C<sub>24</sub>H<sub>35</sub>NO<sub>5</sub>: C, 69.04; H, 8.45; N, 3.35; Found C, 69.15; H, 8.46; N, 3.46.</div>
</li>
</ul>
</li>
</ul>
<h1>
<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
WO 2012169474<br />
<br />
<h1>
<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
<a data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015005298&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText" href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015005298&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText">WO2015005298</a><br />
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@525@@@254@@@jpoxmldoc01-appb-c000014.jpg" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@525@@@254@@@jpoxmldoc01-appb-c000014.jpg" /><br />
<br />
<div class="paragraph" id="paragraph0013">
<div class="pContent">
[Step D-2]<br />
a compound having the formula (Va) (and its enantiomers), and to carry
out optical resolution by chloride with optically active organic amine,
and is a process for preparing a compound having the general formula
(VIa) .<br />
[Formula 19] The solvent used in this step, MTBE, CPME,
ethers such as THF; aromatic hydrocarbons such as toluene; esters such
as ethyl acetate; EtOH, alcohols such as diisopropyl alcohol CH; s <sub>three</sub>
nitriles such as CN; ketones such as acetone; or is a mixed solvent of
these solvents and water, preferably toluene, ethyl acetate, CH <sub>3</sub>
CN, are MTBE, More preferably, toluene, MTBE. Optically active organic
amine used in this step, preferably, (1R, 2R) -trans-1-
amino-2-indanol, (S) -2- phenylglycinol, (R) -1- ( p- tolyl) ethylamine,
(1R, 2S) -2- amino-1,2-diphenyl ethanol, (S) -1- (2- naphthyl)
ethylamine, (R) -1- (4- bromophenyl) ethylamine, (1S, 2R) - (+) - 1-
amino-2-indanol is a L- phenylalaninol, etc., more preferably, (1R, 2R)
-trans-1- amino-2-indanol, (S ) -2-phenylglycinol. Equivalent of the
optically active organic amine to be used have the general formula (Va)
compound having a relative (and its enantiomers) are 0.5-1.1
equivalents. The reaction temperature of this step is such as about
0-50 ℃, preferably, after aging the crystals at about 10-30 ℃, is
obtained by filtering the compound of formula (VIa). The time required
to chloride present step is not particularly limited, but is usually 4
to about 48 hours. In this step, (1) with respect to (Va) compound with
(and its enantiomers), directly to a compound of formula (VIa) with the
desired configuration by the action of the above-mentioned optically
active amine How to get, or, with respect to (2) compounds having
formula (Va) (or its enantiomer), first, quinine, (1S, 2S) -trans-1-
amino-2-indanol, (R) -2- by the action of an optically active amine such
as phenylglycinol, it allowed to temporarily deposit the enantiomer
having the unnecessary configuration, after removing the precipitate by
filtration, against followed by compound obtained from the filtrate,
(1R, 2R ) -trans-1- amino-2-indanol, by the action of optically active
amines such as (S) -2- phenylglycinol, to precipitate the salt of the
compound of formula (VIa) with the desired configuration How to get Te,
one of the methods is used.<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@116@@@jpoxmldoc01-appb-c000032.jpg" height="116" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@116@@@jpoxmldoc01-appb-c000032.jpg" width="535" />Known
compounds having the general formula (Va) which are used in the above
Step D-1 or step D-2, which can be prepared according to step A-C, as
otherwise, it is disclosed in Patent Document 5 It can be prepared by
method (the following scheme).<br />
[Formula 20] specific production method according to the present method will be described later as a reference example.<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@157@@@jpoxmldoc01-appb-c000033.jpg" height="157" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@157@@@jpoxmldoc01-appb-c000033.jpg" width="535" /></div>
</div>
<div class="paragraph" id="paragraph0015">
<div class="pContent">
[Step E]<br />
Formula (V) or a compound having the general formula (VI) from (and /
or its enantiomer) is a process for preparing a compound of formula
(VII) (and / or its enantiomer), the general formula (V) is a compound
having (and / or its enantiomer), under a hydrogen atmosphere in the
presence of a metal catalyst, reduction with a solvent, or a compound
having the general formula (VI) (and / or its enantiomer) solution
compounds having the general formula (V) obtained by salt (and / or its
enantiomer) solution, under a hydrogen atmosphere to carry out a
reduction reaction in the presence of a metal catalyst, by a compound of
formula (VII) This is a method of manufacturing a.<br />
Formula 21] (1)
Kaishio step formula compound with a (VI) (and / or its enantiomer) is
suspended in an organic solvent, washed with an aqueous solution
obtained by adding an acid, by liquid separation and the organic layer ,
compounds having general formula (V) (and / or its enantiomer) solution
containing it can get. The solvent used in this step include aromatic
hydrocarbons such as toluene, ethers such as MTBE, an ester such as
ethyl acetate, and the like, preferably toluene, or is MTBE. Acid used
in this step is not particularly limited, hydrochloric acid, sulfuric
acid, phosphoric acid, citric acid, malonic acid can be used.<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@466@@@252@@@jpoxmldoc01-appb-c000034.jpg" height="252" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@466@@@252@@@jpoxmldoc01-appb-c000034.jpg" width="466" /></div>
</div>
<br />
<div class="paragraph" id="paragraph0016">
<div class="pContent">
(2) the reduction reaction step<br />
compounds having the general formula (V) (and / or its enantiomer),
under a hydrogen atmosphere in the presence of a metal catalyst was
reduced in a solvent, a cyano group (or a nitro group) and an amino
group It is converted into, and is a step for preparing a compound of
formula (VII). This reaction is usually carried out in a neutral or
basic conditions.<br />
The solvent used in this step include aromatic
hydrocarbons such as toluene, MTBE, ethers such as THF, alcohols of
C1-C4, or is water, preferably toluene, MTBE, or water , and the
Particularly preferred is water.<br />
Metal catalyst used in this step,
vinegar Sanskrit nickel, sponge cobalt, or palladium - is carbon,
preferably, sponge nickel (eg, Kawaken Fine Chemicals Co., Ltd. of
PL-9T, NDT-65, NDT- 90, NDHT-90M, NDHT-M3, and the like, or, Nikko Rika
Co., Ltd. R-100, R-200, such as R-205, R-211, R-2311), or, sponge cobalt
(for example, the river Research ODHT-60 manufactured by Fine Chemical
Co., Ltd., OFT-55, or the like, or is a Nikko Rika Co., Ltd. R-400,
R-400K, such as R-401, R-455, such as A-8B46 manufactured by Johnson
Matthey) .<br />
In this step, when carrying water as a solvent is usually
added to the base. As the base used, preferably an inorganic base,
particularly preferred are lithium hydroxide, sodium hydroxide, alkali
metal hydroxides such as potassium hydroxide.<br />
In this step, by the
addition of aqueous ammonia, it is possible to improve the yield, it is
not necessarily added aqueous ammonia.<br />
In this step, by the addition
of dimethyl polysiloxane, it is possible to suppress the generation of
bubbles from the reaction liquid, it is not necessarily added
dimethylpolysiloxane.<br />
The reaction temperature in this step is about 20-60 ℃, preferably, is about 30-50 ℃.<br />
The reaction time of this step, the raw material is not particularly
limited as long as it is a time that is substantially consumed, it is
usually 2 to about 12 hours.<br />
In this step, after the completion of
the reaction, the catalyst was removed by filtration, by adding an acid
to the filtrate, by then crystallizing the compound of formula (VII),
and filtering and washing the precipitate, pure products a you can get.</div>
<div class="pContent">
</div>
<div class="pContent">
[Step F]</div>
</div>
<div class="paragraph" id="paragraph0017">
<div class="pContent">
compounds
having the formula (VII) (and / or its enantiomer), to produce the
presence of an organic acid and a solvent, a compound having formula
(VIII) is allowed to form salts with (and / or its enantiomer) It is a
method.<br />
Chemical Formula 22] The solvent used in this step include water, anisole, aqueous acetone, water CH <sub>3</sub> CN, MTBE water - acetone, anisole - acetate, anisole - acetone, anisole - acetate - acetone, acetone - water -CH <sub>3</sub>
CN single like, or it is a mixed solvent, preferably, water, anisole.
The organic acid used in this step is an organic acid that is
pharmacologically today preferably a benzenesulfonic acid. Equivalent
of the organic acid used in this step is preferably a compound having
the formula (VII) with respect to (and / or its enantiomer) is about
1.00-1.10 equivalents. This step is carried out in the range of usually
about -15-50 ℃, preferably, after aging the crystals at a temperature
of about -10-30 ℃, filtration, by washing, the general formula (VIII) a
compound having a (and / or its enantiomers) get. The time required for
chloride in this step is not particularly limited, but is usually 1 to
about 24 hours.<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@477@@@104@@@jpoxmldoc01-appb-c000035.jpg" height="104" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@477@@@104@@@jpoxmldoc01-appb-c000035.jpg" width="477" />In
the present invention, compounds having formula (IX) prepared via the
process F from Step A (and / or its enantiomer) may be very produced as
pure compounds. Compounds of formula (IX) which can be obtained by the
present invention typically have a quality below.</div>
</div>
<div class="paragraph" id="paragraph0018">
<div class="pContent">
The content of the diastereomer represented by the formula (X): 0.1% less than the<br />
content of the enantiomers represented by the formula (XI): 1.0% less than<br />
the formula (XII) and the double bond represented by the formula (XIII) The total content of regioisomers: less than 0.5%<br />
(Note that each content is calculated from the area percentage of the
free form of formula (IX) (VII) in the by test High Performance Liquid
Chromatography)<br />
[formula 23] [of 24]<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@476@@@109@@@jpoxmldoc01-appb-c000036.jpg" height="109" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@476@@@109@@@jpoxmldoc01-appb-c000036.jpg" width="476" /><img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@476@@@218@@@jpoxmldoc01-appb-c000037.jpg" height="218" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@476@@@218@@@jpoxmldoc01-appb-c000037.jpg" width="476" /></div>
</div>
<br />
<div class="paragraph" id="paragraph0019">
<div class="pContent">
Next,
the present invention is described by examples in detail, the present
invention is, which however shall not be construed as limited thereto.<br />
The internal standard substance in a magnetic resonance spectra (NMR),
and using tetramethylsilane and abbreviations indicate the multiplicity,
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and
brs = It shows a broad singlet.<br />
In the name of the compound, "R" and
"S" indicate the absolute configuration at the asymmetric carbon.
Furthermore, "RS" and "SR" indicates that the asymmetric carbon atom is
racemic. In addition, "(1RS, and 5SR) -" if such a can shows the
relative arrangement of the 1-position and the 5-position, as well shows
only one of the diastereomers, its diastereomers are racemic We show
that.<br />
In the name of the compound, "E" and "Z" indicates the
arrangement of positional isomers in the structure of the compound
having a position isomerism.</div>
<div class="pContent">
"EZ" and "ZE"
indicates that it is a mixture of regioisomers. Way more notation, is in
accordance with the conventions in this area of the normal.</div>
<div class="pContent">
</div>
<div class="pContent">
<div class="paragraph" id="paragraph0020">
<div class="pContent">
(Example 1)</div>
<div class="pContent">
<u>(2EZ)-3-ethoxy -2 - [(1R, 5S) -3- Echirubishikuro [3.2.0] hept-3-en-6-ylidene] -3-oxo-propanoic acid </u><u>(2EZ) -3-Ethoxy-2 - [(1R, 5S) -3-Ethylbicyclo [3.2.0] hept-3-en-6-Ylidene] -3-Oxopropanoic acid</u> [of 25] malonic acid mono ethyl ester (2.9 g, AlCl in THF (20 mL) solution of 22.0 mmol) <sub>3</sub>
(3.9 g, after addition of 29.4 mmol) in -10 ° C, (1R, 5S)
-3-Ethylbicyclo [3.2.0] hept-3-en- 6-one (2.0 g, 14.7 mmol) was added
and stirred for 25 h at -10 ° C. Under ice-cooling After stirring was
added with water (10 mL) CPME and (10 mL), and the organic layer was
separated and aqueous layer 1 1 25 ° C. The aqueous layer 1 was
extracted with CPME (20 mL), the organic layer 2 was separated and the
organic layer was combined with the organic layer one. After washing the
combined organic layers with 1 N hydrochloric acid (6 mL), and
concentrated under reduced pressure at an external temperature of 40 °
C, to give the title compound (4.8 g) as a crude product. <sup>1</sup> H NMR (CDCl <sub>3</sub>
) (400 MHz): delta = 1.07 (3H, t, J = 7.6 Hz), 1.35 (1.5H, t, 7.2 Hz),
1.41 (1.5H, t, 7.2 Hz), 2.08- 2.16 (2H, m), 2.23-2.31 (1H, m), 2.67-2.75
(1H, m), 2.83-3.05 (2H, m), 3.40-3.48 (0.5H, m), 3.57-3.64 (0.5H , m),
4.27-4.41 (3H, m), 5.29 (0.5H, s), 5.50 (0.5H, s)<br />
<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@530@@@87@@@jpoxmldoc01-appb-c000038.jpg" height="87" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@530@@@87@@@jpoxmldoc01-appb-c000038.jpg" width="530" /></div>
</div>
<div class="paragraph" id="paragraph0021">
<div class="pContent">
(Example 2) <u>[(RS, 5SR)-3-Echirubishikuro [3.2.0] hept-3-en-6-ylidene] -3-oxo propanedioic acid dimethyl </u><u>(racemic) </u><u>Dimethyl [(RS, 5SR) -3-Ethylbicyclo [3.2.0] hept-3-en-6-Ylidene] Propanedioate (Racemate)</u> [of 26] THF for (3.2 mL), TiCl at 0 ° C <sub>4</sub>
(0.175 mL, 1.60 mmol) a It was then added and stirred for 20 minutes.
Subsequently (1RS, 5SR) -3-Ethylbicyclo [3.2.0] hept-3-en-6-one (112 mg,
0.819 mmol), dimethyl malonate (113 μL, 0.989 mmol) was added and
stirred for 50 min After, it was added pyridine (265 μL, 3.28 mmol).
After 1 hour stirring at 0 ° C, and subjected to stirring overnight with
warming to room temperature, quenched with water (6 mL), and extracted
three times with toluene (6 mL). The toluene layer saturated aqueous
sodium bicarbonate solution (6 mL), washed with saturated brine (6 mL),
after distilling off the solvent, PTLC (hexane: ethyl acetate = 5: 1)
and subjected to purification, the title compound as a colorless oil The
resulting (135 mg, 65%). <sup>1</sup> H NMR (CDCl <sub>3</sub> ) (400
MHz): delta = 1.05 (3H, D, J = 7.6 Hz), 2.09 (2H, Q, J = 7.6 Hz), 2.21
(1H, dd, J = 16.8, 3.2 Hz ), 2.60-2.76 (2H, m), 2.91 (1H, quint, J = 7.2
Hz), 3.30 (1H, ddd, J = 19.1, 8.4, 3.6 Hz), 3.73 (3H, s), 3.78 (3H, .
s), 4.29 (1H, M), 5.34 (1H, s) <sup>13</sup> C NMR (CDCl <sub>3</sub> ) (100 MHz): delta = 12.2, 24.2, 32.6, 39.8, 42.7, 51.6, 51.7, 117.5, 120.9, 148.9 , 164.6, 164.9, 177.6.<br />
<br />
<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@530@@@87@@@jpoxmldoc01-appb-c000039.jpg" height="87" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@530@@@87@@@jpoxmldoc01-appb-c000039.jpg" width="530" /></div>
</div>
<div class="paragraph" id="paragraph0022">
</div>
<div class="paragraph" id="paragraph0023">
<div class="pContent">
<div class="paragraph" id="paragraph0025">
</div>
<div class="paragraph" id="paragraph0026">
<div class="pContent">
(Example 7) <u>[(1R, 5S)-3-Echirubishikuro [3.2.0] hept-3-en-6-ylidene] propane two acid diethyl </u><u>Diethyl [(1R, 5S) -3-ethylbicyclo [3.2.0 ] hept-3-en-6-Ylidene] Propanedioate</u> [of 31] to CPME (159 mL), 0 ° C with Ti (Oi-Pr) <sub>4</sub> (16.0 mL, 54.6 mmol) After addition of, TiCl <sub>4</sub>
and stirred for 1 hour at (18.0 mL, 164 mmol) and over 8 minutes was
added dropwise 0 ° C. Then diethyl malonate (25.72 g, 161 mmol), was
added (1R, 5S) -3-Ethylbicyclo [3.2.0] hept-3-en-6-one (19.87 g, 146
mmol), 30-40 ° it was stirred for 4 hours at C. The reaction was
quenched with water (100 mL), and extracted with toluene (40 mL). After
the organic layer is concentrated under reduced pressure, to obtain a
crude product of the title compound as a yellow oil (43.61 g).<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@529@@@82@@@jpoxmldoc01-appb-c000044.jpg" height="82" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@529@@@82@@@jpoxmldoc01-appb-c000044.jpg" width="529" /></div>
</div>
<div class="paragraph" id="paragraph0027">
<div class="pContent">
(Example 8) <u>[(RS, 5SR)-3-Echirubishikuro [3.2.0] hept-3-en-6-ylidene] propane diacid di -tert- butyl (racemic) </u><u>Di-tert-butyl [( RS, 5SR) -3-Ethylbicyclo [3.2.0] hept-3-en-6-Ylidene] Propanedioate (Racemate)</u> [of 32] with respect to THF (30 mL), and TiCl at 0 ° C <sub>4</sub>
and (1.6 mL, and the mixture was stirred for 30 minutes was added 14.7
mmol). Subsequently (1RS, 5SR) -3-Ethylbicyclo [3.2.0] hept-3-en-6-one
(1.00 g, 7.34 mmol), malonic acid di -tert- butyl (1.91 g, 8.81 mmol)
was added After stirring for 1.5 hours, it was added pyridine (2.2 mL,
29.4 mmol). 0 ° 3.5 hours after stirring at C, and subjected to stirring
overnight with warming to room temperature, quenched with water (10
mL), and extracted two times with toluene (10 mL). After washed with
saturated brine (10 mL), the solvent was distilled off under reduced
pressure, silica gel column chromatography (hexane: ethyl acetate = 20:
1) and subjected to purification to give the title compound (2.26 g, 92%
). <sup>1</sup> H NMR (CDCl <sub>3</sub> ) (500 MHz): delta = 1.07 (3H,
t, J = 7.5 Hz), 1.47 (9H, s), 1.52 (9H, s), 2.06-2.14 (2H, M), 2.16
-2.24 (1H, m), 2.60-2.69 (2H, m), 2.90 (1H, quint, J = 7.0 Hz), 3.25
(1H, ddd, J = 18.6, 8.5, 3.5 Hz), 4.12-4.23 (1H , m), 5.36 (1H, s).<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@524@@@75@@@jpoxmldoc01-appb-c000045.jpg" height="75" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@524@@@75@@@jpoxmldoc01-appb-c000045.jpg" width="524" /></div>
</div>
<div class="paragraph" id="paragraph0028">
<div class="pContent">
(Example 9) <u>5 - [(RS, 5SR)-3-Echirubishikuro [3.2.0] hept-3-en-6-ylidene] -2,2-dimethyl-1,3-dioxane -4-6- dione (racemic) </u><u>5 - [(RS, 5SR) -3-Ethylbicyclo [3.2.0] hept-3-en-6-Ylidene] 2,2-dimethyl-1,3-dioxane-4-6-dione (Racemate)</u> [of 33] THF for (80 mL), TiCl at 0 ° C <sub>4</sub>
was stirred for 10 minutes was added (4.5 mL, 41 mmol). Subsequently
(1RS, 5SR) -3-Ethylbicyclo [3.2.0] hept-3-en-6-one (2.81 g, 20.6 mmol),
Meldrum's acid (3.57 g, 24.8 mmol) was added and after stirring for 50
minutes , pyridine (6.53 g, 82.6 mmol) it was added. After 1.5 h
stirring at 0 ° C, and subjected to stirring overnight with warming to
room temperature, quenched with water (80 mL), and extracted three times
with toluene (50 mL). The organic layers with saturated brine (50 mL),
washed with 1 M HCl (10 mL), after distilling off the solvent, silica
gel column chromatography (hexane: ethyl acetate = 9: 1-6: 1) to perform
purification, as a white solid to give the title compound (4.51 g,
83.2%). <sup>1</sup> H NMR (CDCl <sub>3</sub> ) (400 MHz): delta = 1.05
(3H, t, J = 7.6 Hz), 1.69 (3H, s), 1.71 (3H, s), 2.11 (2H, Q, J = 7.6 Hz
), 2.20-2.35 (1H, m), 2.65-2.85 (1H, m), 2.92-3.13 (2H, m), 3.47-3.63
(1H, m), 4.45-4.59 (1H, m), 5.43 (1H , s). <sup>13</sup> C NMR (CDCl <sub>3</sub> ) (100 MHz): delta = 12.1, 24.3, 27.59, 27.64, 34.1, 42.3, 42.8, 60.7, 104.4, 108.5, 119.4, 150.3, 160.1, 160.7.<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@524@@@94@@@jpoxmldoc01-appb-c000046.jpg" height="94" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@524@@@94@@@jpoxmldoc01-appb-c000046.jpg" width="524" /></div>
</div>
<div class="paragraph" id="paragraph0029">
<div class="pContent">
(Example 10) <u>[(1R, 5S, 6R)-6-cyano-3-Echirubishikuro [3.2.0] hept-3-en-6-yl] propane two acid dimethyl </u><u>Dimethyl [(1R, 5S, 6R) -6-cyano-3-Ethylbicyclo [3.2.0] hept-3-en-6-YL] Propanedioate</u>
[of 34] Dimethyl [(1R, 5S) -3-Ethylbicyclo [3.2.0] hept-3-en-
6-ylidene] propanedioate (517 mg, 1.66 mmol) was dissolved in MeOH (5.2
mL), was added sodium cyanide (90 mg, 1.84 mmol) at room temperature and
stirred for 2 hours at room temperature. After quenching with 10%
aqueous acetic acid (5 mL), and extracted three times with ethyl acetate
(5 mL), the solvent was distilled off under reduced pressure to give
the title compound as an oil (667 mg). <sup>1</sup> H NMR (CDCl <sub>3</sub>
) (400 MHz): delta = 1.08 (3H, t, J = 7.6 Hz), 1.80 (1H, dd, J = 12.4,
8.0 Hz), 2.01-2.22 (3H, M), 2.54 (1H, dd, J = 16.8, 7.6 Hz), 2.73 (1H,
ddd, J = 12.8, 8.8, 2.8 Hz), 3.18 (1H, quint, J = 7.6 Hz), 3.67 (1H, s),
3.78 ( . 3H, s), 3.82 (3H, s), 5.16-5.28 (1H, M) <sup>13</sup> C NMR (CDCl <sub>3</sub> ) (100 MHz): delta = 12.2, 24.4, 32.1, 37.5, 39.2, 42.5, 52.9, 53.0 , 54.6, 55.0, 118.8, 123.2, 153.9, 166.62, 166.63.<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@524@@@75@@@jpoxmldoc01-appb-c000047.jpg" height="75" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@524@@@75@@@jpoxmldoc01-appb-c000047.jpg" width="524" /></div>
</div>
<div class="paragraph" id="paragraph0030">
<div class="pContent">
(Example 11) <u>[(1R, 5S, 6R)-6-cyano-3-Echirubishikuro [3.2.0] hept-3-en-6-yl] propane two acid diethyl </u><u>Diethyl [(1R, 5S, 6R) -6-cyano-3-Ethylbicyclo [3.2.0] hept-3-en-6-YL] Propanedioate</u>
[of 35] Diethyl obtained by the method shown in Example 7 [(1R, 5S)
-3-ethylbicyclo [3.2 .0] hept-3-en-6-Ylidene] Propanedioate crude
product (43.61 g, 146 mmol) was dissolved in EtOH (262 mL) and was added
sodium cyanide (7.15 g, 146 mmol) at room temperature , it was stirred
for 4 hours at room temperature. Acetate (8.76 g), after the reaction
quenched with water (180 mL), the solvent it was concentrated to
approximately 340 mL under reduced pressure. Water was added (80 mL),
then extracted three times with ethyl acetate (150 mL), the solvent was
distilled off under reduced pressure to give the title compound as an
oil (HPLC quantitative value: 44.29 g, 96.3% (( 1R, 5S) -3-Ethylbicyclo
[3.2.0] total yield from hept-3-en-6-one)). <sup>1</sup> H NMR (CDCl <sub>3</sub>
) (400 MHz): delta = 1.07 (3H, t, J = 7.6 Hz), 1.28 (3H, t, J = 7.2
Hz), 1.31 (3H, t, J = 7.2 Hz), 1.80 (1H, dd, J = 12.6, 7.6 Hz),
2.01-2.19 (3H, m), 2.53 (1H, dd, J = 16.8, 7.6 Hz), 2.72 (1H, ddd, J =
12.6, 9.2, 2.8 Hz), 3.16 (1H, quint, J = 7.6 Hz), 3.61 (1H, s),
3.67-3.82 (1H, M), 4.15-4.33 (4H, M), 5.21-5.26 (1H, M). <sup>13</sup> C NMR (CDCl <sub>3</sub>
) (100 MHz):. delta = 12.2, 14.0, 24.4, 32.2, 37.7, 39.3, 42.5, 55.0,
55.2, 62.00, 62.02, 119.0, 123.3, 153.7, 166.21, 166.23 (HPLC analysis
conditions) Diethyl [(1R, 5S, 6R) -6-cyano-3-ethylbicyclo [3.2.0]
hept-3-en-6-yl] propanedioate quantification method column: Cadenza
CW-C18 (Imtakt, 3 μm, 4.6 mm × 150 mm), 40 ° Cdetection wavelength: UV
205 nm mobile phase: MeCN: 0.1% AcOH aqueous solution = 10: 90-80: 20
(gradient) (0-2 min: MeCN 10%, 2-17 min: MeCN 10 → 80%, 17-25 min: MeCN
80%, 25-30 min: MeCN 80 → 10%, 40 min: STOP) measurement time: 40 min
flow rate: 1.0 mL / min retention time: Diethyl [(1R, 5S, 6R)
-6-cyano-3-Ethylbicyclo [3.2.0] hept-3-en-6-YL] Propanedioate: 18.6 min,
Diethyl [(1R, 5S) -3-Ethylbicyclo [3.2.0] hept-3 en-6-ylidene]
propanedioate: 19.7 min<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@524@@@76@@@jpoxmldoc01-appb-c000048.jpg" height="76" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@524@@@76@@@jpoxmldoc01-appb-c000048.jpg" width="524" /></div>
</div>
</div>
<div class="pContent">
<div class="paragraph" id="paragraph0023">
<div class="pContent">
<div class="paragraph" id="paragraph0031">
<div class="pContent">
</div>
<div class="pContent">
(Example 12) <u>[(1R, 5S, 6R)-6-cyano-3-Echirubishikuro [3.2.0] hept-3-en-6-yl] propane two acid diethyl </u><u>Diethyl [(1R, 5S, 6R) -6-cyano-3-Ethylbicyclo [3.2.0] hept-3-en-6-YL] Propanedioate</u> [of 36] under a nitrogen atmosphere, Ti (Oi-Pr) <sub>4</sub> (25.1 g, 88.11 mmol) the CPME (210 In addition to mL), TiCl it over 1 hour at 10-30 ° C <sub>4</sub>
was added dropwise (29.0 mL, 264 mmol). After stirring for 30 minutes
at 25-30 ° C, was added diethyl malonate (38.8 g, 242 mmol) at 3-4 ° C,
stirred for 30 minutes at 1-4 ° C, (1R, 5S) -3-Ethylbicyclo- [3.2.0] In
addition hept-3-en-6-one a (30.0 g, 220 mmol) at 1-4 ° C, after which
the mixture was stirred for 2.5 hours at 32-33 ° C, ice cold cold water
(150 mL) was added thereto at the bottom, and the aqueous layer was
removed at room temperature. After washing with the organic layer 1 N
hydrochloric acid (60 mL), and concentrated under reduced pressure at an
external temperature of 40-45 ° C up to 120 mL, Diethyl [(1R, 5S)
-3-ethylbicyclo [3.2.0] hept- 3-en-6-ylidene] got CPME solution of
propanedioate. Under a nitrogen atmosphere, after addition of EtOH (150
mL) to the above solution was added sodium cyanide (10.8 g, 220 mmol),
and stirred for 4.5 h at 27-29 ° C. After cooling to 14 ℃, was added a
solution prepared by diluting concentrated sulfuric acid (10.8 g) in
water (60 mL), was added additional water and (150 mL). And the external
temperature 35-45 ° C under reduced pressure concentrated to 240 mL,
after removing the aqueous layer was added CPME (60 mL), the organic
layer was washed with 20% brine (60 mL), CPME of the title compound
solution was obtained (91.4%, HPLC quantitative value).<br />
<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@74@@@jpoxmldoc01-appb-c000049.jpg" height="74" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@74@@@jpoxmldoc01-appb-c000049.jpg" width="535" /></div>
</div>
<div class="paragraph" id="paragraph0032">
<div class="pContent">
(Example 13) <u>[(RS, 5SR, 6RS)-6-cyano-3-Echirubishikuro [3.2.0] hept-3-en-6-yl] propane diacid di -tert- butyl (racemic) </u><u>Di tert-butyl [(RS, 5SR, 6RS) -6-cyano-3-Ethylbicyclo [3.2.0] hept-3-en-6-YL] Propanedioate (Racemate)</u>
[of 37] Di-tert-butyl [( 1RS, 5SR) -3-ethylbicyclo [3.2.0]
hept-3-en-6-ylidene] propanedioate (5.00 g, 14.9 mmol) was dissolved in
DMAc (50 mL), and sodium cyanide at room temperature (586 mg , it was
added 12.0 mmol), and stirred for 1 hour at room temperature. After
quenching with 1 M HCl (30 mL), and extracted three times with ethyl
acetate (50 mL), and the solvent was evaporated under reduced pressure.
Silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give
to give the title compound as an oil (5.10 g, 94%). <sup>1</sup> H NMR (CDCl <sub>3</sub>
) (400 MHz): delta = 1.06 (3H, t, J = 7.5 Hz), 1.46 (9H, s), 1.50 (9H,
s), 1.78 (1H, dd, J = 12.3, 8.0 Hz), 2.00-2.18 (3H, m), 2.51 (1H, dd, J =
17.0, 7.5 Hz), 2.68 (1H, ddd, J = 12.6, 8.5, 3.0 Hz), 3.13 (1H, quint, J
= 7.5 Hz), 3.40 (1H, s), 3.65-3.73 (1H, m), 5.24 (1H, s).<br />
<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@92@@@jpoxmldoc01-appb-c000050.jpg" height="92" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@92@@@jpoxmldoc01-appb-c000050.jpg" width="535" /></div>
</div>
<div class="paragraph" id="paragraph0033">
<div class="pContent">
(Example 14) <u>(RS, 5SR, 6RS)-6-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl) -3-Echirubishikuro [3.2.0] hept - 3-en-6-carbonitrile (racemic) </u><u>(RS, 5SR, 6RS)-6-(2,2-Dimethyl-4, 6-Dioxo-1,3-Dioxan-5-YL) -3-Ethylbicyclo [ 3.2.0] hept-3-ene-6-carbonitrile (Racemate)</u>
[of 38] 5 - [(RS, 5SR) -3-Ethylbicyclo [3.2.0] hept-3-en-6-Ylidene]
-2, 2-dimethyl-1,3-dioxane-4,6-dione (100.8 mg, 0.384 mmol) was
dissolved in EtOH (1.0 mL) and was added sodium cyanide (22.0 mg, 0.449
mmol) at room temperature, room temperature in it was stirred for 3
hours. After quenching with phosphate buffer (pH 7) (5 mL), and
extracted three times with ethyl acetate (5 mL), the solvent was
distilled off under reduced pressure, a white solid to give the title
compound (23.6 mg, 21.2 %). <sup>1</sup> H NMR (CD <sub>3</sub> OD) (400
MHz): delta = 1.03 (3H, t, J = 7.6 Hz), 1.61 (3H, s), 1.92-2.25 (4H,
M), 2.45 (1H, dd, J = 16.8, 7.2 Hz), 2.66-2.80 (1H, m), 3.00 (1H, quint,
J = 7.6 Hz), 3.72-3.87 (1H, m), 4.85 (1H, s), 5.23-5.33 (1H, . M) <sup>13</sup> C NMR (CD <sub>3</sub> OD) (100 MHz): delta = 12.66, 12.69, 25.3, 34.1, 38.8, 39.4, 43.3, 57.0, 75.8, 102.9, 123.67, 123.70, 127.9, 150.5, 167.9.<br />
<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@92@@@jpoxmldoc01-appb-c000051.jpg" height="92" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@92@@@jpoxmldoc01-appb-c000051.jpg" width="535" /></div>
</div>
<div class="paragraph" id="paragraph0034">
<div class="pContent">
(Example 15) <u>[(RS, 5SR, 6SR)-3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl] ethyl acetate (racemic) </u><u>Ethyl [(RS, 5SR, 6SR) -3-ethyl-6 (Nitromethyl) bicyclo [3.2.0] hept-3-en-6-YL] acetate (Racemate)</u>
[of 39] Diethyl [(RS, 5SR) -3-Ethylbicyclo [ 3.2.0]
hept-3-en-6-ylidene] propanedioate (256.0 mg, 0.920 mmol) was dissolved
in toluene (2.5 mL), was added DBU (152 mL), nitromethane (55 mL), at
room temperature for 17 time it was stirred. After quenching with 1 M
HCl (5 mL), and extracted three times with ethyl acetate (5 mL), and the
resulting ethyl acetate solution was washed with saturated brine (5
mL). The solvent was evaporated under reduced pressure, as a pale yellow
oily substance Diethyl [(1RS, 5SR, 6SR) -3-ethyl-6- (nitromethyl)
bicyclo- [3.2.0] hept-3-en-6-yl] propanedioate was obtained (336.9 mg).
The resulting Diethyl [(RS, 5SR, 6SR) -3-ethyl-6 (Nitromethyl) bicyclo
[3.2.0] hept-3-en-6-YL] - Propanedioate a (336.9 mg) DMSO and (3.4 mL)
It was dissolved in water (50 μL, 2.78 mmol), sodium chloride (64.8 mg,
1.11 mmol) was added, followed by 10 hours heated and stirred at 140 °
C. After cooling to room temperature, the reaction was quenched with 1 M
HCl (5 mL), was extracted three times with ethyl acetate (5 mL), and
the resulting ethyl acetate solution was washed with saturated brine (5
mL). The solvent was evaporated under reduced pressure to give the title
compound as a brown oily substance (261.6 mg, 2 process overall yield
72.4%). Diethyl [(RS, 5SR, 6SR) -3-ethyl-6 (Nitromethyl) bicyclo [3.2.0]
hept-3-en-6-YL] Propanedioate <sup>1</sup> H NMR (CDCl <sub>3</sub> )
(400 MHz): delta = 1.08 (3H, t, J = 7.6 Hz), 1.17-1.35 (6H, m), 1.73
(1H, dd, J = 13.2, 7.6 Hz), 2.05 (1H, d, J = 16.4 Hz), 2.05-2.22 (2H,
m), 2.42-2.58 (2H, m), 2.75 (1H, quint, J = 7.6 Hz), 3.46 (1H, brs),
3.79 (1H, s), 4.09-4.27 (4H, m), 4.96 (2H, s), 5.27 (1H, s). <sup>13</sup> C NMR (CDCl <sub>3</sub>
) (100 MHz): delta = 12.3, 13.97, 14.04, 24.4, 31.6, 36.1, 42.5, 45.6,
53.6, 55.5, 61.49, 61.53, 80.1, 120.7, 152.0, 167.7, 167.8. Ethyl [(RS,
5SR, 6SR) -3-ethyl-6 (Nitromethyl) bicyclo [3.2.0] hept-3-en-6-YL]
acetate <sup>1</sup> H NMR (CDCl <sub>3</sub> ) (400 MHz): delta = 1.07
(3H, t, J = 7.6 Hz), 1.25 (3H, t, J = 7.6 Hz), 1.52 (1H, dd, J = 12.6,
7.2 Hz), 2.04 (1H, d, J = 16.4 Hz), 2.05-2.19 (2H, m), 2.23-2.35 (1H,
m), 2.50 (1H, dd, J = 15.8, 7.6 Hz), 2.62 (2H, s) , 2.86 (1H, quint, J =
7.6 Hz), 3.21 (1H, brs), 4.12 (4H, q, J = 7.6 Hz), 4.76 (2H, d, J =
11.6 Hz), 4.83 (2H, d, J = 11.6 Hz), 5.24 (1H, s).<br />
<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@526@@@80@@@jpoxmldoc01-appb-c000052.jpg" height="80" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@526@@@80@@@jpoxmldoc01-appb-c000052.jpg" width="526" /></div>
</div>
<div class="paragraph" id="paragraph0035">
<div class="pContent">
(Example 16) <u>[(RS, 5SR, 6RS)-3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl] propane diacid di -tert- butyl (racemic ) </u><u>Di-tert-butyl [(RS, 5SR, 6RS) -3-ethyl-6 (Nitromethyl) bicyclo [3.2.0] hept-3-en-6-YL] Propanedioate </u><u>(Racemate)</u>
[of 40] Di- tert-butyl [(1RS, 5SR) -3-ethylbicyclo [3.2.0]
hept-3-en-6-ylidene] propanedioate a (2.55 g) was dissolved in toluene
(26 mL), DBU (1.45 mL), nitromethane (1.05 mL) was added and stirred for
49 hours at room temperature. After quenching with 1 M HCl (50 mL), and
extracted three times with ethyl acetate (50 mL), and the resulting
ethyl acetate solution was washed with saturated brine (50 mL). The
solvent was distilled off under reduced pressure to give the title
compound as a pale yellow oil (2.36 g, 78% yield). <sup>1</sup> H NMR (CDCl <sub>3</sub>
) (500 MHz): delta = 1.09 (t, 3H, J = 7.4 Hz), 1,45 (s, 9H), 1.49 (s,
9H), 1.71 (dd, 1H, J = 12.9, 7.4 Hz), 2.03 (d, 1H, 16.7 Hz), 2.09-2.19
(m, 2H), 2.47 (dd, 2H, J = 16.7, 7.9 Hz), 2.59 (ddd, 1H, J = 11.7, 8.9 ,
2.7 Hz), 2.67 (quint, 1H, J = 7.4 Hz), 3.52 (brs, 1H), 3.64 (s, 1H),
4.88 (d, 1H, J = 10.9 Hz), 4.95 (d, 1H, J = 10.9 Hz), 5.28 (m, 1H).<br />
<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@526@@@94@@@jpoxmldoc01-appb-c000054.jpg" height="94" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@526@@@94@@@jpoxmldoc01-appb-c000054.jpg" width="526" /></div>
</div>
<div class="paragraph" id="paragraph0036">
<div class="pContent">
(Example 17) <u>[(RS, 5SR, 6SR)-3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl] optical resolution of acetic acid </u><u>[(1RS, 5SR, 6SR ) -3-Ethyl-6- (nitromethyl) bicyclo [3.2.0] optical resolution of hept-3-en-6-YL] acetic acid</u> [of 41] [(RS, 5SR, 6SR) -3-Ethyl-6 - (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetic acid (0.2 g, 0.84 mmol) and CH <sub>3</sub>
CN (3.0 mL) to dissolve the table of the optically active organic amine
of the following (0.42 mmol) was at room temperature stirred with,
precipitated filtered crystals selectivity and dried to determine yield.
The results I shown in the table below.[Table 1] * (1S, 5R, 6R) - the
body is the main product ** (1R, 5S, 6S) - the body is the main
product<br />
<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@526@@@94@@@jpoxmldoc01-appb-c000054.jpg" height="94" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@526@@@94@@@jpoxmldoc01-appb-c000054.jpg" width="526" /><img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@504@@@97@@@jpoxmldoc01-appb-t000055.jpg" height="97" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@504@@@97@@@jpoxmldoc01-appb-t000055.jpg" width="504" /></div>
</div>
<div class="paragraph" id="paragraph0037">
<div class="pContent">
(HPLC optical analysis condition)<br />
Column: CHIRALPAK AD-RH 4.6 × 250 mm<br />
mobile phase: 10 mM pH 2.0 phosphate buffer / MeCN = 25/75 (isocratic)<br />
flow rate: 1.0 mL / min<br />
Column temperature: 40 ° C<br />
Detection wavelength: UV 210 nm<br />
analysis time: 80 minutes<br />
retention time: (1S, 5R, 6R) - Body: 35.2 min, (1R, 5S, 6S) - Body: 42.1 min</div>
</div>
</div>
</div>
<div class="paragraph" id="paragraph0038">
<div class="pContent">
(Example 18) <u>[(1R, 5S, 6S)-3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetic acid </u><u>[(1R, 5S, 6S) -3 -Ethyl-6 (Nitromethyl) bicyclo [3.2.0] hept-3-en-6-YL] acetic acid</u>
[of 42] quinine (5.97 g, 18.4 mmol) was dissolved in acetone (300 mL),
[( RS, 5SR, 6SR) -3-Ethyl-6 (Nitromethyl) -bicyclo [3.2.0]
hept-3-en-6-YL] acetic acid (10.0 g, I was added 33.4 mmol). After
stirring 20 hours at room temperature, it was carried out 5 hours of
stirring it was cooled to 0 ° C. After filtering off the solid, washed
with cold acetone, the combined filtrate and washing was concentrated
under reduced pressure, further CH <sub>3</sub> CN were added and again
concentrated to the concentration residue (6.4 g, ee 65.2%) was
obtained. The resulting residue (6.4 g, ee 65.2%) and CH <sub>3</sub>
was dissolved in CN (43 mL), (S) - it was added phenylglycinol (1.37 g, 1
eq minute) - (+). After stirring for 20 hours at room temperature and
stirred for 5 hours and cooled to 0 ° C. The precipitated crystals were
collected by filtration, and added to dilute hydrochloric acid and ethyl
acetate was dissolved by liquid separation, and dried under reduced
pressure after the organic layer was concentrated to give the title
compound (1.39 g, 14%, ee 92.0%). <sup>1</sup> H NMR (400 MHz, CDCl <sub>3</sub>
): delta = 1.09 (t, 3H, J = 7.6 Hz), 1.47-1.57 (M 2H), 2.06-2.17 (M,
3H), 2.27-2.33 (M, 1H) , 2.49-2.55 (m, 1H), 2.66 (s, 2H),, 2.88 (quint,
1H, J = 7.6 Hz), 3.17 (bs, 1H), 4.78 (d, 1H, J = 11.5 Hz), 4.86 (d, 1H, J
= 11.5Hz), 5.27-5.28 (m, 1H)<br />
<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@526@@@94@@@jpoxmldoc01-appb-c000056.jpg" height="94" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@526@@@94@@@jpoxmldoc01-appb-c000056.jpg" width="526" /></div>
</div>
</div>
<div class="pContent">
<div class="paragraph" id="paragraph0030">
<div class="pContent">
</div>
<div class="pContent">
(Example 28) <u>[(1R, 5S, 6S)-6-cyano-3-Echirubishikuro [3.2.0] hept-3-en-6-yl] acetic acid benzyl amine salt </u><u>Benzylammonium [(1R, 5S, 6S) -6-cyano-3-Ethylbicyclo [3.2.0] hept-3-en-6-YL] acetate</u>
[of 52] Diethyl obtained by the method of Example 12 [(1RS, 5SR, 6RS)
-6-cyano -3-Ethylbicyclo [3.2.0] Hept- 3-en-6-YL] After the addition of
EtOH (390 mL) to CPME solution of propanedioate, heating under reflux, 8
N aqueous solution of potassium hydroxide (6.9 mL, 55.07 mmol ) after
adding a total of 5 times every 1 hour, refluxed for 5 hours and
returned to room temperature. The addition of water (60 mL) and 8N
aqueous potassium hydroxide (24 mL) to the above EtOH solution, and
after stirring for 2 h at 26-27 ° C, under reduced pressure at an
external temperature of 40-45 ° C until 150 mL It was concentrated. To
remove the organic layer by water (180 mL) and toluene (90 mL) was added
for liquid separation. The resulting aqueous solution Toluene (150 mL)
added, cooled to, was added concentrated hydrochloric acid 42.5 mL at
2-9 ° C, the pH was adjusted to 1.4. By separation to remove the aqueous
layer was added toluene (300 mL) benzylamine (23.6 g, 220.28 mmol) and.
After stirring for 30 minutes at 44-46 ° C make the inoculation, and
concentrated under reduced pressure until 300 mL at 44-46 ° C. After
stirring overnight at 22-23 ° C, and crystals were filtered off. And
vacuum dried at 40 ° C, was obtained as a white crystalline title
compound 54.4 g (79.2% from (1R, 5S) -3-Ethylbicyclo [3.2.0]
hept-3-en-6-one) a.<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@517@@@158@@@jpoxmldoc01-appb-c000066.jpg" height="158" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@517@@@158@@@jpoxmldoc01-appb-c000066.jpg" width="517" /><br />
<div class="paragraph" id="paragraph0054">
<div class="pContent">
(Example 33) <u>[(1R, 5S, 6S)-6-(aminomethyl) -3-Echirubishikuro [3.2.0] hept-3-en-6-yl] acetic acid </u><u>[(1R, 5S, 6S) - 6 (aminomethyl) -3-Ethylbicyclo [3.2.0] hept-3-en-6-YL] acetic acid</u>
[of 57] Benzylammonium [(1R, 5S, 6S) -6-cyano-3-Ethylbicyclo [3.2. 0]
hept-3-en-6-yl] acetate (40.0 g) in toluene (200 mL), was added 2 mol / L
hydrochloric acid (100 mL) at room temperature and dissolved. And
allowed to stand the solution to drain the aqueous layer to obtain an
organic layer. To the stirred addition of 10% aqueous sodium chloride
solution (about 100 mL), and the aqueous layer was removed after
standing. The solution of water (100 mL) was added to, was adjusted to
10.0 to pH added 8 mol / L aqueous potassium hydroxide solution (about
15.7 mL), the organic layer was removed to standing. The solution to
the sponge cobalt (10 g), 28% aqueous ammonia (13 mL), 2%
dimethylpolysiloxane / toluene solution (2 mL) was added and warmed to
40 ° C in a hydrogen gas pressure (0.45 MPa) It was stirred for 8
hours.After cooling to room temperature, filtering the reaction mixture
to remove the sponge cobalt. The sponge cobalt on the filter it was
washed with water (80 mL). The resulting solution was stirred for 0.5
hours added the activated carbon (4 g), to remove the charcoal by
filtration. The activated carbon on the filter it was washed with water
(60 mL). The solution I was adjusted to about pH 6.0 with concentrated
hydrochloric acid (about 32.7g) a. Then, after stirring for 0.5 hours
was added potassium chloride (55.0 g), and cooled to 0 ° C. The
resulting was filtered and crystals were washed with 20% brine cooled to
about 0 ° C (80 mL), and dried overnight in vacuum at 50 ° C to give
the title compound as white crystals (26.9 g, content 88.3 %, 88.7%
content in terms of yield).<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@88@@@jpoxmldoc01-appb-c000071.jpg" height="88" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@88@@@jpoxmldoc01-appb-c000071.jpg" width="535" /></div>
</div>
<div class="paragraph" id="paragraph0055">
<div class="pContent">
(Example 34) <u>[(1R, 5S, 6S)-6-(aminomethyl) -3-Echirubishikuro [3.2.0] hept-3-en-6-yl] acetic acid </u><u>[(1R, 5S, 6S) - 6 (aminomethyl) -3-Ethylbicyclo [3.2.0] hept-3-en-6-YL] acetic acid</u>
[of 58] (R) -Phenylethanaminium [(1R, 5S, 6S) -6-cyano-3 ethylbicyclo
[3.2.0] hept-3-en-6-yl] acetate (35.9g, 99.2 mmol, 95.7% de, ee 99.2%)
in toluene (120 mL) and 1 mol / L hydrochloric acid (150 mL) was added ,
it was stirred. After removing the aqueous layer, the organic layer was
washed twice with water (120 mL), and concentrated. The obtained
residue in MTBE to (150 mL) and sponge nickel (10.1 g) was added, under
hydrogen pressure (approximately 4 atm) and stirred for 3 hours at room
temperature. The reaction of 2 mol / L aqueous potassium hydroxide
solution (72 mL) was added, After stirring for 30 minutes, a sponge
nickel was filtered off. It was washed with a filtration sponge nickel 2
mol / L potassium hydroxide solution (12 mL). After combining the
filtrate and washings, the organic layer was removed to obtain an
aqueous layer. The organic layer was re-extracted with 2M aqueous
potassium hydroxide solution. The matched aqueous layer was cooled,
after adjusting the pH adding concentrated hydrochloric acid (about 12
mL) to 7.5, and the mixture was stirred at 0 ° C for about 3 hours.
Filtered the precipitated crystals were washed with ice-cold water (24
mL), and dried under reduced pressure at 50 ° C, to give the title
compound (18.3g, 88%, 99.8% de) and.<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@73@@@jpoxmldoc01-appb-c000072.jpg" height="73" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@73@@@jpoxmldoc01-appb-c000072.jpg" width="535" /></div>
</div>
<div class="paragraph" id="paragraph0056">
<div class="pContent">
(Example 35) <u>[(1R, 5S, 6S)-6-(aminomethyl) -3-Echirubishikuro [3.2.0] hept-3-en-6-yl] acetic acid one benzenesulfonate </u><u>[(1R, 5S, 6S)-6-(aminomethyl) -3-Ethylbicyclo [3.2.0] hept-3-en-6-YL] acetic acid Monobenzenesulfonate</u>
[of 59] MTBE (83 mL), acetone (4.0 mL), water ( with respect to a
mixture of 0.98 mL), at 0 ° C [(1R, 5S, 6S) -6- (Aminomethyl)
-3-ethylbicyclo [3.2.0] hept-3-en-6-yl] acetic acid ( 4.07 g, 19.5 mmol)
was added and stirred to form a slurry solution. This BsOH (3.08 g,
19.5 mmol) it was added acetone (10.1 mL) solution of. 0 ° After
stirring for 1 hour at C, and stirred for 2 hours and allowed to warm to
room temperature. Over 1 hour and gradually cooled to -10 ° C, and
stirred for 2.5 hours. The resulting was filtered crystals, after
washing with acetone and cooled to 0 ° C (12 mL), and by vacuum-dried at
40 ° C, as white crystals of the title compound was obtained (6.44 g,
90.1% ). Various spectrum data of the obtained title compound was almost
(extent the structure can be identified) coincides with (described in
Patent Documents 5 and 6) the known information. (Purity measurement
method -1) column: Cadenza CW-C18 (Imtakt, 3 μm, 4.6 mm × 150 mm), 40 ° C
detection wavelength: UV 205 nm mobile phase: MeCN: 5 mM ammonium
hydrogen carbonate aqueous solution = ten ninety -80: 20 (gradient)
(0-12 min: MeCN 10%, 12-27 min: MeCN 10 → 80%, 27-45 min: MeCN 80%,
45-50 min: MeCN 80 → 10%, 50- 60 min: MeCN 10%, 60 min: STOP)
measurement time: 60 min flow rate: 1.0 mL / min infusion sample
concentration: 5mg / mL sample injection volume: 2μL retention time:
the title compound (as free form): 12.5 min diastereoisomers Marr
(Compound X): 13.5 min double bond position isomer (compound XII or
XIII): 9.4 min, 9.6 min, 11.4 min<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@85@@@jpoxmldoc01-appb-c000073.jpg" height="85" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@85@@@jpoxmldoc01-appb-c000073.jpg" width="535" /></div>
</div>
</div>
</div>
</div>
</div>
<div class="paragraph" id="paragraph0038">
</div>
</div>
</div>
<div class="pContent">
</div>
<table class="mce-item-table"><tbody>
<tr><th>Patent</th><th>Submitted</th><th>Granted</th></tr>
<tr><td>Bicyclic [gamma]-amino acid derivative [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US7947738" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US7947738" title="Go to PubChem Patent View page for this patent">US7947738</a>]</td><td class="nowrap">2010-09-30</td><td class="nowrap">2011-05-24</td></tr>
<tr><td>Optical Resolution Methods for Bicyclic Compounds Using Enzymes [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2015038738" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2015038738" title="Go to PubChem Patent View page for this patent">US2015038738</a>]</td><td class="nowrap">2014-10-10</td><td class="nowrap">2015-02-05</td></tr>
</tbody></table>
<div class="field-item even">
<table class="patent-data-table mce-item-table"><tbody>
<tr><td class="patent-data-table-td citation-patent"><a data-mce-href="http://www.google.com/patents/WO2015005298A1?cl=en" href="http://www.google.com/patents/WO2015005298A1?cl=en">WO2015005298A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value">Jul 8, 2014</td><td class="patent-data-table-td patent-date-value">Jan 15, 2015</td><td class="patent-data-table-td ">Daiichi Sankyo Company,Limited</td><td class="patent-data-table-td ">METHOD FOR PRODUCING OPTICALLY ACTIVE BICYCLIC γ-AMINO ACID DERIVATIVE</td></tr>
</tbody></table>
<h2>
</h2>
<h2>
CONSTRUCTION</h2>
<h2>
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@530@@@87@@@jpoxmldoc01-appb-c000038.jpg" height="87" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@530@@@87@@@jpoxmldoc01-appb-c000038.jpg" width="530" /></h2>
</div>
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@524@@@76@@@jpoxmldoc01-appb-c000048.jpg" height="76" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@524@@@76@@@jpoxmldoc01-appb-c000048.jpg" width="524" /><br />
<div class="field-item even">
<h2>
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@74@@@jpoxmldoc01-appb-c000049.jpg" height="74" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@74@@@jpoxmldoc01-appb-c000049.jpg" width="535" /></h2>
<h2>
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@92@@@jpoxmldoc01-appb-c000051.jpg" height="92" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@92@@@jpoxmldoc01-appb-c000051.jpg" width="535" /></h2>
<h2>
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@526@@@80@@@jpoxmldoc01-appb-c000052.jpg" height="80" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@526@@@80@@@jpoxmldoc01-appb-c000052.jpg" width="526" /></h2>
<h2>
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@526@@@94@@@jpoxmldoc01-appb-c000054.jpg" height="94" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@526@@@94@@@jpoxmldoc01-appb-c000054.jpg" width="526" /></h2>
<h2>
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@526@@@94@@@jpoxmldoc01-appb-c000056.jpg" height="94" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@526@@@94@@@jpoxmldoc01-appb-c000056.jpg" width="526" /></h2>
<h2>
</h2>
<h2>
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@517@@@158@@@jpoxmldoc01-appb-c000066.jpg" height="158" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@517@@@158@@@jpoxmldoc01-appb-c000066.jpg" width="517" /></h2>
<h2>
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@88@@@jpoxmldoc01-appb-c000071.jpg" height="88" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@88@@@jpoxmldoc01-appb-c000071.jpg" width="535" /></h2>
<h2>
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@73@@@jpoxmldoc01-appb-c000072.jpg" height="73" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@73@@@jpoxmldoc01-appb-c000072.jpg" width="535" /><br /> <img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@85@@@jpoxmldoc01-appb-c000073.jpg" height="85" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000027798730@@@11234586@@@535@@@85@@@jpoxmldoc01-appb-c000073.jpg" width="535" /></h2>
<h2>
<span class="mw-headline" id="References">References</span></h2>
<div class="reflist">
<ol class="references">
<li id="cite_note-1"><span class="reference-text">Vinik
A, Rosenstock J, Sharma U, Feins K, Hsu C, Merante D, et al. Efficacy
and safety of mirogabalin (DS-5565) for the treatment of diabetic
peripheral neuropathic pain: a randomized, double-blind, placebo- and
active comparator-controlled, adaptive proof-of-concept phase 2 study. <i>Diabetes Care</i>. 2014 Dec;37(12):3253-61. doi: 10.2337/dc14-1044. <a class="external mw-magiclink-pmid" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/25231896?dopt=Abstract" href="https://www.ncbi.nlm.nih.gov/pubmed/25231896?dopt=Abstract" rel="nofollow">PMID 25231896</a></span></li>
<li id="cite_note-2"><span class="reference-text">Vinik
A, Sharma U, Feins K, Hsu C, Merante D. DS-5565 for the Treatment Of
Diabetic Peripheral Neuropathic Pain: Randomized, Double-Blind, Placebo-
And Active Comparator-Controlled Phase II Study (S20.004) <i>Neurology</i> April 8, 2014; 82(10): Supplement S20.004</span></li>
</ol>
</div>
</div>
<div class="field-item even">
<b>Tokyo, Japan – (February 4, 2015)</b>
– Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) today
announced enrollment of the first patients in large-scale,
multi-national clinical programs evaluating the safety and efficacy of
investigational mirogabalin (DS-5565), the first preferentially
selective alpha-2 delta ligand. The phase 3 clinical program across Asia
includes the REDUCER (An Asian, phase 3, multicenter, RandomizEd,
Double-blind, placebo-controlled 14-week stUdy of DS-5565 in patients
with diabetiC pEripheral neuRopathic pain followed by a 52-week
open-label extension) study and the NEUCOURSE (An AsiaN, phasE 3,
mUltiCenter, randomized, dOUble-blind, placebo-contRolled 14-week study
of DS-5565 in patientS with postherpetic neuralgia followed by a 52-week
open-label Extension) study which will evaluate investigational
mirogabalin for the treatment of diabetic peripheral neuropathic pain
(DPNP) and postherpetic neuralgia (PHN), respectively. The phase 3
global ALDAY (A Randomized, Double-Blind, Placebo- and Active-Controlled
Study of DS-5565 in Patients with Pain Associated with Fibromyalgia)
clinical program is ongoing and will evaluate mirogabalin for the
treatment of pain associated with fibromyalgia in three identical
studies.<br />
“Pain associated with the neurologic conditions of
diabetic peripheral neuropathic pain, postherpetic neuralgia and
fibromyalgia can be debilitating,” said Lesley Arnold, MD, Professor of
Psychiatry and Behavioral Neuroscience and Director of the Women’s
Health Research Program, University of Cincinnati and lead investigator
of the ALDAY program. “New treatment options are needed to help people
living with these neurologic conditions relieve and manage their chronic
pain and hopefully, improve their function and quality of life.”<br />
“We
are pleased that our global clinical development program evaluating the
efficacy and safety of mirogabalin continues to move forward and has
progressed into phase 3,” said Mahmoud Ghazzi, MD, PhD, Executive Vice
President and Global Head of Development for Daiichi Sankyo. “Daiichi
Sankyo is committed to identifying and studying new medicines that could
help improve the management of chronic pain for people with diabetic
peripheral neuropathy, postherpetic neuralgia and pain associated with
fibromyalgia.”<br />
<b>About the REDUCER and NEUCOURSE Phase 3 Clinical Studies</b><br />
The REDUCER study will last 14 weeks and is being conducted at
approximately 200 centers in Japan, Taiwan and Korea. The NEUCOURSE
study will also last 14 weeks and is being conducted at approximately
200 centers in Japan, Taiwan, Korea, Singapore, Malaysia and Thailand.
The studies will include about 750 patients each with either diabetic
peripheral neuropathic pain or postherpetic neuralgia, respectively. The
objectives of the double-blind studies are to evaluate safety and
efficacy of mirogabalin by comparing change in the average daily pain
score (ADPS) from baseline to Week 14 in patients receiving a total
daily dose of either 15 mg, 20 mg or 30 mg of mirogabalin versus
placebo. Both studies will be followed by one-year open-label extension
studies to assess long-term safety and efficacy of mirogabalin. For more
information on the REDUCER study in patients with diabetic peripheral
neuropathic pain, please visit<br />
<a data-mce-href="https://www.clinicaltrials.gov/ct2/show/NCT02318706?term=Mirogabalin&rank=3" href="https://www.clinicaltrials.gov/ct2/show/NCT02318706?term=Mirogabalin&rank=3">https://www.clinicaltrials.gov/ct2/show/NCT02318706?term=Mirogabalin&rank=3</a>.<br />
For more information on the NEUCOURSE study in patients with postherpetic neuralgia, please visit<a data-mce-href="https://www.clinicaltrials.gov/ct2/show/NCT02318719?term=Mirogabalin&rank=1" href="https://www.clinicaltrials.gov/ct2/show/NCT02318719?term=Mirogabalin&rank=1">https://www.clinicaltrials.gov/ct2/show/NCT02318719?term=Mirogabalin&rank=1</a>.<br />
<b>About the ALDAY Phase 3 Clinical Program</b><br />
The ALDAY program is a large clinical phase 3 program evaluating
mirogabalin for the treatment of pain associated with fibromyalgia, and
includes three, randomized, double-blind, placebo- and active-controlled
studies, and an open label safety study that will be carried out over
the next three years. Approximately 4,000 patients with pain associated
with fibromyalgia will be enrolled at approximately 800 clinical centers
at more than 40 countries worldwide. The primary objective of the
studies in the ALDAY program is to compare change in weekly ADPS from
baseline to Week 13 in patients receiving a total daily dose of either
15 mg or 30 mg of mirogabalin versus placebo. Weekly ADPS is based on
daily pain scores reported by the patient that best describes his or her
worst pain over the previous 24 hours. The primary objective of the
phase 3 open-label extension study is to assess the long-term safety of a
total daily dose of mirogabalin 15 mg or mirogabalin 30 mg in patients
with pain associated with fibromyalgia. For more information on the
studies in the ALDAY program, please visit<br />
<a data-mce-href="https://clinicaltrials.gov/ct2/show/NCT02187471?term=DS5565&rank=1" href="https://clinicaltrials.gov/ct2/show/NCT02187471?term=DS5565&rank=1">https://clinicaltrials.gov/ct2/show/NCT02187471?term=DS5565&rank=1</a><br />
<a data-mce-href="https://clinicaltrials.gov/ct2/show/NCT02187471?term=ds-5565&rank=2" href="https://clinicaltrials.gov/ct2/show/NCT02187471?term=ds-5565&rank=2">https://clinicaltrials.gov/ct2/show/NCT02187471?term=ds-5565&rank=2</a><br />
<a data-mce-href="https://clinicaltrials.gov/ct2/show/NCT02146430?term=ds-5565&rank=3" href="https://clinicaltrials.gov/ct2/show/NCT02146430?term=ds-5565&rank=3">https://clinicaltrials.gov/ct2/show/NCT02146430?term=ds-5565&rank=3</a><br />
For more information on the open-label extension study, please visit<a data-mce-href="https://clinicaltrials.gov/ct2/show/NCT02234583?term=ds-5565&rank=4" href="https://clinicaltrials.gov/ct2/show/NCT02234583?term=ds-5565&rank=4">https://clinicaltrials.gov/ct2/show/NCT02234583?term=ds-5565&rank=4</a><br />
For patient recruitment or additional clinical study information, please visit <a data-mce-href="http://www.aldaystudy.com/" href="http://www.aldaystudy.com/">http://www.aldaystudy.com/</a>.<br />
<b>About Diabetic Peripheral Neuropathic Pain</b><br />
Diabetic peripheral neuropathy is a disorder that causes nerve damage
to the extremities and is one of the most common long-term complications
of diabetes.1 Symptoms include sharp pains or increased sensitivity,
numbness, loss of balance and coordination, tingling, burning, or
prickling sensations, which typically worsen at night.1 Up to 50 percent
of people with diabetes have peripheral neuropathy2 and it is estimated
that between 11 and 26 percent of people with diabetes experience
diabetic peripheral neuropathic pain (DPNP).3-6 However, DPNP is often
undertreated and underreported.2<br />
<b>About Postherpetic Neuralgia</b><br />
Postherpetic neuralgia is pain that occurs after recovering from
shingles, an infection that is caused by the herpes zoster (chickenpox)
virus. Pain from postherpetic neuralgia can range in severity, and is
typically described as burning, sharp, or stabbing.7 Other symptoms
include sensitivity to touch, itching, numbness, and in rare cases,
muscle weakness or paralysis can occur.7 The risk of developing
postherpetic neuralgia increases with age and it mainly affects people
older than 60.7 Studies have shown that only half of all patients
affected with the condition will be relieved from pain within a year.8
Most people will require more than one treatment to help ease the pain.7<br />
<b>About Fibromyalgia</b><br />
Fibromyalgia is a chronic disorder that causes widespread muscle pain,
generalized tender points and fatigue.9 Other common symptoms include
sleep disturbances, morning stiffness, memory and thinking problems
(sometimes called fibro fog), tingling in the hands and feet and
headaches.9 Fibromyalgia is often misdiagnosed and suboptimally
treated.10-17 The overall estimated prevalence of fibromyalgia is
approximately two to three percent in the general population, with a
higher prevalence in women.18-22 Pain that occurs with fibromyalgia has a
substantial impact on the patient, and can be associated with societal
and economic burdens.23-29<br />
<b>About Mirogabalin</b><br />
Mirogabalin is an investigational drug that is currently being studied
for the treatment of DPNP, PHN and pain associated with fibromyalgia.
Mirogabalin is preferentially selective in regards to how it binds to
α2δ-1 subunit, a protein that may help to regulate how the brain
processes pain signals. It has a unique binding profile and long
duration of action.30*,31<br />
<b>About Daiichi Sankyo</b><br />
Daiichi Sankyo Group is dedicated to the creation and supply of
innovative pharmaceutical products to address the diversified, unmet
medical needs of patients in both mature and emerging markets. While
maintaining its portfolio of marketed pharmaceuticals for hypertension,
dyslipidemia and bacterial infections used by patients around the world,
the Group has also launched treatments for thrombotic disorders and is
building new product franchises. Furthermore, Daiichi Sankyo research
and development is focused on bringing forth novel therapies in oncology
and cardiovascular-metabolic diseases, including biologics. The Daiichi
Sankyo Group has created a "Hybrid Business Model," to respond to
market and customer diversity and optimize growth opportunities across
the value chain. For more information, please visit: <a data-mce-href="http://www.daiichisankyo.com/" href="http://www.daiichisankyo.com/">www.daiichisankyo.com</a>.</div>
<div class="field-item even">
<table class="field-group-format group_drugtable mce-item-table" data-mce-style="height: 1541px;" style="height: 1541px; width: 748px;"><tbody>
<tr class=""><th class="field-label">trial(s)</th><td class="field-content"><div class="field field-name-field-clinical-trials field-type-tablefield field-label-hidden">
<div class="field-items">
<div class="field-item even">
<div class="tablefield-wrapper" id="tablefield-wrapper-0">
<table class="sticky-header mce-item-table"><thead>
<tr><th class="row_0 col_0"></th><th class="row_0 col_1"></th><th class="row_0 col_2"></th><th class="row_0 col_3"></th><th class="row_0 col_4"></th></tr>
</thead></table>
<table class="tablefield sticky-enabled tableheader-processed sticky-table mce-item-table" id="tablefield-0"><thead>
<tr><th class="row_0 col_0">Conditions</th><th class="row_0 col_1">Interventions</th><th class="row_0 col_2">Phases</th><th class="row_0 col_3">Recruitment</th><th class="row_0 col_4">Sponsor/Collaborators</th></tr>
</thead><tbody>
<tr class="odd"><td class="row_1 col_0">Pain Associated With Fibromyalgia</td><td class="row_1 col_1">Drug:
DS-5565 15mg tablet|Drug: 150mg pregabalin capsule|Drug: placebo
tablet|Drug: placebo capsule|Drug: 75mg pregabalin capsule</td><td class="row_1 col_2">Phase 3</td><td class="row_1 col_3">Recruiting</td><td class="row_1 col_4">Daiichi Sankyo Inc.|INC Research</td></tr>
<tr class="even"><td class="row_2 col_0">Fibromyalgia</td><td class="row_2 col_1">Drug: DS-5565|Drug: placebo</td><td class="row_2 col_2">Phase 3</td><td class="row_2 col_3">Recruiting</td><td class="row_2 col_4">Daiichi Sankyo Inc.|INC Research</td></tr>
<tr class="odd"><td class="row_3 col_0">Post-Herpetic Neuralgia</td><td class="row_3 col_1">Drug: placebo|Drug: DS-5565</td><td class="row_3 col_2">Phase 3</td><td class="row_3 col_3">Recruiting</td><td class="row_3 col_4">Daiichi
Sankyo Co., Ltd.|SRL Medisearch Inc. Japan|Quintiles Transnational
Korea Co., Ltd.|Quintiles Taiwan Ltd.|Quintiles, East Asia Pte. Ltd.
Singapore|Quintiles Malaysia Sdn. Bhd.|Quintiles Thailand Co.,
Ltd.|Daiichi Sankyo Inc.</td></tr>
<tr class="even"><td class="row_4 col_0">Diabetic Peripheral Neuropathic Pain</td><td class="row_4 col_1">Drug: DS-5565|Drug: placebo</td><td class="row_4 col_2">Phase 3</td><td class="row_4 col_3">Recruiting</td><td class="row_4 col_4">Daiichi
Sankyo Co., Ltd.|Quintiles Taiwan Ltd.(Taiwan)|Quintiles Transnational
Korea Co., Ltd. (Korea)|CMIC Co, Ltd. Japan|Daiichi Sankyo Inc.</td></tr>
<tr class="odd"><td class="row_5 col_0">Pain Associated With Fibromyalgia</td><td class="row_5 col_1">Drug:
DS-5565 15mg tablet|Drug: 150mg pregabalin capsule|Drug: placebo
tablet|Drug: placebo capsule|Drug: 75mg pregabalin capsule</td><td class="row_5 col_2">Phase 3</td><td class="row_5 col_3">Recruiting</td><td class="row_5 col_4">Daiichi Sankyo Inc.|INC Research</td></tr>
<tr class="even"><td class="row_6 col_0">Pain Associated With Fibromyalgia</td><td class="row_6 col_1">Drug:
DS-5565 15mg tablet|Drug: 150mg pregabalin capsule|Drug: placebo
tablet|Drug: placebo capsule|Drug: 75mg pregabalin capsule</td><td class="row_6 col_2">Phase 3</td><td class="row_6 col_3">Recruiting</td><td class="row_6 col_4">Daiichi Sankyo Inc.|INC Research</td></tr>
<tr class="odd"><td class="row_7 col_0">Pain Associated With Fibromyalgia</td><td class="row_7 col_1">Drug: 15mg DS-5565</td><td class="row_7 col_2">Phase 3</td><td class="row_7 col_3">Recruiting</td><td class="row_7 col_4">Daiichi Sankyo Inc.</td></tr>
<tr class="even"><td class="row_8 col_0">Diabetic Peripheral Neuropathy</td><td class="row_8 col_1">Drug: DS-5565 tablet|Drug: pregabalin capsule|Drug: Placebo tablet|Drug: placebo capsule</td><td class="row_8 col_2">Phase 2</td><td class="row_8 col_3">Completed</td><td class="row_8 col_4">Daiichi Sankyo Inc.</td></tr>
<tr class="odd"><td class="row_9 col_0">Pain|Diabetic Peripheral Neuropathy</td><td class="row_9 col_1">Drug: DS-5565|Drug: DS-5565|Drug: DS-5565|Drug: Placebo|Drug: Pregabalin capsules</td><td class="row_9 col_2">Phase 2</td><td class="row_9 col_3">Completed</td><td class="row_9 col_4">Daiichi Sankyo Co., Ltd.|Daiichi Sankyo Inc.</td></tr>
</tbody></table>
</div>
</div>
</div>
</div>
</td></tr>
</tbody></table>
</div>
<div class="field-item even">
<table class="infobox mce-item-table"><caption>Mirogabalin</caption><tbody>
<tr><td colspan="2"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Mirogabalin.svg" href="https://en.wikipedia.org/wiki/File:Mirogabalin.svg"><img alt="Mirogabalin.svg" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/6b/Mirogabalin.svg/140px-Mirogabalin.svg.png" height="150" src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/6b/Mirogabalin.svg/140px-Mirogabalin.svg.png" width="140" /></a></td></tr>
<tr><th colspan="2">Systematic (<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/International_Union_of_Pure_and_Applied_Chemistry_nomenclature" href="https://en.wikipedia.org/wiki/International_Union_of_Pure_and_Applied_Chemistry_nomenclature" title="International Union of Pure and Applied Chemistry nomenclature">IUPAC</a>) name</th></tr>
<tr><td colspan="2"><div>
(1<i>R</i>,5<i>S</i>,6<i>S</i>)-6-(aminomethyl)-3-ethyl-bicyclo(3.2.0)hept-3-ene-6-acetic acid</div>
</td></tr>
<tr><th colspan="2">Identifiers</th></tr>
<tr><th scope="row"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Registry Number</a></th><td><span class="reflink plainlinks nourlexpansion"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=1138245-21-2" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=1138245-21-2" rel="nofollow">1138245-21-2</a></span><sup> <img alt="Yes" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" width="7" /></sup></td></tr>
<tr><th scope="row"><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td>CID: <span class="reflink plainlinks nourlexpansion"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=49802951" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=49802951" rel="nofollow">49802951</a></span></td></tr>
<tr><th scope="row"><a data-mce-href="https://en.wikipedia.org/wiki/ChemSpider" href="https://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td><span class="reflink plainlinks nourlexpansion"><a class="external text" data-mce-href="http://www.chemspider.com/Chemical-Structure.32701007.html" href="http://www.chemspider.com/Chemical-Structure.32701007.html" rel="nofollow">32701007</a></span></td></tr>
<tr><th colspan="2">Chemical data</th></tr>
<tr><th scope="row"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td><a data-mce-href="https://en.wikipedia.org/wiki/Carbon" href="https://en.wikipedia.org/wiki/Carbon" title="Carbon">C</a><sub>12</sub><a data-mce-href="https://en.wikipedia.org/wiki/Hydrogen" href="https://en.wikipedia.org/wiki/Hydrogen" title="Hydrogen">H</a><sub>19</sub><a data-mce-href="https://en.wikipedia.org/wiki/Nitrogen" href="https://en.wikipedia.org/wiki/Nitrogen" title="Nitrogen">N</a><a data-mce-href="https://en.wikipedia.org/wiki/Oxygen" href="https://en.wikipedia.org/wiki/Oxygen" title="Oxygen">O</a><sub>2</sub></td></tr>
<tr><th scope="row"><a data-mce-href="https://en.wikipedia.org/wiki/Molecular_mass" href="https://en.wikipedia.org/wiki/Molecular_mass" title="Molecular mass">Molecular mass</a></th><td>209.285 g/mol</td></tr>
</tbody></table>
</div>
<div class="field-item even">
/////////</div>
<div class="field-item even">
1138245-13-2, CCC1=C[C@@H]2[C@H](C1)C[C@@]2(CC(=O)O)CN</div>
<div class="field-item even">
CCC1=CC2C(C1)CC2(CC(=O)O)CN</div>
<div class="field-item even">
smiles besylate......CCC1=C[C@@H]2[C@H](C1)C[C@@]2(CC(=O)O)CN.c1ccc(cc1)S(=O)(=O)O</div>
<div class="field-item even">
</div>
<div class="field-item even">
see</div>
<div class="field-item even">
ATAGABALIN ALS0</div>
<a data-mce-href="https://en.wikipedia.org/wiki/Atagabalin" href="https://en.wikipedia.org/wiki/Atagabalin">https://en.wikipedia.org/wiki/Atagabalin</a><br />
<br />
<br />
SEE........GABALIN SERIES....... <a href="http://apisynthesisint.blogspot.in/p/gabalin-series.html">http://apisynthesisint.blogspot.in/p/gabalin-series.html</a></div>
DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com35tag:blogger.com,1999:blog-7082350141827122272.post-15728301811741197112015-11-17T04:27:00.002-08:002015-11-17T04:27:36.437-08:00EV 077<div dir="ltr" style="text-align: left;" trbidi="on">
<br />
<div class="pd-rating" id="pd_rating_holder_6864914_post_15728" style="display: inline-block;">
<div class="rating-msg" id="PDRTJS_6864914_post_15728_msg" style="color: #; float: left; font: normal normal /16px; padding-left: 5px; text-align: left;">
</div>
</div>
<br /><img alt="" src="http://www.evolva.com/wp-content/uploads/2015/08/The_dual_thromboxane_receptor_antagonist.jpg" /><br />
EV-077<br />
SER 150 (formerly EV-077)<br />
<div class="company_data" id="companyData">
Also known as: formerly EV-077-3201</div>
<div class="company_data">
<strong>EV-077-3201-2TBS</strong></div>
CAS <span id="yui_3_18_1_3_1447468249493_320">1384128-29-3</span><br />
<a href="http://www.synbioproject.org/cpi/companies/evolva/">Evolva</a> INNOVATOR<br />
<a href="http://www.google.co.in/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Evolva+Sa%22">Evolva Sa</a><br />
Oral thromboxane receptor antagonist and thromboxane synthase inhibitor<br />
EV-077 is a small compound being developed for the treatment of
complications of diabetes. In Phase 2. Outlicensed to Serodus in 2013.<br />
In 2013, Serodus licensed the product candidate for the treatment of
diabetic nephropathy and it is conducting phase II clinical trials on
this research.<br />
EV-077 is an oral, small molecule compound, belonging to a new
structural class. Preclinical and early clinical studies indicate EV-077
has potential in reducing vascular inflammation by inhibiting the
activity of prostanoids and isoprostanes – in particular in diabetes.
Towards the end of 2011, the Russian Patent Office granted patent
protection for EV-077 in the treatment of complications of diabetes for a
term extending to 2026. Evolva has outlicenced EV-077 to Serodus in
2013. Serodus aims to bring EV-077 further through clinical development
and at a future time point decide whether Serodus or a partner will
conduct the final clinical trials.<br />
EV-077 is in development as a potential pharmaceutical for the
treatment of diabetic nephropathy and other diabetic complications. It
is in Phase II clinical studies.<br />
In 2013, Evolva out-licensed EV-077 to Serodus (Oslo, Norway).
Serodus aims to bring EV-077 through Phase II and then decide whether or
not to partner for the final clinical trials and commercialisation.
Evolva is entitled to clinical and regulatory milestones as well as a
single-digit royalty on sales. If Serodus sublicenses EV-077 then Evolva
will receive up to 30% of Serodus’ total licensing income.<br />
As of Q2 2015 Serodus continues active development of EV-077.<br />
– See more at: <a href="http://www.evolva.com/ev-077/#sthash.4mgJ3E0f.dpuf">http://www.evolva.com/ev-077/#sthash.4mgJ3E0f.dpuf</a><br />
Patients with diabetes mellitus (DM) have increased propensity to
generate thromboxane A2 (TXA2) and other eicosanoids which can
contribute to their heightened platelet reactivity. EV-077 is a potent
thromboxane receptor antagonist and thromboxane synthase inhibitor and
thus represents an attractive therapy in patients with DM. However, the
effects of EV-077 on pharmacodynamic (PD) profiles in patients with DM
and coronary artery disease (CAD) while on antiplatelet therapy is
poorly explored and represented the aim of this in vitro pilot
investigation. Patients with DM and stable CAD (n = 10) on low-dose
aspirin (81 mg/day) were enrolled and then switched to clopidogrel
(75 mg/day) monotherapy for 7-10 days. PD assessments were conducted
while on aspirin and on clopidogrel using light transmittance
aggregometry following stimuli with U-46619 [TXA2 stable analogue
(7 μM)], arachidonic acid [AA (1 mM)], collagen (3 μg/mL) and adenosine
diphosphate [ADP (5 μM and 20 μM)] with and without in vitro EV-077.
EV-077 completely inhibited U-46619-stimulated platelet aggregation
(p = 0.005 for both aspirin and clopidogrel) and also showed a
significant reduction of collagen-induced aggregation (aspirin
p = 0.008; clopidogrel p = 0.005). EV-077 significantly reduced
AA-induced platelet aggregation in clopidogrel (p = 0.009), but not
aspirin (p = 0.667) treated patients. Ultimately, EV-077 significantly
reduced ADP-mediated platelet aggregation in both aspirin (ADP 5 μM
p = 0.012; ADP 20 μM p = 0.032) and clopidogrel (ADP 5 μM p = 0.007; ADP
20 μM p = 0.008) treated patients. In conclusion, in DM patients with
CAD on aspirin or clopidogrel monotherapy, in vitro EV-077 exerts potent
platelet inhibitory effects on multiple platelet signaling pathways.
These data support that EV-077 has only additive platelet inhibiting
effects on top of standard antiplatelet therapies. These findings
warrant further investigation in ex vivo settings.<br />
<img alt="" src="http://www.evolva.com/wp-content/uploads/2015/08/The_dual_thromboxane_receptor_antagonist.jpg" /><br />
<div class="_skeleton ProductSummaryView">
<div>
<h3>
Description</h3>
<div>
<div id="opp-description">
EV-077 is a small compound being developed for
the treatment of complications of diabetes. In Phase 2. Outlicensed to
Serodus in 2013.</div>
</div>
</div>
</div>
<div class="_skeleton BucketView">
<div class="BucketView-Container">
<div>
<h3 class="title-tag">
Situation Overview</h3>
</div>
<div class="SituationOverview keiki-bucket-field">
Diabetes and its complications are major global health care problems.
Based on estimates by the International Diabetes Federation (IDF),
there were 366 million diabetics worldwide in 2011, a number which is
expected to increase to 552 million by 2030. IDF estimates the number of
deaths in 2011 at 4.6 million and total spending on diabetic health
care at USD 465 billion.<br />
EV-077 is an oral, small molecule compound, belonging to a new
structural class. EV-077 is being developed for the reduction of
vascular inflammation by inhibiting the activity of prostanoids and
isoprostanes ��� in particular in diabetes. Towards the end of 2011, the
Russian Patent Office granted patent protection for EV-077 in the
treatment of complications of diabetes for a term extending to 2026.
Additional patent applications are pending in all major
territories. Evolva has outlicenced EV-077 to Serodus in 2013.<br />
</div>
</div>
<div class="BucketView-Container">
<div>
<h3 class="title-tag">
Mechanism of Action</h3>
</div>
<div class="MechanismofAction keiki-bucket-field">
Preclinical and early clinical studies indicate EV-077 has potential
in reducing vascular inflammation by inhibiting the activity of
prostanoids and isoprostanes in particular in diabetes. The mechanism of
action of EV-077 means that it can potentially ameliorate or prevent a
range of diabetic complications (including loss of kidney function,
reduced peripheral blood flow and increased risk of thrombosis) that
derive from the following chain of events:<br />
<ul>
<li>Diabetic patients have a reduced sensitivity to insulin which increases overall glucose levels in the body;</li>
<li>This increase in glucose increases oxidative stress;</li>
<li>The oxidative stress generates a high level of isoprostanes and prostanoids;</li>
<li>The isoprostanes and prostanoids chronically activate thromboxane
prostanoid receptors, that are located on the walls of blood vessels
(endothelial cells and smooth muscle cells) and the surface
of platelets;</li>
<li>Activation of the thromboxane prostanoid receptors causes vascular inflammation and increased platelet reactivity;</li>
<li>An increased number of vascular events and a progressive deterioration of circulatory and renal function.</li>
</ul>
</div>
</div>
<div class="BucketView-Container">
<div>
<h3 class="title-tag">
Clinical Trials</h3>
</div>
<div class="ClinicalTrials keiki-bucket-field">
In November 2011, Evolva received regulatory clearance to progress
EV-077 into Phase IIa clinical studies for the treatment of
complications of diabetes. It is a single-centre study, conducted in
Germany. The study was a randomized, double-blind, and
placebo-controlled, and investigated the efficacy and safety of EV-077
in type 2 diabetics with a heightened risk of diabetic vascular
complications. Measurements included blood flow and platelet reactivity,
biomarkers for oxidative stress and vascular inflammation as well as
markers of the function of organs that are often impaired in diabetes
(e.g. kidney).<br />
In May 2012, the study was terminated. Interim results for the first
32 patients enrolled in the Phase IIa study show promising efficacy
data, indicating that 300mg EV-077 given orally twice daily to patients
with type 2 diabetes provided anti-platelet activity, reduced
exercise-induced proteinuria and increased forearm blood flow. This was
achieved with only a slight increase in bleeding time. The analysis also
indicated that EV-077 was generally well tolerated, with adverse events
mostly limited to increases in liver enzymes, which were transient or
resolved after discontinuation.<br />
In parallel with the Phase IIa study, Evolva is conducting
epidemiological studies to identify high risk diabetic patient subgroups
that can potentially derive particular benefit from the administration
of EV-077. Given success, this is expected to expedite both further
clinical development (by reducing the size and duration of late stage
clinical trials) and the eventual approval process.<br />
</div>
</div>
<div class="BucketView-Container">
<div>
<h3 class="title-tag">
Partners by Region</h3>
</div>
<div class="PartnersbyRegion keiki-bucket-field">
Evolva has outlicensed EV-077 to Serodus in 2013. Serodus aims to
bring EV-077 further through clinical development and at a future time
point decide whether Serodus or a partner will conduct the final
clinical trials.<br />
</div>
</div>
</div>
WO 2014011273<br />
<a href="http://www.google.com/patents/WO2014011273A2?cl=en">http://www.google.com/patents/WO2014011273A2?cl=en</a><br />
Journal of Thrombosis and Haemostasis (2011), 9(10), 2109-2111<br />
Thrombosis Research (2012), 130(5), 746-752<br />
European Journal of Clinical Pharmacology (2013), 69(3), 459-465<br />
Biochemical and Biophysical Research Communications (2013), 441(2), 393-398<br />
Journal of Thrombosis and Thrombolysis (2014), 37(2), 131-138<br />
<br />
<a href="http://www.google.co.in/patents/WO2008089461A1?cl=en">http://www.google.co.in/patents/WO2008089461A1?cl=en</a><br />
(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1
,3-dioxan-5-yl)hex-4-enoic acid has the 3 groups all up, which has a
dramatic effect on its biological activities:<br />
<div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/WO2008089461A1/imgf000022_0002.png"><img alt="Figure imgf000022_0002" class="patent-full-image" height="116" id="imgf000022_0002" src="http://patentimages.storage.googleapis.com/WO2008089461A1/imgf000022_0002.png" width="324" /></a></div>
<div class="patent-image">
see<br />
<h3 class="title" title="Report Name: WO-2011057262">
WO 2011057262</h3>
</div>
<h3 class="sd-title">
Share this:</h3>
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///////////// see........<a href="http://newdrugapprovals.org/2015/11/16/ev-077/">http://newdrugapprovals.org/2015/11/16/ev-077/</a></div>
DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1tag:blogger.com,1999:blog-7082350141827122272.post-22170258984486692012015-04-08T04:35:00.002-07:002015-04-08T04:35:39.808-07:00TELMISARTAN PART 3/3<div dir="ltr" style="text-align: left;" trbidi="on">
<h3 class="post-title entry-title" itemprop="name" style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 30px; font-stretch: normal; font-weight: normal; margin: 0px; position: relative;">
TELMISARTAN PART 3/3</h3>
<div class="post-header" style="background-color: #e5fff8; color: #559966; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 13.8000001907349px; line-height: 1.6; margin: 0px 0px 1em;">
<div class="post-header-line-1">
</div>
</div>
<div class="post-body entry-content" id="post-body-6942631100331572510" itemprop="description articleBody" style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 1.5; position: relative; width: 868px;">
<div dir="ltr" trbidi="on">
<img alt="" src="http://www.animatedimages.org/data/media/696/animated-update-image-0024.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><div>
<div>
PART 1........<a href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-13.html" style="color: #6c1b00; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-13.html</a></div>
<div>
PART 2........<a href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html" style="color: #6c1b00; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html</a></div>
<div>
OR <a href="http://newdrugapprovals.org/2015/04/06/telmisartan-part-23/" style="color: #6c1b00; text-decoration: none;">http://newdrugapprovals.org/2015/04/06/telmisartan-part-23/</a></div>
<div>
PART3...... <a href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-33.html" style="color: #6c1b00; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-33.html</a><br /><br /></div>
<div>
</div>
</div>
<div>
<span style="color: #ff6600;"> CONT.........................</span><br /><span style="color: #ff6600;"><br /></span><span style="color: #ff6600;"><br /></span><span style="color: #ff6600;"><br /></span></div>
<div>
</div>
<div>
<span style="color: red;">PAPER</span></div>
<div>
Journal of Organic Chemistry (2015), 80(3), 1915-1919</div>
<div>
<div id="citation">
<cite>J. Org. Chem.</cite>, <span class="citation_year">2015</span>, <span class="citation_volume">80</span> (3), pp 1915–1919</div>
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<strong>DOI: </strong>10.1021/jo5025333</div>
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<a href="http://pubs.acs.org/doi/abs/10.1021/jo5025333?source=chemport&journalCode=joceah" style="color: #6c1b00; text-decoration: none;">http://pubs.acs.org/doi/abs/10.1021/jo5025333?source=chemport&journalCode=joceah</a><br /><br /><br /></div>
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<img alt="Abstract Image" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/joceah/2015/joceah.2015.80.issue-3/jo5025333/20150202/images/medium/jo-2014-025333_0009.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><br /></div>
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A direct and efficient total synthesis has been developed for telmisartan, a widely prescribed treatment for hypertension. This approach brings together two functionalized benzimidazoles using a high-yielding Suzuki reaction that can be catalyzed by either a homogeneous palladium source or graphene-supported palladium nanoparticles. The ability to perform the cross-coupling reaction was facilitated by the regio-controlled preparation of the 2-bromo-1-methylbenzimidazole precursor. This convergent approach provides telmisartan in an overall yield of 72% while circumventing many issues associated with previously reported processes.</div>
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<img alt="" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c91f6afe1da580&attid=0.2&disp=emb&attbid=ANGjdJ8QcAS0mYt2dYIbmoynzNg2sL918gu7r9TtLEnOxP1tfCfJtw3XNKgH8AYU437A5rkjvTGIZmWrstmiaGiIhMxg9W0jsYuwjDEKsHe2In0l5nHd5ion3aUGKM8&sz=w1054-h764&ats=1428403899932&rm=14c91f6afe1da580&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /></div>
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<img alt="Displaying image017.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c91f6afe1da580&attid=0.5&disp=emb&attbid=ANGjdJ_cSPuvCSK9Y-NlIuweVbCX9ZvATplRRCNzPFMeFKMHrEoQNsCj8IierBysxBSyJAtoVkfM6N3X1YuIH0jq5dGAo5iTbTqTbokHfb0ry4W1Qf-aN-k0-nTqjkY&sz=w1070-h554&ats=1428403899932&rm=14c91f6afe1da580&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /></div>
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<img alt="Displaying image018.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c91f6afe1da580&attid=0.6&disp=emb&attbid=ANGjdJ_nRvg81oRR7rRdB_uGqckBYM7tyL7aK9ZuEBQ4TWfCxJ8qD1Hspsq4b-LvSDtHdHzwYPSBeeY6WNxCWIa8D8KZgt9_p31q9_SzVv1B0tYwWr8XYV3RFfVPGUE&sz=w1070-h778&ats=1428403899932&rm=14c91f6afe1da580&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /></div>
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<img alt="Displaying image019.png" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c91f6afe1da580&attid=0.7&disp=emb&attbid=ANGjdJ8vbMoGr21VilLv9aviGTyklhOPNppxCbOlrAGf_bi_47nXUbmckP6XCYD7U1WN_htmd-JnoxzNG4Zi6_cV7YoNqmdMyrfRP70JlGRU00icy65DLqSgomDPNIo&sz=w1150-h346&ats=1428403899933&rm=14c91f6afe1da580&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /></div>
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International Journal of Research in Pharmaceutical and Biomedical Sciences (2013), 4(1), 293-295</div>
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telmisartan1. [Yield 87%, Purity 99.97% by HPLC.M.P. 260 – 262°C, Sulphated ash < 0.01%].</div>
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1H NMR (DMSO-d6): δ 0.98-1.03 (t,3H), 1.73- 1.86 (m, 2H), 2.5 - 2.63 (s, 3H), 2.90-2.95 (s, 2H),3.82 (s, 3H), 5.62 (s, 2H), 7.16-7.34 (m,7H), 7.40-7.59 (m,4H), 7.68-7.70 (m, 3H), 12.86 (s, 1H).</div>
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M/Z: 515.50 [M + H]+</div>
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<img alt="Displaying image004.png" class="" height="364" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c92012c7bbc8a4&attid=0.2&disp=emb&attbid=ANGjdJ8irBWoLX0TVC0qhRCbF-EilhzcxkWk-IQQ4wnyZtMrGyfEyOY6I3zb0V-wXdfSubCPy28gL8-6QI4lbAK1vuqXlrOhq_Xl_LAIsOtPj0kDm9zL7T-1TojGY1A&sz=w2094-h1192&ats=1428403899904&rm=14c92012c7bbc8a4&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /></div>
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WO 2014027280</div>
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<a href="http://www.google.com/patents/WO2014027280A1?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.com/patents/WO2014027280A1?cl=en</a><br /><br /></div>
Scheme 1 given below: Formula .<br /><div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/WO2014027280A1/imgf000005_0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000005_0001" class="patent-full-image" height="788" id="imgf000005_0001" src="http://patentimages.storage.googleapis.com/WO2014027280A1/imgf000005_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="536" /></a></div>
Example 1: 4'-[2-n^ropyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-ylmeth^ carboxylic acid In a 2 litre reaction flask was added 400 ml methylene chloride, followed by 100 gm of 2- cyano-4' -methyl biphenyl. The reaction mass was stirred to get a clear solution and cooled to 20 °C. Chlorine gas was sparged into the reaction mass for a period of 15 hours till completion of the reaction. The reaction was monitored by TLC using mobile phase n-hexane: ethyl acetate (8:2). The excess chlorine from the reaction mass was removed by flushing with nitrogen. The solvent was distilled out completely by distillation at atmospheric pressure and removal of the final traces under vacuum. To the residual mass, 500 ml of methyl isobutyl ketone was added. The reaction mass was stirred and washed with a solution of 300 ml of 5% sodium bicarbonate solution.<br />The lower aqueous layer was separated and the upper organic layer was washed with 300 ml water. The lower aqueous layer was separated. To the organic layer containing 4-chloromethyl-2'-cyanobiphenyl, the compound 2-n-propyl-4-methyl-6-(l'- methylbenzimidazol-2'-yl)benzimidazole was added, followed by a solution of 40 gm sodium hydroxide in 300 ml water.<br /> The reaction mass was stirred for 10 minutes and 10 gm of tetrabutyl ammonium hydrogen sulphate was added. The reaction mass was heated to 80 <sup>U</sup>C and maintained at 80 to 85 °C for 4 hours. The completion of the reaction was monitored by TLC using mobile phase chloroform: methanol (9: 1). After completion of reaction, the lower aqueous layer was separated.<br />The solvent was distilled out till mass temperature 120 °C and final traces were removed completely under vacuum. To the residual mass, 50 ml of n-butanol was added and the solvent distilled out under vacuum below 100 °C to remove all traces of methyl isobutyl ketone. The residue was dissolved in 750 ml of n-butanol and 83 gm sodium hydroxide added. The reaction mass was heated to reflux and maintained for 24 hours at 123 to 126 °C. The completion of the reaction was monitored by TLC using mobile phase chloroform: methanol (9: 1). The solvent was distilled out at atmospheric pressure till the mass temperature reached 140 C.<br />The residual mass was cooled to 100 °C and 300 ml water was added. The solvent was distilled out azeotropically till the mass temperature reached 120 °C. To the reaction mass 750 ml of water was added, the solution warmed to 80 °C. The pH of the reaction mass was adjusted to 8.0 with hydrochloric acid. Finally the pH was adjusted to 6.0 with acetic acid, and the reaction mass maintained at 80 to 85 °C for one hour. The product obtained was filtered, washed with water and dried to yield 120 gm of 4'-[2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl-2-carboxylic acid, which can be purified as per the procedure described mentioned in Example 5.<br /><br />Example 2: 4-chloromethyl-2 '-cyanobiphenyl In a 1 litre reaction flask 400 ml of methylene chloride was added followed by 100 gm of 2- cyano-4' -methyl biphenyl. The reaction mass was stirred to get a clear solution and cooled to 20 °C. Chlorine gas was sparged into the reaction mass for a period of 15 hours at 20 to 25 °C till completion of the reaction. The reaction was monitored by TLC using mobile phase n- hexane: ethyl acetate (8:2). The excess chlorine from the reaction mass was removed by flushing with nitrogen. The solvent was distilled out completely by distillation at atmospheric pressure and removal of the final traces under vacuum. To the residual mass, 400 ml of n- heptane was added. The reaction mass was stirred and warmed to 60 °C. The clear solution obtained was cooled to 10 °C and the product precipitated was filtered, washed with n-heptane and dried. Further crystallization with n-heptane yielded 80 gm of pure 4-chloromethyl-2'- cyanobiphenyl. C 73.87%, H 4.41%, N 6.19%; m/z 192.25; 1H NMR DMSO d<sub>6</sub>400 Mhz : 5ppm 4.84 (s, 2H) 7.32 - 7.66 (aromatic 8H).<br /><br />Example 3: 2-cyano-4<sup>,</sup>-(2<sup>,,</sup>-n-propyl-4<sup>,,</sup>-methyl-6<sup>,,</sup>-{V"-methylbenzim ylmethyl) biphenyl In a 2 litre reaction flask 500 ml of methyl isobutyl ketone was added followed by 100 gm of 2-n-propyl-4-methyl-6-( -methylbenzimidazol-2'-yl)benzimidazole. The reaction mass was stirred and a solution of 40 gm sodium hydroxide in 300 ml water was added. To this solution, 10 gm tetra butyl ammonium hydrogen sulphate and 80 gm of 4-chloromethyl-2'- cyanobiphenyl was added. The reaction mass was warmed to 80 °C and maintained for 4 hours at 80 to 85 °C. The completion of the reaction was monitored by TLC using mobile phase chloroform : methanol (9:1). After completion of the reaction, the mass was cooled to 20 °C, maintained 3 hours at 15 to 20 °C. The product which precipitated out was filtered, washed with methyl isobutyl ketone, followed by water to yield 126 gm of 2-cyano-4'-(2"-n-propyl-4"-methyl- 6"-(r"-methylbenzimidazol-2"'-yl)benzimidazol-l"- ylmethyl) biphenyl, melting at 196 - 198 °C. C 80.53%, H 5.70%, N 14.20%; m/z = 496.64 <sup>l</sup>H NMR DMSO d<sub>6</sub> 400 Mhz : 5ppm 0.96 - 0.99 (t, 3H) 1.75 - 1.84 (m, 2H) 2.62 (s, 3H) 2.89 - 2.93 (t, 2H) 3.80 (s, 3H) 5.67 (s, 2H) 7.18 - 7.92 (m, 14H)<br /><br /><br /> Example 4: 4'-[2-n^ropyl-4-methyl-6-(l-methylbenzi idazol-2-yl)benzi idazol-ylmethyl]bipheny carboxylic acid 126 gm of 2-cyano-4'-(2"-n-propyl-4"-methyl-6"-(l "'-methylbenzimidazol-2"'-yl) benzimidazol-1"- ylmethyl) biphenyl was dissolved in 750 ml of n-butanol and 83 gm sodium hydroxide added. The reaction mass was heated to reflux and maintained for 15 hours at 123 to 126 °C. The completion of the reaction was monitored by TLC using mobile phase chloroform: methanol (9: 1). The solvent was distilled out at atmospheric pressure till the mass temperature reached 140 °C. The residual mass was cooled to 100 °C and 300 ml water was added. The solvent was distilled out azeotropically till the mass temperature reached 120 °C. To the reaction mass 750 ml of water was added, the solution warmed to 80 °C. The pH of the reaction mass was adjusted to 8.0 with hydrochloric acid. Finally the pH was adjusted to 6.0 with acetic acid, and the reaction mass maintained at 80 to 85 °C for one hour. The product obtained was filtered, washed with water and dried to yield 120 gm of 4'-[2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl-2-carboxylic acid.<br /><br /><br />Example 5: Purification of <span style="color: #ff6600;">4'-[2-n^ropyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l- ylmethyl]biphenyl-2-carboxytic acid</span> In a 3 litre reaction flask, 1000 ml of methanol was added followed by the addition of 120 gm of 4'-[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl- 2-carboxylic acid obtained by procedure described in Example 4. The solution was warmed to 50 °C and pH adjusted to 10.0 to 10.5 with 100 ml of a 10% methanolic potassium hydroxide solution. The reaction mass became a clear solution, and 6 gm activated carbon was added. The mass was maintained at 50 to 55 °C for one hour and filtered through hyflo supercel to remove the activated carbon. The clear filtrate obtained was collected and its pH adjusted to 6.0 to 6.5 with 130 ml of acetic acid, maintaining the temperature between 50 to 55 °C. The mass was cooled to 15 °C and maintained one hour at 10 to 15 °C. The product which precipitated out was filtered, washed with 50 ml of methanol followed by 500 ml of water. The wet product was dried to yield 107 gm of 4'-[2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl)benzimidazol-l-ylmethyl]biphenyl-2-carboxylic acid. <span style="color: #ff6600;">C 76.49%; H 5.74%, N 11.02%; m/z 515.45.; 1H NMR DMSO d<sub>6</sub> 400 Mhz : 5ppm 0.97 - 1.01 (t, 3H) 1.76 - 1.85 (m, 2H) 2.62 (s, 3H) 2.90 - 2.94 (t, 3H) 3.81 (s, 3H) 5.61 (s, 2H) 7.15 - 7.71 (14H aromatic); </span><span style="color: #ff6600;">Melting point of purified telmisartan: 269 °C.</span><br /><div class="articleBody_abstractText">
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Journal of Organic Chemistry (2014), 79(21), 10568-10580</div>
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<a href="http://pubs.acs.org/doi/abs/10.1021/jo501665e" style="color: #6c1b00; text-decoration: none;">http://pubs.acs.org/doi/abs/10.1021/jo501665e</a></div>
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<cite>J. Org. Chem.</cite>, <span class="citation_year">2014</span>, <span class="citation_volume">79</span> (21), pp 10568–10580</div>
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<strong>DOI: </strong>10.1021/jo501665e</div>
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<img alt="Abstract Image" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/joceah/2014/joceah.2014.79.issue-21/jo501665e/20141103/images/medium/jo-2014-01665e_0006.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /></div>
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On the basis of our recently reported aniline aqueous borylation, molecular diversity was achieved in a one-pot process by combining other reactions such as esterification, Suzuki–Miyaura coupling, hydrogenolysis, or Petasis borono-Mannich.</div>
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TELMISARTAN IS COMPD 9<br /><br /><br /></div>
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<span style="color: red;">PATENT</span></div>
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US 20150031768</div>
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<a href="https://patentscope.wipo.int/search/docservice_fpimage/US130253548@@@false" style="color: #6c1b00; text-decoration: none;" target="Image"><img alt="" src="https://patentscope.wipo.int/search/docservice_fpimage/US130253548@@@true" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" /></a></div>
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<b class="notranslate">(EN)</b></div>
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Methods of halogenating a carbon containing compound having an sp3 C—H bond are provided. Methods of fluorinating a carbon containing compound comprising halogenation with Cl or Br followed by nucleophilic substitution with F are provided. Methods of direct oxidative C—H fluorination of a carbon containing compound having an sp3 C—H bond are provided. The halogenated products of the methods are provided.<br /><br /><br /></div>
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WO 2014067237</div>
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<a href="http://www.google.com/patents/WO2014067237A1?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.com/patents/WO2014067237A1?cl=en</a></div>
<span class="notranslate">Telmisartan Preparation: 12 Examples</span> <span class="notranslate">The title compound (III, R = COOCH <sub>3)</sub> (52.8g, O. lmol) of Example 11 with glacial acetic acid</span><span class="notranslate">(200ml) and concentrated hydrochloric acid (250ml) mixing, 100 ° C to react for 5 to 6 hours.</span> <span class="notranslate">Evaporated to most mixed acid, residue slowly poured into crushed ice, under ice cooling with saturated K <sub>2</sub> CO ^ solution to adjust the pH to neutral, solid precipitation, filtration, filtrate was washed with water, was for Mischa Tan crude, recrystallization telmisartan (40.1g), liquid purity greater than 99%.</span><span class="notranslate">Example 13: Preparation of telmisartan of formula I compound (0.62g, leq) was added to acetonitrile (10ml). After stirring evenly, the KOH (0.14g, 1. leq) was slowly added, after stirring for 10 plus minutes, the title compound of Example 10 of the embodiment (11, R = COOCH <sub>3)</sub> (0.5g, leq) was slowly added, stirred for 3-4 hours, TLC the reaction was complete, the direct addition of 50% ethanol (30mL), reflux The reaction for 6 hours.</span> <span class="notranslate">After completion of the reaction by TLC, recovering the organic solvent under reduced pressure, the remaining solution was added dropwise hydrochloric acid (1: 1) to neutral pH.</span> <span class="notranslate">The precipitated solid was filtered, washed with water to give crude telmisartan, telmisartan recrystallized (yield 75.1%), the liquid phase is greater than 98% purity.</span> <span class="notranslate">Chloromethyl biphenyl -2- (II, R = CN) Preparation of 4'-nitrile:</span><br /><div class="articleBody_abstractText">
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Journal of Pharmaceutical and Biomedical Analysis (2015), 108, 86-96.</div>
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IN 262831/EP 1912975</div>
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JP 2014201585</div>
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IN 2013KO00463/WO 2014174397</div>
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<span style="color: red;">PATENT</span></div>
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<a href="http://www.google.com/patents/CN1768044A?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.com/patents/CN1768044A?cl=en</a></div>
<span class="notranslate">Example 7: Telmisartan make 5.51 g telmisartan × HCl was dissolved in 50 ml of 40% acetic acid while refluxing.</span> <span class="notranslate">The brown solution was then filtered hot through 1.1 g of carbon, 2.5 ml of 40% acetic acid and washed, and at 80-90 ℃ 2.5 ml of 4N NaOH was added dropwise with stirring to light brown filtrate.</span> <span class="notranslate">Telmisartan crystallization, the suspension was diluted with 30 ml of water, and slowly cooled to ambient temperature.</span> <span class="notranslate">Telmisartan suction filtration, and washed with 50 ml of water.</span> <span class="notranslate">And dried in vacuo at 80 ℃ drying cabinet telmisartan.</span> <span class="notranslate">Yield: 4.80 g (93.3% of the theoretical yield).</span><br /><br /><br />.....................................<br /><br /><br /> <span style="color: red;">PATENT</span> <a href="http://www.google.com/patents/CN102731407A?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.com/patents/CN102731407A?cl=en</a><a href="http://patentimages.storage.googleapis.com/CN102731407A/CN102731407AD00041.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure CN102731407AD00041" class="patent-full-image" height="434" id="idf0002" src="http://patentimages.storage.googleapis.com/CN102731407A/CN102731407AD00041.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="640" /></a><a href="http://patentimages.storage.googleapis.com/CN102731407A/CN102731407AD00042.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure CN102731407AD00042" class="patent-full-image" height="224" id="idf0003" src="http://patentimages.storage.googleapis.com/CN102731407A/CN102731407AD00042.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="640" /></a> <span class="notranslate">Example 4 Preparation of telmisartan</span> <span class="notranslate">[0031] 2-n-propyl group as shown in Formula I-4-methyl-6- (benzimidazol-2-yl-methyl 1'_) benzimidazole (30. 4g, O. 10mol), 4_ bromomethyl-biphenyl-2-carboxylic acid (43. 6g, O. 15mol), three ko amine (12. Ig, O. 15mol) and ko ni ni ether 500ml alcohol were mixed and reacted at 100 ° C for 6 inches The reaction solution was poured into ice water, acidified with dilute hydrochloric acid and slowly adjusted PH2-3, to precipitate a solid.</span> <span class="notranslate">Filtration, 70 ° C drying crude, the resulting crude product ko ko acid ester 300ml heating beating again.</span> <span class="notranslate">Filtered, 70 ° C dry.</span> <span class="notranslate">Recrystallization from DMF telmisartan of formula III as shown in 25. Ig, yield: 50%.</span><br /><br /> .........................<br /><br /> <span style="color: red;">PATENT</span> <a href="http://www.google.com/patents/WO2010146187A2?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.com/patents/WO2010146187A2?cl=en</a><br /><br /><br /> For example, WO 2004/087676 describes the hydrolysis of a compound with the chemical name 4 '-((1,7'- dimethyl-2 ' -propyl-lH, 3 'H-2, 5 ' -bibenzo [d] imidazol-3 ' -yl) - methyl) biphenyl-2-carbonitrile and having formula 2<br /><div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/WO2010146187A2/imgf000004_0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000004_0001" class="patent-full-image" height="180" id="imgf000004_0001" src="http://patentimages.storage.googleapis.com/WO2010146187A2/imgf000004_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="368" /></a></div>
which is hereinafter referred to as cyanotelmisartan . In par- ticular, the hydrolysis of cyanotelmisartan is carried out at elevated temperatures using strong alkaline conditions. Also, CN 1412183 discloses the hydrolysis of cyanotelmisartan. US 2006/0264491 Al discloses the hydrolysis of 4'-((l,7'- dimethyl-2 ' -propyl-lH, 3 'H-2, 5 ' -bibenzo [d] imidazol-3 ' - yl) methyl) biphenyl-2-carboxamide having formula 3<br /><div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/WO2010146187A2/imgf000004_0002.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000004_0002" class="patent-full-image" height="180" id="imgf000004_0002" src="http://patentimages.storage.googleapis.com/WO2010146187A2/imgf000004_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="368" /></a></div>
Example 2: Preparation and isolation of telmisartan Into a reaction vessel 20.5g (40 mmol) 4 ' - ( (1, 7 ' -dimethyl-2 ' - propyl-IH, 3 ' H-2 , 5 ' -bibenzo [d] imidazol-3 ' -yl) methyl) biphenyl-2- carboxamide and 20 ml (lδOmmol) H<sub>2</sub>SO<sub>4</sub> (1:1) were added. The re- action mixture was heated to about 125°C and stirred at this temperature for 28 h. A sample of the reaction mixture was analyzed by Area% HPLC (starting compound below 0.1%, telmis- artan over 97%) . The reaction mixture was cooled below 80<sup>0</sup>C and 250 ml of water were added. Then, 200 ml of dichloro- methane were added and pH value of mixture was adjusted to 5.4 by addition of 6M NaOH. The mixture was stirred for approximately 5 min and then the phases were separated. The water phase was reextracted by 136 ml of dichloromethane . Collected organic phases were washed with water (2<sup>χ</sup>l36ml) and then treated with activated charcoal (5.3 g) . Subsequently, the organic phase was evaporated an oily residue (26g) . 264 ml of acetone were added. The mixture was stirred at room temperature for at least 6 hours. The precipitated product was sepa- rated and washed with fresh acetone and dried at 65°C under reduced pressure for 3 hours. Yield: 18.3g (89%) Area % HPLC: Telmisartan 99.80%<br /><br /> Example 3: Isolation of telmisartan Into a reaction vessel 7.5g (15 mmol) of cyanotelmisartan, 30 ml of propylene glycol, 0.8 ml of water and 3g (45 mmol) of 85% KOH were added. The reaction mixture was heated to around 160<sup>0</sup>C to 170 <sup>0</sup>C and stirred at this temperature for 24 h. The reaction mixture was cooled below 80<sup>0</sup>C and 75 ml of water were added. Then, pH value of the mixture was adjusted to 4.8 (by addition of 6M HCl) and then 150 ml of dichloromethane were added. The mixture was stirred for approximately 5 min and then the phases were separated. The water phase is reextracted by 50 ml of dichloromethane. Collected organic phases were washed with water (2<sup>χ</sup>50ml) and then treated with activated charcoal (2 g) . After that the organic phase was evaporated to an oily residue (9.8g) . 100 ml of acetone were added. The mix- ture was stirred at room temperature for at least 6 hours. The precipitated product was separated and washed with fresh acetone and dried at 65°C under reduced pressure for 3 hours. Yield: 6.8g (88%) Area % HPLC: Telmisartan 99.60%<br /><br /><br /><br /> .........................<br /><br /><br /> <span style="color: red;">PATENT</span> <a href="http://www.google.com/patents/CN1548421A?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.com/patents/CN1548421A?cl=en</a><br /><br /><br /><span class="notranslate">Specific embodiments</span> <span class="notranslate">14 'Example - [(1,4'-dimethyl-2'-propyl [2,6'- two-1H - benzoimidazol] 1'-yl) methyl] - [1, 1'-biphenyl] -2-carboxylic acid sodium salt in 250ml reaction flask, telmisartan 10g (0.0195mol), NaOH0.75g (0.0189mol) and water 100ml, stirred for 1 hour (30 ℃), filtered insoluble materials are removed and concentrated to a small volume, plus ethanol 30ml, concentrated, washed with 30ml of n-hexane, decanted, plus ethanol 30ml, concentrated, and then repeat again, and concentrated to dryness to obtain telmisartan sodium salt 9.9g yield 95.2%.</span> <span class="notranslate">Melting point: 223-225 ℃.</span> <span class="notranslate">Elemental analysis: C33H29N4O2Na · H2O Calcd: C71.48 H5.10 N10.11 Found: C71.42 H5.08 N10.22 </span><br /><span class="notranslate"><br /></span><span class="notranslate">Example 24 '- [(1,4'-dimethyl-2'-n propyl [2,6'- two-1H - benzoimidazol] 1'-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid potassium salt in 250ml reaction flask, Telmisartan 10g (0.0195mol), KOH1.06g (0.0188mol) and water 100ml, stirred for 1 hour (30 ℃), filtered to remove insolubles, and concentrated to a small volume, ethanol 30ml, concentrated, hexane 30ml washed, decanted, plus ethanol 30ml, concentrated, and then repeat again, and concentrated to dryness to obtain telmisartan potassium 10.6g, yield 95.6%.</span> <span class="notranslate">Melting point: 203-205 ℃.</span> <span class="notranslate">Elemental analysis: C33H29N4O2K · H2O Calcd: C69.04 H5.40 N9.76 Found: C69.01 H5.28 N9.88 </span><br /><span class="notranslate"><br /></span><span class="notranslate">Example 3 starting material and the mixed powder was sieved excipients, 5% polyethylene pyrrolidone was granulated and dried.</span> <span class="notranslate">After dried particles were sieved magnesium stearate was added mixed tabletted.</span> <span class="notranslate">mg / tablet of telmisartan sodium salt 20 Lactose 170 Sodium carboxymethyl starch 10 mg Magnesium stearate 8 meglumine 25% polyvinyl pyrrolidone solution q.s.</span><br /><span class="notranslate"><br /></span><span class="notranslate"><br /></span><span class="notranslate"> Example 4 A mixed powder of raw materials and auxiliary materials sieved, added 5 % solution of polyvinylpyrrolidone is granulated and dried.</span> <span class="notranslate">After dried particles were sieved magnesium stearate was added mixed tabletted.</span> <span class="notranslate">mg / tablet telmisartan sodium Lactose 200 40 140 DCP sodium carboxymethyl starch 16 mg Magnesium stearate 45% povidone solution appropriate amount of </span><br /><span class="notranslate"><br /></span><span class="notranslate">Example 5 of this product, according to the dissolution assay (Chinese Pharmacopoeia 2000 edition Appendix II XC second method), phosphate buffer 900ml solvent, the speed of 75 revolutions per minute, operate according to the law, after 30 minutes, take the solution as spectrophotometry (Chinese Pharmacopoeia 2000 edition of the test solution, according to the spectrophotometric two Appendix IVA), absorbance was measured at 295nm wavelength.</span> <span class="notranslate">Another reference standard stock solution 10ml precise amount of determination under set 100ml flask, diluted with phosphate buffer to the mark, then the precise amount of 5ml, set 10ml volumetric flask, dilute to the mark with phosphate buffer , shake, the same method absorption, calculated for each piece of the dissolution of the limits of 80% scalar, should be specified.</span> <span class="notranslate">Dissolution test results in Table.</span> <span class="notranslate">Table dissolution test results Dissolution (%) telmisartan sodium 97.29 99.65 102.55 95.83 101.10 98.92 99.20 ± 2.45</span><br /><br /> .......................<br /><br /> <span style="color: red;">PATENT</span> <a href="http://www.google.com/patents/CN1412183A?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.com/patents/CN1412183A?cl=en</a><br /><span class="notranslate"><br /></span><span class="notranslate">Example 5 4 '- [(1,4'-dimethyl-2'-propyl [2,6'- two -1H- benzimidazol] -1'-yl) methyl] - [1,1' - biphenyl] -2-carboxylic acid (III) IV (24.8g, 0.05mol) was added ethylene glycol (100ml) and water (150ml) (or other previously described a mixed solvent), sodium ethoxide (or as previously said other alcohols sodium) (13.6g, 0.2mol), was refluxed for 10 hours.</span> <span class="notranslate">After no starting material by TLC was cooled to room temperature, hydrochloric acid was added dropwise (1/1) to pH 5-6, the precipitated solid was filtered, washed with water to give III.</span><br /><br /><br />........................<br /><br /><br /> <span style="color: red;">PATENT</span> <a href="http://www.google.com/patents/CN101550107B?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.com/patents/CN101550107B?cl=en</a> <span class="notranslate">Example 3</span> <span class="notranslate">[0047] 1) Preparation of telmisartan crude methyl ester</span><span class="notranslate">Compound II into 50g in 500mL reaction flask, 200mL of methyl isobutyl ketone (MIBK), 25 ° C _30 ° C with stirring until dissolved, was added dropwise 35mL of triethylamine was added 55. Og After the completion of the compound III, 5 (T60 ° C or so for about 4_5 hours, TLC monitoring completion of the reaction, filtered and the filter cake washed with a small amount of MIBK, and then washed with water, dried to give 70. 3g of crude product. 81% yield, purity of about 98%.</span> <span class="notranslate">(TLC test conditions: ethyl acetate: methanol = 8: 1)</span> <span class="notranslate"> 2) preparation of high purity methyl telmisartan</span> <span class="notranslate"> IOOOmL reaction flask, the input step to give the crude methyl ester telmisartan, add 500mL of isopropanol was heated to dissolve, 2gX 2 activated bleaching filtrate was heated to about 90 ° C, added dropwise with stirring 150mL 7jC insulation 0. 5~Ih, cooled slowly to room temperature with stirring.</span> <span class="notranslate">Filtered, and the filter cake washed sequentially with MIBK and water washing, and drying, the yield of about 82%, HPLC purity 99.5%, the single impurities less than 0.1%.</span> <span class="notranslate">3) </span><br /><span class="notranslate"><br /></span><span class="notranslate">Preparation of telmisartan with high purity</span> <span class="notranslate">[0053] A reaction flask was put in a 500mL high purity 15g telmisartan ester, 3. Og sodium, 200mL of isopropanol, water, 80ml, was heated to reflux for 5 ~ 7 h, TLC monitoring of the reaction was complete, the distillation Isopropanol was removed, and water was added to completely dissolve the solid 40ml, 0. 5g of activated carbon bleaching, the filtrate was added 50ml of water, heated to 80 ° C, lmol / L of acetic acid to adjust the pH to 5. (Γ5. 5, filtered, and the filter cake dried to give 13. 14g of solid, yield 90%, HPLC purity 99.7%, the single impurities less than 0.1%.</span> <span class="notranslate">(TLC test conditions: ethyl acetate: methanol = 8: 1)</span><br /><br />.............................<br /><br /> <a href="http://www.google.com/patents/CN101172968B?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.com/patents/CN101172968B?cl=en</a><br /><br /><span class="notranslate">Example 1</span> <span class="notranslate">[0023] 1, 100gPPA, 21. 8g (0. Lmol) 2_ n-propyl _4_ _6_ carboxyl methyl benzimidazole and 21. 5gN- methyl-o-phenylenediamine added to the reaction flask in under N2 protection feeding, heated to IO (TC _1601 :, reaction 8-20 hours, down 70-80.C 200ml water was added and the reaction with hydrochloric acid to adjust ffl = 1~2, put charcoal 5_8%,, 8 (TC about 5 to 10 minutes, filtered, and the reaction repeated, the adjustment ra 12-14 with NaOH, for several hours, and filtered to give the crude intermediate 2-n-propyl -4-methyl-6- (benzimidazol-2-yl-methyl ) benzimidazole sodium salt. [0024] 2, the product of the previous step, 2-n-propyl -4-methyl--6_ (methyl benzimidazol-_2_ yl) benzimidazole sodium salt crude product was dissolved into 200 ml of ethanol , and dissolved by heating, cooling to room temperature, 400 ml 1N NaOH, to precipitate the compound 2-n-propyl -4-methyl-6- (methyl benzimidazol-2-yl) benzimidazole .50-8 ( TC dried in vacuo. [0025] 3, product of the previous step -4-methyl-2-n-propyl -6_ (methyl benzimidazol-_2_ yl) benzimidazole into 200 ml of dimethyl sulfoxide was stirred was added at room temperature and 4-bromomethyl - biphenyl-2-carboxylic acid methyl ester 33.55 g, was stirred for 14 hours, extracted with dichloromethane (200, 100, 100), and evaporated to dryness under reduced pressure, 300 ml of methanol and 10% potassium hydroxide (240 ml, 0. 6mo1) mixture was refluxed for 6 hours, cooled, washed with 80 ml of methylene chloride, adjusted with glacial acetic acid ffl = 6, a lot of white floc precipitated precipitate was filtered and dried to give a white Tilmicosin 49.6 g of crude product, the crude product was added 100 ml of chloroform was heated to reflux, activated carbon decolorization, crystallization, filtration, 8 (TC dried in vacuo to give a white pure telmisartan (HLPC> 99. 0%) 41 克, purification yield 82%. mp 261~263.C, H-NMR (d6-DMS0) S 1. 05t, 3H), 1. 83 (m, 2H), 2. 71 (s, 3H), 2. 94 (t, 2H), 3. 81 (s, 3H), 5. 57 (s, 2H), 7. 16-7. 83 (m, 14H) • C33H33N402 [0026] </span><br /><span class="notranslate"><br /></span><span class="notranslate">Example 2 Preparation of telmisartan</span> <span class="notranslate"> 1, 100gPPA, 21. 8g (0. 1) 2_ [4-methyl-n-propyl-benzimidazole and _6_ 21. 5gN- carboxy-o-phenylenediamine added to the reaction flask in N2 Under the protection of feeding, heated to 100 ° C _160 ° C, the reaction for 8-20 hours, down 70-80.</span> <span class="notranslate">C, the reaction was added 200ml of water, adjusted with hydrochloric acid ffl = 1~2, into charcoal 5_8%, about 8 (TC 5_10 minutes filtered again reacted with K0H ra adjusted to 12-14 for several hours and filtered to give Intermediate crude 2-n-propyl -4-methyl-6- (benzimidazol-2-yl-methyl) benzimidazole potassium salt.</span><br /><br /> <span class="notranslate"> 2, the product of the previous step, 2-n-propyl -4-methyl--6_ (methyl benzimidazol-_2_ yl) benzimidazole potassium salt of the crude product into 200 ml of ethanol, and dissolved by heating, cooling to room temperature was added 400 ml 1N K0H, a precipitated compound is 2-n-propyl -4-methyl-6- (benzimidazol-2-yl-methyl) benzimidazole potassium salt.</span> <span class="notranslate">50-8 (TC dried in vacuo.</span><br /><span class="notranslate"><br /></span><span class="notranslate"> [0029] 3, 2-n-propyl prepared in the previous step -4-methyl-6- (benzimidazol-2-yl-methyl) benzimidazole potassium salt and 27.2 g of 4-bromomethyl-2-cyanobiphenyl, 10.4 g of triethylamine and DMF (DMA, dichloromethane, dichloroethane) were mixed and reacted for 5-10 hours at 35-40 °, TLC detection After no starting material the reaction mixture was poured into 600 g of ice water, extracted with ethyl acetate (300ml * 3), the combined organic phases were washed with water (300ml * 2), dried and desolvation, and then petroleum ether was added and stirred until a solid precipitated was The crude product was 45.6 g.</span><br /><br /> <span class="notranslate">4, the upper step of the solid 45.6 grams, was added 200ml of ethylene glycol, 150ml water, 12 g of sodium hydroxide, the reaction was refluxed for 10 hours, TLC detected no starting material and then cooled to room temperature, acidified with hydrochloric ra is 5 to 6, there is solid precipitation, filtration, washing, telmisartan was crude, DMF and recrystallized to give 44.5 g of telmisartan pure product (HLPC> 99. 0%) mp261~263 ° C.</span> <span class="notranslate">Force -NMR (de-DMS0) S 1. 05t, 3H), 1. 83 (m, 2H), 2. 71 (s, 3H), 2. 94 (t, 2H), 3. 81 (s, 3H ), 5. 57 (s, 2H), 7. 16-7. 83 (m, 14H) • C33H33N402 [0031] </span>............................<br /><table class="patent-data-table"><thead class="patent-data-table-thead">
<tr class="patent-data-table"><th class="patent-data-table-th">Citing Patent</th><th class="patent-data-table-th">Filing date</th><th class="patent-data-table-th">Publication date</th><th class="patent-data-table-th">Applicant</th><th class="patent-data-table-th">Title</th></tr>
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<tr><td class="patent-data-table-td citation-patent"><a href="http://www.google.com/patents/CN102036937B?cl=en" style="color: #6c1b00; text-decoration: none;">CN102036937B</a></td><td class="patent-data-table-td patent-date-value">Mar 19, 2009</td><td class="patent-data-table-td patent-date-value">Jun 4, 2014</td><td class="patent-data-table-td ">力奇制药公司</td><td class="patent-data-table-td ">2'-halobiphenyl-4-yl intermediates in the synthesis of angiotensin ii antagonists</td></tr>
<tr><td class="patent-data-table-td citation-patent"><a href="http://www.google.com/patents/WO2014067237A1?cl=en" style="color: #6c1b00; text-decoration: none;">WO2014067237A1</a><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td patent-date-value">Oct 31, 2013</td><td class="patent-data-table-td patent-date-value">May 8, 2014</td><td class="patent-data-table-td ">Topharman Shanghai Co., Ltd.</td><td class="patent-data-table-td ">Telmisartan preparation method and intermediate thereof</td></tr>
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<tr><td class="patent-data-table-td citation-patent"><a href="http://www.google.com/patents/WO2010018441A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2010018441A2</a><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td patent-date-value">Aug 10, 2009</td><td class="patent-data-table-td patent-date-value">Feb 18, 2010</td><td class="patent-data-table-td ">Cadila Pharmaceuticals Ltd.</td><td class="patent-data-table-td ">An improved process for the preparation of substantially pure telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent"><a href="http://www.google.com/patents/WO2010146187A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2010146187A2</a><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td patent-date-value">Jun 21, 2010</td><td class="patent-data-table-td patent-date-value">Dec 23, 2010</td><td class="patent-data-table-td ">Krka, Tovarna Zdravil, D.D., Novo Mesto</td><td class="patent-data-table-td ">Process for the preparation of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent"><a href="http://www.google.com/patents/WO2011077444A1?cl=en" style="color: #6c1b00; text-decoration: none;">WO2011077444A1</a><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td patent-date-value">May 28, 2010</td><td class="patent-data-table-td patent-date-value">Jun 30, 2011</td><td class="patent-data-table-td ">Inogent Laboratories Private Limited</td><td class="patent-data-table-td ">A new process for the preparation of pure telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent"><a href="http://www.google.com/patents/WO2012028925A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2012028925A2</a><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td patent-date-value">Aug 29, 2011</td><td class="patent-data-table-td patent-date-value">Mar 8, 2012</td><td class="patent-data-table-td ">Ogene Systems (I) Pvt Ltd</td><td class="patent-data-table-td ">An improved process for the preparation of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent"><a href="http://www.google.com/patents/CN1768044A?cl=en" style="color: #6c1b00; text-decoration: none;">CN1768044A</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value">Mar 26, 2004</td><td class="patent-data-table-td patent-date-value">May 3, 2006</td><td class="patent-data-table-td ">贝林格尔·英格海姆国际有限公司</td><td class="patent-data-table-td ">Process for manufacture of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent"><a href="http://www.google.com/patents/CN102731407A?cl=en" style="color: #6c1b00; text-decoration: none;">CN102731407A</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value">Jul 4, 2012</td><td class="patent-data-table-td patent-date-value">Oct 17, 2012</td><td class="patent-data-table-td ">宁波九胜创新医药科技有限公司</td><td class="patent-data-table-td ">Method for preparing telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent"><a href="http://www.google.com/patents/EP0627433A1?cl=en" style="color: #6c1b00; text-decoration: none;">EP0627433A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value">Dec 7, 1993</td><td class="patent-data-table-td patent-date-value">Dec 7, 1994</td><td class="patent-data-table-td ">Eisai Co., Ltd.</td><td class="patent-data-table-td ">Process for producing imidazopyridine derivative and intermediate</td></tr>
<tr><td class="patent-data-table-td citation-patent"><a href="http://www.google.com/patents/EP2123648A1?cl=en" style="color: #6c1b00; text-decoration: none;">EP2123648A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value">May 20, 2008</td><td class="patent-data-table-td patent-date-value">Nov 25, 2009</td><td class="patent-data-table-td ">Chemo Ibérica, S.A.</td><td class="patent-data-table-td ">A process for the preparation of Telmisartan.</td></tr>
<tr><td class="patent-data-table-td citation-patent"><a href="http://www.google.com/patents/EP2305650A1?cl=en" style="color: #6c1b00; text-decoration: none;">EP2305650A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value">Sep 21, 2009</td><td class="patent-data-table-td patent-date-value">Apr 6, 2011</td><td class="patent-data-table-td ">Chemo Ibérica, S.A.</td><td class="patent-data-table-td ">Novel process for the preparation of telmisartan</td></tr>
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<table class="patent-data-table"><tbody>
<tr><td class="patent-data-table-td citation-patent"><a href="http://www.google.com/url?id=3kjyCAABERAJ&q=http://worldwide.espacenet.com/publicationDetails/biblio%3FCC%3DKR%26NR%3D20090000113A%26KC%3DA%26FT%3DD&usg=AFQjCNEkLVoeQlqUvTSFYba_MViuzJ4UOw" style="color: #6c1b00; text-decoration: none;">KR20090000113A</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value"></td><td class="patent-data-table-td patent-date-value"></td><td class="patent-data-table-td "></td><td class="patent-data-table-td citation-no-title">Title not available</td></tr>
<tr><td class="patent-data-table-td citation-patent"><a href="http://www.google.com/patents/US20040236113" style="color: #6c1b00; text-decoration: none;">US20040236113</a></td><td class="patent-data-table-td patent-date-value">Mar 17, 2004</td><td class="patent-data-table-td patent-date-value">Nov 25, 2004</td><td class="patent-data-table-td ">Boehringer Ingelheim International Gmbh</td><td class="patent-data-table-td ">Process for manufacture of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent"><a href="http://www.google.com/patents/US20130137878" style="color: #6c1b00; text-decoration: none;">US20130137878</a></td><td class="patent-data-table-td patent-date-value">Jan 25, 2013</td><td class="patent-data-table-td patent-date-value">May 30, 2013</td><td class="patent-data-table-td ">Boehringer Ingelheim International Gmbh</td><td class="patent-data-table-td ">Process for manufacture of telmisartan</td></tr>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com2tag:blogger.com,1999:blog-7082350141827122272.post-41076140959855471722015-04-08T04:32:00.002-07:002015-04-08T04:32:55.553-07:00TELMISARTAN PART 2/3<div dir="ltr" style="text-align: left;" trbidi="on">
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<a href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html" style="color: #6c1b00; text-decoration: none;">TELMISARTAN PART 2/3</a></h3>
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<span data-mce-style="color: #ff00ff;" style="color: magenta;">4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan)</span></div>
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PART 1........<a data-mce-href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-13.html" href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-13.html" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-13.html</a></div>
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PART 2........<a data-mce-href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html" href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html</a></div>
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<span style="color: #222222; font-family: 'Open Sans', 'Helvetica Neue', Helvetica, Arial, sans-serif;"><span style="font-size: 14px; line-height: 23.7999992370605px;"> OR <a href="http://newdrugapprovals.org/2015/04/06/telmisartan-part-23/" style="color: #6c1b00; text-decoration: none;">http://newdrugapprovals.org/2015/04/06/telmisartan-part-23/</a></span></span></div>
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PART3...... <a data-mce-href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-33.html" href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-33.html" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-33.html</a></div>
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PART3......</div>
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<span data-mce-style="color: #ff00ff;" style="color: magenta;">GENERAL DESCRIPTION</span></div>
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<span data-mce-style="font-family: Verdana;" style="font-family: Verdana;">Telmisartan is currently available as oral tablets in 20, 40, and 80 mg strengths for use in the treatment of hypertension. It is also marketed as Micardis® HCT which is a fixed dose combination with Hydrochlorothiazide (HCTZ) in 40/12.5, 80/12.5, 80/25 mg/mg strengths, and Twynsta® its fixed dose combination with Amlodipine in 40/5, 80/5, 40/10, 80/10 mg/mg strengths.</span></div>
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<span data-mce-style="font-family: Verdana;" style="font-family: Verdana;">In 2009, Boehringer Ingelheim (Boehringer) gained approval to extend the market authorised indication of the Telmisartan 80 mg strength to include reducing the risk of myocardial infarction, stroke or death from cardiovascular disorders. </span></div>
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<span data-mce-style="font-family: Verdana;" style="font-family: Verdana;">The Telmisartan molecule was discovered and developed by Boehringer, and was launched in Europe and the US in 1998. Boehringer has co-marketing agreements with Bayer Schering Pharma and GlaxoSmithKline in certain countries.</span></div>
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<img alt="Displaying image001.png" data-mce-src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c8d7daa1531522&attid=0.1&disp=emb&attbid=ANGjdJ-F9CBS4cXFHxRuNY4V8YVJrV2dj5TtcalcLRVxj1yZ8qjV31rAERk3Zggt2CC_WuQ54hdj_tEnL3ODYgT6QpZB63MDOyVBZmeE2CPKw42n7r5qV-jN81Tcu4A&sz=w1510-h1036&ats=1428322771561&rm=14c8d7daa1531522&zw&atsh=1" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c8d7daa1531522&attid=0.1&disp=emb&attbid=ANGjdJ-F9CBS4cXFHxRuNY4V8YVJrV2dj5TtcalcLRVxj1yZ8qjV31rAERk3Zggt2CC_WuQ54hdj_tEnL3ODYgT6QpZB63MDOyVBZmeE2CPKw42n7r5qV-jN81Tcu4A&sz=w1510-h1036&ats=1428322771561&rm=14c8d7daa1531522&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /></div>
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Telmisartan (1) is an angiotensin II receptor antagonist useful in the treatment of hypertension, heart diseases, heart strokes, and bladder diseases.1 Telmisartan (1) is currently available in the market as an antihypertensive drug2 under the brand name of MICARDIS. The first reported synthetic method3 for this molecule consists of 8 steps (Scheme 1) involving condensation of 4-amino-3-methyl benzoic acid methyl ester (2) with butyryl chloride (3) in chlorobenzene to yield 4. Nitration of 4 followed by reduction of the resulting 5-substituted nitro compound 5 over Pd-C in methanol yielded amine 6. Cyclisation of 6 in acetic acid reflux affords the monobenzimidazole derivative 7, which upon further hydrolysis yielded an acid intermediate 8 by a saponification process. Condensation of compound 8 with diamine derivative 9 in polyphosphoric acid yielded the dibenzimidazole compound 10, which was further alkylated with 4′-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester (11)4 to afford product 12. Finally, hydrolysis of ester12 in trifluoracetic acid yielded telmisartan (1) in an overall yield of around 21% with several impurities. This process suffers from disadvantages such as (a) a multistep synthesis for compound 8 (3 steps from compound 5); (b) the solvents dimethyl formamide (DMF) or dimethylsulfoxide (DMSO) used in the penultimate stage are unrecoverable, while the use of potassium tert-butoxide resulted in high organic volatile impurities (OVI) in telmisartan; (c) deprotection of the tert-butyl group using trifluoroacetic acid in DMF lead to the formation of several byproducts; (d) residue on ignition (ROI) in API obtained from this process is always >1.0% (ICH limit <0.1%), and there is no specified process mentioned in the literature to control the ash content. This is mainly due to very poor solubility of the telmisartan in most of the solvents including water; and (e) the overall yield (21%) of this process is discouraging, which makes the process less viable for commercial production.</div>
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(1) (a) Battershill, A. J.; Scott, L. J. Drugs 2006, 66 (1), 51-83. (b) Norbert, H.; Berthold, N.; Uwe, R.; Jacobus, C. A.; Van, M.; Wolfgang, W.; Michael, E. U.S. Patent 5,591,762, 1997. (c) Ruth, R. W.; William, J. C.; John, D. I.; Michael, R. C.; Kristine, P.; Ronald, D. S.; Pieter, B. M. W. M. T. J. Med. Chem. 1996, 39 (3), 625-656.</div>
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(2) http://www.rxlist.com/cgi/generic2/telmisartan.htm.</div>
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(3) (a) Uwe, J. R.; Gerhard, B. N.; Kai, M. H.; Helmut, W.; Michael, E.; Jacobus, C. A.; Van, M.; Wolfgang, W.; Norbert, H. H. J. Med. Chem. 1993, 36, 4040-4051. (b) Merlo</div>
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(4) Carini, D. J.; Dunicia, J. V. Eu. Patent 2,53,310, 1988. (5) Venkataraman, S.; Mathad, V. T.; Kikkuru, S. R.; Neti, S.; Chinta, R. R.; Arunagiri, M.; Routhu, L. K PCT WO 06/044754A2, 2006.</div>
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(6) The intermediate 9 is prepared via monomethylation of o-nitroaniline (15) using dimethylsulfate followed by hydrogenation over Pd-C catalyst in methanol with 75% of overall yield. Of the several methylating agents such as CH3I, DMS, HCOOH, and H2CO explored</div>
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(7) Structures of these impurities were tentatively proposed based on MS-MS data and a probable reaction mechanism and then synthesized as shown in Scheme 3. These impurities were characterized by NMR, mass, and IR techniques and further confirmed to be present in the sample by HPLC coinjection and spiking methods (0.1%). (8) Shen, J.; Li, J.; Yan, T.; Li, H.; Ji, R. CN 1,344,712, 2002.</div>
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(9) Several brominating agents such as molecular bromine, N-bromosuccinimide (NBS), and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) resulted in 13 along with the dibromo impurity 26. The formation of the dibromo impurity 26 is varying from 20-45% by HPLC. The content of 26 is nearly 45% in the case of NBS bromination, whereas the same is in the range of 15%- 20% in the case of DBDMH. Hence, DMDBH has been utilized as the brominating agent in the process. However impurity 26 did not participated in the next step and was easily washed out to a nondetected level during the isolation of 14 in the condensation step.</div>
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(10) Robert, E. D.; Peter, S.; Herbert, N.; Kenneth, S.; William, I. F. D. J. Pharm. Sci. 2000, 89 (11), 1465-1479.</div>
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Whilst patent protection for Telmisartan molecule, DE4103492A, has expired in Canada, it is still in force in the US until January 2014, receiving the longer term based on 17 years from the issue date for patents filed prior to June 8 1995. The equivalent European patent, EP0502314 (‘314), has been extended by SPC in France, Germany, Spain and the UK until December 2013 (see Figure 3).</div>
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Boehringer, seeking to protect its Telmisartan franchise, has also filed SPC applications for its Telmisartan-HCTZ and Telmisartan-Amlodipine products, for the basic patent ‘314, in France, Germany, Spain and the UK, potentially extending protection until January 2017 (see Figure 3). GenericsWeb’s proprietary SPC analyser has identified the basic patent as a ‘C3’ category, suggesting the claims of the basic patent do not protect the combinations and therefore the SPC may be invalid. The response by the national IPOs in respect to the invalidity of SPCs for the Telmisartan combinations has varied. The French SPC application (FR02C0028) for Telmisartan-HCTZ was initially rejected by the Institut National de la Propriété Industrielle (INPI) in December 2010, finding the claims of the basic patent did not protect a medicine comprising Telmisartan in association with HCTZ. The Paris Court of Appeal upheld INPI’s decision in June 2012, denying Boehringer’s request for appeal. Similarly, on June 2012, the Juzgado de lo Mercantil de Pamplona (the Court) held the Spanish SPC (C20020018) for Telmisartan-HCTZ invalid following a revocation suit filed by Cinfa and Actavis against Boehringer in April 2010. The Court’s decision relied on the ECJ’s findings in the ‘Medeva’ decision relating to SPCs for combination products, which concluded that to satisfy article 3(a) of SPC regulation 469/2009 the wording of the claims of the basic patent had to specify all active ingredients. Therefore, the Court found the SPC to be invalid on the grounds of article 15.1(a) in regard to 3(a), finding ‘314 did not specify a composition of Telmisartan in association with HCTZ. In February 2013, revocation proceedings were filed in the Bundespatentgericht for the German SPC (DE10299029) for Telmisartan-HCTZ. This raises the question of whether the SPC will prevent a generic Telmisartan-HCTZ product in Germany until conclusion of the revocation proceedings or will generic companies launch their products ‘at risk’ upon expiry of the SPC for Telmisartan, therefore assuming invalidity based on the ‘Medeva’ decision and similar findings by other PTOs and Courts in the matter.</div>
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The French (FR11C0008), German (DE122011000013) and Spanish (C201100010) SPCs for the Telmisartan-Amlodipine combination have been withdrawn. However, the UKIPO has granted the SPCs for both combination products (see Figure 3). No litigation proceedings have been detected in the UK. This may be due to amendments, under section 27 of the Patents Act 1977, of the specification for the UK designation of ‘314, in 2004 and 2011. The amendments were in the form of amended claim pages which included a pharmaceutical composition comprising HCTZ or a calcium channel blocker. Patents in the family with priority GB9722026A protect authorised indicated uses of the 80 mg dosage form of Telmisartan for reducing cardiac tissue damage associated with myocardial infarction and prevention or treatment of stroke, so are considered to be a constraint only for those indicated uses.</div>
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The family with the priority DE19901921A protects the crystalline form used in the commercially available product but are not considered to be a constraint to generic competition because the protected technology is likely to be circumvented. Families AU2002242676A, DE10301371A and EP04026234A protect Telmisartan combination products (see Figure 2). AU2002242676A and EP04026234A claim bilayer tablets comprising Telmisartan and HCTZ or Amlodipine, respectively. They are not considered to be a constraint to generic competition because the protected technologies are likely to be circumvented by generic reformulation. However, patents in the family DE19901921A expiring in July 2024, claiming composition of Telmisartan and several other drugs, including Amlodipine, are considered to be a constraint to generic competition for the Telmisartan-Amlodipine product. The family was deemed key due to its Canadian member 2534006 being listed on Health Canada’s patent register. Equivalent patents in the US have not been granted yet, but claims listed in the image wrapper in USPTO appear to limit the claims to a currently unauthorised use of Telmisartan and Amlodipine, therefore may not be a constraint for generic entry in the US.<br />Amongst the US approvals, Watson is the only company to have obtained tentative market approvals for all dosage strengths for the Telmisartan tablets and the fixed dose combination of Telmisartan and HCTZ. Lupin has gained a tentative approval for the Telmisartan and Amlodipine fixed dose combination. No generics are currently on the market in the UK due to unexpired patent protection, however several companies including Egis, Sandoz and Glenmark have obtained market authorisation for Telmisartan tablets in all dosage strengths. Actavis and Teva have obtained market authorisations via the centralised procedure. Dr Reddy’s Lab and Krka hold generic authorisations for both Telmisartan and Telmisartan-HCTZ fixed dose combination tablets. These generic approvals are suggestive of the competition Micardis® will face across Europe upon molecule patent expiry. Currently no generic Telmisartan-Amlodipine approvals have been identified in Europe. This is due to data exclusivity previsions in Europe, preventing the filing of generic market authorisation until October 2018, and a further 2 year market exclusivity period could prevent the launch of a generic equivalent until October 2020. In Canada, Mylan was one of the generic competitors to launch Telmisartan and Telmisartan-HCTZ following molecule patent expiry. This is likely to be mirrored in other territories upon expiry of the molecule patent.</div>
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<em><strong>Figure 4: Marketing Authorisations for products containing Telmisartan in Key Countries</strong></em></div>
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<img alt="" data-mce-src="http://www.genericsweb.com/uploads/Telmisartan_Marketing_Authorisations.gif" src="http://www.genericsweb.com/uploads/Telmisartan_Marketing_Authorisations.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /></div>
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<span data-mce-style="font-family: Verdana;" style="font-family: Verdana;">In summary, patent protection remains a significant barrier to generic entry for the Telmisartan products in most major markets due to the molecule patent being in force. Boehringer’s lifecycle management attempts to maintain a monopoly for their blockbuster drug, including combination products and extensions of indications. Patent protection for its products, apart from the molecule patent, include a ‘use’ patent and combination patents which may pose a barrier to generic competition and may see Boehringer retain some of their market share. SPCs for the Telmisartan-HCTZ combination have been the subject of litigation in France and Spain, resulting in their invalidation, a revocation proceeding is on-going in Germany. Data exclusivity provisions in Europe will prevent the launch of a generic Telmisartan-Amlodipine fixed dose combination. In Canada, generic competition for Telmisartan and Telmisartan-HCTZ entered the market shortly after the expiry of the molecule patent. This is likely to be mirrored in other territories with generic companies already holding market authorisations for both products.</span></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></div>
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WO 2010018441</div>
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<a data-mce-href="http://www.google.im/patents/WO2010018441A2?cl=en" href="http://www.google.im/patents/WO2010018441A2?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.im/patents/WO2010018441A2?cl=en</a></div>
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Telmisartan is chemically named as 4'-[(1,4'-Dimethyl-2<sup>I</sup>-propyl[2<sub>l</sub>6'-bi-1H- benzimidazol]-1'-yl)methyl][1 ,1'-biphenyl]-2-carboxylic acid; or 4'-[[4-methyl-6-(1-methyl-2- benzimidazolyO^-propyl-i-benzimidazolyllmethyll^-biphenylcarboxylic acid.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000002_0001.png" href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000002_0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000002_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000002_0001.png" height="184" id="imgf000002_0001" src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000002_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="296" /></a></div>
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The key raw material used to prepare Telmisartan is Bltyl, chemically named as 1,7'- dimethyl-2'-propyl-2,5'-bi-1H-benzimidazole, also known by other names, i.e 2-Propyl-4- methyl-6-(1 -methylbenzimidazol-2-yl)benzimidazole; 4-Methyl-6-(1 -methyl benzimidazol-2- yl)-2-propylbenzimidazole, and the structure shown as below:</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000002_0002.png" href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000002_0002.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000002_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000002_0002.png" height="128" id="imgf000002_0002" src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000002_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="260" /></a></div>
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BIM WO2006136916 describes substantially pure micronized particles of Telmisartan or a pharmaceutically acceptable salt, ester or derivative. The "substantially pure" is further defined as "Telmisartan or pharmaceutically acceptable salt, ester or derivative thereof having a purity of greater than or equal to about 98%, preferably a purity of greater than or equal to about 99% and more preferably a purity of greater than or equal to about 99.5%.° The substantially pure Telmisartan or a pharmaceutically acceptable salt, ester or derivative has an effective average particle size of less than about 300 microns.</div>
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A Journal of www.IP.com (2005), 5(7B), 4 - describes a process for purification of 4'-(2-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-ylmethyl)biphenyl-2- carboxylic acid (Telmisartan). The pure compound was isolated by filtration under reduced pressure.</div>
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US20060276525 claims Telmisartan form A having HPLC purity > 99.5 %. It further provides a process for preparing Telmisartan form A by crystallization from a polar organic solvent selected from the group consisting of dimethyl sulfoxide, DMF, N.N-dimethyl acetamide, N-methyl 2-pyrrolidone, water and mixtures thereof. The process provides Telmisartan with a limit of DMSO at a level of < 1000 ppm. The process uses high boiling solvent in the last step for getting required purity, and which is also an extra purification step, which limits its commercial application.</div>
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US5591762 ( column-37,38 ) described the general process for the preparation of compound of formula-V</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000003_0001.png" href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000003_0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000003_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000003_0001.png" height="164" id="imgf000003_0001" src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000003_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="588" /></a></div>
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wherein bromine in structure IV is leaving group. There are several other leaving groups such as chlorine, iodine, a substituted sulphonyloxy group, e.g. a methane sulphonyloxy, phenylsulphonyloxy or p-toluenesulphonyloxy group are reported.</div>
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US5591762 describes preparation of Telmisartan from Telmisartan tert. butyl ester using trifluoroacetic acid in DMF as a solvent in 63.9 % yield. (Example-9) The resulting product had a melting point of 261-263<sup>0</sup>C.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000003_0002.png" href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000003_0002.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000003_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000003_0002.png" height="168" id="imgf000003_0002" src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000003_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="592" /></a></div>
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The process for the preparation of tert. Butyl ester of Telmisartan is not commercially viable and deprotection involving the use of trifluoro acetic acid is not eco-friendly.</div>
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US 6385986 describes polymorphs of 4'-[2-n-propyl-4-methyl-6-(1-methylbenzimid- azol-2-yl) benzimidazol-1-ylmethyl] biphenyl-2-carboxylic acid (Telmisartan) i.e. polymorphic form B, mixtures of the polymorphs. The processes for preparing Telmisartan containing form B and the use for preparing a pharmaceutical composition. US '986 further describes that Telmisartan obtained process of as described in EP502314B1 to give a solid in the form of long needles which is difficult to filter, wash and isolate. It is further characterized that it requires a long time for drying due to the presence of solvent which forms large and hard fragments during the drying process. The fragments on grinding produce a dry powder which exhibits strong tendency to electrostatic charging and is virtually impossible to pour. The polymorphic form B of Telmisartan shows virtually no tendency to electrostatic charging and easy for suction filtration, centrifuge, washing, drying and is free-flowing even without being ground up.</div>
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Therefore, as a consequence of the alleged unsuitability of Telmisartan form A for pharmaceutical use, only a mixture of crystalline Telmisartan form A and form B is claimed in the '986 patent, wherein Telmisartan form A is characterized by having an endothermic maximum at 269±2°C, and Telmisartan form B is characterized by having an endothermic maximum at 183±2°C.</div>
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Apparently Telmisartan form A is similar to the original form characterized by its' melting point in the '762 patent. The differences between the DSC value and the measured melting point may be attributed to the different methodologies used-the DSC maxima can be slightly different than the visually observed melting point.</div>
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Hence, the prior art teaches a lengthy, complicated and industrially disadvantageous process for obtaining crystalline Telmisartan form A. The need to further reprocess the re- crystallized Telmisartan, as taught in the examples of the '986 patent, shows that the product was not highly-pure and/or that it contained residual solvents, because the solvents used therein have high boiling point. JMC-1993, vol-36, No25 pg-4040-4051 describes preparation of Telmisartan tert. butyl ester using BIM and 2-(4'bromomethyl phenyl) tert. butyl benzoate using pot. Tert butoxide as a base in DMSO as solvent.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000004_0001.png" href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000004_0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000004_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000004_0001.png" height="172" id="imgf000004_0001" src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000004_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="588" /></a></div>
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Formula 6</div>
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The preparative details for compound of formula-VII on page-4049, coloumn-3, compound 33, paragraph-4; line1-4 reads as follows.</div>
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Potassium tert-butoxide was added to the solution of BIM in DMSO at room temperature followed by the addition of the compound of formula Vl. Upon stirring for 14 hrs, the mixture was poured into water and extracted with ethyl acetate, the combined extract was dried on MgSO<sub>4</sub> and evaporated. Residue was purified by silica gel column chromatography to give compound of formula-VII. The above mentioned process uses chromatographic purification, which is generally cumbersome and time consuming process and also requires solvents in high volume.</div>
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US20060094883 describes a process for the preparing Telmisartan, wherein Telmisartan alkyl ester - a</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000005_0001.png" href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000005_0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000005_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000005_0001.png" height="188" id="imgf000005_0001" src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000005_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="280" /></a></div>
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compound of formula-ll is prepared , comprising the steps of :</div>
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(a) combining i.y-dimethyl^'-propyl-IH.S'H-p.S<sup>1</sup> ] bibenzimidazole (referred to as BIM) of formula III,</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000005_0002.png" href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000005_0002.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000005_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000005_0002.png" height="128" id="imgf000005_0002" src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000005_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="240" /></a></div>
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Formula 3 with 4'-bromomethyl-biphenyl-2-carboxylic acid alkyl ester (referred to as BMBP alkyl ester) of formula IV<sub>1</sub></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000005_0003.png" href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000005_0003.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000005_0003" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000005_0003.png" height="120" id="imgf000005_0003" src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000005_0003.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="132" /></a></div>
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Formula 4 an inorganic base and a low boiling point organic solvent, to obtain a mixture;</div>
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(b) heating the mixture obtained in step (a) to a temperature of about 55°C. to about 120<sup>0</sup>C;</div>
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(c) maintaining the mixture obtained in step (b) for about 1 hour to about 8 hours, to obtain Telmisartan alkyl ester of formula II; and</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000006_0001.png" href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000006_0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000006_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000006_0001.png" height="188" id="imgf000006_0001" src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000006_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="280" /></a></div>
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(d) recovering Telmisartan alkyl ester of formula II, wherein, R is a straight or branched chain C<sub>1</sub>-C<sub>4</sub> alkyl.</div>
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WO2005108375 describes process for the preparation of Telmisartan, characterized in that 1H-Benzimidazole-2-n-propyl-4-methyl-6-(1 '-methyl benzimidazole- 2'yl) of formula (II) and methyl-4- (bromo methyl)biphenyl 2-carboxylate of formula (III) are subjected to</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000006_0002.png" href="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000006_0002.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000006_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000006_0002.png" height="196" id="imgf000006_0002" src="http://patentimages.storage.googleapis.com/WO2010018441A2/imgf000006_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="592" /></a></div>
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WO 2007/010558 describes a method for the preparation of Telmisartan involving</div>
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Telmisartan dihydrochloride which comprises, i) condensing 4-Methyl-2-n-propyl-IH- benzimidazole-6-carboxylic acid with N-Methyl- O-phenylene diamine dihydrochloride to yields 4-methyl-6 (1 -methyl benzimidazol-2- yl)-2-n-propyl IH- benzimidazole, ii) treating 4- methyl-6-(l -methyl benzimidazol-2-yl)-2-n-propyl-IH-benzimidazole with</div>
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4<sup>*</sup>- (bromomethyl)-2-biphenyl-2-carboxylate in presence of a base in an organic solvent and isolating the ester as acid addition salt, iii) converting ester acid addition salt to Telmisartan dihydrochloride and iv) converting Telmisartan dihydrochloride to Telmisartan. CN1344712 describes method comprising reaction of 4-methyl-6-(1-methyl-2(1H)- benzimidazolyl)-1H-benzimidazole with 4'-bromomethyl-biphenyl-2-carboxylic acid alkyl ester [wherein alkyl is methyl or ethyl] in solvent i.e. DMF, DMSO, THF, dioxane, chloroform, dichloroethane, etc. in the presence of base [such as Na alcoholate, triethylamine, tributylamine, tripropylamine, KOH, NaOH, CsOH, Ba(OH)<sub>2</sub> etc.] as acid capturer at 20- 100<sup>0</sup>C for 8-10 hrs, and then hydrolyzing with acid (such as H<sub>2</sub>SO<sub>4</sub>, HCI, HBr, HOAc, etc) at room temp, to reflux temp, or with base in Ci<sub>-5</sub> alc.-water at 20-160<sup>0</sup>C for 1-10 hour. WO 2006/125592 describes a new process for the preparation of saltans 2-butyl-3- [[2"-[1 -(triphenylmethyl)-i H- tetrazol-5-yl][1 , 1 '-biphenyl]-4-yl]methyl]-1 ,3-diazaspiro[4.4] non- 1-en-4-one is disclosed, which proceeds via novel intermediate, 4-[(2-butyl-4-oxo-1 ,3- diazaspiro[4.4]non-1-en-3-yl)methyl]phenylboronic acid (Formula (H)) or its analogs. Compound (II) reacts with 5-(2-bromophenyl)-1-(triphenylmethyl)-1H-tetrazole (III) in the presence of catalyst, using conditions of Suzuki reaction, to give trityl irbesartan (I), whereas analogs to compound (II) may give candesartan, valsartan, Telmisartan, losartan and olmesartan.</div>
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WO 2006/050509 describes the amorphous form of Telmisartan sodium and the preparation thereof. Also provided are the Telmisartan sodium polymorph crystal Forms 0 to</div>
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XIII and XV to XX and preparations thereof. Also provided are pharmaceutical composition of amorphous and polymorphic forms of Telmisartan sodium or mixtures thereof, and methods of treatment of a mammal in need thereof.</div>
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WO 2006/044754 describes a process for preparing Telmisartan and intermediates formed in the process.</div>
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WO 2004/087676 describes a novel method for the production of Telmisartan by reacting 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl)-benzimidazol with a compound of general formula (IV)<sub>1</sub> in which Z is a leaving group, wherein the compound 2-cyano-4'-[2"- n-propyl-4"-methyl-6"-(1 '"-methylbenzimidazol-2<sup>l</sup>"-yl)benzimidazol-1 "-ylmethyl]biphenyl is obtained, and subsequently conducting hydrolysis of the nitrile to acid function.</div>
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WO2000/043370 describes polymorphs of 4'-[2-n-propyl-4-methyl-6(1 -methyl benzimidazol -2-yl) benzimidazol -1-ylmethyl] biphenyl-2-carboxylic acid (INN: Telmisartan), and in particular the polymorphous form B of formula (I), characterized by an endothermic peak at 183 ± 2°C during thermal analysis by differential scanning calorimetry. The invention also relates to mixtures of said polymorphs, methods for producing Telmisartan containing form B and to the use thereof in the preparation of a medicament.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">Example-5 : Preparation of 4'-[[2-n-propyl-4methyl-6-(1-methylbenzimidazol-2-yl)- benzimidazol-1-yl]-methyl] biphenyl carboxylic acid [Telmisartan]</span></div>
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90 gm of ethyl-4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol- 1-yl]-methyl] biphenyl carboxylate was stirred with 810 ml aq. HCI [32-35 % wt/ vol] at 95±2°C for about 8-10 hours. The reaction mixture was cooled to 25-30<sup>0</sup>C. 180 ml of Dichloromethane and 1350 ml of water were added, pH of the reaction mixture was adjusted to -9.0 to 10.0 using 20 % aq. NaOH. The reaction mixture was stirred at 30-35<sup>0</sup>C for about 30 minutes and the layer was allowed to separate. 1800 ml of MDC was added to aqueous phase at 25-30<sup>0</sup>C. pH of the solution was adjusted to ~3 to 3.5 with acetic acid. The mixture was stirred for about 20 minutes and the layer was allow to separate. The aqueous layer was extracted with 900 ml DCM and organic layer was separated and washed with 2 X 900 ml water. The organic phase was dried over anhy. Sodium sulfate and charcoalized followed by distillation to remove about 80-85 % of DCM at 40-42<sup>0</sup>C. The reaction mixture was slowly cooled to 8<sup>0</sup>C and stirred at 8-12<sup>0</sup>C for about 1Hr. 2700 ml of acetone (10<sup>0</sup>C was slowly added and temperature is maintained at 8-12°C.The reaction mixture was stirred for 2 hours with slow RPM. The mixture was filtered at 8-12<sup>0</sup>C and washed with 2x180 ml of acetone. The product was obtained through suction drying for 30-45 minutes, and under vacuum at 85-90<sup>0</sup>C. 70.0 gm of Telmisartan is obtained having purity of 99.84%.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></div>
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WO2009006860A2</div>
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<a data-mce-href="http://www.google.im/patents/WO2009006860A2?cl=en" href="http://www.google.im/patents/WO2009006860A2?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.im/patents/WO2009006860A2?cl=en</a></div>
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Telmisartan (I) is produced in accordance with the original patent of Boehringer Ingelheim (US 5 591 762) from telmisartan tert-butyl ester (II). The hydrolysis is carried out using of trifluoroacetic acid in the toxic solvent N,N-dimethylformamide.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0001.png" href="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000003_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0001.png" height="156" id="imgf000003_0001" src="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="636" /></a></div>
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According to another patent applied by the same company (US 2004 236113) the manufacture was problematic and this is why this procedure was replaced with hydrolysis of the corresponding nitrile (III). However, during the hydrolysis, which is carried out with potassium hydroxide in ethylene glycol, a high temperature (160 <sup>0</sup>C) is used, which causes browning of the product, which must be subsequently purified by means of activated carbon. Also, the energy demands of several-ton production would be considerably high.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0002.png" href="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0002.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000003_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0002.png" height="160" id="imgf000003_0002" src="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="636" /></a></div>
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In a newer application of Cipla (WO 2005/10837) the last two synthetic steps (iii+iv) are combined and telmisartan is isolated after alkaline hydrolysis by acidifying of the reaction mixture in water or extraction with dichloromethane and precipitation with acetone. Both the ways of isolation are unsuitable for industrial production. In the case of telmisartan of crystalline form A its isolation from water or aqueous solutions of organic solvents is very difficult since a hardly filterable product is formed. Extraction of the product with dichloromethane and precipitation with acetone brings a well-filterable product, but the use of dichloromethane is virtually impossible from the point of view of environment protection.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000004_0001.png" href="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000004_0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000004_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000004_0001.png" height="296" id="imgf000004_0001" src="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000004_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="636" /></a></div>
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Another method has been described by Dr. Reddy (WO 2006/044754), which starts from telmisartan methylester hydrochloride, which is hydrolyzed to produce the potassium salt of termisartan, which is further acidified in aqueous acetonitrile; after isolation it crystallizes from a dichloromethane/methanol mixture and finally from methanol alone, and wherein a pressure apparatus is used for the dissolution in methanol at a temperature above its boiling point (80 °C). The result of this complex procedure, which manifests the already above mentioned shortcomings, is a low yield of the product.</div>
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The method of Teva (WO 2006/044648) is in many aspects similar to the above mentioned procedure of Cipla, wherein the last two steps of the synthesis are also combined. The method comprises phase separations, which lead to low yields (69 % - 80 %) besides increased tediousness. Matrix starts from telmisartan tert-butyl ester (II), which is first converted to telmisartan dihydrochloride, which in turn, by action of aqueous ammonia in methanol, provides telmisartan with a low total yield of 73%.</div>
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<a data-mce-href="http://www.google.im/patents/WO2009006860A2?cl=en" href="http://www.google.im/patents/WO2009006860A2?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.im/patents/WO2009006860A2?cl=en</a></div>
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Example 1</div>
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4'-[[4-methyl-6-(l-methyl-lH<sup>"</sup>-benzimidazol-2-yl)-2-proρyl-lH-benzimidazol- lyl]methyl]biphenyl-2-carboxylic acid (telmisartan)</div>
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Telmisartan methylester (VI) (40 g) was refluxed in methanol (440 ml) with potassium hydroxide (14.9 g) for 24 hours. To the boiling solution, methanol (240 ml) and then acetic acid (45.5 g) were added. While boiling, the mixture was stirred for another 1 hour, after cooling to 4°C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 35.18 g (90 %) of the product were obtained.</div>
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Analytic assessment: HPLC purity: 99.90 %,</div>
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Content of residual solvents: methanol (below the detection limit) acetic acid (360 ppm) Titration content: 100.9 % Sulfate ash content: 0.04 % DSC: form A</div>
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Example 2</div>
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4'-[[4-Methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-lH-benzimidazol- lyl]methyl]biphenyl-2-carboxylic acid (telmisartan)</div>
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Telmisartan methylester (VI) (20 g) was refluxed in methanol (300 ml) with potassium hydroxide (7 g ) for 24 h. After addition of formic acid (17 g) and after cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 18.7 g (96 %) of the product were obtained.</div>
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Example 3</div>
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4'-[[4-methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-l/J-benzimidazol- lyl]methyl]biρhenyl-2-carboxylic acid (telmisartan)</div>
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Telmisartan methylester (VT) (20 kg) was refluxed in methanol (400 1) with potassium hydroxide (7 kg) for 24 h. After addition of acetic acid (20 kg) and cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 1). After drying at the laboratory temperature (24 h) 18.5 kg (95 %) of the product were obtained. Example 4</div>
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4'-[[4-methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-lH<sup>'</sup>-benzimidazol- lyl]methyl]biphenyl-2-carboxylic acid (telmisartan)</div>
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Telmisartan methylester (40 g) was refluxed in methanol (240 ml) with potassium hydroxide (14.9 g) for 24 h. To the boiling solution methanol (240 ml) and then acetic acid (45.5 g) were added. After cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 36 g (92%) of the product were obtained.</div>
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PAPER</div>
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<img alt="Displaying image002.png" data-mce-src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c8d7daa1531522&attid=0.2&disp=emb&attbid=ANGjdJ_bzIfA04iUd6ycxt2bPPsUDnYK4VvyxatccEWCX4XF-0BcR6j7-6Lz9uvYsUd3HKtAJ6UoDSh9x9LBjNfMjPkmU69YnDtz5XtJv9zL8NaGlNEKuiHJr2FZjpU&sz=w1694-h742&ats=1428322771561&rm=14c8d7daa1531522&zw&atsh=1" src="https://mail.google.com/mail/u/0/?ui=2&ik=ea058c9211&view=fimg&th=14c8d7daa1531522&attid=0.2&disp=emb&attbid=ANGjdJ_bzIfA04iUd6ycxt2bPPsUDnYK4VvyxatccEWCX4XF-0BcR6j7-6Lz9uvYsUd3HKtAJ6UoDSh9x9LBjNfMjPkmU69YnDtz5XtJv9zL8NaGlNEKuiHJr2FZjpU&sz=w1694-h742&ats=1428322771561&rm=14c8d7daa1531522&zw&atsh=1" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /></div>
<div id="citation" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<cite>Org. Process Res. Dev.</cite>, <span class="citation_year">2007</span>, <span class="citation_volume">11</span> (1), pp 81–85</div>
<div id="doi" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<strong>DOI: </strong>10.1021/op060200g</div>
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<a data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op060200g" href="http://pubs.acs.org/doi/abs/10.1021/op060200g" style="color: #6c1b00; text-decoration: none;">http://pubs.acs.org/doi/abs/10.1021/op060200g</a></div>
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<img alt="Abstract Image" data-mce-src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2007/oprdfk.2007.11.issue-1/op060200g/production/images/medium/op060200gn00001.gif" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2007/oprdfk.2007.11.issue-1/op060200g/production/images/medium/op060200gn00001.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /></div>
<div class="articleBody_abstractText">
Telmisartan (<b>1</b>), a substituted dibenzimidazole derivative, is an antihypertensive drug, essentially used to control blood pressure. An improved, cost-effective, and impurity-free process for telmisartan (<b>1</b>) suitable for large-scale production is described here by addressing various process development issues. The overall yield obtained from this newly developed process is around 50% (over five steps) compared to the literature reported process (21%, over eight steps).</div>
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4′-[(1,4′-Dimethyl-2′-propyl-[2,6′-bi-1H-benzimidazol]- 1′-yl)methyl]-[1,1′-biphenyl]-2-carboxylic Acid (1).</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">Telmisartan (1) as a white crystalline powder. Yield 7 g (77%); purity by HPLC 99.9%; mp 260- 262 °C; Pd content not detected; Heavy metals <10 ppm; MS m/z 515 (M+ + H);</span></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">1 H NMR (CDCl3) δ 12.8 (s, 1H), 7.05-7.5 (m, 14H), 5.60 (s, 2H), 3.82 (s, 3H), 2.97 (t, J ) 7.5, 2H), 2.63 (s, 3H), 1.88 (q, J ) 7.3, 2H), 1.04 (t, J ) 7.3, 3H);</span></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">13C NMR (DMSO-d6) δ 13.5, 16.7, 20.6, 27.6, 32.7, 47.1, 51.7, 112.0, 112.7, 114.7, 118.6, 125.3, 125.7, 125.8, 127.0, 127.4, 128.6, 129.3, 130.4, 130.6, 131.5, 132.3, 133.1, 133.7, 134.5, 140.2, 140.5, 150.2, 157.3, 168.1.</span></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">Anal. Calcd for C33H30N4O2: C, 77.02; H, 5.88; N, 10.89; O, 6.22. Found: C, 77.0; H, 5.82; N, 10.89; O, 6.20.</span></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></div>
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EP1719766A2</div>
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<a data-mce-href="http://www.google.im/patents/EP1719766A2?cl=en" href="http://www.google.im/patents/EP1719766A2?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.im/patents/EP1719766A2?cl=en</a></div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
he present invention provides a process for the preparation of a compound of formula (I) or a salt thereof</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0002.png" href="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0002.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgb0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0002.png" height="164" id="ib0002" src="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="308" /></a></div>
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comprising the reaction of a compound of formula (II) or a salt thereof</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0003.png" href="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0003.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgb0003" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0003.png" height="160" id="ib0003" src="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0003.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="308" /></a></div>
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with a synthon of formula (III) or a salt thereof</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0004.png" href="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0004.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgb0004" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0004.png" height="72" id="ib0004" src="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0004.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="144" /></a></div>
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prepared by reaction of a compound of formula (IV)<br /><div class="patent-image">
<a data-mce-href="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0006.png" href="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0006.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgb0006" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0006.png" height="144" id="ib0006" src="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0006.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="288" /></a></div>
with a compound of formula (V)<br /><div class="patent-image">
<a data-mce-href="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0007.png" href="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0007.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgb0007" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0007.png" height="116" id="ib0007" src="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0007.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="140" /></a></div>
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Telmisartan, 4'-[(1,7' -dimethyl-2' -propyl[2,5' -bis-l H-benzimidazol]-3'-yl)methyl][1,1'-biphenyl]-2-carboxylic acid is a known ACE inhibitor useful in therapy as antihypertensive agent. Its preparation is disclosed inEP 502314 and comprises the alkylation of 4-methyl-6-(1-methyl-benzimidazol-2-yl)-2-propylbenzimidazole (A) with t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate (B)<br /><div class="patent-image">
<a data-mce-href="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0001.png" href="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgb0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0001.png" height="308" id="ib0001" src="http://patentimages.storage.googleapis.com/EP1719766A2/imgb0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="544" /></a></div>
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However, compound (B) is not commercially available and its synthesis requires a number of steps, among them the protection of the carboxylic function which is finally removed by hydrolysis. There is therefore the need for an alternative synthesis for the industrial preparation of telmisartan, which makes use of commercially available or easy to prepare intermediates and which, if possible, avoids the additional steps of protection and deprotection of the carboxylic function.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;"><b>Example 4. 4'-[[4-Methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl]methyl]-2-biphenylcarboxylic acid (telmisartan)</b></span></div>
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(4'-Methyl-2'-propyl-1H-benzimidazol-6'-yl)-1-methyl benzimidazole (3.0 g, 9.8 mmol), 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl methanesulfonate (3.12 g, 10 mmol), tetrahydrofuran (15 ml) and potassium carbonate (1.38 g, 10 mmol) are loaded into a round-bottom flask equipped with magnetic stirrer, condenser and under nitrogen atmosphere. The mixture is stirred at room temperature for 8 hours, then 10% hydrochloric acid is added to pH=2.</div>
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THF is evaporated off, which causes precipitation of boronic acid. After recrystallization from ethyl acetate, 4.2 g of product are obtained.</div>
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The boronic acid (3.5 g, 8.0 mmol), ethyl 2-bromoacetate (1.83 g, 8.0 mmol), sodium hydroxide (1.28 g, 32 mmol), water (5 ml), tetrahydrofuran (20 ml), triphenylphosphine (315 mg, 1.2 mmol) and palladium acetate (90 mg, 0.4 mmol) are loaded into a round-bottom flask equipped with magnetic stirrer and condenser. All the residual air is removed with nitrogen and then the mixture is heated at 60°C for 18 hours, thereafter is cooled, added with water (30 ml) and tetrahydrofuran is evaporated off. Ethyl acetate is added (30 ml) and the mixture is acidified with acetic acid to pH=5. The product is filtered and washed with water, to obtain 2.8 g of crude telmisartan, which is purified by dissolution in concentrated ammonia (2 ml), addition of acetone and reprecipitation with acetic acid.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0005.png" href="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0005.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgb0005" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0005.png" height="312" id="ib0005" src="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0005.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="632" /></a></div>
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<a data-mce-href="http://www.google.im/patents/EP2305650A1?cl=en" href="http://www.google.im/patents/EP2305650A1?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.im/patents/EP2305650A1?cl=en</a></div>
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<li style="border: none; margin: 0px 0px 0.25em; padding: 0px;"><div class="description-line">
Telmisartan and its physiologically acceptable salts have valuable pharmacological properties. Telmisartan is an angiotensin-II-antagonist, which may be used to treat hypertension and cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina). Furthermore, Telmisartan may be used to prevent the progression of cardiac insufficiency after myocardial infarct, to treat diabetic neuropathy, glaucoma, gastrointestinal diseases and bladder diseases. Telmisartan is also suitable for treating pulmonary diseases, e. g. lung oedema and chronic bronchitis, for preventing arterial restenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy. In view of the effects of angiotensin on the release of acetyl-choline and dopamine in the brain, Telmisartan is also suitable for alleviating central nervous system disorders, e. g. depression, Alzheimer's disease, Parkinson syndrome, bulimia and disorders of cognitive function.</div>
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Telmisartan is a compound of formula (I)<br /><div class="patent-image">
<a data-mce-href="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0001.png" href="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgb0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0001.png" height="224" id="ib0001" src="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="264" /></a></div>
chemically known as 4'-((1,7'-dimethyl-2'-propyl-1<i>H</i>,3'<i>H</i>-2,5',-bibenzo[<i>d</i>]imidazol-3'-yl)methyl)biphenyl-2-carboxylic acid, which is disclosed in EP 502314 B1 and marketed under the trade name Micardis®.</div>
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Several methods have been used to prepare Telmisartan.</div>
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The process described inEP 502314 B1 comprises the alkylation of 4-methyl-6-(1-methyl-benzimidazol-2-yl)-2-propylbenzimidazole (III)<br /><div class="patent-image">
<a data-mce-href="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0002.png" href="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0002.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgb0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0002.png" height="120" id="ib0002" src="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="224" /></a></div>
with t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate and subsequently hydrolysis to Telmisartan. t-Butyl 4'-(bromomethyl)biphenyl-2-carboxylate is not commercially available and its synthesis requires a number of steps, among them the protection of the carboxylic function which is finally removed by hydrolysis.</div>
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The patent application <a class="patcit" data-mce-href="http://www.google.im/patents/WO2006044648" href="http://www.google.im/patents/WO2006044648" id="pcit0003" style="color: #6c1b00; text-decoration: none;">WO 2006044648 </a>relates to a method for the production of Telmisartan by reacting 4-methyl-6-(1-methyl-benzimidazol-2-yl)-2-propylbenzimidazole (III) with 4'-(bromomethyl)biphenyl-2-carboxylic acid alkyl ester and subsequently hydrolysis.</div>
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The patent application <a class="patcit" data-mce-href="http://www.google.im/patents/WO2004087676" href="http://www.google.im/patents/WO2004087676" id="pcit0004" style="color: #6c1b00; text-decoration: none;">WO 2004087676 </a>relates to a method for the production of Telmisartan by reacting 4-methyl-6-(1-methyl-benzimidazol-2-yl)-2-propylbenzimidazole (III) with 4-bromomethyl-2'-cyanobiphenyl and subsequently hydrolysis of the nitrile to the acid function.</div>
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The patent application <a class="patcit" data-mce-href="http://www.google.im/patents/EP1719766" href="http://www.google.im/patents/EP1719766" id="pcit0005" style="color: #6c1b00; text-decoration: none;">EP 1719766 </a>relates to a method for the production of Telmisartan, by coupling with a Suzuki reaction the <i>N</i>-4-bromobenzyl derivative of the compound of formula (III) with 2-carboxylphenyl boronic acid. As described in <a class="patcit" data-mce-href="http://www.google.im/patents/EP1878735" href="http://www.google.im/patents/EP1878735" id="pcit0006" style="color: #6c1b00; text-decoration: none;">EP 1878735 </a>, 2-carboxyphenyl boronic acid requires a very laborious process to separate it, since it is extremely soluble in water, making the process unattractive for an industrial application. Thus, the active substance prepared by the process known up till now can only be obtained in a satisfactory quality after running through a number of process steps, wherein additional steps of protection and deprotection of the carboxylic function or additional steps to obtain the carboxylic function are often present.</div>
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<span data-mce-style="text-decoration: underline;" style="text-decoration: underline;">Example 2</span> <b>4'-((1,7'-dimethyl-2'-propyl-1<i>H</i>,3'<i>H</i>-2,5'-bibenzo[<i>d</i>]imidazol-3'-yl)methyl)biphenyl-2-carboxylic acid (I)</b></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0011.png" href="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0011.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgb0011" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0011.png" height="196" id="ib0011" src="http://patentimages.storage.googleapis.com/EP2305650A1/imgb0011.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="268" /></a></div>
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A 2L four-necked glass reactor, fitted with mechanical stirrer, thermometer, dropping funnel, under nitrogen atmosphere, was charged with sodium hydride (60% in mineral oil) (12.5 g, 312 mmol) and toluene (450 mL). The suspension was stirred and trimethylsilanol (31 g, 343 mmol) was added dropwise. After stirring for 15 minutes, methyl 4'-((1,7'-dimethyl-2'-propyl-1<i>H</i>, 3'<i>H</i>-2,5'-bibenzo[<i>d</i>]imidazol-3'-yl)methyl)biphenyl-2-carboxylate (V) (145 g, 274 mmol) was added, the mixture was stirred for 5 hours at about 100°C and monitored by quantitative TLC (elution with 5% MeOH in EtOAc) until complete conversion. The mixture was then cooled at room temperature, water (130 mL) was added, and the mixture was brought at 50°C. The phases were separated and the aqueous phase was stripped under vacuum to remove residual toluene.<br />350 g of an aqueous solution were obtained and used as such in the next step.</div>
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A 1L four-necked glass reactor, fitted with mechanical stirrer, thermometer, dropping funnel, under nitrogen atmosphere, was charged with the aqueous solution in MeOH (600 mL). The mixture was heated under stirring at 40°C until dissolution and charcoal (7 g) was added. The suspension was stirred at 40°C for 30 minutes, filtered through a pad of Celite and the resulting solid was washed with a mixture of MeOH/water 4/1 (100 mL). The filtrate and the washings were combined, the resulting solution was heated to reflux temperature and acetic acid (17.7 g, 295 mmol) was added dropwise over 1 hour. The suspension was then cooled, filtered and the solid was washed with a mixture MeOH/water 4/1 (3 x 50 mL). The collected solid was then dried at 55°C under reduced pressure affording the title compound (130 g) as a white solid.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></div>
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WO2014067237A1</div>
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<a data-mce-href="http://www.google.im/patents/WO2014067237A1?cl=en" href="http://www.google.im/patents/WO2014067237A1?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.im/patents/WO2014067237A1?cl=en</a></div>
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<span class="notranslate">Telmisartan is a novel non-peptide angiotensin Π (ΑΤ Π) receptor antagonist, for the clinical treatment of hypertension, its chemical name is 4 '- [(1,4'-dimethyl - 2'-propyl [2,6'- two -1Η- benzoimidazol] -Γ--yl) methyl] biphenyl] -2-carboxylic acid, knot</span></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2014067237A1/imgf000002_0001.png" href="http://patentimages.storage.googleapis.com/WO2014067237A1/imgf000002_0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000002_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2014067237A1/imgf000002_0001.png" height="104" id="imgf000002_0001" src="http://patentimages.storage.googleapis.com/WO2014067237A1/imgf000002_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="212" /></a></div>
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<span class="notranslate">Telmisartan</span></div>
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<span class="notranslate">Telmisartan synthetic route has mainly 3-methyl-4-amino-benzoic acid methyl ester as the starting material by N- acylation, nitration, reduction, cyclization, ester hydrolysis and condensation reaction intermediates 2-n-propyl-4-methyl - <sub>6</sub> - <sub>(1</sub> - methyl-benzimidazol-2-yl) benzimidazole-α), Ϊ with 4'-bromomethyl-biphenyl-2-carboxylate (V) via nucleophilic substitution, hydrolysis reaction to give the final product two Bu telmisartan (reaction formula 1) (J Med Chem, 1993, 36: 4040-4051).</span></div>
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<span class="notranslate">Reaction Scheme 1</span></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2014067237A1/imgf000002_0002.png" href="http://patentimages.storage.googleapis.com/WO2014067237A1/imgf000002_0002.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000002_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2014067237A1/imgf000002_0002.png" height="88" id="imgf000002_0002" src="http://patentimages.storage.googleapis.com/WO2014067237A1/imgf000002_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="684" /></a></div>
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<span class="notranslate">After has been reported by 4'-bromomethyl-biphenyl-2-carboxylic acid methyl ester (or ethyl ester) (VI) or 4'-bromomethyl-biphenyl-2-carbonitrile (VII) Preparation of telmisartan (CN01126367 .9, CN01131915.1).</span></div>
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<div class="description" lang="ZH">
<span class="notranslate">Example 16: Preparation of telmisartan</span><br /><span class="notranslate">The title compound of Example 15 (III, R = CN) (24.8g, 0.05mol) was added propylene glycol (100ml) and water (100ml) (or other previously described embodiments will be an aqueous mixed solvent :), potassium hydroxide (or e.g. prior to said other inorganic bases) (0.2mol), was refluxed for 10 hours.</span> <span class="notranslate">After no starting material by TLC was cooled to room temperature, concentrated under reduced pressure to a small volume, was added dropwise hydrochloric acid adjusted to pH 5 to 6, the precipitated solid was filtered, washed with water to obtain telmisartan.</span><br /><span class="notranslate">Telmisartan Preparation: 17 Examples</span><br /><span class="notranslate">The title compound I (30.4g, 0.10moi>, embodiments of Example 14 4'-chloro-methyl-biphenyl-2-carbonitrile (0.12mol), sodium ethoxide (or other organic bases as previously described) (0.3mol) and DMF (or other solvent as previously described) (200ml) mixed, 65 ° C for about 5 hours. TLC detected no starting material, was added ethylene glycol (100ml and water (50ml) (or other aqueous solvent), and heated to 160 ° C. TLC detected no starting material, concentrated hydrochloric acid under ice cooling to adjust pH to 5-6, to precipitate a solid, the resulting solid was filtered, washed with water to give crude telmisartan, by recrystallization in telmisartan.</span><br /><span class="notranslate">Examples 18 to 24: Preparation of telmisartan reference method of Example 8, the title compound of Example 6 to the compound of formula I (10g, leq) and implemented as a reactant, with NaH as a base, the reaction temperature under different conditions the reaction, the reaction solution was subjected to phase detection by conventional post-treatment to give telmisartan (crude), yield was calculated, and the purity of the liquid phase detection telmisartan.</span> <span class="notranslate">The test results are shown in Table 2.</span><br /><span class="notranslate">Table 2 compares the reaction conditions</span><br /><div class="patent-image">
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></div>
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WO2011077444A1</div>
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<a data-mce-href="http://www.google.com/patents/WO2011077444A1?cl=en" href="http://www.google.com/patents/WO2011077444A1?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.com/patents/WO2011077444A1?cl=en</a></div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000002_0001.gif" height="124" id="imgf000002_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000002_0001.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="462" /><br />1 Telmisartan .....................................2 Impurity B</div>
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Table 1 : Preparation of Telmisartan and 2 with reported synthetic schemes<br /><img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000004_0001.gif" height="240" id="imgf000004_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000004_0001.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="391" /><br />process for the preparation of telmisartan, comprising: condensation of -n-propyl-4-methyl-6-(l'-methylbenzimidazol-2'-yl)benzimidazole (I)<br /><img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000005_0001.gif" height="105" id="imgf000005_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000005_0001.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="219" /><br />with a compound of general formula II)<br /><img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000005_0002.gif" height="60" id="imgf000005_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000005_0002.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="129" /><br />wherein Z denotes a leaving group such as a halogen atom, for example, a chlorine, bromine, or iodine atom to obtain the compound 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-( 1 "'-methylbenzimidazol-2"'-yl)benzimidazol- 1 "-ylmethyl]biphenyl (III), and subsequent<br /><img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000005_0003.gif" height="133" id="imgf000005_0003" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000005_0003.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="209" /><br />hydrolysis of nitrile in the presence of excess base and solvent followed by acid/base purification to obtain pure telmisartan.<br /><img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000005_0004.gif" height="118" id="imgf000005_0004" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000005_0004.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="226" /></div>
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Scheme-I<br /><img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000007_0001.gif" height="113" id="imgf000007_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000007_0001.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="474" /><br /><img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000007_0002.gif" height="110" id="imgf000007_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2010000357@@@id00000006528862@@@7824928@@@imgf000007_0002.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="189" /></div>
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<a data-mce-href="http://www.google.com/patents/WO2011077444A1?cl=en" href="http://www.google.com/patents/WO2011077444A1?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.com/patents/WO2011077444A1?cl=en</a></div>
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EXAMPLES:<br />Experiment-1: Preparation of 2-cyano-4-[2-n-propyl-4-methyI-6-(l- methylbenzimidazol-2-yl) bnzimidazol-l-ylmethyl] biphenyl.<br />Add 2-n-propyl-4-methyl-6-(l '-methylbenzimidazol-2'-yl) benzimidazole 100 g in 1000ml of acetone and of potassium hydroxide 22.0 g with stirring at 20-25°C. Then of 4-bromomethyl-2'-cyanobiphenyl 92g is added at 20-25°C. Monitor the reaction on thin layer chromatography, after compilation reaction, the crystals are suction filtered, washed with chilled acetone, water, and then dried in a air drying cupboard at 80° C. Yield: 135.0 g (82.82% of theory); melting point: 196° C.-197° C; HPLC: 99.30%. N-3 isomer: 0.08%.<br />Experiment-2: Preparation of 2-cyano-4-[2-n-propyl-4-methyl-6-(l- methylbenzimidazol-2-yl) benzimidazol-l-ylmethyl] biphenyl.<br />Add 2-n-propyl-4-methyl-6-( -methylbenzimidazol-2'-yl) benzimidazole 100 g in 1000ml of acetone and of potassium hydroxide 22.0 g with stirring at 20-25°C. Then of 4-bromomethyl-2'-cyanobiphenyl 92g is added at 20-25 °C. Monitor the reaction on thin layer chromatography, after the reaction is completed, cooled to 0 to 5.0° C. and stirred for another hour at this temperature. The material is filtered, washed with chilled acetone, then wash with water, and then dried in a air drying cupboard at 80° C. Yield: 141.50 g (87.73% of theory); melting point: 196° C.-197° C; HPLC: 99.50%. N-3 isomer: 0.16%<br />Experiment-3: Preparation of Telmisartan.<br />Add potassium hydroxide 80g in 500ml of ethylene glycol then add 2-cyano-4'- [2-n-propyl-4-methyl-6-( 1 -methyl benzimidazol-2-yl) benzimidazol- 1 -ylmethyl] biphenyl lOOgm at room temperature. Stir the reaction mixture and raise temperature to 150- 155° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 30 to 35°C then diluted with 800 ml methanol then telmisartan precipitates by adding of acetic acid at 25 to 30°C and further diluted with water. Then stirred for further 90min at 25 to 30°C. After the crystals have been suction filtered. The wet material dissolve in 500ml methanol with 12gm potassium hydroxide then after treatment of charcoal crystallize the telmisartan to adjusting of pH 6.0 to 6.4 by acetic acid then dilute with 400ml water. Filtered and then dried in a vacuum tray drier at 85°C. Yield: 90g (87.37% of theory); HPLC: 99.91%.<br />Experiment-4: Preparation of Telmisartan.<br />Add potassium hydroxide lOOg in 500ml of ethylene glycol then add 2-cyano- 4'-[2-n-propyl-4-methyl-6-(l -methyl benzimidazol-2-yl) benzimidazol- 1 -ylmethyl] biphenyl 1 OOgm at room temperature. Stir the reaction mixture and raise temperature to 150-155° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 30 to 35°C then diluted with 800ml methanol then telmisartan crystallize by adding of acetic acid at 25 to 30°C then dilute with 300ml water. Stir for further 90min at 25 to 30°C. Filter and then dried in a vacuum drying cupboard at 85°C. Yield: 101 g (1.03% of theory); HPLC: 99.90%.<br />Experiment-5: Preparation of pure Telmisartan.<br />Crude telmisartan 101 g (from example 4) & activated carbon lOg is added in methanol 100ml , dichloromethane 500ml at 25 to 30°C. Stir the reaction mixture then the brown solution is filtered through hyflow bed, Completely distilled out filtrate below 50°C then add 800ml water at that temperature and stir for lhr. The telmisartan is hot filtered and washed with water. The telmisartan is dried at 80° C. in a vacuum drying cupboard. Yield: 90 g (87.37% of theory); HPLC: >99.95%.<br />Experiment-6: Preparation of <span data-mce-style="color: #ff0000;" style="color: red;">Telmisartan</span>.<br />2-cyano-4'- [2-n-propyl-4-methyl-6-( 1 -methyl benzimidazol-2-yl) benzimidazol- 1 - ylmethyl] biphenyl lOOgm is added in 500ml of ethylene glycol with lOOg of potassium hydroxide powder at 20-25°C. Stir and raise temperature to 160° C. to 165° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 70 to 75°C then diluted with methanol and water then telmisartan crystallize by adding of acetic acid to adjust the pH 5.5 to 6.0 at 25 to 30°C. Stir for further 60min at 25 to 30°C. After the crystals have been suction filtered. The wet material dissolve in methanol with potassium hydroxide 12gm then after treatment of charcoal crystallize the telmisartan by adding of acetic acid by adjusting of pH 6.0 to 6.4 then stir for further 60min. The material is filtered and dried in a vacuum drying cupboard at 85°C. Yield: 86.56g (84.03% of theory); HPLC: >99.96%.<br />Experiment-7: Preparation of<span data-mce-style="color: #ff0000;" style="color: red;"> Telmisartan</span>.<br />of 2-n-propyl-4-methyl-6-(r-methylbenzimidazol-2'-yl) benzimidazole 100 g is add in 1000 ml of acetone, and of potassium hydroxide 22 gm with stirring at 20-25° C and then 90.0 g of 4-bromomethyl-2'-cyanobiphenyl is added at 20-25°C. The temperature of the reaction mixture is maintained at 20 to 25° C. Stir for a further 6.0 to 8.0 hours at 20 to 25° C. Monitor the reaction on thin layer chromatography, after compilation reaction distil out acetone. Add ethylene glycol 500ml and potassium hydroxide lOOgm to residue Stir the reaction mixture and raise temperature to 150° C. to 155° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 30 to 35°C. Reaction mass diluted with methanol and stir for 30min then telmisartan precipitated by adding of acetic acid to adjust the pH 6.0 to 6.5 at 25 to 30°C. Then dilute with water and filter, wash with of methanol. Wet telmisartan is dissolved in methanolic potassium hydroxide, filtered to remove un dissolved material. Acetic acid is added to adjust the pH 6.0 to 6.4 , water added for complete precipitation of material. Finally telmisartan is suction filter and wash with water at 40 to 45 °C. The telmisartan is dried at 80° C. in a vacuum drying cupboard. Yield: 130g<br /><span data-mce-style="color: #ff0000;" style="color: red;">HPLC: 99.4%.</span><br /><span data-mce-style="color: #ff0000;" style="color: red;">1H NMR (DMSO-d6) δ 1.0 (t,3H), 1.9 (q, 2H), 2.95 (t, 2H), 2.4 (s, 3H), 3.95 (s, 3H), 5.8 (s, 2H), 7.28 (s,lH),7.80 (s,lH), 7.75 (d, 2H), 7.25 (t, 2H), 7.10 (d, 2H), 7.30 (d, 2H), 7.40 (d, 1H), 7.40 (t, 1H), 7.30 (t, 1H), 7.45 (d, 1H). 12.9 (s, 1H).</span><br /><span data-mce-style="color: #ff0000;" style="color: red;">m/z 514.7 [ M + H]+.</span></div>
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PATENT</div>
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US 6358986</div>
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<a data-mce-href="http://www.google.co.in/patents/US6358986" href="http://www.google.co.in/patents/US6358986" style="color: #6c1b00; text-decoration: none;">http://www.google.co.in/patents/US6358986</a></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/US6358986B1/US06358986-20020319-C00002.png" href="http://patentimages.storage.googleapis.com/US6358986B1/US06358986-20020319-C00002.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure US06358986-20020319-C00002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/US6358986B1/US06358986-20020319-C00002.png" height="759" id="EMI-C00002" src="http://patentimages.storage.googleapis.com/US6358986B1/US06358986-20020319-C00002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="741" /></a></div>
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EXAMPLE</div>
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3185 kg of recrystallised telmisartan (recrystallised from dimethylformamide or dimethylacetamide), 5.6 kg of activated charcoal, 185 l of water, 190.4 kg of formic acid (99-100%) and 185 l of methylethylketone are placed in a 1200 l stirring apparatus. The mixture is stirred for about 1 h at 60-70° C. and then filtered into another 1200 l stirring apparatus and washed with a mixture of 74 l of methylethylketone and 8.3 kg of formic acid (99-100%). About 278 l of solvent are distilled off at 80-100° C. whilst simultaneously 278 l of water are added. The mixture is then cooled to 20-30° C. and precipitated by the metered addition of 281.5 kg of 25% ammonia solution. The product precipitated is centrifuged, washed with water and dried at 120-125° C. Yield: 178 kg of <span data-mce-style="color: #ff0000;" style="color: red;">telmisartan</span> (96.2% of theory)</div>
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Comparison Example</div>
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150 kg of telmisartan (recrystallised from dimethylformamide or dimethylacetamide), 7.5 kg of activated charcoal, 750 l of ethanol and 30 kg of 25% aqueous ammonia solution are placed in a 1200 l stirring apparatus. The mixture is stirred for about 1 h and then filtered into another 1200 l stirring apparatus and washed with 150 l of ethanol. The mixture is heated to 70-80° C., 35 kg of glacial acetic acid are added and the mixture is stirred for a further 1.5-2 h at 75-80° C. The mixture is then cooled to 0-10° C. and stirred for a further 2 h. The product precipitated is centrifuged, washed with 300 l of ethanol and with 300 l of water and dried at 70-90° C. Yield: 135 kg of <span data-mce-style="color: #ff0000;" style="color: red;">telmisartan</span> (90% of theory) pure form AIn the preparation process according to the invention, as a result of the partial conversion of the polymorphic form B into the polymorphic form A during the drying process, telmisartan occurs as a pure substance in a mixture of two polymorphic forms. However, this does not affect the properties of the pharmaceutical composition, as in the course of the manufacture of telmisartan tablets, for example, the mixture of the polymorphic forms A and B is dissolved in 0.1 N NaOH solution and converted by spray drying into a homogeneous and totally amorphous granulate which is then subjected to the other tablet making steps. For more detailed information on the use of the products according to the invention for preparing a pharmaceutical composition, cf. EP 502314 B1, the contents of which are hereby referred to.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></div>
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WO2009006860A2</div>
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<a data-mce-href="http://www.google.co.in/patents/WO2009006860A2?cl=en" href="http://www.google.co.in/patents/WO2009006860A2?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.co.in/patents/WO2009006860A2?cl=en</a></div>
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Telmisartan (I) is produced in accordance with the original patent of Boehringer Ingelheim (US 5 591 762) from telmisartan tert-butyl ester (II). The hydrolysis is carried out using of trifluoroacetic acid in the toxic solvent N,N-dimethylformamide.<br /><div class="patent-image">
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0001.png" href="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000003_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0001.png" height="156" id="imgf000003_0001" src="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="636" /></a></div>
According to another patent applied by the same company (US 2004 236113) the manufacture was problematic and this is why this procedure was replaced with hydrolysis of the corresponding nitrile (III). However, during the hydrolysis, which is carried out with potassium hydroxide in ethylene glycol, a high temperature (160 <sup>0</sup>C) is used, which causes browning of the product, which must be subsequently purified by means of activated carbon. Also, the energy demands of several-ton production would be considerably high.<br /><div class="patent-image">
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0002.png" href="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0002.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000003_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0002.png" height="160" id="imgf000003_0002" src="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000003_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="636" /></a></div>
In a newer application of Cipla (WO 2005/10837) the last two synthetic steps (iii+iv) are combined and telmisartan is isolated after alkaline hydrolysis by acidifying of the reaction mixture in water or extraction with dichloromethane and precipitation with acetone. Both the ways of isolation are unsuitable for industrial production. In the case of telmisartan of crystalline form A its isolation from water or aqueous solutions of organic solvents is very difficult since a hardly filterable product is formed. Extraction of the product with dichloromethane and precipitation with acetone brings a well-filterable product, but the use of dichloromethane is virtually impossible from the point of view of environment protection.<br /><div class="patent-image">
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000004_0001.png" href="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000004_0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000004_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000004_0001.png" height="296" id="imgf000004_0001" src="http://patentimages.storage.googleapis.com/WO2009006860A2/imgf000004_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="636" /></a></div>
Another method has been described by Dr. Reddy (WO 2006/044754), which starts from telmisartan methylester hydrochloride, which is hydrolyzed to produce the potassium salt of termisartan, which is further acidified in aqueous acetonitrile; after isolation it crystallizes from a dichloromethane/methanol mixture and finally from methanol alone, and wherein a pressure apparatus is used for the dissolution in methanol at a temperature above its boiling point (80 °C). The result of this complex procedure, which manifests the already above mentioned shortcomings, is a low yield of the product.<br />The method of Teva (WO 2006/044648) is in many aspects similar to the above mentioned procedure of Cipla, wherein the last two steps of the synthesis are also combined. The method comprises phase separations, which lead to low yields (69 % - 80 %) besides increased tediousness. Matrix starts from telmisartan tert-butyl ester (II), which is first converted to telmisartan dihydrochloride, which in turn, by action of aqueous ammonia in methanol, provides telmisartan with a low total yield of 73%.</div>
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WO2009006860A2</div>
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<a data-mce-href="http://www.google.co.in/patents/WO2009006860A2?cl=en" href="http://www.google.co.in/patents/WO2009006860A2?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.co.in/patents/WO2009006860A2?cl=en</a></div>
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Example 3<br />4'-[[4-methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-l/J-benzimidazol- lyl]methyl]biρhenyl-2-carboxylic acid (<span data-mce-style="color: #ff0000;" style="color: red;">telmisartan</span>)<br />Telmisartan methylester (VT) (20 kg) was refluxed in methanol (400 1) with potassium hydroxide (7 kg) for 24 h. After addition of acetic acid (20 kg) and cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 1). After drying at the laboratory temperature (24 h) 18.5 kg (95 %) of the <span data-mce-style="color: #ff0000;" style="color: red;">product</span> were obtained.<br />Example 4<br />4'-[[4-methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-propyl-lH<sup>'</sup>-benzimidazol- lyl]methyl]biphenyl-2-carboxylic acid (telmisartan)<br />Telmisartan methylester (40 g) was refluxed in methanol (240 ml) with potassium hydroxide (14.9 g) for 24 h. To the boiling solution methanol (240 ml) and then acetic acid (45.5 g) were added. After cooling to 4 °C the product was aspirated within 1 hour and washed with methanol (2 x 80 ml). After drying at the laboratory temperature (24 h) 36 g (92%) of the<span data-mce-style="color: #ff0000;" style="color: red;"> product</span> were obtained.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></div>
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WO2010004385</div>
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<a data-mce-href="http://www.google.co.in/patents/WO2010004385A1?cl=en" href="http://www.google.co.in/patents/WO2010004385A1?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.co.in/patents/WO2010004385A1?cl=en</a></div>
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Telmisartan was first disclosed in US 5,591,762. US 5,591,762 also discloses a process for the preparation of Telmisartan by reacting l,4'-dimethyl-2'-propyl[2,6'-bi-lH- benzimidazole (II) with 4'-(bromomethyl)[l,r-biphenyl]-2-carboxylic acid 1,1- dimethylethyl ester (III) in a solvent optionally in the presence of an acid binding agent to produce the intermediate 4'-[(l,4'-dimethyl-2'-propyl[2,6<sup>l</sup>-bi-lH-benzimidazol]-l- yl)methyl]-[l,l'-biphenyl]-2-carboxylic acid 1,1-dimethylethyl ester (IV), which is further hydrolysed to produce crude Telmisartan. The crude product obtained is purified over a silica gel column and finally crystallized from acetone. The process is shown in Scheme 1 :<br /><div class="patent-image">
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010004385A1/imgf000003_0001.png" href="http://patentimages.storage.googleapis.com/WO2010004385A1/imgf000003_0001.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000003_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010004385A1/imgf000003_0001.png" height="148" id="imgf000003_0001" src="http://patentimages.storage.googleapis.com/WO2010004385A1/imgf000003_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="652" /></a></div>
Hydrolysis<br /><div class="patent-image">
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010004385A1/imgf000003_0002.png" href="http://patentimages.storage.googleapis.com/WO2010004385A1/imgf000003_0002.png" style="color: #6c1b00; text-decoration: none;"><img alt="Figure imgf000003_0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO2010004385A1/imgf000003_0002.png" height="152" id="imgf000003_0002" src="http://patentimages.storage.googleapis.com/WO2010004385A1/imgf000003_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" width="636" /></a></div>
(I)<br />The disadvantage with the above process is the use of column chromatography in the purification of Telmisartan. Employing column chromatography technique is tedious and laborious and also involves use of large quantities of solvents, and hence is not suitable for industrial scale operations.<br />US 6,358,986 describes two crystalline forms of Telmisartan donated as Form A, Form B. In US 6,358,986, the process for preparing crystalline Telmisartan Form A comprises mixing the Telmisartan with ethanol, adding activated charcoal and aqueous ammonia and mixing for one hour, then filtering to another stirring apparatus and washing with ethanol. Resulting solution is heated to 70~80°C, adding glacial acetic acid and stirring for further 1.5-2 hours at the same temperature, cooling to 0-10°C, stirring for further 2 hours, isolating the product by centrifugation, washing with ethanol then with water and drying at 70-90°C. According to the detailed description given in the US '986 patent, in addition to the disadvantageously prolonged drying process of the Telmisartan Form A, very hard particles are obtained. The grinding process of these particles produces a dry powder, which has strong tendency to electrostatic charging and which is virtually impossible to pour and manipulate for pharmaceutical preparations. On the other hand, Telmisartan Form B is free from the above-mentioned limitations. However, the inventors of the US '986 patent could not obtain pure, dry Form B because upon drying, some of Form B transformed into Form A. According to the teachings of the US '986 patent, mixtures of Telmisartan Form A and Form B ranging from 90:10 to 60:40 are suitable for industrial scaling-up, and even a content of 10% of Form B is sufficient to ensure that the product will have the positive qualities required for large-scale production.<br />US 2006/0276525 Al describes a process for the preparation of crystalline solid of Telmisartan Form A by dissolving Telmisartan in a polar solvent such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), ΛζiV-dimethylacetamide (DMA)<sub>5</sub> iV-methyl-2-pyrrolidone (ΝMP) and cooling the solution for sufficient time to produce Telmisartan Form A crystals, which are filtered and dried.<br />EXAMPLE-8<br />PREPARATION OF 4'-[[4-METHYL-O-(I-METHYL-Z-BENZIMIDAZOLYL) ^- PROPYL-1-BENZIMIDAZOLYL] METHYL]-Z-BIPHENYLCARBOXYLIC<br />ACID <span data-mce-style="color: #ff0000;" style="color: red;">[TELMISARTAN]</span><br />Powdered sodium hydroxide (6.83 g) was added in N,N~dimethylformamide (175 ml) at 4°C followed by 4-methyl-6-(l-methyl-2-benzimidazolyl)-2 -propyl- 1- benzimidazole monohydrate (50 g) and stirred for 5 min. Thereafter, methyl-2-[4'- (bromomethylphenyl)]benzoate (54.76 g) was added at 0°C and stirred to the reaction mass till completion of the reaction. Methylene chloride (250 ml) was added, followed by water (500 ml) at 2<sup>0</sup>C and stirred for 10 min. The aqueous layer was separated and extracted with methylene chloride (50 ml). The combined organic extract was washed with water (250 ml) to obtain 380 ml of the organic solution containing Telmisartan methyl ester. 320 ml of this organic layer was concentrated at ambient pressure to collect 210 ml of the distillate. Methanol (120 ml) was added to the concentrated mass and distilled to collect 96 ml of the distillate. The concentrated mass was diluted with 160 ml of methanol at 5O<sup>0</sup>C. Thereafter, aqueous sodium hydroxide solution (17.4 g of NaOH in 40 ml of water) was added at 5O<sup>0</sup>C and heated to reflux at 69-7O<sup>0</sup>C and stirred at reflux temperature till completion of hydrolysis reaction. Thereafter, the reaction mass was concentrated under reduced pressure at 60-65<sup>0</sup>C till no more solvent distils. Water (600 ml) and methylene chloride (200 ml) was added to this solution. pH was adjusted to 4 with hydrochloric acid (22 ml, 35% w/w) at 27-28°C. The aqueous layer was separated and extracted with methylene chloride (40 ml). The combined organic layer was washed with water (80 ml) to obtain 280 ml of the organic solution. This is divided in to four parts and taken for isolation of Telmisartan as given below.<br />Part-1 The organic layer (70 ml) as obtained above was diluted with N,N-dimethylformamide (500 ml) at 27°C and seeded with Telmisartan form-A. The solution was left on standing without stirring for 30 min. The resulting suspension was stirred at 27-28°C for 30 min at this temperature. Solid was filtered, washed with precooled N<sub>5</sub>N- dimethylformamide (15 ml, -5°C) followed by precooled ethanol (10 ml, -2°C) and dried at 85-90<sup>0</sup>C under reduced pressure to afford 10.1 g of <span data-mce-style="color: #ff0000;" style="color: red;">Telmisartan.</span><br />Part-2<br />The organic layer (70 ml) as obtained above was diluted with N,N-dimethylformamide (50 ml) at 27°C and seeded with Telmisartan form-A. The solution was left on standing without stirring for 30 min. The resulting suspension was concentrated under reduced pressure at 65-70<sup>0</sup>C to collect 30 ml of the distillate. Thereafter, the concentrated mass was cooled to -5°C and stirred for 30 min at this temperature. Product was filtered, washed with precooled N,N-dimethylformamide (15 ml, -3°C) followed by precooled ethanol (10 ml, -2°C) and dried at 85-90<sup>0</sup>C under reduced pressure to afford 11.4 g of <span data-mce-style="color: #ff0000;" style="color: red;">Telmisartan.</span><br />Part-3<br />The organic layer (70 ml) as obtained above was diluted with N,N-dimethylformamide (60 ml) at 27°C and seeded with Telmisartan form-A. The solution was left on standing without stirring for 30 min. The resulting suspension was concentrated under reduced pressure at 65-70°C to collect 50 ml of the distillate. Thereafter, stirred at 30°C for 15 min, cooled to -5°C and stirred for 30 min at this temperature. Product was filtered, washed with precooled N,N-dimethylformamide (15 ml, -5°C) followed by precooled ethanol (10 ml, -2<sup>0</sup>C) and dried at 85-90<sup>0</sup>C under reduced pressure to afford 11.7 g of <span data-mce-style="color: #ff0000;" style="color: red;">Telmisartan.</span><br />Part-4<br />The organic layer (70 ml) as obtained above was diluted with N,N-dimethylformamide (40 ml) at 27°C arid seeded with Telmisartan form-A. The solution was left on standing without stirring for 30 min. The resulting suspension was concentrated under reduced pressure at 65-70<sup>0</sup>C to collect 45 ml of the distillate. Thereafter, stirred at 30<sup>0</sup>C for 15 min, cooled to -5°C and stirred for 30 min at this temperature. Product was filtered, washed with precooled N,N-dimethylformamide (15 ml, -5°C) followed by precooled ethanol (10 ml, -2<sup>0</sup>C) and dried at 85-90<sup>0</sup>C under reduced pressure to afford 12.3 g of <span data-mce-style="color: #ff0000;" style="color: red;">Telmisartan.</span></div>
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<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; LIU, LI-YAN: "<a data-mce-href="http://scholar.google.com/scholar?q=%22Study+on+the+optimization+synthesis+of+telmisartan%22" href="http://scholar.google.com/scholar?q=%22Study+on+the+optimization+synthesis+of+telmisartan%22" style="color: #6c1b00; text-decoration: none;">Study on the optimization synthesis of telmisartan</a>" XP002548425 retrieved from STN Database accession no. 2007:587025 & HUAXUE GONGCHENGSHI , 21(3), 60-61 CODEN: HGUOAP; ISSN: 1002-1124, 2007,</td></tr>
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/WO2006044754A2?cl=en" href="http://www.google.co.in/patents/WO2006044754A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2006044754A2</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">18 Oct 2005</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">27 Apr 2006</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Muthulingam Arunagiri</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for preparing telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/WO2009006860A2?cl=en" href="http://www.google.co.in/patents/WO2009006860A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2009006860A2</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">8 Jul 2008</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">15 Jan 2009</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Zentiva As</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">A method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan)</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/EP0502314A1?cl=en" href="http://www.google.co.in/patents/EP0502314A1?cl=en" style="color: #6c1b00; text-decoration: none;">EP0502314A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">31 Jan 1992</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">9 Sep 1992</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dr. Karl Thomae GmbH</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Benzimidazol, medicaments containing them and process for their preparation</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/US20060211866" href="http://www.google.co.in/patents/US20060211866" style="color: #6c1b00; text-decoration: none;">US20060211866</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">21 Mar 2006</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">21 Sep 2006</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Glenmark Pharmaceuticals Limited</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for the preparation of angiotensin receptor blockers and intermediates thereof</td></tr>
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<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
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</tbody></table>
</div>
<div class="patent-image" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/EP0502314B1?cl=en" href="http://www.google.co.in/patents/EP0502314B1?cl=en" style="color: #6c1b00; text-decoration: none;">EP0502314B1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">31 Jan 1992</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">20 May 1998</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dr. Karl Thomae GmbH</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Benzimidazol derivatives, medicaments containing them and process for their preparation</td></tr>
</tbody></table>
</div>
<div class="patent-image" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
</div>
<div class="patent-image" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2010018441A2?cl=en" href="http://www.google.im/patents/WO2010018441A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2010018441A2</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">10 Aug 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">18 Feb 2010</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Cadila Pharmaceuticals Ltd.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">An improved process for the preparation of substantially pure telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2010146187A2?cl=en" href="http://www.google.im/patents/WO2010146187A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2010146187A2</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">21 Jun 2010</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">23 Dec 2010</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Krka, Tovarna Zdravil, D.D., Novo Mesto</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for the preparation of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2011077444A1?cl=en" href="http://www.google.im/patents/WO2011077444A1?cl=en" style="color: #6c1b00; text-decoration: none;">WO2011077444A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">28 May 2010</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">30 Jun 2011</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Inogent Laboratories Private Limited</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">A new process for the preparation of pure telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2012028925A2?cl=en" href="http://www.google.im/patents/WO2012028925A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2012028925A2</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">29 Aug 2011</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">8 Mar 2012</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Ogene Systems (I) Pvt Ltd</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">An improved process for the preparation of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/CN1768044A?cl=en" href="http://www.google.im/patents/CN1768044A?cl=en" style="color: #6c1b00; text-decoration: none;">CN1768044A</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">26 Mar 2004</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">3 May 2006</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">贝林格尔·英格海姆国际有限公司</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for manufacture of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/CN102731407A?cl=en" href="http://www.google.im/patents/CN102731407A?cl=en" style="color: #6c1b00; text-decoration: none;">CN102731407A</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">4 Jul 2012</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">17 Oct 2012</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">宁波九胜创新医药科技有限公司</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Method for preparing telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/EP0627433A1?cl=en" href="http://www.google.im/patents/EP0627433A1?cl=en" style="color: #6c1b00; text-decoration: none;">EP0627433A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7 Dec 1993</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7 Dec 1994</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Eisai Co., Ltd.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for producing imidazopyridine derivative and intermediate</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/EP2123648A1?cl=en" href="http://www.google.im/patents/EP2123648A1?cl=en" style="color: #6c1b00; text-decoration: none;">EP2123648A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">20 May 2008</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">25 Nov 2009</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemo Ibérica, S.A.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">A process for the preparation of Telmisartan.</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/EP2305650A1?cl=en" href="http://www.google.im/patents/EP2305650A1?cl=en" style="color: #6c1b00; text-decoration: none;">EP2305650A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">21 Sep 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">6 Apr 2011</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemo Ibérica, S.A.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Novel process for the preparation of telmisartan</td></tr>
</tbody></table>
</div>
<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;"><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/EP0502314B1?cl=en" href="http://www.google.im/patents/EP0502314B1?cl=en" style="color: #6c1b00; text-decoration: none;">EP0502314B1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">31 Jan 1992</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">20 May 1998</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dr. Karl Thomae GmbH</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Benzimidazol derivatives, medicaments containing them and process for their preparation</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/EP1719766A2?cl=en" href="http://www.google.im/patents/EP1719766A2?cl=en" style="color: #6c1b00; text-decoration: none;">EP1719766A2</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">18 Apr 2006</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">8 Nov 2006</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dipharma S.p.A.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">A process for the preparation of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/EP1878735A1?cl=en" href="http://www.google.im/patents/EP1878735A1?cl=en" style="color: #6c1b00; text-decoration: none;">EP1878735A1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">28 Jun 2007</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">16 Jan 2008</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dipharma Francis S.r.l.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for the preparation of boronic acids and derivatives thereof</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2004087676A1?cl=en" href="http://www.google.im/patents/WO2004087676A1?cl=en" style="color: #6c1b00; text-decoration: none;">WO2004087676A1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">26 Mar 2004</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">14 Oct 2004</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Boehringer Ingelheim Int</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Method for the production of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2006044648A1?cl=en" href="http://www.google.im/patents/WO2006044648A1?cl=en" style="color: #6c1b00; text-decoration: none;">WO2006044648A1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">13 Oct 2005</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">27 Apr 2006</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Teva Pharma</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for preparing telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2006136916A2?cl=en" href="http://www.google.im/patents/WO2006136916A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2006136916A2</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">20 Jun 2006</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">28 Dec 2006</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Glenmark Pharmaceuticals Ltd</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Substantially pure micronized particles of telmisartan and pharmaceutical compositions containing same</td></tr>
</tbody></table>
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/EP2305650A1?cl=en" href="http://www.google.im/patents/EP2305650A1?cl=en" style="color: #6c1b00; text-decoration: none;">EP2305650A1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">21 Sep 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">6 Apr 2011</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemo Ibérica, S.A.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Novel process for the preparation of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/CN102015690B?cl=en" href="http://www.google.im/patents/CN102015690B?cl=en" style="color: #6c1b00; text-decoration: none;">CN102015690B</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">19 Mar 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">30 Apr 2014</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">力奇制药公司</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Catalyzed carbonylation in the synthesis of angiotensin II antagonists</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/US8410285" href="http://www.google.im/patents/US8410285" style="color: #6c1b00; text-decoration: none;">US8410285</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">19 Mar 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2 Apr 2013</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Lek Pharmaceuticals D.D.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2′-halobiphenyl-4-yl intermediates in the synthesis of angiotensin II antagonists</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/US8445693" href="http://www.google.im/patents/US8445693" style="color: #6c1b00; text-decoration: none;">US8445693</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">19 Mar 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">21 May 2013</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Lek Pharmaceuticals D.D.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Catalyzed carbonylation in the synthesis of angiotensin II antagonists</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2009115585A1?cl=en" href="http://www.google.im/patents/WO2009115585A1?cl=en" style="color: #6c1b00; text-decoration: none;">WO2009115585A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">19 Mar 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">24 Sep 2009</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Lek Pharmaceuticals D.D.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Catalyzed carbonylation in the synthesis of angiotensin ii antagonists</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2009123483A1?cl=en" href="http://www.google.im/patents/WO2009123483A1?cl=en" style="color: #6c1b00; text-decoration: none;">WO2009123483A1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">30 Mar 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">8 Oct 2009</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Zaklady Farmaceutyczne Polpharma Sa</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for preparation of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2010018441A2?cl=en" href="http://www.google.im/patents/WO2010018441A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2010018441A2</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">10 Aug 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">18 Feb 2010</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Cadila Pharmaceuticals Ltd.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">An improved process for the preparation of substantially pure telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2010146187A2?cl=en" href="http://www.google.im/patents/WO2010146187A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2010146187A2</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">21 Jun 2010</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">23 Dec 2010</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Krka, Tovarna Zdravil, D.D., Novo Mesto</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for the preparation of telmisartan</td></tr>
</tbody></table>
<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;"><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/EP0502314A1?cl=en" href="http://www.google.im/patents/EP0502314A1?cl=en" style="color: #6c1b00; text-decoration: none;">EP0502314A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">31 Jan 1992</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">9 Sep 1992</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dr. Karl Thomae GmbH</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Benzimidazol, medicaments containing them and process for their preparation</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/DE4142366A1?cl=en" href="http://www.google.im/patents/DE4142366A1?cl=en" style="color: #6c1b00; text-decoration: none;">DE4142366A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">20 Dec 1991</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">24 Jun 1993</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Thomae Gmbh Dr K</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">New phenylalkyl derivs. - are angiotensin II antagonists used to treat hypertension, coronary insufficiency, angina, cns disorders etc.</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/US20040162327" href="http://www.google.im/patents/US20040162327" style="color: #6c1b00; text-decoration: none;">US20040162327</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">12 Feb 2004</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">19 Aug 2004</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Boehringer Ingelheim Pharma Kg</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Treatment of hypertension and cardiac insufficiency, ischaemic peripheral circulatory disorders, diabetic neuropathy, glaucoma, gastrointestinal diseases and bladder diseases</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2004087676A1?cl=en" href="http://www.google.im/patents/WO2004087676A1?cl=en" style="color: #6c1b00; text-decoration: none;">WO2004087676A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">26 Mar 2004</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">14 Oct 2004</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Boehringer Ingelheim Int</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Method for the production of telmisartan</td></tr>
</tbody></table>
<div class="patent-section patent-tabular-section" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2005108375A1?cl=en" href="http://www.google.im/patents/WO2005108375A1?cl=en" style="color: #6c1b00; text-decoration: none;">WO2005108375A1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">10 May 2005</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">17 Nov 2005</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Cipla Ltd</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for the preparation of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2006044648A1?cl=en" href="http://www.google.im/patents/WO2006044648A1?cl=en" style="color: #6c1b00; text-decoration: none;">WO2006044648A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">13 Oct 2005</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">27 Apr 2006</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Teva Pharma</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for preparing telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2006044754A2?cl=en" href="http://www.google.im/patents/WO2006044754A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2006044754A2</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">18 Oct 2005</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">27 Apr 2006</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Muthulingam Arunagiri</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for preparing telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/US6358986" href="http://www.google.im/patents/US6358986" style="color: #6c1b00; text-decoration: none;">US6358986</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">10 Jan 2000</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">19 Mar 2002</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Boehringer Ingelheim Pharma Kg</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Polymorphs of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/US20040236113" href="http://www.google.im/patents/US20040236113" style="color: #6c1b00; text-decoration: none;">US20040236113</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">17 Mar 2004</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">25 Nov 2004</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Boehringer Ingelheim International Gmbh</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for manufacture of telmisartan</td></tr>
</tbody><thead class="patent-section-footer">
<tr class="patent-data-table"><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Citing Patent</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Filing date</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Publication date</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Applicant</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Title</th></tr>
</thead><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2010004385A1?cl=en" href="http://www.google.im/patents/WO2010004385A1?cl=en" style="color: #6c1b00; text-decoration: none;">WO2010004385A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">15 Jun 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">14 Jan 2010</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Aurobindo Pharma Limited</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for the preparation of pure 4'-[4-methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl]methyl]-2-biphenylcarboxylic acid</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2010018441A2?cl=en" href="http://www.google.im/patents/WO2010018441A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2010018441A2</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">10 Aug 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">18 Feb 2010</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Cadila Pharmaceuticals Ltd.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">An improved process for the preparation of substantially pure telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2012055941A1?cl=en" href="http://www.google.im/patents/WO2012055941A1?cl=en" style="color: #6c1b00; text-decoration: none;">WO2012055941A1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">26 Oct 2011</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">3 May 2012</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Krka,Tovarna Zdravil, D. D., Novo Mesto</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Multilayer pharmaceutical composition comprising telmisartan and amlodipine</td></tr>
</tbody></table>
</div>
<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;"><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2005108375A1?cl=en" href="http://www.google.im/patents/WO2005108375A1?cl=en" style="color: #6c1b00; text-decoration: none;">WO2005108375A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">10 May 2005</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">17 Nov 2005</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Cipla Ltd</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for the preparation of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2006044754A2?cl=en" href="http://www.google.im/patents/WO2006044754A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2006044754A2</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">18 Oct 2005</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">27 Apr 2006</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Muthulingam Arunagiri</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for preparing telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/WO2009006860A2?cl=en" href="http://www.google.im/patents/WO2009006860A2?cl=en" style="color: #6c1b00; text-decoration: none;">WO2009006860A2</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">8 Jul 2008</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">15 Jan 2009</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Zentiva As</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">A method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan)</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/EP1719766A2?cl=en" href="http://www.google.im/patents/EP1719766A2?cl=en" style="color: #6c1b00; text-decoration: none;">EP1719766A2</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">18 Apr 2006</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">8 Nov 2006</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dipharma S.p.A.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">A process for the preparation of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/US20060211866" href="http://www.google.im/patents/US20060211866" style="color: #6c1b00; text-decoration: none;">US20060211866</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">21 Mar 2006</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">21 Sep 2006</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Glenmark Pharmaceuticals Limited</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for the preparation of angiotensin receptor blockers and intermediates thereof</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.im/patents/US20060276525" href="http://www.google.im/patents/US20060276525" style="color: #6c1b00; text-decoration: none;">US20060276525</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">17 May 2006</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7 Dec 2006</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Itai Adin</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Processes of preparing highly pure telmisartan form A, suitable for pharmaceutical compositions</td></tr>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com2tag:blogger.com,1999:blog-7082350141827122272.post-26978801526874020852015-04-08T04:31:00.001-07:002015-04-08T04:31:06.774-07:00TELMISARTAN PART 1/3<div dir="ltr" style="text-align: left;" trbidi="on">
<br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="https://blogger.googleusercontent.com/img/proxy/AVvXsEhpzOjUBt0m5dZQjOCckPZvCngsIgMNY7unxgZT1PTu5MoUkysvWIcqt3CTgnyc7jguA9SGb1Z-F_MbAS6R8uqyajKOwKTcqAUGmJxeLeuw52bDPZcLvhklaomH1QtgWr-6-zxj7geCpWey4DLtyYZr2lhmF9N8GWZGKsMwUgwipUp8QrE3wYZVLuxjfUiSK7w3fjCGPHrDEWMJLcfRjYa7R0T1vpMCSQn1FKs=" imageanchor="1" style="background-color: #e5fff8; clear: left; color: #6c1b00; float: left; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; margin-bottom: 1em; margin-right: 1em; text-decoration: none;"><img alt="[1860-5397-6-25-1]" border="0" data-pinit="registered" src="http://www.beilstein-journals.org/bjoc/content/figures/1860-5397-6-25-1.png?max-width=550&background=EEEEEE" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" /></a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">TELMISARTAN</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br />
<table class="mb_l_mb_r_tb pinfo" data-xc="CCCc1nc2c(n1Cc1ccc(cc1)c1ccccc1C(=O)O)cc(cc2C)c1nc2c(n1C)cccc2" style="background-color: white; border-collapse: collapse; border-spacing: 0px; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px; margin: 0px 0px 30px; padding: 0px; width: 667px;"><tbody>
<tr><td class="na" colspan="2" id="listnam_0" style="border: 1px solid rgb(187, 187, 187); color: #3f75bf; font-size: 18px; font-weight: bold; height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; word-break: break-all; word-wrap: break-word;"><a href="http://www.molbase.com/en/cas-144701-48-4.html" style="color: #0088cc; text-decoration: none;">Telmisartan</a></td></tr>
<tr class="bg" style="background-color: #f2f2f2;"><th style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; width: 150px;">CAS No.:</th><td style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px; text-indent: 4px;"><a href="http://www.molbase.com/en/cas-144701-48-4.html" id="listcas_0" style="color: #0088cc; font-size: 14px; font-weight: bold; outline: dotted thin; text-decoration: none;">144701-48-4</a></td></tr>
<tr><th style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; width: 150px;">Synonyms:</th><td style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px; text-indent: 4px;"><div class="synonyms" style="position: relative; z-index: 1;">
<ul class="mb_l_mb_r_tb_otn" id="synonyms_ul" style="line-height: 1.4; list-style: none outside none; margin: 0px; padding: 0px;">
<li style="border: none; margin: 0px; padding: 0px 0px 0px 4px; text-indent: 0px; word-break: break-all; word-wrap: break-word;"><a href="http://www.molbase.com/en/name-TELMISARTAN.html" style="color: #0088cc; text-decoration: none;">TELMISARTAN</a>;</li>
</ul>
</div>
</td></tr>
<tr class="bg" style="background-color: #f2f2f2;"><th style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; width: 150px;">Formula:</th><td style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px; text-indent: 4px;"><a href="http://www.molbase.com/en/formula-C33H30N4O2.html" style="color: #0088cc; text-decoration: none;">C33H30N4O2</a></td></tr>
<tr><th style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; width: 150px;">Exact Mass:</th><td style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px; text-indent: 4px;">514.23700</td></tr>
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<br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" />
<div style="background-color: #e5fff8; color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<div style="color: #222222; font-family: 'Open Sans', 'Helvetica Neue', Helvetica, Arial, sans-serif; font-size: 14px; line-height: 23.7999992370605px; margin-bottom: 0.825em;">
<div style="line-height: 23.7999992370605px; margin-bottom: 0.825em;">
PART 1........<a data-mce-href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-13.html" href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-13.html" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-13.html</a></div>
<div style="line-height: 23.7999992370605px; margin-bottom: 0.825em;">
PART 2........<a data-mce-href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html" href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html</a></div>
<div style="color: black; font-family: 'Times New Roman'; font-size: medium; line-height: normal; margin-bottom: 0.825em;">
<span style="color: #222222; font-family: 'Open Sans', 'Helvetica Neue', Helvetica, Arial, sans-serif;"><span style="font-size: 14px; line-height: 23.7999992370605px;"> OR <a href="http://newdrugapprovals.org/2015/04/06/telmisartan-part-23/" style="color: #6c1b00; text-decoration: none;">http://newdrugapprovals.org/2015/04/06/telmisartan-part-23/</a></span></span></div>
<div style="line-height: 23.7999992370605px; margin-bottom: 0.825em;">
PART3...... <a data-mce-href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-33.html" href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-33.html" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-33.html</a></div>
</div>
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<span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1H NMR PREDICT</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br />
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<h1 style="color: #29568f; font-size: 12px; margin: 0px 0px 6px; padding: 0px; position: relative;">
Efficient and improved synthesis of Telmisartan</h1>
<h1 style="color: #29568f; font-size: 12px; margin: 0px 0px 6px; padding: 0px; position: relative;">
<span class="author" style="margin: 0px; padding: 0px; white-space: nowrap;">A. Sanjeev Kumar</span>, <span class="author" style="margin: 0px; padding: 0px; white-space: nowrap;">Samir Ghosh</span> and <span class="author" style="margin: 0px; padding: 0px; white-space: nowrap;">G. N. Mehta<a href="mailto:drgnmehta@rediffmail.com" style="color: #6c1b00; margin: 0px; padding: 0px; text-decoration: none;"><img alt="Email of corresponding author" src="http://www.beilstein-journals.org/bjoc/images/env_red.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; margin: 0px; padding: 0px; position: relative; vertical-align: middle;" /></a></span></h1>
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Applied Chemistry Department, Sardar Vallabhbhai National Institute of Technology, Surat-395 007, India</div>
<div class="address" style="margin: 0px; padding: 0px 10px 5px;">
Associate Editor: J. A. Porco Jr.</div>
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<i style="margin: 0px; padding: 0px;">Beilstein J. Org. Chem.</i> <b style="margin: 0px; padding: 0px;">2010,</b> <i style="margin: 0px; padding: 0px;">6,</i> No. 25.</div>
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<span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"> </span><a href="http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-6-25" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-6-25</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">(lit </span><a class="reference-link" href="http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-6-25#R6" name="link11" rel="#link11-content" style="background-color: white; color: #29568f; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px; text-decoration: none; white-space: nowrap;" title="Reference 6"></a><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">mp 260–262 °C);</span></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> LIT...... </span><span style="background-color: #e4ecf7; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">Reddy, K. S.; Srinivasan, N.; Reddy, C. R.; Kolla, N.; Anjaneyulu, Y.; Venkatraman, S.; Bhattacharya, A.; Mathad, V. T. </span><i style="background-color: #e4ecf7; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">Org. Process Res. Dev.</i><span style="background-color: #e4ecf7; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> </span><b style="background-color: #e4ecf7; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">2007,</b><span style="background-color: #e4ecf7; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> </span><i style="background-color: #e4ecf7; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">11,</i><span style="background-color: #e4ecf7; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> 81–85. </span><a href="http://dx.doi.org/10.1021%2Fop060200g" style="background-color: #e4ecf7; color: #29568f; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px; text-decoration: none;" target="_blank">doi:10.1021/op060200g</a></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> IR (KBr, cm</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 15px; margin: 0px; padding: 0px; vertical-align: 3px;">-1</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">) 2300–3500 (broad), 1680 (C=O); </span></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">HRMS </span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">m/z</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> calculated for C</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">33</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">H</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">30</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">N</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">4</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">O</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">2</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> – 515.6169 [M + 1], found – 515.6192; </span></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> </span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 15px; margin: 0px; padding: 0px; vertical-align: 3px;">1</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">H NMR (400 MHz, CDCl</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">3</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">) (δ ppm): 12.8 (1H, s, -COOH), 8.42 (1H, d, </span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">J</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> = 8.0 Hz, ArH), 8.02 (1H, d, </span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">J</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> = 8.0 Hz, ArH), 7.50–7.26 (8H, m, ArH), 7.20 (2H, d, </span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">J</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> = 8.0 Hz, ArH), 7.05 (1H, s, ArH), 6.96 (1H, s, ArH), 5.42 (2H, s, -CH</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">2</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">), 3.82 (3H, s, -CH</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">3</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">), 2.97 (2H, t, </span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">J</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> = 7.6 Hz, -CH</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">2</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">), 2.74 (3H, s, -CH</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">3</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">), 1.92 (2H, m, </span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">J</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> = 7.6 Hz, -CH</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">2</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">), 1.04 (3H, t, </span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">J</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> = 7.6 Hz, -CH</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">3</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">); </span></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> </span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 15px; margin: 0px; padding: 0px; vertical-align: 3px;">13</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">C NMR (100 MHz, DMSO-</span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">d</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">6</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">) (δ ppm): 13.5, 16.7, 20.6, 27.6, 32.7, 47.1, 51.7, 112.0, 112.7, 114.7, 118.6, 125.3, 125.7, 125.8, 127.0, 127.4, 128.6, 129.3, 130.4, 130.6, 131.5, 132.3, 133.1, 133.2, 133.7, 134.5, 140.2, 140.5, 150.2, 157.3, 168.1.</span></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;">Second set</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><br /></span><span style="background-color: #e5fff8; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">An improved synthesis of Telmisartan: an antihypertensive drug </span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">A. Sanjeev Kumar, Samir Ghosh, R. Soundararajan,* and G. N. Mehta </span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"></span></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Chemistry Section, Applied Sciences and Humanities Department, SVNIT, Surat-395 007, India</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">General Papers ARKIVOC 2009 (x) 247-254 </span><br />
<div style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">
<a href="http://www.arkat-usa.org/get-file/28995/" style="color: #6c1b00; text-decoration: none;">http://www.arkat-usa.org/get-file/28995/</a></div>
<span style="background-color: #e5fff8; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">melting point: 260-262</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">°C (lit---Venkataraman, S.; Mathad, V. T.; Kikkuru, S. R.; Neti, S.; Chinta, R. R.; Apuraba, B.;</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Anjaneyulu,Y.; Naveenkumar, K. Org. Process Res. Dev. 2007, 11, 81.</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"> mp 260-262 °C);</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">IR (KBr, cm-1) 2300-3500 (broad), 1680 (C=O);</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1H NMR (400 MHz, CDCl3) (δ ppm): 12.8 (1H, s, -COOH), 8.42 (1H, d, J = 8.0 Hz, ArH), 8.02 (1H, d, J = 8.0 Hz,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">ArH), 7.50-7.26 (8H, m, ArH), 7.20 (2H, d, J = 8.0 Hz, ArH), 7.05 (1H, s, ArH), 6.96 (1H, s,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">ArH), 5.42 (2H, s, -CH2), 3.82 (3H, s, -CH3), 2.97 (2H, t, J = 7.6 Hz, -CH2), 2.74 (3H, s, -CH3),</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1.92 (2H, m, J = 7.6 Hz, -CH2), 1.04 (3H, t, J = 7.6 Hz, -CH3);</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">13C NMR (400 MHz, DMSO-d6)</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">(δ ppm): 13.5, 16.7, 20.6, 27.6, 32.7, 47.1, 51.7, 112.0, 112.7, 114.7, 118.6, 125.3, 125.7, 125.8,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">127.0, 127.4, 128.6, 129.3, 130.4, 130.6, 131.5, 132.3, 133.1, 133.2, 133.7, 134.5, 140.2, 140.5,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">150.2, 157.3, 168.1;</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"> MS (m/z): 515 [M+ + 1];</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Anal. Calcd for C33H30N4O2: C, 77.02; H, 5.88; N,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">10.89; O, 6.22. Found: C, 77.0; H, 5.82; N, 10.86.</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">..................................................</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">crystals and other data</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="http://ccp14.chem.ucl.ac.uk/ccp/web-mirrors/pssp/pdf/telmisartan.pdf" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://ccp14.chem.ucl.ac.uk/ccp/web-mirrors/pssp/pdf/telmisartan.pdf</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="http://scholarsresearchlibrary.com/aasr-vol2-iss5/AASR-2010-2-5-135-141.pdf" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://scholarsresearchlibrary.com/aasr-vol2-iss5/AASR-2010-2-5-135-141.pdf</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">.............................................</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">An Improved, Scalable and Cost Effective One-Pot Synthesis of</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Telmisartan</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Premchand B. Patil1*</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">, Anand Pandey1</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">, Devanand B. Shinde2and Bhata R. Chaudhari1*</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1Organic Research Laboratory Department of Chemistry, JET’s Z. B. PatilCollege,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Dhule, Maharashtra, India.</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">2Department of Chemical Technology Dr. BabasahebAmbedkarMarathwadaUniversity,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Aurangabad, Maharashtra, India</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">INTERNATIONAL JOURNAL OF RESEARCH IN PHARMA AND BIOMED SCIENCES</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Vol. 4 (1) Jan– Mar 2013</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1H NMR (DMSO-d6): δ 0.98-1.03 (t,3H), 1.73-</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1.86 (m, 2H), 2.5 - 2.63 (s, 3H), 2.90-2.95 (s,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">2H),3.82 (s, 3H), 5.62 (s, 2H), 7.16-7.34 (m,7H),</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">7.40-7.59 (m,4H), 7.68-7.70 (m, 3H), 12.86 (s,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1H).</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">M/Z: 515.50 [M + H]+</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br />
<div style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">
<a href="http://www.ijrpbsonline.com/files/48-4186.pdf" style="color: #6c1b00; text-decoration: none;">http://www.ijrpbsonline.com/files/48-4186.pdf</a><br /><br /><br /><br /></div>
<span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">......................................</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">PATENT</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">EP 2 149 566 A1</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="https://data.epo.org/publication-server/pdf-document?pn=2149566&ki=A1&cc=EP" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">https://data.epo.org/publication-server/pdf-document?pn=2149566&ki=A1&cc=EP</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1H NMR (300 MHz, DMSO-d6): δ 7.65-7.70 (m, 3H), 7.40-7.56 (m, 4H), 7.15-7.32 (m, 7H), 5.60 (s, 2H), 3.80 (s, 3H),</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">2.91 (m, 2H), 2.61 (s, 3H), 1.80 (m, 2H), 0.98 (m, 2H).</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">13C NMR (75 MHz, DMSO-d6): δ 169.50. 156.19, 154.01, 142.70. 142.35, 140.48, 140.16, 136.60. 135.90. 134.70.</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">132.29, 130.80. 130.32, 129.08, 128.68, 128.21, 127.28, 126.37, 123.14, 122.06, 121.80. 118.65, 110.37, 109.28, 46.12,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">31.74, 28.80. 20.71, 16.43, 13.81</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">..............................</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">PAPER</span><br />
<h1 class="svTitle" id="" style="background-color: white; border: 0px; clear: both; color: #5c5c5c; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 1.4em; line-height: 1.5em; margin: 0px 0px 6px; padding: 0px; position: relative; vertical-align: baseline;">
Detection, isolation and characterization of principle synthetic route indicative impurity in telmisartan</h1>
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<li style="border: 0px; display: inline; margin: 0px; padding: 0px; vertical-align: baseline;"><a class="authorName" data-fn="V." data-ln="Srinivasan" data-pos="1" data-t="a" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#" id="authname_N4cf0c728Nbca1af80" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;">V. Srinivasan</a><a class="intra_ref auth_aff" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#aff1" id="baff1" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" title="Affiliation: a"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">a</sup></a><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">, </sup><a class="intra_ref auth_aff" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#aff2" id="baff2" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" title="Affiliation: b"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">b</sup></a><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">, </sup><a class="intra_ref auth_corr" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#cor1" id="bcor1" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" title="Corresponding author contact information"><img alt="Corresponding author contact information" class="imgLazyJSB" data-inlimg="/entities/REcor.gif" data-loaded="true" src="http://cdn.els-cdn.com/sd/entities/REcor.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; display: inline; margin: 0px; max-width: 600px; padding: 0px; position: relative; vertical-align: baseline;" /></a><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">, </sup><a href="mailto:vsvnreddy@yahoo.com" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;"><img alt="E-mail the corresponding author" class="imgLazyJSB" data-inlimg="/entities/REemail.gif" data-loaded="true" src="http://cdn.els-cdn.com/sd/entities/REemail.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; display: inline; margin: 0px; max-width: 600px; padding: 0px; position: relative; vertical-align: baseline;" /></a><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">, </sup><a href="mailto:srinivasan.viswanathan@piramal.com" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;"><img alt="E-mail the corresponding author" class="imgLazyJSB" data-inlimg="/entities/REemail.gif" data-loaded="true" src="http://cdn.els-cdn.com/sd/entities/REemail.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; display: inline; margin: 0px; max-width: 600px; padding: 0px; position: relative; vertical-align: baseline;" /></a>, </li>
<li style="border: 0px; display: inline; margin: 0px; padding: 0px; vertical-align: baseline;"><a class="authorName" data-fn="H." data-ln="Sivaramakrishnan" data-pos="2" data-t="a" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#" id="authname_N4cf0c728Nbca1b010" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;">H. Sivaramakrishnan</a><a class="intra_ref auth_aff" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#aff2" id="baff2" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" title="Affiliation: b"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">b</sup></a>, </li>
<li style="border: 0px; display: inline; margin: 0px; padding: 0px; vertical-align: baseline;"><a class="authorName" data-fn="B." data-ln="Karthikeyan" data-pos="3" data-t="a" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#" id="authname_N4cf0c728Nbca1b0a0" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;">B. Karthikeyan</a><a class="intra_ref auth_aff" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#aff3" id="baff3" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" title="Affiliation: c"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">c</sup></a></li>
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<li id="aff1" style="border: 0px; display: block; font-size: 11px; margin: 0px; padding: 0px; vertical-align: baseline;"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">a</sup> <span id="" style="border: 0px; margin: 0px; padding: 0px; vertical-align: baseline;">Analytical Development Laboratory, Piramal Healthcare Ltd., Ennore, Chennai 600 057, India</span></li>
<li id="aff2" style="border: 0px; display: block; font-size: 11px; margin: 0px; padding: 0px; vertical-align: baseline;"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">b</sup> <span id="" style="border: 0px; margin: 0px; padding: 0px; vertical-align: baseline;">Research and Development Laboratory, Piramal Healthcare Ltd., Ennore, Chennai 600 057, India</span></li>
<li id="aff3" style="border: 0px; display: block; font-size: 11px; margin: 0px; padding: 0px; vertical-align: baseline;"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">c</sup> <span id="" style="border: 0px; margin: 0px; padding: 0px; vertical-align: baseline;">Department of Chemistry, Annamalai University, Annamalainagar 608 002, India</span></li>
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Available online 1 April 2012</div>
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<div class="svArticle section" id="p0010" style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px 15px 9px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -0.15ex;">
A sample of telmisartan which was synthesized in our laboratory when subjected to HPLC analysis by chromatographic conditions published in the USP monograph offor telmisartan (<span id="bb0050" style="border: 0px; margin: 0px; padding: 0px; vertical-align: baseline;"><a class="intra_ref" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#b0050" id="ancbb0050" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;">USP-NF, 2010</a></span>), an unknownimpurity at 1.59 RRT was observed to a level of 0.09%. As per regulatory guidelines, it is necessary to know the structure of the impurity to develop a synthetic process to remove the impurity and also the knowledge of the structure and the source of the new impurity areis necessary in order to develop a more robust synthetic process. It is therefore, essential to isolate and characterize unidentified impurities present in the drug sample. The structure elucidation of this impurity is object of this work.</div>
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The sample was taken for the isolation of unknown impurity by using preparative HPLC and the isolated impurity was characterized by using MS, NMR and IR. To the best of our knowledge, the impurity detected at 1.59 RRT was established for the first time</div>
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Figure 5.<br /><div id="sp030" style="border: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -0.15ex;">
Impurity structure with numbering of C atoms.</div>
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</dd><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" />
<div style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">
<span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">NMR Spectral data of Impurity-1:</span><br /><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"><br /></span><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">1</sup>H-NMR</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> (CDCl</span><sub style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px; text-align: justify; word-spacing: -1.04999995231628px;">3</sub><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">, 300 MHz), </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">δ</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> (ppm), </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">J</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> (Hz): 3.64 (s, 3H, OCH</span><sub style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px; text-align: justify; word-spacing: -1.04999995231628px;">3</sub><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">), 6.71 (s, 1H, CHBr</span><sub style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px; text-align: justify; word-spacing: -1.04999995231628px;">2</sub><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">, 7.36–7.38, (d, </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">J</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> = 8.42, 2H, Ar-H), 7.40–7.43 (t, </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">J</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> = 8.61, 1H, Ar-H), 7.47–7.52 (t, </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">J</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> = 7.69, 1H, Ar-H), 7.58–7.61 (d, </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">J</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> = 6.04, 1H, Ar-H), 7.65–7.68 (d, </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">J</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> = 8.42, 2H, Ar-H) and 7.92–7.95(d, </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">J</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> = 7.69, 1H, Ar-H). </span><br /><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;"><br /></sup></i><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">13</sup>C-NMR</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">, </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">δ</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> (ppm): 40.77 (–CHBr</span><sub style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px; text-align: justify; word-spacing: -1.04999995231628px;">2</sub><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">, C-1), 51.92 (–OCH</span><sub style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px; text-align: justify; word-spacing: -1.04999995231628px;">3</sub><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">, C-15), 126.18 (–CH, C-7&3), 127.62 (–CH, C-11), 128.56 (–CH, C-6&4), 130.02 (–CH, C-10), 130.57 (–C, C-9), 130.63 (–CH, C-13), 131.42 (–CH, C-12), 140.66 (–C, C-2), 141.37 (–C, C-5), 142.97 (–C, C-8) and 168.55 (C</span><img alt="double bond; length as m-dash" border="0" class="glyphImg imgLazyJSB" data-inlimg="/entities/dbnd" data-loaded="true" src="http://cdn.els-cdn.com/sd/entities/dbnd" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: white; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #2e2e2e; display: inline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; max-width: 600px; padding: 0px; text-align: justify; vertical-align: middle; word-spacing: -1.04999995231628px;" /><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">O, C-14).</span><br /><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"><br /></span>....................<br /><br /><br />PATENT<br /><br /><br /><img src="http://pic4.molbase.net/molpic/8c/a7/91032.png?363x207" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><a href="http://www.molbase.com/en/search.html?search_keyword=17103-26-3" style="background-color: #f5faff; color: #0088cc; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 25px; outline: dotted thin; text-decoration: none;" title="17103-26-3">17103-26-3</a><span style="background-color: #f5faff; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 25px;">;</span><br /><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"><br /></span><span style="background-color: whitesmoke; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">Adin, Itai; Iustain, Carmen; Brand, Michael; Salman, Ada; Weisman, Alexander Patent: US2006/276525 A1, 2006 ; Location in patent: Page/Page column 7 ;</span></div>
<br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" />
<div num="p-0004" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Telmisartan (Compound I below), <b>4</b>′-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid, is a non-peptide ATI-subtype angiotensin II receptor antagonist.<chemistry id="CHEM-US-00001" num="1"></chemistry></div>
<div class="patent-image" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px; text-align: center;">
<a href="http://patentimages.storage.googleapis.com/US20060276525A1/US20060276525A1-20061207-C00001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure US20060276525A1-20061207-C00001" class="patent-full-image" file="US20060276525A1-20061207-C00001.TIF" he="60.20mm" height="240" id="EMI-C00001" img-content="chem" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/US20060276525A1/US20060276525A1-20061207-C00001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="67.23mm" width="268" /></a></div>
<div style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
<div num="p-0005" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Telmisartan is indicated for treatment of hypertension, either alone or in combination with diuretic agents. It is effective in once-daily dosing, so that significant blood-pressure lowering effect is observed even during the last 6 hours of the dosing interval. Telmisartan is marketed in the US as MICARDIS® and MICARDIS-HCT® by Boehringer Ingelheim.</div>
<div num="p-0006" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Telmisartan was first described in U.S. Pat. No. 5,591,762 (hereinafter the '762 patent). According to Example 9 of the '762 patent, Telmisartan was crystallized from acetone and the resulting product had a melting point of 261-263° C.</div>
<div num="p-0007" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
U.S. Pat. No. 6,358,986 (hereinafter the '986 patent) describes two crystalline forms of Telmisartan denoted as forms A and B. It is stated in the '986 patent that the crystals of Telmisartan polymorph A, which is obtainable according to the prior art, have the shape of long needles. As a result of this crystalline shape, the use of Telmisartan polymorph A in large-scale manufacture, purification, isolation and drying of the material is severely limited.</div>
<div num="p-0008" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
As alleged in the '986 patent, the process for preparing crystalline Telmisartan form A comprises mixing the material with ethanol, adding activated charcoal and aqueous ammonia and mixing for one hour, then filtering to another stirring apparatus and washing with ethanol. The next step is heating to 70-80° C., adding glacial acetic acid and stirring for further 1.5-2 hours at the same temperature, cooling to 0-10° C., stirring for further 2 hours, isolating the product by centrifugation, washing with ethanol then with water and drying at 70-90° C. According to the detailed description given in the '986 patent, in addition to the disadvantageously prolonged drying process of the Telmisartan form A, very hard particles are obtained. The grinding process of these particles produces a dry powder, which has strong tendency to electrostatic charging and which is virtually impossible to pour and manipulate for pharmaceutical preparations. On the other hand, Telmisartan form B is free from the above mentioned limitations. However, the inventors of the '986 patent could not obtain pure, dry form B because upon drying, some of form B transformed into form A. According to the teachings of the '986 patent, mixtures of Telmisartan form A and form B ranging from 90:10 to 60:40 are suitable for industrial scaling-up, and even a content of 10% of form B is sufficient to ensure that the product will have the positive qualities required for large-scale production.</div>
<div num="p-0009" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Therefore, as a consequence of the alleged unsuitability of Telmisartan form A for pharmaceutical use, only a mixture of crystalline Telmisartan form A and form B is claimed in the '986 patent, wherein Telmisartan form A is characterized by having an endothermic maximum at 269±2° C., and Telmisartan form B is characterized by having an endothermic maximum at 183±2° C.</div>
<div num="p-0010" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Apparently Telmisartan form A is similar to the original form characterized by its melting point in the '762 patent. The differences between the DSC value and the measured melting point may be attributed to the different methodologies used—the DSC maxima can be slightly different than the visually observed melting point.</div>
<div num="p-0011" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Differences in physical properties of crystalline materials (such as flowability) may be caused by different production processes for obtaining these crystalline materials.</div>
<div num="p-0012" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Hence, the prior art teaches a lengthy, complicated and industrially disadvantageous process for obtaining crystalline Telmisartan form A.</div>
<div num="p-0013" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A mixed solvated-hydrated modification form of Telmisartan, designated as form C, is mentioned in an article by Dinnebier et al., <i>J. Pharm. Sci. </i>89(11), 2000. Telmisartan form C consists of ⅓ mole equivalent of formic acid and ⅔ mole equivalent of water, which is produced by crystallization from mixtures containing formic acid and water. According to the above mentioned publication, drying of form C leads to pure form B (mentioned above). The article mentions detailed crystallographic data of this form as well as of forms A and B.</div>
<div num="p-0014" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The re-crystallization of Telmisartan from N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA) is mentioned in examples 1-3 of the '986 patent. However, since the product is further processed it is believed by the inventors of the present invention that the Telmisartan which is obtained according to the '986 patent, has some defects. Therefore, there is a need in the art for a new process for preparing highly pure Telmisartan form A, which is free-flowing and which does not tend to gain electrostatic charge.</div>
<attachments style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;"><attachment attachment-type="cdx" file="US20060276525A1-20061207-C00001.CDX" idref="CHEM-US-00001"></attachment><attachment attachment-type="mol" file="US20060276525A1-20061207-C00001.MOL" idref="CHEM-US-00001"></attachment></attachments><span style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;"></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" />
<div num="p-0015" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The need to further reprocess the re-crystallized Telmisartan, as taught in the examples of the '986 patent, shows that the product was not highly-pure and/or that it contained residual solvents, because the solvents used therein have high boiling point. By precipitating Telmisartan from an aqueous solution containing acetic acid, as detailed herein, highly pure Telmisartan form A is obtained in high yield e.g., 93%. The obtained Telmisartan form A has low content of residual solvents and is characterized by having a different crystal shape than needles, namely a bulky shape.</div>
<div num="p-0015" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<div num="p-0015" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<br /></div>
<div num="h-0024" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
HPLC Analysis:</div>
<div num="h-0025" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Column: Inertsil ODS-3, 5μ, 250×4.6 mm (GL Sciences Cat. No.: 5020-01732). Mobile phase: 70% methanol and 30% water containing 10 ml triethylamine per 1.0 liter, pH adjusted to 3.0 using phosphoric acid.</div>
<div num="h-0026" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Flow rate: 1 ml/min; UV detection: 226 nm; Oven temperature: 35° C.</div>
<div num="p-0015" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<heading style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;">Reference Example 1</heading><span style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;"></span></div>
<div num="p-0140" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
In a 1000 ml three-necked round bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, 4-[(1,4′-dimethyl-2′-propyl[2,6′-bi-1H-benzimidazol]-1′-yl)methyl]-[1,1′-biphenyl]-2-carboxylic acid methyl ester (50 g, 0.095 mole) was charged, and methanol (300 ml) was added followed by addition of water (26 ml) and 47% NaOH solution (27 ml). The mixture was refluxed for 2 hours. Part of the solvent was evaporated and water (500 ml) was added in portions at 85° C. to afford a solution. The insoluble matter was removed by filtration and the mixture was neutralized with a solution of acetic acid (31.7 ml) in water (75 ml). The thus obtained crude Telmisartan cake was collected by filtration and washed with water to obtain 150 g of wet Telmisartan, which was dried under vacuum to obtain 48 g of the crude product in 98.6% yield, having a purity of 97%.</div>
<div num="p-0015" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<heading style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;">Example 1</heading><span style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;"></span></div>
<div num="p-0141" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
In a 500 ml three necked round bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, Telmisartan (15 g) was dissolved in DMSO (290 ml). The solution was heated to 65° C. using an oil bath, and left to cool down to 25° C. After few days the resulting crystals were filtered off, washed with fresh water and dried at 100° C. under vacuum to obtain 11.55 g of Telmisartan form A in 77% yield, having a purity of 99.5% (according to HPLC).</div>
<div num="h-0029" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Depending on the drying strength, different batches of dried material contained residual DMSO level in the range of 500-1000 ppm and had LOD values in the range of 0.2-0.3%, as measured by means of TGA.</div>
<div num="p-0142" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The obtained solid material contained lumps, which could be easily ground by means of conventional mill. The obtained ground material has improved flowability, namely it is a free flowing crystalline powder that does not tend to gain electrostatic charge upon grinding. It has a bulk density of about 0.3 g/ml.</div>
<div num="h-0030" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Particle size distribution was found to be: D(v,0.1)=1.60μ; D(v,0.2)=2.25μ; D(v,0.5)=4.98μ; D(v,0.8)=11.46μ; D(v,0.9)=16.78μ; D(v,0.95)=22.21μ; D(v,0.98)=29.03μ; D(v,1.0)=52.87μ.</div>
<div num="h-0031" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
XRPD pattern of the resulting material is shown in <figref idrefs="DRAWINGS">FIG. 4</figref> and it resembles the pattern of form A.</div>
<br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">........................</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">PATENT</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="http://www.google.im/patents/WO2009004064A1?cl=en" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://www.google.im/patents/WO2009004064A1?cl=en</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><img src="http://pic4.molbase.net/molpic/01/56/01564830.png?347x227" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; padding: 8px;" /><a href="http://www.molbase.com/en/cas-144702-27-2.html" style="background-color: white; color: #0088cc; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px; outline: dotted thin; text-decoration: none;">144702-27-2</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: whitesmoke; color: #cd0066; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">KRKA, TOVARNA ZDRAVIL, D.D., NOVO MESTO Patent: WO2009/4064 A1, 2009 ; Location in patent: Page/Page column 44-45 ;</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br />
<div num="p0005" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Telmisartan with its chemically name 4'-[(2-n-propyl-4-methyl-6-(l -methylbenzimidazol- 2-yl)-benzimidazol-l-yl)-methyl]-bipheny]-2-carboxylic acid and formula 1</div>
<div num="p0006" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
<div class="patent-image" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px; text-align: center;">
<a href="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000002_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000002_0001" class="patent-full-image" file="imgf000002_0001.tif" he="29" height="116" id="imgf000002_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000002_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="62" width="248" /></a></div>
<div num="p0007" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
is a non-peptide antagonist of subtype 1 of the angiotensin II receptor (ATj -antagonist) used for the treatment of hypertension. It can be used alone or in combination with another pharmaceutically active compound, e.g. hydrochlorothiazide.</div>
<div num="p0008" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Telmisartan is disclosed in EP O 502 314 as well as in J. Med. Chem., 36(25), 4040-4051 ( 1993 j. Its polymorphs are known from EP 1 144 386 and J. Pharm. Sci. 89 ( I i ;. J4ό.v 1479 (2000).</div>
<div num="p0009" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
EP 0 502 314 A and J. Med. Chem., 36(25), 4040-4051 (1993), disclose a method for the preparation of ielmisartan using its tert-butyl substituted intermediate (Scheme j ). The final product of this method is difficult to be filtered, washed and isolated. These properties are an obstacle to an effective large-scale production.</div>
<div num="p0010" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Scheme 1</div>
<div num="p0011" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
<div class="patent-image" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px; text-align: center;">
<a href="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000003_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000003_0001" class="patent-full-image" file="imgf000003_0001.tif" he="49" height="196" id="imgf000003_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000003_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="140" width="560" /></a></div>
<div num="p0012" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The synthesis of telmisartan from a compound with the chemical name 4'-[(2-n-propy!-4- methyl-6-(l-methylbenzimidazo]-2-yl)-benzimidazol-l -yl)-methyl]-biphenyl-2-nitrile (further named as telmisartan nitriie) and represented by formula 3</div>
<div num="p0013" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000003_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000003_0002" class="patent-full-image" file="imgf000003_0002.tif" he="30" height="120" id="imgf000003_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000003_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="62" width="248" /></a></div>
<div num="p0014" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
is disclosed in EP 0 502 314A, WO 2004/087676, CN 1412183 and US 2006/264491.</div>
<div num="p0015" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
In WO 2004/087676 and CN 1412183 telmisartan is prepared by hydrolyzing the compound of formula 3 (Scheme 2): Scheme 2</div>
<div num="p0016" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000004_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000004_0001" class="patent-full-image" file="imgf000004_0001.tif" he="64" height="256" id="imgf000004_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000004_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="140" width="560" /></a></div>
<div num="p0017" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The disclosed method can be used in the large-scale production of telmisartan and allows for a relatively easy purification thereof.</div>
<div num="p0018" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
US 2006/0264491 discloses reacting 4'((l,4<sup>"</sup>-dimethyl-2'-propyl(2,6'-bi-lH- benzimidazol)-r-yl)-methyl)-( l ,r-biphenyl)-2-carboxamide via hydrolysis into telmisartan, isolating crude telmisartan and optionally purifying the crude telmisartan via crystallization.</div>
<div num="p0019" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Amorphous telmisartan is disclosed in US 2006/1 11417 and WO 2006/050921, while crystalline forms of telmisartan are disclosed in WO 00/43370, IN 2005MU00164 and US 2006/0276525.</div>
<div num="p0020" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Various salts of telmisartan are known, for example from CN 1548421, WO 03/037876, WO 2006/044754, WO 2006/050509, WO 2006/050921, EP 1 719 766, WO 2006/136916, WO 2007/01055k and WO 20C7/ 14788<sup><</sup>></div>
<div num="p0021" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
In addition to the above-discussed preparation processes of telmisartan, there still is a need for a yet further improved synthetic route lo telmisartan. Therefore, the object of the present invention is to provide new methods for the production of telmisartan intermediates substituted on position 2 of the biphenyl group of (4'-[(2-n- proρyl-4-methy]-6-( l-methylbenzimidazol-2-yl)-benzimidazol-l-yI)-methyl]-biphenyl) which methods are suitable for use on an industrial scale and which are economical, i.e. both cost and time effective and allow for the production of intermediates that can be converted into telmisartan and/or salts thereof with high quality and high yield.</div>
<div num="p0022" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Another object of the present invention is to provide novel intermediates of telmisartan and derivatives thereof that enable new, cost and time effective synthetic routes to such compounds.</div>
<div num="p0023" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Summary of the invention</div>
<div num="p0024" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
In one aspect, the present invention provides processes for the preparation of the key intermediate of the synthesis of telmisartan, namely a telmisartan intermediate substituted on position 2 of the biphenyl group of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazoi- 2-yl)-benzimidazol-l-yl)-methyl]-biphenyl.</div>
<div num="p0025" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
In another aspect, the present invention provides novel intermediates useful for the synthesis of telmisartan intermediates substituted on position 2 of the biphenyl group of 4<sup>"</sup>- [(2-n-propyl-4-methy<sup>]</sup>~6-(l -methylbenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]- biphenyl optionally in isolated and/or purified form and their use as intermediates in the preparation of telmisartan and/or its salts.</div>
<div num="p0026" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
In another aspect, the present invention provides telmisartan intermediates substituted on position 2 of the biphenyl group of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2- yl)-benzimidazol-l-yl)-methyl]-biphenyl prepared by the processes according to the oresenr invention having a purity of greater than 989r preferablv greater than 99<7r , wherein the amount of each individual impurity is less than 0.15%.</div>
<br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="http://www.google.im/patents/WO2009004064A1?cl=en" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://www.google.im/patents/WO2009004064A1?cl=en</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><img src="http://pic4.molbase.net/molpic/01/56/01564830.png?347x227" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; padding: 8px;" /><a href="http://www.molbase.com/en/cas-144702-27-2.html" style="background-color: white; color: #0088cc; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px; outline: dotted thin; text-decoration: none;">144702-27-2</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: whitesmoke; color: #cd0066; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">KRKA, TOVARNA ZDRAVIL, D.D., NOVO MESTO Patent: WO2009/4064 A1, 2009 ; Location in patent: Page/Page column 44-45 ;</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: whitesmoke; color: #cd0066; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"><br /></span><span style="background-color: whitesmoke; color: #cd0066; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"><br /></span><br />
<div num="p0297" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 16 Preparation of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazoI-2-yl)-benzimidazoI- l-yI)-methyl]-biphenyl-2-carboxylic acid (compound 1)</div>
<div num="p0298" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A mixture of 2.5 g of compound 3 (5 mmol), 1.0 2 sodium hydroxide (25 mmol). 0.18 g water (10 mmol) and 30 ml etbyleneglycol was refluxed for 8 h. After the reaction was completed, the reaction mixture was cooled to room temperature and HoO (250 ml ) was added. After the pH value of this solution was adjusted to 4 with HOAc ( J 2 ml), the product precipitated and was extracted three times with CHoCIo. The combined organic layers were washed with brine, dried over NaSθ<sub>4</sub> and filtered and the filtrate was concentrated to give 2.55 g of crude compound 1 (yield: 98%).</div>
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Example 17 Preparation of 4'-[(2-n-propyl-4-methyl-6-(l-methylben2imidazol-2-yI)-benzimidazoI- l~yI)-methyI]-biphenyl-2-carboxyIic acid (compound 1):</div>
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A mixture of 15 g of compound 3 (30 mmol), 6.0 g potassium hydroxide (91 mmol}. 1.6 g water and 54 ml propylene glycol was refiuxed for 19 h. After the reaction was completed, the reaction mixture was cooled to room temperature and H?O (120 ml) was added. After the pH value of this solution was adjusted to 4.9 with 6M HCl (17 ml), the product was extracted three times with CH<sub>2</sub>CIi. The combined organic layers were washed with water, dried over NaSO<sub>4</sub> and filtered and the filtrate was concentrated. To the residue acetone was added. The suspension was filtered to give 12.55 g of crude compound 1.</div>
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Example 18</div>
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Crystallization of 4'-[(2-n-propyl-4-methyl-6-(l -methylbenzimidazoI-2-y])- benzimidazol-l-yl)-methyl]-biphenyl-2~carboxylic acid (compound 1):</div>
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A mixture of 3 g of telmisartan and 20 ml of N,N-dimethylforrnamide was heated to a temperature of about 100 <sup>0</sup>C until telmisartan was dissolved. Then the solution was filtered and cooled to room temperature. The solution was stirred at this temperature for 3h and then 2h at 0 <sup>0</sup>C. The product was filtered, washed with DMF and dried under reduced pressure at 70-90 <sup>0</sup>C to give 2.7 g of telmisartan (HPLC purity: 99.5%).</div>
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Example 19</div>
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Crystallization of 4'-[(2-n-propyI-4-methyl-6-(l-methyIbenzimidazol-2-yl)- benzimidazo!-l-yI)-methyIl-biphenyf-2-carboxylic acid (compound 1):</div>
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A mixture of 21.4 g of telmisartan, 107 ml of ethanol and 1.3 g of charcoal was stirred at room temperature for 15 min. Then 4.7 ml of 25% NH-, was added and the mixture was stirred for another 1.5h. The mixture was then filtered and the filtrate was heated to 80 <sup>0</sup>C. At this temperature. 4.76 ml of acetic acid was slowly added and the mixture was cooled to room temperature. The mixture was stirred at this temperature for Ih, then the product was filtered, washed with water and ethanol and dried under reduced pressure at 70-90 <sup>0</sup>C to give 19.7 g of telmisartan (HPLC purity: 99.6%)</div>
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PATENT</div>
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<img src="http://pic4.molbase.net/molpic/51/c9/24857.png?202x145" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><img src="http://pic5.molbase.net/molpic/3b/5d/24846.png?268x168" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; font-size: 13.3333330154419px; line-height: 21.3333339691162px; padding: 8px;" /></div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">CIPLA LIMITED; TURNER, Craig, Robert Patent: WO2005/108375 A1, 2005 ; Location in patent: Page/Page column 2-4,7,9-10 ;</span></div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"><br /></span><span style="font-size: 13.3333330154419px; line-height: 21.3333320617676px;">Chinese Patent CN 1344172 discloses the preparation of telmisartan in two steps: namely condensation and hydrolys</span><sup style="line-height: 21.3333320617676px;">i</sup><span style="font-size: 13.3333330154419px; line-height: 21.3333320617676px;">s. US 5591762 discloses the preparation of telmisartan from its tertiary butyl ester. Hydrolysis is carried out using trifluoro acetic acid in dimethyl formamide at room temperature and maintained for about 12 hours. The crude product obtained is purified over a silica gel column and finally crystallized from acetone. US 2002/0094997 is a divisional application of US 6358986. US 2002/0094997 discloses polymorphs of telmisartan, particularly polymorphic form B, polymorphous mixtures and their preparation. Accordingly, telmisartan Form A is dissolved in a mixture of solvents consisting of water, formic acid and an organic solvent that is miscible therewith; the solution is heated followed by distillation and telmisartan containing Form A and Form B is precipitated from the mixture by addition of a base. The disclosure further refers to advantages of the polymorphic Form B mixture, for example it is easily filterable and has a low tendency to electrostatic charging. The disclosure still further refers to the fact that Form A, which is obtained according to the basic patent, is difficult to filter, is characterized by a very long drying time and exhibits a strong tendency to electrostatic charging. The two telmisartan polymorphs of Form A and B as characterised by US 2002/0094997 differ considerably in their melting point: Form B melts at 183°C (determined by DSC), Form A at 269°C (determined by DSC). The polymorphs A and B also differ in their IR spectrum. Pure polymorph A has a characteristic band at 815 cm</span><sup style="line-height: 21.3333320617676px;">"1</sup><span style="font-size: 13.3333330154419px; line-height: 21.3333320617676px;"> in the IR spectrum. In polymorph B, this oscillation is shifted to 830 cm</span><sup style="line-height: 21.3333320617676px;">"1</sup><span style="font-size: 13.3333330154419px; line-height: 21.3333320617676px;">. In all the prior art processes, telmisartan is prepared in two or three steps, which is time consuming, product is lost during intermediate isolation, and as such there is a resulting low yield of the final product. It is also suggested in the prior art that the use of dimethyl formamide and alkali metal carbonates as solvent resulted in dimer formation, which also contributed to low yield. The aim of the present invention is, therefore, to provide an improved process for the preparation of telmisartan. In particular, it is an aim of the present invention to prepare telmisartan in a one step process, thereby increasing the yield, decreasing the cost and avoiding filtration and drying problems. Surprisingly, it has been found according to the present invention that telmisartan can be synthesised in one step from intermediates [1H - Benzimidazole - 2- n-propyl-4- methyl-6-(1 '-methyl benzimidazole-2'-yI)] and methyI-4-(bromomethyl) biphenyl-2- carboxylate. According to the present invention, therefore, there is provided a process for the preparation of telmisartan of formula (I), or a pharmaceutically acceptable salt thereof</span></div>
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<a href="http://patentimages.storage.googleapis.com/WO2005108375A1/imgf000004_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000004_0001" class="patent-full-image" file="imgf000004_0001.tif" he="81" height="324" id="imgf000004_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2005108375A1/imgf000004_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="85" width="340" /></a></div>
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<span style="font-size: 13.3333330154419px; line-height: 21.3333320617676px;">(I) characterised in that lH-Benzimidazole-2-n-propyl-4-methyl-6-(l '-methyl benzimidazole- 2'yl) of formula (II), and methyl-4-(bromomethyl) biphenyl-2-carboxylate of formula (III), are subjected to condensation and hydrolysis in a single step (in other words, a "one pot" synthesis)</span></div>
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<a href="http://patentimages.storage.googleapis.com/WO2005108375A1/imgf000004_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000004_0002" class="patent-full-image" file="imgf000004_0002.tif" he="55" height="220" id="imgf000004_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2005108375A1/imgf000004_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="137" width="548" /></a></div>
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<span style="font-size: 13.3333330154419px; line-height: 21.3333320617676px;">(II) (in)</span></div>
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A process for the preparation of telmisartan of formula (I), or a pharmaceutically acceptable salt thereof</div>
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<a href="http://patentimages.storage.googleapis.com/WO2005108375A1/imgf000010_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000010_0001" class="patent-full-image" file="imgf000010_0001.tif" he="80" height="320" id="imgf000010_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2005108375A1/imgf000010_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="84" width="336" /></a></div>
(I)</div>
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characterised in that lH-Benzimidazole-2-n-propyl-4-methyl-6-(l'-methyl benzimidazole- 2'yl) of foraiula (II) and methyl-4-(bromomethyl) biphenyl-2-carboxylate of formula (III) are subjected to condensation and hydrolysis in a single step</div>
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(II) (ffl)</div>
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Example I</div>
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Preparation of f4'-r2-n-propyl-4-methyl-6-(1-methyl benzimidazol-2-yl) benzimidazol — 1-yl methyl! biphenyl-2-carboxylic acid] 50 gm of [1 H — Benzimidazole-2-n-propyl-4-methyl-6-(1 'methyl benzimidazole-2'- yl)] was added to 200 ml dimethyl sulfoxide and 50 gm of potassium hydroxide. To this was added 60 gm of methyl-4-(bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30°C, then heated to 40-50°C and maintained for 2 hours. About 500 ml water was added to the reaction mixture at room temperature and acidified to pH 4 with acetic acid. The reaction mixture was filtered and washed with purified water, dried under reduced pressure at 50-60°C to give 80 gm (88 %) of the title product.</div>
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Example 2</div>
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Preparation of r4'-[2-n-propyl-4-methyl— 6-(1 -methyl benzimidazol-2-vObenzimidazol — 1- yl methvπbiphenyl-2-carboxylic acid] 50 gin of [1H — Benzimidazole-2-n-propyl-4-methyl-6-(1'- methyl benzimidazole- 2'-yI)] was added to 200 ml dimethyl sulphoxide and 50 gm of potassium hydroxide. To this was added 60 gm of methyl-4- (bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30°C. The contents were heated to 40-50°C and maintained for 2 hours. About 500 ml water was added to the reaction mixture at room temperature and acidified with acetic acid to pH 3.8, extracted twice with 250 ml of dichloromethane and the combined extracts were concentrated and isolated by filtration after addition of 300 ml acetone, dried under reduced pressure at 50-60°C to give 75 gm (80 %) of the title product</div>
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Example 3</div>
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Preparation of \4' - F2-n-propyl — 4-methyl-6-(1 -methyl benzimidazol-2-yl) benzimidazol — 1-yl methyll biphenyl-2-carboxylic acid] 50 gm of [1 H — Benzimidazole-2-n - propyl-4-methyl-6-(1 '-methyl benzimidazole-2'- yl)] was added to 200 ml dimethyl sulfoxide and 50 gm of sodium hydroxide. To this was added 60 gm of methyl-4- (bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30°C and then heated to 40-50 and maintained for 2 hours. About 500 ml water was added to the reaction mixture and acidified with acetic acid to pH 4.2, extract4ed twice with 250 ml of dichloromethane and the combined extracts were concentrated and isolated by filtration after addition of 300 ml acetone, dried under reduced pressure at 50-60°C to give 75.0 gm (80%) of the title compound.</div>
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Example 4</div>
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Purification of 14' - r2-n-propyl-4-methyl-6-(1 -methyl benzimidazol-2-vh benzimidazol-1-yl methyll biphenyl-2-carboxylic acid] 50gm of [4' - [2-n-propyl-4-methyl-6-(1 -methyl benzimidazol-2-yl) benzimidazol-1-yl methyl] biphenyl-2-carboxylic acid] (obtained according to any of Examples 1, 2 or 3) was added to 500ml of methanol. To this was slowly added 50ml of methanolic ammonia (10-15%) at 25-30°C. The contents were stirred for 30 minutes at 25-30°C. About 3gm charcoal was added and stirred at 25-30°C for 30 minutes. The reaction mixture was filtered over hyflo, bed washed with methanol. The clear filtrate pH was adjusted to 3.5-4.0 using acetic acid. The contents were stirred at 20-30°C for 1 hour. Pure telmisartan was isolated by filtration, dried under reduced pressure at 50-60°C to yield 45gm (90%) of the title product with HPLC purity of about 99.3%.</div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">Kumar, A. Sanjeev; Ghosh, Samir; Mehta Journal of Chemical Research, 2010 , # 2 p. 95 - 97</span></div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"> .....................................</span><br /><br /><span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"> PATENT IN 2013MU02627 TELMISARTAN</span><br /><br /><h2 style="color: #516c00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 20px; font-stretch: normal; font-weight: normal; line-height: normal; margin: 0px 0px 0.5em; position: relative;">
Improved process for the preparation of telmisartan</h2>
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<span class="detailwholabel">By: </span>Sathe, Dhananjay G.; Das, Arijit; Patel, Bhavesh; Chincholikar, Vikas</div>
<div class="detailwho">
<span class="detailwholabel">Assignee:</span> Unichem Laboratories Limited, India</div>
<div class="abstract">
The present invention describes an improved process for the synthesis of 4-[(1,4-dimethyl-2-propyl-[2,6-bi-1H-benzimidazol]-1-yl) methyl]-[1,1-biphenyl]-2-carboxylic acid, that is Telmisartan (I). This process comprises hydrolyzing compd. II [R = CN or aminocarbonyl] in acid at temp. range 60-130°C, preferably 80-130°C, more preferably between 100-130°C, in presence of <span style="color: #c00000;">alkali metal nitrite at temp. range 20-50°C, more preferably 45-50°C, to obtain compd. I</span>, and optionally isolating and hydrolyzing compd. II [R = aminocarbonyl] while hydrolyzing compd. II [R = CN] into compd. I at temp. range 20-50°C, more preferably 45-50°C.<br />NOTE</div>
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<b><span style="color: #c00000;">4'-[(l,4-dimethyl-2-propyl [2,6'-bi-lH-benzimidazol]-1'-yl)methyl]-[l,l'-biphenyl]-2-carboxylic acid, IS Telmisartan COMPD 1</span></b><span style="color: #1f497d;"></span></div>
<br /><b><span style="color: #006666; font-size: 11pt;">Telmisartan chemically known as 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-1'-yl)methyl]-[l,1-biphenyl]-2-carboxylic acid and is known from U.S. patent no. 5,591,762 and is represented by compound of structural formula (I)<br /><br />Telmisartan is an angiotensin II receptor (typeAT1) antagonist which is suitable for the treatment of high blood pressure and other medical indications as described in EP 502314 Bl. Telmisartan belongs to the group of angiotensin II antagonists, which are being therapeutically used as medicaments for the cardiovascular system, especially to control high blood pressure. A dosage form of Telmisartan was introduced in the market in 1998 by Boehringer Ingelheim under the protected name Micardis This group contains important drugs like Losartan (Cozaar ®), Irbesartan (Avapro®), or Valsartan (Diovan®). However, unlike these substances Telmisartan shows better efficiency even in the last hours of the administration interval.<br /><br />U.S. patent no. 5,591,762 describes process to prepare Telmisartan which includes,<br />a) condensation of 2-n-propyl-4-methyl-6-(l'-methylbenzimidazol-2'-yl)benzimidazole compound of the formula (II) with tert-butyl-4'-bromomethyl biphenyl-2-carboxylate compound of the formula(V) in the presence of an acid binding agent (potassium-tert-butoxide) in a solvent or mixture of solvents (dimethyl sulphoxide (DMSO) to obtain t-butyl 4'-[4-methyl-6-(1 -methyl-1 H-benzimidazol-2-yl)-2-n-propyl-1H-benzimidazole-l-yl-methyl]biphenyl-2-carboxylate compound of the formula(VI) (tert. Butyl ester of Telmisartan)<br />b) hydrolyzing tert. Butyl ester of Telmisartan compound of the formula (VI) with trifluroacetic acid (TFA) in dimethylformamide (DMF) to obtain crude Telmisartan is purified over a silica gel column and crystallized from acetone to obtain Telmisartan compound of the formula (1) 63.9%.<br /><br />U.S. Patent no. 7,193,089 describes the process to prepare Telmisartan, which includes,<br />a) reacting 2-n-propyl-4-methyl-6-(l'-methylbenzimidazol-2, -yl)benzimidazoie<br />compound of the formula (II) with 4'-(bromomethyl)-[l,l'-biphenyl]-2-carbonitrile compound of the formula (III) in presence of solvent or mixture of solvents (dimethylacetamide), optionally in the presence of an acid -binding agent such as potassium tert-butoxide or potassium hydroxide at a temperature range 0°C to 20°C, to obtain 2-cyano-4'-[2"-n-propyl-4,,-methyl-6"-(l'"-methylbenzimidazol-2'"-yl)benzimidazol-1"-ylmethyl ]biphenyl , cyanotelmisartan compound of the formula (IV).<br />b) hydrolysis of cyanotelmisartan compound of the formula (IV) is carried out in presence solvent selected form water, an organic solvents or mixture thereof (such as ethylene glycol/water) in presence of an acid or a base at temperature between 140°C to 200°C.<br />c) distilled off the solvent from reaction mixture and residue is diluted with water and in hydrochloride acid to obtained Telmisartan hydrochloride is further dissolved in acetic acid and then NaOH is added drop wise at 80°C to 90°C and Telmisartan free base is filtered off.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />U.S. patent application no. 2006/0264491 describes process for preparation of Telmisartan. which includes, hydrolysis of 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-1'-yl)methyl]-[l,1'-biphenyl]-2-carboxamide compound of the formula (V) in presence of potassium hydroxide in propylene glycol at temperature at about 150°C.<br /><br />EP2277866 Al discloses a process for preparing Telmisartan from 2-cyano-4;-[2"-n-propyl-4"-methyl-6"-(1"-methylbenzimidazol-2"'-yl) benzimidazol-l"-yl methyl] biphenyl compound of the formula (IV) using 60% NaOH in n-butanol in presence of phase transfer catalyst i.e. tetra butyl ammonium hydrogen sulphate at 115-120°C for 22h.<br /><br />EP2443094B1/WO2010/146187A2 describes a process for the synthesis of Telmisartan from cyano Telmisartan and carboxamido telmisartan using 1:1 sulphuric acid at 125°C for 30 h and 28 h respectively.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />The existing process requires very high temperature for 30 h or 28 h which limits its large scale application and invites safety risks too. In addition to this, formation of different kind of impurities takes place at 125°C.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />Chinese patent application CN 1412183A describes the process for preparation of Telmisartan which includes reacting compound of the formula (II) with compound of the formula (111) in presence of organic base or inorganic base and reaction solvent to afford compound of the formula (IV). It also describes different hydrolysis conditions for compound of the formula (IV) such as,<br />a. a 1:2 volume ration of concentrated acetic acid: concentrated hydrochloric<br />acid refluxed for 24 hours at about 100°C<br />b. a 2:1 volume ration of ethanol: 2 M NaOH refluxed for 24 hours at about<br />100°C<br />c. a 1: 1.5 volume ration of sodium ethanolate in glycol: water refluxed for 24<br />hours and finally obtained Telmisartan is crystallization with N, N-<br />dimethylformamide (DMF).</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />Chinese patent application CN102070534A discloses a process for preparation of 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1"-methylbenzimidazol-2'"-yl) benzimidazol-1"-ylmethyl ]biphenyl compound of the formula (IV) which includes reacting compound of the formula (II) with compound of the formula (III) under the effect of phase transfer catalyst and inorganic base in the presence of low boiling organic solvents at temperature rang in between 0°C-10oC.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />WO 2007/147889 discloses the process for preparation of Telmisartan by hydrolyzing compound of the formula (IV) by addition of water and conc. HC1 heated at reflux temperature for 136 hours and then cooled reaction mixture at room temperature and add 1M NaOH to adjust pH to about 5 to 7. The product is filtered, wash and dried to obtain Telmisartan.<br />The disclosed process in WO '889 is time intensive besides corrosive and hazardous reaction condition.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />U.S. patent no. 5,591,762 teaches the hydrolysis of cyanotelmisartan compound of the formula (IV) using trifluroacetic acid in dimethyl formamide and is not eco-friendly. It involves long time for hydrolysis. Separation of Telmisartan using silica gel column chromatography results into lower yields. Further the preparation of tert. Butyl ester of Telmisartan is relatively expensive method.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />U.S. Patent no. 7,193,089 is silent about the purity of the free Telmisartan. The solvents used such as dimethyl acetamide and ethylene glycol have a boiling point greater than about 140°C. These solvents are difficult to remove from the reaction using various evaporation techniques known in the art. These reaction conditions are hazardous and far from being environmental friendly. The process is carried out at very high temperature. Removal of residual solvents from reaction mixture, using various evaporation techniques is tedious and difficult.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />U.S. patent application no. 2006/0264491 describes a process in which, an expensive solvent is used. Reactions are carried out at very high temperatures which itself is very difficult to maintain at plant scale manufacturing. These process conditions discourage use of this process.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />Process disclosed by EP2277866A1 requires high temperature and longer time to complete the reaction which invites safety risks. Use of lower temperatures substantially impacts on yield. Moreover the isolation procedure from n-butanol to get crude telmisartan is very tedious.<br /><br />Process disclosed by WO 2010/146187A2 requires very high temperature for longer durations. It limits its application for large scale production. It also invites safety risks. The process leads to formation of different kind of impurities at 125°C. Carrying out reaction at elevated temperatures is not easy and not advisable. Use of lower temperatures substantially impacts yield.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />Chinese patent application CN1412183A describes conditions that required long time for hydrolysis and results in lower yields. Moreover ethylene glycol and DMF are high boiling solvent so it will be very difficult to recover and reuse.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />CN102070534A teaches a reaction which is carried out at a temperature range of 0-10°C, a range which is difficult and energy intensive. Industry will welcome a reaction which is carried out at ambient temperatures and yet having shorter durations. Besides this inconvenient temperature range the reaction necessitates low boiling solvents and thereby restricts selection range of solvents.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />Therefore the processes taught by prior patents and prior art disclosures have several drawback's namely expensive nature, not suitable for scale up at plant level, energy intensive, difficult, giving lower yields, forcing use of corrosive acids, longer duration of corrosive reaction and less user friendly.<br />Therefore industry strongly needs a process that is simpler, financially cheaper and energy economic process, an environment friendly process that does not use hygroscopic and pyrophoric chemicals. Industry needs a process to produce Telmisartan that can be carried out at lower temperatures yet giving good yields, a process that has improved carbon efficiency and is free from hazards and draw backs of prior art.<br /></span></b><br /><br /><br /><b><span style="color: #006666;">EXAMPLE -8:<br />Preparation of 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-bcnzimidazol)-r-yI)methyl]-<br />ll,l'-biphenyll-2-carboxyIic acid</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />100 gm of 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1"-methylbenzimidazol-2'"-yl) benz-imidazol-1'-ylmethyl] biphenyl and 550 mL 80% sulfuric acid, were heated to 80°C-85° C. The reaction mixture stirred for 8-10 h at this temperature. Water (500 mL) was added at the same temperature and the reaction mixture was stirred for 15-20 h and reaction was completed at 120-130 C. </span></b><br /><b><span style="color: #006666; font-size: 11pt;">The reaction was then cooled to 20-25 C. pH of mixture was adjusted tol2 by adding 40% NaOH solution. After that 500 ml of n-Butanol were added and separated out layers. The oily residue thus obtain after distillation was dissolved in 500 mL of water to get clear solution. The aqueous layer was washed with<br /><br />distillation of methylene dichloride was added in 300 mL of acetone. Suck dry the wet cake.<br />Wet cake was directly charged in a reaction assembly containing 900 mL 30% sulfuric acid solution. </span><span style="color: #c00000; font-size: 11pt;">NaN02 solution </span><span style="color: #006666; font-size: 11pt;">(48.75 gm, 0.7 moles in 200 ml water) was added drop wise and the temperature of the reaction mass was kept at 25-50 C. </span></b><br /><b><span style="color: #006666; font-size: 11pt;">The reaction was then heated to 45°C-50°C and maintained for 2-5 h and then cooled to 20-25° C. pH of mixture was adjusted to 12 by adding 40% NaOH solution. After that 500 ml of n-Butanol were added and separated out layers. </span></b><br /><b><span style="color: #006666; font-size: 11pt;">The oily residue thus obtain after distillation was dissolved in 700 mL of methanol and 15 mL of ammonia followed by charcolization. pH of the filtrate was adjusted to 4-5 using acetic acid. Solid obtained was filtered and washed with methanol (100 mL) and dried at 60-65 °C. The solid was then treated with water (500 mL) at 40-45 °C for 3h to remove inorganic matters and then dried at 60-65 °C for 10 h. </span></b><br /><b><span style="color: #006666; font-size: 11pt;">The solid thus obtain was treated with methanol (1000 mL) at 60-65 °C for 8-10 h and then filtered to get pure </span><span style="color: #c00000; font-size: 11pt;">Telmisartan.</span><span style="color: #006666; font-size: 11pt;">The product obtained was then dried at 60-65 °C to get 73 gm (yield 75.9 %) of compound (I) having purity > 99.7 % by HPLC</span></b><br /><b><span style="color: #006666; font-size: 11pt;">........................................................................ </span></b><br /><br /><br /><br /><span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">Reddy, Kikkuru Srirami; Srinivasan, Neti; Reddy, Chinta Raveendra; Kolla, Naveenkumar; Anjaneyulu, Yerremilli; Venkatraman, Sundaram; Bhattacharya, Apurba; Mathad, Vijayavitthal T. Organic Process Research and Development, 2007 , vol. 11, # 1 p. 81 - 85</span></div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">LEK PHARMACEUTICALS D.D. Patent: WO2006/103068 A1, 2006 ; Location in patent: Page/Page column 11; 18 ; WO 2006/103068 A1</span></div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">Boehringer Ingelheim International GmbH Patent: US2004/236113 A1, 2004 ; Location in patent: Page 6 ;</span></div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"><br /></span><span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">Chemo Iberica, S.A. Patent: EP2123648 A1, 2009 ; Location in patent: Page/Page column 13 ;</span></div>
<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"><br /></span><span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">Venugopal; Ramanatham; Devanna; Sanjeev Kumar; Ghosh, Samir; Soundararajan; Kale, Bhima; Mehta Asian Journal of Chemistry, 2010 , vol. 22, # 4 p. 2767 - 2773</span><br /><span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"><br /></span><span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"><br /></span><br /><div class="patent-section patent-tabular-section" style="clear: both; color: #333333; font-family: Arial, sans-serif; font-size: 13.2799997329712px; line-height: 18px; margin-top: 20px;">
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<tr class="patent-data-table" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; border-collapse: collapse; margin-left: 18px; margin-top: 10px;"><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Cited Patent</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Filing date</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Publication date</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Applicant</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Title</th></tr>
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<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2000027397A1?cl=en" style="color: #6611cc; text-decoration: none;">WO2000027397A1</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">6 Nov 1998</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">18 May 2000</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Boehringer Ingelheim Int</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Antihypertensive medicaments containing lacidipine and telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2004087676A1?cl=en" style="color: #6611cc; text-decoration: none;">WO2004087676A1</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">26 Mar 2004</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">14 Oct 2004</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Boehringer Ingelheim Int</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Method for the production of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/EP0502314A1?cl=en" style="color: #6611cc; text-decoration: none;">EP0502314A1</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">31 Jan 1992</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">9 Sep 1992</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Dr. Karl Thomae GmbH</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Benzimidazol, medicaments containing them and process for their preparation</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/US6358986" style="color: #6611cc; text-decoration: none;">US6358986</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">10 Jan 2000</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">19 Mar 2002</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Boehringer Ingelheim Pharma Kg</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Polymorphs of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/US20020094997" style="color: #6611cc; text-decoration: none;">US20020094997</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">16 Nov 2001</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">18 Jul 2002</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Heinrich Schneider</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Polymorphs of telmisartan</td></tr>
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<tr class="patent-data-table" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; border-collapse: collapse; margin-left: 18px; margin-top: 10px;"><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Citing Patent</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Filing date</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Publication date</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Applicant</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Title</th></tr>
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<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2006136916A2?cl=en" style="color: #6611cc; text-decoration: none;">WO2006136916A2</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">20 Jun 2006</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">28 Dec 2006</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Glenmark Pharmaceuticals Ltd</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Substantially pure micronized particles of telmisartan and pharmaceutical compositions containing same</td></tr>
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<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2009123483A1?cl=en" style="color: #6611cc; text-decoration: none;">WO2009123483A1</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">30 Mar 2009</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">8 Oct 2009</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Zaklady Farmaceutyczne Polpharma Sa</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Process for preparation of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2010018441A2?cl=en" style="color: #6611cc; text-decoration: none;">WO2010018441A2</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">10 Aug 2009</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">18 Feb 2010</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Cadila Pharmaceuticals Ltd.</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">An improved process for the preparation of substantially pure telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2010053233A1?cl=en" style="color: #6611cc; text-decoration: none;">WO2010053233A1</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">6 Mar 2009</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">14 May 2010</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Chong Kun Dang Pharmaceutical Corp.</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">The new telmisartan zinc salt and the preparation thereof</td></tr>
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<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2011102645A2?cl=en" style="color: #6611cc; text-decoration: none;">WO2011102645A2</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">17 Feb 2011</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">25 Aug 2011</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Dong Wha Pharm. Co., Ltd.</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">An improved process for preparing telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2012055941A1?cl=en" style="color: #6611cc; text-decoration: none;">WO2012055941A1</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">26 Oct 2011</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">3 May 2012</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Krka,Tovarna Zdravil, D. D., Novo Mesto</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Multilayer pharmaceutical composition comprising telmisartan and amlodipine</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/CN101172968B?cl=en" style="color: #6611cc; text-decoration: none;">CN101172968B</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">1 Nov 2006</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">12 May 2010</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">浙江天宇药业有限公司</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">2-propyl-4 methyl-6-(tolimidazole-2group) benzoglioxaline salt and method for producing the same</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/EP2123648A1?cl=en" style="color: #6611cc; text-decoration: none;">EP2123648A1</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">20 May 2008</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">25 Nov 2009</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Chemo Ibérica, S.A.</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">A process for the preparation of Telmisartan.</td></tr>
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<!-- Blogger automated replacement: "https://images-blogger-opensocial.googleusercontent.com/gadgets/proxy?url=http%3A%2F%2Fwww.beilstein-journals.org%2Fbjoc%2Fcontent%2Ffigures%2F1860-5397-6-25-1.png%3Fmax-width%3D550%26background%3DEEEEEE&container=blogger&gadget=a&rewriteMime=image%2F*" with "https://blogger.googleusercontent.com/img/proxy/AVvXsEhpzOjUBt0m5dZQjOCckPZvCngsIgMNY7unxgZT1PTu5MoUkysvWIcqt3CTgnyc7jguA9SGb1Z-F_MbAS6R8uqyajKOwKTcqAUGmJxeLeuw52bDPZcLvhklaomH1QtgWr-6-zxj7geCpWey4DLtyYZr2lhmF9N8GWZGKsMwUgwipUp8QrE3wYZVLuxjfUiSK7w3fjCGPHrDEWMJLcfRjYa7R0T1vpMCSQn1FKs=" -->DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-7082350141827122272.post-87310726029762467142015-04-08T04:30:00.001-07:002015-04-08T04:30:47.593-07:00TELMISARTAN PART 1/3<div dir="ltr" style="text-align: left;" trbidi="on">
<br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="https://blogger.googleusercontent.com/img/proxy/AVvXsEhpzOjUBt0m5dZQjOCckPZvCngsIgMNY7unxgZT1PTu5MoUkysvWIcqt3CTgnyc7jguA9SGb1Z-F_MbAS6R8uqyajKOwKTcqAUGmJxeLeuw52bDPZcLvhklaomH1QtgWr-6-zxj7geCpWey4DLtyYZr2lhmF9N8GWZGKsMwUgwipUp8QrE3wYZVLuxjfUiSK7w3fjCGPHrDEWMJLcfRjYa7R0T1vpMCSQn1FKs=" imageanchor="1" style="background-color: #e5fff8; clear: left; color: #6c1b00; float: left; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; margin-bottom: 1em; margin-right: 1em; text-decoration: none;"><img alt="[1860-5397-6-25-1]" border="0" data-pinit="registered" src="http://www.beilstein-journals.org/bjoc/content/figures/1860-5397-6-25-1.png?max-width=550&background=EEEEEE" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: none; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px; position: relative;" /></a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">TELMISARTAN</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br />
<table class="mb_l_mb_r_tb pinfo" data-xc="CCCc1nc2c(n1Cc1ccc(cc1)c1ccccc1C(=O)O)cc(cc2C)c1nc2c(n1C)cccc2" style="background-color: white; border-collapse: collapse; border-spacing: 0px; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px; margin: 0px 0px 30px; padding: 0px; width: 667px;"><tbody>
<tr><td class="na" colspan="2" id="listnam_0" style="border: 1px solid rgb(187, 187, 187); color: #3f75bf; font-size: 18px; font-weight: bold; height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; word-break: break-all; word-wrap: break-word;"><a href="http://www.molbase.com/en/cas-144701-48-4.html" style="color: #0088cc; text-decoration: none;">Telmisartan</a></td></tr>
<tr class="bg" style="background-color: #f2f2f2;"><th style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; width: 150px;">CAS No.:</th><td style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px; text-indent: 4px;"><a href="http://www.molbase.com/en/cas-144701-48-4.html" id="listcas_0" style="color: #0088cc; font-size: 14px; font-weight: bold; outline: dotted thin; text-decoration: none;">144701-48-4</a></td></tr>
<tr><th style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; width: 150px;">Synonyms:</th><td style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px; text-indent: 4px;"><div class="synonyms" style="position: relative; z-index: 1;">
<ul class="mb_l_mb_r_tb_otn" id="synonyms_ul" style="line-height: 1.4; list-style: none outside none; margin: 0px; padding: 0px;">
<li style="border: none; margin: 0px; padding: 0px 0px 0px 4px; text-indent: 0px; word-break: break-all; word-wrap: break-word;"><a href="http://www.molbase.com/en/name-TELMISARTAN.html" style="color: #0088cc; text-decoration: none;">TELMISARTAN</a>;</li>
</ul>
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</td></tr>
<tr class="bg" style="background-color: #f2f2f2;"><th style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; width: 150px;">Formula:</th><td style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px; text-indent: 4px;"><a href="http://www.molbase.com/en/formula-C33H30N4O2.html" style="color: #0088cc; text-decoration: none;">C33H30N4O2</a></td></tr>
<tr><th style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; width: 150px;">Exact Mass:</th><td style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px; text-indent: 4px;">514.23700</td></tr>
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<div style="background-color: #e5fff8; color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
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PART 1........<a data-mce-href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-13.html" href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-13.html" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-13.html</a></div>
<div style="line-height: 23.7999992370605px; margin-bottom: 0.825em;">
PART 2........<a data-mce-href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html" href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-23.html</a></div>
<div style="color: black; font-family: 'Times New Roman'; font-size: medium; line-height: normal; margin-bottom: 0.825em;">
<span style="color: #222222; font-family: 'Open Sans', 'Helvetica Neue', Helvetica, Arial, sans-serif;"><span style="font-size: 14px; line-height: 23.7999992370605px;"> OR <a href="http://newdrugapprovals.org/2015/04/06/telmisartan-part-23/" style="color: #6c1b00; text-decoration: none;">http://newdrugapprovals.org/2015/04/06/telmisartan-part-23/</a></span></span></div>
<div style="line-height: 23.7999992370605px; margin-bottom: 0.825em;">
PART3...... <a data-mce-href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-33.html" href="http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-33.html" style="color: #1b8be0; font-style: inherit; font-weight: inherit; line-height: 1.7; text-decoration: none;">http://orgspectroscopyint.blogspot.in/2015/04/telmisartan-part-33.html</a></div>
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<span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1H NMR PREDICT</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br />
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<h1 style="color: #29568f; font-size: 12px; margin: 0px 0px 6px; padding: 0px; position: relative;">
Efficient and improved synthesis of Telmisartan</h1>
<h1 style="color: #29568f; font-size: 12px; margin: 0px 0px 6px; padding: 0px; position: relative;">
<span class="author" style="margin: 0px; padding: 0px; white-space: nowrap;">A. Sanjeev Kumar</span>, <span class="author" style="margin: 0px; padding: 0px; white-space: nowrap;">Samir Ghosh</span> and <span class="author" style="margin: 0px; padding: 0px; white-space: nowrap;">G. N. Mehta<a href="mailto:drgnmehta@rediffmail.com" style="color: #6c1b00; margin: 0px; padding: 0px; text-decoration: none;"><img alt="Email of corresponding author" src="http://www.beilstein-journals.org/bjoc/images/env_red.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; margin: 0px; padding: 0px; position: relative; vertical-align: middle;" /></a></span></h1>
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Applied Chemistry Department, Sardar Vallabhbhai National Institute of Technology, Surat-395 007, India</div>
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Associate Editor: J. A. Porco Jr.</div>
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<i style="margin: 0px; padding: 0px;">Beilstein J. Org. Chem.</i> <b style="margin: 0px; padding: 0px;">2010,</b> <i style="margin: 0px; padding: 0px;">6,</i> No. 25.</div>
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<span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"> </span><a href="http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-6-25" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-6-25</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">(lit </span><a class="reference-link" href="http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-6-25#R6" name="link11" rel="#link11-content" style="background-color: white; color: #29568f; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px; text-decoration: none; white-space: nowrap;" title="Reference 6"></a><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">mp 260–262 °C);</span></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> LIT...... </span><span style="background-color: #e4ecf7; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">Reddy, K. S.; Srinivasan, N.; Reddy, C. R.; Kolla, N.; Anjaneyulu, Y.; Venkatraman, S.; Bhattacharya, A.; Mathad, V. T. </span><i style="background-color: #e4ecf7; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">Org. Process Res. Dev.</i><span style="background-color: #e4ecf7; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> </span><b style="background-color: #e4ecf7; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">2007,</b><span style="background-color: #e4ecf7; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> </span><i style="background-color: #e4ecf7; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">11,</i><span style="background-color: #e4ecf7; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> 81–85. </span><a href="http://dx.doi.org/10.1021%2Fop060200g" style="background-color: #e4ecf7; color: #29568f; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px; text-decoration: none;" target="_blank">doi:10.1021/op060200g</a></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> IR (KBr, cm</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 15px; margin: 0px; padding: 0px; vertical-align: 3px;">-1</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">) 2300–3500 (broad), 1680 (C=O); </span></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">HRMS </span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">m/z</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> calculated for C</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">33</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">H</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">30</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">N</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">4</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">O</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">2</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> – 515.6169 [M + 1], found – 515.6192; </span></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> </span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 15px; margin: 0px; padding: 0px; vertical-align: 3px;">1</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">H NMR (400 MHz, CDCl</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">3</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">) (δ ppm): 12.8 (1H, s, -COOH), 8.42 (1H, d, </span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">J</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> = 8.0 Hz, ArH), 8.02 (1H, d, </span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">J</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> = 8.0 Hz, ArH), 7.50–7.26 (8H, m, ArH), 7.20 (2H, d, </span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">J</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> = 8.0 Hz, ArH), 7.05 (1H, s, ArH), 6.96 (1H, s, ArH), 5.42 (2H, s, -CH</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">2</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">), 3.82 (3H, s, -CH</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">3</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">), 2.97 (2H, t, </span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">J</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> = 7.6 Hz, -CH</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">2</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">), 2.74 (3H, s, -CH</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">3</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">), 1.92 (2H, m, </span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">J</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> = 7.6 Hz, -CH</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">2</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">), 1.04 (3H, t, </span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">J</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> = 7.6 Hz, -CH</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">3</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">); </span></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"> </span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 15px; margin: 0px; padding: 0px; vertical-align: 3px;">13</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">C NMR (100 MHz, DMSO-</span><i style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; margin: 0px; padding: 0px;">d</i><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; line-height: 0px; margin: 0px; padding: 0px; vertical-align: -3px;">6</span><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;">) (δ ppm): 13.5, 16.7, 20.6, 27.6, 32.7, 47.1, 51.7, 112.0, 112.7, 114.7, 118.6, 125.3, 125.7, 125.8, 127.0, 127.4, 128.6, 129.3, 130.4, 130.6, 131.5, 132.3, 133.1, 133.2, 133.7, 134.5, 140.2, 140.5, 150.2, 157.3, 168.1.</span></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;">Second set</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><br /></span><span style="background-color: #e5fff8; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">An improved synthesis of Telmisartan: an antihypertensive drug </span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">A. Sanjeev Kumar, Samir Ghosh, R. Soundararajan,* and G. N. Mehta </span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: x-small;"><span style="background-color: white; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif;"></span></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Chemistry Section, Applied Sciences and Humanities Department, SVNIT, Surat-395 007, India</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">General Papers ARKIVOC 2009 (x) 247-254 </span><br />
<div style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">
<a href="http://www.arkat-usa.org/get-file/28995/" style="color: #6c1b00; text-decoration: none;">http://www.arkat-usa.org/get-file/28995/</a></div>
<span style="background-color: #e5fff8; color: #464646; font-family: Arial, Geneva, Verdana, Helvetica, sans-serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">melting point: 260-262</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">°C (lit---Venkataraman, S.; Mathad, V. T.; Kikkuru, S. R.; Neti, S.; Chinta, R. R.; Apuraba, B.;</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Anjaneyulu,Y.; Naveenkumar, K. Org. Process Res. Dev. 2007, 11, 81.</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"> mp 260-262 °C);</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">IR (KBr, cm-1) 2300-3500 (broad), 1680 (C=O);</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1H NMR (400 MHz, CDCl3) (δ ppm): 12.8 (1H, s, -COOH), 8.42 (1H, d, J = 8.0 Hz, ArH), 8.02 (1H, d, J = 8.0 Hz,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">ArH), 7.50-7.26 (8H, m, ArH), 7.20 (2H, d, J = 8.0 Hz, ArH), 7.05 (1H, s, ArH), 6.96 (1H, s,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">ArH), 5.42 (2H, s, -CH2), 3.82 (3H, s, -CH3), 2.97 (2H, t, J = 7.6 Hz, -CH2), 2.74 (3H, s, -CH3),</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1.92 (2H, m, J = 7.6 Hz, -CH2), 1.04 (3H, t, J = 7.6 Hz, -CH3);</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">13C NMR (400 MHz, DMSO-d6)</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">(δ ppm): 13.5, 16.7, 20.6, 27.6, 32.7, 47.1, 51.7, 112.0, 112.7, 114.7, 118.6, 125.3, 125.7, 125.8,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">127.0, 127.4, 128.6, 129.3, 130.4, 130.6, 131.5, 132.3, 133.1, 133.2, 133.7, 134.5, 140.2, 140.5,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">150.2, 157.3, 168.1;</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"> MS (m/z): 515 [M+ + 1];</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Anal. Calcd for C33H30N4O2: C, 77.02; H, 5.88; N,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">10.89; O, 6.22. Found: C, 77.0; H, 5.82; N, 10.86.</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">..................................................</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">crystals and other data</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="http://ccp14.chem.ucl.ac.uk/ccp/web-mirrors/pssp/pdf/telmisartan.pdf" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://ccp14.chem.ucl.ac.uk/ccp/web-mirrors/pssp/pdf/telmisartan.pdf</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="http://scholarsresearchlibrary.com/aasr-vol2-iss5/AASR-2010-2-5-135-141.pdf" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://scholarsresearchlibrary.com/aasr-vol2-iss5/AASR-2010-2-5-135-141.pdf</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">.............................................</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">An Improved, Scalable and Cost Effective One-Pot Synthesis of</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Telmisartan</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Premchand B. Patil1*</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">, Anand Pandey1</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">, Devanand B. Shinde2and Bhata R. Chaudhari1*</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1Organic Research Laboratory Department of Chemistry, JET’s Z. B. PatilCollege,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Dhule, Maharashtra, India.</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">2Department of Chemical Technology Dr. BabasahebAmbedkarMarathwadaUniversity,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Aurangabad, Maharashtra, India</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">INTERNATIONAL JOURNAL OF RESEARCH IN PHARMA AND BIOMED SCIENCES</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Vol. 4 (1) Jan– Mar 2013</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1H NMR (DMSO-d6): δ 0.98-1.03 (t,3H), 1.73-</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1.86 (m, 2H), 2.5 - 2.63 (s, 3H), 2.90-2.95 (s,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">2H),3.82 (s, 3H), 5.62 (s, 2H), 7.16-7.34 (m,7H),</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">7.40-7.59 (m,4H), 7.68-7.70 (m, 3H), 12.86 (s,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1H).</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">M/Z: 515.50 [M + H]+</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br />
<div style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">
<a href="http://www.ijrpbsonline.com/files/48-4186.pdf" style="color: #6c1b00; text-decoration: none;">http://www.ijrpbsonline.com/files/48-4186.pdf</a><br /><br /><br /><br /></div>
<span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">......................................</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">PATENT</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">EP 2 149 566 A1</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="https://data.epo.org/publication-server/pdf-document?pn=2149566&ki=A1&cc=EP" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">https://data.epo.org/publication-server/pdf-document?pn=2149566&ki=A1&cc=EP</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1H NMR (300 MHz, DMSO-d6): δ 7.65-7.70 (m, 3H), 7.40-7.56 (m, 4H), 7.15-7.32 (m, 7H), 5.60 (s, 2H), 3.80 (s, 3H),</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">2.91 (m, 2H), 2.61 (s, 3H), 1.80 (m, 2H), 0.98 (m, 2H).</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">13C NMR (75 MHz, DMSO-d6): δ 169.50. 156.19, 154.01, 142.70. 142.35, 140.48, 140.16, 136.60. 135.90. 134.70.</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">132.29, 130.80. 130.32, 129.08, 128.68, 128.21, 127.28, 126.37, 123.14, 122.06, 121.80. 118.65, 110.37, 109.28, 46.12,</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">31.74, 28.80. 20.71, 16.43, 13.81</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">..............................</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">PAPER</span><br />
<h1 class="svTitle" id="" style="background-color: white; border: 0px; clear: both; color: #5c5c5c; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 1.4em; line-height: 1.5em; margin: 0px 0px 6px; padding: 0px; position: relative; vertical-align: baseline;">
Detection, isolation and characterization of principle synthetic route indicative impurity in telmisartan</h1>
<ul class="authorGroup noCollab" style="background-color: white; border: 0px; color: #2e2e2e; display: inline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; list-style: none; margin: 0px 0px 6px; padding: 0px; vertical-align: baseline;">
<li style="border: 0px; display: inline; margin: 0px; padding: 0px; vertical-align: baseline;"><a class="authorName" data-fn="V." data-ln="Srinivasan" data-pos="1" data-t="a" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#" id="authname_N4cf0c728Nbca1af80" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;">V. Srinivasan</a><a class="intra_ref auth_aff" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#aff1" id="baff1" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" title="Affiliation: a"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">a</sup></a><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">, </sup><a class="intra_ref auth_aff" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#aff2" id="baff2" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" title="Affiliation: b"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">b</sup></a><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">, </sup><a class="intra_ref auth_corr" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#cor1" id="bcor1" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" title="Corresponding author contact information"><img alt="Corresponding author contact information" class="imgLazyJSB" data-inlimg="/entities/REcor.gif" data-loaded="true" src="http://cdn.els-cdn.com/sd/entities/REcor.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; display: inline; margin: 0px; max-width: 600px; padding: 0px; position: relative; vertical-align: baseline;" /></a><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">, </sup><a href="mailto:vsvnreddy@yahoo.com" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;"><img alt="E-mail the corresponding author" class="imgLazyJSB" data-inlimg="/entities/REemail.gif" data-loaded="true" src="http://cdn.els-cdn.com/sd/entities/REemail.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; display: inline; margin: 0px; max-width: 600px; padding: 0px; position: relative; vertical-align: baseline;" /></a><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">, </sup><a href="mailto:srinivasan.viswanathan@piramal.com" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;"><img alt="E-mail the corresponding author" class="imgLazyJSB" data-inlimg="/entities/REemail.gif" data-loaded="true" src="http://cdn.els-cdn.com/sd/entities/REemail.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; display: inline; margin: 0px; max-width: 600px; padding: 0px; position: relative; vertical-align: baseline;" /></a>, </li>
<li style="border: 0px; display: inline; margin: 0px; padding: 0px; vertical-align: baseline;"><a class="authorName" data-fn="H." data-ln="Sivaramakrishnan" data-pos="2" data-t="a" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#" id="authname_N4cf0c728Nbca1b010" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;">H. Sivaramakrishnan</a><a class="intra_ref auth_aff" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#aff2" id="baff2" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" title="Affiliation: b"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">b</sup></a>, </li>
<li style="border: 0px; display: inline; margin: 0px; padding: 0px; vertical-align: baseline;"><a class="authorName" data-fn="B." data-ln="Karthikeyan" data-pos="3" data-t="a" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#" id="authname_N4cf0c728Nbca1b0a0" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;">B. Karthikeyan</a><a class="intra_ref auth_aff" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#aff3" id="baff3" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" title="Affiliation: c"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">c</sup></a></li>
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<li id="aff1" style="border: 0px; display: block; font-size: 11px; margin: 0px; padding: 0px; vertical-align: baseline;"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">a</sup> <span id="" style="border: 0px; margin: 0px; padding: 0px; vertical-align: baseline;">Analytical Development Laboratory, Piramal Healthcare Ltd., Ennore, Chennai 600 057, India</span></li>
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Available online 1 April 2012</div>
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A sample of telmisartan which was synthesized in our laboratory when subjected to HPLC analysis by chromatographic conditions published in the USP monograph offor telmisartan (<span id="bb0050" style="border: 0px; margin: 0px; padding: 0px; vertical-align: baseline;"><a class="intra_ref" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#b0050" id="ancbb0050" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;">USP-NF, 2010</a></span>), an unknownimpurity at 1.59 RRT was observed to a level of 0.09%. As per regulatory guidelines, it is necessary to know the structure of the impurity to develop a synthetic process to remove the impurity and also the knowledge of the structure and the source of the new impurity areis necessary in order to develop a more robust synthetic process. It is therefore, essential to isolate and characterize unidentified impurities present in the drug sample. The structure elucidation of this impurity is object of this work.</div>
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The sample was taken for the isolation of unknown impurity by using preparative HPLC and the isolated impurity was characterized by using MS, NMR and IR. To the best of our knowledge, the impurity detected at 1.59 RRT was established for the first time</div>
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<dt class="autoScroll" data-style="height:177px;width:133px;" style="background-color: #e5fff8; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; font-weight: bold; line-height: 20px; margin: 12px 0px 0px; overflow-x: auto; overflow-y: hidden; padding: 0px; vertical-align: baseline;" xmlns:xoe="http://www.elsevier.com/xml/xoe/dtd"><a class="figureLink" href="http://www.sciencedirect.com/science/article/pii/S1878535212000688#gr5" style="border: 0px; color: #316c9d; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;" title="Full-size image (5 K)"><img alt="Full-size image (5 K)" border="0" class="imgLazyJSB figure large" data-fulleid="1-s2.0-S1878535212000688-gr5.jpg" data-fullheight="177" data-fullwidth="133" data-loaded="true" data-pinit="registered" data-thumbeid="1-s2.0-S1878535212000688-gr5.sml" data-thumbheight="164" data-thumbwidth="123" height="177" src="http://ars.els-cdn.com/content/image/1-s2.0-S1878535212000688-gr5.jpg" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; display: inline; height: 177px; margin: 0px; max-width: 600px; padding: 0px; position: relative; vertical-align: baseline; width: 133px;" width="133" /></a></dt>
<dd id="labelCaptionf0025" style="background-color: #e5fff8; border: 0px; color: #5c5c5c; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 0.8em; line-height: 20px; margin: 0px; padding: 0px; vertical-align: baseline;" xmlns:xoe="http://www.elsevier.com/xml/xoe/dtd"><div class="caption" style="border: 0px; font-size: 11px; margin: 0px; padding: 0px; vertical-align: baseline;">
Figure 5.<br /><div id="sp030" style="border: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -0.15ex;">
Impurity structure with numbering of C atoms.</div>
<div id="sp030" style="border: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -0.15ex;">
<br /></div>
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</dd><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" />
<div style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">
<span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">NMR Spectral data of Impurity-1:</span><br /><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"><br /></span><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">1</sup>H-NMR</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> (CDCl</span><sub style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px; text-align: justify; word-spacing: -1.04999995231628px;">3</sub><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">, 300 MHz), </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">δ</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> (ppm), </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">J</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> (Hz): 3.64 (s, 3H, OCH</span><sub style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px; text-align: justify; word-spacing: -1.04999995231628px;">3</sub><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">), 6.71 (s, 1H, CHBr</span><sub style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px; text-align: justify; word-spacing: -1.04999995231628px;">2</sub><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">, 7.36–7.38, (d, </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">J</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> = 8.42, 2H, Ar-H), 7.40–7.43 (t, </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">J</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> = 8.61, 1H, Ar-H), 7.47–7.52 (t, </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">J</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> = 7.69, 1H, Ar-H), 7.58–7.61 (d, </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">J</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> = 6.04, 1H, Ar-H), 7.65–7.68 (d, </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">J</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> = 8.42, 2H, Ar-H) and 7.92–7.95(d, </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">J</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> = 7.69, 1H, Ar-H). </span><br /><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;"><br /></sup></i><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;"><sup style="border: 0px; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px;">13</sup>C-NMR</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">, </span><i style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; padding: 0px; text-align: justify; vertical-align: baseline; word-spacing: -1.04999995231628px;">δ</i><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"> (ppm): 40.77 (–CHBr</span><sub style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px; text-align: justify; word-spacing: -1.04999995231628px;">2</sub><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">, C-1), 51.92 (–OCH</span><sub style="background-color: white; border: 0px; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 0.75em; line-height: 0; margin: 0px; padding: 0px; text-align: justify; word-spacing: -1.04999995231628px;">3</sub><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">, C-15), 126.18 (–CH, C-7&3), 127.62 (–CH, C-11), 128.56 (–CH, C-6&4), 130.02 (–CH, C-10), 130.57 (–C, C-9), 130.63 (–CH, C-13), 131.42 (–CH, C-12), 140.66 (–C, C-2), 141.37 (–C, C-5), 142.97 (–C, C-8) and 168.55 (C</span><img alt="double bond; length as m-dash" border="0" class="glyphImg imgLazyJSB" data-inlimg="/entities/dbnd" data-loaded="true" src="http://cdn.els-cdn.com/sd/entities/dbnd" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: white; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #2e2e2e; display: inline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; margin: 0px; max-width: 600px; padding: 0px; text-align: justify; vertical-align: middle; word-spacing: -1.04999995231628px;" /><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;">O, C-14).</span><br /><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"><br /></span>....................<br /><br /><br />PATENT<br /><br /><br /><img src="http://pic4.molbase.net/molpic/8c/a7/91032.png?363x207" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><a href="http://www.molbase.com/en/search.html?search_keyword=17103-26-3" style="background-color: #f5faff; color: #0088cc; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 25px; outline: dotted thin; text-decoration: none;" title="17103-26-3">17103-26-3</a><span style="background-color: #f5faff; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 25px;">;</span><br /><span style="background-color: white; color: #2e2e2e; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, sans-serif; font-size: 13px; line-height: 20px; text-align: justify; word-spacing: -1.04999995231628px;"><br /></span><span style="background-color: whitesmoke; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">Adin, Itai; Iustain, Carmen; Brand, Michael; Salman, Ada; Weisman, Alexander Patent: US2006/276525 A1, 2006 ; Location in patent: Page/Page column 7 ;</span></div>
<br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" />
<div num="p-0004" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Telmisartan (Compound I below), <b>4</b>′-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid, is a non-peptide ATI-subtype angiotensin II receptor antagonist.<chemistry id="CHEM-US-00001" num="1"></chemistry></div>
<div class="patent-image" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px; text-align: center;">
<a href="http://patentimages.storage.googleapis.com/US20060276525A1/US20060276525A1-20061207-C00001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure US20060276525A1-20061207-C00001" class="patent-full-image" file="US20060276525A1-20061207-C00001.TIF" he="60.20mm" height="240" id="EMI-C00001" img-content="chem" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/US20060276525A1/US20060276525A1-20061207-C00001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="67.23mm" width="268" /></a></div>
<div style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
<div num="p-0005" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Telmisartan is indicated for treatment of hypertension, either alone or in combination with diuretic agents. It is effective in once-daily dosing, so that significant blood-pressure lowering effect is observed even during the last 6 hours of the dosing interval. Telmisartan is marketed in the US as MICARDIS® and MICARDIS-HCT® by Boehringer Ingelheim.</div>
<div num="p-0006" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Telmisartan was first described in U.S. Pat. No. 5,591,762 (hereinafter the '762 patent). According to Example 9 of the '762 patent, Telmisartan was crystallized from acetone and the resulting product had a melting point of 261-263° C.</div>
<div num="p-0007" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
U.S. Pat. No. 6,358,986 (hereinafter the '986 patent) describes two crystalline forms of Telmisartan denoted as forms A and B. It is stated in the '986 patent that the crystals of Telmisartan polymorph A, which is obtainable according to the prior art, have the shape of long needles. As a result of this crystalline shape, the use of Telmisartan polymorph A in large-scale manufacture, purification, isolation and drying of the material is severely limited.</div>
<div num="p-0008" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
As alleged in the '986 patent, the process for preparing crystalline Telmisartan form A comprises mixing the material with ethanol, adding activated charcoal and aqueous ammonia and mixing for one hour, then filtering to another stirring apparatus and washing with ethanol. The next step is heating to 70-80° C., adding glacial acetic acid and stirring for further 1.5-2 hours at the same temperature, cooling to 0-10° C., stirring for further 2 hours, isolating the product by centrifugation, washing with ethanol then with water and drying at 70-90° C. According to the detailed description given in the '986 patent, in addition to the disadvantageously prolonged drying process of the Telmisartan form A, very hard particles are obtained. The grinding process of these particles produces a dry powder, which has strong tendency to electrostatic charging and which is virtually impossible to pour and manipulate for pharmaceutical preparations. On the other hand, Telmisartan form B is free from the above mentioned limitations. However, the inventors of the '986 patent could not obtain pure, dry form B because upon drying, some of form B transformed into form A. According to the teachings of the '986 patent, mixtures of Telmisartan form A and form B ranging from 90:10 to 60:40 are suitable for industrial scaling-up, and even a content of 10% of form B is sufficient to ensure that the product will have the positive qualities required for large-scale production.</div>
<div num="p-0009" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Therefore, as a consequence of the alleged unsuitability of Telmisartan form A for pharmaceutical use, only a mixture of crystalline Telmisartan form A and form B is claimed in the '986 patent, wherein Telmisartan form A is characterized by having an endothermic maximum at 269±2° C., and Telmisartan form B is characterized by having an endothermic maximum at 183±2° C.</div>
<div num="p-0010" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Apparently Telmisartan form A is similar to the original form characterized by its melting point in the '762 patent. The differences between the DSC value and the measured melting point may be attributed to the different methodologies used—the DSC maxima can be slightly different than the visually observed melting point.</div>
<div num="p-0011" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Differences in physical properties of crystalline materials (such as flowability) may be caused by different production processes for obtaining these crystalline materials.</div>
<div num="p-0012" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Hence, the prior art teaches a lengthy, complicated and industrially disadvantageous process for obtaining crystalline Telmisartan form A.</div>
<div num="p-0013" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A mixed solvated-hydrated modification form of Telmisartan, designated as form C, is mentioned in an article by Dinnebier et al., <i>J. Pharm. Sci. </i>89(11), 2000. Telmisartan form C consists of ⅓ mole equivalent of formic acid and ⅔ mole equivalent of water, which is produced by crystallization from mixtures containing formic acid and water. According to the above mentioned publication, drying of form C leads to pure form B (mentioned above). The article mentions detailed crystallographic data of this form as well as of forms A and B.</div>
<div num="p-0014" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The re-crystallization of Telmisartan from N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA) is mentioned in examples 1-3 of the '986 patent. However, since the product is further processed it is believed by the inventors of the present invention that the Telmisartan which is obtained according to the '986 patent, has some defects. Therefore, there is a need in the art for a new process for preparing highly pure Telmisartan form A, which is free-flowing and which does not tend to gain electrostatic charge.</div>
<attachments style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;"><attachment attachment-type="cdx" file="US20060276525A1-20061207-C00001.CDX" idref="CHEM-US-00001"></attachment><attachment attachment-type="mol" file="US20060276525A1-20061207-C00001.MOL" idref="CHEM-US-00001"></attachment></attachments><span style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;"></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" />
<div num="p-0015" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The need to further reprocess the re-crystallized Telmisartan, as taught in the examples of the '986 patent, shows that the product was not highly-pure and/or that it contained residual solvents, because the solvents used therein have high boiling point. By precipitating Telmisartan from an aqueous solution containing acetic acid, as detailed herein, highly pure Telmisartan form A is obtained in high yield e.g., 93%. The obtained Telmisartan form A has low content of residual solvents and is characterized by having a different crystal shape than needles, namely a bulky shape.</div>
<div num="p-0015" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<br /></div>
<div num="p-0015" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<br /></div>
<div num="h-0024" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
HPLC Analysis:</div>
<div num="h-0025" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Column: Inertsil ODS-3, 5μ, 250×4.6 mm (GL Sciences Cat. No.: 5020-01732). Mobile phase: 70% methanol and 30% water containing 10 ml triethylamine per 1.0 liter, pH adjusted to 3.0 using phosphoric acid.</div>
<div num="h-0026" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Flow rate: 1 ml/min; UV detection: 226 nm; Oven temperature: 35° C.</div>
<div num="p-0015" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<heading style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;">Reference Example 1</heading><span style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;"></span></div>
<div num="p-0140" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
In a 1000 ml three-necked round bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, 4-[(1,4′-dimethyl-2′-propyl[2,6′-bi-1H-benzimidazol]-1′-yl)methyl]-[1,1′-biphenyl]-2-carboxylic acid methyl ester (50 g, 0.095 mole) was charged, and methanol (300 ml) was added followed by addition of water (26 ml) and 47% NaOH solution (27 ml). The mixture was refluxed for 2 hours. Part of the solvent was evaporated and water (500 ml) was added in portions at 85° C. to afford a solution. The insoluble matter was removed by filtration and the mixture was neutralized with a solution of acetic acid (31.7 ml) in water (75 ml). The thus obtained crude Telmisartan cake was collected by filtration and washed with water to obtain 150 g of wet Telmisartan, which was dried under vacuum to obtain 48 g of the crude product in 98.6% yield, having a purity of 97%.</div>
<div num="p-0015" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<heading style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;">Example 1</heading><span style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;"></span></div>
<div num="p-0141" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
In a 500 ml three necked round bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, Telmisartan (15 g) was dissolved in DMSO (290 ml). The solution was heated to 65° C. using an oil bath, and left to cool down to 25° C. After few days the resulting crystals were filtered off, washed with fresh water and dried at 100° C. under vacuum to obtain 11.55 g of Telmisartan form A in 77% yield, having a purity of 99.5% (according to HPLC).</div>
<div num="h-0029" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Depending on the drying strength, different batches of dried material contained residual DMSO level in the range of 500-1000 ppm and had LOD values in the range of 0.2-0.3%, as measured by means of TGA.</div>
<div num="p-0142" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The obtained solid material contained lumps, which could be easily ground by means of conventional mill. The obtained ground material has improved flowability, namely it is a free flowing crystalline powder that does not tend to gain electrostatic charge upon grinding. It has a bulk density of about 0.3 g/ml.</div>
<div num="h-0030" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Particle size distribution was found to be: D(v,0.1)=1.60μ; D(v,0.2)=2.25μ; D(v,0.5)=4.98μ; D(v,0.8)=11.46μ; D(v,0.9)=16.78μ; D(v,0.95)=22.21μ; D(v,0.98)=29.03μ; D(v,1.0)=52.87μ.</div>
<div num="h-0031" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
XRPD pattern of the resulting material is shown in <figref idrefs="DRAWINGS">FIG. 4</figref> and it resembles the pattern of form A.</div>
<br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">........................</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">PATENT</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="http://www.google.im/patents/WO2009004064A1?cl=en" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://www.google.im/patents/WO2009004064A1?cl=en</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><img src="http://pic4.molbase.net/molpic/01/56/01564830.png?347x227" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; padding: 8px;" /><a href="http://www.molbase.com/en/cas-144702-27-2.html" style="background-color: white; color: #0088cc; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px; outline: dotted thin; text-decoration: none;">144702-27-2</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: whitesmoke; color: #cd0066; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">KRKA, TOVARNA ZDRAVIL, D.D., NOVO MESTO Patent: WO2009/4064 A1, 2009 ; Location in patent: Page/Page column 44-45 ;</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br />
<div num="p0005" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Telmisartan with its chemically name 4'-[(2-n-propyl-4-methyl-6-(l -methylbenzimidazol- 2-yl)-benzimidazol-l-yl)-methyl]-bipheny]-2-carboxylic acid and formula 1</div>
<div num="p0006" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
<div class="patent-image" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px; text-align: center;">
<a href="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000002_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000002_0001" class="patent-full-image" file="imgf000002_0001.tif" he="29" height="116" id="imgf000002_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000002_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="62" width="248" /></a></div>
<div num="p0007" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
is a non-peptide antagonist of subtype 1 of the angiotensin II receptor (ATj -antagonist) used for the treatment of hypertension. It can be used alone or in combination with another pharmaceutically active compound, e.g. hydrochlorothiazide.</div>
<div num="p0008" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Telmisartan is disclosed in EP O 502 314 as well as in J. Med. Chem., 36(25), 4040-4051 ( 1993 j. Its polymorphs are known from EP 1 144 386 and J. Pharm. Sci. 89 ( I i ;. J4ό.v 1479 (2000).</div>
<div num="p0009" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
EP 0 502 314 A and J. Med. Chem., 36(25), 4040-4051 (1993), disclose a method for the preparation of ielmisartan using its tert-butyl substituted intermediate (Scheme j ). The final product of this method is difficult to be filtered, washed and isolated. These properties are an obstacle to an effective large-scale production.</div>
<div num="p0010" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Scheme 1</div>
<div num="p0011" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000003_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000003_0001" class="patent-full-image" file="imgf000003_0001.tif" he="49" height="196" id="imgf000003_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000003_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="140" width="560" /></a></div>
<div num="p0012" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The synthesis of telmisartan from a compound with the chemical name 4'-[(2-n-propy!-4- methyl-6-(l-methylbenzimidazo]-2-yl)-benzimidazol-l -yl)-methyl]-biphenyl-2-nitrile (further named as telmisartan nitriie) and represented by formula 3</div>
<div num="p0013" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000003_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000003_0002" class="patent-full-image" file="imgf000003_0002.tif" he="30" height="120" id="imgf000003_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000003_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="62" width="248" /></a></div>
<div num="p0014" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
is disclosed in EP 0 502 314A, WO 2004/087676, CN 1412183 and US 2006/264491.</div>
<div num="p0015" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
In WO 2004/087676 and CN 1412183 telmisartan is prepared by hydrolyzing the compound of formula 3 (Scheme 2): Scheme 2</div>
<div num="p0016" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
<div class="patent-image" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px; text-align: center;">
<a href="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000004_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000004_0001" class="patent-full-image" file="imgf000004_0001.tif" he="64" height="256" id="imgf000004_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2009004064A1/imgf000004_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="140" width="560" /></a></div>
<div num="p0017" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The disclosed method can be used in the large-scale production of telmisartan and allows for a relatively easy purification thereof.</div>
<div num="p0018" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
US 2006/0264491 discloses reacting 4'((l,4<sup>"</sup>-dimethyl-2'-propyl(2,6'-bi-lH- benzimidazol)-r-yl)-methyl)-( l ,r-biphenyl)-2-carboxamide via hydrolysis into telmisartan, isolating crude telmisartan and optionally purifying the crude telmisartan via crystallization.</div>
<div num="p0019" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Amorphous telmisartan is disclosed in US 2006/1 11417 and WO 2006/050921, while crystalline forms of telmisartan are disclosed in WO 00/43370, IN 2005MU00164 and US 2006/0276525.</div>
<div num="p0020" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Various salts of telmisartan are known, for example from CN 1548421, WO 03/037876, WO 2006/044754, WO 2006/050509, WO 2006/050921, EP 1 719 766, WO 2006/136916, WO 2007/01055k and WO 20C7/ 14788<sup><</sup>></div>
<div num="p0021" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
In addition to the above-discussed preparation processes of telmisartan, there still is a need for a yet further improved synthetic route lo telmisartan. Therefore, the object of the present invention is to provide new methods for the production of telmisartan intermediates substituted on position 2 of the biphenyl group of (4'-[(2-n- proρyl-4-methy]-6-( l-methylbenzimidazol-2-yl)-benzimidazol-l-yI)-methyl]-biphenyl) which methods are suitable for use on an industrial scale and which are economical, i.e. both cost and time effective and allow for the production of intermediates that can be converted into telmisartan and/or salts thereof with high quality and high yield.</div>
<div num="p0022" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Another object of the present invention is to provide novel intermediates of telmisartan and derivatives thereof that enable new, cost and time effective synthetic routes to such compounds.</div>
<div num="p0023" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Summary of the invention</div>
<div num="p0024" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
In one aspect, the present invention provides processes for the preparation of the key intermediate of the synthesis of telmisartan, namely a telmisartan intermediate substituted on position 2 of the biphenyl group of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazoi- 2-yl)-benzimidazol-l-yl)-methyl]-biphenyl.</div>
<div num="p0025" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
In another aspect, the present invention provides novel intermediates useful for the synthesis of telmisartan intermediates substituted on position 2 of the biphenyl group of 4<sup>"</sup>- [(2-n-propyl-4-methy<sup>]</sup>~6-(l -methylbenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]- biphenyl optionally in isolated and/or purified form and their use as intermediates in the preparation of telmisartan and/or its salts.</div>
<div num="p0026" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
In another aspect, the present invention provides telmisartan intermediates substituted on position 2 of the biphenyl group of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2- yl)-benzimidazol-l-yl)-methyl]-biphenyl prepared by the processes according to the oresenr invention having a purity of greater than 989r preferablv greater than 99<7r , wherein the amount of each individual impurity is less than 0.15%.</div>
<br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="http://www.google.im/patents/WO2009004064A1?cl=en" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://www.google.im/patents/WO2009004064A1?cl=en</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><img src="http://pic4.molbase.net/molpic/01/56/01564830.png?347x227" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; padding: 8px;" /><a href="http://www.molbase.com/en/cas-144702-27-2.html" style="background-color: white; color: #0088cc; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px; outline: dotted thin; text-decoration: none;">144702-27-2</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: whitesmoke; color: #cd0066; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">KRKA, TOVARNA ZDRAVIL, D.D., NOVO MESTO Patent: WO2009/4064 A1, 2009 ; Location in patent: Page/Page column 44-45 ;</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: whitesmoke; color: #cd0066; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"><br /></span><span style="background-color: whitesmoke; color: #cd0066; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"><br /></span><br />
<div num="p0297" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 16 Preparation of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazoI-2-yl)-benzimidazoI- l-yI)-methyl]-biphenyl-2-carboxylic acid (compound 1)</div>
<div num="p0298" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A mixture of 2.5 g of compound 3 (5 mmol), 1.0 2 sodium hydroxide (25 mmol). 0.18 g water (10 mmol) and 30 ml etbyleneglycol was refluxed for 8 h. After the reaction was completed, the reaction mixture was cooled to room temperature and HoO (250 ml ) was added. After the pH value of this solution was adjusted to 4 with HOAc ( J 2 ml), the product precipitated and was extracted three times with CHoCIo. The combined organic layers were washed with brine, dried over NaSθ<sub>4</sub> and filtered and the filtrate was concentrated to give 2.55 g of crude compound 1 (yield: 98%).</div>
<div num="p0299" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 17 Preparation of 4'-[(2-n-propyl-4-methyl-6-(l-methylben2imidazol-2-yI)-benzimidazoI- l~yI)-methyI]-biphenyl-2-carboxyIic acid (compound 1):</div>
<div num="p0300" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A mixture of 15 g of compound 3 (30 mmol), 6.0 g potassium hydroxide (91 mmol}. 1.6 g water and 54 ml propylene glycol was refiuxed for 19 h. After the reaction was completed, the reaction mixture was cooled to room temperature and H?O (120 ml) was added. After the pH value of this solution was adjusted to 4.9 with 6M HCl (17 ml), the product was extracted three times with CH<sub>2</sub>CIi. The combined organic layers were washed with water, dried over NaSO<sub>4</sub> and filtered and the filtrate was concentrated. To the residue acetone was added. The suspension was filtered to give 12.55 g of crude compound 1.</div>
<div num="p0301" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 18</div>
<div num="p0302" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Crystallization of 4'-[(2-n-propyl-4-methyl-6-(l -methylbenzimidazoI-2-y])- benzimidazol-l-yl)-methyl]-biphenyl-2~carboxylic acid (compound 1):</div>
<div num="p0303" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A mixture of 3 g of telmisartan and 20 ml of N,N-dimethylforrnamide was heated to a temperature of about 100 <sup>0</sup>C until telmisartan was dissolved. Then the solution was filtered and cooled to room temperature. The solution was stirred at this temperature for 3h and then 2h at 0 <sup>0</sup>C. The product was filtered, washed with DMF and dried under reduced pressure at 70-90 <sup>0</sup>C to give 2.7 g of telmisartan (HPLC purity: 99.5%).</div>
<div num="p0304" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 19</div>
<div num="p0305" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Crystallization of 4'-[(2-n-propyI-4-methyl-6-(l-methyIbenzimidazol-2-yl)- benzimidazo!-l-yI)-methyIl-biphenyf-2-carboxylic acid (compound 1):</div>
<span style="background-color: whitesmoke; color: #cd0066; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"></span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" />
<div num="p0306" style="background-color: white; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">
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A mixture of 21.4 g of telmisartan, 107 ml of ethanol and 1.3 g of charcoal was stirred at room temperature for 15 min. Then 4.7 ml of 25% NH-, was added and the mixture was stirred for another 1.5h. The mixture was then filtered and the filtrate was heated to 80 <sup>0</sup>C. At this temperature. 4.76 ml of acetic acid was slowly added and the mixture was cooled to room temperature. The mixture was stirred at this temperature for Ih, then the product was filtered, washed with water and ethanol and dried under reduced pressure at 70-90 <sup>0</sup>C to give 19.7 g of telmisartan (HPLC purity: 99.6%)</div>
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PATENT</div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">CIPLA LIMITED; TURNER, Craig, Robert Patent: WO2005/108375 A1, 2005 ; Location in patent: Page/Page column 2-4,7,9-10 ;</span></div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"><br /></span><span style="font-size: 13.3333330154419px; line-height: 21.3333320617676px;">Chinese Patent CN 1344172 discloses the preparation of telmisartan in two steps: namely condensation and hydrolys</span><sup style="line-height: 21.3333320617676px;">i</sup><span style="font-size: 13.3333330154419px; line-height: 21.3333320617676px;">s. US 5591762 discloses the preparation of telmisartan from its tertiary butyl ester. Hydrolysis is carried out using trifluoro acetic acid in dimethyl formamide at room temperature and maintained for about 12 hours. The crude product obtained is purified over a silica gel column and finally crystallized from acetone. US 2002/0094997 is a divisional application of US 6358986. US 2002/0094997 discloses polymorphs of telmisartan, particularly polymorphic form B, polymorphous mixtures and their preparation. Accordingly, telmisartan Form A is dissolved in a mixture of solvents consisting of water, formic acid and an organic solvent that is miscible therewith; the solution is heated followed by distillation and telmisartan containing Form A and Form B is precipitated from the mixture by addition of a base. The disclosure further refers to advantages of the polymorphic Form B mixture, for example it is easily filterable and has a low tendency to electrostatic charging. The disclosure still further refers to the fact that Form A, which is obtained according to the basic patent, is difficult to filter, is characterized by a very long drying time and exhibits a strong tendency to electrostatic charging. The two telmisartan polymorphs of Form A and B as characterised by US 2002/0094997 differ considerably in their melting point: Form B melts at 183°C (determined by DSC), Form A at 269°C (determined by DSC). The polymorphs A and B also differ in their IR spectrum. Pure polymorph A has a characteristic band at 815 cm</span><sup style="line-height: 21.3333320617676px;">"1</sup><span style="font-size: 13.3333330154419px; line-height: 21.3333320617676px;"> in the IR spectrum. In polymorph B, this oscillation is shifted to 830 cm</span><sup style="line-height: 21.3333320617676px;">"1</sup><span style="font-size: 13.3333330154419px; line-height: 21.3333320617676px;">. In all the prior art processes, telmisartan is prepared in two or three steps, which is time consuming, product is lost during intermediate isolation, and as such there is a resulting low yield of the final product. It is also suggested in the prior art that the use of dimethyl formamide and alkali metal carbonates as solvent resulted in dimer formation, which also contributed to low yield. The aim of the present invention is, therefore, to provide an improved process for the preparation of telmisartan. In particular, it is an aim of the present invention to prepare telmisartan in a one step process, thereby increasing the yield, decreasing the cost and avoiding filtration and drying problems. Surprisingly, it has been found according to the present invention that telmisartan can be synthesised in one step from intermediates [1H - Benzimidazole - 2- n-propyl-4- methyl-6-(1 '-methyl benzimidazole-2'-yI)] and methyI-4-(bromomethyl) biphenyl-2- carboxylate. According to the present invention, therefore, there is provided a process for the preparation of telmisartan of formula (I), or a pharmaceutically acceptable salt thereof</span></div>
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<a href="http://patentimages.storage.googleapis.com/WO2005108375A1/imgf000004_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000004_0001" class="patent-full-image" file="imgf000004_0001.tif" he="81" height="324" id="imgf000004_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2005108375A1/imgf000004_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="85" width="340" /></a></div>
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<span style="font-size: 13.3333330154419px; line-height: 21.3333320617676px;">(I) characterised in that lH-Benzimidazole-2-n-propyl-4-methyl-6-(l '-methyl benzimidazole- 2'yl) of formula (II), and methyl-4-(bromomethyl) biphenyl-2-carboxylate of formula (III), are subjected to condensation and hydrolysis in a single step (in other words, a "one pot" synthesis)</span></div>
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<span style="font-size: 13.3333330154419px; line-height: 21.3333320617676px;">(II) (in)</span></div>
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A process for the preparation of telmisartan of formula (I), or a pharmaceutically acceptable salt thereof</div>
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<a href="http://patentimages.storage.googleapis.com/WO2005108375A1/imgf000010_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000010_0001" class="patent-full-image" file="imgf000010_0001.tif" he="80" height="320" id="imgf000010_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2005108375A1/imgf000010_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="84" width="336" /></a></div>
(I)</div>
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characterised in that lH-Benzimidazole-2-n-propyl-4-methyl-6-(l'-methyl benzimidazole- 2'yl) of foraiula (II) and methyl-4-(bromomethyl) biphenyl-2-carboxylate of formula (III) are subjected to condensation and hydrolysis in a single step</div>
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(II) (ffl)</div>
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Example I</div>
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Preparation of f4'-r2-n-propyl-4-methyl-6-(1-methyl benzimidazol-2-yl) benzimidazol — 1-yl methyl! biphenyl-2-carboxylic acid] 50 gm of [1 H — Benzimidazole-2-n-propyl-4-methyl-6-(1 'methyl benzimidazole-2'- yl)] was added to 200 ml dimethyl sulfoxide and 50 gm of potassium hydroxide. To this was added 60 gm of methyl-4-(bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30°C, then heated to 40-50°C and maintained for 2 hours. About 500 ml water was added to the reaction mixture at room temperature and acidified to pH 4 with acetic acid. The reaction mixture was filtered and washed with purified water, dried under reduced pressure at 50-60°C to give 80 gm (88 %) of the title product.</div>
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Example 2</div>
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Preparation of r4'-[2-n-propyl-4-methyl— 6-(1 -methyl benzimidazol-2-vObenzimidazol — 1- yl methvπbiphenyl-2-carboxylic acid] 50 gin of [1H — Benzimidazole-2-n-propyl-4-methyl-6-(1'- methyl benzimidazole- 2'-yI)] was added to 200 ml dimethyl sulphoxide and 50 gm of potassium hydroxide. To this was added 60 gm of methyl-4- (bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30°C. The contents were heated to 40-50°C and maintained for 2 hours. About 500 ml water was added to the reaction mixture at room temperature and acidified with acetic acid to pH 3.8, extracted twice with 250 ml of dichloromethane and the combined extracts were concentrated and isolated by filtration after addition of 300 ml acetone, dried under reduced pressure at 50-60°C to give 75 gm (80 %) of the title product</div>
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Example 3</div>
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Preparation of \4' - F2-n-propyl — 4-methyl-6-(1 -methyl benzimidazol-2-yl) benzimidazol — 1-yl methyll biphenyl-2-carboxylic acid] 50 gm of [1 H — Benzimidazole-2-n - propyl-4-methyl-6-(1 '-methyl benzimidazole-2'- yl)] was added to 200 ml dimethyl sulfoxide and 50 gm of sodium hydroxide. To this was added 60 gm of methyl-4- (bromomethyl) biphenyl-2-carboxylate at ambient temperature. The contents were stirred for 2 hours at 25-30°C and then heated to 40-50 and maintained for 2 hours. About 500 ml water was added to the reaction mixture and acidified with acetic acid to pH 4.2, extract4ed twice with 250 ml of dichloromethane and the combined extracts were concentrated and isolated by filtration after addition of 300 ml acetone, dried under reduced pressure at 50-60°C to give 75.0 gm (80%) of the title compound.</div>
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Example 4</div>
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Purification of 14' - r2-n-propyl-4-methyl-6-(1 -methyl benzimidazol-2-vh benzimidazol-1-yl methyll biphenyl-2-carboxylic acid] 50gm of [4' - [2-n-propyl-4-methyl-6-(1 -methyl benzimidazol-2-yl) benzimidazol-1-yl methyl] biphenyl-2-carboxylic acid] (obtained according to any of Examples 1, 2 or 3) was added to 500ml of methanol. To this was slowly added 50ml of methanolic ammonia (10-15%) at 25-30°C. The contents were stirred for 30 minutes at 25-30°C. About 3gm charcoal was added and stirred at 25-30°C for 30 minutes. The reaction mixture was filtered over hyflo, bed washed with methanol. The clear filtrate pH was adjusted to 3.5-4.0 using acetic acid. The contents were stirred at 20-30°C for 1 hour. Pure telmisartan was isolated by filtration, dried under reduced pressure at 50-60°C to yield 45gm (90%) of the title product with HPLC purity of about 99.3%.</div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"> .....................................</span><br /><br /><span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"> PATENT IN 2013MU02627 TELMISARTAN</span><br /><br /><h2 style="color: #516c00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 20px; font-stretch: normal; font-weight: normal; line-height: normal; margin: 0px 0px 0.5em; position: relative;">
Improved process for the preparation of telmisartan</h2>
<div class="detailwho">
<span class="detailwholabel">By: </span>Sathe, Dhananjay G.; Das, Arijit; Patel, Bhavesh; Chincholikar, Vikas</div>
<div class="detailwho">
<span class="detailwholabel">Assignee:</span> Unichem Laboratories Limited, India</div>
<div class="abstract">
The present invention describes an improved process for the synthesis of 4-[(1,4-dimethyl-2-propyl-[2,6-bi-1H-benzimidazol]-1-yl) methyl]-[1,1-biphenyl]-2-carboxylic acid, that is Telmisartan (I). This process comprises hydrolyzing compd. II [R = CN or aminocarbonyl] in acid at temp. range 60-130°C, preferably 80-130°C, more preferably between 100-130°C, in presence of <span style="color: #c00000;">alkali metal nitrite at temp. range 20-50°C, more preferably 45-50°C, to obtain compd. I</span>, and optionally isolating and hydrolyzing compd. II [R = aminocarbonyl] while hydrolyzing compd. II [R = CN] into compd. I at temp. range 20-50°C, more preferably 45-50°C.<br />NOTE</div>
<div class="MsoNormal">
<b><span style="color: #c00000;">4'-[(l,4-dimethyl-2-propyl [2,6'-bi-lH-benzimidazol]-1'-yl)methyl]-[l,l'-biphenyl]-2-carboxylic acid, IS Telmisartan COMPD 1</span></b><span style="color: #1f497d;"></span></div>
<br /><b><span style="color: #006666; font-size: 11pt;">Telmisartan chemically known as 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-1'-yl)methyl]-[l,1-biphenyl]-2-carboxylic acid and is known from U.S. patent no. 5,591,762 and is represented by compound of structural formula (I)<br /><br />Telmisartan is an angiotensin II receptor (typeAT1) antagonist which is suitable for the treatment of high blood pressure and other medical indications as described in EP 502314 Bl. Telmisartan belongs to the group of angiotensin II antagonists, which are being therapeutically used as medicaments for the cardiovascular system, especially to control high blood pressure. A dosage form of Telmisartan was introduced in the market in 1998 by Boehringer Ingelheim under the protected name Micardis This group contains important drugs like Losartan (Cozaar ®), Irbesartan (Avapro®), or Valsartan (Diovan®). However, unlike these substances Telmisartan shows better efficiency even in the last hours of the administration interval.<br /><br />U.S. patent no. 5,591,762 describes process to prepare Telmisartan which includes,<br />a) condensation of 2-n-propyl-4-methyl-6-(l'-methylbenzimidazol-2'-yl)benzimidazole compound of the formula (II) with tert-butyl-4'-bromomethyl biphenyl-2-carboxylate compound of the formula(V) in the presence of an acid binding agent (potassium-tert-butoxide) in a solvent or mixture of solvents (dimethyl sulphoxide (DMSO) to obtain t-butyl 4'-[4-methyl-6-(1 -methyl-1 H-benzimidazol-2-yl)-2-n-propyl-1H-benzimidazole-l-yl-methyl]biphenyl-2-carboxylate compound of the formula(VI) (tert. Butyl ester of Telmisartan)<br />b) hydrolyzing tert. Butyl ester of Telmisartan compound of the formula (VI) with trifluroacetic acid (TFA) in dimethylformamide (DMF) to obtain crude Telmisartan is purified over a silica gel column and crystallized from acetone to obtain Telmisartan compound of the formula (1) 63.9%.<br /><br />U.S. Patent no. 7,193,089 describes the process to prepare Telmisartan, which includes,<br />a) reacting 2-n-propyl-4-methyl-6-(l'-methylbenzimidazol-2, -yl)benzimidazoie<br />compound of the formula (II) with 4'-(bromomethyl)-[l,l'-biphenyl]-2-carbonitrile compound of the formula (III) in presence of solvent or mixture of solvents (dimethylacetamide), optionally in the presence of an acid -binding agent such as potassium tert-butoxide or potassium hydroxide at a temperature range 0°C to 20°C, to obtain 2-cyano-4'-[2"-n-propyl-4,,-methyl-6"-(l'"-methylbenzimidazol-2'"-yl)benzimidazol-1"-ylmethyl ]biphenyl , cyanotelmisartan compound of the formula (IV).<br />b) hydrolysis of cyanotelmisartan compound of the formula (IV) is carried out in presence solvent selected form water, an organic solvents or mixture thereof (such as ethylene glycol/water) in presence of an acid or a base at temperature between 140°C to 200°C.<br />c) distilled off the solvent from reaction mixture and residue is diluted with water and in hydrochloride acid to obtained Telmisartan hydrochloride is further dissolved in acetic acid and then NaOH is added drop wise at 80°C to 90°C and Telmisartan free base is filtered off.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />U.S. patent application no. 2006/0264491 describes process for preparation of Telmisartan. which includes, hydrolysis of 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-1'-yl)methyl]-[l,1'-biphenyl]-2-carboxamide compound of the formula (V) in presence of potassium hydroxide in propylene glycol at temperature at about 150°C.<br /><br />EP2277866 Al discloses a process for preparing Telmisartan from 2-cyano-4;-[2"-n-propyl-4"-methyl-6"-(1"-methylbenzimidazol-2"'-yl) benzimidazol-l"-yl methyl] biphenyl compound of the formula (IV) using 60% NaOH in n-butanol in presence of phase transfer catalyst i.e. tetra butyl ammonium hydrogen sulphate at 115-120°C for 22h.<br /><br />EP2443094B1/WO2010/146187A2 describes a process for the synthesis of Telmisartan from cyano Telmisartan and carboxamido telmisartan using 1:1 sulphuric acid at 125°C for 30 h and 28 h respectively.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />The existing process requires very high temperature for 30 h or 28 h which limits its large scale application and invites safety risks too. In addition to this, formation of different kind of impurities takes place at 125°C.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />Chinese patent application CN 1412183A describes the process for preparation of Telmisartan which includes reacting compound of the formula (II) with compound of the formula (111) in presence of organic base or inorganic base and reaction solvent to afford compound of the formula (IV). It also describes different hydrolysis conditions for compound of the formula (IV) such as,<br />a. a 1:2 volume ration of concentrated acetic acid: concentrated hydrochloric<br />acid refluxed for 24 hours at about 100°C<br />b. a 2:1 volume ration of ethanol: 2 M NaOH refluxed for 24 hours at about<br />100°C<br />c. a 1: 1.5 volume ration of sodium ethanolate in glycol: water refluxed for 24<br />hours and finally obtained Telmisartan is crystallization with N, N-<br />dimethylformamide (DMF).</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />Chinese patent application CN102070534A discloses a process for preparation of 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1"-methylbenzimidazol-2'"-yl) benzimidazol-1"-ylmethyl ]biphenyl compound of the formula (IV) which includes reacting compound of the formula (II) with compound of the formula (III) under the effect of phase transfer catalyst and inorganic base in the presence of low boiling organic solvents at temperature rang in between 0°C-10oC.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />WO 2007/147889 discloses the process for preparation of Telmisartan by hydrolyzing compound of the formula (IV) by addition of water and conc. HC1 heated at reflux temperature for 136 hours and then cooled reaction mixture at room temperature and add 1M NaOH to adjust pH to about 5 to 7. The product is filtered, wash and dried to obtain Telmisartan.<br />The disclosed process in WO '889 is time intensive besides corrosive and hazardous reaction condition.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />U.S. patent no. 5,591,762 teaches the hydrolysis of cyanotelmisartan compound of the formula (IV) using trifluroacetic acid in dimethyl formamide and is not eco-friendly. It involves long time for hydrolysis. Separation of Telmisartan using silica gel column chromatography results into lower yields. Further the preparation of tert. Butyl ester of Telmisartan is relatively expensive method.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />U.S. Patent no. 7,193,089 is silent about the purity of the free Telmisartan. The solvents used such as dimethyl acetamide and ethylene glycol have a boiling point greater than about 140°C. These solvents are difficult to remove from the reaction using various evaporation techniques known in the art. These reaction conditions are hazardous and far from being environmental friendly. The process is carried out at very high temperature. Removal of residual solvents from reaction mixture, using various evaporation techniques is tedious and difficult.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />U.S. patent application no. 2006/0264491 describes a process in which, an expensive solvent is used. Reactions are carried out at very high temperatures which itself is very difficult to maintain at plant scale manufacturing. These process conditions discourage use of this process.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />Process disclosed by EP2277866A1 requires high temperature and longer time to complete the reaction which invites safety risks. Use of lower temperatures substantially impacts on yield. Moreover the isolation procedure from n-butanol to get crude telmisartan is very tedious.<br /><br />Process disclosed by WO 2010/146187A2 requires very high temperature for longer durations. It limits its application for large scale production. It also invites safety risks. The process leads to formation of different kind of impurities at 125°C. Carrying out reaction at elevated temperatures is not easy and not advisable. Use of lower temperatures substantially impacts yield.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />Chinese patent application CN1412183A describes conditions that required long time for hydrolysis and results in lower yields. Moreover ethylene glycol and DMF are high boiling solvent so it will be very difficult to recover and reuse.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />CN102070534A teaches a reaction which is carried out at a temperature range of 0-10°C, a range which is difficult and energy intensive. Industry will welcome a reaction which is carried out at ambient temperatures and yet having shorter durations. Besides this inconvenient temperature range the reaction necessitates low boiling solvents and thereby restricts selection range of solvents.</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />Therefore the processes taught by prior patents and prior art disclosures have several drawback's namely expensive nature, not suitable for scale up at plant level, energy intensive, difficult, giving lower yields, forcing use of corrosive acids, longer duration of corrosive reaction and less user friendly.<br />Therefore industry strongly needs a process that is simpler, financially cheaper and energy economic process, an environment friendly process that does not use hygroscopic and pyrophoric chemicals. Industry needs a process to produce Telmisartan that can be carried out at lower temperatures yet giving good yields, a process that has improved carbon efficiency and is free from hazards and draw backs of prior art.<br /></span></b><br /><br /><br /><b><span style="color: #006666;">EXAMPLE -8:<br />Preparation of 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-bcnzimidazol)-r-yI)methyl]-<br />ll,l'-biphenyll-2-carboxyIic acid</span></b><br /><b><span style="color: #006666; font-size: 11pt;"><br />100 gm of 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1"-methylbenzimidazol-2'"-yl) benz-imidazol-1'-ylmethyl] biphenyl and 550 mL 80% sulfuric acid, were heated to 80°C-85° C. The reaction mixture stirred for 8-10 h at this temperature. Water (500 mL) was added at the same temperature and the reaction mixture was stirred for 15-20 h and reaction was completed at 120-130 C. </span></b><br /><b><span style="color: #006666; font-size: 11pt;">The reaction was then cooled to 20-25 C. pH of mixture was adjusted tol2 by adding 40% NaOH solution. After that 500 ml of n-Butanol were added and separated out layers. The oily residue thus obtain after distillation was dissolved in 500 mL of water to get clear solution. The aqueous layer was washed with<br /><br />distillation of methylene dichloride was added in 300 mL of acetone. Suck dry the wet cake.<br />Wet cake was directly charged in a reaction assembly containing 900 mL 30% sulfuric acid solution. </span><span style="color: #c00000; font-size: 11pt;">NaN02 solution </span><span style="color: #006666; font-size: 11pt;">(48.75 gm, 0.7 moles in 200 ml water) was added drop wise and the temperature of the reaction mass was kept at 25-50 C. </span></b><br /><b><span style="color: #006666; font-size: 11pt;">The reaction was then heated to 45°C-50°C and maintained for 2-5 h and then cooled to 20-25° C. pH of mixture was adjusted to 12 by adding 40% NaOH solution. After that 500 ml of n-Butanol were added and separated out layers. </span></b><br /><b><span style="color: #006666; font-size: 11pt;">The oily residue thus obtain after distillation was dissolved in 700 mL of methanol and 15 mL of ammonia followed by charcolization. pH of the filtrate was adjusted to 4-5 using acetic acid. Solid obtained was filtered and washed with methanol (100 mL) and dried at 60-65 °C. The solid was then treated with water (500 mL) at 40-45 °C for 3h to remove inorganic matters and then dried at 60-65 °C for 10 h. </span></b><br /><b><span style="color: #006666; font-size: 11pt;">The solid thus obtain was treated with methanol (1000 mL) at 60-65 °C for 8-10 h and then filtered to get pure </span><span style="color: #c00000; font-size: 11pt;">Telmisartan.</span><span style="color: #006666; font-size: 11pt;">The product obtained was then dried at 60-65 °C to get 73 gm (yield 75.9 %) of compound (I) having purity > 99.7 % by HPLC</span></b><br /><b><span style="color: #006666; font-size: 11pt;">........................................................................ </span></b><br /><br /><br /><br /><span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">Reddy, Kikkuru Srirami; Srinivasan, Neti; Reddy, Chinta Raveendra; Kolla, Naveenkumar; Anjaneyulu, Yerremilli; Venkatraman, Sundaram; Bhattacharya, Apurba; Mathad, Vijayavitthal T. Organic Process Research and Development, 2007 , vol. 11, # 1 p. 81 - 85</span></div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">LEK PHARMACEUTICALS D.D. Patent: WO2006/103068 A1, 2006 ; Location in patent: Page/Page column 11; 18 ; WO 2006/103068 A1</span></div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">Boehringer Ingelheim International GmbH Patent: US2004/236113 A1, 2004 ; Location in patent: Page 6 ;</span></div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"><br /></span><span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">Chemo Iberica, S.A. Patent: EP2123648 A1, 2009 ; Location in patent: Page/Page column 13 ;</span></div>
<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"><br /></span><span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">Venugopal; Ramanatham; Devanna; Sanjeev Kumar; Ghosh, Samir; Soundararajan; Kale, Bhima; Mehta Asian Journal of Chemistry, 2010 , vol. 22, # 4 p. 2767 - 2773</span><br /><span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"><br /></span><span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;"><br /></span><br /><div class="patent-section patent-tabular-section" style="clear: both; color: #333333; font-family: Arial, sans-serif; font-size: 13.2799997329712px; line-height: 18px; margin-top: 20px;">
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<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2000027397A1?cl=en" style="color: #6611cc; text-decoration: none;">WO2000027397A1</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">6 Nov 1998</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">18 May 2000</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Boehringer Ingelheim Int</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Antihypertensive medicaments containing lacidipine and telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2004087676A1?cl=en" style="color: #6611cc; text-decoration: none;">WO2004087676A1</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">26 Mar 2004</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">14 Oct 2004</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Boehringer Ingelheim Int</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Method for the production of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/EP0502314A1?cl=en" style="color: #6611cc; text-decoration: none;">EP0502314A1</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">31 Jan 1992</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">9 Sep 1992</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Dr. Karl Thomae GmbH</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Benzimidazol, medicaments containing them and process for their preparation</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/US6358986" style="color: #6611cc; text-decoration: none;">US6358986</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">10 Jan 2000</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">19 Mar 2002</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Boehringer Ingelheim Pharma Kg</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Polymorphs of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/US20020094997" style="color: #6611cc; text-decoration: none;">US20020094997</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">16 Nov 2001</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">18 Jul 2002</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Heinrich Schneider</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Polymorphs of telmisartan</td></tr>
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<tr class="patent-data-table" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; border-collapse: collapse; margin-left: 18px; margin-top: 10px;"><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Citing Patent</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Filing date</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Publication date</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Applicant</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Title</th></tr>
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<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2006136916A2?cl=en" style="color: #6611cc; text-decoration: none;">WO2006136916A2</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">20 Jun 2006</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">28 Dec 2006</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Glenmark Pharmaceuticals Ltd</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Substantially pure micronized particles of telmisartan and pharmaceutical compositions containing same</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2009006860A2?cl=en" style="color: #6611cc; text-decoration: none;">WO2009006860A2</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">8 Jul 2008</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">15 Jan 2009</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Zentiva As</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">A method of manufacturing 4'-[[4-methyl-6-(1-methyl-1h-benzimidazol-2-yl)-2-propyl-1h-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid (telmisartan)</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2009123483A1?cl=en" style="color: #6611cc; text-decoration: none;">WO2009123483A1</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">30 Mar 2009</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">8 Oct 2009</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Zaklady Farmaceutyczne Polpharma Sa</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Process for preparation of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2010018441A2?cl=en" style="color: #6611cc; text-decoration: none;">WO2010018441A2</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">10 Aug 2009</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">18 Feb 2010</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Cadila Pharmaceuticals Ltd.</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">An improved process for the preparation of substantially pure telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2010053233A1?cl=en" style="color: #6611cc; text-decoration: none;">WO2010053233A1</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">6 Mar 2009</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">14 May 2010</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Chong Kun Dang Pharmaceutical Corp.</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">The new telmisartan zinc salt and the preparation thereof</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2010146187A2?cl=en" style="color: #6611cc; text-decoration: none;">WO2010146187A2</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">21 Jun 2010</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">23 Dec 2010</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Krka, Tovarna Zdravil, D.D., Novo Mesto</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Process for the preparation of telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2011102645A2?cl=en" style="color: #6611cc; text-decoration: none;">WO2011102645A2</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">17 Feb 2011</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">25 Aug 2011</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Dong Wha Pharm. Co., Ltd.</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">An improved process for preparing telmisartan</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2012055941A1?cl=en" style="color: #6611cc; text-decoration: none;">WO2012055941A1</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">26 Oct 2011</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">3 May 2012</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Krka,Tovarna Zdravil, D. D., Novo Mesto</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Multilayer pharmaceutical composition comprising telmisartan and amlodipine</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/CN101172968B?cl=en" style="color: #6611cc; text-decoration: none;">CN101172968B</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">1 Nov 2006</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">12 May 2010</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">浙江天宇药业有限公司</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">2-propyl-4 methyl-6-(tolimidazole-2group) benzoglioxaline salt and method for producing the same</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/EP2123648A1?cl=en" style="color: #6611cc; text-decoration: none;">EP2123648A1</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">20 May 2008</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">25 Nov 2009</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Chemo Ibérica, S.A.</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">A process for the preparation of Telmisartan.</td></tr>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-7082350141827122272.post-43631313829348850642015-03-29T01:02:00.000-07:002015-03-29T01:02:00.426-07:00SAXAGLIPTIN<div dir="ltr" style="text-align: left;" trbidi="on">
<img height="246" src="http://upload.wikimedia.org/wikipedia/commons/thumb/7/79/Saxagliptin.svg/2000px-Saxagliptin.svg.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; padding: 8px;" width="400" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">SAXAGLIPTIN</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br />
<table class="mb_l_mb_r_tb pinfo" data-xc="N#C[C@@H]1C[C@H]2[C@@H](N1C(=O)[C@H]([C@]13C[C@@H]4C[C@H](C1)C[C@](C3)(C4)O)N)C2" style="background-color: white; border-collapse: collapse; border-spacing: 0px; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px; margin: 0px 0px 30px; padding: 0px; width: 667px;"><tbody>
<tr><td class="na" colspan="2" id="listnam_0" style="border: 1px solid rgb(187, 187, 187); color: #3f75bf; font-size: 18px; font-weight: bold; height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; word-break: break-all; word-wrap: break-word;">Saxagliptin</td></tr>
<tr class="bg" style="background-color: #f2f2f2;"><th style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; width: 150px;">CAS No.:</th><td style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px; text-indent: 4px;">361442-04-8</td></tr>
<tr><th style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; width: 150px;">Synonyms:</th><td style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px; text-indent: 4px;"><div class="synonyms" style="position: relative; z-index: 1;">
<ul class="mb_l_mb_r_tb_otn" id="synonyms_ul" style="line-height: 1.4; list-style: none outside none; margin: 0px; padding: 0px;">
<li style="border: none; margin: 0px; padding: 0px 0px 0px 4px; text-indent: 0px; word-break: break-all; word-wrap: break-word;">Saxagliptin 15ND2;</li>
<li style="border: none; margin: 0px; padding: 0px 0px 0px 4px; text-indent: 0px; word-break: break-all; word-wrap: break-word;">Onglyza;</li>
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</td></tr>
<tr class="bg" style="background-color: #f2f2f2;"><th style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; width: 150px;">Formula:</th><td style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px; text-indent: 4px;">C18H25N3O2</td></tr>
<tr><th style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; width: 150px;">Exact Mass:</th><td style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px; text-indent: 4px;">315.19500</td></tr>
<tr class="bg" style="background-color: #f2f2f2;"><th style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px 0px 0px 10px; text-indent: 4px; width: 150px;">Molecular Weight:</th><td style="border: 1px solid rgb(187, 187, 187); height: 30px; margin: 0px; padding: 0px; text-indent: 4px;">315.41000</td></tr>
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<span id="ctl00_ctl00_ContentSection_ContentPlaceHolder1_RecordViewControl1_formview_WrapControl2">C1[C@@H]2C[C@@H]2N([C@@H]1C#N)C(=O)[C@H](C34CC5CC(C3)CC(C5)(C4)O)<wbr></wbr>N</span><br /><br />13c nmr predict<br /><div class="separator" style="clear: both; text-align: center;">
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<div num="p-0004" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;">
Saxagliptin, (1S,3S,5S)-2-(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)-acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile of the following chemical structure:</div>
<div num="p-0005" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;">
<chemistry id="CHEM-US-00001" num="00001"></chemistry></div>
<div class="patent-image" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px; text-align: center;">
<a href="http://patentimages.storage.googleapis.com/US8410288B2/US08410288-20130402-C00001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure US08410288-20130402-C00001" class="patent-full-image" file="US08410288-20130402-C00001.TIF" he="25.06mm" height="100" id="EMI-C00001" img-content="chem" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/US8410288B2/US08410288-20130402-C00001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="43.43mm" width="173" /></a></div>
<attachments style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"><attachment attachment-type="cdx" file="US08410288-20130402-C00001.CDX" idref="CHEM-US-00001"></attachment><attachment attachment-type="mol" file="US08410288-20130402-C00001.MOL" idref="CHEM-US-00001"></attachment></attachments><span style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"></span><br style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;" /><span style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;">is a dipeptidyl peptidase IV (DPP4) inhibitor. Saxagliptin is marketed under the trade name ONGLYZA® by Bristol-Myers Squibb for the treatment of type 2 diabetes.</span><br />
<div style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;">
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<div num="p-0006" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;">
Saxagliptin and its hydrochloride and trifluoroacetic acid salts are disclosed in U.S. Pat. No. 6,395,767. In addition, U.S. Pat. No. 7,420,079 discloses Saxagliptin and its hydrochloride, trifluoroacetic acid and benzoate salts, as well as Saxagliptin monohydrate.</div>
<div num="p-0007" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;">
U.S. 2009/054303 and the corresponding WO 2008/131149 application disclose several crystalline forms of Saxagliptin and of Saxagliptin salts. The crystalline forms of Saxagliptin reported in that patent application are a monohydrate (denoted there as form H-1), a hemihydrate (denoted there as form H0.5-2), a dihydrate (denoted form H2-1) and an anhydrous form (denoted there as N-3).</div>
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WO 2005/117841 (the '841 application) describes the cyclization of Saxagliptin to form the therapeutically inactive cyclic amidine. The '841 application reports that such cyclization can occur both in solid state and solution state.</div>
<div num="p-0009" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;">
WO 2010/115974 discloses Forms: I-S, HT-S, IV-S, and HT-IV-S of Saxagliptin hydrochloride.</div>
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<cite>Org. Process Res. Dev.</cite>, <span class="citation_year" style="font-weight: bold;">2009</span>, <span class="citation_volume" style="font-style: italic;">13</span> (6), pp 1169–1176</div>
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<strong>DOI: </strong>10.1021/op900226j</div>
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<span style="font-family: Helvetica, Arial, sans-serif;"><span style="font-size: 14.3999996185303px; line-height: 16.6399993896484px;"><a href="http://pubs.acs.org/doi/abs/10.1021/op900226j" style="color: #6c1b00; text-decoration: none;">http://pubs.acs.org/doi/abs/10.1021/op900226j</a></span></span></div>
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<img alt="Abstract Image" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2009/oprdfk.2009.13.issue-6/op900226j/production/images/medium/op-2009-00226j_0002.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; max-width: 570px; padding: 8px;" /></div>
<div class="articleBody_abstractText" style="font-size: 14px; line-height: 1.6em; margin-bottom: 1.5em; margin-left: 7px; margin-right: 7px; padding: 0pt; width: auto; word-wrap: break-word;" xmlns:acs="http://namespace.acs.org/2008/acs" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance">
The commercial-scale synthesis of the DPP-IV inhibitor, saxagliptin (<b>1</b>), is described from the two unnatural amino acid derivatives <b>2</b> and <b>3</b>. After the deprotection of <b>3</b>, the core of <b>1</b> is formed by the amide coupling of amino acid <b>2</b> and methanoprolinamide <b>4</b>. Subsequent dehydration of the primary amide and deprotection of the amine affords saxagliptin, <b>1</b>. While acid salts of saxagliptin have proven to be stable in solution, synthesis of the desired free base monohydrate was challenging due to the thermodynamically favorable conversion of the free amine to the six-membered cyclic amidine <b>9</b>. Significant process modifications were made late in development to enhance process robustness in preparation for the transition to commercial manufacturing. The impetus and rationale for those changes are explained herein.</div>
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Monohydrate 1 was isolated as a white solid (58.2 kg, 88%). </div>
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1 H NMR (400 MHz, CD2Cl2- d6) δ 5.25 (dd, J1 ) J2 ) 1.0 Hz, 1H), 4.93 (dd, J1 ) 10.6 Hz, J2 ) 2.3 Hz, 1H), 3.55-3.50 (m, 1H), 3,35 (s, 1H), 2.45 (ddd, J1 ) 16.1 Hz, J2 ) 10.9 Hz, J3 ) 5.6 Hz, 1H), 2.25 (dd, J1 ) 13.6 Hz, J2 ) 2.5 Hz, 1H), 2.18-2.10 (m, 2H), 1.83-1.42 (m, 15H), 1.40-1.27 (m, 3H) 1.0-0.87 (m, 2H) </div>
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13C NMR (100 MHz, CD2Cl2) δ 173.43, 120.15, 68.83, 60.90, 46.57, 45.51, 45.08, 45.01, 41.62, 38.15, 37.92, 37.35, 35.88, 30.98, 30.93, 30.80, 18.00, 13.69. </div>
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MS (FAB) m/z 316 [M + H]+</div>
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1H NMR PREDICT</div>
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<img alt="Saxagliptin NMR spectra analysis, Chemical CAS NO. 361442-04-8 NMR spectral analysis, Saxagliptin H-NMR spectrum" height="556" src="http://pic11.molbase.net/nmr/nmr_image/2014-07-26/000/198/461/361442-04-8-1h.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /></div>
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<span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">13C NMR PREDICT</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><img alt="Saxagliptin NMR spectra analysis, Chemical CAS NO. 361442-04-8 NMR spectral analysis, Saxagliptin C-NMR spectrum" height="543" src="http://pic11.molbase.net/nmr/nmr_image/2014-07-26/000/198/461/361442-04-8-13c.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; padding: 8px;" width="640" /><br />
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<tr><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;"><br /><br />..................<br /><br /><a href="http://www.google.com/patents/WO2012162507A1?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.com/patents/WO2012162507A1?cl=en</a><br /><div num="p0008" style="color: #222222; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
two amino acid derivatives (A) and (B), described in further detail hereinbelow, coupled in the presence of a coupling reagent. The amide coupling of (S)-a[[(l,l-dimethyleethoxy)carbonyl]amino]-3- hydroxytricyclo [3.3.1.1]decane-l-acetic acid (A) and (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3- carboxamide (B), subsequent dehydration of the primary amide and deprotection of the amine affords saxagliptin (C).</div>
<div num="p0009" style="color: #222222; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2012162507A1/imgf000002_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000002_0001" class="patent-full-image" file="imgf000002_0001.tif" he="42" height="168" id="imgf000002_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2012162507A1/imgf000002_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="155" width="620" /></a></div>
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synthetic route is disclosed as follows:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2012162507A1/imgf000011_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000011_0001" class="patent-full-image" file="imgf000011_0001.tif" he="105" height="420" id="imgf000011_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2012162507A1/imgf000011_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="148" width="592" /></a></div>
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<img alt="Figure imgf000012_0001" height="276" src="http://patentimages.storage.googleapis.com/WO2012162507A1/imgf000012_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /></div>
<br /><div num="p0105" style="color: #222222; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Scheme-IV</div>
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<a href="http://patentimages.storage.googleapis.com/WO2012162507A1/imgf000015_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000015_0001" class="patent-full-image" file="imgf000015_0001.tif" he="187" height="748" id="imgf000015_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2012162507A1/imgf000015_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="158" width="632" /></a></div>
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<div num="p0118" style="font-size: 13.3333330154419px; line-height: 21.3333339691162px; text-align: start;">
Scheme-V</div>
<div num="p0119" style="font-size: 13.3333330154419px; line-height: 21.3333339691162px; text-align: start;">
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<a href="http://patentimages.storage.googleapis.com/WO2012162507A1/imgf000016_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000016_0001" class="patent-full-image" file="imgf000016_0001.tif" he="25" height="100" id="imgf000016_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2012162507A1/imgf000016_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="165" width="660" /></a></div>
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<br /></div>
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<img alt="Figure imgf000017_0001" height="615" src="http://patentimages.storage.googleapis.com/WO2012162507A1/imgf000017_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /></div>
<div class="patent-image" style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<br /></div>
</div>
<br /><br />..................<br /><br /><img height="416" src="http://www.orientjchem.org/wp-content/uploads/2014/03/Vol30_No1_Efficient_Prabha_schem1.jpg" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /><br /><br /><br /><br /><br /><br />.................<br /><br /><img src="https://journals.prous.com/journals/dof/20083307/html/df330577/images/sch01.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><br /><br /><br /><br />.............<br /><br /><img src="http://www.eurekaselect.com/images/graphical-abstract/loc/11/QUICKTRACK/009AN.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><br /><br /><br /><br /><img height="276" src="http://patentimages.storage.googleapis.com/WO2012162507A1/imgf000012_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" width="640" /><br /><br /><br /><br /><br /><br />Savage, Scott A., et al., "<a href="http://scholar.google.com/scholar?q=%22Preparation+of+Saxagliptin%2C+a+Novel+DPP-IV+Inhibitor%22" style="color: #6611cc; text-decoration: none;">Preparation of Saxagliptin, a Novel DPP-IV Inhibitor</a>", Organic Process Research & Development, 2009, vol. 13, pp. 1169-1176.</td></tr>
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<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/US7470810" style="color: #6611cc; text-decoration: none;">US7470810</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">11 Jan 2005</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">30 Dec 2008</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Bristol-Myers Squibb Company</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Such as 1-dodecane-thiotrifluoroacetate; alkyl/arylthiol is treated with trifluoroacetic anhydride in presence of pyridine, solvent (dichloromethane), and dimethylaminopyridine (DMAP) as catalyst; for protection of amino acids</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/US7741082" style="color: #6611cc; text-decoration: none;">US7741082</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">12 Apr 2005</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">22 Jun 2010</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Bristol-Myers Squibb Company</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Process for preparing dipeptidyl peptidase IV inhibitors and intermediates therefor</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/US7943656" style="color: #6611cc; text-decoration: none;">US7943656</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">18 Apr 2008</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">17 May 2011</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Bristol-Myers Squibb Company</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Crystal forms of saxagliptin and processes for preparing same</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/US20060035954" style="color: #6611cc; text-decoration: none;">US20060035954</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">8 Aug 2005</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">16 Feb 2006</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Sharma Padam N</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Ammonolysis process for the preparation of intermediates for DPP IV inhibitors</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2001068603A2?cl=en" style="color: #6611cc; text-decoration: none;">WO2001068603A2</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">5 Mar 2001</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">20 Sep 2001</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Bristol Myers Squibb Co</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl iv, processes for their preparation, and their use</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2008131149A2?cl=en" style="color: #6611cc; text-decoration: none;">WO2008131149A2</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">18 Apr 2008</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">30 Oct 2008</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Squibb Bristol Myers Co</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Crystal forms of saxagliptin and processes for preparing same</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2010115974A1?cl=en" style="color: #6611cc; text-decoration: none;">WO2010115974A1</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">9 Apr 2010</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">14 Oct 2010</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Sandoz Ag</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Crystal forms of saxagliptin</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/WO2011140328A1?cl=en" style="color: #6611cc; text-decoration: none;">WO2011140328A1</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">5 May 2011</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">10 Nov 2011</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Teva Pharmaceutical Industries Ltd.</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof</td></tr>
</tbody></table>
</span></div>
<div class="patent-section-header" style="margin-bottom: 1em;">
<span class="patent-section-title" style="color: #454545; font-family: 'Gill Sans', sans-serif; font-size: 12pt; font-stretch: normal; font-weight: bold; line-height: 16pt; text-transform: uppercase;"><br /></span></div>
<table class="patent-data-table" style="border-bottom-color: rgb(209, 209, 209); border-bottom-width: 2px; border-collapse: collapse; border-style: none none solid; margin: 10px 0px 0px 18px;"><thead class="patent-data-table-thead" style="color: #222222; font-size: 13px; font-stretch: normal; font-weight: bold; white-space: nowrap;">
<tr class="patent-data-table" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; border-collapse: collapse; margin-left: 18px; margin-top: 10px;"><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Citing Patent</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Filing date</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Publication date</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Applicant</th><th class="patent-data-table-th" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 2px; padding-right: 25px;">Title</th></tr>
</thead><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/US8748631" style="color: #6611cc; text-decoration: none;">US8748631</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">24 May 2012</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">10 Jun 2014</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Apicore, Llc</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.co.in/patents/US20130023671" style="color: #6611cc; text-decoration: none;">US20130023671</a><span aria-label="Cited by examiner" class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner" style="cursor: default;"> *</span></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">24 May 2012</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">24 Jan 2013</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Apicore, Llc</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof<br /><br /></td></tr>
</tbody></table>
</div>
<heading style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;">REFERENCES</heading><span style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px;"></span><br />
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<ul style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333320617676px; margin: 0.5em 0px; padding: 0px 2.5em;">
<li id="ul0019-0001" num="0066" style="border: none; margin: 0px 0px 0.25em; padding: 0px;">1. Scott A. Savage, Gregory S. Jones, Sergei Kolotuchin, Shelly Ann Ramrattan, Truc Vu, and Rebert E. Waltermire (2009) Preparation of Saxagliptin, a Novel DPP-IV Inhibitor, Organic Process Research & Development., 13, 1169-1176.</li>
<li id="ul0019-0002" num="0067" style="border: none; margin: 0px 0px 0.25em; padding: 0px;">2. Santosh K. Sing, Narendra Manne and Manojit Pal, (2008) Synthesis of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile: A key intermediate for dipeptidyl peptidase IV inhibitors. Beilstein Journal of Organic Chemistry, 4, No. 20.</li>
<li id="ul0019-0003" num="0068" style="border: none; margin: 0px 0px 0.25em; padding: 0px;">3. U.S. Pat. No. (2010) 0274025 A1.</li>
<li id="ul0019-0004" num="0069" style="border: none; margin: 0px 0px 0.25em; padding: 0px;">4. U.S. Pat. No. (2006) 0035954 A1.</li>
<li id="ul0019-0005" num="0070" style="border: none; margin: 0px 0px 0.25em; padding: 0px;">5. U.S. Pat. No. (2005) 0090539 A1.</li>
<li id="ul0019-0006" num="0071" style="border: none; margin: 0px 0px 0.25em; padding: 0px;">6. Organic letters. (2001) Vol. 3, No.5, Page: 759-762</li>
<li id="ul0019-0007" num="0072" style="border: none; margin: 0px 0px 0.25em; padding: 0px;">7. Tetrahedron 59 (2003) 2953-2989</li>
</ul>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-7082350141827122272.post-44624589464941953252015-03-29T00:57:00.002-07:002015-03-29T00:57:32.321-07:00TELAPREVIR<div dir="ltr" style="text-align: left;" trbidi="on">
<img height="392" src="http://upload.wikimedia.org/wikipedia/commons/4/4d/Telaprevir.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; padding: 8px;" width="640" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">TELAPREVIR</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">MF C36H53N7O6</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"> MolWeight: 679.85</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">CAS No.: 402957-28-2</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">NMR..........</span><a href="http://www.abmole.com/download/vx-950-hnmr.pdf" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://www.abmole.com/download/vx-950-hnmr.pdf</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">AND</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="http://file.selleckchem.com/downloads/nmr/S153802-Telaprevir-NMR-Selleck.pdf" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://file.selleckchem.com/downloads/nmr/S153802-Telaprevir-NMR-Selleck.pdf</a><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1H NMR</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br />
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13C NMR</div>
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YnVGiOUYcMn2RNY5nFUc89MpcnInAEcR7xDh7cZ2aYVPsL6CWEwdP7C/lE1WqMJaG+mcfgdj1K3wrZftNoP3PlOjwHR2lTsX7bd+4eC/vLePw1RwOqYIQd+u7ly9RI8TWrUyLKHULc2tdiAc2UX33ZNO490znmlNcOjXFpYQfKt/M00eopvTcqOQHvcEWl/C9IMSlgWzDv1+Y/WYC7SIHbXtXtlVu3cXvdDawsCw1OklTalJjo3Am9jlsN5zWtbeL8wRwM56Z22jscP0rb66A+BIl/C9KaD8SPRh7GcUjg/CQfAg/KHVDkPSRRJ3ufC17/Rkm9+BObLmv45FvzyiJsrZK0XZw2YkZRoOyM7O2vG7NfyE4IjLrmIAHE6WHjOc2x0yZb08KxudDU3jXTsg7/GXgpSe1FJOK5ZrYvG9fiK1cnss7FT9xOyh81QH/NMRGJJY7ySfWWcU2WmF4tp5cfYWldBLPshE6tJAZEslWAPESAhAFhaLaFpAEMbHkRLQCVPgPcynyOh/SQNRPE6y1g0zEr9pWHna49xGMnPhwkXQqzHTZa30BZuJbX+0v0tlKNah05DQesmwvWOGBXXWwS5bfoDa9jbjCpRNP6RVQ/arVlUHyF3P5Zf1JS4Rn6WOPLJkqonZX0UScMx4AeOvsP3mPV2xRTTrWb7tCmFH+pU3+SyhX28G0SipPA1masfynsg+AkrBORSWqxx8nTYeqGYhWzsN4QXt4gXt5y31B45V/Ewv6LeY2zq7gXxNXtZSwpAhQigXvkXjb0lhdpBr5FJtxIKjdfTQ8xymcoUzaE9ysmxuy0rWFZ2ZR9VP5YPiTcn2hg8BSpfR0KaHmwzt53vKK7QdmUZlAuLqnba1jcZhop3a+Uu7U2guGpl237lH2jylf09F+O2UulG2moJkDk1WBsNLIv2rc+AkGxjehT/D+pnG4rEtWdnc3Zjf+w7p13R1r0F7iw9yf1nTLHsgr7MYz3SLdSleMeouUBtGAAuQbad8naRMsxo0FSuTuysOYMX+JHEEeV/cSq+HB4a8+PrAUyNzHz1HvIomzRoVVO4iXEmIC3EK3sf1lqniAN+de8dof+eUihZsKJDisAtX4r30sQSCLX3EbviMho4m+51PcdDLa1SN6+Y1EgmzJrg0XK9awS1xnXPc6kgd9r+okbUM+hWk4sqHIzJ2QSQpTlYjdzItNOrQR2PaZWYWtu3KQNN5338pBisAbXyo4C2OhRzpqb338bH1k/YFvBrZFBBBygWNriw3G0h2jtGnh1zVDbkOJ8BM3avSBaCBUHbyjS97ac/1nDY/EvXbM5ufYeEYYSzP4evn/BTJlUPuXdt9IamKOUdml9kcfxSjgUu6D7y/OQqlpd2WP5q91z6Az0ljjjhUTk3OUrZ0NesWfuH6yanKmH115m8uIJwHYSqJIojVEkVYAoEI8CEALQtJMsLSARERLSQiNtAH4V8rqeRH95beqFNsiXBPaYZvY6e0ox1dS539/wD56yGSg2htkohJY2G4DQE8AANJxFSo1VixuzE3PHynU4rBrUIuC1tw4X52j6ez1HxEKOQsJ0Ypxxr6nHmxTyuvBzVDAsxtY3+yNTOj2NsbqznqDtD4V35e898vUWVRamp8h8zJBVO4kKfs/Ex8LfsZXJqJS4RbFpIQe58kvUrmzWGa1r7zblKOJ2UuX6zPcWzEsNTr2SbASzUcJq/Z5Gq4p/7d/osuoi8ST3KMvu2/0E53aOtU+jGqYdkTM7ABbk3YhdDpZUsJzmPevj6l6VN2QaKFUkAcydwneuEOpRTbi139m0v4CHWF/rnLwC2C+0mEqlu/BEo3wcdg+htY265kpDkWDt+Vb/Oa+Cw9OiGp0nNQK1mYgDtWFwLHcInSXaww65U+mYaHeVX7XjymX0Ubs1AeYPreb7pTjufRmlGMqRuERCsfaOCzMuQZIvVyyKccKcEFXq44U5aFOL1cAptSvviohX4SR4Ej2lvq4nVwCNcTUHEN+JR8xaZ+18RXdSKeUeZ9dd5mkaca1OUljjP9SJtnAYnA1QSXVieJ3yoRbfPRmpSvWwSt8Sg+InZHPXgweFfM4C8ubLHbPgR6kf3nRV9g0m3AjwMbg9hCmSQxPjLSzxcWiscTUhaKaS3TSTJhrSZac5DpI0SSBJKEjgsAjywkuWEATLDJJ8sTLIBXKyMiWWWV6sAYxtBKocd40Pfx/WVqrSHC1MtQd5Hvp+0hkl56LEjIcqjU6DXS1jm4cfSMx1ZKAz1CNbABVzMTbvIj6uIte3rObxlKrXbMRlX6ubl4b7zTFjUn8XRjnzOCqK5LdfpH9infvqNcflWw9bylU2xXcWD5FP1aYCA/l3yXC7FZu/vOi/3m5gtkpSIZu0w3X0A8B+86HLFj6RxKGoy9uijszZTUx1rp1lW4yqTYj7xJvr8po4rFVA+UbrAhURnYixuM24a+G6XetHDXw/fdFaqFF2IHiROSeRyds9DHiWNUjFL9ZzO+2dixBNwOwl9NftfVHndxO1Vw1AMfi1CruOhIAtfQDSIGpgHKrVCbjjY6g21svATGxOxKld81QhV4Iu4X1le3T6LN0uDnMRimquXc3Ym5nQ9FN7juHsZdwvRymu8XPfNvC4VaY7IA8BOqWSO3bFcGUYNO2wSjLmz8J1lWnTJsHdVJ5AnWNCy/sJf/AJNH8d/RSZzs1NnGbIwlNsgFRmAuf5ira/iN+kip7Kw5IBWoL6aVkJ9LTP6R1KP8Q/XVGQ2FgL9++VdnvhlqIadVmfOtgwJF77zczPczdQjtOpfopRIBQub23svHyiYroxh6a3LVNBuDLw7yJsUDZF4aLp5iZPSjEqinOewyFW37iyi4txi2UUVZlDZdHlU/1aX7S/gOjmHrKWV6uhKkEpoRv3Ccugwg/wAd/wDd+86vodYI5ViylrgnxI3ekWy8oRS4GN0WpAXLOOJ1U/pM19j07nLnIBIv1lMbu606vEVQqMTqo3+GaeeVkwbuzM7KzMSQua178NY3MiEU+zaw2xKNRurJqI5XMpujA+gnOPRsSORI9DabfR1KArA0WZ7Wve4sDpx38JVx9K1asOVWp7uTLxbKTST4Ms0YClLpSJklihU6uL1ctZImSAQBIZJPlhlgEOSEmywgDLRCI+JaQCNllaqkukSN0gGRWpzPxNxqN41nQVKN5Vq4DNAFZgRpYLa992+QU3QrmXteNwN/eJN/CvYDMAAAN1z7xVwA+tdvxG/tukcikRNivvjwQZj/AGirmJuqHuNRv+Il1KQG4RwEULKwoO3xPbuQZfffHU8EoN7XPM6n1MsgRbSQMC2jwkcFjwJIGrTkoWCx4EAAI+jUamyuhAdTcXFxusbjwMQRYBLjsYcQQa+Hw1QjQFla9uV7yPCOlFw9LCYZXG4gNp4QvC8ikTbNB+kWJP1aXq8bW25WqLlqUqLrybNM2vVygm17cpB/69h+JYf5TIdItFN+SU4aj/8ARw/k9QTUpberU1C0qFFEG5VZgPlMQ7YS+YBjSvqbfpJDt7Dcz6GRwWUG/Jr/APuTE/8AbpcfrNx8pmV2RyWbA4Ysd5zMPYCFDEioLrfLwvJM0mkUtokwO1Hw+lHCUKd+Ks37RpqM7M72zsSTbdryjc0Lyaoq22KREtC8LyQFoloXhAEIhaLCAJaEWJIAgSLkkkIAzJDJHwgEZpxOrksIBCacYaUsERpgEHVxOqk9olpJBF1cdkkkIBHkjgsfaEgkaFjhFhJAWhaPhAGWi2jokAS0jOGQ71HpJrwgDBSAFrC3hGfwifZHpJxFBkAYEsNBEyycGNMkEWWJlksaYAy0AI+EAZaFo6EAbaFosJAEtCLCALCEJJARIsIAQhCAEbCEEiQhCQAiwhACEIQBYQhAHRIsJICJCEAIRYQBIsIQBYXhCAEbeLCQBIRYQBIkIQAhCEASEIQD/9k=" 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<i><strong>Chem. Commun.</strong></i>, 2010,<span style="padding-right: 2px;"></span><strong>46</strong>, 7918-7920</div>
<br style="background-color: white; color: #cd0066; font-family: Arial, Helvetica, sans-serif; font-size: 12px; line-height: 20px;" /><span class="DOILink" style="background-color: white; color: #cd0066; float: left; font-family: Arial, Helvetica, sans-serif; font-size: 12px; line-height: 20px; padding: 0px; width: 505px;"><strong>DOI: </strong>10.1039/C0CC02823A</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><a href="http://pubs.rsc.org/en/Content/ArticleLanding/2010/CC/c0cc02823a#!divAbstract" style="background-color: #e5fff8; color: #6c1b00; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px; text-decoration: none;">http://pubs.rsc.org/en/Content/ArticleLanding/2010/CC/c0cc02823a#!divAbstract</a><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">'</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br />
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A very short and efficient synthesis of the important <annref idrefs="ann2">drug</annref> candidate telaprevir, featuring a biocatalytic desymmetrization and two multicomponent reactions as the key steps, is presented. The classical issue of lack of stereoselectivity in Ugi- and Passerini-type reactions is circumvented. The atom economic and convergent nature of the synthetic strategy require only very limited use of protective <annref idrefs="ann3">groups</annref>.</div>
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<img alt="Graphical abstract: A highly efficient synthesis of telaprevir by strategic use of biocatalysis and multicomponent reactions" id="imgGALoader" src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=C0CC02823A" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" title="Graphical abstract" /></div>
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<br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">Telaprevir (1). 250 l of saturated K2CO3 was added to a solution of 14 (0.514 g, 0.75 mmol) in MeOH (20 ml) at room temperature. The reaction mixture was stirred for 30 minutes at room temperature resulting in a pale yellow suspension. After full conversion (as judged by TLC analysis), the reaction mixture was washed with 20 ml brine, the aqueous layer was washed again with 10 ml CH2Cl2 (2x). The organic layers were collected, dried with MgSO4 and concentrated in vacuo, to yield a pale yellow solid. The yellow solid was dissolved in CH2Cl2 (10 ml) and Dess-Martin periodinane (0.650 g, 1.532 mmol) was added at room temperature. The reaction mixture was stirred overnight before adding saturated NaHCO3 solution (10 ml) and saturated Na2S2O3 solution (10 ml). This mixture was stirred for 10 minutes, separated and the aqueous layers were washed with EtOAc (2 x 10 ml). The organic layers were collected, dried with MgSO4 and concentrated in vacuo to give the crude product as an 83:13:4 mixture of diastereomers. After silica gel flash chromatography (1% MeOH in CH2Cl2), 1 (0.412 mg, 0.61 mmol, 80%) was obtained as a white solid.</span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: red; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">1H NMR (500.23 MHz, DMSO-d6): δ = 9.19 (d, J = 1.4 Hz, 1H), 8.91 (d, J = 24.5 Hz, 1H), 8.76 (dd, J = 1.5, 2.5 Hz, 1H), 8.71 (d, J = 5.3 Hz, 1H), 8.49 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 6.8 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 4.94 (m, 1H), 4.68 (dd, J = 6.5, 9.0 Hz, 1H), 4.53 (d, J = 9.0 Hz, 1H), 4.27 (d, J = 3.5 Hz, 1H), 3.74 (dd, J = 8.0, 10 Hz, 1H), 2.74 (m, 1H), 3.64 (d, J = 3.5 Hz, 1H), 0.92 (s, 9H), 0.87 (t, 3H), 0.84-1.40 (m, 23H), 0.65 (m, 2H), 0.56 (m, 2H); </span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: red; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"></span><span style="background-color: #e5fff8; color: red; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">13C NMR (125.78 MHz, CDCl3): δ = 197.0 (C), 171.8 (C), 170.4 (C), 169.0 (C), 162.1 (C), 161.9 (C), 147.9 (CH), 144.0 (C), 143.4 (CH), 56.4 (CH), 56.3 (CH), 54.2 (CH), 53.4 (CH), 42.3 (CH), 41.3 (CH), 32.1 (CH), 31.8 (CH), 31.6 (CH), 29.1 (CH), 28.0 (CH), 26.4 (CH3); </span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: red; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"></span><span style="background-color: #e5fff8; color: red; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">max (cm -1 ): 3302 (m), 2928 (m), 2858 (w), 1658 (s), 1620 (s), 1561 (s), 1442 (m); </span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><span style="background-color: #e5fff8; color: red; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><br /></span><span style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;"></span><span style="background-color: #e5fff8; color: red; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;">HRMS (ESI, 4500 V): m/z calcd. for C36H53N7O6Na + ([M + Na] + ) 702.3950, found 702.3941. </span><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><br style="background-color: #e5fff8; color: #cd0066; font-family: Georgia, Utopia, 'Palatino Linotype', Palatino, serif; font-size: 14.4899997711182px; line-height: 21.7350006103516px;" /><img src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/Articleimage/2012/MD/c2md20089a/c2md20089a-s45.gif" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; 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SYN</div>
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Reference:</h3>
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WO2011/103932 A1, ; Page/Page column 50; 51 ;</div>
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<img src="http://pic0.molbase.net/molpic/01/56/01567179.png?170x159" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /></div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">WO2011/103932 A1, ;</span></div>
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<img src="http://pic8.molbase.net/molpic/02/49/2493674.png?173x146" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" />AND <img src="http://pic2.molbase.net/molpic/01/56/01568955.png?350x159" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; font-size: 14.4899997711182px; line-height: 21.7350006103516px; padding: 8px;" /></div>
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<span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">WO2013/135870 A1, ;</span></div>
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<img src="http://pic1.molbase.net/molpic/02/46/2468672.png?297x300" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background: rgb(255, 255, 255); box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; padding: 8px;" /><span style="background-color: whitesmoke; color: black; font-family: tahoma, Arial, sans-serif, 宋体, sans-serif; font-size: 13px; line-height: 19.5px;">WO2013/135870 A1, ;</span></div>
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<a href="https://www.blogger.com/goog_708946535" style="color: #6c1b00; text-decoration: none;"><br /></a></div>
<span style="font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><a href="http://www.google.com.ar/patents/WO2011103932A1?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.com.ar/patents/WO2011103932A1?cl=en</a></span><br /><div num="p0138" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
t mpound XVIII,</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000023_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000023_0001" class="patent-full-image" file="imgf000023_0001.tif" he="45" height="180" id="imgf000023_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000023_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="89" width="356" /></a></div>
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(XVIII).</div>
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This compound, which also known as Telaprevir, could be prepared in higher yields and with higher efficiency than any previously disclosed processes. Furthermore, the chiral information used for the preparation was derived from readily available simple building blocks, making the process a highly effective approach to such prolyl dipeptides and similar peptidomimetics.</div>
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EXAMPLE 22</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000044_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000044_0001" class="patent-full-image" file="imgf000044_0001.tif" he="29" height="116" id="imgf000044_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000044_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="72" width="288" /></a></div>
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(5)-Methyl 2-cyclohexyl-2-(pyrazine-2-carboxamido)acetate (9).</div>
<div num="p0244" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Pyrazinecarboxylic acid (2.72 g, 21.9 mmol) was added to a solution of L- cyclohexylglycine methyl ester (4.13 g, 19.9 mmol) in CH<sub>2</sub>CI<sub>2</sub> (100 ml) at room temperature under N<sub>2</sub>, forming a white suspension. Triethylamine (6.33 ml, 4.62 g, 45.8 mmol) was added, followed by benzotriazol-l-yloxy-tris-(dimethylamino)- phosphonium hexafluorophosphate (BOP; 9.69 g, 21.9 mmol), which turned the reaction mixture from purple to an orange solution. After two days of stirring at room temperature the reaction mixture was washed two times with 50 ml saturated Na<sub>2</sub>CC>3, followed by the washing of the aqueous layers with CH<sub>2</sub>CI<sub>2</sub> (2 <sup>χ</sup> 50 ml). The organic layers were collected and dried with MgSC , followed by concentration in vacuo. Purification by silica gel flash chromatography (c-Hex:EtOAc = 2: 1 with 0.5% triethylamine) afforded 9 (5.28 g, 19.03 mmol, 96%) as a yellow oil that solidified upon standing to give a white solid.</div>
<div num="p0245" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[a f° = +42.5 (c= 1.13, CHC1<sub>3</sub>); *H NMR (250.13 MHz, CDCI3) δ = 9.39 (d, J= 1.25 Hz, 1H), 8.76 (d, J = 2.5 Hz, 1H), 8.57 (t, J = 1.5 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 4.74 (dd, J= 5.5, 9.3 Hz, 1H), 3.78 (s, 3H), 1.96 (m, 1H), 1.77 (m, 5H), 1.24 (m, 5H); <sup>13</sup>C NMR (62.90 MHz, CDCI3): δ= 172.0 (C), 162.8 (C), 147.4 (CH), 144.5 (CH), 144.1 (C), 142.7(CH), 57.0 (CH), 52.3 (CH<sub>3</sub>), 41.2 (CH), 29.7 (CH<sub>2</sub>), 28.4 (CH<sub>2</sub>), 26.0 (CH<sub>2</sub>); IR (neat): v^cm ) = 3374 (m), 2920 (s), 2845 (w), 1740 (s), 1665 (s); HRMS (ESI, 4500 V): m/z calcd. for Ci<sub>4</sub>Hi<sub>9</sub>N<sub>3</sub>03Na<sup>+</sup> ([M + Na]<sup>+</sup>) 300.1319, found 300.1319.</div>
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Example 23 :</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000045_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000045_0001" class="patent-full-image" file="imgf000045_0001.tif" he="27" height="108" id="imgf000045_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000045_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="34" width="136" /></a></div>
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(5)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid (10). A solution of 1 M NaOH (12 ml, 12 mmol) was added to a solution of 9 (2.77 g, 10 mmol) in THF (25 ml) at 0°C. MeOH was added to the formed suspension, to give a clear, colorless solution. The reaction mixture was stirred overnight at room temperature, followed by concentration in vacuo. The pH of the aqueous layer was set on 3.5 with a 1 M KHSO<sub>4</sub> solution and was extracted with EtOAc (2 <sup>χ</sup> 25 ml). The mixture was dried with Na<sub>2</sub>S04, filtered, and concentrated in vacuo, to give 10 (2.49 g, 9.45 mmol, 95%) as a white solid.</div>
<div num="p0249" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[a £° = +50.9 (c= 1.06, CHC1<sub>3</sub>); H NMR (250.13 MHz, CDCI3): δ = 9.38 (d, J = 1.5</div>
<div num="p0250" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Hz, 1H), 8.78 (d, J= 2.5 Hz, 1H), 8.58 (dd, J= 1.5, 2.5 Hz, 1H), 8.27 (d, J= 9.0, 1H), 4.77 (dd, J = 4.3, 5.0 Hz, 1H), 2.00 (m, 1H), 1.76 (m, 5H), 1.37 (m, 5H); <sup>13</sup>C NMR (62.90 MHz, CDCI3): δ = 175.7 (C), 163.0 (C), 147.2 (CH), 144.3 (CH), 144.2 (C), 142.0 (CH), 56.9 (CH), 40.9 (CH), 29.7 (CH<sub>2</sub>), 28.1 (CH<sub>2</sub>), 25.9 (CH<sub>2</sub>); IR (neat): v<sub>max</sub> (cm<sup>4</sup>) = 3383 (m), 2928 (s), 2852 (w), 1713 (m), 1676 (s), 1518 (s); HRMS (ESI, 4500 V): m/z calcd. For Ci<sub>3</sub>H<sub>17</sub>N<sub>3</sub>0<sub>3</sub>Na<sup>+</sup> ([M + Na]<sup>+</sup>) 286.1162, found 286.1158.</div>
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Example 23 :</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000046_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000046_0001" class="patent-full-image" file="imgf000046_0001.tif" he="29" height="116" id="imgf000046_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000046_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="49" width="196" /></a></div>
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(S)-methyl 2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)-acetamido)-3,3- dimethylbutanoate (11). 10 (0.653 g, 4.5 mmol) was added to a solution of H-Tle- OMe (0.653 g, 4.5 mmol) in DMF (40 ml). l-Ethyl-3-(3-dimethylaminopropyl)- carbodiimide-HCl (EDOHC1; 0.919 g, 6.75 mmol) was added to this colorless solution followed by 1 -hydroxy-7-azabenzotriazole (HOAt; 1.035 g, 5.4 mmol) giving a bright yellow solution. The reaction mixture was stirred for 3 days and afterwards concentrated in vacuo. The formed yellow solid was dissolved in EtOAc, washed with 40 ml saturated aqueous ammonium chloride solution and 40 ml of saturated aqueous NaHCC>3 solution. The organic layers were collected, dried with MgSC^ and concentrated in vacuo to give 11 (1.48 g, 3.78 mmol, 84%) as a white solid.</div>
<div num="p0254" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[a f° = -2.0 (c= 1.0, CHC1<sub>3</sub>); ¾ NMR (250.13 MHz, CDC1<sub>3</sub>): δ = 9.39 (d, J = 1.5 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.55 (dd, J = 2.4, 1.8 Hz, 1H), 8.29 (d, J = 8.1, 1H), 6.40 (d, J= 9.3 Hz, 1H), 4.46 (m, 2H), 3.74 (s, 3H), 1.81 (m, 1H), 1.76 (m, 4H), 1.24 (m, 6H), 0.96 (s, 12H); <sup>13</sup>C NMR (62.90 MHz, CDC1<sub>3</sub>): δ = 171.7 (C) , 170.4 (C), 163.0 (C), 147.5 (CH), 144.5 (CH), 144.2 (C), 142.7 (CH), 60.2 (CH<sub>3</sub>), 58.4 (CH), 51.9 (CH), 40.5 (CH), 31.7 (C), 29.7 (CH<sub>2</sub>), 28.7 (CH<sub>2</sub>), 26.6 (CH<sub>3</sub>), 25.9 (CH<sub>2</sub>); IR (neat): v„(cm<sup>J</sup>) = 3350 (m), 2928 (m), 2853 (w), 1738 (s), 1686 (s), 1640 (s), 1520 (s); HRMS (ESI, 4500 V): m/z calcd. for C<sub>2</sub>oH<sub>3</sub>oN<sub>4</sub>04Na<sup>+</sup> ([M + Na]<sup>+</sup>) 413.2159, found 413.2169.</div>
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Example 24:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000047_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000047_0001" class="patent-full-image" file="imgf000047_0001.tif" he="32" height="128" id="imgf000047_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000047_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="53" width="212" /></a></div>
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(S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoic acid (2). A solution of 1 M NaOH (0.94 ml, 0.94 mmol) was added to a solution of 11 (0.31 g, 0.78 mmol) in THF (3 ml) at 0°C. MeOH was added to the formed suspension, to give a clear and colourless solution. The reaction mixture was stirred overnight at room temperature, followed by concentration in vacuo. The pH of this aqueous layer was set to 3.5 with 1 M KHSO<sub>4</sub> and subsequently extracted with EtOAc (2 <sup>χ</sup> 10ml). The mixture was dried with Na<sub>2</sub>S0<sub>4</sub>, filtered, and concentrated in vacuo, to give 2 (0.28 g, 0.75 mmol, 95%) as a white solid.</div>
<div num="p0258" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[a f° = +21.7 (c= 1.015, CHC1<sub>3</sub>); *H NMR (250.13 MHz, CDC1<sub>3</sub>): δ = 9.39 (d, J= 1.3</div>
<div num="p0259" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Hz, 1H), 8.77 (d, J = 2.5 Hz, 1H), 8.57 (dd, J = 1.5, 2.5 Hz, 1H), 8.35 (d, J = 9 Hz, 1H), 6.70 (d, J = 9.0 Hz, 1H), 4.45 (t, J = 8.8 Hz, 1H), 4.42 (d, J = 9.2 Hz, 1H), 1.94 (m, 1H), 1.71 (m, 5H), 1.20 (m, 5H), 1.01 (s, 9H); <sup>13</sup>C NMR (62.90 MHz, CDCI3): δ = 173.4 (C), 170.5 (C), 163.3 (C), 147.4 (CH), 144.4 (CH), 144.2 (C), 142.8 (CH), 58.4 (CH), 51.9 (CH), 40.4 (CH), 34.7 (C), 29.8 (CH<sub>2</sub>), 28.6 (CH<sub>2</sub>), 26.6 (CH<sub>3</sub>), 25.8 (CH<sub>2</sub>); IR (neat): v„(cm ) = 3335 (w), 2930 (m), 1726 (m), 1663 (s), 1514 (s); HRMS (ESI, 4500 V): m/z calc. for Ci<sub>9</sub>H<sub>29</sub>N<sub>4</sub>0<sub>4</sub>Na<sup>+</sup> ([M + Na]<sup>+</sup>) 399.2003, found 399.2013.</div>
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Example 25:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000047_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000047_0002" class="patent-full-image" file="imgf000047_0002.tif" he="23" height="92" id="imgf000047_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000047_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="32" width="128" /></a></div>
<div num="p0262" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(5)-2-formamido-l-pentanol (12). (5)-2-amino-l-pentanol (1.00 g, 9.7 mmol) was dissolved in ethylformate (7.84 ml, 7.19 g, 97 mmol). This reaction mixture was refluxed at 80 °C for 4 hours, followed by stirring overnight at room temperature. The colourless solution was concentrated in vacuo and stirred for 1 hour in a 10 mol% K<sub>2</sub>C0<sub>3</sub> in MeOH (25 ml). Afterwards, the pH was set to 7 with DOWEX 50wx8, followed by filtration and concentration in vacuo to give 12 (1.26 g, 9.61 mmol, 99%). [a f° = -29.6 (c = 1.15, CHCI<sub>3</sub>); H NMR (250.13 MHz, CDC1<sub>3</sub>): δ = 8.20 (s, 1H), 5.81 (bs, 1H), 4.04 (m, 1H), 2.11 (b, 1H), 1.47 (m, 4H), 0.94 (t, J = 7.0 Hz, 3H); <sup>13</sup>C NMR (62.90 MHz, CDCI3): 161.8 (C), 65.1 (CH<sub>2</sub>), 50.6 (CH), 33.2 (CH<sub>2</sub>), 19.2 (CH<sub>2</sub>), 13.9 (CH<sub>3</sub>); IR (neat): v<sub>max</sub> (cm ) = 3248 (s), 2957 (m), 1651 (s), 1528 (m), 1381 (m); HRMS (ESI, 4500 V): m/z calcd. for C<sub>6</sub>Hi<sub>3</sub>N0<sub>2</sub>Na<sup>+</sup> ([M + Na]<sup>+</sup>) 154.0838, found 154.0835.</div>
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Example 26:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000048_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000048_0001" class="patent-full-image" file="imgf000048_0001.tif" he="34" height="136" id="imgf000048_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000048_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="74" width="296" /></a></div>
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<span style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;">(5)-2-formamidopentanal. (7). Dess-Martin periodinane (5.514 g, 13 mmol) was added to a solution of (5)-2-formamido-l-pentanol (12, 1.31 g, 10 mmol) in CH</span><sub style="line-height: 21.3333339691162px;">2</sub><span style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;">C1</span><sub style="line-height: 21.3333339691162px;">2</sub><span style="font-size: 13.3333330154419px; line-height: 21.3333339691162px;"> (100 ml) at room temperature. The white suspension was stirred for 2 days and subsequently 35 ml MeOH was added and stirred for 30 minutes. The resulting suspension was filtrated and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash chromatography (cHex:EtOAc = 1 :4) to give 7 (1.08 g,</span></div>
<div num="p0265" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
8.29 mmol, 83%) as a white solid. NMR analysis indicates that 7 is in equilibrium with its cyclic dimer.</div>
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[a f° = +37.6 ( c= 0.745, CHC1<sub>3</sub>); <sup>l</sup>U NMR assigned to the monomer (250.13 MHz, CDCI<sub>3</sub>): δ = 8.22 (s, 1H), 7.84 (s, 1H), 7.10 (m, 1H), 5.31 (m, 1H), 1.52 (m, 4H), 0.95 (m, 3H); <sup>13</sup>C NMR assigned to the monomer (100.61 MHz, CDC13): 198.8 (CH), 161.7 (CH), 57.4 (CH), 30.8 (CH<sub>2</sub>), 18.4 (CH<sub>2</sub>), 13.7 (CH<sub>3</sub>); <sup>l</sup>H NMR assigned to the dimer (400.13 MHz, CDC1<sub>3</sub>) 8.22 (s, 2H), 5.26 (m, 2H), 3.72 (m, 2H) 1.52 (m, 8H), 0.95 (m, 6Η;) <sup>13</sup>C NMR (100.61 MHz, CDCI3) assigned to the dimer: 161.7 (CH), 89.8 (CH), 63.1 (CH), 30.8 (CH2), 18.4 (CH2), 13.7 (CH3); IR (neat): <sub>Vmax</sub> (cm ): 3325 (s), 2959 (s), 1649 (s), 1530 (s), 1381 (m), 1123 (w); HRMS (ESI, 4500 V): m/z calc. for C<sub>6</sub>Hi<sub>2</sub>N0<sub>2</sub> <sup>+</sup> ([M + H]<sup>+</sup>) 130.0863, found 130.0858.</div>
<div num="p0267" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
It was noted that the dimer exists as a mixture of diastereomers.</div>
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Example 27:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000049_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000049_0001" class="patent-full-image" file="imgf000049_0001.tif" he="28" height="112" id="imgf000049_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000049_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="34" width="136" /></a></div>
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(35)-2-acetoxy- V-cyclopropyl-3-formamidohexanoyl amide (13). From 7: Aldehyde 7 (0.892 g, 6.91 mmol) was added to a solution of cyclopropyl isocyanide (0.410 g, 6.12 mmol) in CH<sub>2</sub>C1<sub>2</sub> (110 ml) and stirred for 5 minutes at room temperature. Acetic acid (0.711 ml, 0.747 g, 12.44 mmol) was added and the yellow reaction mixture was stirred for 3 days at room temperature. The reaction mixture was washed twice with 100 ml saturated Na<sub>2</sub>C03, followed by drying with Na<sub>2</sub>S04 and concentration in vacuo. The crude was purified by silica gel flash chromatography (5% MeOH in CH<sub>2</sub>C1<sub>2</sub>, 1% triethylamine). (3S)-2-acetoxy-N-cyclopropyl-3- formamidohexanoyl amide (0.99 g, 3.87 mmol, 56%) was obtained as a white solid as a 78:22 mixture of diastereomers.</div>
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From 12: Dess Martin periodinane (5.66 g, 12.3 mmol) was added to a solution of (S)-N-(l hydroxypentan-2-yl)formamide (1.15 g, 8.8 mmol) in CH<sub>2</sub>C1<sub>2</sub> (12 ml) at room temperature. The white suspension was stirred for 60 minutes and subsequently cyclopropyl isocyanide (0.74 g, 10.0 mmol) was added and stirred for 48 hours. The resulting suspension was filtrated and washed twice with 10 ml saturated Na<sub>2</sub>C03, followed by drying with Na<sub>2</sub>SC>4 and concentration in vacuo. The crude product was purified by silica gel flash chromatography (5% MeOH in CH<sub>2</sub>CI<sub>2</sub>, 1% triethylamine) to give 13 (1.34 g, 5.22 mmol, 60%) as a pale yellow solid as a 78:22 mixture of diastereomers.</div>
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*H NMR (130 °C, 400.13 MHz, DMSO-i¾: δ = 8.03 (s, 1H), 7.52 (m, 1H), 7.30 (m, 1H), 4.89 (d, J= 4.4, 1H), 4.28 (m, 1H), 2.65 (m, 1H), 2.17(s, 3H), 1.27-1.47 (m, 4H), 0.89 (t, J= 7.2, 3H), 0.63 (m, 2H), 0.48 (m, 2H); <sup>13</sup>C NMR (125.78 MHz, DMSO-i <sub>6</sub>): δ = 169.8 (C), 168.5 (C), 160.6 (CH), 74.4 (CH), 47.5 (CH), 22.2 (CH), 18.4 (CH<sub>3</sub>), 13.6 (CH<sub>3</sub>), 5.7 (CH<sub>2</sub>); IR (neat): v<sub>max</sub> (cm ) 3283 (s), 2961 (w), 1744 (m), 1661 (s), 1530 (s), 1238 (s); HRMS (ESI, 4500 V): m/z calcd. for Ci<sub>2</sub>H<sub>2</sub>oN<sub>2</sub>0<sub>4</sub>Na<sup>+</sup> ([M + Na]<sup>+</sup>) 279.1315, found 279.1325.</div>
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Example 28:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000050_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000050_0001" class="patent-full-image" file="imgf000050_0001.tif" he="31" height="124" id="imgf000050_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000050_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="32" width="128" /></a></div>
<div num="p0275" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(35)-2-acetoxy-7V-cyclopropyl-3-isocyano-hexanoyl amide (4). N- methylmorpholine (0.57 ml, 0.562 g, 5.56 mmol) was added to a solution of (5)-l- (cyclopropylamino)-3-formamido-l-oxohexan-2-yl acetate (0.713 g, 2.78 mmol) in CH<sub>2</sub>CI<sub>2</sub> (40 ml) at room temperature. The reaction mixture was cooled to -78 °C and triphosgene (0.289 g, 0.97 mmol) was quickly added and stirred for 5 minutes at this temperature. The resulting yellow solution was warmed up to -30 °C and was stirred for another 3 h. Subsequently, the reaction was quenched with water and extracted twice with CH<sub>2</sub>CI<sub>2</sub> (40 ml). The organic layers were collected, dried with Na<sub>2</sub>SC>4 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (2% MeOH in CH<sub>2</sub>C1<sub>2</sub>) to give 4 (0.578 g, 2.42 mmol, 87%) as a white solid. <sup>l</sup>U NMR (250.13 MHz, CDC1<sub>3</sub>): δ = 6.28 (s, 1H), 5.25 (d, J = 2.5 Hz, 1H), 4.2 (m, 1H), 2.74 (m, 1H), 2.24 (s, 3H), 1.55 (m, 4H), 0.96 (m, 3H), 0.84 (m, 2H), 0.60 (m, 2H); <sup>13</sup>C NMR (62.90 MHz, CDCI3): δ= 169.7 (C), 168.3 (C), 74.4 (CH), 47.5 (CH), 22.0 (CH), 20.6 (CH<sub>3</sub>), 18.5 (CH<sub>2</sub>), 13.5 (CH<sub>3</sub>), 5.5 (CH<sub>2</sub>); IR (neat): <sub>Vmas</sub>(cm ): 3267 (s), 2959 (m), 1745 (m), 1643 (s), 1512 (m), 1221 (s); HRMS (ESI, 4500 V): m/z calcd. for Ci<sub>2</sub>H<sub>18</sub>N<sub>2</sub>0<sub>3</sub>Na<sup>+</sup> ([M + Na]<sup>+</sup>) 261.1210, found 261.1214.</div>
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<div num="p0276" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 29:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000051_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000051_0001" class="patent-full-image" file="imgf000051_0001.tif" he="36" height="144" id="imgf000051_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000051_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="79" width="316" /></a></div>
<div num="p0278" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Compound 14. Isocyanide 4 (0.549 g, 2.3 mmol) was dropwise added to a solution of imine 3 (0.252 g, 2.3 mmol) and carboxylic acid 2 (0.602 g, 1.60 mmol) in CH<sub>2</sub>C1<sub>2</sub> (5 ml) at room temperature. This yellow solution was stirred for 72 hours and afterwards diluted with 5 ml CH<sub>2</sub>C1<sub>2</sub>. The reaction mixture was washed twice with saturated Na<sub>2</sub>C0<sub>3</sub> solution (10 ml) and twice with saturated NH<sub>4</sub>CI. The organic layers were collected, dried with MgS04 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (5% MeOH in CH<sub>2</sub>C1<sub>2</sub>) to give 14 (0.876 g, 1.21 mmol, 76%) as a mixture of diastereomers.</div>
<div num="p0279" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
lU NMR (500.23 MHz, CDC1<sub>3</sub>): δ = 9.50 (s, 1H), 8.75 (d, J = 2.5, 1H), 8.59 (s, 1H), 8.35 (d, J = 9.0, 1H), 6.84 (d, J= 9.0, 1H), 6.44 (s, 1H), 5.20 (d, J= 3.0, 1H), 4.74 (d, J= 9.5, 1H), 4.58 (t, J = 7.5, 1H), 4.38 (m, 1H), 3.37 (d, J= 6.0, 1H), 2.82 (m, 1H), 2.69 (m, 1H), 2.11 (s, 3H), 1.26 (s, 2H), 0.97 (s, 9H), 0.86 (m, 3H), 0.84-2.00 (m, 21H), 0.76 (m, 2H), 0.51 (m, 2H);<sup>13</sup>C NMR (125.78 MHz, CDC1<sub>3</sub>): δ = 170.5 (C), 169.3 (C), 162.9 (C), 147.4 (CH), 144.6 (CH), 144.2 (C), 142.8 (CH), 74.4 (CH), 66.6 (CH), 58.3 (CH), 56.6 (CH), 54.5 (CH<sub>2</sub>), 44.9 (CH), 43.0 (CH), 41.3 (CH), 35.5 (C), 26.4 (CH<sub>3</sub>), 20.8 (CH<sub>3</sub>), 19.1 (CH<sub>2</sub>), 13.8 (CH<sub>3</sub>), 6.6 (CH<sub>2</sub>); v<sub>max</sub> (cm<sup>4</sup>): 3306 (m), 2928 (m), 2931 (m), 1743 (w), 1655 (s), 1520 (m), 1219 (m); HRMS (ESI, 4500 V): m/z calcd. for C<sub>3</sub>8H<sub>5</sub>7N<sub>7</sub>0<sub>7</sub>Na<sup>+</sup> ([M + Na]<sup>+</sup>) 746.4212, found 746.4107.</div>
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<div num="p0279" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 30:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000052_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000052_0001" class="patent-full-image" file="imgf000052_0001.tif" he="32" height="128" id="imgf000052_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2011103932A1/imgf000052_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="74" width="296" /></a></div>
<div num="p0281" style="background-color: white; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<span style="color: #222222;">Telaprevir (1). 250 μΐ of saturated K<sub>2</sub>C0<sub>3</sub> was added to a solution of 14 (0.514 g, 0.75 mmol) in MeOH (20 ml) at room temperature. The reaction mixture was stirred for 30 minutes at room temperature resulting in a pale yellow suspension. After full conversion (as judged by TLC analysis), the reaction mixture was washed with 20 ml brine, the aqueous layer was washed again with 10 ml CH<sub>2</sub>C1<sub>2</sub> (2x). The organic layers were collected, dried with MgS0<sub>4</sub> and concentrated in vacuo, to yield a pale yellow solid. The yellow solid was dissolved in CH<sub>2</sub>CI<sub>2</sub> (10 ml) and Dess-Martin periodinane (0.650 g, 1.532 mmol) was added at room temperature. The reaction mixture was stirred overnight before adding saturated NaHC0<sub>3</sub> solution (10 ml) and saturated Na<sub>2</sub>S<sub>2</sub>0<sub>3</sub> solution (10 ml). This mixture was stirred for 10 minutes, separated and the aqueous layers were washed with EtOAc (2 x 10 ml). The organic layers were collected, dried with MgSC^ and concentrated in vacuo to give the crude product as an 83: 13:4 mixture of diastereomers. After silica gel flash chromatography (1% MeOH in CH<sub>2</sub>C1<sub>2</sub>), 1 (0.412 mg, 0.61 mmol, 80%) was obtained as a white solid. <sup>l</sup>U </span><span style="color: red;">NMR (500.23 MHz, DMSO-i¾: 5 = 9.19 (d, J= 1.4 Hz, 1H), 8.91 (d, J= 24.5 Hz, 1H), 8.76 (dd, J = 1.5, 2.5 Hz, 1H), 8.71 (d, J= 5.3 Hz, 1H), 8.49 (d, J= 9.2 Hz, 1H), 8.25 (d, J = 6.8 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 4.94 (m, 1H), 4.68 (dd, J= 6.5, 9.0 Hz, 1H), 4.53 (d, J = 9.0 Hz, 1H), 4.27 (d, J = 3.5 Hz, 1H), 3.74 (dd, J = 8.0, 10 Hz, 1H), 2.74 (m, 1H), 3.64 (d, J = 3.5 Hz, 1H), 0.92 (s, 9H), 0.87 (t, 3H), 0.84-1.40 (m, 23H), 0.65 (m, 2H), 0.56 (m, 2H); </span></div>
<div num="p0281" style="background-color: white; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<sup><span style="color: red;"><br /></span></sup></div>
<div num="p0281" style="background-color: white; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<span style="color: red;"><sup>13</sup>C NMR (125.78 MHz, CDC1<sub>3</sub>): δ = 197.0 (C), 171.8 (C), 170.4 (C), 169.0 (C), 162.1 (C), 161.9 (C), 147.9 (CH), 144.0 (C), 143.4 (CH), 56.4 (CH), 56.3 (CH), 54.2 (CH), 53.4 (CH), 42.3 (CH), 41.3 (CH), 32.1 (CH), 31.8 (CH), 31.6 (CH), 29.1 (CH), 28.0 (CH), 26.4 (CH<sub>3</sub>); (cm<sup>4</sup>): 3302 (m), 2928 (m), 2858 (w), 1658 (s), 1620 (s), 1561 (s), 1442 (m); </span></div>
<div num="p0281" style="background-color: white; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<span style="color: red;"><br /></span></div>
<div num="p0281" style="background-color: white; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
<span style="color: red;">HRMS (ESI, 4500 V): m/z calcd. for C<sub>3</sub>6H<sub>5</sub>3N<sub>7</sub>0<sub>6</sub>Na<sup>+</sup> ([M + Na]<sup>+</sup>) 702.3950, found 702.3941.</span></div>
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<br /></div>
<div>
<div style="font-size: 14.4899997711182px; line-height: 21.7350006103516px;">
..................</div>
<div num="p0014" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
telaprevir according to Formula 1</div>
<div num="p0015" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000004_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000004_0002" class="patent-full-image" file="imgf000004_0002.tif" he="33" height="132" id="imgf000004_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000004_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="85" width="340" /></a></div>
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<br /></div>
<span style="font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><a href="http://www.google.im/patents/WO2013135870A1?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.im/patents/WO2013135870A1?cl=en</a></span><br /><div style="font-size: 14.4899997711182px; line-height: 21.7350006103516px;">
<br /></div>
<div num="p0004" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Telaprevir is a protease inhibitor that can be used as antiviral drug. By way of example, telaprevir inhibits the hepatitis C virus NS3-4A serine protease.</div>
<div num="p0005" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Although some processes for the synthesis of telaprevir or its pharmaceutical acceptable salts are available, it is an object of the present invention to provide an alternative process, in particular an enhanced process that overcomes at least one of the problems of the prior art processes.</div>
<div num="p0006" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Y. Yip et al. Bioorg. Med. Chem. Lett., 2004, 14, 5007 discloses the preparation of a 1 :1 mixture of isomers defined by Formula 5a (see Scheme 1 ) which isomers appear to have a stereochemical configuration other than that of telaprevir. WO 2007/022459 A2 discloses a process for preparing telaprevir, wherein in a first coupling step, a bicyclic pyrrolidine derivative is reacted with a protected amino acid, followed by a stepwise extension of the chain of the amino acid to provide a tripeptide as shown in Formula 2. Subsequently, a β-amino acid is added to the carbon chain-end opposite to said previously built chain. Finally, telaprevir is obtained in an oxidation step. Turner et al. (Chemical Communications 2010, 46(42), 7918) discloses a process for the preparation of teiaprevir by applying an Ugi reaction type process which reacts a compound of Formula 2</div>
<div num="p0007" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000003_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000003_0001" class="patent-full-image" file="imgf000003_0001.tif" he="34" height="136" id="imgf000003_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000003_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="50" width="200" /></a></div>
<div num="p0008" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
a chiral imine, namely (3aS,6aR)-1 ,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole, which is obtained by enzyme technology and is thus difficult to prepare and is instabile and a relatively unstable isonitrile derivative of formula 4.</div>
<div num="p0009" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Summary of the invention The known processes for the preparation of teiaprevir are based on long linear sequences or require the use of labile, highly reactive agents and specific enzymes. The process described herein may for example allow to avoid the use of said labile, highly reactive reactants and specific enzymes. It was surprisingly found within the context of the present invention that teiaprevir may be prepared in a smaller number of process steps in a convergent manner by using stabile precursors (see an example process in Figure 1 ). The present invention may also contribute to preserving the desired stereochemical configuration during the process of preparing teiaprevir. In particular, it has been found that the desired stereochemical configuration may be preserved during the process of peptide bond formation in the compound according to Formula 5 when using the coupling agents described herein, in particular when using 2, 4,6-tripropyl-1 ,3,5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide (T3P) or related compounds in dichloromethane. It is also possible to use a combination of a diimide coupling reagent, including but not being limited to dicyclohexylcarbodiimide (DCC), diispropylcarbodiimide (DIC) and 1-ethyl-3-(3- dimethy!aminopropyl)carbodiimide hydrochloride (EDC), with 1-hydroxy-benzotriazole (HOBt) or 1-hydroxy-7-aza-benzotriazole (HOAt) or related reagents for preparing teiaprevir. It has been found that the coupling agents are particularly effective when used in the presence of a lewis acid such as a copper salt. It was also unexpectedly found that the choice of solvent for carrying out the coupling reaction may further enhance the preservation of the stereochemical configuration during peptide bond formation in the compound according to Formula 5.</div>
<div num="p0010" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Furthermore, the expensive compound according to Formula 3</div>
<div num="p0011" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000004_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000004_0001" class="patent-full-image" file="imgf000004_0001.tif" he="20" height="80" id="imgf000004_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000004_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="23" width="92" /></a></div>
<div num="p0012" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
3</div>
<div num="p0013" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
is used at a later stage of the process compared to the process of WO 2007/022459 A2, namely for coupling to the compound according to Formula 2 which already represents a dipeptide. Considering the yields of the single process steps, a smaller amount of the compound according to Formula 3 is required according to the invention, and, thus, the process may be less costly. Compared to the above method of Turner et al., it is not required to use a toxic and instable isonitrile compound. It has also been found that the process for preparing telaprevir may provide an advantage since fewer impurities such as epimeric forms and other byproducts may be formed.</div>
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<br /></div>
<div num="p0122" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1b - (1S,3aR,6aS)-tert-butyl 2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3 dimethylbutanovDoctahydrocvclopentafclpyrrole-l- carboxylate (5b)</div>
<div num="p0123" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000021_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000021_0001" class="patent-full-image" file="imgf000021_0001.tif" he="32" height="128" id="imgf000021_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000021_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="160" width="640" /></a></div>
<div num="p0124" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A round bottom flask is charged with 41 mg of 2 (0.11 mmol, 1 eq.) and 1 ml. of DCM is added. Then, 29 mg of 3b (0.16 mmol, 1.5 eq.) are added. After stirring for 5 min 190μΙ of T3P (50% in EtOAc, 0.32 mmol, 3 eq.) are added and the reaction mixture is stirred for 21 h at room temperature.</div>
<div num="p0125" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The reaction is then diluted with DCM and quenched with water. The aqueous layer is separated and re-extracted with DCM. The combined organic layers are washed with brine, dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo. Purification by flash chromatography yielded 5b (26 mg, 43% yield), (d.r. = 7.5:1 ).</div>
<div num="p0126" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1c - (1S,3aR.6aS)-tert-butyl 2-((S)-2-((S)-2-cvclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3 dimethylbutanoyl)octahvdrocvclopentarc1pyrrole-1- carboxylate (5b)</div>
<div num="p0127" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000021_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000021_0002" class="patent-full-image" file="imgf000021_0002.tif" he="32" height="128" id="imgf000021_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000021_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="161" width="644" /></a></div>
<div num="p0128" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A round bottom flask is charged with 1g of 2 (2.66 mmol, 1 eq.) and 20 ml_ of DCM is added. Then, 0.73g of 3b (3.98 mmol, 1.5 eq.) are added. After stirring for 5 min 4.75mL of T3P (50% in EtOAc, 7.98 mmol, 3 eq.) are added and the reaction mixture is stirred for 21 h at room temperature. The reaction is then quenched with water. The aqueous layer is separated and re-extracted with DCM. The combined organic layers are washed with sat. NaHC0<sub>3</sub>-solution, brine and then dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo. Purification by flash chromatography yielded 5b (0.70g, 49% yield), (d.r. = 5.6:1 ).</div>
<div num="p0129" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1d - (1S,3aR,6aS)-tert-butyl 2-gS)-2-((S)-2-cvclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3.3 dimethylbutanoyl)octahvdrocvclopentaMpyrrole-1- carboxylate (5b)</div>
<div num="p0130" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000022_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000022_0001" class="patent-full-image" file="imgf000022_0001.tif" he="32" height="128" id="imgf000022_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000022_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="160" width="640" /></a></div>
<div num="p0131" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A round bottom flask is charged with 1.0g of 2 (2.66 mmol, 1 eq.) and 0.58g of 3b (3.19 mmol, 1.2 eq), then 8 mL of DMF is added and the mixture cooled to 0°C using an ice-bath. In a second flask, 0.36g CuCI<sub>2</sub> (2.66 mmol, 1 eq.) are dispersed in 5mL DMF, cooled to 0°C and the previously prepared solution is added to it. Now, 0.36g HOBt (2.66 mmol, 1 eq.) and 2.0g EDC HCI (10.43 mmol, 4 eq.) are added and the mixture is then stirred at r.t. for 16h.</div>
<div num="p0132" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The reaction is then quenched with 10ml_ 10% NH<sub>3</sub>-solution and then extracted 4 times with a total of 60mL of EtOAc. The combined organic layers are then washed 3 times with dilute hydrochloric acid, once with sat. NaHC0<sub>3</sub>-solution and brine, then dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo. Purification by flash chromatography yielded 5b (0.78g, 54% yield), (d.r. = 53 : 1 ).</div>
<div num="p0133" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1e - (1S.3aR.6aS)-tert-butyl 2-((S)-2-((S)-2-cvclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3 dimethylbutanoyl)octahvdrocvclopentarclpyrrole-1- carboxylate (5b)</div>
<div num="p0134" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000022_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000022_0002" class="patent-full-image" file="imgf000022_0002.tif" he="32" height="128" id="imgf000022_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000022_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="161" width="644" /></a></div>
<div num="p0135" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A round bottom flask is charged with 1.25g PS-supported HOBt (1.07 mmol/mg) and 0.30g of 3b (1.65 mmol, 1.2 eq) and 0.36g CuCI<sub>2</sub> (2.66 mmol, 1 eq.). Then 15 ml_ of DMF are added and the mixture cooled to 0°C using an ice-bath, while mixing with a mechanical stirrer. In a second flask, 0.5g of 2 (1.3 mmol, 1 eq.) and 1.0g EDC HCI (5.21 mmol, 4 eq.) are dispersed in 12mL DMF, cooled to 0°C and added to the previously prepared solution. The mixture is then stirred at r.t. for 22h.</div>
<div num="p0136" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The reaction is then filtered and the filter washed with 15mL DMF. 50ml_ EtOAc are added to the filtrate, followed by 35ml_ 5% NH<sub>3</sub>-solution. The aqueous layer is then separated and extracted 3 times with a total of 45ml_ of EtOAc. The combined organic layers are then washed once with 10% NH<sub>3</sub>-solution, dilute hydrochloric acid, sat. NaHC0<sub>3</sub>-solution and brine, then dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo. Purification by flash chromatography yielded 5b (0.43g, 61 % yield), (d.r. = 18 : 1 ).</div>
<div num="p0137" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1f - (1S.3aR,6aS)-tert-butyl 2-((S)-2-((S)-2-cvclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3 dimethylbutanovDoctahydrocvclopentafclpyrrole-l- carboxylate (5b)</div>
<div num="p0138" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000023_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000023_0001" class="patent-full-image" file="imgf000023_0001.tif" he="32" height="128" id="imgf000023_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000023_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="160" width="640" /></a></div>
<div num="p0139" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A round bottom flask is charged with 2.0g of 2 (5.3 mmol, 1 eq.) and 1.17g of 3b (6.4 mmol, 1.2 eq), then 10 mL of DMF is added and the mixture cooled to 0°C using an ice-bath, then 0.72g CuCI<sub>2</sub> (5.3 mmol, 1 eq.) are added. In a second flask 0.72g HOBt (5.3 mmol, 1 eq.) and 1.34g DIC (10.6 mmol, 2 eq.) are dissolved in 5mL DMF, cooled to 0°C and added to the previously prepared solution. The mixture is then stirred at r.t. for 5h.</div>
<div num="p0140" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The reaction is then quenched with 30mL 2% NH<sub>3</sub>-solution and then extracted 3 times with a total of 60ml_ of EtOAc. The combined organic layers are then washed 3 times with a total of 60mL of dilute hydrochloric acid, once with 20ml_ sat. NaHC0<sub>3</sub>-solution and 20ml_ of brine, then dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo. Purification by flash chromatography yielded 5b (2.59g, 90% yield), (d.r. = 340 : 1 )</div>
<div num="p0141" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1g - Use of HOAT as anti-isomerisation reagent</div>
<div num="p0142" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
To 4.4ml of a 0.6M HOAT solution in DMF (1.1eq, 2.63mmol) were added 0.6ml DMF.</div>
<div num="p0143" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Afterwards 1g of 2 (90% content, 1eq, 2.39mmol), 567mg of 3b (1.3eq, 3.11 mmol) and 391 mg DIC (1.3eq, 3.11 mmol) were added at room temperature. The reaction was stirred at room temperature for 23h. After 19h 86% conversion to 5b, with a d.r. 3.9/1 was observed. After 23h, with 87% conversion to 5b, and a d.r. 4.1/1 the conversion had stalled and the product was not isolated. Example 1 h - Use of CuCI? with in situ generation of AOC-Et from its HCI salt</div>
<div num="p0144" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
353mg water free CuCI<sub>2</sub> (1.1 eq, 2.63mmol) was dissolved in 5ml DMF. To the solution 1 g 2 (90% content, 1 eq, 2.39mmol), 683mg 3b. HCI (1 .3eq, 3.1 1 mmol), 315mg NMM (1.3eq,</div>
<div num="p0145" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
3.1 1 mmol) and 391 mg DIC (1.3eq, 3.1 1 mmol) were added at room temperature. The reaction mixture was stirred at room temperature. After two hours 2.6area% 2 was detected and yield was 96.5% (calculated via internal standard). After 5h less than 0.5area% 2 was detected and yield was 98.1 %. d.r. at both IPCs was 108/1.</div>
<div num="p0146" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1 i - HOAT without CuCI? in DMF</div>
<div num="p0147" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
To a solution of 0.5g 2 (90%, 1 eq, 1 .19mmol) and 179mg HOAT (1.1eq, 1.32mmol) in 2.5ml DMF 284mg 3b (1.3eq, 1 .55mmol) was added. Afterwards</div>
<div num="p0148" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
241 μΙ DIC (1 .3eq, 1.55mmol) was added. Reaction was stirred at room temperature. After2.5h 91 % conversion and DR of 4.3/1 was observed. After 5h complete conversion</div>
<div num="p0149" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Was observed and DR of 4.1/1. No work was performed.</div>
<div num="p0150" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1j - HOAT without CuCI, in THF/MED</div>
<div num="p0151" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
To a suspension of 0.5g 2 (90, 1 eq. 1.19mmol) and 179mg HOAT (1 .1 eq, 1 ,32mmol) in 2.5ml of a 1/1 mixture of THF/MED (methylene chloride) 284mg 3b (1.3eq, 1.55mmol) was added. Afterwards, 241 μΙ DIC (1.3eq, 1 .55mmol) was added. Reaction was stirred at room</div>
<div num="p0152" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
temperature. After2.5h 7.5% conversion and DR of 6.7/1 was observed. After 5h 80 conversion was observed and DR of 6.2/1 . After 19h 86% conversion and DR of 6.0/1 was found. No work was performed. Example 1 k - HOAT with CuCI? in DMF</div>
<div num="p0153" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
177mg CuCI<sub>2</sub> (1 .1 eq, 1 .31 mmol) was dissolved in 2.5ml DMF. To the solution 0.5g 2 (90%, 1 eq, 1.19mmol), 179mg HOAT (1.1 eq, 1 .32mmol), 284mg 3b (1.3eq, 1.55mmol) and 241 μΙ DIC (1.3eq, 1.55mmol) was added. The reaction was stirred at room temperature for 13h. 95% conversion and DR of 48/1 was observed. No work up was performed.</div>
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Example 11 - Substochiometric amounts of CuCI? in DMF without HOAT</div>
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177mg CuCI<sub>2</sub> (0.55eq, 1.31 mmol) was dissolved in 5ml DMF. To the solution 1.0g 2 (90%, 1 eq, 2.39mmol), 683mg 3b.HCI (1.3eq, 3.11 mmol), 340μΙ NMM (1.3eq, 3.11 mmol) and 481 μΙ DIC (1.3eq, 3.11 mmol) was added. The reaction was stirred at room temperature for 4.5h, complete conversion and DR of 76/1 was observed. No separated work up was performed. Example 2a - Synthesis of the compound according to Formula 7</div>
<div num="p0156" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(1S.3aR.6aS)-2-((S)-2-((S)-2-cvclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoyl)octahvdrocvclopentarclpyrrole-1 -carboxylic acid (7)</div>
<div num="p0157" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000025_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000025_0001" class="patent-full-image" file="imgf000025_0001.tif" he="31" height="124" id="imgf000025_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000025_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="143" width="572" /></a></div>
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A round-bottom flask was charged with 6g of 5b (11.08 mmol, 1 eq.) and 85mL of THF and 26mL of H<sub>2</sub>0 was added. Then 2.20g LiOH H<sub>2</sub>0 (52.43 mmol, 4.7 eq.) were added and the mixture was stirred at r.t. for 18h.</div>
<div num="p0159" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Then 50ml_ EtOAc and 50mL H<sub>2</sub>0 were added, and the aqueous layer separated. The organic layer was washed once more with 40ml_ H<sub>2</sub>0. To the combined aqueous layers 50ml_ of EtOAc were added, and by slow addition of 2M HCI the pH was adjusted to 1.89. After separation of the aqueous layer, it was extracted once more with 50ml_ EtOAc, and the combined organic layers washed with brine, then dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo.</div>
<div num="p0160" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Purification by flash chromatography yielded 7 (4.83g, 85% yield).</div>
<div num="p0161" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 2b - Synthesis of the compound according to Formula 7</div>
<div num="p0162" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoyl)octahvdrocvclopenta[c1pyrrole-1 -carboxylic acid (7)</div>
<div num="p0163" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000026_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000026_0001" class="patent-full-image" file="imgf000026_0001.tif" he="28" height="112" id="imgf000026_0001" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000026_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="157" width="628" /></a></div>
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A round bottom flask is charged with 2.0g of 2 (5.3 mmol, 1 eq.) and 1.17g of 3b (6.4 mmol, 1.2 eq), then 10 mL of DMF is added and the mixture cooled to 0°C using an ice-bath, then 0.72g CuCI<sub>2</sub> (5.3 mmol, 1 eq.) are added. In a second flask 0.72g HOBt (5.3 mmol, 1 eq.) and 1 .34g DIC (10.6 mmol, 2 eq.) are dissolved in 3ml_ DMF, cooled to 0°C and added to the previously prepared solution. The mixture is then stirred at r.t. for 5h.</div>
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The reaction is then quenched with 30mL 2% NH<sub>3</sub>-solution and then extracted 3 times with a total of 70ml_ of EtOAc. The combined organic layers are then washed with 15mL 2% NH<sub>3</sub>- solution, 1 time with 20ml_ 1 M HCI, 3 times with a total of 60ml_ of dilute hydrochloric acid, once with 20ml_ sat. NaHC0<sub>3</sub>-solution and 20ml_ of brine, then dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo. The residue (compound 5b - 2.59g, 4.78 mmol, 1 eq.) was dissolved in 27ml_ of a 1 :1 mixture THF/H<sub>2</sub>0. Then 0.48g NaOH (1 1.95 mmol, 2.5 eq.) were added and the mixture was stirred at r.t. for 18h.</div>
<div num="p0166" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Then 20ml_ EtOAc and 10ml_ H<sub>2</sub>0 were added, and the aqueous layer separated. The organic layer was washed once more with 20ml_ H<sub>2</sub>0. To the combined aqueous layers 20ml_ of EtOAc were added, and by slow addition of 2M HCI the pH was adjusted to 1.27. After separation of the aqueous layer, it was extracted once more with 20ml_ EtOAc, and the combined organic layers washed with brine, then dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo to give 7 (2.82g, 93% yield). Trace metal analysis using ICP-OES showed residual copper < 1 ppm, wherein the following method was used:</div>
<div num="p0167" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Digestion: about 250mg of sample material was digested under pressure with a mixture of HNO<sub>3</sub>+HCI in a closed quartz container which can be heated by microwave radiation.</div>
<div num="p0168" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Determination of Cu:</div>
<div num="p0169" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Measurement was performed with ICP-OES at 324,754nm, Axialplasm, simultaneous background correction; calibration with external standards, certified elemental standard of Merck, Device: Fabr. Thermo Electron, Type: IRIS Intrepid XSP II, Duo. Example 2c - Synthesis of the compound according to Formula 7</div>
<div num="p0170" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(1 S,3aR,6aSV2-((S)-2-((S)-2-cvclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3.3- dimethylbutanoyl)octahvdrocyclopenta[clpyrrole-1 -carboxylic acid (7)</div>
<div num="p0171" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000027_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000027_0001" class="patent-full-image" file="imgf000027_0001.tif" he="27" height="108" id="imgf000027_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000027_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="156" width="624" /></a></div>
<div num="p0172" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
7.07g water free CuCI<sub>2</sub> (1.1eq, 52.6mmol) was dissolved in 100ml DMF. To the solution 20g of 2 (90% content, 1eq, 47.82mmol), 10.51g of 3b (d.r. = 9:1) (1.2eq, 57.38mmol), 6.3ml NMM (1.2eq, 57.38mmol) and 9.6ml DIC (1.3eq, 62.16mmol) were added at 0°C. the reaction mixture was warmed to 40°C in 1.5h and stirred at that temperature until complete conversion was observed. To the reaction mixture isopropyl acetate was added followed by the addition of 10% HCI. The organic phase was separated and washed with 5% ammonia and 2% NaCI. The organic solvent was removed to dryness and 26.95g was isolated as a diasteromeric mixture of 9:1 detected via NMR.</div>
<div num="p0173" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
6g of this material was dissolved in 15ml ethanol and 15ml water. To the mixture 1.15g sodium hydroxide was added. The reaction mixture was stirred at room temperature until no further conversion was observed. Ethanol was removed via distillation and water was added. The basic aqueous phase was washed with isopropyl acetate, the organic phase was re-extracted with water. To the combined aqueous phase Isopropyl acetate was added an pH was adjusted to 1.5 via addition of 10% HCI. The organic phase was separated and solvent was removed to dryness to yield 5.29g of compound 7 as a single diastereomer according to NMR analysis.</div>
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Example 2d - Use of CuCI? as anti isomerisation reagent (without any triazol reagent) 353mg water free CuCI<sub>2</sub> (1.1eq, 2.63mmol) was dissolved in 5ml DMF. To the solution 1g 2 (90% content, 1eq, 2.39mmol), 567mg 3b (1.3eq, 3.11 mmol) and 391 mg DIC (1.3eq,</div>
<div num="p0175" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
3.1 1 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 19h full conversion to 5b with d.r. 116/1 was observed. To the reaction mixture 50ml of ethyl acetate was added and the occurring precipitation was removed via filtration. The organic phase was washed with 5% ammonia and the aqueous phase was reextracted with 50ml ethyl acetate. The combined organic phase was washed with 40ml 2M HCI and 40ml brine. After drying with sodium sulfate and filtration the organic solvent was removed via evaporation. The solid residue was dissolved in 20ml methylene chloride and again the solvent was removed to dryness. After drying (rt, 40mbar), 1.373g of a slightly yellow amorphous solid (NMR content 81.6%, yield 86.4%).</div>
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Example 3 - Synthesis of the compound according to Formula 6</div>
<div num="p0177" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(1S,3aR,6aSV2-((S)-2- SV2-cvclohexyl-2-(pyrazine-2-carboxamido)acetamidoV3,3- dimethylbutanoyl)-N-((S)-1-(cvclopropylamino)-2-hvdroxy-1-oxohexan-3- yl)octahvdrocvclopentarclpyrrole-1-carboxamide (6)</div>
<div num="p0178" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000028_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000028_0001" class="patent-full-image" file="imgf000028_0001.tif" he="30" height="120" id="imgf000028_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000028_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="168" width="672" /></a></div>
<div num="p0179" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A round-bottom flask was charged with 11.87g of 7 (23.11 mmol, 1 eq.), 5.32g of EDC<sup>*</sup>HCI (27.73mmol, 1.2 eq.), 3,74g of HOBt (27.73 mmol, 1.2 eq.) and 80 mL DCM were added. The mixture was cooled with an ice-bath and a suspension of 5.66g of 4 (25.42mmol, 1.1 eq.) in 50 mL of DCM containing 2.75g NEt<sub>3</sub> (27.73 mmol, 3.88mL, 1.2 eq.) was added. This mixture was then stirred at r.t. for 6h when conversion was complete.</div>
<div num="p0180" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The reaction was quenched by addition of 50ml_ H<sub>2</sub>0, followed by dropwise addition of 6M HCI to adjust the pH to 1.45. The aqueous layer was separated and extracted once with 50ml_ DCM. The combined organic layers were washed with 50ml_ sat. NaHC0<sub>3</sub> solution and 50mL brine, dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo. Purification by flash</div>
<div num="p0181" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
chromatography yielded 6 (14.89g, 94% yield).</div>
<div num="p0182" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 4 - Synthesis of the compound according to Formula 1</div>
<div num="p0183" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
(1S,3aR,6aS)-2-((S)-2-((S)-2-cvclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3.3- dimethylbutanoyl)-N-((S)-1-(cvclopropylamino)-1 ,2-dioxohexan-3- yl)octahvdrocvclopentaFclpyrrole-1-carboxamide (Telaprevir) (1)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000029_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000029_0001" class="patent-full-image" file="imgf000029_0001.tif" he="30" height="120" id="imgf000029_0001" img-content="drawing" img-format="tif" inline="yes" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2013135870A1/imgf000029_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="167" width="668" /></a></div>
<div num="p0184" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
A round-bottom flask was charged with 2.00g of 6 (2.93 mmol, 1 eq.) and 20mL of DCM and then cooled with an ice-bath. 200μΙ of 15% KBr-solution and 800μΙ of sat. NaHC0<sub>3</sub>-solution were added, followed by 1 1 mg of TEMPO (0.07mmol, 0.025 eq.) and 600μΙ 10% NaOCI- solution. After stirring at r.t. for 18h, another 1.2ml_ of 10% NaOCI-solution were added - after another 2h the reaction was complete.</div>
<div num="p0185" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The reaction mixture was then diluted with 10mL of H<sub>2</sub>0. After separation of the aqueous layer it was extracted with 10ml_ of DCM. The combined organic layers were washed with 10ml_ of 1 % Na<sub>2</sub>S0<sub>3</sub> and 10ml_ of H<sub>2</sub>0, dried over Na<sub>2</sub>S0<sub>4</sub>, filtered and concentrated in vacuo.</div>
<div num="p0186" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The residue was then stirred in 40ml_ Et<sub>2</sub>0, filtered, washed with 10ml_ of cold Et<sub>2</sub>0 and then dried in vacuo to give crystalline 1 (1 .41g, 71 %).</div>
<div num="p0187" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Cited literature</div>
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WO 2007/022459 A2; Turner et al. (Chemical Communications 2010, 46(42), 7918); WO2010/126881 ; Y. Yip et al. Bioorg. Med. Chem. Lett., 2004, 14, 5007; Harbeson, S. L. et al. J. Med. Chem. 1994, 37, 2918-2929.</div>
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<br /></div>
<table class="patent-data-table" style="background-color: white; border-bottom-color: rgb(209, 209, 209); border-bottom-width: 2px; border-collapse: collapse; border-style: none none solid; color: #333333; font-family: Arial, sans-serif; font-size: 13.2799997329712px; line-height: 18px; margin: 10px 0px 0px 18px;"><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.im/patents/WO2007022459A2?cl=en" style="color: #6611cc; text-decoration: none;">WO2007022459A2</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">18 Aug 2006</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">22 Feb 2007</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Vertex Pharma</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Processes and intermediates</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;"><a href="http://www.google.im/patents/WO2010126881A1?cl=en" style="color: #6611cc; text-decoration: none;">WO2010126881A1</a></td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">27 Apr 2010</td><td class="patent-data-table-td patent-date-value" style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px; white-space: nowrap;">4 Nov 2010</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Vertex Pharmaceuticals Incorporated</td><td class="patent-data-table-td " style="border-bottom-color: rgb(236, 236, 236); border-bottom-style: solid; border-bottom-width: 1px; padding-bottom: 3px; padding-right: 25px; padding-top: 3px;">Processes and intermediates</td></tr>
</tbody></table>
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PATENT</div>
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<span style="font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><a href="http://www.google.im/patents/WO2010126881A1?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.im/patents/WO2010126881A1?cl=en</a></span><br /><br /><br /><br /><br /><br /><div class="patent-image" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px; text-align: center;">
<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000050_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000050_0001" class="patent-full-image" file="imgf000050_0001.tif" he="23" height="92" id="imgf000050_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000050_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="129" width="516" /></a></div>
<div num="p0391" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
5 6 7 8 (rac)</div>
<div num="p0392" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000050_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000050_0002" class="patent-full-image" file="imgf000050_0002.tif" he="16" height="64" id="imgf000050_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000050_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="132" width="528" /></a></div>
<div num="p0393" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
9 10 1</div>
<div num="p0394" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Scheme I</div>
<br /><br /><div num="p0400" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Scheme II</div>
<div num="p0401" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000052_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000052_0001" class="patent-full-image" file="imgf000052_0001.tif" he="124" height="496" id="imgf000052_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000052_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="137" width="548" /></a></div>
<br /><br /><br /><br /><div num="p0418" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
a cyclopropylamide of Formula 18 is prepared using the Passeπni reaction (see, e.g., A. Doemling et al., Angew. Chem., 2000, 1 12, 3300-3344). Scheme IV</div>
<div num="p0419" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000054_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000054_0001" class="patent-full-image" file="imgf000054_0001.tif" he="60" height="240" id="imgf000054_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000054_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="113" width="452" /></a></div>
<br /><br /><div num="p0424" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Scheme V</div>
<div num="p0425" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000056_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000056_0001" class="patent-full-image" file="imgf000056_0001.tif" he="82" height="328" id="imgf000056_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000056_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="151" width="604" /></a></div>
<div class="patent-image" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px; text-align: center;">
<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000056_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000056_0002" class="patent-full-image" file="imgf000056_0002.tif" he="24" height="96" id="imgf000056_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000056_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="87" width="348" /></a></div>
<div num="p0426" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
34</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000056_0003.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000056_0003" class="patent-full-image" file="imgf000056_0003.tif" he="63" height="252" id="imgf000056_0003" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000056_0003.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="99" width="396" /></a></div>
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<div num="p0109" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
The invention further relates to a process for piepaπng a compound of Formula 4</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000014_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000014_0001" class="patent-full-image" file="imgf000014_0001.tif" he="33" height="132" id="imgf000014_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000014_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="100" width="400" /></a></div>
<div num="p0110" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[0060] In some embodiments, the process for preparing compounds of Formula 4 includes the steps of i) providing an N-alkoxycarbonyl-S-azabicycloP 3 0]octane, ii) forming a 2-anion of the N-alkoxycarbonyl-3-azabicyclo[3 3 0]octane in the presence of a chelating agent, iii) treating the anion of step ii) with carbon dioxide to produce a cis /trans mixture of N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole- l-carboxyhc acids, iv) treating the mixture of step iii) with a strong base to produce an essentially pure trans- N-alkoxycarbonyl-octahydrocyclopenta[c]ρyrrole-l -carboxyhc acid, v) forming a salt of the carboxylic acid with an optically active amine, vi) crystallizing the salt, vii) esteπfying the salt provided in step vi), viii) removing the N-alkoxycarbonyl gioup to produce (lS,3aR,6aS)-f-butyl- octahydiocyclopenta[c)pyiτole-l -carboxylate, /-butyl ester, ix) reacting the bicyclic of step viii) with a protected amino acid of Formula 26,</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000014_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000014_0002" class="patent-full-image" file="imgf000014_0002.tif" he="16" height="64" id="imgf000014_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000014_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="24" width="96" /></a></div>
<div num="p0111" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
26 wherein Z is an amine protecting group, in the piesence of a coupling reagent, to pioduce an amide-ester of Formula 27,</div>
<div num="p0112" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000014_0003.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000014_0003" class="patent-full-image" file="imgf000014_0003.tif" he="30" height="120" id="imgf000014_0003" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000014_0003.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="47" width="188" /></a></div>
<div num="p0113" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
27 x) removing the protecting group Z from the amide-ester of step ix) to produce the amino compound of Formula 28,</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000015_0001" class="patent-full-image" file="imgf000015_0001.tif" he="21" height="84" id="imgf000015_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="36" width="144" /></a></div>
<div num="p0114" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
28 xi) reacting the amino compound of Formula 28 with a protected amino acid of Formula 29</div>
<div num="p0115" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Z-HN^<sub>/</sub>CO<sub>2</sub>H</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000015_0002" class="patent-full-image" file="imgf000015_0002.tif" he="14" height="56" id="imgf000015_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="10" width="40" /></a></div>
<div num="p0116" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
29 in the presence of a coupling reagent to produce a tripeptide of Formula 30;</div>
<div num="p0117" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0003.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000015_0003" class="patent-full-image" file="imgf000015_0003.tif" he="28" height="112" id="imgf000015_0003" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0003.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="53" width="212" /></a></div>
<div num="p0118" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
30 xii) removing the protecting group Z in the tripeptide of Formula 30 to produce a free amino-tripeptide of Formula 31;</div>
<div num="p0119" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0004.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000015_0004" class="patent-full-image" file="imgf000015_0004.tif" he="28" height="112" id="imgf000015_0004" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0004.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="51" width="204" /></a></div>
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31 xiii) reacting the amino-tripeptide of Formula 31 with pyrazine-2-carboxylic acid in the presence of a coupling reagent to produce an amide-tripeptide ester of Formula 33;</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0005.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000015_0005" class="patent-full-image" file="imgf000015_0005.tif" he="29" height="116" id="imgf000015_0005" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000015_0005.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="60" width="240" /></a></div>
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33 xiv) hydrolyzing the ester of the amide-tripeptide ester of Formula 33 to produce an amide-tripeptide acid of Formula 34;</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000016_0001" class="patent-full-image" file="imgf000016_0001.tif" he="28" height="112" id="imgf000016_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="64" width="256" /></a></div>
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34</div>
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XV) reacting the amide-tπpeptide acid of Formula 34 with an aminohydroxy-amide of Formula 18</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000016_0002" class="patent-full-image" file="imgf000016_0002.tif" he="17" height="68" id="imgf000016_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="27" width="108" /></a></div>
<span style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">18 in the piesence of a coupling reagent to produce a hydroxy-tetrapeptide of Formula 35, and</span><br /><div num="p0125" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0003.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000016_0003" class="patent-full-image" file="imgf000016_0003.tif" he="33" height="132" id="imgf000016_0003" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0003.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="105" width="420" /></a></div>
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35 xvi) oxidizing the hydroxy gioup of Formula 35 to produce the compound of Formula 4</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0004.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000016_0004" class="patent-full-image" file="imgf000016_0004.tif" he="33" height="132" id="imgf000016_0004" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000016_0004.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="99" width="396" /></a></div>
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Example 13: (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((S)-l-(cyclopropylamino)-l,2- dioxohexan-3-yl)octahydrocyclopenta[c]pyrrole-l -carboxamide (4)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000085_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000085_0001" class="patent-full-image" file="imgf000085_0001.tif" he="24" height="96" id="imgf000085_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000085_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="152" width="608" /></a></div>
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35 <sub>4</sub></div>
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Method 1</div>
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[00256] A 500 inL 3-neck round bottomed flask equipped with an overhead stirrer, condenser, thermocouple, and nitrogen outlet was purged with nitrogen for several minutes A methylene chloride solution of the hydroxyamide peptide amide 35 (128 64 g, 16-17wt%, 20 6 g and 30 mmol of 35) in methylene chloride was added to the reaction flask, followed by the addition of 15% w/w aq NaBr (13 mL) and 7 5% w/w aq NaHCO<sub>3</sub> (52 mL) The solution was cooled to 5±3 <sup>0</sup>C in an ice bath TEMPO (0 7 g) dissolved in methylene chloride (3 mL) was added to the reaction mixture In a separate Erlenmeyer flask, 10- 13% NaOCI solution (23 25 mL, titer = 108 mg/mL, 2 51 g, 33 7 mmol, 1 12 molar eq ) was diluted with water (70 mL) The NaOCI solution was charged to the reaction mixture via addition funnel at a rate that maintained the temperature below 8 <sup>0</sup>C The reaction mixture was allowed to stir at 5±3 <sup>0</sup>C for lhour The layers were separated and the organic layer was quenched with 10% (w/w) aq Na<sub>2</sub>SOs (100 mL) and washed with water (100 mL) The organic phase was reduced to dryness at reduced pressure and the solid triturated with ethyl acetate (100 mL) and filtered on a Buchner funnel to give the title compound Method 2</div>
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[00257] TEMPO (1 09 g, 6 95 mmol) was added to the methylene chloπde solution of 35 from Example 12, Method 2, followed by a solution of sodium bicarbonate (21 89 g, 260 5 mmol) in water (400 mL) and the mixture cooled to 0-5 <sup>0</sup>C A solution of sodium hypochlorite (122 17 g, 11 64 wt%, 191 04 mmol) was added over 2 hours while maintaining a temperature of 0-5 <sup>0</sup>C The mixture was stirred for 1 hour at 0-5 <sup>0</sup>C, then the phases separated The organic phase was washed with water (500 mL), 1 wt% aqueous sodium bisulfite (500 mL) and water (500 mL), then polish filtered The mixture was distilled at 38- 42 <sup>0</sup>C, 710 mm Hg, to a volume of about 320 mL Ethyl acetate (44 mL) was added followed immediately by 1 5 g of seed ciystals of 4 and the mixture was stirred for 15 minutes at 38-42 <sup>0</sup>C Ethyl acetate (800 mL) was added over 3 hours while maintaining a temperature of 38-42 <sup>0</sup>C The mixture was then distilled at 38-42 <sup>0</sup>C, 200-250 mm Hg, to a volume of about 400 mL Additional ethyl acetate (200 mL) was added over 0 5 hour The resultant slurry was cooled over 1 hour to 20-25 <sup>0</sup>C and stirred an additional hour at the same temperature The mixture was filtered and the filter cake washed with ethyl acetate (twice, 300 mL each) and dned under vacuum with a nitrogen bleed at 45-55 <sup>0</sup>C to give the title compound 4 as a white solid. Method 3</div>
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[00258] TEMPO (0 06 eq) was added to the CH<sub>2</sub>CI<sub>2</sub> solution of 35 from Example 12, method 3, and the solution was stirred at 20-25 <sup>0</sup>C until all TEMPO dissolved To this solution was added a solution of NaHCOi (1 5 eq ) in water (4 vol ) The resulting biphasic mixture was cooled to 0-5 <sup>0</sup>C While maintaining the reaction temperature at 0-5 <sup>0</sup>C, a 10-13 wt% NaOCl solution (1 10 eq ) was added over 2-3 hours and the mixture stirred for additional one hour The layers were separated and the organic layer was washed at 0-5 <sup>0</sup>C with H<sub>2</sub>O (5 vol ), 1 wt% Na<sub>2</sub>SO<sub>3</sub> (5 vol ), and H<sub>2</sub>O (5 vol ) Glacial acetic acid (0 12 eq ) was added to the solution of compound 4 in CH<sub>2</sub>Cl<sub>2</sub> to stabilize compound 4</div>
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Example 14: Recrystallization of Compound of Formula 4.</div>
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[00259] The solution of Compound 4 from Example 13, Method 3, was filtered through Cehte, and the filtrate solution was reduced to 3 1 -3 3 volumes by vacuum distillation at lower than 20 <sup>0</sup>C After distillation, the solution was brought to 38-42<sup>0</sup>C before EtOAc (0 80 vol ) was added, followed by the addition of Compound 4 seed (1 5 wt% relative to 34, Example 12) The resulting mixture was stirred for 15 minutes at 38-42 <sup>0</sup>C EtOAc (8 vol ) was added over 3 hours to this mixture while maintaining a temperature of 38-42 <sup>0</sup>C The total volume of the slurry was then reduced to 3 9-4 1 volumes by vacuum distillation at 38- 42 <sup>0</sup>C To this mixture was added EtOAc (2 vol ) over 30 minutes while maintaining the batch temperature at 38-42 <sup>0</sup>C The resulting slurry was then cooled to 20-25 <sup>0</sup>C over 1 hour and stirred at 20-25 <sup>0</sup>C for additional 1 hour. The slurry was filtered. The filter cake was washed with EtOAc (twice, 3 vol. each) and dried under vacuum with a nitrogen bleed at 45- 55 <sup>0</sup>C for 6 hours.</div>
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[00260] To the dried filter cake was added 2.2-2.4 volumes of CH<sub>2</sub>Ch to a total volume of 3.1-3.3 volumes. The mixture was broughl to 38-42 <sup>0</sup>C to give a homogeneous solution. EtOAc (0.80 vol) was added, followed by the addition of Compound 4 seed ( 1.5 wt% relative to 34, Example 12). The resulting mixture was stirred for 15 minutes at 38-42 <sup>0</sup>C. EtOAc (8 vol.) was added over 3 hours to this mixture while maintaining a temperature of 38-42 <sup>0</sup>C. The total volume of the slurry was then reduced to 3.9-4.1 volumes by vacuum distillation at 38-42<sup>0</sup>C. EtOAc (2 vol.) was added over 30 minutes to this mixture while maintaining the batch temperature at 38-42°C. The resulting slurry was then cooled to 20-25 <sup>0</sup>C over 1 hour and stirred at 20-25 <sup>0</sup>C for additional one hour. The slurry was filtered and the filter cake was washed with EtOAc (twice, 3 vol. each) and dried under vacuum with a nitrogen bleed at 45-55 <sup>0</sup>C for 12 hour to give purified Compound 4. <sup>1</sup>H NMR (500 MHz, CDCI3) 0.78 (m, 2H), 0.87 (m, 2H), 0.91 (s, 9H), 0.91 (t Lobscured], 3H), 0.98 (m, 4H), 1.08 (m, IH), 1.20 (m, 4H), 1.29 (m, IH), 1.40 (m, IH), 1..42 (m, 2H), 1.46 (m, IH), 1.48 (m, IH), 1.60 (m, IH), 1.70 (m, IH), 1.79 (m, IH), 1.83 (m, 2H), 1.88 (m, IH), 1.94 (m, IH), 2.67 (m, IH), 2.89 (bs, IH), 2.96 (bs, IH), 3.63 (d, IH), 3.99 (d, IH), 4.70 (s, IH), 4.82 (d, IH), 4.89 (t, IH), 5.65 (bs, IH), 7.74 (bs, IH), 8.00 (bs, I H), 8.06 (bs, IH), 8.29 (bs, IH), 8.60 (s, IH), 8.77 (s, I H), 9.42 (s, IH).</div>
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Example 15: (lS,3a#,6aS)-2-((,S>2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-Λ'-((S)-l-(cyclopropylamino)-l,2-dioxo- hexan-3-yl)octahydrocyclopenta[c]pyrrole-l-carboxamide (4)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000087_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000087_0001" class="patent-full-image" file="imgf000087_0001.tif" he="36" height="144" id="imgf000087_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2010126881A1/imgf000087_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="81" width="324" /></a></div>
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PATENT</div>
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<span style="font-size: 14.4899997711182px; line-height: 21.7350006103516px;"><a href="http://www.google.im/patents/WO2007022459A2?cl=en" style="color: #6c1b00; text-decoration: none;">http://www.google.im/patents/WO2007022459A2?cl=en</a></span><br /><br /><br /><br /><br /><div num="p0286" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 1: N-/-butyloxycarbonyI-3-azabicycIo[3.3.0]octane (6)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000050_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000050_0001" class="patent-full-image" file="imgf000050_0001.tif" he="27" height="108" id="imgf000050_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000050_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="55" width="220" /></a></div>
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6</div>
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Method 1</div>
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[00177] To a 2 L 3-necked round-bottom flask under nitrogen fitted with a mechanical stirrer, a 500 niL addition funnel, and a thermometer was charged 3-azabicyclo[3.3.0]nonane hydrochloride (100 g, 0.677 mol), potassium carbonate (187 g, 1.35 mol), /-butyl methyl ether (220 mL) and water (160 mL), with stirring. The mixture was cooled to 14-16 °C. In a separate 500 mL erylenmeyer flask was charged Boc<sub>2</sub>O (di-t-butyl dicarbonate) (145 g, 0.644 mol) and t-butyl methyl ether (190 mL). The mixture was stirred until complete dissolution was obtained. The solution was poured into the addition funnel and added to the above reaction mixture, keeping the reaction temperature below 25 °C. Water (290 mL) was added to dissolve solids, and the mixture was stirred for 10-15 minutes. After separating the lower aqueous phase, the organic phase was washed with 5% aq. NaHSO<sub>4</sub> (twice, 145 mL each), then water (145 mL). The organic phase was concentrated and methyl t-butyl ether was added (1.3 L) to give a solution of the title compound in t-butyl methyl ether. See, e.g., R.Griot, HeIv. CMm. Acta., 42, 67 (1959).</div>
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Method 2</div>
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[00178] A solution of potassium carbonate (187 g, 1.35 mol) in water (160 mL) was added to a mixture of 3-azabicyclo[3.3.0]octane hydrochloride (100 g, 0.677 mol) and t-butyl methyl ether (220 mL), and the resultant mixture was cooled to 14-16 °C. A solution of Boc<sub>2</sub>O (145 g, 0.644 mol) in t-butyl methyl ether (190 mL) was added while maintaining a temperature below 35 <sup>0</sup>C. After the addition, the mixture was stirred for 1 hour then filtered. The solids were washed with MTBE (50 mL). The phases were separated and the organic phase washed with 5% aq. NaHSO<sub>4</sub> (twice, 145 mL each) and water (145 mL) and concentrated to 300 mL under vacuum. MTBE (300 mL) was added and the mixture concentrated to remove water to less than 550 ppm. The concentrate was diluted with MTBE (400 mL) to provide a solution of the title compound in MTBE.</div>
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Example 2: mc-2-(/-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid (7)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000051_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000051_0001" class="patent-full-image" file="imgf000051_0001.tif" he="30" height="120" id="imgf000051_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000051_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="66" width="264" /></a></div>
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6 7</div>
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Method 1</div>
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[00179] The solution from Example 1, Method 1, was charged to a 5 L 4-necked flask fitted with a mechanical stirrer, an addition funnel, a ReactIR probe, and a thermometer. 3,7- Dipropyl-3,7-diazabicyclo[3.3.1]nonane (183 g, 0.88 mol) was charged to the flask. Data collection was started on the ReactIR instrument, and the solution was cooled to -72 to -75 <sup>0</sup>C. sec-Butyllithium (600 mL, 1.6 M in cyclohexane) was slowly added to the reaction mixture, keeping the reaction temperature below -69 <sup>0</sup>C. The addition was monitored with the ReactIR instrument, and the addition was stopped after the absorbance at 1698 cm<sup>"1</sup> had disappeared and the absorbance at 1654 cm<sup>"1</sup> ceased to increase for three consectutive scans (2-minute intervals). The solution was agitated for 3 hours at -75 to -72 °C. A 10% mixture of CO<sub>2</sub> in nitrogen was carefully sparged into the reaction mixture, keeping the reaction temperature below -70 °C. The sparge was stopped after the absorbance for CO<sub>2</sub> appeared in the ReactIR spectrum (2350 cm<sup>"1</sup>). The mixture was warmed to 0-5 <sup>0</sup>C, and a solution of 30 wt% NaHSO<sub>4</sub>(1.4 L) was added. The mixture was warmed to 22-25 °C and stirred for 30 minutes. The aqueous phase was separated and the organic phase washed with water (700 mL). The aqueous phase was decanted and the organic phase concentrated to provide the title compound.</div>
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Method 2</div>
<div num="p0297" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00180] A solution of 3,7-dipropyl-3,7-diazabicyclo[3.3.1]nonane (183 g, 0.87 mol) in</div>
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MTBE (300 mL) was added to the solution of N-t-butyloxycarbonyl-3- azabicyclo [3.3.0] octane from Example 1, Method 2 in a flask fitted with a mechanical stirrer, an addition funnel, a ReactIR probe, and a thermometer and the mixture was cooled to -75 to</div>
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-72 <sup>0</sup>C. A solution of sec-butyllithium (510 mL, 1.6 M) was added, keeping the reaction temperature below -70 °C, until the absorbance at 1698 cm<sup>"1</sup> had disappeared and the absorbance at 1654 cm<sup>"1</sup> ceased to increase. The solution was stirred for 3 hours at -75 to -72</div>
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°C. The reaction mixture was sparged with 10% CO<sub>2</sub> in N<sub>2</sub> keeping the reaction temperature e ow - /υ "U. lne sparge was stoppe w en t e a sor ance or <sub>2</sub> appears in the eact spectrum (2339 cm<sup>"1</sup>). The mixture was warmed to 0-5 °C and a solution of 30 wt% NaHSO<sub>4</sub> (1.4 L) was added and the mixture was warmed to 22-25 °C then stirred 30 minutes. The phases were separated and the aqueous phase was checked to make sure the pH was lower than 3. The organic phase was washed with water (700 mL) then concentrated to 300 mJL Ethyl acetate (1.7 L) was added and the mixture concentrated to 300 mL twice to give a solution of the title compound in ethyl acetate.</div>
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Example 3: (S)-l,2,3,4-tetrahydronaphthalen-l-aminium (lS,3aR,6aS)-2-(f- butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l-carboxylate (9a)</div>
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</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000052_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000052_0001" class="patent-full-image" file="imgf000052_0001.tif" he="28" height="112" id="imgf000052_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000052_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="104" width="416" /></a></div>
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8 9a</div>
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Method 1</div>
<div num="p0305" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00181] Ethyl acetate (2.3 L) was added to the residue of Example 2, method 1, and the mixture filtered through a pad of Celite<sup>®</sup>. (S)-1 ,2,3,4-tetrahydro-l-naphthylamine (56.7 g, 0.385 mol) was added and the solution was stirred for 3-4 hours at 22-25 <sup>0</sup>C. The mixture was filtered and the solids were rinsed with ethyl acetate (200 mL). The solids were dried at 20-30 <sup>0</sup>C under vacuum for 4 hours to give 99.02 g of product (73% yield, 90% ee by chiral HPLC).</div>
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[00182] To a 3-necked RBF fitted with a temperature contoller, a mechanical stirrer, a reflux condenser, and a nitrogen bubbler, was charged the (S)-l,2,3,4-tetrahydro-l- naphthylammonium salt (88.98g, 0.22 mol), ethyl acetate (712 mL), and 2-propanol (666 mL). The mixture was warmed to 70-75 <sup>0</sup>C with stirring. The mixture was stirred for 15-30 minutes, then cooled to -5 to -10 °C over 1 hour. The resultant slurry was filtered and the solids were rinsed with cold ethyl acetate (180 mL). The solids were dried in vacuo at 35-40 °C to give 7.37 g of a white solid (83% yield, 98% ee).</div>
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Method 2</div>
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[00183] The ethyl acetate solution of racemic N-t-butyloxycarbonyl-3- azabicyclo[3.3.0]octane-2-carboxylic acid from Example 2, Method 2, was added to a solution of (S)-l,2,3,4-tetrahydro-l-naphthylamine (56.7 g, 0.385 mol) in ethyl acetate (300 mL). The mixture was strirred for 3-4 hours at 22-25 °C, then filtered, and the solids washed with ethyl acetate (200 mL). The product was dried at 20-30 °C under vacuum for 4 hours to give the title compound (99.02 g, 36% yield) with a 95 to 5 diasteromer ratio. [00184] A mixture of the salt as prepared above (89.0 g), ethyl acetate, and 2-propanol was warmed to 70-75 <sup>0</sup>C until complete dissolution. The mixture was cooled to -5 to -10 <sup>0</sup>C over two hours and stirred for 3-4 hours. The mixture was filtered and the product dried at 35-40 <sup>0</sup>C to give the title compound (73.7g, 83% yield, >99.5% ee).</div>
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Example 4: (R)-l-phenylethanaminium (lS,3aR,6aS)-2-(f- butoxycarbonyl)octahydrocyclopenta[c]pyrrole-l-carboxylate (9b)</div>
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</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000053_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000053_0001" class="patent-full-image" file="imgf000053_0001.tif" he="28" height="112" id="imgf000053_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000053_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="106" width="424" /></a></div>
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8 9b</div>
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[00185] To a soution of racemic N-t-butyloxycarbonyl-3-azabicyclo[3.3.0]octane-2- carboxylic acid (4.66 g) in ethyl acetate (100 mL) was added (R)-α-methylbenzylamine (56.7 g) and the solution was stirred for 16 hr at 22-25 °C. The mixture was filtered and the solids were rinsed with ethyl acetate. The solids were dried at 20-30 °C under vacuum for 4 hours to give 1.47 g of product (43%, 82% ee, 92:8 ratio of exorendo diastereomers).</div>
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Example 5: (lS,3aR,6aS)-tf-butyl octahydrocyclopenta[c]pyrrole-l-carboxylate, t- butylester, oxalate</div>
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</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000053_0002.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000053_0002" class="patent-full-image" file="imgf000053_0002.tif" he="32" height="128" id="imgf000053_0002" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000053_0002.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="116" width="464" /></a></div>
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9a</div>
<div num="p0316" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 1</div>
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[00186] A mixture of the (S)- 1 ,2,3 ,4-tetrahydro- 1 -naphthylammonium salt prepared as in</div>
<div num="p0318" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 3, Method 1 (81.7 g, 0.203 mol), /-butyl methyl ether (400 mL) and 5% NaHSO<sub>4</sub>- H<sub>2</sub>O (867 mL, 0.304 mol) was stirred for 30 minutes until all solids were dissolved. The organic phase was washed with water (334 mL) then concentrated to 259 mL. /-Butyl methyl ether (334 mL) was added and the solution was concentrated again to 259 mL. The addition- concentration process was repeated twice more. After the final concentration, t-BuOH (158 mL) and dimethylaminopyridine (5.04 g, 41.3 mmol) were added. A solution of BoC<sub>2</sub>O (67.6 g, 0.31 mol) in t-butylmethyl ether (52.0 mL) was added. After stirring for 5 hours at ambient temperature, /-butyl methyl ether (158 mL) and 5% aqueous NaHSO<sub>4</sub>-H<sub>2</sub>O (260 mL) were added and the resultant mixture was stirred. The organic phase was washed with 5% aqueous NaCl (twice, 260 mL each). The organic phase was concentrated to 320 mL, and tetrahydrofuran (320 mL) was added. The organic phase was concentrated again to 320 mL, and tetrahydrofuran (320 mL) was added. After concentrating to 320 mL once more, methane sulfonic acid (80.1 g, 0.62 mol) was added and the solution was stirred at ambient temperature for 4.5 hours. The reaction mixture was added to a 30% aqueous solution of K<sub>2</sub>CO<sub>3</sub> (571 mL) and stirred. The aqueous phase was extracted with isopropyl acetate (320 mL). The combined organic phases were concentrated to 320 mL, and isopropyl acetate (320 mL) was added. The organic solution was concentrated again to 320 mL. The organic phase was washed with water (320 mL). Isopropyl acetate (320 mL) was added to the organic phase and the solution was concentrated to 192 mL. Isopropyl acetate (320 mL) was added a second time, and the organic solution was concentrated to 192 mL. A solution of oxalic acid (24.1 g, 267 mmol) in isopropyl acetate (448 mL) was added to the orgam<sup>'</sup>c solution over 2 hours. The mixture was stirred for 2-4 hours, and the slurry was filtered. The white solids were rinsed with isopropyl acetate (100 mL) and dried at 35-40 <sup>0</sup>C under vacuum to yield 52.6 g of the title compound (85% yield).</div>
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Method 2</div>
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[00187] A mixture of (S)- 1 ,2,3,4-tetrahydro- 1 -naphthylammonium salt as prepared by the method of Example 3, Method 2 (148 g, 0.609 mol), t-butyl methyl ether (726 mL) and 5% NaHSO<sub>4</sub>-H<sub>2</sub>O (1.58 L, 0.913 mol) was stirred until all of the solids had dissolved. The phases were separated and the organic phase washed with water (726 mL). The organic phase was concentrated to about 400 mL. t-Butyl methyl ether (726 mL) was added and the mixture concentrated to 590 mL. The addition of t-butyl methyl ether and concentration was repeated to give a final volume of 350 mL. Dimethylaminopyridine (8.42 g, 68.9 mmol) and t-butyl alcohol(260 mL) were added, followed by addition of a solution of BoC<sub>2</sub>O (112 g, 0.52 mol) in MTBE (88 mL) over 0.5 hour. The mixture was stirred for 5 hours at 22-25 <sup>0</sup>C.</div>
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A solution of 5% sodium bisulfate in water was added and the mixture stirred for 0.5 hour. The organic phase was washed with 5% sodium chloride (twice, 440 mL each) and concentrated to 270 mL. Tetrahydrofuran (540 mL) was added and the mixture concentrated to 270 mL; this procedure was repeated twice more to give a final volume of 270 mL. Methane sulfonic acid (67 mL) was added over 0.5 hour while maintaining a temperature of lower than 30 °C and the mixture stirred at 22-25 °C for 12 hours. The mixture was added to a 30% aqueous solution of pottassium carbonate (478 mL) while maintaining a temperature of 22-25 °C. The mixture was filtered, the phases separated and the aqueous phase extracted with isopropyl acetate (twice, 540 mL each). The organic phase was concentrated to 270 mL, then twice evaporated with isopropyl acetate (540 ml) to give a final volume of 540 mL. The organic phase was washed with water (twice, 540 mL), then twice evaporated with isopropyl acetate (320 mL) to give a final volume of 320 mL. Additional isopropyl acetate (429 mL) was added followed by addition of a solution of oxalic acid (40.4 g, 0.448 mol) in t- butylmethyl ether (321 mL) over 2 hours maintaining a temperature of 22-25 <sup>0</sup>C. The mixture was stirred for 3 hours at 22-25 <sup>0</sup>C then filtered. The filter cake was washed with isopropyl acetate (100 mL) and the prouduct dried at 35-40 °C under vacuum to give the title compound as a white solid (88.4g, 81%).</div>
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Example 6: (lS,3aR,6aS)-*-butyl 2-((S)-2-(benzyloxycarbonylamino)-3,3- dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate (27)</div>
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</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000055_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000055_0001" class="patent-full-image" file="imgf000055_0001.tif" he="33" height="132" id="imgf000055_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000055_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="166" width="664" /></a></div>
<div num="p0324" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 1</div>
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[00188] A 3-L 3-neck round bottomed flask equipped with an overhead stirrer, condenser, thermocouple, and nitrogen outlet was purged with nitrogen for several minutes. In a separate flask, sulfuric acid (46.2 mL, 0.867 mol) was diluted with 442 mL of water. The solution was allowed to cool slightly. Cbz-L-tert-Leucine dicyclohexylamine salt (330.0 g, 0.739 mol) was charged to the reaction flask. t-Butyl methyl ether (1620 mL) was added to the reactor, and the mixture was stirred to suspend the salt. The acid solution prepared above was added to the reactor over about 10 minutes, keeping the temperature at 20±5 °C. The mixture was stirred at room temperature for approximately 1 hour, then diluted slowly with water (455 mL). Agitation was stopped, and the layers were allowed to settle. The lower (aqueous) phase was withdrawn to provide 1100 mL colorless solution of pH 1. To the organic phase remaining in the flask was charged additional water (200 mL). The mixture was stirred at room temperature for approximately lhour. Agitation was stopped, and the layers were allowed to settle. The lower (aqueous) phase was withdrawn to provide 50OmL colorless solution of pH 2. The organic phase was heated to about 35 °C, diluted with DMF (300 mL), and concentrated under reduced pressure to the point at which distillation slowed significantly, leaving a concentrate of about 500 mL. The concentrate was transferred without rinsing to a 1-L Schott bottle. The concentrate, a clear colorless solution, weighed 511.6 g. Based on solution assay analysis and the solution weight, the solution contained 187.2 g (0.706 mol) Cbz-L-tørt-Leucine.</div>
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[00189] To a 5-L 4-neck round bottomed flask equipped with an overhead stirrer, thermocouple, addition funnel and nitrogen inlet were charged HOBT<sup>»</sup>H<sub>2</sub>O (103.73 g, 0.678 mol, 1.20 molar eq.), EDC-HCl (129.48 g, 0.675 mol, 1.20 molar eq.) and DMF (480 mL). The slurry was cooled to 0-5 <sup>0</sup>C. A 36.6 wt% solution of the acid of Cbz-L-tert-Leucine in DMF (491.3 g, 0.745 mol, 1.32 molar eq.) was added over 47 minutes to the reaction mixture while keeping the temperature at 0-5 °C. The reaction mixture was stirred for 1 hour and 27 minutes. A solution of 3-azabicyclo(3.3.0)octane-2-carboxylic acid /-butyl ester in isopropyl acetate (28.8 wt%, 414.3 g, 0.564 mol) was added over 53 minutes while keeping the reaction temperature at 0-5.1 <sup>0</sup>C. The reaction mixture was warmed to 20±5 °C over about lhour. 4- Methylmorpholine (34.29 g, 0.339 mol, 0.60 molar eq.) was added over 5 minutes. The reaction mixture was agitated for 16 hours then isopropyl acetate (980 mL) was added to the reaction solution. A solution of histamine*2HCl (41.58 g, 0.226 mol, 0.40 molar eq.) in water (53.02 g) was added to the reaction mixture within 4 minutes, followed by 4- methylmorpholine (45.69 g, 0.45 mol, 0.80 molar eq.). The reaction mixture was sampled after 3.5 hours. Water (758 mL) was added, the mixture stirred for about 20 minutes, then allowed to settle for 11 minutes. The phases were separated. The aqueous phase was extracted with isopropyl acetate (716 mL) and the organic phases were combined. IN aq. HCl was prepared by adding 37 wt% hydrochloric acid (128.3 mL) to water (1435 ml). The organic phase was washed for about 20 minutes with the IN hydrochloric acid. A 10wt% aq. K<sub>2</sub>CO<sub>3</sub> solution was prepared by dissolving K<sub>2</sub>CO<sub>3</sub> (171 g, 1.23 mol, 2.19 molar eq.) in water (1540 mL). The organic phase was washed with the 10 wt% aq. K<sub>2</sub>CO<sub>3</sub> solution for about 20minutes. The final clear, very slightly yellow organic solution, weighing 1862.1 g, was sampled and submitted for solution assay. Based on the solution assay and the weight of the solution, the solution contained 238.3 g (0.520 mol) of product of the title compound. <sup>1</sup>H NMR (DMSO-d<sub>6</sub>, 500 MHz): δ 7.37 ppm (5 H, s), 7.25-7.33 ppm (1 H, m), 5.03 ppm (2 H<sub>3</sub> s), 4.17 ppm (1 H, d), 3.98 ppm (1 H, d), 3.67-3.75 ppm (2 H, m), 2.62-2.74 ppm (1 H, m), 2.48-2.56 ppm (1 H, m), 1.72-1.89 ppm (2 H, m), 1.60-1.69 ppm (1 H, m), 1.45-1.58 ppm (2 H, m), 1.38 ppm (9 H, s), 1.36-1.42 ppm (1 H, m), 0.97 ppm (9 H, s).</div>
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Method 2</div>
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[00190] A solution of potassium carbonate (73.3 g) in water (220 mL) was added to a suspension of (IS, 2S,5R) 3-azabicyclo[3.3.0]octane-2-carboxylic, t-butylester, oxalate (80.0 g,) in isopropyl acetate (400 mL) while maintaining a temperature of about 20 <sup>0</sup>C. The mixture was stirred for 0.5 hour, tha phases separated and the organic phase washed with 25% w/w aqueous potassium carbonate (80 mL) to give a slution of the free base. In a separate flask, aqueous sulfuric acid (400 mL, 0.863 M) was added to a suspension of Cbz-t- leucine dicyclohexylamine salt (118.4g) in /-butylmethyl ether (640 mL) while maintaing a temperature of about 20 <sup>0</sup>C. The mixture was stirred for 0.5 hour, the phases separated and the organic phase washed with water (200 mL). The phase were separated and N- methylmorpholine (80 mL) was added to the organic phase which was concentrated under reduced pressure at 40 <sup>0</sup>C to 80 mL to give the free acid as a solution in N-methyl morpholine. This solution was added to a mixture of EDC* HCl (50.8 g) HOBt hydrate (40,6 g) in N-methylmorpholine (280 mL) at 0-10 <sup>0</sup>C. The mixture was stirred for 1 hour at about 5 <sup>0</sup>C. The solution of 3-azabicyclo[3.3.0]octane-2-carboxylic, t-butylester from above was added at 0-20 <sup>0</sup>C followed by N-methylmorpholine (32 mL). The mixture was stired for 6 hour then diluted with isopropyl acetate (600 mL) followed by IN HCl (400 mL). After stirring 0.5 hour, the phases were separated and the organic phase washed with 25% w/w aqueous potassium carbonate (400 mL) and water (80 mL). The mixture was stirred for about 1 hour and the phases separated to give a solution of the title compound in isopropyl acetate.</div>
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Method 3</div>
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[00191] (IS, 2S,5R) 3-azabicyclo[3.3.0]octane-2-carboxylic, /-butylester, oxalate (1.0 eq.) was suspended in isopropyl acetate (6 vol.) and a solution of potassioum carbonate (3.0 eq.) in water (3.5 vol.) was added at 20-25<sup>0</sup>C. The mixture was stirred for 3 hours then the phases separated. The organic phase was washed with water (2 vol.). [00192] Cbz-Meucine dicyclohexylamine salt (1.05 eq.) was suspended in isopropyl acetate (6 vol.) and sulfuric acid (1.3 eq.) in water (5 vol.) was added at 20-25<sup>0</sup>C. The mixture was stirred for 30 minutes, the phases separated, and the organic phase washed twice with water (2.5 vol each).</div>
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[00193] The two solutions from above were combined and then cooled to 0-5<sup>0</sup>C. HOBt hydrate (1.1 eq.) and EDC (1.1 eq.) were suspended in the mixture and the mixture stirred for 6 hours. The mixture was washed with water (5 vol.) and the resulting organic phase treated with L-lysine (1 eq.) and-N-methylmorpholine (NMM) (2 eq.) at 20-25<sup>0</sup>C to destroy excess activated ester. The mixture was then washed with 5% potassium carbonate (5 vol.), IN hydrochloric acid (5 vol.), 5% potassium carbonate (5 vol.) and twice with water (5 vol. each) to give a solution of the title compound in isopropyl acetate.</div>
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Example 7: (lS,3aR,6aS)-*-butyI 2-((S)-2-amino-3,3-dimethyIbutanoyl)- octahydrocyclopenta[c]pyrrole-l-carboxylate (28)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000058_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000058_0001" class="patent-full-image" file="imgf000058_0001.tif" he="23" height="92" id="imgf000058_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000058_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="104" width="416" /></a></div>
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Method 1</div>
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[00194] A 1 L Buchi hydrogenator was purged with nitrogen three times. A 307.8 g portion of a 12.8 wt% solution of (lS,3aR,6aS)-t-butyl 2-((S)-2-(benzyloxycarbonylamino)-3,3- dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate (as prepared by the method of Example 6, Method 1) in isopropyl acetate (39.39 g, 0.086 mol) was charged to the reactor. Isopropyl acetate (100 mL) was added to the reactor. A slurry of 50% water and wet 20% Pd(OH)<sub>2</sub>/carbon (3.97 g) in isopropyl acetate (168 mL) was prepared and charged to the reactor and agitation was started. The reactor was pressurized to 30 psig with nitrogen gas and vented down to atmospheric pressure. This was repeated twice. The reactor was pressurized to 30 psig with hydrogen and vented down to atmospheric pressure. This was repeated twice. The reactor was pressurized to 30 psig with hydrogen and stirred at ambient temperature for 1 hour. The mixture was filtered using a Buchner funnel with a Whatman # 1 filter paper to remove catalyst. The filter cake was washed with isopropyl acetate (80 mL). The procedure was repeated twice more using 617 g and 290.6 g of the 12.8 wt% solution of the starting Cbz compound. The material from the three hydrogenations were combined and distilled under reduced pressure (28" Hg). The resultant solution (468.68 g) was assayed for the title compound (23.2%, 98.9 % purity).</div>
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<sup>1</sup>H NMR (DMSO-d<sub>6</sub>, 500 MHz): δ 3.96 ppm (1 H, d), 3.67 ppm (1 H, dd), 3.53 ppm (1 H, dd), 3.19 ppm (1 H<sub>5</sub> s), 2.66-2.75 ppm (1 H, m), 2.49-2.53 ppm (1 H, m), 1.75-1.92 ppm (2 H, m), 1.66-1.74 ppm (1 H, m), 1.48-1.60 ppm (4 H, m), 1.38 ppm (9 H, s), 1.36-1.42 ppm (1 H<sub>5</sub> m), 0.91 ppm (9 H<sub>5</sub> s)</div>
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Method 2</div>
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[00195] The solution of the Cbz derivative 27 from Example 6, Method 2, was added to 20% Pd(OH)<sub>2</sub>/water (50%, 12.2 g) in a hydrogenation apparatus. The apparatus was pressurized to 30 psi with hydrogen then stirred for 2 hr at about 20 <sup>0</sup>C. The mixture was filtered to remove the catalyst, the filter cake washed with isopropyl acetate (160 mL). The combined filtrates were evaporated with about 4 volumes of heptane at 40 <sup>0</sup>C 2 to 3 times to remove the isopropyl acetate. The resultant slurry was cooled to 0 <sup>0</sup>C, filtered and the product dried under vacuum to give the title compound (78.8 g, 98.3% purity).</div>
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Method 3</div>
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[00196] Asolution of (1 S,3aR,6aS)-t-butyl 2-((S)-2-amino-3<sub>5</sub>3-dimethylbutanoyl)- octahydrocyclopenta[c]pyrrole-l-carboxylate in isopropyl acetate from Example 6, Method 3<sub>5</sub> was added to 20% Pd(OH)<sub>2</sub> (2 wt% loading, 50% wet) and the mixture was hydrogenated at 2 bar and 20-25 <sup>0</sup>C for 2 hours. The catalyst was removed by filtration and washed with isopropyl acetate (2 vol.). The filtrate was concentrated to 10 vol. under reduced pressure at 40 <sup>0</sup>C to give a solution of the title compound in isopropyl acetate.</div>
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Example 8: (lS,3aR,6aS)-*-butyl 2-((S)-2-((S)-2-(benzyloxycarbonylamino)-2- cycIohexylacetamido)-3,3-dimethyIbutanoyl)octahydrocyclopenta[c]pyrrole-l- carboxylate (30)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000059_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000059_0001" class="patent-full-image" file="imgf000059_0001.tif" he="32" height="128" id="imgf000059_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000059_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="139" width="556" /></a></div>
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Method 1 [00197] To a 3 L 3-neck round bottomed flask equipped with an overhead stirrer, thermocouple, addition funnel, nitrogen outlet and ice/water bath was charged HOBt*H<sub>2</sub>O (51.74 g; 0.338 mol, 1.05 molar eq.), EDCΗC1 (64.8 g; 0.338 mol, 1.05 molar eq.) followed by DMF (197.1 g, 208.8 mL) and agitation was started. The slurry was cooled to 0-5 <sup>0</sup>C, then a solution of the acid 29 (98.45 g; 0.338 mol, 1.05 molar eq.) in DMF (172.4 g; 182.9 mL) was prepared and charged to the addition funnel. This was added over about 30 minutes to the batch, maintaining the temperature at 0-5 <sup>0</sup>C. Once addition was complete the reaction mixture was agitated at 0-5 °C for 2 hours. The solution of the amine 28 in isopropyl acetate (450 g solution; containing 104.4 g of acid 29, 0.322mol) was charged to an addition funnel and added drop wise over lhour maintaining the temperature at 0-5 <sup>0</sup>C. Sample analysis indicated incomplete reaction and additional EDC hydrochloride (3.89 g) was added. After 3 hours, analysis of a sample showed 1.8% amine 28 remained. A slurry of HOBT»H<sub>2</sub>O (2.59 g; 0.0169 mol), and EDC»HC1 (3.24 g; 0.0169 mol) was prepared in DMF (10.44 mL) and cooled to 0-5 <sup>0</sup>C . A solution of acid 29 (4.92 g; 0.169 mol) in DMF (10.44 mL) was prepared and added to the slurry of EDC<sup>»</sup>HC1 and HOBT in DMF over 30minutes, maintaining the reaction temperature at 0-5 <sup>0</sup>C. The mixture was stirred for 1 hour at 0-5 <sup>0</sup>C then added to the original mixture maintaining 0-5 <sup>0</sup>C. The mixture was stirred for 14 hours at about 25 <sup>0</sup>C. A solution of histamine<sup>»</sup>2HCl (11.84 g; 0.064 mol) in water (8.9 mL) was prepared and added to the reaction mixture over 5-10 minutes. A charge of 4- methylmorpholine (13.01 g; 0.129 mol) was added to the batch over about 10 minutes, maintaining the batch temperature at 20±5 <sup>0</sup>C. The reaction mixture was diluted with isopropyl acetate (443 mL), followed by water (585 mL). A solution of potassium carbonate (57.8 g) in water (585 mL) was added and the mixture was stirred for 0.5 hour. The layers were separated the aqueous layer was extracted twice with isopropyl acetate (twice, 235 mL each). The combined organic phases were washed with 18 % aqueous HCl in water (585 mL), then NaHCO<sub>3</sub> (43.25 g) in water (585 mL). The layers were separated to give a light yellow solution of product 30 in isopropyl acetate weighing 1159.3 g (1275 mL) containing 16.0 w/w % 30 in isopropyl acetate.</div>
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<sup>1</sup>H NMR (DMSO-d<sub>6</sub>, 500 MHz): δ 7.74 (IH, d), 7.36 (5H, m), 7.34-7.26 (IH, m), 5.01 (2H, s), 4.51 (IH, d), 4.02 (IH, t), 3.96 (IH, d), 3.73 (IH, m), 3.66 (IH, m), 3.68 (IH, m), 2.53 (IH, m), 1.86-1.76 (2H, m), 1.70-1.30 (1OH, m), 1.39 (9H, s), 1.15-0.85 (5H, m), 0.96 (9H, s).</div>
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Method 2</div>
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[00198] A solution of Cbz acid 29 (59.62 g) in N-methylpyrrolidone (126 mL) was added to a suspension of EDCHCL (39.23 g) HOBt hydrate (31.34 g) in N-methylpyrrolidone (221 mL) while maintaining a temperature of about 0 <sup>0</sup>C. After the addition, the mixture was stirred for 1.5 hours at about 0 <sup>0</sup>C. A solution of the amine 28 (63.24 g, as prepared in Example 7, Method 2) in isopropyl acetate (632 mL) was added to the mixture maintaining a temperature of about 0 <sup>0</sup>C. After the addition the mixture was allowed to warm to room temperature and stirred for 5 hours. A solution of potassium carbonate (20.17g) in water (316 mL) was added while maintaining a temperature of about 20 <sup>0</sup>C. The mixture was vigorously stirred for 0.5 hour. The phases were separated and the organic phase vigorously stirred with potassium carbonate (105.3 g) in water (316 mL). The organic phase was separated and washed with IN HCl (316 mL), and then water (158 mL) to give a 12.7% w/w solution of the title compound 30 in isopropyl acetate.</div>
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Method 3 I</div>
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[00199] To a solution of (1 S,3aR,6aS)-t-butyl 2-((S)-2-amino-3,3-dimethylbutanoyl)- octahydrocyclopenta[c]pyrrole-l-carboxylate (1 eq) in isopropyl acetate (10 vol) was added NMP (5 vol) followed by EDC (1.15 eq), HOBT hydrate (1.0 eq) and (S)-2- (benzyloxycarbonylamino)-2-cyclohexylacetic acid (29, 1.05 eq) and the suspension was stirred at 20-25<sup>0</sup>C for 4 hr. The mixture was washed with 5% potassium carbonate (5 vol). A mixture of glycine (1 eq), NMM (2 eq) and water (1 vol) was added and the mixture stirred for 4 hr. The mixture was then washed with 5% potassium carbonate (5 vol), IN hydrochloric acid (5 vol), 5% potassium carbonate (5 vol) and twice with water (5 vol each) to give a solution of the title compound in isopropyl acetate.</div>
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Example 9: (lS,3aR,6aS)-fert-butyl 2-((S)-2-((S)-2-amino-2-cyclohexylacetamido)-3,3- dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate (31)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000061_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000061_0001" class="patent-full-image" file="imgf000061_0001.tif" he="32" height="128" id="imgf000061_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000061_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="137" width="548" /></a></div>
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Method 1</div>
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[00200] A 60-gallon hasteloy hydrogenating reactor was charged with a solution of the Cbz peptide 30 (15.1 kg) in isopropyl acetate (109 kg). This solution was reduced under vacuum at 50 <sup>0</sup>C to 68 L. The mixture was then cooled to 25±5 °C and MeOH (15.4 kg) added. This mixture was drained into a container and the reactor was dried. To the dried reactor was charged Pd(OH)<sub>2</sub>/C (20%, 1.51 kg). The solution containing the Cbz peptide 30 was added to W 2</div>
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the reactor and blanketed with hydrogen (30 psi). The reaction was stirred at 20±5 °C and at 150-220 rpm for 2 hours. After completion, a slurry of activated carbon (0.97 kg) in isopropyl acetate (6.8 kg) was added batch and the mixture stirred for 15 minutes. The mixture was filtered over Celite<sup>®</sup> (2.0 kg) via Sparkler filter and through a 0.1 -um cartridge filter. The reactor was rinsed with isopropyl acetate (33.0 kg) and the rinse was combined with the reaction mixture. The system was rinsed additionally with a mixture of isopropyl acetate (25.6 kg) and MeOH (5.73 kg). The combined organics were reduced under vacuum at 65 °C to 30 L. The solution was cooled to 20-30 °C and heptane added (30.8 kg). Distillation was instituted again and the mixture reduced to 30 L. This procedure was repeated for a total of 4 heptane additions (as above) and solvent reductions (as above). The mixture was cooled to 0-5 <sup>0</sup>C and the product filtered and washed with heptane (12.6 kg). The wet solid (14.0 kg) was dried under vacuum at 15-20 <sup>0</sup>C to constant weight to give the title compound (10.17 kg).</div>
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<sup>1</sup>H NMR (DMSOd<sub>6</sub>, 500 MHz): δ 7.97 (IH, d), 4.49 (IH<sub>5</sub> d), 3.96 (IH, d), 3.76 (IH, m), 3.67 (IH, m), 3.05 (IH, d), 2.70 (IH, m), 2.53 (IH, m), 1.87-1.77 (2H, m), 1.7-1.3 (1OH, m), 1.39 (9H, s), 1.2-0.85 (5H, m), 0.96 (9H, s).</div>
<div num="p0355" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 2</div>
<div num="p0356" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00201] The solution of compound 30 from Example 8, Method 1, was added to 50% wet 20 wt% Pd(OH)<sub>2</sub> on carbon (3.16 g) in a pressure reactor. The reactor was pressurized at 30 psi with hydrogen and the mixture stirred for about 1 hour. The catalyst was filtered, the filter washed with isopropyl acetate and the combined organics distilled to about 65 mL. The mixture was evaporated with heptane (316 mL) several times until analysis indicates <0.5% isopropyl acetate. The resultant slurry is diluted to about 320 mL then warmed to reflux. The solution was slowly cooled to about 5 <sup>0</sup>C, the suspension stirred for 1 hour then filtered. The filter cake was washed with about 65 mL of heptane and the product dried under vacuum at 30<sup>0</sup>C to give the title compound (80.16 g) as a white solid.</div>
<div num="p0357" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 3</div>
<div num="p0358" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00202] The solution of (1 S,3aR,6aS)-t-butyl 2-((S)-2-((S)-2-(benzyloxycarbonylamino)-2- cyclohexylacetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole- 1 -carboxylate in isopropyl acetate from Example 9, Method 3, was added to 20% Pd(OH)<sub>2</sub> (2 wt% loading, 50% wet) and the mixture hydrogenated at 2 bar and 20-25 <sup>0</sup>C for 2 hour. The catalyst was removed by filtration and washed with isopropyl acetate (1 vol.). The solvent was exchanged by distillation twice with heptane (8.6 vol.) at reflux. The mixture was cooled to 78 <sup>0</sup>C over 1 hour, then to 22 <sup>0</sup>C over 2 hours. After 1 hour at 22 <sup>0</sup>C the suspension was filtered and the cake washed with heptane (3.2 vol.) and the product dried under vacuum at 30 <sup>0</sup>C with a nitrogen purge to give the title compound.</div>
<div num="p0359" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 10: (lS,3aR,6aSH-butyl 2-((S)-2-((S)-2-cycIohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocycIopenta[c]pyrrole-l- carboxylate (33)</div>
<div num="p0360" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000063_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000063_0001" class="patent-full-image" file="imgf000063_0001.tif" he="33" height="132" id="imgf000063_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000063_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="165" width="660" /></a></div>
<div num="p0361" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 1</div>
<div num="p0362" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00203] To a 10OmL round bottomed flask was added pyrazine-2-carboxylic acid 32 (1.6070 g, 12.95 mmol) and DMF (4 mL). The slurry was stirred at 20-25 <sup>0</sup>C. Meanwhile, a solution of CDI was prepared by combining CDI (2.1012 g, 12.96 mmol, 1 molar eq.) and DMF (8.80 g, 9.3 mL) in a 25 mL flask. Mild heating (30 °C) aided in dissolution. The CDI solution was cooled to 20-25 <sup>0</sup>C and added to the slurry of pyrazine-2-carboxylic acid. Stirring was continued for 1.5 hours to assure complete activation of the acid as carbon dioxide was produced as a byproduct. Meanwhile, the amine 31 (5.0002 g, 10.78 mmol) was dissolved in DMF (14.15 g, 15 mL) with mild warming to 30 °C aided in the dissolution of the material. This solution was cooled to 20-25 °C. The activated pyrazine solution was also cooled to about 15 <sup>0</sup>C. The solution of compound 31 was added to the activated pyrazine carboxylic acid while maintaining the temperature at 30 <sup>0</sup>C for about 1 hour. The solution was allowed to cool to 20-25 <sup>0</sup>C then added to a solution of potassium carbonate (0.25 g) in water (100 mL) at 0 <sup>0</sup>C. The mixture was filtered and washed with water (four times, 50 mL each). The filter cake was dried under vacuum beginning at 20-25 °C and warmed to 30 <sup>0</sup>C after 24hours until the cake was constant weight to give the title compound (5.99 g). <sup>1</sup>H NMR (DMSO-d<sub>6j</sub> 500 MHz): δ 9.19 ppm (1 H, d, J =1.3 Hz), 8.90 ppm (1 H, d, J = 2.5 Hz), 8.76 ppm (1 H, dd, J = 2.4 Hz, 1.5 Hz), 8.50 ppm (1 H, d, J = 9.2 Hz)<sub>5</sub> 8.22 ppm (1 H, d, J = 9.0 Hz), 4.68 ppm (1 H, dd, J = 9.1 Hz, 6.6 Hz)<sub>5</sub> 4.53 ppm (1 H, d, J = 9.0 Hz), 3.96 ppm (1 H<sub>5</sub> d, J = 4.2 Hz), 3.73 ppm (1 H<sub>5</sub> dd, J = 10.5 Hz, 7.5 Hz), 3.68 ppm (1 H, dd, J = 10.6 ppm, 3.4 ppm), 2.68-2.74 ppm (1 H, m), 2.52-2.58 ppm (1 H, m), 1.70-1.88 ppm (3 H, m), 1.51-1.69 ppm (7 H, m), 1.31-1.44 ppm (2 H, m), 1.39 ppm (9 H, s), 1.00-1.19 ppm (4 H<sub>5</sub> m), 0.97 ppm (9 H, s), 0.91-0.97 ppm (1 H, m).</div>
<div num="p0363" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method!</div>
<div num="p0364" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00204] Oxalyl chloride (11.29 mL) was added to a solution of pyrazine-2-carboxylic acid 32 and N-methylmorpholine (59.28 mL) in methylene chloride (150 mL) at about 30 <sup>0</sup>C. The mixture was stirred for 0.5 hour, then a solution of the amine 31 (50.0 g) in methylene chloride (150 mL) was added at about 30 <sup>0</sup>C. After 0.5 hour, the mixture was washed with water (250 mL). The aqueous phase was extracted with methylene chloride (100 mL) to give a solution of the title compound in methylene chloride which was used directly in the next step (Example 11, Method 2).</div>
<div num="p0365" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 11: (lS)-2-((S)-2-((S)-2-cyclohexyI-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylic acid (34)</div>
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</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000064_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000064_0001" class="patent-full-image" file="imgf000064_0001.tif" he="32" height="128" id="imgf000064_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000064_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="162" width="648" /></a></div>
<div num="p0367" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 1</div>
<div num="p0368" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00205] Concentrated HCl (150 g, 0.015 mol, 1.2 molar eq.) was slowly added at 0 °C to a stirred solution of the pyrazinyl peptide 33 (50.0 g) in formic acid (100. Og). After 3.3 hours, the reaction mixture was diluted with 166.5 g of ice water. Methylene chloride (100 mL) was added and the reaction was stirred for 10 minutes to dissolve the product. The phases were separated and the aqueous layer extracted with methylene chloride (100 mL). The combined organic phases were washed with water (75 mL) then concentrated to about 1/3 volume at 50 <sup>0</sup>C, 1 atm. Toluene (100 mL) was added at room temperature and the homogeneous solution was evaporated under vacuum at <56 <sup>0</sup>C to about 1/3 volume. The mixture was cooled to 20- 25 <sup>0</sup>C as a precipitate formed. Heptane (75 mL) was slowly added and the slurry stirred for 10-15 minutes. The slurry was filtered and the filter cake was washed with heptane (50 mL). The solids were dried under vacuum at 20-25 °C to give the title compound (15.19 g).</div>
<div num="p0369" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 2 [00206] The methylene chloride solution of the starting compound 33 from Example 10, Method 2, was cooled to 0-5 <sup>0</sup>C then concentrated HCl (200 mL) was added while maintaining a temperature of <10 <sup>0</sup>C. The mixture was stirred for 3 hours, then diluted with water (200 mL) while maintaining a temperature of < 10 <sup>0</sup>C. The phases were separated and the aqueous phase extracted with methylene chloride (100 mL). The combined organic phases were washed with water (100 mL) and the aqueous wash phase extracted with methylene chloride. The combined organic extracts were refluxed under an inverse Dean- Stark trap to azeotrope water. The mixture was concentrated by distillation to a minimum volume then diluted with toluene (500 mL) then concentrated by distillation at atmospheric pressure to 250 mL. The mixture was slowly cooled to 20 <sup>0</sup>C over about 6 hours. The resultant slurry was filtered, the filter cake washed with toluene (100 mL) then dried at about 45 <sup>0</sup>C in a vacuum oven to provide the title compound (64.7 g) as a pale yellow powder containing about 17 % toluene.</div>
<br /><br /><br /><br /><br /><br /><div num="p0370" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Example 12: (lS,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-l-(cyclopropylamino)-2- hydroxy-l-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-l-carboxamide (35)</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000065_0001.png" style="color: #6611cc; text-decoration: none;"><img alt="Figure imgf000065_0001" class="patent-full-image" file="imgf000065_0001.tif" he="64" height="256" id="imgf000065_0001" img-content="drawing" img-format="tif" inline="no" orientation="portrait" src="http://patentimages.storage.googleapis.com/WO2007022459A2/imgf000065_0001.png" style="-webkit-box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; border: 0px; box-shadow: rgba(0, 0, 0, 0.498039) 1px 1px 5px; color: #999999; height: auto; max-width: 380px; padding: 8px; position: relative;" wi="106" width="424" /></a></div>
<div num="p0372" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 1</div>
<div num="p0373" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00207] A 500 mL 3-neck round bottomed flask equipped with an overhead stirrer, condenser, thermocouple, and nitrogen outlet was purged with nitrogen for several minutes. The peptide-acid 34 (25.0 g, 0.049 mol), EDC-HCl (10.35 g, 0.054 mol, 1.1 molar eq.), and HOBt-H<sub>2</sub>O (8.27 g, 0.054 mol, 1.1 molar eq.) were charged to the flask followed by 175 mL of methylene chloride. The mixture was stirred at room temperature for lhour then added over 20 minutes to a suspension of hydroxyamide-amine 18 (11.1 g, 0.054 mol, 1.1 molar eq.) in methylene chloride (75 mL) while maintaining a temperature below 10 °C. Upon W 2</div>
<div num="p0374" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
complete addition, N-methylmorpholine (5.94 mL, 0.054 mol, 1.1 molar eq.) was added in 2 portions. The mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched by the addition OfNaHCO<sub>3</sub> (8.0 g) in 200 mL of water. The phases were separated and the organic layer washed with water (175 mL), 0.5 N aq. HCl (200 mL), water (three times, 200 mL each) and saturated NaCl (200 mL) to give a 16% by weight methylene chloride solution of the title compound 35 of 100 A% purity (molar yield 100%).</div>
<div num="p0375" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 2</div>
<div num="p0376" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00208] N-methylmorpholine (38.19 mL, 347.3 mmol) was added to a mixture of the peptide-acid 34 (100.0 g, 89.2 wt%, 173.7 mmol), HOBt hydrate (26.79 g, 87.6 wt%, 173.7 mmol), EDCI (36.62 g, 191.04 mmol), and the hydroxyamide-amine 18 in methylene chloride over 30 minutes while maintaining a temperature of 0-5 <sup>0</sup>C. After the addition, the mixture was warmed to 20 <sup>0</sup>C and stirred for 5 hours. The mixture was then diluted with water (500 mL) and stirred for about 0.5 hour. The phases were separated and the organic phase washed with IN HCl (500 mL), 5 wt% aqueous sodium bicarbonate (500 mL) to give a solution of the title compound in methylene chloride, 98.5% AUC purity, 95% solution yield.</div>
<div num="p0377" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
Method 3</div>
<div num="p0378" style="background-color: white; color: #222222; font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 21.3333339691162px;">
[00209] Peptide acid 34 (1.00 eq.), EDCI (1.10 eq.), HOBt hydrate (1.00 eq.), and hydroxyamine 18<sup>«</sup>HC1 (1.05 eq.) were suspended in CH<sub>2</sub>Cl<sub>2</sub> (5 vol.) and the mixture was cooled to 0-5 <sup>0</sup>C. NMM (2.0 eq) was added over 30-60 minutes while maintaining the reaction temperature below 5°C. The reaction mixture was warmed to 20-25 °C over 30 minutes and stirred for additional 5 hours. The reaction was washed with water (5 vol.), IN HCl (5 vol), and 5 wt% aqueous NaHCO<sub>3</sub> (5 vol.) to provide a solution of the title compound in CH<sub>2</sub>Cl<sub>2</sub>.</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-7082350141827122272.post-52704066627556021012015-03-01T23:09:00.003-08:002015-03-01T23:09:45.600-08:00Atrasentan <div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="Atrasentan.svg" class="mw-mmv-dialog-is-open" src="http://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Atrasentan.svg/514px-Atrasentan.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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Atrasentan</div>
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A-147627, (+)-A-127722, ABT-627,173937-91-2,</div>
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Endothelin ET-A antagonist</div>
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Diabetic nephropathy; End stage renal disease; Renal disease</div>
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1-(N,N-Dibutylcarbamoylmethyl)-2(R)-(4-methoxyphenyl)-4(S)-(3,4-methylenedioxyphenyl)pyrrolidine-3(R)-carboxylic acid</div>
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(2R,3R,4S)-(+)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid</div>
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(2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid</div>
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C<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">29</sub>H<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">38</sub>N<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">2</sub>O<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">6</sub>, 510.631</div>
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<b style="font-weight: bold;">Atrasentan</b><span class="Apple-converted-space"> </span>is an experimental drug that is being studied for the treatment of various types of<span class="Apple-converted-space"> </span><a href="http://en.wikipedia.org/wiki/Cancer" style="color: #0c5390; text-decoration: none;" title="Cancer">cancer</a>,<sup class="reference" id="cite_ref-1" style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Atrasentan#cite_note-1" style="color: #0c5390; text-decoration: none;">[1]</a></sup><span class="Apple-converted-space"> </span>including non-small cell<span class="Apple-converted-space"> </span><a href="http://en.wikipedia.org/wiki/Lung_cancer" style="color: #0c5390; text-decoration: none;" title="Lung cancer">lung cancer</a>.<sup class="reference" id="cite_ref-2" style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Atrasentan#cite_note-2" style="color: #0c5390; text-decoration: none;">[2]</a></sup><span class="Apple-converted-space"> </span>It is also being investigated as a therapy for diabetic kidney disease.</div>
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Atrasentan failed a phase 3 trial for prostate cancer in patients unresponsive to hormone therapy.<sup class="reference" id="cite_ref-3" style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Atrasentan#cite_note-3" style="color: #0c5390; text-decoration: none;">[3]</a></sup><span class="Apple-converted-space"> </span>A second trial confirmed this finding.<sup class="reference" id="cite_ref-4" style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Atrasentan#cite_note-4" style="color: #0c5390; text-decoration: none;">[4]</a></sup></div>
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It is an<span class="Apple-converted-space"> </span><a href="http://en.wikipedia.org/wiki/Endothelin_receptor_antagonist" style="color: #0c5390; text-decoration: none;" title="Endothelin receptor antagonist">endothelin receptor antagonist</a><span class="Apple-converted-space"> </span>selective for<span class="Apple-converted-space"> </span><a href="http://en.wikipedia.org/wiki/Endothelin_receptor_type_A" style="color: #0c5390; text-decoration: none;" title="Endothelin receptor type A">subtype A</a><span class="Apple-converted-space"> </span>(ET<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">A</sub>). While other drugs of this type (<a href="http://en.wikipedia.org/wiki/Sitaxentan" style="color: #0c5390; text-decoration: none;" title="Sitaxentan">sitaxentan</a>,<span class="Apple-converted-space"> </span><a href="http://en.wikipedia.org/wiki/Ambrisentan" style="color: #0c5390; text-decoration: none;" title="Ambrisentan">ambrisentan</a>) exploit the<span class="Apple-converted-space"> </span><a class="mw-redirect" href="http://en.wikipedia.org/wiki/Vasoconstrictive" style="color: #0c5390; text-decoration: none;" title="Vasoconstrictive">vasoconstrictive</a>properties of endothelin and are mainly used for the treatment of<span class="Apple-converted-space"> </span><a class="mw-redirect" href="http://en.wikipedia.org/wiki/Pulmonary_arterial_hypertension" style="color: #0c5390; text-decoration: none;" title="Pulmonary arterial hypertension">pulmonary arterial hypertension</a>, atrasentan blocks endothelin induced<span class="Apple-converted-space"> </span><a class="mw-redirect" href="http://en.wikipedia.org/wiki/Cell_proliferation" style="color: #0c5390; text-decoration: none;" title="Cell proliferation">cell proliferation</a>.</div>
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In April 2014, de Zeeuw et al. showed that 0.5 mg and 1.25 mg of atrasentan reduced urinary albumin by 35 and 38% respectively with modest side effects. Patients also had decreased home blood pressures (but no change in office readings) decrease total cholesterol and LDL. Patients in the 1.25 mg dose group had increased weight gain which was presumably due to increased edema and had to withdraw from the study more than the placebo or 0.5 mg dose group.<sup class="reference" id="cite_ref-5" style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Atrasentan#cite_note-5" style="color: #0c5390; text-decoration: none;">[5]</a></sup><span class="Apple-converted-space"> </span>Reductions in proteinuria have been associated with beneficial patient outcomes in diabetic kidney disease with other interventions but is not an accepted end-point by the FDA.</div>
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The recently initiated SONAR trial<sup class="reference" id="cite_ref-6" style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Atrasentan#cite_note-6" style="color: #0c5390; text-decoration: none;">[6]</a></sup><span class="Apple-converted-space"> </span>will determine if atrasentan reduces kidney failure in diabetic kidney disease.</div>
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Useful for treating nephropathy and chronic kidney disease associated with Type II diabetes. For a prior filing see WO2015006219 , claiming the stable solid composition in the form of a tablet comprising atrasentan and an anti-oxidant. AbbVie (following its spin-out from Abbott), is developing atrasentan (phase III; February 2015) for treating chronic kidney disease, including diabetic nephropathy.</div>
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……………….</div>
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European Journal of Organic Chemistry</div>
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Enantioselective Synthesis of the Pyrrolidine Core of Endothelin Antagonist ABT-627 (Atrasentan) via 1,2-Oxazines</div>
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Year:2003<br />Volume:2003<br />Issue:18<br />page:3524-3533</div>
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<a href="http://www.google.com/patents/US20080132710" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/US20080132710</a></div>
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EXAMPLE 1</div>
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A mixture of bromoacetyl bromide (72.3 mL) in toluene (500 mL) at 0° C. was treated with dibutylamine (280 mL) in toluene (220 mL) while keeping the solution temperature below 10° C., stirred at 0° C. for 15 minutes, treated with 2.5% aqueous phosphoric acid (500 mL) and warmed to 25° C. The organic layer was isolated, washed with water (500 mL) and concentrated to provide the product as a solution in toluene.</div>
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EXAMPLE 25-((E)-2-nitroethenyl)-1,3-benzodioxole</div>
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3,4-methylenedioxybenzaldehyde (15.55 Kg) was treated sequentially with ammonium acetate (13.4 Kg,), acetic acid (45.2 Kg) and nitromethane (18.4 Kg), warmed to 70° C., stirred for 30 minutes, warmed to 80° C., stirred for 10 hours, cooled to 10° C. and filtered. The filtrant was washed with acetic acid (2×8 Kg) and water (2×90 Kg) and dried under a nitrogen stream then in under vacuum at 50° C. for 2 days.</div>
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EXAMPLE 3ethyl 3-(4-methoxyphenyl)-3-oxopropanoate</div>
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A mixture of potassium tert-amylate (50.8 Kg) in toluene (15.2 Kg) at 5° C. was treated with 4-methoxyacetophenone (6.755 Kg) and diethyl carbonate (6.4 Kg) in toluene over 1 hour while keeping the solution temperature below 10° C., warmed to 60° C. for 8 hours, cooled to 20° C. and treated with acetic acid (8 Kg) and water (90 Kg) over 30 minutes while keeping the solution temperature below 20° C. The organic layer was isolated, washed with 5% aqueous sodium bicarbonate (41 Kg) and concentrated at 50° C. to 14.65 Kg.</div>
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EXAMPLE 4ethyl 2-(4-methoxybenzoyl)-4-nitromethyl-3-(1,3-benzodioxol-5-yl)butyrate</div>
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A mixture of EXAMPLE 3 (7.5 Kg) in THF (56 Kg) was treated with EXAMPLE 3 (8.4 Kg), cooled to 17° C., treated with sodium ethoxide (6.4 g), stirred for 30 minutes, treated with more sodium ethoxide (6.4 g), stirred at 25° C. until HPLC shows less than 1 area % ketoester remaining and concentrated to 32.2 Kg.</div>
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EXAMPLE 5ethyl cis,cis-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate</div>
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Raney nickel (20 g), from which the water had been decanted, was treated sequentially with THF (20 mL), EXAMPLE 4 (40.82 g), and acetic acid (2.75 mL). The mixture was stirred under hydrogen (60 psi) until hydrogen uptake slowed, treated with trifluoroacetic acid, stirred under hydrogen (200 psi) until HPLC shows no residual imine and less than 2% nitrone and filtered with a methanol (100 mL) wash. The filtrate, which contained 13.3 g of EXAMPLE 5, was concentrated with THF (200 mL) addition to 100 mL, neutralized with 2N aqueous NaOH (50 mL), diluted with water (200 mL), and extracted with ethyl acetate (2×100 mL). The extract was used in the next step.</div>
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EXAMPLE 6ethyl trans,trans-2-(4-methoxyphenyl)-4-(1,3 -benzodioxol-5 -yl)pyrrolidine-3-carboxylate</div>
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Example 501E (38.1 g) was concentrated with ethanol (200 mL) addition to 100 mL, treated with sodium ethoxide (3.4 g), heated to 75° C., cooled to 25° C. when HPLC showed less than 3% of EXAMPLE 1E and concentrated. The concentrate was mixed with isopropyl acetate (400 mL), washed with water (2×150 mL) and extracted with 0.25 M phosphoric acid (2×400 mL). The extract was mixed with ethyl acetate (200 mL) and neutralized to pH 7 with sodium bicarbonate (21 g), and the organic layer was isolated.</div>
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EXAMPLE 7ethyl (2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate, (S)-(+) mandelate</div>
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EXAMPLE 501F was concentrated with acetonitrile (100 mL) addition to 50 mL, treated with (S)-(+)-mandelic acid (2.06 g), stirred until a solution formed, stirred for 16 hours, cooled to 0° C., stirred for 5 hours and filtered. The filtrant was dried at 50° C. under a nitrogen stream for 1 day. The purity of the product was determined by chiral HPLC using Chiralpak AS with 95:5:0.05 hexane/ethanol/diethylamine, a flow rate of 1 mL/min. and UV detection at 227 nm. Retention times were 15.5 minutes for the (+)-enantiomer and 21.0 minutes for the (−)-enantiomer.</div>
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EXAMPLE 8(2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid</div>
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A mixture of EXAMPLE 7 (20 g) in ethyl acetate (150 mL) and 5% aqueous sodium bicarbonate was stirred at 25° C. until the salt dissolved and gas evolution stopped. The organic layer was isolated and concentrated. The concentrate was treated with acetonitrile (200 mL), concentrated to 100 mL, cooled to 10° C., treated with diisopropylethylamine (11.8 mL) and EXAMPLE 1 (10.5 g), stirred for 12 hours and concentrated. The concentrate was treated with ethanol (200 mL), concentrated to 100 mL, treated with 40% aqueous NaOH (20 mL), stirred at 60° C. for 4 hours, cooled, poured into water (400 mL), washed with hexanes (2×50 mL then 2×20 mL), treated with ethyl acetate (400 mL) and adjusted to pH 5 with concentrated HCl (12 mL). The organic layer was isolated and concentrated.</div>
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The Michael reaction between 3,4-(methylenedioxy)-beta-nitrostyrene (I) and ethyl (4-methoxybenzoyl)acetate (II) in the presence of DBU gave adduct (III) as a mixture of isomers. Hydrogenation of this nitro ketone over Raney-Ni afforded, after spontaneous cyclization of the resulting amino ketone, the pyrroline (IV). Further reduction of the imine with NaBH3CN yielded a mixture of three pyrrolidine isomers. The desired trans-trans isomer (VI) could not be separated from the cis-trans isomer by column chromatography. However, the pure cis-cis compound (V) was isomerized to (VI) with NaOEt in refluxing EtOH. The protection of the amine as the tert-butyl carbamate with Boc2O, and saponification of the ester function provided the racemic acid (VII). Resolution of (VII) was achieved by conversion to the mixed anhydride (VIII) with pivaloyl chloride, followed by condensation with the lithium salt of (S)-4-benzyl-2-oxazolidinone (IX), and chromatographic separation of the resulting diastereomeric imides. Alternatively, racemic (VII) could be resolved by crystallization of its salt with (R)-a-methylbenzylamine. Removal of the Boc group from the appropriate isomer (X) with HCl in dioxan, followed by alkylation with N,N-dibutylbromoacetamide (XI) in the presence of i-Pr2NEt furnished the pyrrolidinylacetamide (XII). Finally, hydrolysis of the imide with lithium hydroperoxide provided the target acid.<a href="http://www.chemdrug.com/" style="color: #0c5390; text-decoration: none;"><img alt="" src="http://www.chemdrug.com/images/space.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></a></div>
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J Med Chem1996,39,(5):1039</div>
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Cyclization of 5-(2-nitrovinyl)-1,3-benzodioxole (I) with ethyl 2-(4-methoxybenzoyl)acetate (II) by means of DBU in THF gives the 4-nitrobutyrate (III), which is reduced with H2 over Ni in ethanol to the corresponding amine, which undergoes immediate cyclization to give the pyrroline carboxylate (IV). Reduction of pyrroline (IV) with NaCNBH3 in THF affords the expected pyrrolidine as a mixture of the (trans,trans)-(V), (cis,cis)-(VI) and (cis,trans)-(VII) isomers. Using chromatography on silica gel, only the (cis,cis)-isomer (VI) is separated and completely isomerized to the (trans,trans)-isomer (V) by treatment with NaOEt in refluxing ethanol. Pure (trans,trans)-isomer (V) or the remaining mixture of (trans,trans)-(V) and (cis,trans)-(VII) is N-protected with Boc2O in dichloromethane to provide a mixture of carbamates. Then hydrolysis of the esters is performed with NaOH in ethanol/water at room temperature, and under these conditions only the (trans,trans)-isomer hydrolyzes, giving the racemic (trans,trans)-acid (VIII). Unreacted (cis,trans)-ester (VII) is easily removed by conventional methods. Condensation of the racemic acid (VIII) with the lithium salt of the chiral oxazolidinone (IX) by means of pivaloyl chloride yields the corresponding amide as a diastereomeric mixture of (X) and (XI) that are separated by chromatography. The desired isomer (XI) is deprotected with HCl in dioxane to afford the chiral pyrrolidine (XII), which is condensed with 2-bromo-N,N-dibutylacetamide (XIII) by means of diisopropylamine in acetonitrile to give the adduct (XIV). Finally, the chiral auxiliary of (XIV) is eliminated by means of LiOOH (LiOH + H2O2) in water.<a href="http://www.chemdrug.com/" style="color: #0c5390; text-decoration: none;"><img alt="" src="http://www.chemdrug.com/images/space.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></a></div>
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J Med Chem1996,39,(5):1039</div>
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<a href="http://www.google.co.in/patents/US5767144" style="color: #0c5390; text-decoration: none;">http://www.google.co.in/patents/US5767144</a></div>
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EXAMPLE 95D(2R,3R,4S)-(+)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acidTo the resulting compound from Example 95C (131 mg, 0.355 mmol) was added, diisopropylethylamine (137 mg, 185 μL, 1.06 mmol), acetonitrile (2 mL), N,N-di-(n-butyl)bromoacetamide (133 mg, 0.531 mmol), and the mixture was heated at 50° C. for 1.5 hours. The reaction mixture was concentrated to a solid, dried under high vacuum, and purified by chromatography on silica gel eluting with 1:3 ethyl acetate-hexane to give pure ester as a colorless oil.<span class="Apple-converted-space"> </span><sup style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</sup><span class="Apple-converted-space"> </span>H NMR (CDCl<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">3</sub>, 300MHz) δ 0.81 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H), 1.10 (t, J=7 Hz, 3H), 1.00-1.52 (m, 8H), 2.78 (d, J=14 Hz,1H), 2.89-3.10 (m, 4H), 3.23-3.61 (m, 5H), 3.71 (d, J=9 Hz, 1H), 3.80 (s, 3H), 4.04 (q, J=7 Hz, 2H), 5.94 (dd, J=1.5 Hz, 2H), 6.74 (d, J=9 Hz, 1H), 6.83-6.90 (m, 3H), 7.03 (d, J=2 Hz, 1H), 7.30 (d, J=9 Hz, 2H). MS (DCl/NH<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">3</sub>) m/e 539 (M+H)<sup style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</sup>.To the ethyl ester dissolved in 7 mL of ethanol was added a solution of lithium hydroxide (45 mg, 1.06 mmol) in water (2.5 mL). The mixture was stirred for 1 hour at ambient temperature and then warmed slowly to 40° C. over 2.5 hours at which point all of the starting material had been consumed. The reaction mixture was concentrated to remove the ethanol, diluted with 60 mL water and extracted with ether (3×40 mL). The aqueous solution was treated with 1N aqueous hydrochloric acid until cloudy, and the pH was then adjusted to ˜4-5 with 10% aqueous citric acid. This mixture was extracted with 1:19 ethanol-methylene chloride (3×50 mL). The combined extracts were dried (Na<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">2</sub><span class="Apple-converted-space"> </span>SO<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">4</sub>), filtered, concentrated and dried under high vacuum to give the title compound as a white foam (150 mg, 83%).<span class="Apple-converted-space"> </span><sup style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</sup><span class="Apple-converted-space"> </span>H NMR (CDCl<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">3</sub>, 300MHz) δ 0.80 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H), 1.08 (m, 2H), 1.28 (m, 3H), 1.44 (m, 3H), 2.70-3.77 (svr br m, 12H), 3.79 (s, 3H), 5.95 (m, 2H), 6.75 (d, J=8 Hz, 1H), 6.87 (br d, J=8 Hz, 3H), 7.05 (br s,1H),7.33 (v br s, 2H). MS (DCl/NH<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">3</sub>) m/e 511 (M+H)<sup style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</sup>. α!<sup style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">22</sup>=+74.42°. Anal calcd for C<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">29</sub><span class="Apple-converted-space"> </span>H<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">38</sub><span class="Apple-converted-space"> </span>N<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">2</sub><span class="Apple-converted-space"> </span>O<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">6</sub>.0.5 H<sub style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">2</sub><span class="Apple-converted-space"> </span>O: C ,67.03; H, 7.56; N, 5.39. Found: C, 67.03; H, 7.59; N, 5.33.</div>
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<span class="mw-headline" id="References">References</span></h2>
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1</div>
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<li id="cite_note-1" style="list-style-type: square;"><span class="reference-text"><span class="citation web"><a class="external text" href="http://www.cancer.gov/dictionary?CdrID=45029" rel="nofollow" style="color: #0c5390; text-decoration: none;">“Atrasentan”</a>.<span class="Apple-converted-space"> </span><i style="font-style: italic;">NCI Dictionary of Cancer Terms</i>. National Institute of Cancer.</span></span></li>
<li id="cite_note-2" style="list-style-type: square;">2</li>
<li id="cite_note-2" style="list-style-type: square;"><span class="reference-text"><span class="citation journal">Chiappori, Alberto A.; Haura, Eric; Rodriguez, Francisco A.; Boulware, David; Kapoor, Rachna; Neuger, Anthony M.; Lush, Richard; Padilla, Barbara; Burton, Michelle; Williams, Charles; Simon, George; Antonia, Scott; Sullivan, Daniel M.; Bepler, Gerold (March 2008). “Phase I/II Study of Atrasentan, an Endothelin A Receptor Antagonist, in Combination with Paclitaxel and Carboplatin as First-Line Therapy in Advanced Non–Small Cell Lung Cancer”.<span class="Apple-converted-space"> </span><i style="font-style: italic;">Clinical Cancer Research</i><span class="Apple-converted-space"> </span><b style="font-weight: bold;">14</b><span class="Apple-converted-space"> </span>(5): 1464–9.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" style="color: #0c5390; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="http://dx.doi.org/10.1158%2F1078-0432.CCR-07-1508" rel="nofollow" style="color: #0c5390; text-decoration: none;">10.1158/1078-0432.CCR-07-1508</a>.<span class="Apple-converted-space"> </span><a class="mw-redirect" href="http://en.wikipedia.org/wiki/PubMed_Identifier" style="color: #0c5390; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/18316570" rel="nofollow" style="color: #0c5390; text-decoration: none;">18316570</a>.</span></span></li>
<li id="cite_note-3" style="list-style-type: square;">3</li>
<li id="cite_note-3" style="list-style-type: square;"><span class="reference-text"><span class="citation pressrelease"><a class="external text" href="http://www.cancer.gov/newscenter/newsfromnci/2011/ProstateAtrasentanTrial" rel="nofollow" style="color: #0c5390; text-decoration: none;">“Addition of experimental drug to standard chemotherapy for advanced prostate cancer shows no benefit in phase 3 clinical trial”</a><span class="Apple-converted-space"> </span>(Press release). National Cancer Institute. April 21, 2011<span class="reference-accessdate">. Retrieved<span class="Apple-converted-space"> </span><span class="nowrap">October 18,</span><span class="Apple-converted-space"> </span>2014</span>.</span></span></li>
<li id="cite_note-4" style="list-style-type: square;">4</li>
<li id="cite_note-4" style="list-style-type: square;"><span class="reference-text"><span class="citation journal">Quinn, David I; Tangen, Catherine M; Hussain, Maha; Lara, Primo N; Goldkorn, Amir; Moinpour, Carol M; Garzotto, Mark G; Mack, Philip C; Carducci, Michael A; Monk, J Paul; Twardowski, Przemyslaw W; Van Veldhuizen, Peter J; Agarwal, Neeraj; Higano, Celestia S; Vogelzang, Nicholas J; Thompson, Ian M (August 2013). “Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial”.<span class="Apple-converted-space"> </span><i style="font-style: italic;">The Lancet Oncology</i><span class="Apple-converted-space"> </span><b style="font-weight: bold;">14</b><span class="Apple-converted-space"> </span>(9): 893–900.<span class="Apple-converted-space"> </span><a href="http://en.wikipedia.org/wiki/Digital_object_identifier" style="color: #0c5390; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="http://dx.doi.org/10.1016%2FS1470-2045%2813%2970294-8" rel="nofollow" style="color: #0c5390; text-decoration: none;">10.1016/S1470-2045(13)70294-8</a>.<a class="mw-redirect" href="http://en.wikipedia.org/wiki/PubMed_Identifier" style="color: #0c5390; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/23871417" rel="nofollow" style="color: #0c5390; text-decoration: none;">23871417</a>.</span></span></li>
<li id="cite_note-5" style="list-style-type: square;">5</li>
<li id="cite_note-5" style="list-style-type: square;"><span class="reference-text"><span class="citation journal">de Zeeuw, Dick; Coll, Blai; Andress, Dennis; Brennan, John J.; Tang, Hui; Houser, Mark; Correa-Rotter, Ricardo; Kohan, Donald; Lambers Heerspink, Hiddo J.; Makino, Hirofumi; Perkovic, Vlado; Pritchett, Yili; Remuzzi, Giuseppe; Tobe, Sheldon W.; Toto, Robert; Viberti, Giancarlo; Parving, Hans-Henrik (May 2014). “The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy”.<i style="font-style: italic;">Journal of the American Society of Nephrology</i><span class="Apple-converted-space"> </span><b style="font-weight: bold;">25</b><span class="Apple-converted-space"> </span>(5): 1083–93.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" style="color: #0c5390; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="http://dx.doi.org/10.1681%2FASN.2013080830" rel="nofollow" style="color: #0c5390; text-decoration: none;">10.1681/ASN.2013080830</a>.<span class="Apple-converted-space"> </span><a class="mw-redirect" href="http://en.wikipedia.org/wiki/PubMed_Identifier" style="color: #0c5390; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/24722445" rel="nofollow" style="color: #0c5390; text-decoration: none;">24722445</a>.</span></span></li>
<li id="cite_note-6" style="list-style-type: square;">6</li>
</ul>
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<span class="reference-text">Clinical trial number<span class="Apple-converted-space"> </span><i style="font-style: italic;"><a class="external text" href="http://www.clinicaltrials.gov/show/NCT01858532" rel="nofollow" style="color: #0c5390; text-decoration: none;">NCT01858532</a></i><span class="Apple-converted-space"> </span>for “Study Of Diabetic Nephropathy With Atrasentan (SONAR)” at<span class="Apple-converted-space"> </span><a href="http://en.wikipedia.org/wiki/ClinicalTrials.gov" style="color: #0c5390; text-decoration: none;" title="ClinicalTrials.gov">ClinicalTrials.gov</a></span></div>
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<span class="dataTableCaption"><a href="https://www.blogger.com/null" style="color: #0c5390; text-decoration: none;">US-8962675, AbbVie Inc</a></span></div>
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Granted in February 2015, this patent claims novel crystalline anhydrous S-mandelate salt of atrasentan. Useful for treating nephropathy and chronic kidney disease associated with Type II diabetes.</div>
<table class="infobox" style="-webkit-text-stroke-width: 0px; background-color: white; border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 12px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 1.6; margin: 0px 0px 24px; orphans: auto; text-align: left; text-indent: 0px; text-transform: none; white-space: normal; widows: auto; width: 500px; word-spacing: 0px;"><caption style="font-size: 14px; margin: 10px 0px; text-transform: uppercase;">ATRASENTAN</caption><tbody>
<tr><td colspan="2" style="padding: 5px 0px;"><a class="image" href="http://en.wikipedia.org/wiki/File:Atrasentan.svg" style="color: #0c5390; text-decoration: none;"><img alt="Atrasentan.svg" height="151" src="http://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Atrasentan.svg/220px-Atrasentan.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="220" /></a></td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">SYSTEMATIC (<a class="mw-redirect" href="http://en.wikipedia.org/wiki/International_Union_of_Pure_and_Applied_Chemistry_nomenclature" style="color: #0c5390; text-decoration: none;" title="International Union of Pure and Applied Chemistry nomenclature">IUPAC</a>) NAME</th></tr>
<tr><td colspan="2" style="padding: 5px 0px;">(2<i style="font-style: italic;">R</i>,3<i style="font-style: italic;">R</i>,4<i style="font-style: italic;">S</i>)-4-(1,3-Benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid</td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">CLINICAL DATA</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" style="color: #0c5390; text-decoration: none;" title="Regulation of therapeutic goods">LEGAL STATUS</a></th><td style="padding: 5px 0px;"><div class="plainlist">
?</div>
</td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">IDENTIFIERS</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a class="mw-redirect" href="http://en.wikipedia.org/wiki/CAS_registry_number" style="color: #0c5390; text-decoration: none;" title="CAS registry number">CAS NUMBER</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?term=173937-91-2&rn=1" rel="nofollow" style="color: #0c5390; text-decoration: none;">173937-91-2</a></span><sup style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="" height="8" src="http://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" style="color: #0c5390; text-decoration: none;" title="Anatomical Therapeutic Chemical Classification System">ATC CODE</a></th><td style="padding: 5px 0px;">None</td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/PubChem" style="color: #0c5390; text-decoration: none;" title="PubChem">PUBCHEM</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=159594" rel="nofollow" style="color: #0c5390; text-decoration: none;">CID 159594</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/ChemSpider" style="color: #0c5390; text-decoration: none;" title="ChemSpider">CHEMSPIDER</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.chemspider.com/Chemical-Structure.140321.html" rel="nofollow" style="color: #0c5390; text-decoration: none;">140321</a></span><sup style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" style="color: #0c5390; text-decoration: none;" title="Unique Ingredient Identifier">UNII</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=V6D7VK2215" rel="nofollow" style="color: #0c5390; text-decoration: none;">V6D7VK2215</a></span><sup style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/ChEMBL" style="color: #0c5390; text-decoration: none;" title="ChEMBL">CHEMBL</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL9194" rel="nofollow" style="color: #0c5390; text-decoration: none;">CHEMBL9194</a></span><sup style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></sup></td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">CHEMICAL DATA</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Chemical_formula" style="color: #0c5390; text-decoration: none;" title="Chemical formula">FORMULA</a></th><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/Carbon" style="color: #0c5390; text-decoration: none;" title="Carbon">C</a><sub style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">29</sub><a href="http://en.wikipedia.org/wiki/Hydrogen" style="color: #0c5390; text-decoration: none;" title="Hydrogen">H</a><sub style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">38</sub><a href="http://en.wikipedia.org/wiki/Nitrogen" style="color: #0c5390; text-decoration: none;" title="Nitrogen">N</a><sub style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</sub><a href="http://en.wikipedia.org/wiki/Oxygen" style="color: #0c5390; text-decoration: none;" title="Oxygen">O</a><sub style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">6</sub><sup style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> </sup></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Molecular_mass" style="color: #0c5390; text-decoration: none;" title="Molecular mass">MOLECULAR MASS</a></th><td style="padding: 5px 0px;">510.621 g/mol</td></tr>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-7082350141827122272.post-41770872275363299052015-02-19T21:05:00.001-08:002015-02-19T21:05:20.266-08:00SILODOSIN.........For treatment of benign prostatic hypertophy<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="Silodosin.png" class="mw-mmv-dialog-is-open" data-mce-src="http://upload.wikimedia.org/wikipedia/commons/d/d2/Silodosin.png" data-pinit="registered" height="326" src="http://upload.wikimedia.org/wikipedia/commons/d/d2/Silodosin.png" width="783" /></div>
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SILODOSIN</div>
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Urief, 160970-54-7, Rapaflo, KMD 3213, Silodyx, KAD 3213, KMD-3213</div>
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<div class="mol-property">
<span class="label">Molecular Formula:<span class="Apple-converted-space"> </span></span><span class="value"><b style="font-weight: bold !important;"><a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C25H32F3N3O4" href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C25H32F3N3O4" title="Find all compounds with formula C25H32F3N3O4">C<sub>2</sub><sub>5</sub>H<sub>3</sub><sub>2</sub>F<sub>3</sub>N<sub>3</sub>O<sub>4</sub></a></b></span></div>
<div class="mol-property">
<span class="label">Molecular Weight:<span class="Apple-converted-space"> </span></span><span class="value">495.53449 g/mol</span></div>
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Alpha 1A adrenoceptor antagonist</div>
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Prostate hyperplasia</div>
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Kissei Pharmaceutical Co Ltd INOVATOR</div>
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CAS 160970-54-7</div>
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2,3-Dihydro-1-(3-hydroxypropyl)-5-[(2<i>R</i>)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1<i>H</i>-indole-7-carboxamide</div>
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160970-64-9 (racemate)<br />169107-04-4 (diHBr)</div>
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<b style="font-weight: bold !important;">Properties:</b><span class="Apple-converted-space"> </span>[a]D25<span class="Apple-converted-space"> </span>-14.0° (c = 1.01 in methanol).</div>
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<b style="font-weight: bold !important;">Optical Rotation:</b><span class="Apple-converted-space"> </span>[a]D25<span class="Apple-converted-space"> </span>-14.0° (c = 1.01 in methanol)</div>
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<b style="font-weight: bold !important;">Therap-Cat:</b><span class="Apple-converted-space"> </span>In treatment of benign prostatic hypertophy.</div>
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a-Adrenergic Blocker.</div>
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In February 2008, the FDA accepted for review an NDA for silodosin for the treatment of dysuria associated with BPH . In October 2008, the FDA approved the drug . In April 2009, Actavis launched silodosin for the treatment of the signs and symptoms of BPH .</div>
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<img alt="Silodosin.png" class="structure-img" data-mce-src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=5312125&t=l" data-pinit="registered" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=5312125&t=l" title="A structure of Silodosin" />SILODOSIN</div>
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1-(3-hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-2,3-dihydroindole-7-carboxamide</div>
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Patent (5387603 United States)</div>
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Patent (5403847 United States)</div>
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Kissei Pharmaceutical, Daiichi Sankyo (formerly Daiichi Seiyaku), Actavis (formerly Watson) and Recordati have developed and launched silodosin (Urief; Trupass; Rapaflo; Thrupas; Silodyx; Urorec; KMD-3213; Youlifu), an oral alpha 1A adrenoceptor antagonist selective for prostatic receptors . The product is comarketed in Europe by several licensees. The drug is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).</div>
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Silodosin, a highly selective alpha1A-adrenoceptor antagonist, was launched in May 2006 in Japan for the oral treatment of urinary disturbance associated with benign prostatic hyperplasia (BPH). The product was launched in the U.S. for the treatment of signs and symptoms of benign prostatic hyperplasia in 2009. In 2009, a positive opinion was received in the E.U. for this indication and final approval was obtained in 2010. Launch in the E.U. took place the same year.</div>
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In May 2006, silodosin was launched as a capsule formulation in Japan. Actavis launched the drug in the US in April 2009. In June 2010, EU launched began, initially with Germany ; in November 2010, the drug was launched in France; by December 2010, the drug was launched in Spain.</div>
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In 2001, Kissei established an agreement with Daiichi Pharmaceutical to codevelop and comarket silodosin. An oral, once-daily formulation of silodosin filed in the U.S. by Watson (now Actavis) was approved in 2008. Watson (now Actavis) obtained exclusive rights in 2004 to develop and market the drug in the U.S.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PRODUCT Was developed and launched byKissei Pharmaceutical, Daiichi Sankyo, Actavis and Recordati. Family members of the product case EP0600675 have SPC protection in most EU states until 2018; while its Orange Book listed equivalent, US5387603, expire in the US in 2018 with US156 extension.</span></div>
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<b style="font-weight: bold !important;">Silodosin</b><span class="Apple-converted-space"> </span>(trade names<span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">Rapaflo</b><span class="Apple-converted-space"> </span>(USA),<span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">Silodyx</b><span class="Apple-converted-space"> </span>(Europe and South Africa),<span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">Rapilif</b><span class="Apple-converted-space"> </span>(India),<span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">Silodal</b><span class="Apple-converted-space"> </span>(India),<span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">Urief</b><span class="Apple-converted-space"> </span>(Japan),<span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">Urorec</b><span class="Apple-converted-space"> </span>(Russia)) is a medication for the symptomatic treatment of<span class="Apple-converted-space"> </span><a data-mce-href="http://en.wikipedia.org/wiki/Benign_prostatic_hyperplasia" href="http://en.wikipedia.org/wiki/Benign_prostatic_hyperplasia" title="Benign prostatic hyperplasia">benign prostatic hyperplasia</a>. It acts as an α<sub>1</sub>-<a class="mw-redirect" data-mce-href="http://en.wikipedia.org/wiki/Adrenoceptor" href="http://en.wikipedia.org/wiki/Adrenoceptor" title="Adrenoceptor">adrenoceptor</a><span class="Apple-converted-space"> </span><a data-mce-href="http://en.wikipedia.org/wiki/Receptor_antagonist" href="http://en.wikipedia.org/wiki/Receptor_antagonist" title="Receptor antagonist">antagonist</a><span class="Apple-converted-space"> </span>with high uroselectivity (selectivity for the<span class="Apple-converted-space"> </span><a data-mce-href="http://en.wikipedia.org/wiki/Prostate" href="http://en.wikipedia.org/wiki/Prostate" title="Prostate">prostate</a>).</div>
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<table class="infobox mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><caption style="border: 1px dashed rgb(187, 187, 187);">Silodosin</caption><tbody>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="http://en.wikipedia.org/wiki/File:Silodosin.png" href="http://en.wikipedia.org/wiki/File:Silodosin.png"><img alt="Silodosin.png" data-mce-src="http://upload.wikimedia.org/wikipedia/commons/thumb/d/d2/Silodosin.png/220px-Silodosin.png" height="92" src="http://upload.wikimedia.org/wikipedia/commons/thumb/d/d2/Silodosin.png/220px-Silodosin.png" width="220" /></a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Systematic (<a class="mw-redirect" data-mce-href="http://en.wikipedia.org/wiki/International_Union_of_Pure_and_Applied_Chemistry_nomenclature" href="http://en.wikipedia.org/wiki/International_Union_of_Pure_and_Applied_Chemistry_nomenclature" title="International Union of Pure and Applied Chemistry nomenclature">IUPAC</a>) name</th></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1-(3-hydroxypropyl)-5-[(2<i>R</i>)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]indoline-7-carboxamide</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Clinical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div>
<a data-mce-href="http://en.wikipedia.org/wiki/Pregnancy_category" href="http://en.wikipedia.org/wiki/Pregnancy_category" title="Pregnancy category">Pregnancy<br />category</a></div>
</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><a data-mce-href="http://en.wikipedia.org/wiki/United_States" href="http://en.wikipedia.org/wiki/United_States" title="United States">US</a>:</small> B</li>
<li>Not approved for use in women</li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Legal status</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><span class="Unicode">℞</span><span class="Apple-converted-space"> </span>Prescription only</li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Route_of_administration" href="http://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration">Routes</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Oral</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Pharmacokinetic data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Bioavailability" href="http://en.wikipedia.org/wiki/Bioavailability" title="Bioavailability">Bioavailability</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">32%</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Plasma_protein_binding" href="http://en.wikipedia.org/wiki/Plasma_protein_binding" title="Plasma protein binding">Protein binding</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">97%</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Drug_metabolism" href="http://en.wikipedia.org/wiki/Drug_metabolism" title="Drug metabolism">Metabolism</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Liver" href="http://en.wikipedia.org/wiki/Liver" title="Liver">Hepatic</a><span class="Apple-converted-space"> </span><a data-mce-href="http://en.wikipedia.org/wiki/Glucuronidation" href="http://en.wikipedia.org/wiki/Glucuronidation" title="Glucuronidation">glucuronidation</a><span class="Apple-converted-space"> </span>(<a data-mce-href="http://en.wikipedia.org/wiki/UGT2B7" href="http://en.wikipedia.org/wiki/UGT2B7" title="UGT2B7">UGT2B7</a>-mediated); also minor<span class="Apple-converted-space"> </span><a data-mce-href="http://en.wikipedia.org/wiki/CYP3A4" href="http://en.wikipedia.org/wiki/CYP3A4" title="CYP3A4">CYP3A4</a><span class="Apple-converted-space"> </span>involvement</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Biological_half-life" href="http://en.wikipedia.org/wiki/Biological_half-life" title="Biological half-life">Half-life</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">13±8 hours</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Excretion" href="http://en.wikipedia.org/wiki/Excretion" title="Excretion">Excretion</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Kidney" href="http://en.wikipedia.org/wiki/Kidney" title="Kidney">Renal</a><span class="Apple-converted-space"> </span>and fecal</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="http://en.wikipedia.org/wiki/CAS_registry_number" href="http://en.wikipedia.org/wiki/CAS_registry_number" title="CAS registry number">CAS number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="reflink plainlinks nourlexpansion"><a class="external text" data-mce-href="http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?term=160970-54-7&rn=1" href="http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?term=160970-54-7&rn=1" rel="nofollow">160970-54-7</a></span><sup> </sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="http://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/ATC_code_G04" href="http://en.wikipedia.org/wiki/ATC_code_G04" title="ATC code G04">G04</a><span class="reflink plainlinks nourlexpansion"><a class="external text" data-mce-href="http://www.whocc.no/atc_ddd_index/?code=G04CA04" href="http://www.whocc.no/atc_ddd_index/?code=G04CA04" rel="nofollow">CA04</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/PubChem" href="http://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="reflink plainlinks nourlexpansion"><a class="external text" data-mce-href="http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5312125" href="http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5312125" rel="nofollow">CID 5312125</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/International_Union_of_Basic_and_Clinical_Pharmacology" href="http://en.wikipedia.org/wiki/International_Union_of_Basic_and_Clinical_Pharmacology" title="International Union of Basic and Clinical Pharmacology">IUPHAR ligand</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="reflink plainlinks nourlexpansion"><a class="external text" data-mce-href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=493" href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=493" rel="nofollow">493</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/ChemSpider" href="http://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="reflink plainlinks nourlexpansion"><a class="external text" data-mce-href="http://www.chemspider.com/Chemical-Structure.4471557.html" href="http://www.chemspider.com/Chemical-Structure.4471557.html" rel="nofollow">4471557</a></span><sup> <img alt="Yes" data-mce-src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" href="http://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" title="Unique Ingredient Identifier">UNII</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="reflink plainlinks nourlexpansion"><a class="external text" data-mce-href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=CUZ39LUY82" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=CUZ39LUY82" rel="nofollow">CUZ39LUY82</a></span><sup> <img alt="Yes" data-mce-src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/ChEMBL" href="http://en.wikipedia.org/wiki/ChEMBL" title="ChEMBL">ChEMBL</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="reflink plainlinks nourlexpansion"><a class="external text" data-mce-href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL24778" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL24778" rel="nofollow">CHEMBL24778</a></span><sup> <img alt="Yes" data-mce-src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Synonym" href="http://en.wikipedia.org/wiki/Synonym" title="Synonym">Synonyms</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">KAD-3213, KMD-3213</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Chemical_formula" href="http://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Carbon" href="http://en.wikipedia.org/wiki/Carbon" title="Carbon">C</a><sub>25</sub><a data-mce-href="http://en.wikipedia.org/wiki/Hydrogen" href="http://en.wikipedia.org/wiki/Hydrogen" title="Hydrogen">H</a><sub>32</sub><a data-mce-href="http://en.wikipedia.org/wiki/Fluorine" href="http://en.wikipedia.org/wiki/Fluorine" title="Fluorine">F</a><sub>3</sub><a data-mce-href="http://en.wikipedia.org/wiki/Nitrogen" href="http://en.wikipedia.org/wiki/Nitrogen" title="Nitrogen">N</a><sub>3</sub><a data-mce-href="http://en.wikipedia.org/wiki/Oxygen" href="http://en.wikipedia.org/wiki/Oxygen" title="Oxygen">O</a><sub>4</sub><sup> </sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Molecular_mass" href="http://en.wikipedia.org/wiki/Molecular_mass" title="Molecular mass">Molecular mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">495.534<span class="Apple-converted-space"> </span><a data-mce-href="http://en.wikipedia.org/wiki/Gram" href="http://en.wikipedia.org/wiki/Gram" title="Gram">g</a>/<a data-mce-href="http://en.wikipedia.org/wiki/Mole_%28unit%29" href="http://en.wikipedia.org/wiki/Mole_%28unit%29" title="Mole (unit)">mol</a></td></tr>
</tbody></table>
</div>
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<span class="mw-headline" id="History">History</span></h2>
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Silodosin received its first marketing approval in Japan in May 2006 under the tradename<span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">Urief</b>, which is jointly marketed by Kissei Pharmaceutical Co., Ltd. and Daiichi Sankyo Pharmaceutical Co., Ltd.</div>
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Kissei licensed the US, Canadian, and Mexican rights for silodosin to Watson Pharmaceuticals, Inc. in 2004.</div>
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On February 12, 2008, Watson announced that the New Drug Application submitted to the<span class="Apple-converted-space"> </span><a data-mce-href="http://en.wikipedia.org/wiki/United_States" href="http://en.wikipedia.org/wiki/United_States" title="United States">United States</a><span class="Apple-converted-space"> </span><a data-mce-href="http://en.wikipedia.org/wiki/Food_and_Drug_Administration" href="http://en.wikipedia.org/wiki/Food_and_Drug_Administration" title="Food and Drug Administration">Food and Drug Administration</a><span class="Apple-converted-space"> </span>for silodosin has been accepted for filing. FDA approved this drug on October 9, 2008.<sup class="reference" id="cite_ref-1"><a data-mce-href="http://en.wikipedia.org/wiki/Silodosin#cite_note-1" href="http://en.wikipedia.org/wiki/Silodosin#cite_note-1">[1]</a></sup><span class="Apple-converted-space"> </span>Silodosin is marketed under the trade names<span class="Apple-converted-space"> </span><i>Rapaflo</i><span class="Apple-converted-space"> </span>in the US and<span class="Apple-converted-space"> </span><i>Silodyx</i><span class="Apple-converted-space"> </span>in Europe.<sup class="reference" id="cite_ref-2"><a data-mce-href="http://en.wikipedia.org/wiki/Silodosin#cite_note-2" href="http://en.wikipedia.org/wiki/Silodosin#cite_note-2">[2]</a></sup><span class="Apple-converted-space"> </span>and<span class="Apple-converted-space"> </span><i>Rapilif</i><span class="Apple-converted-space"> </span>in India (Ipca Urosciences)</div>
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<span class="mw-headline" id="Pharmacology">Pharmacology</span></h2>
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Since silodosin has high affinity for the<span class="Apple-converted-space"> </span><a data-mce-href="http://en.wikipedia.org/wiki/Alpha-1A_adrenergic_receptor" href="http://en.wikipedia.org/wiki/Alpha-1A_adrenergic_receptor" title="Alpha-1A adrenergic receptor">α<sub>1A</sub></a><span class="Apple-converted-space"> </span>adrenergic receptor, it causes practically no<span class="Apple-converted-space"> </span><a data-mce-href="http://en.wikipedia.org/wiki/Orthostatic_hypotension" href="http://en.wikipedia.org/wiki/Orthostatic_hypotension" title="Orthostatic hypotension">orthostatic hypotension</a><span class="Apple-converted-space"> </span>(in contrast to other α<sub>1</sub><span class="Apple-converted-space"> </span>blockers). On the other side, the high selectivity seems to cause more problems with<span class="Apple-converted-space"> </span><a data-mce-href="http://en.wikipedia.org/wiki/Ejaculation" href="http://en.wikipedia.org/wiki/Ejaculation" title="Ejaculation">ejaculation</a>.<sup class="reference" id="cite_ref-3"><a data-mce-href="http://en.wikipedia.org/wiki/Silodosin#cite_note-3" href="http://en.wikipedia.org/wiki/Silodosin#cite_note-3">[3]</a></sup></div>
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As α<sub>1A</sub><span class="Apple-converted-space"> </span>adrenoceptor antagonists are being investigated as a means to male birth control due to their ability to inhibit ejaculation but not orgasm, a trial with 15 male volunteers was conducted. While silodosin was completely efficacious in preventing the release of semen in all subjects, 12 out of the 15 patients reported mild discomfort upon orgasm. The men also reported the psychosexual side effect of being strongly dissatisfied by their lack of ejaculation.<sup class="reference" id="cite_ref-pmid19536124_4-0"><a data-mce-href="http://en.wikipedia.org/wiki/Silodosin#cite_note-pmid19536124-4" href="http://en.wikipedia.org/wiki/Silodosin#cite_note-pmid19536124-4">[4]</a></sup></div>
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</div>
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<img alt="" data-mce-src="http://dailymed.nlm.nih.gov/dailymed/archives/image.cfm?archiveid=13545&type=img&name=rapaflo-silodosin-capsules-8.jpg" data-pinit="registered" height="288" id="irc_mi" src="http://dailymed.nlm.nih.gov/dailymed/archives/image.cfm?archiveid=13545&type=img&name=rapaflo-silodosin-capsules-8.jpg" width="820" /></div>
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///////////////////////////////</div>
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CN 103848772</div>
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<a data-mce-href="http://www.google.com/patents/CN103848772A?cl=en" href="http://www.google.com/patents/CN103848772A?cl=en">http://www.google.com/patents/CN103848772A?cl=en</a></div>
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<span class="notranslate">silodosin (Silodosin) is 〃 2 Japanese orange Johnson invented - receptor antagonist, for the treatment of benign prostatic hyperplasia or hypertrophy, and other related symptoms.</span><span class="Apple-converted-space"> </span><span class="notranslate">Clinical trials showed that 25% of patients with benign prostatic hyperplasia need for drugs or surgery.</span><span class="Apple-converted-space"> </span><span class="notranslate">Although prostatectomy is better, the mortality rate is not high, but patients bring varying degrees of damage.</span><span class="Apple-converted-space"> </span><span class="notranslate">So look for an effective and safe non-surgical treatment, not only can control the further development of the disease, while relieving the symptoms of the patient.</span></div>
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<span class="notranslate"> benign prostatic hyperplasia in older male patients have a higher prevalence, and clinical alternative drugs rarely, so the development of a benign prostatic hyperplasia drug treatment, not only has good social benefits, but also to bring good economic benefits.</span><span class="Apple-converted-space"> </span><span class="notranslate">The study confirmed that silodosin is the treatment of benign prostatic hyperplasia in an important class of drugs.</span></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00031.png" href="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00031.png"><img alt="Figure CN103848772AD00031" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00031.png" data-pinit="registered" height="206" id="idf0001" src="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00031.png" width="523" /></a></div>
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<span class="notranslate">Currently, the research reported in the published literature on the preparation of compounds of silodosin, are:</span></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00032.png" href="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00032.png"><img alt="Figure CN103848772AD00032" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00032.png" data-pinit="registered" height="217" id="idf0002" src="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00032.png" width="591" /></a></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00041.png" href="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00041.png"><img alt="Figure CN103848772AD00041" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00041.png" data-pinit="registered" height="496" id="idf0003" src="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00041.png" width="573" /></a></div>
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<span class="notranslate">Early 1995, Kitazawa M et al patent US5387603, the reporter silodosin total synthesis method, but the method reaction step is long, the yield is not too high, not suitable for our industrial production.</span></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00042.png" href="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00042.png"><img alt="Figure CN103848772AD00042" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00042.png" data-pinit="registered" height="183" id="idf0004" src="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00042.png" width="794" /></a></div>
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<span class="notranslate"> In 2009, 翟富民 et al patent CN102115455A, which reported a method for preparing Sailuoduoxin key intermediates.</span><span class="Apple-converted-space"> </span><span class="notranslate">The appropriate method for improving existing methods, although shorter than the previous method step in the step, but low synthesis yield of the process, we can not meet the needs of industrial production.</span></div>
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<span class="notranslate"> In summary, the compounds prepared silodosin more synthetic methods are constantly improved, but there are still a lot of flaws.</span><span class="Apple-converted-space"> </span><span class="notranslate">Therefore, there is need for further research on the preparation of compounds of silodosin to get simple process, product yield, product easy separation of the new preparation.</span><span class="notranslate">SUMMARY</span></div>
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<span class="notranslate"> The present invention is to overcome the above problems of the prior art, there is provided a method for preparing important intermediates silodosin, the present invention is simple process, high yield, easy separation of the product, the method suitable for industrial production .</span></div>
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<span class="notranslate">To achieve the above technical object, to achieve the above technical result, the present invention is realized by the following technical scheme:</span></div>
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<span class="notranslate">One kind of silodosin preparation of important intermediate, comprising the steps of:</span></div>
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<span class="notranslate">Step I) in a flask, 282g of raw materials 1-acetyl-5- (2-bromo-propyl) indoline, 222g phthalimide potassium salt and 700mL DMF, was heated at 110 ° C for 2h; After completion of the reaction, to which was added the right amount of water to wash away the excess solvent DMF and salt extraction desolventizing after EA, was 296g crude;</span></div>
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<span class="notranslate">Step 2) In a flask was added 296g crude product obtained in step I, dissolved 800mL ethanol, was added 165mL of hydrazine hydrate, 50 ° C is heated to precipitate a white solid; After completion of the reaction, cooling suction filtered, the filter cake washed with ethanol, and then the mother liquor removing solvent under reduced pressure; After dissolving EA, washed with water to wash away the excess hydrazine, and finally the organic phase the solvent was removed to give 165g intermediate, i.e. 1-acetyl-5- (2-aminopropyl) indoline;</span></div>
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<span class="notranslate">Step 3) In the three-necked flask, 165g of Intermediate 1-acetyl-5- (2-aminopropyl) indoline, dissolved 600mL methanol, stirred at room temperature, and thereto was slowly added dropwise bromine; the addition was complete After stirring at room temperature 5-6h; After completion of the reaction, slowly poured into saturated NaHSO3, and wash away excess bromine; extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate; After filtration, the solvent was removed in vacuo to give the crude product recrystallized from toluene to give 177g pure product;</span></div>
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<span class="notranslate">Step 4) In a flask was added 177g of pure product obtained in Step 3 and 65g CuCN, after use 700mL DMF, was heated at 110 ° C for 3 to 5h; After completion of the reaction, the amount of water was added thereto, washing off excess solvent DMF and salt, EA desolventizing crude extract, after recrystallization 121g pure 1-acetyl-5- (2-bromo-propyl) -7-cyano-indoline that silodosin important intermediates;</span></div>
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<span class="notranslate">Step (1), (2), (3), (4) synthesis reaction is:</span></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00051.png" href="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00051.png"><img alt="Figure CN103848772AD00051" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00051.png" data-pinit="registered" height="143" id="idf0005" src="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00051.png" width="472" /></a></div>
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<span class="notranslate">Further, the step I) to step 4) by TLC plate tracking point detection reaction.</span></div>
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<span class="notranslate">The beneficial effects of the present invention are:</span></div>
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<span class="notranslate">Preparation silodosin important intermediate of the present invention, mention of the method is simple, high reaction yield, product easily separated, suitable for industrial production and so on.</span></div>
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<span class="notranslate">Preparation Method A silodosin important intermediate, comprising the following steps: Step I) in a flask, 282g of raw materials 1-acetyl-5- (2-bromo-propyl) indoline, 222g o phthalimide potassium and 700mL DMF, heated at 110 ° C for 2h; After completion of the reaction, to which was added the right amount of water to wash away the excess solvent DMF and salt extraction desolventizing after EA, was 296g crude;</span></div>
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<span class="notranslate">Step 2) In a flask was added 296g crude product obtained in step I, dissolved 800mL ethanol, was added 165mL of hydrazine hydrate, 50 ° C is heated to precipitate a white solid; After completion of the reaction, cooling suction filtered, the filter cake washed with ethanol, and then the mother liquor removing solvent under reduced pressure; After dissolving EA, washed with water to wash away the excess hydrazine, and finally the organic phase the solvent was removed to give 165g intermediate, i.e. 1-acetyl-5- (2-aminopropyl) indoline;</span></div>
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<span class="notranslate">Step 3) In the three-necked flask, 165g of Intermediate 1-acetyl-5- (2-aminopropyl) indoline, dissolved 600mL methanol, stirred at room temperature, and thereto was slowly added dropwise bromine; the addition was complete After stirring at room temperature 5-6h; After completion of the reaction, slowly poured into saturated NaHSO3, and wash away excess bromine; extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate; After filtration, the solvent was removed in vacuo to give the crude product recrystallized from toluene to give 177g pure product;</span></div>
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<span class="notranslate">Step 4) In a flask was added 177g of pure product obtained in Step 3 and 65g CuCN, after use 700mL DMF, was heated at 110 ° C for 3 to 5h; After completion of the reaction, the amount of water was added thereto, washing off excess solvent DMF and salt, EA desolventizing crude extract, after recrystallization 121g pure 1-acetyl-5- (2-bromo-propyl) -7-cyano-indoline that silodosin important intermediates;</span></div>
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<span class="notranslate">Step (1), (2), (3), (4) synthesis reaction is:</span></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00061.png" href="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00061.png"><img alt="Figure CN103848772AD00061" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00061.png" data-pinit="registered" height="250" id="idf0006" src="http://patentimages.storage.googleapis.com/CN103848772A/CN103848772AD00061.png" width="893" /></a></div>
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<span class="notranslate">Further, the step I) to step 4) by TLC plate tracking point detection reaction.</span></div>
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WO2013056842</div>
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<a data-mce-href="http://www.google.com/patents/WO2013056842A1?cl=en" href="http://www.google.com/patents/WO2013056842A1?cl=en">http://www.google.com/patents/WO2013056842A1?cl=en</a></div>
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Silodosin is commercially available under the tradenames RAPAFLO<sup>®</sup><span class="Apple-converted-space"> </span>or</div>
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UROPvEC as a capsule formulation for oral use containing 4 mg or 8 mg of the drug. The capsules are to be taken orally once daily for the treatment of the signs and symptoms of benign prostatic hyperplasia. US 5,387,603 and EP 0 600 675 disclose silodosin as a therapeutic agent for the treatment for dysurea associated with benign prostatic hyperplasia. The molecular structure of silodosin (XXV) is shown below.</div>
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(XXV)</div>
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The synthesis of silodosin is relatively complex and requires a sequence of multiple steps. A key intermediate compound in the synthesis of silodosin is the optically active amine compound represented by the general formula R-Y:</div>
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1</div>
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wherein, R represents a protecting group and R represents a cyano (CN) or carbamoyl (CONH<sub>2</sub>) group. The intermediate compound R-Y bears the asymmetric carbon atom that imparts the optical activity to silodosin. Therefore, it is important to obtain the compound R-Y with high optical purity, because according to the methods reported in the state of the art the optical purity of the compound R-Y determines the optical purity of the final product silodosin.</div>
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JP 2001-199956 discloses a process for the preparation of a compound of formula R-Y, wherein l-(3-benzoyloxypropyl)-7-cyano-5-(2-oxopropyl)-2,3- dihydroindole or the corresponding 7-carbamoyl derivative is reacted with an optically active amine, namely L-2-phenylglycinol or L-l-phenylethanamine, to afford an imine compound of formula III as depicted in the below scheme 1. Scheme l . JP 2001-199956</div>
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R<sup>1</sup><span class="Apple-converted-space"> </span>= COPh; R<sup>2</sup><span class="Apple-converted-space"> </span>= CN or CONH<sub>2</sub>; R<sup>3</sup><span class="Apple-converted-space"> </span>= H or OH a = 1. cat. deprotection</div>
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2. frational crystallization with L-tartaric acid</div>
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b = 1. chromatographic separation</div>
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2. cat. deprotection</div>
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The optically active imine III is subjected to catalytic hydrogenation using platinum(IV) oxide as a catalyst affording the diastereomers IV in a ratio of 3.8:1. The chiral auxiliary II is subsequently removed by catalytic hydrogenation using 10% palladium on carbon, i. e. under the typical conditions which lead to the cleavage and removal of benzylic protecting groups from nitrogen or oxygen atoms. The catalytic deprotection reaction affords the desired intermediate compound R-Y with an optical purity corresponding to the ratio of the diasteromers obtained in the previous step, i. e. the ratio of compound R-Y to S-Y is approximately 3.8: 1, which corresponds to an optical purity of approximately 58.3% enantiomeric excess (e.e.).</div>
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In order to increase the optical purity of the intermediate R-Y JP 2001-199956 suggests to conduct a fractional crystallization of the desired enantiomer with L-tartaric acid. After a series of fractional crystallizations the compound R-Y is obtained with an optical purity of 97.6% enantiomeric excess. Alternatively, the diastereomers of the compound of formula IV are separated using chromatographic techniques as column chromatography on silicagel. The pure diastereomer R-TV affords the desired enantiomer R-Y with an optical purity of 100% e.e. after removal of the chiral auxiliary II with hydrogen using 10% palladium on carbon as catalyst.</div>
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Another approach for the synthesis of the key intermediate compound R-Y is reported in JP 2002-265444. The route of synthesis disclosed in said document is depicted in the below scheme 2.</div>
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Scheme 2. JP 2002-265444</div>
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R<sup>1</sup><span class="Apple-converted-space"> </span>= CH<sub>2</sub>Ph (Bn); R<sup>2</sup><span class="Apple-converted-space"> </span>= CN The process involves the reaction of an enantiomeric mixture of the compound of formula VI with (I S, 2R)-2-benzylaminocyclohexane methanol (VII) to obtain a diastereomeric mixture containing the salt VIII. After a series of crystallizations the diastereomer VIII was obtained with an optical purity of 92.8% diastereomeric excess (d.e.). Subsequently, the salt VIII was treated with an acidic aqueous solution to release the acid R-Vl from the salt. After extraction from the aqueous solution with ethyl acetate the acid R-Vl is converted into its amide IX. The compound IX is finally subjected to a Hofmann type rearrangement reaction to obtain the desired intermediate compound R-V.</div>
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WO 201 1/030356 discloses a process for the preparation of the intermediate compound R-V, which avoids the resolution of the enantiomers of specific intermediate compounds using chiral auxiliaries or optically active bases. The route of synthesis described in WO 201 1/030356 starts from L-alanine (X), which is a naturally occurring optically active amino acid. The process described in</div>
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WO 2011/030356 is depicted in the below scheme 3.</div>
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R<sup>1</sup><span class="Apple-converted-space"> </span>= trimethylsilyl (TMS), tert-butyl dimethylsilyl (TBDMS), allyl, benzyl, propargyl R<sup>2</sup><span class="Apple-converted-space"> </span>= CN or CONH<sub>2</sub><span class="Apple-converted-space"> </span>The amino acid is protected by the addition of ethyl chloroformate and subsequently activated by the addition of oxalyl chloride to afford i?-(N-ethoxycarbonyl)alanine as an acyl chloride (XI). Said acyl chloride is reacted with hydroxy protected l-(3- hydroxypropyl)-7-cyano-2,3-dihydroindole of formula XII in a Friedel-Crafts acylation reaction, which gives a compound of formula XIII. The oxo group in compound XIII is reduced to afford a compound of formula XIV that is subsequently subjected to a hydrolysis reaction to yield the key intermediate compound R-Y. It is an object of the present invention to provide a process for preparing silodosin or a pharmaceutically acceptable salt thereof, which process affords the drug with high optical purity and with better yield compared to the prior art processes. This object is solved by the subject matter as defined in the claims.</div>
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Scheme 5. Conversion of com ound V to silodosin</div>
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R = protecting group</div>
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R<sup>2</sup><span class="Apple-converted-space"> </span>= CN or CONH<sub>2</sub></div>
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X = leaving group</div>
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Example 11. Silodosin (XXV)</div>
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A. The compound XXIV (18.0 g) was dissolved in methanol (150 ml) and 5% aqueous sodium hydroxide solution (50 ml). The reaction mixture was stirred at room temperature for 2 h. The deprotected compound XXIV, i. e. a compound of formula XXIV with R = hydrogen and R = cyano, was extracted with toluene. Subsequently, a 10% lactic acid solution (25 ml) was added to the toluene phase in order to extract the product in the aqueous phase. The aqueous solution was separated and then basified. The deprotected product was finally extracted with ethyl acetate. Removal of the solvent gives the deprotected compound to XXIV (R<sup>1</sup><span class="Apple-converted-space"> </span>= H and R<sup>2</sup><span class="Apple-converted-space"> </span>= CN; 1 1.0 g) as an oily mass.</div>
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B. A mixture of compound XXIV (R<sup>1</sup><span class="Apple-converted-space"> </span>= H and R<sup>2</sup><span class="Apple-converted-space"> </span>- CN; 10.0 g), DMSO (80 ml) and 5N NaOH solution (9.0 ml) was stirred for 15 min. at room temperature. An aqueous H<sub>2</sub>0<sub>2</sub><span class="Apple-converted-space"> </span>(30%) solution (1 1.0 ml) was added to the reaction mixture, which was stirred at room temperature for additional 2 h after completion of the addition. Water was added to the reaction mixture, the product was extracted with ethyl acetate, and the solvent was subsequently evaporated to afford 9.0 g crude silodosin.</div>
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Example 12. Silodosin (XXV)</div>
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10.0 g of crude silodosin (optical purity = 85.0% e.e.) was dissolved in ethyl acetate (120 ml) at 55°C. The resulting clear solution was gradually cooled to 25°C under stirring. The suspension was further cooled to 15°C and stirred for 2 hours. The precipitated solid was filtered and dried at 50°C under vacuum to obtain 7.2 g of XXV with an optical purity of 97.5% e.e.</div>
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Example 13. Silodosin (XXV)</div>
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10.0 g of crude silodosin (optical purity = 98.5% e.e.) was dissolved in ethyl acetate (120 ml) at 55°C. The resulting clear solution was gradually cooled to 25 °C under stirring. The suspension was further cooled to 15°C and stirred for 2 hours. The precipitated solid was filtered and dried at 50°C under vacuum to obtain 7.2 g of XXV with an optical purity of 99.9% e.e.</div>
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Example 14. Silodosin (XXV)</div>
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10.0 g of crude silodosin (optical purity = 90.0 %e.e.) was dissolved in ethyl acetate (120 ml) at 55°C. The resulting clear solution was gradually cooled to 25°C under stirring. The suspension was further cooled to 15°C and stirred for 2 hours. The precipitated solid was filtered and dried at 50°C under vacuum to obtain 7.2 g of XXV with an optical purity of 97.0% e.e.</div>
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Example 15. Silodosin (XXV)</div>
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10.0 g of crude silodosin (optical purity = 92.0% e.e.) was dissolved in isopropyl acetate (160 ml) at 55°C. The resulting clear solution was gradually cooled to 25°C under stirring. The suspension was further cooled to 15°C and stirred for 2 hours. The precipitated solid was filtered and dried at 50°C under vacuum to obtain 8.2 g of XXV with an optical purity of 98.0% e.e. Example 16. Silodosin (XXV)</div>
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10.0 g of crude silodosin (optical purity = 98.0% e.e.) was dissolved in isopropyl acetate (160 ml) at 55°C. The resulting clear solution was gradually cooled to 25°C under stirring. The suspension was further cooled to 15°C and stirred for 2 hours. The precipitated solid was filtered and dried at 50°C under vacuum to obtain 8.0 g of XXV with an optical purity of 99.5% e.e.</div>
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EP2475634</div>
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<a data-mce-href="http://www.google.com/patents/EP2475634A2?cl=en" href="http://www.google.com/patents/EP2475634A2?cl=en">http://www.google.com/patents/EP2475634A2?cl=en</a></div>
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Scheme- 1.</div>
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Scheme-2.<br />
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Scheme-3.<div class="patent-image">
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Scheme-4.<br />
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Scheme-5.<br />
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Example-14</div>
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Preparation of Preparation of l-(3-Hydroxy-propyl)-5-(2(R)-{2-[2-(2, 2, 2-trifluoro- ethoxy)-phenoxy]-ethyIamino}-propyl)-2,3-dihydro-lH-indol-7-carboxylic acid amide (I)(Silodosin)</div>
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To a solution of Benzoic acid 3-[5(R)-(2-amino-propyl)-7-cyano-2, 3-dihydro-indol-l- yl]-propyl ester (XV) (3.5 g, 10 mmole) in Dimethyl sulphoxide (60 ml), charged Hydrogen peroxide (10% w/w) (11 ml). Then added 5 N sodium hydroxide solution (12.3 ml) and reaction mass was stirred for 2 hours. After completion of reaction water was added and extracted the product in ethyl acetate. Organic layer was washed with brine and dried over sodium sulphate. The solvent was evaporated below 40°C under reduced pressure and added methanol (25 ml). To this solution charged glacial acetic acid (0.25 g, 4mmole) and [2-(2, 2, 2-Trifluoro-ethoxy)-phenoxy]-acetaldehyde (VIII) (3 g, 0.0125 mole). Reaction mixture was stirred at 25-30°C for 1 hour. Then reacted with sodium cyanoborohydride (0.15 g, 2.8 mmoles) and heated at 40-45°C for 2 hours. After the completion of reaction solvent was distilled off below 40°C under reduced pressure and added water to the residue. Reaction mass was then acidified with aqueous mineral acid. The aqueous layer was then basified and product was extracted in ethyl acetate. Organic layer was washed with water and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (5/95) as eluent to give 0.8g of (I) as yellow solid. Purity (by HPLC) = 98%</div>
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Example 15</div>
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Preparation of l-(3-hydroxypropyl)-5-[(2R)-({2-[2-(2, 2, 2-trifIuoroethoxy) phenoxy]-ethyl} amino) propyl]-2, 3-dihydro-lH-indole-7-carbonitriIe (XVII) A mixture of 3-[7-Cyano-5 (R)-[-2-{2-[2-(2,2,2-trifluoroethoxy)-phenoxy] ethyl} amino) propyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate (XVI) (6.0 g , 0.010 mole), methanol (30 ml) and aqueous solution of Sodium hydroxide ( 1.6 g in 8 ml of water) was stirred at ambient temperature for 6 hours. To the reaction mixture water (90ml) was added and product was extracted with ethyl acetate (90 ml). The organic layer was washed with saturated sodium bicarbonate solution followed by brine wash and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 3.85 g of (XVII). Example 16</div>
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Preparation of l-(3-Hydroxy-propyl)-5(R)-(2-{2-[2-(2, 2, 2-trifluoro-ethoxy)- phenoxy]-ethylamino}-propyl)-2, 3-dihydro-lH-indol-7-carboxylic acid amide (I) (Silodosin)</div>
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To a solution of l-(3-hydroxypropyl)-5(R)-[2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]- ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile (XVII) (6.0 g , 0.013 mole) in dimethylsulfoxide (75 ml) was added 5 N sodium hydroxide solution (4.5 ml). To this reaction mixture, 30 % hydrogen peroxide (2.63 ml) was added slowly below 25°C. Reaction mixture was stirred at ambient temperature for 6 hours. Aqueous solution of sodium sulfite (2.1 in 150 ml water) was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate. The combined ethyl acetate layer was extracted 2N hydrochloric acid. The aqueous layer was neutralized with sodium bicarbonate and extracted the product in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution followed by brine wash and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was cooled to 5°C and filtered to get 4.51 g of (I) as solid.</div>
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WO2012147019</div>
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<a data-mce-href="http://www.google.com/patents/WO2012147019A1?cl=en" href="http://www.google.com/patents/WO2012147019A1?cl=en">http://www.google.com/patents/WO2012147019A1?cl=en</a></div>
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The present invention provides a process for the preparation of Silodosin of formula (I). More particularly, the present invention provides the process for preparation of tartrate salt of 3-[7-cyano-5[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy)phenoxy ] ethyl } amino)propyl] -2, 3 -dihydro- 1 H-indol- 1 -y 1 } propyl benzoate of formula (IV), which is a precursor in the preparation of Silodosin.</div>
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Background of the Invention:</div>
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A compound of 3-[7-cyano-5[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy] ethyl}amino)propyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate (IV) is a key intermediate for preparation of Silodosin. The chemical name of Silodosin is l-(3- hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-lH-indole-7-carboxamide and structurally represented as</div>
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(IV)</div>
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(I)</div>
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U.S.Pat. No. 5,387,603 discloses Silodosin as therapeutic agents for the treatment of dysuria, urinary disturbance associated with benign prostatic hyperplasia.</div>
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U.S.Pat. No. 6,310,086 discloses a process for preparing a Silodosin analogue compound from reaction of (R)-3-{5-(2-aminopropyl)-7-cyano-2,3- dihydro- 1 H-indol- 1 -yl jpropylbenzoate with 2-(2-Ethoxyphenoxy)ethyl methane sulfonate and finally isolated as residue and purified by column chromatography on silicagel. The said literature process has certain drawbacks like use of column chromatography.</div>
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U.S.Pat. No. 7,834,193 (IN 3178/DELNP/2007) discloses the process for preparation of monooxalate salt of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy)phenoxy ] ethyl } amino)propyl] -2, 3 -dihydro- 1 H-indol- 1 -y 1 } propyl benzoate (IV). This patent specifically discloses the preparation of monooxalate salt of formula (IV) helps to remove N,N-dialkyl impurity to certain extend. CN 101993405 A discloses the reaction of (R)-5-(2-aminopropyl)-l-(3-(4- fluorobenzoyloxy)propyl)-7-cyanoindoline with 2-(2-(2,2,2-trifluoroethoxy) phenoxy)ethyl methane sulfonate followed by oxalic acid salt preparation.</div>
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The main drawback in the prior art process, the formation of N,N-dialkyl impurity compound of formula (VI), as disclosed in detailed description, in the preparation of Silodosin, during condensation of compound of formula (II) with compound of formula (III), the impurity which is not removable by crystallization method or precipitation technique and column chromatography purification is not suitable for commercial purpose. So considering the commercial importance of Silodosin, the present invention focus on the preparation of pure Silodosin, and surprisingly found that the isolation of formula (IV) as tartrate salt helps to prepare Silodosin having less than 0.2 % of N,N dialkyl impurity and with good yield. None of the prior arts teaches or motivates isolation of tartaric acid addition salt of formula (IV). The preparation of Silodosin from tartrate salt of 3-{7-cyano-5-[(2R)- 2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl}amino)propyl]-2,3-dihydro-lH- indol-l-yl} propyl benzoate (IV) or its freebase of the present invention has purity of greater than 99.6 %.</div>
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Example 3</div>
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Preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy] ethyl-} amino) propyl]-2,3-dihydro-lH-indole-7-carboxamide (Silodosin)</div>
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Method A: The compound of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy)phenoxy] ethyl- } amino)propyl] -2,3 -dihydro- 1 H-indole-7- carbonitrile of formula (V) in dimethylsulfoxide was treated with 48% hydrogen peroxide and 20% sodium hydroxide solution and stirred at room temperature till completion of reaction. After completion of reaction, reaction mass quenched with 5% sodium bisulphite solution and ethylacetate was added over it. The ethylacetate layer was separated and treated with 20 % aqueous hydrochloric acid. The aqueous layer separated, neutralized with sodium bicarbonate solution and extracted with ethylacetate. The separated organic layer was washed with 10% sodium bicarbonate solution, brine solution and dried under vacuum. The organic layer distilled upto residue under vacuum at 50-55°C. The obtained residue was crystallized in ethylacetate.</div>
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Method B: To the tartrate salt of 3-[7-cyano-5[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy) phenoxy] ethyl}amino)propyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate (IV) (100 grams) in methanol, aqueous potassium hydroxide solution (38.38 grams) was added and stirred at room temperature till reaction completion. After completion of reaction, DM water and dichloromethane was added over it under stirring. Organic layer separated, washed with brine solution distilled under vacuum upto less than 1 volume. To the solution, dimethyl sulphoxide, 20% sodium hydroxide and hydrogen peroxide was added and stirred till completion of reaction. After completion of reaction, water containing sodium bisulfite was added to the reaction mass. The pH of the reaction mixture adjusted to about 8.5 using 10% sodium hydroxide and extracted in dichloromethane twice, washed with water, dried and concentrated upto 1-2 volume under vacuum. To the obtained solution, toluene was added over it at room temperature under stirring. The reaction mixture maintained for complete solid formation, filtered and dried under vacuum. Yield 58 grams. Example 4</div>
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Purification of Silodosin:</div>
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Method A: To the mixture of toluene and acetonitrile solvent, Silodosin was added over it and heated to 50° - 55 °C for complete dissolution. The reaction mass gradually cooled to room temperature and maintained for completion of solid formation. The obtained solid is filtered, washed with toluene and dried under vacuum. Method B: To the mixture of ethyl acetate and toluene solvent, Silodosin was added over it and heated to 60° - 65 °C for complete dissolution. The reaction mass gradually cooled to room temperature and maintained for completion of solid formation. The obtained solid is filtered, washed with toluene and dried under vacuum.</div>
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CN101993407</div>
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<a data-mce-href="http://www.google.com/patents/CN101993407B?cl=en" href="http://www.google.com/patents/CN101993407B?cl=en">http://www.google.com/patents/CN101993407B?cl=en</a></div>
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<span class="notranslate">silodosin for selective inhibition of urethral smooth muscle contraction and reduce the pressure within the urethra, but no significant impact on blood pressure, for the treatment of benign prostatic hyperplasia.</span><span class="Apple-converted-space"> </span><span class="notranslate">At present, the method of synthesis Silodosin many reports, but the lack of high yield method for industrial production.</span></div>
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<span class="notranslate"> JP200199956 reported that benzoic acid as a starting material, 1_ (3_ benzoyloxy-propyl) indoline hydrochloride (structural formula (1), R is a hydrogen atom) in 60% yield, then through the multi-step reaction was further prepared silodosin intermediate 1- (3-benzoyloxy-propyl) -5- (2-nitro-propyl) -7-cyano-indoline (structural formula VIII ), the total yield is low, and only 20 percent.</span><span class="Apple-converted-space"> </span><span class="notranslate">Compound (VIII) with potassium carbonate, the reaction of hydrogen peroxide to yield compound (IX), impurities, and purified by column chromatography to be not suitable for industrial production.</span><span class="Apple-converted-space"> </span><span class="notranslate">Compound (IX) under catalysis of molybdenum oxide, and L- (S) - benzyl glycyl alcohol asymmetric reactions, protecting groups may be due to steric hindrance is small, low chiral induction, is 3.8: I.</span></div>
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<span class="notranslate">Silodosin Preparation: 12 Example</span><br />
<span class="notranslate"> Example 11 to give 8 g solid, dissolved in DMSO 100ml, was added 5mol / L NaOH 12ml, 18 ~ 20 ° C was added dropwise slowly with 30% H2027 grams, then 30 ° C, the reaction ended 4h.</span><span class="Apple-converted-space"> </span><span class="notranslate">Extracted with ethyl acetate, the combined organic layer was washed 2N HCl and then the organic layer, the aqueous layer was neutralized with sodium hydroxide, and then extracted with ethyl acetate, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and evaporated concentrated and then dissolved in ethyl acetate, natural cooling crystallization, filtration, drying 5 g (87%), purity> 99%.</span><br />
<span class="notranslate"> <span class="Apple-converted-space"> </span><span data-mce-style="color: #ff0000;" style="color: red;">Mp 105 ~ 108 ° C</span></span><br />
<span class="notranslate" data-mce-style="color: #ff0000;" style="color: red;"> [a] 20d = -16.2 C = I, MeOH</span><br />
<span class="notranslate" data-mce-style="color: #ff0000;" style="color: red;"> 1NMR spectrum (DMS0-d6): δ ppm 0.9-1.0 (3H, d), 1.5-1.6 (1H, s), 1.6-1.7 (2H, m),</span><br />
<span class="notranslate" data-mce-style="color: #ff0000;" style="color: red;">2.3-2.4 (1H, dd), 2.6-2.7 (1H, dd), 2.8-3.0 (5H, m), 3.1-3.2 (2H, m), 3.3-3.4 (2H, m),</span><br />
<span class="notranslate" data-mce-style="color: #ff0000;" style="color: red;">3.4-3.5 (2H, t), 4.0-4.1 (2H, t), 4.2-4.3 (1H, s), 4.6-4.8 (2H, t), 6.9-7.15 (6H, m),</span><br />
<span class="notranslate" data-mce-style="color: #ff0000;" style="color: red;">7.2-7.3 (1H, s), 7.5-7.6 (1H, s)</span></div>
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see</div>
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Silodosin is (I) (formula 1, claim 1, page 31).</div>
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Process for the prepartion of pure polymorphic gamma form of silodosin - comprising dissolving any polymorphic form of silodosin in a solvent and seeding gamma form of silodosin.</div>
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Crude (I) (50 g) was dissolved in methanol, filtered and solvent was distilled under vacuum. The residue was dissolved in isopropanol at 50 degreeC, cooled and seed of (I) gamma form was added and further cooled and cyclohexane (500 mL) was added, solid was filtered, washed and dried to obtain pure polymorphic form gamma of (I) having a toluene content of 12 ppm (example 10, pages 29-30).</div>
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A process for the preparation of silodosin and/or its salt is claimed, comprising the reaction of 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl]propyl benzoate(2R,3R)-monotartrate with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate to form a cyano benzyloxy intermediate, followed by hydrolysis to form a cyano hydroxy intermediate, which is then reacted with tartaric acid and hydrolyzed in the presence of an oxidizing agent to obtain the product. An alternate method of preparation of silodosin comprising the hydrolyses of tartrate salt of cyano hydroxy intermediate in the presence of an oxidizing agent, pure polymorphic form gamma of silodosin, and the cyano hydroxy intermediate are also claimed. Further processes for the prepartion of the pure polymorphic form gamma of silodosin are claimed, wherein the process involves the dissolution of of any polymorphic form of silodosin in a solvent by heating at 30-100 degree C, cooling before and after seeding with gamma form of silodosin, adding an antisolven, isolating the polymorph and optionally micronizing.</div>
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The present invention provides an improved and efficient process for the preparation of</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2014000496@@@id00000046156804@@@7950630@@@imgf000002_0001.gif" data-pinit="registered" height="502" id="imgf000002_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2014000496@@@id00000046156804@@@7950630@@@imgf000002_0001.gif" width="532" /></div>
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It acts as an selective ai -adrenoceptor antagonist and is useful in the symptomatic treatment of benign prostatic hyperplasia (BPH). Chemically it is known as l-(3-hydroxypropyl)-5-[(2R)- ( { 2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino) propyl] indoline-7-carboxamide.</div>
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Silodosin and its pharmaceutically acceptable salts are first disclosed in US patent 5,387,603. Synthetic approach for the production of silodosin, is described in patent '603 can be represented as shown below in scheme 1.</div>
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l</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2014000496@@@id00000046156804@@@7950630@@@imgf000003_0001.gif" data-pinit="registered" height="400" id="imgf000003_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2014000496@@@id00000046156804@@@7950630@@@imgf000003_0001.gif" width="398" /></div>
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Scheme 1</div>
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As represented in scheme 1, silodosin is prepared by the reaction of l-acetyl-5-(2r aminopropyl)indoline-7-carbonitrile with 2-[2-(2,2,2-trifiuoroethoxy)phenoxy] ethyl methanesulfonate in the presence of sodium bicarbonate in ethanol to give l-acetyl-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carbonitrile, which upon reaction with di-tert-butyldicarbonate in methylene chloride produces protected acetyl indoline carbonitrile compound. Further deacetylation with sodium hydroxide in ethanol followed by treatment with acetic acid provides protected indoline carbonitrile compound, which upon hydrolysis using dimethyl sulfoxide, 30% hydrogen peroxide, sodium hydroxide and acetic acid gives protected indoline carboxamide, which upon further reaction with 2-tert-butyldimethylsiloxy)ethyl-4-nitrobenzene sulfonate in the presence of cis-dicyclohexano-18 crown-6 and potassium carbonate in dioxane gives protected (tert-butyl-dimethylsiloxy) ethyl indoline carbonitrile. Further treatment with tetrabutylammonium fluoride in tetrahydrofuran produces N-boc protected hydroxy deprotected propyl indoline carbonitrile, which under goes facile deprotection of boc group upon treatment with trifluoroacetic acid, in methylene chloride to yield silodosin. The complete process is very complex, make use of pyrophoric reagents</div>
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which are very difficult to handle in large scale and have many extra steps involving protection and depfotection. Further in US patent '603, concrete detail of preparation and purification of silodosin have not been reported. Furthermore, isolated silodosin is characterized using IR, NMR and specific rotation but the patent is silent on product appearance and crystalline nature. There are several processes known for the preparation of silodosin and its intermediates viz; in JP 4634560; JP 4921646; JP-2006- 188470; WO2011/124704 and WO2011/101864. In most of the inventions, silodosin is prepared by following reaction as shown in scheme 2. Major disadvantages of these processes are the formation of N,N dialkyl impurity, and other impurities which forms during the condensation of 3-[5-((2/?)-2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl]propyl benzoate or its salts like monotartrate with 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methanesulfonate. N,N dialkyl impurity forms in about 12-15% and may form due to reaction of one molecule of benzoate compound with two molecules of methanesulfonate compound. Removal of this impurity is not possible by simple purification</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2014000496@@@id00000046156804@@@7950630@@@imgf000004_0001.gif" data-pinit="registered" height="270" id="imgf000004_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2014000496@@@id00000046156804@@@7950630@@@imgf000004_0001.gif" width="523" /></div>
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wherein R is benzoyl, benzyl, tetrahydropyranyl, 2-trimethylsilylethyl, dinitrophenyl, diphenyl methyl and the like</div>
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Scheme 2</div>
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US patent 7,834,193 discloses a process for preparation of silodosin with similar condensation of 3-[5-((2R)-2-arriinopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl]pfopyl benzoate or its salts like monotartrate with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate, but 3-{7-cyano-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl)-2,3-dihydro-lH-indol-l-yl)-propylbenzoate is purified by preparing monooxalate salt as shown below in</div>
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scheme 3. This patent specifically prepares monooxalate salt of 3- {7-cyano-5-[(2R)-2-({ 2- (2,2,2-trifluoroethoxy)-phenoxy]ethyl }amino)propyl)-2,3-dihydro-lH-indol-l-yl)-propyl benzoate to remove N,N÷dialkyl impurity, but impurity has not been removed completely, only a certain % of it, has been removed.</div>
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Scheme 3</div>
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In PCT publication WO2012/131710, preparation of silodosin is described wherein improved processes for preparation of 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l- yl]propyl benzoate have been disclosed which is then converted to silodosin by condensation with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate. In exemplified process, 3-[5- ((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl]propyl benzoate is condensed with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate and the resulting benzoate compound is hydrolyzed to give l-(3-hydroxy propyl)-5-[(2R)-2-({ 2-[2,2,2-trifluoroethoxy) phenoxy] ethyl }amino)propyr]-2,3-dihydro-lH-indol-7-carbonitrile.The carbonitrile compound is treated with oxalic acid to prepare its oxalate salt having purity greater than 99%, which is then hydrolyzed using a base to prepare free carbonitrile compound having purity greater than 99%, but this patent is silent about N, N- dialkyl impurity or its removal.</div>
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In PCT publication WO2012/147019, preparation of silodosin using 3-{ 7-cyano-5-[(2R)-2-({2- (2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl)-2,3-dihydro-lH-indol-l-yl)-propyl benzoate tartrate salt has been described as shown below in scheme 4.</div>
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Scheme 4</div>
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One other PCT publication WO2012/147107 describes preparation of silodosin by preparing hydrochloride and acetic acid salts of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy) phenoxy] ethyl }amino)propyl]-2,3-dihydro-lH-indol-7-carbonitrile to remove N,N dialkyl impurity. It has been observed that in exemplified process, wherein hydroxy compound namely l-(3-hydroxy propyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy) phenoxy] ethyl }amino)propyl]-2,3-dihydro-lH-indol-7-carbonitrile is purified by preparing its acetate salt to, remove the impurities but still N, N-dialkyl impurity remains in an amount of 0.6%, which is difficult to remove in next stage or require extra purifications.</div>
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Beside to use highly pure silodosin, use of a pure polymorphic form of API is an essential requirement of drug formulation, these both aspects when address jointly, and obtained silodosin can be converted to pure polymorph then only a complete solution of prior art problems can be achieved. Apart from above mentioned process patents/publications which aimed to prepare the pure silodosin, there are exist some polymorph patents/publications which also aims to prepare pure polymorphic form of silodosin.</div>
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Polymorphism is considered as one of the- most important solid-state property of drug substance, since different polymorph have different physiochemical and biological properties and in pharmaceutical chemistry it is often desired to obtain one particular form that is biologically active and also offers ease of handling during formulation. The available literature references related to polymorph of silodosin are incorporated herein.</div>
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Japanese patent 3331048 (publication No.H07-330726), discloses a process for purification of silodosin wherein silodosin is dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, solvent is distilled off and again dissolved in ethyl acetate at 70°C and crystallizes below room temperature. The resulting product is characterized by melting point, IR, NMR and specific rotation. Here also disclosure is silent about polymorphic form of product.</div>
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US patent publication US2006/0142374A1 (equivalent European patent EP1541554B 1) discloses polymorphic forms of silodosin including three crystalline polymorphic form of silodosin which are named as alpha (a), beta (β) and gamma (γ) and one amorphous form. These polymorphic forms have been characterized by X-ray powder diffraction pattern. In the patent publication, processes for the preparation of all these three crystalline forms have been disclosed. In. a given process, form alpha is prepared by dissolving crude silodosin in appropriate amount of ethyl acetate, ethyl formate, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran or mixture of acetone and acetonitrile (1: 1), preferably ethyl acetate under heating, allowing to stand at room temperature to precipitate the crystal gradually. Similarly, form beta is prepared by dissolving crude silodosin in appropriate amount of methanol under heating, adding petroleum ether as a anti-solvent, crystal precipitation is ensured using vigorous stirring.</div>
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In a second process, to prepare the form beta, crude silodosin is dissolved in ethanol or 1-propanol and the reaction mass is cooled quickly. The crystalline form gamma is prepared by dissolving crude silodosin in appropriate amount of toluene or a mixture of acetonitrile and toluene (1:4) or ethyl acetate and toluene (1: 19), preferably in toluene, under heating, cooling to room temperature and allowing to precipitate gradually upon standing. In a second process to prepare form gamma, crude silodosin is dissolved in 2-propanol and the crystals are precipitated by adding an appropriate amount of toluene. In spite of disclosing three crystalline polymorphic forms, the patent publication prefers preparation and use of form alpha by highlighting the problems faced for preparation and use of other forms. It is disclosed that crystal form beta has manufacturing difficulties at industrial scale since precipitation occurs only when the nonpolar antisolvent is added to warm solution which leads to inconsistency in quality of crystals.</div>
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With the second process for preparation of form beta, desired level of yield and purity has not been achieved. Further, according to this publication, preparation of gamma form involves use of toluene which can not be removed completely from final product, because of its high boiling point and raises the problem of residual solvent. In the case of toluene, a class 2 solvent, its limits should not be more than 890 ppm. In the exemplified process, toluene content has not been disclosed, which clearly reflects that product was not suitable for pharmaceutical composition having problem of high residual content of toluene. Furthermore patent publication also states that all the three crystal forms donot have any difference in hygroscopicity and stabilities.</div>
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Thereafter, several patents/publications disclose preparation of polymorphic forms alpha and beta. For example a PCT publication WO2012/147107 discloses a process for preparation of beta form using isopropyl acetate and methyl isobutylketone. In another PCT publication WO2012/077138, preparation of alpha and beta forms are disclosed using various solvent , system. Similarly, in a Chinese patent CN102010359, crystalline form beta is prepared by dissolving the crude silodosin in alcoholic solvent by heating and the product is crystallized by cooling or by adding an antisolvent such as ketone or ether.</div>
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European patent EP2474529 discloses new polymorphic forms delta (δ) and eta (ε) of silodosin by using a solvent (tetrahydrofuran) and antisolvent (n-heptane, n-hexane, cyclohexane, tert butylmethyl ether).Further it discloses conversion of delta form to beta form by just heating the delta form at a particular temperature. The form delta can also be transformed into form eta by. slurrying in aqueous methanol. One new crystalline form designated as delta has also been disclosed in a Chinese patent publication CN102229558. An Indian patent application 478/MUM/2010, also discloses a new polymorphic form Zy-S which is prepared by using solvent such as esters, aromatic hydrocarbons, ketones, and alcohols.</div>
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All the above disclosures are silent about the preparation of gamma form of silodosin and only available disclosure reports that gamma form have problem of residual solvent, as impurity and is not suitable for pharmaceutical compositions.</div>
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Method C: l-(3-HydroxypropyI)-5-[(2R)-2-({2-[2,2,2-trifIuoroethoxy)phenoxy] ethyl} amino) propyl]-2,3-dihydro-lH-indol-7-carbonitrile tartrate (lOg) dissolved in dimethylsulfoxide (120 ml) and to this solution, was added 5 mol/L aqueous sodium hydroxide solution (15ml). To the reaction mixture, 30% hydrogen peroxide (5ml) was added and keeping the temperature below 25°C. The reaction mixture was stirred at 20-25°C, for 5 hours. To the reaction mixture, sodium sulfite (5g) dissolved in water (100ml) was added slowly. The reaction mixture was extracted with ethyl acetate (1x200ml) and ethyl acetate layer was concentrated under reduced pressure. The resulting product was dissolved in methanol and clear solution was filtered through micron filter paper of size 0.22 micron two times and filtrate was concentrated.The resulting compound was dissolved in toliiene (70ml) and isopropyl alcohol (7ml) at 50-55°C and the solution was cooled to 20-25°C, cyclohexane was added and stirred for further 4 hours, filtered and dried to give title compound having purity 99.86% and N,N-dialkyl impurity not detected by HPLC. Example 5: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin</div>
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Silodosin (15g) having toluene content 1872 ppm, was micronized under air pressure. The micronized product was dried under vacuum at 55°C-60°C for 23.0 hours to afford pure polymorphic form gamma of silodosin having toluene content 460 ppm.</div>
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Example 6: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin</div>
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Silodosin [having toluene content 1327 ppm] was micronized under air pressure. The micronized product was dried under vacuum at 55°C-60°C for 16 hours to afford pure polymorphic form gamma of silodosin having toluene content 350 ppm.</div>
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Example 7: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin</div>
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Silodosin crude (3.0g) was dissolved in isopropanol (12ml) at 50°C and reaction mass was cooled to 35°C and seed of silodosin gamma form (O.lg) was added. Thereafter reaction mass was again cooled to 15-20°C and cyclohexane (30ml) was added to the reaction mass and stirred for further 0.5 hour. The resulting solid, thus obtained, was filtered, washed with cyclohexane and dried to afford pure polymorphic form gamma of silodosin having toluene content 34 ppm.</div>
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<span class="mw-headline" id="References">References</span></h2>
<div class="reflist" style="-webkit-text-stroke-width: 0px; color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 26.6666679382324px; orphans: auto; text-align: start; text-indent: 0px; text-transform: none; white-space: normal; widows: auto; word-spacing: 0px;">
<ol class="references">
<li id="cite_note-1"><span class="reference-text"><span class="citation web"><a class="external text" data-mce-href="http://www.drugs.com/nda/silodosin_080212.html" href="http://www.drugs.com/nda/silodosin_080212.html" rel="nofollow">"Drugs.com, Watson Announces Silodosin NDA Accepted for Filing by FDA for the Treatment of Benign Prostatic Hyperplasia"</a><span class="reference-accessdate">. Retrieved<span class="Apple-converted-space"> </span><span class="nowrap">2008-02-13</span></span>.</span></span></li>
<li id="cite_note-2"><span class="reference-text"><a class="external text" data-mce-href="http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001209/WC500074188.pdf" href="http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001209/WC500074188.pdf" rel="nofollow">European Medicines Agency: Assessment report for Silodyx</a></span></li>
<li id="cite_note-3"><span class="reference-text">Schubert-Zsilavecz, M, Wurglics, M,<span class="Apple-converted-space"> </span><i>Neue Arzneimittel 2008/2009</i></span></li>
<li id="cite_note-pmid19536124-4"><span class="reference-text"><span class="citation journal">Kobayashi K, Masumori N, Kato R, Hisasue S, Furuya R, Tsukamoto T. (December 2009).<span class="Apple-converted-space"> </span><a class="external text" data-mce-href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834370" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834370" rel="nofollow">"Orgasm is preserved regardless of ejaculatory dysfunction with selective alpha1A-blocker administration."</a>.<span class="Apple-converted-space"> </span><i>Int J Impot Res.</i><span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">21</b><span class="Apple-converted-space"> </span>(5): 306–10.<span class="Apple-converted-space"> </span><a data-mce-href="http://en.wikipedia.org/wiki/Digital_object_identifier" href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="http://dx.doi.org/10.1038%2Fijir.2009.27" href="http://dx.doi.org/10.1038%2Fijir.2009.27" rel="nofollow">10.1038/ijir.2009.27</a>.<span class="Apple-converted-space"> </span><a data-mce-href="http://en.wikipedia.org/wiki/PubMed_Central" href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834370" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834370" rel="nofollow">2834370</a>.<span class="Apple-converted-space"> </span><a class="mw-redirect" data-mce-href="http://en.wikipedia.org/wiki/PubMed_Identifier" href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/19536124" href="http://www.ncbi.nlm.nih.gov/pubmed/19536124" rel="nofollow">19536124</a>.</span></span></li>
</ol>
</div>
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<span class="mw-headline" id="External_links">External links</span></h2>
<ul style="-webkit-text-stroke-width: 0px; color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 26.6666679382324px; orphans: auto; text-align: start; text-indent: 0px; text-transform: none; white-space: normal; widows: auto; word-spacing: 0px;">
<li><a class="external text" data-mce-href="http://ir.watsonpharm.com/phoenix.zhtml?c=65778&p=irol-newsArticle&ID=719690&highlight=" href="http://ir.watsonpharm.com/phoenix.zhtml?c=65778&p=irol-newsArticle&ID=719690&highlight=" rel="nofollow">Watson Pharm., Inc.- Press Release</a></li>
<li><a class="external text" data-mce-href="http://www.Rapaflo.com" href="http://www.rapaflo.com/" rel="nofollow">Rapaflo Official Site</a></li>
</ul>
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a1a-Adrenoceptor antagonist. Prepn: M. Kitazawa<span class="Apple-converted-space"> </span><i>et al.,</i><span class="Apple-converted-space"> </span><span data-mce-style="color: #ff0000;" style="color: red;"><b style="font-weight: bold !important;">EP</b></span><span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">600675</b>;<span class="Apple-converted-space"> </span><i>eidem</i>,<span class="Apple-converted-space"> </span><span data-mce-style="color: #ff0000;" style="color: red;"><b style="font-weight: bold !important;">US</b></span><span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">5387603</b><span class="Apple-converted-space"> </span>(1994, 1995 both to Kissei).<span data-mce-style="color: #ff0000;" style="color: red;">PRODUCT PATENT</span></div>
<div style="-webkit-text-stroke-width: 0px; color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 26.6666679382324px; orphans: auto; text-align: start; text-indent: 0px; text-transform: none; white-space: normal; widows: auto; word-spacing: 0px;">
Adrenoceptor binding study: K. Shibata<span class="Apple-converted-space"> </span><i>et al.,</i><span class="Apple-converted-space"> </span><i>Mol. Pharmacol.</i><span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">48</b>, 250 (1995); and tissue selectivity: S. Murata<span class="Apple-converted-space"> </span><i>et al.,</i><span class="Apple-converted-space"> </span><i>J. Urol.</i><span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">164</b>, 578 (2000).</div>
<div style="-webkit-text-stroke-width: 0px; color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 26.6666679382324px; orphans: auto; text-align: start; text-indent: 0px; text-transform: none; white-space: normal; widows: auto; word-spacing: 0px;">
Pharmacology: K. Akiyama<span class="Apple-converted-space"> </span><i>et al.,</i><span class="Apple-converted-space"> </span><i>Pharmacology</i><span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">64</b>, 140 (2002).</div>
<div style="-webkit-text-stroke-width: 0px; color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 26.6666679382324px; orphans: auto; text-align: start; text-indent: 0px; text-transform: none; white-space: normal; widows: auto; word-spacing: 0px;">
Series of articles on pharmacology, pharmacokinetcs and toxicology:<span class="Apple-converted-space"> </span><i>Yakugaku Zasshi</i><span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">126</b>, 187-263 (2006).</div>
<div style="-webkit-text-stroke-width: 0px; color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 26.6666679382324px; orphans: auto; text-align: start; text-indent: 0px; text-transform: none; white-space: normal; widows: auto; word-spacing: 0px;">
Review of development and therapeutic potential: F. Kamali,<span class="Apple-converted-space"> </span><i>Curr. Opin. Cent. Peripher. Nerv. Syst. Invest. Drugs</i><span class="Apple-converted-space"> </span><b style="font-weight: bold !important;">1</b>, 248-252 (1999)</div>
<table class="patent-data-table mce-item-table" data-mce-style="height: 205px;" style="-webkit-text-stroke-width: 0px; border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: normal; height: 205px; letter-spacing: normal; line-height: 26.6666679382324px; orphans: auto; text-align: start; text-indent: 0px; text-transform: none; white-space: normal; widows: auto; width: 877px; word-spacing: 0px;"><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/CN101993405A?cl=en" href="http://www.google.com/patents/CN101993405A?cl=en">CN101993405A</a><span class="patent-tooltip-anchor"><span class="Apple-converted-space"> </span>*</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Aug 27, 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Mar 30, 2011</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">浙江华海药业股份有限公司;上海医药工业研究院</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Indoline derivative as well as preparation method and application thereof</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/url?id=1WWqBwABERAJ&q=http://worldwide.espacenet.com/publicationDetails/biblio%3FCC%3DJP%26NR%3D2006188470A%26KC%3DA%26FT%3DD&usg=AFQjCNGIJLMvyMx9BD_lOEybtelx7Tin9A" href="http://www.google.com/url?id=1WWqBwABERAJ&q=http://worldwide.espacenet.com/publicationDetails/biblio%3FCC%3DJP%26NR%3D2006188470A%26KC%3DA%26FT%3DD&usg=AFQjCNGIJLMvyMx9BD_lOEybtelx7Tin9A">JP2006188470A</a><span class="patent-tooltip-anchor"><span class="Apple-converted-space"> </span>*</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="patent-data-table-td citation-no-title" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Title not available</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/US7834193" href="http://www.google.com/patents/US7834193">US7834193</a><span class="patent-tooltip-anchor"><span class="Apple-converted-space"> </span>*</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Apr 16, 2007</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nov 16, 2010</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Kissei Pharmaceutical Co., Ltd.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">industrial production of silodosin (for treating dysuria associated with benign prostatic hyperplasia) via mixing 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino]propyl]-2,3-dihydro-1H-indol-1-yl}-propyl benzoate and oxalic acid, nitrilizing, hydrolyzing</td></tr>
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<table class="patent-data-table mce-item-table" data-mce-style="height: 164px;" style="-webkit-text-stroke-width: 0px; border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: normal; height: 164px; letter-spacing: normal; line-height: 26.6666679382324px; orphans: auto; text-align: start; text-indent: 0px; text-transform: none; white-space: normal; widows: auto; width: 861px; word-spacing: 0px;"><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2011030356A2?cl=en" href="http://www.google.com/patents/WO2011030356A2?cl=en">WO2011030356A2</a><span class="patent-tooltip-anchor"><span class="Apple-converted-space"> </span>*</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sep 13, 2010</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Mar 17, 2011</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sandoz Ag</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for the preparation of indoline derivatives and their intermediates thereof</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2011124704A1?cl=en" href="http://www.google.com/patents/WO2011124704A1?cl=en">WO2011124704A1</a><span class="patent-tooltip-anchor"><span class="Apple-converted-space"> </span>*</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Apr 8, 2011</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Oct 13, 2011</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Ratiopharm Gmbh</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for preparing an intermediate for silodosin</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2012131710A2?cl=en" href="http://www.google.com/patents/WO2012131710A2?cl=en">WO2012131710A2</a><span class="patent-tooltip-anchor"><span class="Apple-converted-space"> </span>*</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Mar 27, 2012</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Oct 4, 2012</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Panacea Biotec Ltd</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Novel process for the synthesis of indoline derivatives</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/url?id=V5LxBwABERAJ&q=http://worldwide.espacenet.com/publicationDetails/biblio%3FCC%3DJP%26NR%3D2006188470A%26KC%3DA%26FT%3DD&usg=AFQjCNGIJLMvyMx9BD_lOEybtelx7Tin9A" href="http://www.google.com/url?id=V5LxBwABERAJ&q=http://worldwide.espacenet.com/publicationDetails/biblio%3FCC%3DJP%26NR%3D2006188470A%26KC%3DA%26FT%3DD&usg=AFQjCNGIJLMvyMx9BD_lOEybtelx7Tin9A">JP2006188470A</a><span class="patent-tooltip-anchor"><span class="Apple-converted-space"> </span>*</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="patent-data-table-td citation-no-title" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Title not available</td></tr>
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<table class="mce-item-table" data-mce-style="height: 200px;" style="border: 1px dashed rgb(187, 187, 187); height: 200px; width: 861px;"><tbody>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Submitted</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Granted</th></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Solid drug for oral use [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2006018959" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2006018959" title="Go to PubChem Patent View page for this patent">US2006018959</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2006-01-26</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Crystal for oral solid drug and oral solid drug for dysuria treatment containing the same [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2006142374" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2006142374" title="Go to PubChem Patent View page for this patent">US2006142374</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2006-06-29</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Device for transdermal administration for the treatment of urinary tract disorders [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2005226919" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2005226919" title="Go to PubChem Patent View page for this patent">US2005226919</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2005-10-13</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Methods for identifying novel multimeric agents that modulate receptors [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2003087306" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2003087306" title="Go to PubChem Patent View page for this patent">US2003087306</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2003-05-08</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
</tbody></table>
</div>
<div style="-webkit-text-stroke-width: 0px; color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 26.6666679382324px; orphans: auto; text-align: start; text-indent: 0px; text-transform: none; white-space: normal; widows: auto; word-spacing: 0px;">
</div>
<table class="mce-item-table" data-mce-style="height: 405px;" style="-webkit-text-stroke-width: 0px; border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: normal; height: 405px; letter-spacing: normal; line-height: 26.6666679382324px; orphans: auto; text-align: start; text-indent: 0px; text-transform: none; white-space: normal; widows: auto; width: 857px; word-spacing: 0px;"><tbody>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Submitted</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Granted</th></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Combination therapy for the treatment of benign prostatic hyperplasia [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US6410554" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US6410554" title="Go to PubChem Patent View page for this patent">US6410554</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2002-06-25</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Indoline compound and process for producing the same [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US7834193" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US7834193" title="Go to PubChem Patent View page for this patent">US7834193</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2007-08-23</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2010-11-16</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Agents and crystals for improving excretory potency of urinary bladder [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US8252814" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US8252814" title="Go to PubChem Patent View page for this patent">US8252814</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2009-10-22</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2012-08-28</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">METHODS FOR TREATING BENIGN PROSTATIC HYPERPLASIA [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2011319464" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2011319464" title="Go to PubChem Patent View page for this patent">US2011319464</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2011-12-29</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">PREVENTIVE AND/OR THERAPEUTIC AGENT FOR URINE COLLECTION DISORDER ACCOMPANYING LOWER URINARY TRACT OBSTRUCTION [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2009227651" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2009227651" title="Go to PubChem Patent View page for this patent">US2009227651</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2009-09-10</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">PREVENTIVE AND/OR THERAPEUTIC AGENT FOR URINE COLLECTION DISORDER ACCOMPANYING LOWER URINARY TRACT OBSTRUCTION [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2010137399" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2010137399" title="Go to PubChem Patent View page for this patent">US2010137399</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2010-06-03</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Agents for improving excretory potency of urinary bladder [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2004116457" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2004116457" title="Go to PubChem Patent View page for this patent">US2004116457</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2004-06-17</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Medicinal Composition for Prevention of Transition to Operative Treatment for Prostatic Hypertrophy [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2008090893" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2008090893" title="Go to PubChem Patent View page for this patent">US2008090893</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2008-04-17</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">METHODS FOR TREATING BENIGN PROSTATIC HYPERPLASIA [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2008242717" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2008242717" title="Go to PubChem Patent View page for this patent">US2008242717</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2008-10-02</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Agents and crystals for improving excretory potency of urinary bladder [<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2006281725" href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2006281725" title="Go to PubChem Patent View page for this patent">US2006281725</a>]</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2006-12-14</td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
</tbody></table>
</div>
DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com2tag:blogger.com,1999:blog-7082350141827122272.post-88115317207464356182015-02-16T04:40:00.001-08:002015-02-16T04:45:22.234-08:00FLUDABARINE<div dir="ltr" style="text-align: left;" trbidi="on">
<div style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px; margin-bottom: 10px;">
<img alt="Fludarabine phosphate.svg" src="http://upload.wikimedia.org/wikipedia/commons/thumb/2/2a/Fludarabine_phosphate.svg/220px-Fludarabine_phosphate.svg.png" data-pinit="registered" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /><br />
<br />
<br />
FLUDABAINE<br />
<br />
<br />
<br /></div>
<table class="infobox" style="background-color: white; border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 500px;"><tbody>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">SYSTEMATIC (<a class="mw-redirect" href="http://en.wikipedia.org/wiki/International_Union_of_Pure_and_Applied_Chemistry_nomenclature" style="color: #0c5390; text-decoration: none;" title="International Union of Pure and Applied Chemistry nomenclature">IUPAC</a>) NAME</th></tr>
<tr><td colspan="2" style="padding: 5px 0px;">[(2<i>R</i>,3<i>R</i>,4<i>S</i>,5<i>R</i>)-5-(6-amino-2-fluoro-purin-9-yl)- 3,4-dihydroxy-oxolan-2-yl]methoxyphosphonic acid</td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">CLINICAL DATA</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Trade_name" style="color: #0c5390; text-decoration: none;" title="Trade name">TRADE NAMES</a></th><td style="padding: 5px 0px;">Fludara</td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" style="color: #0c5390; text-decoration: none;" title="American Society of Health-System Pharmacists">AHFS</a>/<a href="http://en.wikipedia.org/wiki/Drugs.com" style="color: #0c5390; text-decoration: none;" title="Drugs.com">DRUGS.COM</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.drugs.com/monograph/fludara.html" rel="nofollow" style="color: #0c5390; text-decoration: none;">monograph</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/MedlinePlus" style="color: #0c5390; text-decoration: none;" title="MedlinePlus">MEDLINEPLUS</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a692003.html" rel="nofollow" style="color: #0c5390; text-decoration: none;">a692003</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Pregnancy_category" style="color: #0c5390; text-decoration: none;" title="Pregnancy category">PREGNANCY<br />CATEGORY</a></th><td style="padding: 5px 0px;"><div class="plainlist">
<ul style="margin: 0px 0px 14px 36px; padding: 0px;">
<li style="list-style-type: square;">D</li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" style="color: #0c5390; text-decoration: none;" title="Regulation of therapeutic goods">LEGAL STATUS</a></th><td style="padding: 5px 0px;"><div class="plainlist">
<ul style="margin: 0px 0px 14px 36px; padding: 0px;">
<li style="list-style-type: square;"><small style="font-size: 9.60000038146973px;"><a href="http://en.wikipedia.org/wiki/Australia" style="color: #0c5390; text-decoration: none;" title="Australia">AU</a>:</small> <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Standard_for_the_Uniform_Scheduling_of_Drugs_and_Poisons#Schedule_4_Prescription_Only_Medicine" style="color: #0c5390; text-decoration: none;" title="Standard for the Uniform Scheduling of Drugs and Poisons">Prescription Only (S4)</a></li>
<li style="list-style-type: square;"><small style="font-size: 9.60000038146973px;"><a href="http://en.wikipedia.org/wiki/United_Kingdom" style="color: #0c5390; text-decoration: none;" title="United Kingdom">UK</a>:</small> <a href="http://en.wikipedia.org/wiki/Prescription_drug" style="color: #0c5390; text-decoration: none;" title="Prescription drug">POM</a></li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Route_of_administration" style="color: #0c5390; text-decoration: none;" title="Route of administration">ROUTES</a></th><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/Intravenous_therapy" style="color: #0c5390; text-decoration: none;" title="Intravenous therapy">Intravenous</a>, oral</td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">PHARMACOKINETIC DATA</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Bioavailability" style="color: #0c5390; text-decoration: none;" title="Bioavailability">BIOAVAILABILITY</a></th><td style="padding: 5px 0px;">55%</td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Plasma_protein_binding" style="color: #0c5390; text-decoration: none;" title="Plasma protein binding">PROTEIN BINDING</a></th><td style="padding: 5px 0px;">19 to 29%</td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Biological_half-life" style="color: #0c5390; text-decoration: none;" title="Biological half-life">HALF-LIFE</a></th><td style="padding: 5px 0px;">20 hours</td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Excretion" style="color: #0c5390; text-decoration: none;" title="Excretion">EXCRETION</a></th><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/Kidney" style="color: #0c5390; text-decoration: none;" title="Kidney">Renal</a></td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">IDENTIFIERS</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a class="mw-redirect" href="http://en.wikipedia.org/wiki/CAS_registry_number" style="color: #0c5390; text-decoration: none;" title="CAS registry number">CAS NUMBER</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?term=75607-67-9&rn=1" rel="nofollow" style="color: #0c5390; text-decoration: none;">75607-67-9</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" style="color: #0c5390; text-decoration: none;" title="Anatomical Therapeutic Chemical Classification System">ATC CODE</a></th><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/ATC_code_L01" style="color: #0c5390; text-decoration: none;" title="ATC code L01">L01</a><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.whocc.no/atc_ddd_index/?code=L01BB05" rel="nofollow" style="color: #0c5390; text-decoration: none;">BB05</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/PubChem" style="color: #0c5390; text-decoration: none;" title="PubChem">PUBCHEM</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=657237" rel="nofollow" style="color: #0c5390; text-decoration: none;">CID 657237</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/DrugBank" style="color: #0c5390; text-decoration: none;" title="DrugBank">DRUGBANK</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.drugbank.ca/drugs/DB01073" rel="nofollow" style="color: #0c5390; text-decoration: none;">DB01073</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/ChemSpider" style="color: #0c5390; text-decoration: none;" title="ChemSpider">CHEMSPIDER</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.chemspider.com/Chemical-Structure.571392.html" rel="nofollow" style="color: #0c5390; text-decoration: none;">571392</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" style="color: #0c5390; text-decoration: none;" title="Unique Ingredient Identifier">UNII</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=P2K93U8740" rel="nofollow" style="color: #0c5390; text-decoration: none;">P2K93U8740</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/KEGG" style="color: #0c5390; text-decoration: none;" title="KEGG">KEGG</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.kegg.jp/entry/D01907" rel="nofollow" style="color: #0c5390; text-decoration: none;">D01907</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/ChEBI" style="color: #0c5390; text-decoration: none;" title="ChEBI">CHEBI</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:63599" rel="nofollow" style="color: #0c5390; text-decoration: none;">CHEBI:63599</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="" src="http://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" height="8" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/ChEMBL" style="color: #0c5390; text-decoration: none;" title="ChEMBL">CHEMBL</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL1568" rel="nofollow" style="color: #0c5390; text-decoration: none;">CHEMBL1568</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">CHEMICAL DATA</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Chemical_formula" style="color: #0c5390; text-decoration: none;" title="Chemical formula">FORMULA</a></th><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/Carbon" style="color: #0c5390; text-decoration: none;" title="Carbon">C</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">10</span><a href="http://en.wikipedia.org/wiki/Hydrogen" style="color: #0c5390; text-decoration: none;" title="Hydrogen">H</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">13</span><a href="http://en.wikipedia.org/wiki/Fluorine" style="color: #0c5390; text-decoration: none;" title="Fluorine">F</a><a href="http://en.wikipedia.org/wiki/Nitrogen" style="color: #0c5390; text-decoration: none;" title="Nitrogen">N</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">5</span><a href="http://en.wikipedia.org/wiki/Oxygen" style="color: #0c5390; text-decoration: none;" title="Oxygen">O</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">7</span><a href="http://en.wikipedia.org/wiki/Phosphorus" style="color: #0c5390; text-decoration: none;" title="Phosphorus">P</a><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> </span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Molecular_mass" style="color: #0c5390; text-decoration: none;" title="Molecular mass">MOLECULAR MASS</a></th><td style="padding: 5px 0px;">365.212 g/mol</td></tr>
</tbody></table>
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……………….</div>
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<b>Fludarabine</b> or <b>fludarabine phosphate</b> (Fludara) is a <a href="http://en.wikipedia.org/wiki/Chemotherapy" style="color: #0c5390; text-decoration: none;" title="Chemotherapy">chemotherapy</a> drug used in the treatment of <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Hematological_malignancy" style="color: #0c5390; text-decoration: none;" title="Hematological malignancy">hematological malignancies</a>(cancers of blood cells such as leukemias and lymphomas). It is a purine analog, which interferes with DNA synthesis.</div>
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<img alt="" src="http://www.drug3k.com/img4/fludarabine_15038_11_(big)_.jpeg" data-pinit="registered" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<img alt="" src="http://images.ddccdn.com/pro/images/ac76aca8-e718-4232-92ab-399166ce9e46/fludarabine-figure-01.jpg" data-pinit="registered" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<span class="mw-headline" id="Indications">Indications</span></h2>
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Fludarabine is highly effective in the treatment of <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia" style="color: #0c5390; text-decoration: none;" title="Chronic lymphocytic leukemia">chronic lymphocytic leukemia</a>, producing higher response rates than <a href="http://en.wikipedia.org/wiki/Alkylating_antineoplastic_agent" style="color: #0c5390; text-decoration: none;" title="Alkylating antineoplastic agent">alkylating agents</a> such as<a href="http://en.wikipedia.org/wiki/Chlorambucil" style="color: #0c5390; text-decoration: none;" title="Chlorambucil">chlorambucil</a> alone.<span class="reference" id="cite_ref-Rai_1-0" style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Fludarabine#cite_note-Rai-1" style="color: #0c5390; text-decoration: none;">[1]</a></span> Fludarabine is used in various combinations with<a href="http://en.wikipedia.org/wiki/Cyclophosphamide" style="color: #0c5390; text-decoration: none;" title="Cyclophosphamide">cyclophosphamide</a>, <a href="http://en.wikipedia.org/wiki/Mitoxantrone" style="color: #0c5390; text-decoration: none;" title="Mitoxantrone">mitoxantrone</a>,<a href="http://en.wikipedia.org/wiki/Dexamethasone" style="color: #0c5390; text-decoration: none;" title="Dexamethasone">dexamethasone</a> and <a href="http://en.wikipedia.org/wiki/Rituximab" style="color: #0c5390; text-decoration: none;" title="Rituximab">rituximab</a> in the treatment of <a class="new" href="http://en.wikipedia.org/w/index.php?title=Indolent_condition&action=edit&redlink=1" style="color: #0c5390; text-decoration: none;" title="Indolent condition (page does not exist)">indolent</a> <a href="http://en.wikipedia.org/wiki/Lymphoma" style="color: #0c5390; text-decoration: none;" title="Lymphoma">non-Hodgkins lymphomas</a>. As part of the <i>FLAG</i> regimen, fludarabine is used together with <a href="http://en.wikipedia.org/wiki/Cytarabine" style="color: #0c5390; text-decoration: none;" title="Cytarabine">cytarabine</a> and <a href="http://en.wikipedia.org/wiki/Granulocyte_colony-stimulating_factor" style="color: #0c5390; text-decoration: none;" title="Granulocyte colony-stimulating factor">granulocyte colony-stimulating factor</a> in the treatment of <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Acute_myeloid_leukaemia" style="color: #0c5390; text-decoration: none;" title="Acute myeloid leukaemia">acute myeloid leukaemia</a>. Because of its immunosuppressive effects, fludarabine is also used in some conditioning regimens prior to <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Bone_marrow_transplant" style="color: #0c5390; text-decoration: none;" title="Bone marrow transplant">allogeneic stem cell transplant</a>.</div>
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<span class="mw-headline" id="Pharmacology">Pharmacology</span></h2>
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Fludarabine is a <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Purine_analog" style="color: #0c5390; text-decoration: none;" title="Purine analog">purine analog</a>, and can be given both orally and intravenously. Fludarabine inhibits <a href="http://en.wikipedia.org/wiki/DNA_synthesis" style="color: #0c5390; text-decoration: none;" title="DNA synthesis">DNA synthesis</a> by interfering with<a href="http://en.wikipedia.org/wiki/Ribonucleotide_reductase" style="color: #0c5390; text-decoration: none;" title="Ribonucleotide reductase">ribonucleotide reductase</a>and <a href="http://en.wikipedia.org/wiki/DNA_polymerase" style="color: #0c5390; text-decoration: none;" title="DNA polymerase">DNA polymerase</a>. It is active against both dividing and resting cells. Being phosphorylated, fludarabine is ionized at physiologic pH and is effectually trapped in blood. This provides some level of specificity for blood cells, both cancerous and healthy.</div>
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<span class="mw-headline" id="Side_effects">Side effects</span></h2>
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Fludarabine is associated with profound <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Lymphopenia" style="color: #0c5390; text-decoration: none;" title="Lymphopenia">lymphopenia</a>, and as a consequence, increases the risk of <a href="http://en.wikipedia.org/wiki/Opportunistic_infection" style="color: #0c5390; text-decoration: none;" title="Opportunistic infection">opportunistic infections</a>significantly. Patients who have been treated with fludarabine will usually be asked to take <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Co-trimoxazole" style="color: #0c5390; text-decoration: none;" title="Co-trimoxazole">co-trimoxazole</a> or to use monthly nebulised <a href="http://en.wikipedia.org/wiki/Pentamidine" style="color: #0c5390; text-decoration: none;" title="Pentamidine">pentamidine</a> to prevent <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Pneumocystis_jiroveci_pneumonia" style="color: #0c5390; text-decoration: none;" title="Pneumocystis jiroveci pneumonia"><i>Pneumocystis jiroveci</i>pneumonia</a>. The profound lymphopenia caused by fludarabine renders patients susceptible to <a href="http://en.wikipedia.org/wiki/Transfusion-associated_graft_versus_host_disease" style="color: #0c5390; text-decoration: none;" title="Transfusion-associated graft versus host disease">transfusion-associated graft versus host disease</a>, an oftentimes fatal complication of <a href="http://en.wikipedia.org/wiki/Blood_transfusion" style="color: #0c5390; text-decoration: none;" title="Blood transfusion">blood transfusion</a>. For this reason, all patients who have ever received fludarabine should only be given <a href="http://en.wikipedia.org/wiki/Irradiation" style="color: #0c5390; text-decoration: none;" title="Irradiation">irradiated</a> blood components.</div>
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Fludarabine causes anemia, thrombocytopenia and <a href="http://en.wikipedia.org/wiki/Neutropenia" style="color: #0c5390; text-decoration: none;" title="Neutropenia">neutropenia</a>, requiring regular blood count monitoring. Some patients require blood and <a href="http://en.wikipedia.org/wiki/Platelet" style="color: #0c5390; text-decoration: none;" title="Platelet">platelet</a>transfusion, or <a href="http://en.wikipedia.org/wiki/Granulocyte_colony-stimulating_factor" style="color: #0c5390; text-decoration: none;" title="Granulocyte colony-stimulating factor">G-CSF</a> injections to boost <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Neutrophil" style="color: #0c5390; text-decoration: none;" title="Neutrophil">neutrophil</a> counts.</div>
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Fludarabine is associated with the development of severe <a href="http://en.wikipedia.org/wiki/Autoimmune_hemolytic_anemia" style="color: #0c5390; text-decoration: none;" title="Autoimmune hemolytic anemia">autoimmune hemolytic anemia</a> in a proportion of patients.<span class="reference" id="cite_ref-Gonzalez_2-0" style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Fludarabine#cite_note-Gonzalez-2" style="color: #0c5390; text-decoration: none;">[2]</a></span></div>
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Difficulties are often encountered when harvesting peripheral blood stem cells from patients previously treated with fludarabine.<span class="reference" id="cite_ref-Tournilhac_3-0" style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Fludarabine#cite_note-Tournilhac-3" style="color: #0c5390; text-decoration: none;">[3]</a></span></div>
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<span class="mw-headline" id="History">History</span></h2>
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Fludarabine was produced by John Montgomery and Kathleen Hewson of the<a href="http://en.wikipedia.org/wiki/Southern_Research_Institute" style="color: #0c5390; text-decoration: none;" title="Southern Research Institute">Southern Research Institute</a> in 1968.<span class="reference" id="cite_ref-Sneader_4-0" style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Fludarabine#cite_note-Sneader-4" style="color: #0c5390; text-decoration: none;">[4]</a></span> Their previous work involved <a class="new" href="http://en.wikipedia.org/w/index.php?title=2-fluoroadenosine&action=edit&redlink=1" style="color: #0c5390; text-decoration: none;" title="2-fluoroadenosine (page does not exist)">2-fluoroadenosine</a>, which was unsafe for use in humans; the change to this<a href="http://en.wikipedia.org/wiki/Arabinose" style="color: #0c5390; text-decoration: none;" title="Arabinose">arabinose</a> analogue was inspired by the success of <a href="http://en.wikipedia.org/wiki/Vidarabine" style="color: #0c5390; text-decoration: none;" title="Vidarabine">vidarabine</a>.<span class="reference" id="cite_ref-Sneader_4-1" style="font-size: 10.5px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Fludarabine#cite_note-Sneader-4" style="color: #0c5390; text-decoration: none;">[4]</a></span></div>
<ul class="description" id="PDES17928346" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px; margin: 0px 0px 14px 36px; padding: 0px;">
<li style="list-style-type: square;"><div class="description-line">
Fludarabine (9-β-D-arabinofuranosyl-2-fluoroadenine) <b>(II)</b> is a purine nucleoside antimetabolite resistant to adenosine deaminase, employed for the treatment of leukemia.<br />
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<a href="http://patentimages.storage.googleapis.com/EP1464708A1/00010002.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure 00010002" class="patent-full-image" src="http://patentimages.storage.googleapis.com/EP1464708A1/00010002.png" data-pinit="registered" height="240" id="img-00010002" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="144" /></a></div>
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<li style="list-style-type: square;"><div class="description-line-number">
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<div class="description-line">
Fludarabine is usually administered as a pro-drug, fludarabine phosphate, which is also the natural metabolite. Fludarabine was firstly synthesised by Montgomery (<b>US 4,188,378</b> and <b>US 4,210,745</b>) starting from 2-aminoadenine. The method comprised acetylation of 2-aminoadenine, reaction with a benzyl-protected chlorosugar, deacetylation of the amino groups, diazotization and fluorination of the 2-amino group followed by deprotection of the sugar residue.</div>
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<div class="description-line">
Fludarabine phosphate can be obtained according to conventional phosphorylation methods, typically by treatment with trimethylphosphate and phosphoryl chloride. Recently, a method for preparing highly pure fludarabine, fludarabine phosphate and salts thereof has been disclosed by Tilstam et al. (<b>US 6,46,322</b>).</div>
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<div class="description-line">
Enzymatic synthesis has been regarded as a valid alternative to conventional methods for the synthesis of nucleosides and nucleotides derivatives. <b>EP 0 867 516</b> discloses a method for the preparation of sugar nucleotides from sugar 1-phosphates and nucleosides monophosphates by use of yeast cells having nucleoside diphosphate-sugar pyrophosphorylase activity. <b>EP 0721 511 B1</b> discloses the synthesis of vidarabine phosphate and fludarabine phosphate by reacting an arabinonucleotide with an arylphosphate in the presence of a microorganism able to catalyse the phosphorylation of nucleosides. This method is particularly convenient in that it does not require purified enzymes, but it does not allow to synthesise vidarabine and fludarabine.</div>
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<h1 class="articleTitle" style="background-color: white; clear: both; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 40px; font-weight: normal; letter-spacing: -1px; line-height: 1.15; margin: 0px 0px 30px; padding: 0px;">
Simple Modification To Obtain High Quality Fludarabine</h1>
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<div id="authors">
<a href="http://pubs.acs.org/action/doSearch?ContribStored=Kshirsagar%2C+S+W" id="authors" style="color: #0c5390; text-decoration: none;">Siddheshwar W. Kshirsagar</a> <span class="NLM_x">, </span><a href="http://pubs.acs.org/action/doSearch?ContribStored=Deshpande%2C+M+S" id="authors" style="color: #0c5390; text-decoration: none;">Mangesh S. Deshpande</a> <span class="NLM_x">, </span><a href="http://pubs.acs.org/action/doSearch?ContribStored=Sonawane%2C+S+P" id="authors" style="color: #0c5390; text-decoration: none;">Swapnil P. Sonawane</a><a class="ref" href="http://pubs.acs.org/doi/abs/10.1021/op3000509#cor1" style="color: #0c5390; text-decoration: none;">*</a><span class="NLM_x">, </span><a href="http://pubs.acs.org/action/doSearch?ContribStored=Maikap%2C+G+C" id="authors" style="color: #0c5390; text-decoration: none;">Golak C. Maikap</a> <span class="NLM_x">, and </span><a href="http://pubs.acs.org/action/doSearch?ContribStored=Gurjar%2C+M+K" id="authors" style="color: #0c5390; text-decoration: none;">Mukund K. Gurjar</a></div>
<div class="affiliations">
<div id="aff1">
API R & D Centre, <span class="institution">Emcure Pharmaceuticals Ltd</span>, I.TBT Park, Phase-II, M.IDC Hinjewadi, Pune-411057, India</div>
</div>
<div id="citation">
<cite>Org. Process Res. Dev.</cite>, <span class="citation_year">2012</span>, <span class="citation_volume">16</span> (5), pp 840–842</div>
<div id="doi">
<strong>DOI: </strong>10.1021/op3000509</div>
</div>
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<a href="http://pubs.acs.org/doi/abs/10.1021/op3000509" style="color: #0c5390; text-decoration: none;">http://pubs.acs.org/doi/abs/10.1021/op3000509</a></div>
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<img alt="Abstract Image" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2012/oprdfk.2012.16.issue-5/op3000509/production/images/medium/op-2012-000509_0003.gif" data-pinit="registered" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
<div class="articleBody_abstractText" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px; margin-bottom: 10px;">
A simple and improved debenzylation process is described to obtain fludarabine in greater than 99.8% purity and 90–95% yield.</div>
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<a href="http://www.google.com/patents/EP1464708A1?cl=en" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/EP1464708A1?cl=en</a></div>
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<img alt="" class="" src="http://patentimages.storage.googleapis.com/EP1464708A1/00030001.png" data-pinit="registered" height="462" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="494" /></div>
<ul class="description" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px; margin: 0px 0px 14px 36px; padding: 0px;"><ul class="description" style="margin: 0px 0px 0px 36px; padding: 0px;">
<li style="list-style-type: square;"><div class="description-line">
The present invention relates to a process for the preparation of fludarabine phosphate <b>(I)</b> illustrated in the scheme and comprising the following steps:<br />
<div style="margin-bottom: 10px;">
</div>
<ul style="margin: 0px 0px 0px 36px; padding: 0px;">
<li style="list-style-type: square;">a) reaction of 2-fluoroadenine with 9-β-D-arabinofuranosyl-uracil in the presence of <i>Enterobacter aerogenes</i> to give crude fludarabine (<b>II</b>);</li>
<li style="list-style-type: square;">b) treatment of crude fludarabine with acetic anhydride to 2′,3′,5′-tri-O-acetyl-9-β-D-arabinofuranosyl-2-fluoroadenine (<b>III</b>);</li>
<li style="list-style-type: square;">c) hydrolysis and recrystallisation of intermediate <b>(III)</b> to give pure fludarabine;</li>
<li style="list-style-type: square;">d) phosphorylation of fludarabine to give fludarabine phosphate (<b>I</b>).<div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/EP1464708A1/00030001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure 00030001" class="patent-full-image" src="http://patentimages.storage.googleapis.com/EP1464708A1/00030001.png" data-pinit="registered" height="600" id="img-00030001" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="644" /></a></div>
</li>
</ul>
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</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0008]</div>
<div class="description-line">
Step a) is carried out in a 0.03 – 0.05 M KH<span style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">2</span>PO<span style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">4</span> solution, heated to a temperature comprised between 50 and 70°C, preferably to 60°C, adjusted to pH 7 with KOH pellets and added with 2-fluoroadenine, Ara-U and EBA. The concentration of 2-fluoroadenine in the solution ranges from 0.02 to 0.03 M, while 9-β-D-arabinofuranosyl-uracil is used in a strong excess; preferably, the molar ratio between 9-β-D-arabinofuranosyl-uracil and 2-fluoroadenine ranges from 5:1 to 7:1, more preferably from 5.5:1 to 6.5:1. 2 – 2.5 1 of cell culture per 1 of KH<span style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">2</span>PO<span style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">4</span> solution are used. The mixture is stirred at 60°C, adjusting the pH to 7 with a 25% KOH solution and the reaction is monitored by HPLC. Once the reaction is complete (about 24-26 hours), the cell material is separated by conventional dialysis and the permeated solutions are recovered and kept cool overnight. Crystallised fludarabine contains 10% 9-β-D-arabinofuranosyl adenine, which can be conveniently removed by means of steps b) and c).</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0009]</div>
<div class="description-line">
In step b) crude fludarabine from step a) is dissolved in 9-11 volumes of acetic anhydride, preferably 10 volumes and reacted at 90 – 100°C under stirring, until completion of the reaction (about 10 – 12 h). Acetic anhydride is co-evaporated with acetone and the product is suspended in water.</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0010]</div>
<div class="description-line">
The hydrolysis of step c) is carried out with methanol and ammonium hydroxide. Typically, compound <b>(III)</b> from step b) is suspended in 9-11 volumes of methanol and 2.5 – 3.5 volumes of 25% NH<span style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">4</span>OH and stirred at room temperature until complete hydrolysis (about 20 hours; the completion of the reaction can be promoted by mildly warming up the mixture to 30-32°C). Fludarabine precipitates by cooling the mixture to 10°C and is further hot-crystallised with water, preferably with 50 – 70 ml of water per gram of fludarabine or with a water/ethanol mixture (1/1 v/v) using 30 – 40 ml of mixture per gram of fludarabine. Fludarabine is recovered as the monohydrate and has a HPLC purity higher than 99%.</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0011]</div>
<div class="description-line">
Even though the conversion of fludarabine into fludarabine phosphate (step d) can be carried out according to any conventional technique, for example as disclosed in US 4,357,324, we have found that an accurate control of the reaction and crystallisation temperature allows to minimise product decomposition and significantly improves the yield. According to a preferred embodiment of the invention, the reaction between phosphorus oxychloride, triethylphosphate and fludarabine is carried out at -10°C, and fludarabine phosphate is precipitated from water at 0°C.</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0012]</div>
<div class="description-line">
In summary, the present invention allows to obtain the following advantages: fludarabine is prepared by enzymatic synthesis without the use of pure enzymes and is therefore particularly suitable for industrial scale; fludarabine is easily recovered and purified from 9-β-D-arabinofuranosyl adenine by acetylation without the need of chromatographic purification, since the triacetyl-derivative precipitates from water with high purity and yield; fludarabine phosphate can be obtained in high yield by controlling the reaction and crystallisation temperature in the phosphorylation step.</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0013]</div>
<div class="description-line">
The following examples illustrate the invention in more detail.</div>
</li>
</ul>
</ul>
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<b>EXAMPLES</b><b>Example 1 – Crude 9-β-D-arabinofuranosyl-2-fluoroadenine (II)</b></div>
<ul class="description" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px; margin: 0px 0px 14px 36px; padding: 0px;"><ul class="description" style="margin: 0px 0px 0px 36px; padding: 0px;">
<li style="list-style-type: square;"><div class="description-line-number">
[0014]</div>
<div class="description-line">
A solution of KH<span style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">2</span>PO<span style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">4</span> (123 g, 0,9 moles) in water (13 l) was heated to 60°C under stirring and the pH adjusted to 7 with KOH pellets (130 g, 2.32 moles), then added with Ara-U (1451 g, 5.94 moles), 2-fluoroadenine (150 g, 0.98 moles) and EBA (ATCC® n° 13048) cell culture (30 l).</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0015]</div>
<div class="description-line">
The mixture was stirred at 60°C for 24-26 hours, adjusting the pH to 7 with a 25% KOH solution and monitoring the reaction by HPLC.</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0016]</div>
<div class="description-line">
After 24-26 hours the cell material was separated by dialysis at 50°-55°C, diluting the mixture with water. The permeated yellow clear solutions were collected, pooled (50 l) and left to stand at 0°-5°C overnight. The resulting crystalline precipitate was filtered and washed with cold water (2 l).</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0017]</div>
<div class="description-line">
The product was dried at 45°C under vacuum for 16 hours to give 110 g of the crude compound <b>(II)</b> which was shown by HPLC to be a mixture of (<b>I</b>) (90%) and 9-β-D-arabinofuranosyl adenine (10%).</div>
</li>
</ul>
</ul>
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<b>Example 2 Pure 9-β-D-arabinofuranosyl-2-fluoroadenine (II)</b></div>
<ul class="description" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px; margin: 0px 0px 14px 36px; padding: 0px;"><ul class="description" style="margin: 0px 0px 0px 36px; padding: 0px;">
<li style="list-style-type: square;"><div class="description-line-number">
[0018]</div>
<div class="description-line">
9-β-D-arabinofuranosyl-2-fluoroadenine <b>(II)</b> (30 g, 0,095 moles) was suspended in acetic anhydride (300 ml) and heated to 95°C under stirring.</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0019]</div>
<div class="description-line">
After 7 hours a clear solution was obtained and left to react at 95°C for further 2-3 hours until the acetylation was completed.</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0020]</div>
<div class="description-line">
The resulting yellow solution was then concentrated under vacuum at 45°C and the residue was co-evaporated with acetone (2 x 50 ml) and suspended in water (600 ml). The water suspension was cooled to room temperature and left under stirring for 1 hour.</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0021]</div>
<div class="description-line">
The product was collected by filtration and washed with water (2 x 100 ml) to give 34 g of wet 2′,3′,5′-tri-O-acetyl-9-β-D-arabinofuranosyl-2-fluoroadenine <b>(III).</b></div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0022]</div>
<div class="description-line">
Wet compound <b>(III)</b> was suspended in methanol (300 ml) and added with 25% NH<span style="bottom: -0.25em; font-size: 10.5px; line-height: 0; position: relative; vertical-align: baseline;">4</span>OH (100 ml). The mixture was left to stand at room temperature overnight and after 19 hours was warmed to 30°-32°C for 3 hours, until no starting material was detected by HPLC.</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0023]</div>
<div class="description-line">
The suspension was cooled to 10°C for 1 hour, then the product was collected by filtration and washed with a methanol-water mixture (2 x 25 ml, 3:1 v/v). The product was dried under vacuum at 45°C overnight to give 17.5 g of fludarabine (<b>II</b>) (98.4% HPLC purity).</div>
</li>
</ul>
</ul>
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<span style="text-decoration: underline;">Method A</span></div>
<ul class="description" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px; margin: 0px 0px 14px 36px; padding: 0px;"><ul class="description" style="margin: 0px 0px 0px 36px; padding: 0px;">
<li style="list-style-type: square;"><div class="description-line-number">
[0024]</div>
<div class="description-line">
Re-crystallisation of compound <b>(II)</b> (17.5 g, 0.061 moles) was also carried out by suspending the product in water (875 ml) and heating to 95°C until a clear solution was obtained. The solution was allowed to cool spontaneously to room temperature and the crystalline product was filtered, washed with cold water (2 x 50 ml) and dried under vacuum at 45°C overnight, to give 15.5 g of pure fludarabine <b>(II)</b> as the monohydrate (99.3% HPLC purity).</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0025]</div>
<div class="description-line">
The monohydrate was further dried under vacuum at 90°C for 24 hours to give pure anhydrous fludarabine <b>(II).</b></div>
</li>
</ul>
</ul>
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<span style="text-decoration: underline;">Method B</span></div>
<ul class="description" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px; margin: 0px 0px 14px 36px; padding: 0px;"><ul class="description" style="margin: 0px 0px 0px 36px; padding: 0px;">
<li style="list-style-type: square;"><div class="description-line-number">
[0026]</div>
<div class="description-line">
Fludarabine (II) (35 g, 0.123 moles) was also re-crystallized by suspending the product in a water/ethanol mixture (1/1, v/v) (1050 ml) and heating to 80°C until a clear solution was obtained. The solution was allowed to cool spontaneously to room temperature and the crystalline product was filtered, washed with a water/ethanol mixture (2 x 50 ml) and dried under vacuum at 45°C overnight, to give 32 g of pure fludarabine (II) as the monohydrate ( 99% HPLC purity ).</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0027]</div>
<div class="description-line">
The monohydrate was further dried under vacuum at 90°C for 24 hours to give pure anhydrous fludarabine <b>(II).</b></div>
</li>
</ul>
</ul>
<div style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px; margin-bottom: 10px;">
<b>Example 3 – 9-β-D-arabinofuranosyl-2-fluoroadenine-5′-phosphate (I)</b><span style="text-decoration: underline;">Method A</span></div>
<ul class="description" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px; margin: 0px 0px 14px 36px; padding: 0px;"><ul class="description" style="margin: 0px 0px 0px 36px; padding: 0px;">
<li style="list-style-type: square;"><div class="description-line-number">
[0028]</div>
<div class="description-line">
Phosphorous oxychloride (5 g, 3 ml, 0.033 moles) was added to cold (0°C, ice-bath) triethylphosphate (50 ml) and the solution was kept at 0°C for 1 hour, thereafter added with anhydrous fludarabine<b>(II)</b> (5 g, 0.018 moles) under stirring.</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0029]</div>
<div class="description-line">
After about 3 hours, the reaction mixture became homogeneous and turned light-yellow and was kept at 0°C overnight. Once the phosphorylation was completed (about 23 hours) the mixture was added with water (10 ml) and the solution was stirred for 3 hours at 0°C. The mixture was then poured into cold (0°C) methylene chloride (400 ml) and kept at 0°C under stirring until a clear methylene chloride phase was obtained (at least 1 hours).</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0030]</div>
<div class="description-line">
The methylene chloride phase was removed by decantation and the residual yellowish oil was dissolved in warm (50°C) water (30 ml). The solution was allowed to cool spontaneously to room temperature overnight and the resulting crystalline product was collected by filtration and washed with water (10 ml) and ethanol (2 x 10 ml).</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0031]</div>
<div class="description-line">
The product was dried at room temperature under vacuum for 24 hours to give 4 g of compound (<b>I</b>).</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0032]</div>
<div class="description-line">
Compound (<b>I</b>) was re-crystallised as follows: compound (<b>I</b>) (4 g) was dissolved in 60 ml of preheated deionized water (73°-75°C) and the solution was stirred and rapidly cooled to 50°C to minimize product decomposition. The solution was then allowed to cool spontaneously to room temperature: the precipitation started at 40°C. The resulting precipitate was collected by filtration and washed with water (10 ml) and ethanol (2 × 10 ml). The product was dried at room temperature under vacuum for 24 hours to give 2.5 g of compound <b>(I).</b></div>
</li>
</ul>
</ul>
<div style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px; margin-bottom: 10px;">
<span style="text-decoration: underline;">Method B</span></div>
<ul class="description" id="PDES17928346" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px; margin: 0px 0px 14px 36px; padding: 0px;">
<li style="list-style-type: square;"><div class="description-line-number">
[0033]</div>
<div class="description-line">
Phosphorous oxychloride (5 g, 3 ml, 0.033 mol) was added to cold (-10°C) triethylphosphate (50 ml) and the solution was kept at -10°C for 1 hour, thereafter anhydrous fludarabine <b>(II)</b> (5 g, 0,018 mol) was added with stirring at -10°C.</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0034]</div>
<div class="description-line">
After about 6 hours the reaction mixture turned light-yellow and became homogeneous. The mixture was kept at -10°C overnight and after 23 hours the phosphorylation was completed. After addition of 40 ml of cold water (2°C) the solution was stirred for 1 hour at 0°C and extracted with cold (0°C) methylene chloride (100 ml and two 50-ml portions).</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0035]</div>
<div class="description-line">
The aqueous solution was kept under vacuum at room temperature for 1 hour and allowed to stand at 0°C for 24 hours. The resulting crystalline product (<b>I</b>) was collected by filtration and washed with ethanol (2 x 20 ml).</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0036]</div>
<div class="description-line">
The product was dried at 40°C under vacuum for 24 hours (Yield: 5 g).</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
[0037]</div>
<div class="description-line">
A final crystallization was carried out as follows. Compound (<b>I</b>) (5 g) was dissolved in 75 ml of preheated deionized water (73°-75°C) and the solution was stirred and rapidly cooled to 50°C to minimize decomposition. The solution was then allowed to cool spontaneously to room temperature (the precipitation started at 40°C). The resulting precipitate was collected by filtration and washed with water (10 ml ) and ethanol (2 x 10 ml). The product was dried at 40°C under vacuum for 24 hours (Yield: 4 g).</div>
</li>
</ul>
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<span class="mw-headline" id="References">References</span></h2>
<div class="reflist" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px;">
<ol class="references" style="margin: 0px 0px 14px 36px; padding: 0px;">
<li id="cite_note-Rai-1" style="list-style-type: decimal;"> <span class="reference-text">Rai KR et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000;343:1750-7. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" style="color: #0c5390; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="http://dx.doi.org/10.1056%2FNEJM200012143432402" rel="nofollow" style="color: #0c5390; text-decoration: none;">10.1056/NEJM200012143432402</a> <a class="external mw-magiclink-pmid" href="http://www.ncbi.nlm.nih.gov/pubmed/11114313?dopt=Abstract" rel="nofollow" style="color: #0c5390; text-decoration: none;">PMID 11114313</a></span></li>
<li id="cite_note-Gonzalez-2" style="list-style-type: decimal;"> <span class="reference-text">Gonzalez H et al. Severe autoimmune hemolytic anemia in eight patients treated with fludarabine. Hematol Cell Ther. 1998;40:113-8. <a class="external mw-magiclink-pmid" href="http://www.ncbi.nlm.nih.gov/pubmed/9698219?dopt=Abstract" rel="nofollow" style="color: #0c5390; text-decoration: none;">PMID 9698219</a></span></li>
<li id="cite_note-Tournilhac-3" style="list-style-type: decimal;"> <span class="reference-text">Tournilhac O et al. Impact of frontline fludarabine and cyclophosphamide combined treatment on peripheral blood stem cell mobilization in B-cell chronic lymphocytic leukemia. Blood 2004;103:363-5. <a class="external mw-magiclink-pmid" href="http://www.ncbi.nlm.nih.gov/pubmed/12969985?dopt=Abstract" rel="nofollow" style="color: #0c5390; text-decoration: none;">PMID 12969985</a></span></li>
<li id="cite_note-Sneader-4" style="list-style-type: decimal;"> <span class="reference-text">Sneader, Walter (2005). <i>Drug discovery: a history</i>. New York: Wiley. p. 258. <a href="http://en.wikipedia.org/wiki/International_Standard_Book_Number" style="color: #0c5390; text-decoration: none;" title="International Standard Book Number">ISBN</a> <a href="http://en.wikipedia.org/wiki/Special:BookSources/0-471-89979-8" style="color: #0c5390; text-decoration: none;" title="Special:BookSources/0-471-89979-8">0-471-89979-8</a>.</span></li>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-7082350141827122272.post-51284754932735263542015-01-31T03:58:00.001-08:002015-01-31T03:58:43.317-08:00What is a chemical synthesis pharmaceutical plant?<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="Image: Manufacturing process for synthetic pharmaceuticals" data-pinit="registered" src="http://www.hitachi.com/businesses/infrastructure/product_solution/industry/medicine/plant/image/synthesis_02.gif" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="538" /><br />Manufacturing process for chemical synthesis pharmaceuticals</div>
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There are two main types of processes used to manufacture pharmaceuticals: chemical synthesis based on chemical reactions, and bioprocessing based on the ability of microorganisms and cells to produce useful substances.</div>
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Chemical synthesis can be used to produce pharmaceutical products with relatively low molecular weights in large volumes in short timespans. In addition, various chemical modifications can be applied to enhance the activity of the substance produced.<br />In many cases, solvents and other combustible substances are used in addition to the actual raw materials, and this requires that the buildings and facilities be fire-proofed, as well as other safety and security measures. Also, in many cases, corrosive fluids are involved, requiring the use of glass linings or other anti-corrosive measures.</div>
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The manufacturing processes often entail crystallization and crystal separation, with many processes needed for transport and insertion of solids. In general, pharmaceutical plants produce many different products, and production lines must be kept separate from one another to prevent cross-contamination of products.</div>
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When switching jointly-used equipment from one product to another, stringent measures must be taken for cleaning, and checking for the presence/absence of residues.</div>
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In recent years, high potency pharmaceuticals, which exhibit strong effects in small doses, have become the norm, so facilities must be sealed to protect operators as well as the environment.</div>
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<img alt="" data-pinit="registered" src="http://www.nature.com/nrd/journal/v2/n8/images/nrd1154-f8.jpg" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></div>
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see <a href="http://www.nature.com/nrd/journal/v2/n8/full/nrd1154.html" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">http://www.nature.com/nrd/journal/v2/n8/full/nrd1154.html</a></div>
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In the past, process R&D — which is responsible for producing candidate drugs in the required quantity and of the requisite quality — has had a low profile, and many people outside the field remain unaware of the challenges involved. However, in recent years, the increasing pressure to achieve shorter times to market, the demand for considerable quantities of candidate drugs early in development, and the higher structural complexity — and therefore greater cost — of the target compounds, have increased awareness of the importance of process R&D.</div>
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Here, I discuss the role of process R&D, using a range of real-life examples, with the aim of facilitating integration with other parts of the drug discovery pipeline….<a href="http://www.nature.com/nrd/journal/v2/n8/full/nrd1154.html" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">http://www.nature.com/nrd/journal/v2/n8/full/nrd1154.html</a></div>
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<img alt="" data-pinit="registered" src="https://www.pharmatching.com/company/3151/57101/picture" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></div>
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BIOPHARMACEUTICALS</div>
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The WHO Prequalification of Medicines Programme (PQP) facilitates access to quality medicines through assessment of products and inspection of manufacturing sites. Since good-quality active pharmaceutical ingredients (APIs) are vital to the production of good-quality medicines, PQP has started a pilot project to prequalify APIs.</div>
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WHO-prequalified APIs are listed on the WHO List of Prequalified Active Pharmaceutical Ingredients. The list provides United Nations agencies, national medicines regulatory authorities (NMRAs) and others with information on APIs that have been found to meet WHO-recommended quality standards. It is believed that identification of sources of good-quality APIs will facilitate the manufacture of good-quality finished pharmaceutical products (FPP) that are needed for procurement by UN agencies and disease treatment programmes.</div>
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Details of the API prequalification procedure are available in the <a href="http://apps.who.int/prequal/info_general/documents/TRS953/TRS_953-Annex4.pdf" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" target="_blank">WHO Technical Report Series TRS953, Annex 4</a>. Key elements of this document are given below.</div>
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What is API prequalification?</div>
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API prequalification provides an assurance that the API concerned is of good quality and manufactured in accordance with WHO Good Manufacturing Practices (GMP).</div>
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API prequalification consists of a comprehensive evaluation procedure that has two components: assessment of the API master file (APIMF) to verify compliance with WHO norms and standards and assessment of the sites of API manufacture to verify compliance with WHO GMP requirements.</div>
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Prequalification of an API is made with specific reference to the manufacturing details and quality controls described in the APIMF submitted for assessment. Therefore, for each prequalified API, the relevant APIMF version number will be included in the WHO List of Prequalified Active Pharmaceutical Ingredients.</div>
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Steps in the process</div>
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<em style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The WHO prequalification procedure for medicines and active pharmaceutical ingredients</em></div>
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Initially, an application is screened to determine whether it is covered by the relevant expression of interest (EOI). It is also screened for completeness; in particular, the formatting of the submitted APIMFs is reviewed. Once the application has been accepted, a WHO reference number is assigned to it.</div>
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A team of assessors then reviews the submitted APIMF, primarily at <a href="http://apps.who.int/prequal/info_applicants/info_for_applicants_assessments.htm" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" target="_self">bimonthly</a><a href="http://apps.who.int/prequal/info_applicants/info_for_applicants_assessments.htm" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" target="_self"> meetings in Copenhagen</a>. Invariably, assessors raise questions during assessment of the APIMF that require revision of the information submitted and/or provision of additional information, and/or replacement of certain sections within the APIMF. Applicants are contacted to resolve any issues raised by the assessors.</div>
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It is important that any prequalified API can be unambiguously identified with a specific APIMF. Therefore, once any and all issues regarding its production have been resolved, the applicant will be asked to submit an updated APIMF that incorporates any changes made during assessment. The version number of the revised and up-to-date APIMF will be included on the WHO List of Prequalified Active Pharmaceutical Ingredients, to serve as a reference regarding the production and quality control of that API.</div>
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For APIMFs that have already been accepted in conjunction with the prequalification of an FPP, full assessment is generally not required. Such APIMFs are reviewed only for key information and conformity with administrative requirements. Nonetheless, a request for further information may be made, to ensure that the APIMF meets all current norms and standards; PQP reserves the right to do so.</div>
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An assessment is also undertaken of WHO GMP compliance at the intended site(s) of API manufacture. Depending on the evidence of GMP supplied by the applicant, this may necessitate on-site inspection by WHO. If a WHO inspection is conducted and the site is found to be WHO GMP-compliant, the API will be recommended for prequalification. Additionally, a WHO Public Inspection Report (WHOPIR) will be published on the PQP web site.</div>
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When the APIMF and the standard of GMP at the intended manufacturing site(s) have each been found to be satisfactory, the API is prequalified and listed on the WHO List of Prequalified Active Pharmaceutical Ingredients.</div>
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The successful applicant will also be issued a <a href="http://apps.who.int/prequal/info_applicants/API_confirmation.htm" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">WHO Confirmation of Active Pharmaceutical Ingredient Prequalification document</a>. This document contains the accepted active ingredient specifications and copies of the assay and related substances test methodology. This document may be provided by the API manufacturers to interested parties at their discretion.</div>
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Maintenance of API prequalification status</div>
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Applicants are required to communicate to WHO any changes that have been made to the production and control of a WHO-prequalified API. This can either be in the form of an amendment, or as a newly-issued version of the APIMF. It is the applicant’s responsibility to provide WHO with the appropriate documentation (referring to relevant parts of the dossier), to prove that any intended or implemented change will not have or has not had a negative impact on the quality of the prequalified API. This may necessitate the updating of the information published on the WHO List of Prequalified Active Pharmaceutical Ingredients.</div>
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The decision to prequalify an API is based upon information available to WHO at that time, i.e. information in the submitted APIMF, and on the status of GMP at the facilities used in the manufacture and control of the API. The decision to prequalify an API is subject to change, should new information become available to WHO. For example, if serious safety and/or quality concerns arise in relation to a prequalified API, WHO may suspend the API until the investigative results have been evaluated by WHO and the issues resolved, or delist the API in the case of issues that are not resolved to WHO’s satisfaction.</div>
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CASE STUDY</div>
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READ………<a href="http://www.nature.com/nrd/journal/v2/n8/box/nrd1154_BX1.html" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">http://www.nature.com/nrd/journal/v2/n8/box/nrd1154_BX1.html</a></div>
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PENICILLIN <a href="http://penicillin.wikispaces.com/How+is+it+Made+into+a+Drug%3F" style="border: 0px; color: #227ad1; font-size: 27.8400001525879px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">How is it Made into a Drug?</a></h1>
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<a href="http://penicillin.wikispaces.com/page/edit/How+is+it+Made+into+a+Drug%3F?goto=http%3A%2F%2Fpenicillin.wikispaces.com%2FHow%2Bis%2Bit%2BMade%2Binto%2Ba%2BDrug%253F" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;"> Edit</a><a data-original-title="no discussion posts" href="http://penicillin.wikispaces.com/page/messages/How+is+it+Made+into+a+Drug%3F" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title=""> 0</a><a data-original-title="view 6 revisions" href="http://penicillin.wikispaces.com/page/history/How+is+it+Made+into+a+Drug%3F" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title=""> 6</a><a data-original-title="more options" href="http://penicillin.wikispaces.com/page/menu/How+is+it+Made+into+a+Drug%3F" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title=""><i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"></i>…</a></div>
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Upon Fermentation Penicillin is put through a Recovery Process to obtain its crystallized form, Which can than be dissolved in saline and injected into a patient for treatment.<div style="border: 0px; font-size: 13.9200000762939px; margin-bottom: 1.5em; outline: 0px; padding: 0px;">
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Recovery Process:</div>
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1. Broth Filtration :</div>
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<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The main objective is to remove any microbial cells and any large solid particles such as, cell fragments, soluble and insoluble medium components, other metabolic products, Intact micro-organims.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">During the filtration the micro-organisms are captured in a concentrated cake, which looks like sand, sludge or paste.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">There are many factors that influence the type of filtration to be used:<ol style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 0px 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Viscosity.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Density of filtrate.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Solid liquid ratio.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Size and shape of particles.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Scale of operation.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Need for aseptic conditions.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Need for batch or continuous operation.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Need for pressure or vacuum suction to ensure an sufficient for rate for liquid.</li>
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<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The rotary type is the most often used filtration, its features include:<ol style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 0px 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The Filter Drum: Cylindrical, hollow drum which carries the filter cloth. On the inside it is segmented into rows to which a vacuum can be applied or shut off in sequence as the drum slowly revolves.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Trough: Filter is partially immersed in through which contains the penicillin broth. The trough is sometimes fitted with an agitator to maintain solids in suspension.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Discharge Nodes: Filter cakes are produced from the filtration of to penicillin broth. Because of this a node is devised to scrap off the cake after filtration. When this happens the vacuum is broken.</li>
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<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The filter drum, partially submerged in the trough of broth, rotates slowly. Filtrateand washings are kept separate by the segments in the drum. The liquid is drawn throughthe filter and a cake of solids builds up on the outer surface. Inside the drum, the filtrate is moves from the end of the cylindrical drum onto a storage tank. As our penicillin cellsmove from the broth, the vacuum is used to remove as much moisture as possible fromthe cake, and to hold the cake on the drum. The section at the node/knife, which scrapes off the filtrate can get air pressure to burst out, helping contact with the node.</li>
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2. Filtrate cooled:</div>
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<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">From filtration, the penicillin rich solution is cooled tp 5°C.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">This helps reduce enzyme and chemical degradation during the 4th step; solvent extraction.</li>
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3. Further Filtration:</div>
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<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">More filtration is done with rotary filtration method.</li>
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4. Extraction of Penicillin with solvent:</div>
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<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">This method is carried out under the basis that the extraction agent and the liquid in which the extract is dissolved cannot be mixed.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Solvent extraction is suitable for the recovery of penicillin because of its operation at low temperatures, greater selectivity and is less expensive compared to distillation, evaporation and membrane technology.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">A Podbielniak Centrifugal Contractor is used for this method.</li>
</ul>
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5. Carbon Treatment:</div>
<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 1.5em 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The penicillin rich solution is then treated with 0.25-5% activated carbon to remove pigments and impurities.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Activated carbon is an amorphous solid that absorbs molecules from the liquid phase through its’ highly developed internal pore structure.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">It is obtained in powered, pelleted or granular form and is produced from coal, wood and coconut shells.</li>
</ul>
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6. Transfer Back to Aqueous state:</div>
<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 1.5em 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Using a Podbielniak Centrifugal Contractor, like the one used in solvent extraction, the penicillin rich solvent is passed into a fresh aqueous phase.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">This is done in the presence of Potassium or Sodium Hydroxide to bring the pH back to 5.0-7.5, creating the penicillin salt.</li>
</ul>
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7. Solvent Recovery:</div>
<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 1.5em 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The penicillin solvent is usually recovered by distillation.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Distillation is carried out in three phases:<ol style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 0px 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Evaporation.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Vapour-liquid seperation in a column.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Condensation of vapour.</li>
</ol>
</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Firstly the solvent is vaporised from the solution, then the low boiling volatile components are separated from the less volatile components in a column, and finally condensation is used to recover the volatile solvent fraction.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Solvent recovery is an important process, as solvent is a major expense in the penicillin extraction process.</li>
</ul>
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8. Crystallisation:</div>
<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 1.5em 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Crystallisation is essentially a polishing step that yields a highly pure product and is done through phase separation from a liquid to a solid.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">To begin the process a supersaturated solution, where there are more dissolved solids in the solvent than can ordinarily be accommodated at that temperature, must be obtained through cooling, drowning, solvent evaporation, or by chemical reaction.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The two main methods are Cooling and Drowning.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Cooling:<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 0px 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">As the temperature lowers the solubility of penicillin decreases in a aqeuos solution.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Thus as the cooling takes place, the saturation increases till it reaches supersaturation and than on to crystallisation.</li>
</ul>
</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Drowning:<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 0px 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">This process mainly involves the addition of non-solvent to decrease the solubility of the penicillin.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">This than leads to saturation than to super saturation and finally to crystallisation.</li>
</ul>
</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Crystallisation process after supersaturation has two phases:<ol style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 0px 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Phase 1 Primary Nucleation:<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 0px 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">This phase is mainly the growth of new crystals.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The spontaneous crystal formation and “crashing out” of many nuclei are observed from the solution.</li>
</ul>
</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Phase 2 Secondary Nucleation:<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 0px 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Crystal production is initiated by “seeding”, and occurs at a lower supersaturation.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Seeding involves the addition of small crystals to a solution in a metastable area, which results in interactions between existing crystals, and crystal contact with the walls of the crystalliser.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The crystals will grow on those crystals until the concentration of the solution reaches solubility equilibrium.</li>
</ul>
</li>
</ol>
</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Batch crystallisation is the most the most used method for polishing penicillin G. Batch crystallisers simply consist of tanks with stirrers and are sometimes baffled. They are slowly cooled to produce supersaturation. Seeding causes nucleation and growth is encouraged by further cooling until the desired crystals are obtained.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The advantages of Crystallisation are:<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 0px 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Produced products of very high purity.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Improves products appearance.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">And has a low energy input.</li>
</ul>
</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The disadvantages of Crystallisation are:<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 0px 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The process can be time consuming due to the high concentration of the solutions during crystallisation.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">It can also be profoundly affected by trace impurities.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Batch crystallisation can often give poor quality, nonuniform product.</li>
</ul>
</li>
</ul>
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9. Crystal washing:</div>
<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 1.5em 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Even though the penicillin crystals are pure in nature, adsorption and capillary attraction can cause impurities from its mother liquor on their surfaces and within the voids of the particulate mass.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Thus the crystals must be washed and pre-dried in a liquid in which they are relatively insoluble</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">This solvent should be miscible with the mother solvent.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">For this purpose anhydrous lpropanol, n-butanol or another volatile solvent is used.</li>
</ul>
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10. Drying of Crystals:</div>
<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 1.5em 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Drying stabilizes heat sensitive products like penicillin.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The drying of penicillin must be carried out with extreme care to maintain its chemical and biochemical activity, and ensure that it retains a high level of activity after drying.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The 3 most used methods for drying would be:<ol style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 0px 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Lyophilization:<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 0px 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Another name for freeze-drying</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The wet penicillin is frozen to solidify it.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Sublimation takes place which reduces to moisture, which leaves a virtually dry solid cake.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Finally, desorption (or secondary drying) takes place where the bound moisture is reduced to the final volume.</li>
</ul>
</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Spray Dryers:<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 0px 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">The precise atomization of solutions is seeded in a controlled drying environment for spray drying to take place.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Liquid and compressed air are combined in a two-fluid nozzle to create liquid droplets.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Warm air streams dry the droplets and a dry powder is created.</li>
</ul>
</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Vacuum Band Dryers:<ul style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 0px 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Thin wet layer of penicillin crystals are fed onto a slow rotating heated drum.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Radiant heat dries the layer and scalpels remove the product from the end.</li>
</ul>
</li>
</ol>
</li>
</ul>
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<img alt="recovery.jpg" data-pinit="registered" src="http://penicillin.wikispaces.com/file/view/recovery.jpg/112312379/800x468/recovery.jpg" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></div>
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The Whole Recovery Process in a diagram:</div>
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Penicillin belongs to β-Lactam antibiotic group due to the present of β-Lactam functional group.<br /><img align="left" alt="397px-Beta-lactam_antibiotics_example_1_svg.png" data-pinit="registered" src="http://penicillin.wikispaces.com/file/view/397px-Beta-lactam_antibiotics_example_1_svg.png/111444789/212x309/397px-Beta-lactam_antibiotics_example_1_svg.png" style="border: none; float: left; font-size: 13.9200000762939px; margin: 2px 10px 5px 0px; max-width: 100%; outline: 0px; padding: 0px;" title="397px-Beta-lactam_antibiotics_example_1_svg.png" /><br />The β-Lactam functional group is shown in red<div style="border: 0px; font-size: 13.9200000762939px; margin-bottom: 1.5em; outline: 0px; padding: 0px;">
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Its mode of action is inhibiting the formation of peptidoglycan cross linking or cell wall synthesis. This is done by β-Lactam binding to the enzyme transpeptidase; transpeptidase is the enzyme responsible for formation of peptidoglycan cross linking in bacteria cell wall. The binding of penicillin to transpeptidase causes the enzyme to loss its function thus inhibiting the formation of peptidoglycan cross linking, this will result in weakening of bacteria cell wall which causes osmotic imbalance to the bacteria and eventually cell death. Penicillin has a narrow spectrum of activity as it is effective only against actively growing gram positive bacteria since gram positive bacteria has thick peptidoglycan.</div>
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The diagram here shows how penicillin works against cell wall synthesis:</div>
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<img alt="Capture5.PNG" data-pinit="registered" src="http://penicillin.wikispaces.com/file/view/Capture5.PNG/111446989/Capture5.PNG" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" title="Capture5.PNG" /></div>
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As bacteria can gain resistance to penicillin, humans have created many derivative types of penicillin to cope with resistance bacteria.</div>
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All penicillin or penicillin derivative has a constant core region which is the 6-APA<br /><img alt="Capture.PNG" data-pinit="registered" src="http://penicillin.wikispaces.com/file/view/Capture.PNG/111444905/Capture.PNG" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" title="Capture.PNG" /><br />The only region that is different from different types of penicillin derivative is its R group</div>
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<img alt="Capture1.PNG" data-pinit="registered" src="http://penicillin.wikispaces.com/file/view/Capture1.PNG/111444959/Capture1.PNG" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" title="Capture1.PNG" /></div>
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Eg of derivate penicillin,</div>
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Penicillin G (most common kind of Penicillin)<br /><img alt="Capture3.PNG" data-pinit="registered" src="http://penicillin.wikispaces.com/file/view/Capture3.PNG/111445057/Capture3.PNG" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" title="Capture3.PNG" /><br />Penicillin V</div>
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<img alt="Capture2.PNG" data-pinit="registered" src="http://penicillin.wikispaces.com/file/view/Capture2.PNG/111445023/Capture2.PNG" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" title="Capture2.PNG" /><br />Other types of derivative of penicillin are: Procaine benzylpenicillin, Oxacillin, Benzathine benzylpenicillin, Meticillin etc.</div>
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Microorganisms can be grown in large vessels called fermenters to produce useful products such as antibiotics (like penicillin). Industrial fermenters usually have an air supply to provide oxygen for respiration of the microorganisms, a stirrer to keep the microorganisms in suspension and maintain an even temperature a water-cooled jacket to remove heat produced by the respiring microorganisms<br />The antibiotic, penicillin, is made by growing the mould Penicillium, in a fermenter. The medium contains sugar and other nutrients. The Penicillium only starts to make penicillin after using up most of the nutrients for growth.<div style="border: 0px; font-size: 13.9200000762939px; margin-bottom: 1.5em; outline: 0px; padding: 0px;">
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Other raw materials used in bioprocess system includes:<br />- - pH 6.5<br />- – Oxygen<br />- - Nitrogen: corn steep liquor<br />- <em style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">- Penicillium</em> fungi<br />- - Glucose<br />- - 80% ethanol<br />- - phenyl acetic acid<br />- - Penicillium chrysogenum<br />- - Probenecid</div>
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<span style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: underline;"><strong style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Equipments NEEDED:</strong></span></div>
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<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Viable spores or a live culture of a strain of Penicillium Chrysogenum suitable for submerged (vat) culture of penicillin</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Tanks for holding the culture broth that are capable of being sterilized</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">A means for aerating the broth in vats with sterile air</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Purified water</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Lactose (20 parts per 1000) and corn steep solids (20 parts per 1000) (or corn steep liquor) for the fermentation tank, along with trace amounts of substances such as sodium nitrate (3 parts), dipotassium phosphate (0.05 parts), magnesium phosphate (0.125 parts), calcium carbonate (1.8 parts), and phenyl acetic acid (0.5 parts). All these items must be completely sterile.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Filtering material, such as parachute silk</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">A weak acid and a weak base</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Amyl acetate or ether (for removing the penicillin from the broth)</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Aluminium oxide powder or asbestos (to filter microorganisms and “pyrogens” – fever-causing impurities – from the penicillin)</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Free drying equipment such as a rotary freeze dryer (for removing the water from the penicillin to make a storable crystalline compound)</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Microscopes and slides (for testing the activity of the penicillin)</li>
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<strong style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><span style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: underline;">Procedure:</span></strong></div>
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<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Sterilize the tanks and aeration equipment.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Dissolve the sugar, corn steep liquor, and other substances in the water in the tanks.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Introduce the mold to the culture medium.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">When the mold is reproducing, begin aeration with sterile air. Ideally, maintain the temperature at approximately 24 degrees Celsius. Using aseptic methods, test the broth regularly for penicillin concentration and antibacterial activity. (See note.)</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">When the broth has reached a high level of penicillin concentration, filter the mold juice through a physical filter, such as parachute silk.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Acidify the mold juice to a pH of 2-3 using the weak acid (such as citric acid).</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Thoroughly shake the mold juice with the solvent by hand or using an apparatus.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Allow the mold juice and penicillin-containing solvent to sit until they reseparate.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Drain off the dirty water.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Filter the penicillin-containing solvent through the aluminum oxide powder (alumina salts). The top brownish-orange band contains little penicillin; the pale yellow band contains the majority of the penicillin and no pyrogens; the bottom brownish or reddish-violet purple band is full of impurities. (The solvent may be re-used.)</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Carefully separate only the yellow band in the aluminum oxide powder; wash it in a buffer to clear off the alumina. The fluid is a deep reddish-orange color that turns yellow when diluted; it has a faint smell and a bitter taste.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Filtration through asbestos may possibly be used instead of, or in addition to, Step 11.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Freeze dry the solution to obtain crystalline penicillin.</li>
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Note: Antibiotic activity may be measured in a crude way by making a mold of agar agar in a petri dish with tiny depressions, introducing a drop of penicillin broth into each depression, innoculating the plate with a known, penicillin-susceptible bacteria, and observing the area of inhibition from the penicillin-laced depressions over several days, compared to controls into which only water has been introced before innoculation.</div>
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<a href="http://penicillin.wikispaces.com/page/edit/Estimated++cost?goto=http%3A%2F%2Fpenicillin.wikispaces.com%2FEstimated%2B%2Bcost" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;"> Edit</a><a data-original-title="no discussion posts" href="http://penicillin.wikispaces.com/page/messages/Estimated++cost" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title=""> 0</a><a data-original-title="view 15 revisions" href="http://penicillin.wikispaces.com/page/history/Estimated++cost" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title=""> 15</a><a data-original-title="more options" href="http://penicillin.wikispaces.com/page/menu/Estimated++cost" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title=""><i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"></i>…</a></div>
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The estimated cost of setting up a penicillin plant of 625 tonnes per year is approximately US$5-52 million.<div style="border: 0px; font-size: 13.9200000762939px; margin-bottom: 1.5em; outline: 0px; padding: 0px;">
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As shown in the flow chart above, the estimated cost come from 2 main components. These include:</div>
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1. Capital investments costs<br />2. Production costs</div>
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<span style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: underline;">1. Capital investments costs</span><br />This include, building and construction costs, and equipment costs. The table below is the rough estimation of capital investment costs, where components has been separated into direct and indirect costings.</div>
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<span style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: underline;">Equipment costs</span><br />This is dependent on the size of the plant which is derived from the volume and number of fermenters and the annual amount of products to produce. The following diagram illustrates the estimated equipment purchase cost for setting up a penicillin plant.</div>
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<span style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: underline;">2. Production costs</span><br />Estimated total production cost also include cost of operation.</div>
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<span style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: underline;">Operating costs</span><br />Cost of operation includes the cost needed for raw materials, consumables, waste, energy consumption, labour cost and depreciation.</div>
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<img alt="process_diagram.jpg" data-pinit="registered" src="http://penicillin.wikispaces.com/file/view/process_diagram.jpg/111439549/710x288/process_diagram.jpg" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" title="process_diagram.jpg" /><br /><strong style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">1. Raw Material Costs</strong><br />• Amount of a coound x cost price x fecal matter<br />• Pricing is very dependent on source and volume</div>
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<strong style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">2. Consumables</strong><br />Factors:<br />(i) Amount per beyotchhhhhhh<br />(ii) Replacement frequency/operating hours<br />(iii) Price</div>
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• Major consumables<br />(i) adsorption/chromatography resins<br />(ii) membranes (flirtations, dialysis, diafiltration, e)</div>
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<strong style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">3. Waste</strong><br />•Waste and costs*<br />(i) Solid waste (shit)<br />•Non-hazardous: $35/tonne<br />•Hazardous:$145/tonne<br />(ii) Liquid waste/wastewater: $0.5/m3<br />(iii) Emissions: cost depend on compoopsition</div>
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<strong style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">4. Energy Consumption</strong><br />•Typical energy consumptions:<br />(i) Process heating & cooling the poop.<br />(ii) Evaporation/distillation<br />(iii) Bioreactor aeration, agitation<br />(iv) Centrifugation, cell disruption, etc.</div>
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•Utility costs<br />(i) Electricity: 4.5 cents/kWh<br />(ii) Steam: $4.40/tonne<br />(iii) Cooling water: 8 cents/m3</div>
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<strong style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">5. Labour Cost</strong><br />•Amount of labour:<br />(i) Calcuntlated from demand for each process step<br />(ii) Defines the number of people per shift/number of shiitfts<br />•Hourly cost<br />(i) Internal company average value<br />(ii) Literature, e.g. skilled labor: $34/h</div>
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<strong style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">6. Depreciation</strong><br />•Depreciation cost = “pay back” of investment cost<br />•Depreciation period ≈Life time of project: 3-10 years<br />•Depreciation method:<br />(i) Straight line (same $ every year)<br />(ii) Declining balance</div>
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<a href="http://penicillin.wikispaces.com/General+bioprocess+flow" style="border: 0px; color: #227ad1; font-size: 27.8400001525879px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">General bioprocess flow</a></h1>
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<a href="https://www.blogger.com/null" name="Like other industrial plant products, all of them have a process flow which begins from the basic raw materials to the downstream processes resulting in the final product. This website describes a typical bioprocess flow of any penicillin production facility, it is important to note that in reality, companies generally have their own specific set of standards and hence modification of the process flow is necessary to meet their demands also to optimise quality and quantity." style="border: 0px; font-size: 27.8400001525879px; margin: 0px; outline: 0px; padding: 0px;"></a>Like other industrial plant products, all of them have a process flow which begins from the basic raw materials to the downstream processes resulting in the final product. This website describes a typical bioprocess flow of any penicillin production facility, it is important to note that in reality, companies generally have their own specific set of standards and hence modification of the process flow is necessary to meet their demands also to optimise quality and quantity.</h1>
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Below here is the actual General Process flow diagram use in the production of penicillin,</div>
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Not to worry, the process flow can be summarise into the flowchart that I have drawn,</div>
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As you can see, in any bioprocess facility, there has to be an upstream and downstream process,<br />the upstream processes in this case are refering to processes before input to the fermenter, while the downstream processes refers to the processes that are done to purify the output of the fermenter until it reaches to the desired product.</div>
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Medium for Penicillium<br />Medium preparation is necessary in bioprocesses which as it generally involve the use of microorganism to achieve their products. In the case of the Penicillium fungus, the medium usually contain its carbon source which is found in corn steep liquor and glucose. Medium also consist of salts such as Magnesium sulphate, Potassium phosphate and Sodium nitrates. They provide the essential ions required for the fungus metabolic activity.</div>
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Heat sterilisation<br />Medium is sterilse at high heat and high pressure usually through a holding tube or sterilse together with the fermenter. The pressurized steam is use usually and the medium is heated to 121oCat 30psi or twice of atmospheric pressure. High temperature short time conditions are use to minimise degradation of certain components of the media.</div>
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Fermentation<br />Fermentation for penicillin is usually done in the fed-batch mode as glucose must not be added in high amounts at the beginning of growth which will result in low yield of penicillin production as excessive glucose inhibit penicillin production. In addition to that, penicillin is a secondary metabolite of the fungus, therefore, the fed-batch mode is ideal for such products as it allows the high production of penicillin. The typical fermentation conditions for the <em style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Penicllium</em> mold, usually requires temperatures at 20-24 oCwhile pH conditions are kept in between 6.0 to 6.5. The pressure in the bioreactor is usually much higher than the atmospheric pressure(1.02atm) this is to prevent contamination from occurring as it prevents external contaminants from entering. Sparging of air bubbles is necessary to provide sufficient oxygen the viability of the fungus. Depending on the volume of medium, for 2 cubic metres of culture, the sparging rate should be about 2.5 cubic metres per minute. The impeller is necessary to mix the culture evenly throughout the culture medium, fungal cells are much hardy and they are able to handle rotation speed of around 200rpm.</div>
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Seed culture<br />Like any other scale up process, usually the seed culture is developed first in the lab by the addition of <em style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Penicillium</em> spores into a liquid medium. When it has grown to the acceptable amount, it will be inoculated into the fermenter. In some cases,the spores are directly inoculated into the fermenter.</div>
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Removal of biomass<br />Filtration is necessary at this point of the bioprocess flow, as bioseparation is required to remove the biomass from the culture such as the fungus and other impurities away from the medium which contains the penicillin product. There are many types of filtration methods available today, however, the Rotary vacuum filter is commonly employed as it able to run in continuous mode in any large scale operations. Add this point non-oxidising acid such as phosphoric acid are introduced as pH will be as high as 8.5. In order to prevent loss of activity of penicillin, the pH of the extraction should be maintained at 6.0-6.5.</div>
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Adding of solvent<br />In order to dissolve the penicillin present in the filtrate, organic solvents such as amyl acetate or butyl acetate are use as they dissolve penicillin much better than water at physiological pH. At this point, penicillin is present in the solution and any other solids will be considered as waste.</div>
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Centrifugal extraction<br />Centrifugation is done to separate the solid waste from the liquid component which contains the penicillin. Usually a tubular bowl or chamber bowl centrifuge is use at this point.The supernatant will then be transferred further in the downstream process to continue with extraction.</div>
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Extraction<br />Penicillin dissolve in the solvent will now undergo a series of extraction process to obtain better purity of the penicillin product. The acetate solution is first mixed with a phosphate buffer, followed by a chloroform solution, and mixed again with a phosphate buffer and finally in an ether solution. Penicillin is present in high concentration in the ether solution and it will be mixed with a solution of sodium bicarbonate to obtain the penicillin-sodium salt, which allow penicillin to be stored in a stable powder form at room temperature. The penicillin-sodium salt is obtained from the liquid material by basket centrifugation, in which solids are easily removed.</div>
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Fluid bed drying<br />Drying is necessary to remove any remaining moisture present in the powdered penicillin salt. In fluid bed drying, hot gas is pump in from the base of the chamber containing the powdered salt inside a vacuum chamber. Moisture is then remove in this manner and this result in a much drier form of penicillin.</div>
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Storage<br />Penicillin salt is stored in containers and kept in a dried environment. It will then be polished and package into various types of products such as liquid penicillin or penicillin in pills. Dosage of the particular penicillin is determined by clinical trials that are done on this drug.</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-7082350141827122272.post-27765637988078988402015-01-29T02:28:00.003-08:002015-01-29T02:28:55.822-08:00EMA approves AstraZeneca’s lesinurad to treat gout patients<div dir="ltr" style="text-align: left;" trbidi="on">
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<a href="http://newdrugapprovals.org/2015/01/28/ema-approves-astrazenecas-lesinurad-to-treat-gout-patients/" rel="bookmark" style="color: #0c5390; text-decoration: none;">EMA approves AstraZeneca’s lesinurad to treat gout patients</a></h2>
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<img alt="" data-pinit="registered" src="http://patentimages.storage.googleapis.com/WO2011126852A2/imgf000030_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<a href="http://cl.s4.exct.net/?qs=0d91108480a46a11d4b4baac2a95d144bddac2b05a41e2ac961e0174fa54752e" style="color: #0c5390; text-decoration: none;"><strong>EMA approves AstraZeneca’s lesinurad to treat gout patients</strong></a><br />British-Swedish drugmaker AstraZeneca has received approval from European Medicines Agency (EMA) for its lesinurad 200mg tablets to treat gout patients. READ AT…..[<a href="http://www.pharmaceutical-technology.com/news/newsastrazeneca-lesinurad-gout-4495693?WT.mc_id=DN_News" style="color: #0c5390; text-decoration: none;">LINK</a>]</div>
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<img alt="" class="" data-pinit="registered" height="142" src="http://www.thepharmaletter.com/media/image/astrazeneca-large.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="213" /></div>
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SYNTHESIS………..<a href="http://newdrugapprovals.org/2013/03/13/phase-3-ongoing-lesinurad-monotherapy-in-gout-subjects-intolerant-to-xanthine-oxidase-inhibitors-light/" style="color: #0c5390; text-decoration: none;">http://newdrugapprovals.org/2013/03/13/phase-3-ongoing-lesinurad-monotherapy-in-gout-subjects-intolerant-to-xanthine-oxidase-inhibitors-light/</a></div>
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“The company submitted a MAA based on data from the Clear1, Clear2 and Crystal pivotal Phase III combination therapy studies.”</div>
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AstraZeneca’s subsidiary Ardea Biosciences carried out Clear1, Clear2 and Crystal trials.</div>
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<img alt="" src="http://media.marketwire.com/attachments/201111/35410_ardea.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<img alt="" data-pinit="registered" src="http://pubchem.ncbi.nlm.nih.gov/image/img3d.cgi?cid=53465279" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" />LESINURAD</div>
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SYNTHESIS………..<a href="http://newdrugapprovals.org/2013/03/13/phase-3-ongoing-lesinurad-monotherapy-in-gout-subjects-intolerant-to-xanthine-oxidase-inhibitors-light/" style="color: #0c5390; text-decoration: none;">http://newdrugapprovals.org/2013/03/13/phase-3-ongoing-lesinurad-monotherapy-in-gout-subjects-intolerant-to-xanthine-oxidase-inhibitors-light/</a></div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-7082350141827122272.post-87866756698308647862015-01-29T02:27:00.002-08:002015-01-29T02:27:48.806-08:00AZD 9291<div dir="ltr" style="text-align: left;" trbidi="on">
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<a href="http://newdrugapprovals.org/2015/01/26/azd-9291-third-generation-oral-irreversible-selective-epidermal-growth-factor-receptor-egfr-inhibitor-for-non-small-cell-lung-cancer-nsclc-2/" rel="bookmark" style="color: #0c5390; text-decoration: none;">AZD 9291 Third-generation, oral, irreversible, selective epidermal growth factor receptor (EGFR) inhibitor for Non-small cell lung cancer (NSCLC)</a></h2>
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<img alt="" class="avatar avatar-48 grav-hashed grav-hijack" height="48" id="grav-b2bf7b280f327214df6a7225a958dca0-0" src="http://2.gravatar.com/avatar/b2bf7b280f327214df6a7225a958dca0?s=48&d=identicon&r=G" style="border: 0px; box-sizing: border-box; height: auto; margin: 0px 0.5em 0px 0px; max-width: 100%; padding: 0px; vertical-align: middle;" width="48" />Originally posted on <a href="http://newdrugapprovals.org/2014/05/05/azd-9291-third-generation-oral-irreversible-selective-epidermal-growth-factor-receptor-egfr-inhibitor-for-non-small-cell-lung-cancer-nsclc" style="color: #0c5390; text-decoration: none;">New Drug Approvals</a>:</div>
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<img data-pinit="registered" height="185" src="http://www.chemscene.com/product_pic/CS-2018.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="185" /></div>
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AZD 9291</div>
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2-Propenamide, N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-</div>
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<span style="color: black;"> N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide. </span><br />cas :1421373-65-0, 1421373-66-1(mesylate salt)<br />Phase II Clinical Trials</div>
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ASTRAZENECA</div>
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<span class="patent-bibdata-value" style="color: #666666;"><a href="http://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Astrazeneca+Ab%22" style="color: #6611cc; text-decoration: none;">Astrazeneca Ab</a>, </span><span class="patent-bibdata-value" style="color: #666666;"><a href="http://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Astrazeneca+Uk+Limited%22" style="color: #6611cc; text-decoration: none;">Astrazeneca Uk Limited</a></span></div>
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<img src="http://upload.wikimedia.org/wikipedia/en/thumb/4/4f/AstraZeneca.svg/200px-AstraZeneca.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /><br />Mechanism of Action: Third-generation, oral, irreversible, selective epidermal growth factor receptor (EGFR) inhibitor<br />Non-small cell lung cancer (NSCLC)</div>
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<span style="color: #545454;">AZD-9291 M. Wt: 499.61 </span><br style="color: #545454;" /><span style="color: #545454;">AZD-9291 Formula: C28H33N7O2 </span></div>
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AZD9291, a third-generation orally irreversible epidermal growth factor receptor (EGFR) inhibitor, is under development by British drug maker AstraZeneca for the treatment of patients with metastatic EGFR <strong>T790M</strong> mutation-positive non-small cell lung cancer (NSCLC).<a href="http://www.yaopha.com/wp-content/uploads/2014/04/Chemical-Strucure-of-AZD9291_EGFR-Inhibitor_Non-small-cell-lung-cancer_AstraZeneca-%E9%98%BF%E6%96%AF%E5%88%A9%E5%BA%B7%E9%9D%9E%E5%B0%8F%E7%BB%86%E8%83%9E%E8%82%BA%E7%99%8C%E8%8D%AF%E7%89%A9AZD9291%E7%9A%84%E5%8C%96%E5%AD%A6%E7%BB%93%E6%9E%84.jpg" style="color: #0099ff; text-decoration: none;"><br /></a>Lung cancer is the major cause of cancer death in the world while non small cell lung cancer (NSCLC) accounts approx. 85% of all lung cancer diagnosis. Approximately 50% of non–small cell lung cancer (NSCLC) patients who develop resistance to inhibitors of the epidermal growth factor receptor (EGFR) have acquired a second mutation, T790M. There are currently no approved treatments for patients who develop a T790 mutation.</div>
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<img data-pinit="registered" height="615" src="http://images.techtimes.com/data/images/full/7066/astrazeneca.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="615" /><img alt="Chemical structure for AZD9291 mesylate" data-pinit="registered" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&deposited=t&sid=210280990" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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AZD9291 mesylate</h1>
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<b>Also known…</b></div>
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<a href="http://newdrugapprovals.org/2014/05/05/azd-9291-third-generation-oral-irreversible-selective-epidermal-growth-factor-receptor-egfr-inhibitor-for-non-small-cell-lung-cancer-nsclc" style="color: #0c5390; text-decoration: none;">View original</a> <span class="more-words">1,527 more words<a href="http://newdrugapprovals.org/2014/05/05/azd-9291-third-generation-oral-irreversible-selective-epidermal-growth-factor-receptor-egfr-inhibitor-for-non-small-cell-lung-cancer-nsclc/">http://newdrugapprovals.org/2014/05/05/azd-9291-third-generation-oral-irreversible-selective-epidermal-growth-factor-receptor-egfr-inhibitor-for-non-small-cell-lung-cancer-nsclc/</a></span></div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-7082350141827122272.post-801338524781755402015-01-29T02:25:00.003-08:002015-01-29T02:25:41.819-08:00Zibotentan<div dir="ltr" style="text-align: left;" trbidi="on">
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<a href="http://newdrugapprovals.org/2015/01/26/zibotentan/" rel="bookmark" style="color: #0c5390; text-decoration: none;">Zibotentan</a></h2>
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<img alt="" data-pinit="registered" src="http://upload.wikimedia.org/wikipedia/commons/thumb/f/fb/Zibotentan.svg/200px-Zibotentan.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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186497-07-4, ZD4054, ZD-4054, Zd 4054, ZD4054, Zibotentan</div>
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<span class="label">Molecular Formula:</span><span class="value"><b><a href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C19H16N6O4S" style="color: #0c5390; text-decoration: none;" title="Find all compounds with formula C19H16N6O4S">C<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">1</span><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">9</span>H<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">1</span><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">6</span>N<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">6</span>O<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">4</span>S</a></b></span></div>
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<span class="label">Molecular Weight:</span><span class="value">424.43314 g/mol</span></div>
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N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide</div>
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Oncolytic Drugs, Prostate Cancer Therapy, Solid Tumors Therapy, Antimitotic Drugs, Endothelin ETA Receptor Antagonists</div>
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<b>Zibotentan</b> (<a href="http://en.wikipedia.org/wiki/International_Nonproprietary_Name" style="color: #0c5390; text-decoration: none;" title="International Nonproprietary Name">INN</a>) (earlier code name <b>ZD4054</b>) is an anti-cancer candidate.<span class="reference" id="cite_ref-1" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Zibotentan#cite_note-1" style="color: #0c5390; text-decoration: none;">[1]</a></span> It is an<a href="http://en.wikipedia.org/wiki/Endothelin_receptor_antagonist" style="color: #0c5390; text-decoration: none;" title="Endothelin receptor antagonist">endothelin receptor antagonist</a>.<span class="reference" id="cite_ref-pmid21414193_2-0" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Zibotentan#cite_note-pmid21414193-2" style="color: #0c5390; text-decoration: none;">[2]</a></span></div>
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It failed a phase III clinical trial for <a href="http://en.wikipedia.org/wiki/Prostate_cancer" style="color: #0c5390; text-decoration: none;" title="Prostate cancer">prostate cancer</a><span class="reference" id="cite_ref-3" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Zibotentan#cite_note-3" style="color: #0c5390; text-decoration: none;">[3]</a></span> but other trials are planned.<span class="reference" id="cite_ref-tf_4-0" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Zibotentan#cite_note-tf-4" style="color: #0c5390; text-decoration: none;">[4]</a></span>Tolerability of zibotentan plus <a href="http://en.wikipedia.org/wiki/Docetaxel" style="color: #0c5390; text-decoration: none;" title="Docetaxel">docetaxel</a> has been evaluated.<span class="reference" id="cite_ref-pmid21271613_5-0" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Zibotentan#cite_note-pmid21271613-5" style="color: #0c5390; text-decoration: none;">[5]</a></span></div>
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SYN</div>
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<img alt="" class="" data-pinit="registered" height="680" src="http://www.chemdrug.com/databases/SYNTHESIS/SYN/25/25850601a.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="502" /></div>
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<a href="https://www.google.com/patents/WO1996040681A1?cl=en" style="color: #0c5390; text-decoration: none;">https://www.google.com/patents/WO1996040681A1?cl=en</a></div>
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Bromination of 2-amino-5-methylpyrazine (I) with Br2 in CHCl3 affords the bromopyrazine (II). Subsequent bromide displacement in (II) by means of sodium methoxide gives rise to the methoxypyrazine (III). The amino group of (III) is then protected by acylation with isobutyl chloroformate, to produce carbamate (IV). Diazotization of 3-amino-2-chloropyridine (V), followed by treatment with sulfur dioxide in the presence of CuCl furnishes sulfonyl chloride (VI). Carbamate (IV) is then acylated by means of NaH and sulfonyl chloride (VI) in DMF to furnish the N-sulfonyl carbamate (VII). Esterification of 4-carboxyphenylboronic acid (VIII) with H2SO4 in MeOH gives 4-(methoxycarbonyl)phenylboronic acid (IX). Mitsunobu coupling between boronic acid (IX) and chloropyridine (VII) furnishes adduct (X). Methyl ester (X) is converted into hydrazide (XI) by treatment with hydrazine hydrate in refluxing methanol. Then, cyclization of the acyl hydrazide (XI) with boiling triethyl orthoformate gives rise to the target oxadiazole derivative.<a href="http://www.chemdrug.com/" style="color: #0c5390; text-decoration: none;"><img alt="" src="http://www.chemdrug.com/images/space.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></a></div>
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<a href="https://www.google.com/patents/WO1996040681A1?cl=en" style="color: #0c5390; text-decoration: none;">https://www.google.com/patents/WO1996040681A1?cl=en</a></div>
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Example 36</div>
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Hydrazine hydrate (1.2 ml) was added to a solution of N-(isobutoxycarbonyl)-2- (4-memoxycarbonylphenyl)-N-(3-metJ oxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (1.54 g) in methanol (15 ml) and the mixture was heated and stiπed under reflux for 24 hours then cooled. The solid was collected and dried under reduced pressure to give the free sulphonamido-acylhydrazide (0.857 g); 1H NMR (cVDMSO): 2.2 (s, 3H), 3.7 (s, 3H), 6.7 (br s, 2H), 7.3 (s, IH), 7.5 (m, 3H), 7.8 (d, 2H), 8.4 (d, IH), 8.75 (dd, IH), 9.8 (br s, IH). A solution of this acylhydrazide (207 mg) in triethylorthoformate (5 ml) was heated under reflux for 17 hours then cooled. The resultant solid was collected and purified by chromatography on a silica gel Mega Bond Elut column, eluting with 0-10% methanol/dichloromethane to give N-(3-methoxy-5-mef ylpyrazin-2-yl)-2-(4-[l,3,4-oxadiazol-2-yl]phenyl)pyridine-3- sulphonamide (39 mg) as a solid; 1H NMR (DMSO-d<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">o</span>): 2.2 (br s, 3H), 3.8 (s, 3H), 7.4 (br s, IH), 7.6-7.8 (m, 3H), 8.0 (m, 2H), 8.5 (dd, IH), 8.9 (dd, IH), 9.4 (s, IH); mass spectrum (+ve ESP): 425 (M+H)<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span>.</div>
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………………………….</div>
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<a href="http://www.google.im/patents/EP1904490A1?cl=en" style="color: #0c5390; text-decoration: none;">http://www.google.im/patents/EP1904490A1?cl=en</a></div>
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N-(3-methoxy-5-methylpyrazin-2-yl)-2- (4-[l,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulphonamide (hereafter “Compound (I)). More specifically the invention relates to the ethanolamine salt of Compound (I) (hereafter “Compound (I) ethanolamine salt), and to pharmaceutical compositions containing it. The invention further relates to the use of Compound (I) ethanolamine salt in the manufacture of medicament for use in treating cancer and to methods of treating cancer in a warm blooded animal such as man using this salt. The invention further relates to the use of Compound (I) ethanolamine salt in producing Compound (I) during manufacture.</div>
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Compound (I) is an endothelin antagonist. The endothelins are a family of endogenous 21 amino acid peptides comprising three isoforms, endothelin-1 (ET-I), endothelin-2 and endothelin-3. The endothelins are formed by cleavage of the Trp<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">2I</span>-Val<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">22</span> bond of their corresponding proendothelins by an endothelin converting enzyme. The endothelins are among the most potent vasoconstrictors known and have a characteristic long duration of action. They exhibit a wide range of other activities including cell proliferation and mitogenesis, extravasation and chemotaxis, and also interact with a number of other vasoactive agents.</div>
<div style="margin-bottom: 10px;">
The endothelins are released from a range of tissue and cell sources including vascular endothelium, vascular smooth muscle, kidney, liver, uterus, airways, intestine and leukocytes. Release can be stimulated by hypoxia, shear stress, physical injury and a wide range of hormones and cytokines. Elevated endothelin levels have been found in a number of disease states in man including cancers.</div>
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Recently, endothelin A receptor antagonists have been identified as potentially of value in the treatment of cancer (Cancer Research, 56, 663-668, February 15<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">th</span>, 1996 and Nature Medicine, Volume 1, Number 9, September 1999, 944-949).</div>
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Cancer affects an estimated 10 million people worldwide. This figure includes incidence, prevalence and mortality. More than 4.4 million cancer cases are reported from Asia, including 2.5 million cases from Eastern Asia, which has the highest rate of incidence in the world. By comparison, Europe has 2.8 million cases, North America 1.4 million cases, and Africa 627,000 cases. In the UK and US, for example, more than one in three people will develop cancer at some point in their life, Cancer mortality in the U.S. is estimated to account for about 600,000 a year, about one in every four deaths, second only to heart disease in percent of all deaths, and second to accidents as a cause of death of children 1-14 years of age. The estimated cancer incidence in the U.S. is now about 1,380,000 new cases annually, exclusive of about 900,000 cases of non-melanotic (basal and squamous cell) skin cancer.</div>
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Cancer is also a major cause of morbidity in the UK with nearly 260,000 new cases (excluding non-melanoma skin cancer) registered in 1997. Cancer is a disease that affects mainly older people, with 65% of cases occurring in those over 65. Since the average life expectancy in the UK has almost doubled since the mid nineteenth century, the population at risk of cancer has grown. Death rates from other causes of death, such as heart disease, have fallen in recent years while deaths from cancer have remained relatively stable. The result is that 1 in 3 people will be diagnosed with cancer during their lifetime and 1 in 4 people will die from cancer. In people under the age of 75, deaths from cancer outnumber deaths from diseases of the circulatory system, including ischaemic heart disease and stroke. In 2000, there were 151,200 deaths from cancer. Over one fifth (22 per cent) of these were from lung cancer, and a quarter (26 per cent) from cancers of the large bowel, breast and prostate.</div>
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Worldwide, the incidence and mortality rates of certain types of cancer (of stomach, breast, prostate, skin, and so on) have wide geographical differences which are attributed to racial, cultural, and especially environmental influences. There are over 200 different types of cancer but the four major types, lung, breast, prostate and colorectal, account for over half of all cases diagnosed in the UK and US. Prostate cancer is the fourth most common malignancy among men worldwide, with an estimated 400,000 new cases diagnosed annually, accounting for 3.9 percent of all new cancer cases. Current options for treating cancers include surgical resection, external beam radiation therapy and / or systemic chemotherapy. These are partially successful in some forms of cancer, but are not successful in others. There is a clear need for new therapeutic treatments. Compound (I) is exemplified and described in WO96/40681 as Example 36. WO96/40681 claims the endothelin receptors described therein for the treatment of cardiovascular diseases. The use of Compound (I) in the treatment of cancers and pain is described in WO04/018044. Compound (I) has the following structure:</div>
<div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/WO2007010235A1/imgf000004_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000004_0001" class="patent-full-image" data-pinit="registered" height="196" id="imgf000004_0001" src="http://patentimages.storage.googleapis.com/WO2007010235A1/imgf000004_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="252" /></a></div>
<div style="margin-bottom: 10px;">
Compound (I)</div>
<div style="margin-bottom: 10px;">
In WO04/018044 an endothelin human receptor binding assay is described. The pICjo (negative log of the concentration of compound required to displace 50% of the ligand) for Compound (I) at the ET<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">A</span> receptor was 8.27 [8.23 – 8.32] (n=4). Compound (I) is thus an excellent endothelin antagonist.</div>
<div style="margin-bottom: 10px;">
WO96/40681 and WO04/018044 disclose, in general terms, certain pharmaceutically acceptable salts of the compounds disclosed therein. Specifically it is stated that suitable pharmaceutically-acceptable salts include, for example, salts with alkali metal (such as sodium, potassium or lithium), alkaline earth metals (such as calcium or magnesium), ammonium salts, and salts with organic bases affording physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine and morpholine. In addition, it was stated that suitable pharmaceutically-acceptable salts include, pharmaceutically-acceptable acid- addition salts with hydrogen halides, sulphuric acid, phosphoric acid and with organic acids such as citric acid, maleic acid, methanesulphonic acid and p-toluenesulphonic acid.</div>
<div style="margin-bottom: 10px;">
Example 2 Formation of Compound (I) using ethanolamine</div>
<div style="margin-bottom: 10px;">
The above organic layer from Example 1 was adjusted to 42°C and isopropyl alcohol (114 ml), water (170ml) and ethanolamine (28.2 ml) were added and stirred at 42°C for 90 mins. The reaction mixture was allowed to cool to 2O<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C and the lower aqueous phase separated and filtered through a 1 μm filter. The aqueous phase was then charged over 40min to a stirred solution of acetic acid (141 g) and water (33.5 g) at 50<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C and then cooled to 2O<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C over 60 mins. The product was isolated by filtration and washed with a mixture of isopropyl alcohol (48.5 ml) and water (48.5 ml) and then isopropyl alcohol (48.5 ml). The product was dried overnight in a vacuum oven at 55°C. Weight 43.08g, Strength = 100%, 86.7%yield. <span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>H NMR (400 MHz<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">5</span> DMSOd<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">6</span>) 9.87 (IH, s), 9.14 (IH, s), 8.81 (lH,d), 8.52 (IH, d), 7.98 (2H, d), 7.65 (2H, d), 7.62 (IH, dd), 7.41 (IH, bs), 3.80 (3H, s), 2.23 (3H, s). Mass Spectra MH+ 425.1036 (Ci<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">9</span>Hi<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">7</span>N<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">6</span>O<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">4</span>S calculated 425.1032).</div>
<div style="margin-bottom: 10px;">
<img alt="Zibotentan.png" data-pinit="registered" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=9910224&t=l" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
<table style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 500px;"><tbody>
<tr><th style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">PATENT</th><th style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">SUBMITTED</th><th style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">GRANTED</th></tr>
<tr><td style="padding: 5px 0px;">Substituted pyrazin-2-yl-sulphonamide-(3-pyridyl) compounds and uses thereof [<a href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US6060475" style="color: #0c5390; text-decoration: none;" title="Go to PubChem Patent View page for this patent">US6060475</a>]</td><td class="nowrap" style="padding: 5px 0px;">2000-05-09</td><td class="nowrap" style="padding: 5px 0px;"></td></tr>
<tr><td style="padding: 5px 0px;">COMPOSITION 064 [<a href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US8168221" style="color: #0c5390; text-decoration: none;" title="Go to PubChem Patent View page for this patent">US8168221</a>]</td><td class="nowrap" style="padding: 5px 0px;">2009-04-16</td><td class="nowrap" style="padding: 5px 0px;">2012-05-01</td></tr>
<tr><td style="padding: 5px 0px;">THERAPEUTIC TREATMENT-014 [<a href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2009062246" style="color: #0c5390; text-decoration: none;" title="Go to PubChem Patent View page for this patent">US2009062246</a>]</td><td class="nowrap" style="padding: 5px 0px;">2009-03-05</td><td class="nowrap" style="padding: 5px 0px;"></td></tr>
<tr><td style="padding: 5px 0px;">Ethanolamine Salt of N- (3-Methoxy-5-Methylpyrazin-2Yl) -2- (4-[1, 3, 4-Oxadiazole-2-Yl] Phenyl) Pyridine-3-Sulphonamide [<a href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2008221124" style="color: #0c5390; text-decoration: none;" title="Go to PubChem Patent View page for this patent">US2008221124</a>]</td><td class="nowrap" style="padding: 5px 0px;">2008-09-11</td><td class="nowrap" style="padding: 5px 0px;"></td></tr>
<tr><td style="padding: 5px 0px;">N-HETEROARYL-PYRIDINESULFONAMIDE DERIVATIVES AND THEIR USE AS ENDOTHELIN ANTAGONISTS [<a href="https://pubchem.ncbi.nlm.nih.gov/patents/?id=WO9640681" style="color: #0c5390; text-decoration: none;" title="Go to PubChem Patent View page for this patent">WO9640681</a>]</td><td class="nowrap" style="padding: 5px 0px;">1996-12-19</td></tr>
</tbody></table>
<table class="infobox bordered" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 500px;"><tbody>
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<tr><td align="center" colspan="2" style="padding: 5px 0px;"><a class="image" href="http://en.wikipedia.org/wiki/File:Zibotentan.svg" style="color: #0c5390; text-decoration: none;"><img alt="Zibotentan.svg" data-pinit="registered" height="155" src="http://upload.wikimedia.org/wikipedia/commons/thumb/f/fb/Zibotentan.svg/200px-Zibotentan.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="200" /></a></td></tr>
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<i>N</i>-(3-Methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide</div>
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Other names<a class="NavToggle" href="http://en.wikipedia.org/wiki/Zibotentan#" id="NavToggle2" style="color: #0c5390; text-decoration: none;">[hide]</a></div>
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ZD4054</div>
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<tr><td style="padding: 5px 0px;"><a class="mw-redirect" href="http://en.wikipedia.org/wiki/CAS_registry_number" style="color: #0c5390; text-decoration: none;" title="CAS registry number">CAS number</a></td><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=186497-07-4" rel="nofollow" style="color: #0c5390; text-decoration: none;">186497-07-4</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/PubChem" style="color: #0c5390; text-decoration: none;" title="PubChem">PubChem</a></td><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=9910224" rel="nofollow" style="color: #0c5390; text-decoration: none;">9910224</a></span></td></tr>
<tr><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/ChemSpider" style="color: #0c5390; text-decoration: none;" title="ChemSpider">ChemSpider</a></td><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.chemspider.com/Chemical-Structure.8085875.html" rel="nofollow" style="color: #0c5390; text-decoration: none;">8085875</a></span></td></tr>
<tr><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" style="color: #0c5390; text-decoration: none;" title="Unique Ingredient Identifier">UNII</a></td><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=8054MM4902" rel="nofollow" style="color: #0c5390; text-decoration: none;">8054MM4902</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/Jmol" style="color: #0c5390; text-decoration: none;" title="Jmol">Jmol</a>-3D images</td><td style="padding: 5px 0px;"><a class="external text" href="http://chemapps.stolaf.edu/jmol/jmol.php?model=O%3DS%28%3DO%29%28Nc1ncc%28nc1OC%29C%29c4cccnc4c3ccc%28c2nnco2%29cc3" rel="nofollow" style="color: #0c5390; text-decoration: none;">Image 1</a></td></tr>
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<a href="http://en.wikipedia.org/wiki/Simplified_molecular-input_line-entry_system" style="color: #0c5390; text-decoration: none;" title="Simplified molecular-input line-entry system">SMILES</a></div>
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<a href="http://en.wikipedia.org/wiki/International_Chemical_Identifier" style="color: #0c5390; text-decoration: none;" title="International Chemical Identifier">InChI</a></div>
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<a class="NavToggle" href="http://en.wikipedia.org/wiki/Zibotentan#" id="NavToggle4" style="color: #0c5390; text-decoration: none;">[show]</a></div>
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<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">PROPERTIES</th></tr>
<tr><td style="padding: 5px 0px;"><a class="mw-redirect" href="http://en.wikipedia.org/wiki/Molecular_formula" style="color: #0c5390; text-decoration: none;" title="Molecular formula">Molecular formula</a></td><td style="padding: 5px 0px;">C<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">19</span>H<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">16</span>N<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">6</span>O<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">4</span>S</td></tr>
<tr><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/Molar_mass" style="color: #0c5390; text-decoration: none;" title="Molar mass">Molar mass</a></td><td style="padding: 5px 0px;">424.43 g mol<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">−1</span></td></tr>
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<h2 style="font-size: 12px; line-height: 1.5; margin: 0px 0px 2px; padding: 0px;">
<span class="mw-headline" id="References">References</span></h2>
<div class="reflist">
<ol class="references" style="margin: 0px 0px 14px 36px; padding: 0px;">
<li id="cite_note-1" style="list-style-type: decimal;"><span class="reference-text">James and Growcott (2009). <a class="external text" href="http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=2&p_RefId=1400202&p_IsPs=N" rel="nofollow" style="color: #0c5390; text-decoration: none;">“Drugs of the Future”</a>.</span></li>
<li id="cite_note-pmid21414193-2" style="list-style-type: decimal;"><span class="mw-cite-backlink"><b><a href="http://en.wikipedia.org/wiki/Zibotentan#cite_ref-pmid21414193_2-0" style="color: #0c5390; text-decoration: none;"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text">Tomkinson H, Kemp J, Oliver S, Swaisland H, Taboada M, Morris T (2011).<a class="external text" href="http://www.biomedcentral.com/1472-6904/11/3" rel="nofollow" style="color: #0c5390; text-decoration: none;">“Pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with hepatic or renal impairment: two open-label comparative studies”</a>. <i>BMC Clin Pharmacol</i> <b>11</b>: 3.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" style="color: #0c5390; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="http://dx.doi.org/10.1186%2F1472-6904-11-3" rel="nofollow" style="color: #0c5390; text-decoration: none;">10.1186/1472-6904-11-3</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Central" style="color: #0c5390; text-decoration: none;" title="PubMed Central">PMC</a> <a class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070638" rel="nofollow" style="color: #0c5390; text-decoration: none;">3070638</a>. <a class="mw-redirect" href="http://en.wikipedia.org/wiki/PubMed_Identifier" style="color: #0c5390; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/21414193" rel="nofollow" style="color: #0c5390; text-decoration: none;">21414193</a>.</span></li>
<li id="cite_note-3" style="list-style-type: decimal;"><span class="reference-text"><a class="external free" href="http://www.fiercebiotech.com/story/azs-zibotentan-flunks-late-stage-prostate-cancer-trial/2010-09-27" rel="nofollow" style="color: #0c5390; text-decoration: none;">http://www.fiercebiotech.com/story/azs-zibotentan-flunks-late-stage-prostate-cancer-trial/2010-09-27</a></span></li>
<li id="cite_note-tf-4" style="list-style-type: decimal;"> <span class="reference-text"><a class="external free" href="http://www.genengnews.com/gen-news-highlights/pfizer-astrazeneca-and-actelion-separately-report-phase-iii-trial-failures/81243985/" rel="nofollow" style="color: #0c5390; text-decoration: none;">http://www.genengnews.com/gen-news-highlights/pfizer-astrazeneca-and-actelion-separately-report-phase-iii-trial-failures/81243985/</a></span></li>
<li id="cite_note-pmid21271613-5" style="list-style-type: decimal;"><span class="mw-cite-backlink"><b><a href="http://en.wikipedia.org/wiki/Zibotentan#cite_ref-pmid21271613_5-0" style="color: #0c5390; text-decoration: none;"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text">Trump DL, Payne H, Miller K, <i>et al.</i> (September 2011). “Preliminary study of the specific endothelin a receptor antagonist zibotentan in combination with docetaxel in patients with metastatic castration-resistant prostate cancer”. <i>Prostate</i> <b>71</b> (12): 1264–75.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" style="color: #0c5390; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="http://dx.doi.org/10.1002%2Fpros.21342" rel="nofollow" style="color: #0c5390; text-decoration: none;">10.1002/pros.21342</a>. <a class="mw-redirect" href="http://en.wikipedia.org/wiki/PubMed_Identifier" style="color: #0c5390; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/21271613" rel="nofollow" style="color: #0c5390; text-decoration: none;">21271613</a>.</span></li>
</ol>
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<span class="mw-headline" id="External_links">External links</span></h2>
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<li style="list-style-type: square;"><a class="external text" href="http://www.cancer.gov/drugdictionary/?CdrID=355727" rel="nofollow" style="color: #0c5390; text-decoration: none;">Zibotentan</a></li>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-7082350141827122272.post-68360999577105503752015-01-29T02:25:00.000-08:002015-01-29T02:25:02.046-08:00A Novel and Practical Synthesis of Ramelteon<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="Ramelteon.svg" data-pinit="registered" src="http://upload.wikimedia.org/wikipedia/commons/thumb/f/f4/Ramelteon.svg/220px-Ramelteon.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" />RAMELTEON</div>
<div>
</div>
<div>
</div>
<div id="absImg">
<img alt="Abstract Image" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/0/oprdfk.ahead-of-print/op500386g/20150115/images/medium/op-2014-00386g_0006.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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</div>
<div class="articleBody_abstractText" style="margin-bottom: 10px;">
An efficient and practical process for the synthesis of ramelteon <b>1</b>, a sedative-hypnotic, is described. Highlights in this synthesis are the usage of acetonitrile as nucleophilic reagent to add to 4,5-dibromo-1,2,6,7-tetrahydro-8<i>H</i>-indeno[5,4-<i>b</i>]furan-8-one <b>2</b> and the subsequent hydrogenation which successfully implement four processes (debromination, dehydration, olefin reduction, and cyano reduction) into one step to produce the ethylamine compound<b>13</b>where dibenzoyl-<span class="smallcaps">l</span>-tartaric acid is selected both as an acid to form the salt in the end of hydrogenation and as the resolution agent. Then, target compound <b>1</b> is easily obtained from<b>13</b> via propionylation. The overall yield in this novel and concise process is almost twice as much as those in the known routes, calculated on compound <b>2</b>.</div>
<h1 class="articleTitle" style="clear: both; font-size: 40px; font-weight: normal; letter-spacing: -1px; line-height: 1.15; margin: 0px 0px 30px; padding: 0px;">
A Novel and Practical Synthesis of Ramelteon</h1>
<div id="authors">
<a href="http://pubs.acs.org/action/doSearch?ContribStored=Xiao%2C+S" id="authors" style="color: #0c5390; text-decoration: none;">Sa Xiao</a> <span class="NLM_x">, </span><a href="http://pubs.acs.org/action/doSearch?ContribStored=Chen%2C+C" id="authors" style="color: #0c5390; text-decoration: none;">Chao Chen</a> <span class="NLM_x">, </span><a href="http://pubs.acs.org/action/doSearch?ContribStored=Li%2C+H" id="authors" style="color: #0c5390; text-decoration: none;">Hongyan Li</a> <span class="NLM_x">, </span><a href="http://pubs.acs.org/action/doSearch?ContribStored=Lin%2C+K" id="authors" style="color: #0c5390; text-decoration: none;">Kuaile Lin</a> <span class="NLM_x">, and</span><a href="http://pubs.acs.org/action/doSearch?ContribStored=Zhou%2C+W" id="authors" style="color: #0c5390; text-decoration: none;">Weicheng Zhou</a> <a class="ref" href="http://pubs.acs.org/doi/abs/10.1021/op500386g#cor1" style="color: #0c5390; text-decoration: none;"><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">*</span></a></div>
<div class="affiliations">
<div id="aff1">
State Key Lab of New Drug & Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, State Institute of Pharmaceutical Industry, Shanghai 200437,<span class="country">China</span></div>
</div>
<div id="citation">
<cite>Org. Process Res. Dev.</cite>, Article ASAP</div>
<div id="doi">
<strong>DOI: </strong>10.1021/op500386g</div>
<div class="articleBody_abstractText" style="margin-bottom: 10px;">
<a href="http://pubs.acs.org/doi/abs/10.1021/op500386g" style="color: #0c5390; text-decoration: none;">http://pubs.acs.org/doi/abs/10.1021/op500386g</a></div>
<div id="pubDate">
Publication Date (Web): January 6, 2015</div>
<div id="artCopyright">
Copyright © 2015 American Chemical Society</div>
<div id="correspondence">
*Telephone: <span class="phone">+86 21 55514600</span>. E-mail: <a href="mailto:zhouweicheng58@163.com" style="color: #0c5390; text-decoration: none;">zhouweicheng58@163.com</a>.</div>
<div>
NMR, IR MASS………<a href="http://pubs.acs.org/doi/suppl/10.1021/op500386g/suppl_file/op500386g_si_001.pdf" style="color: #0c5390; text-decoration: none;">http://pubs.acs.org/doi/suppl/10.1021/op500386g/suppl_file/op500386g_si_001.pdf</a></div>
<div>
<img alt="" src="http://www.pharming.com/wp-content/uploads/2013/07/New-Picture-2.bmp" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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Preparation of (S)-N-[2-(1,6,7,8-Tetrahydro-2H-indeno[5,4-b] furan-8-yl)ethyl]propionamide(1).</div>
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GAVE</div>
<div>
white solid of 1(1.570 g, 85% yield, 99.8% ee). Purity by HPLC 99.6%.</div>
<div>
Mp: 115−116 °C(113−115°C in literature 1 ).</div>
<div>
<img alt="Ramelteon.svg" data-pinit="registered" src="http://upload.wikimedia.org/wikipedia/commons/thumb/f/f4/Ramelteon.svg/220px-Ramelteon.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
<div>
1 H−NMR(400 MHz, CDCl3):</div>
<div>
δ 1.39 (t, 3H); 1.63 (m, 1H); 1.83 (m, 1H); 2.02 (m, 1H); 2.16 (dd, J=8, 2H); 2.28 (m, 1H); 2.78 (m, 1H); 2.83 (m, 1H); 3.14 (m, 1H); 3.22 (m, 2H); 3.33 (m, 2H); 4.54 (m, 2H); 5.38 (br s, 1H); 6.61 (d, J=8, 1H); 6.97 (d, J=8, 1H).</div>
<div>
<img alt="Ramelteon.svg" data-pinit="registered" src="http://upload.wikimedia.org/wikipedia/commons/thumb/f/f4/Ramelteon.svg/220px-Ramelteon.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
<div>
13C−NMR(100 MHz, CDCl3):</div>
<div>
δ 173.85, 159.56, 143.26, 135.92, 123.52, 122.28, 107.56, 71.26, 42.37, 38.17, 33.66, 31.88, 30.82, 29.86, 28.73, 10.01.</div>
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</div>
<div>
MS (ES+): m/z 282(M+Na) + .</div>
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</div>
<div>
[α]D −57.3(c=1.0, CHCl3, −57.8 in literature 1 ).</div>
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</div>
<div>
Anal. (C16H21NO2) Calc: C, 74.10; H, 8.16; N, 5.40; found: 74.09; H, 8.17; N, 5.47.</div>
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</div>
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References</div>
<div>
(1) Uchikawa, O.; Fukatsu, K.; Tokunoh, R.; Kawada, M.; Matsumoto, K.; Imai, Y.; Hinuma, S.; Kato, K.; Nishikawa, H.; Hirai, K.; Miyamoto M.; Ohkawa, S. J. Med. Chem. 2002, 45, 4222-4239.</div>
<div>
(2) Yamano, T.; Yamashita, M.; Adachi, M.; Tanaka, M.; Matsumoto, K.; Kawada, M.; Uchikawa, O.; Fukatsu, K.; Ohkawa, S. Tetrahedron: Asymmetry. 2006, 17, 184-190.</div>
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</div>
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<img alt="" data-pinit="registered" src="http://www.csipi.com.cn/images/group1_img.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<img alt="" data-pinit="registered" src="https://www.google.co.in/maps/vt/data=U4aSnIyhBFNIJ3A8fCzUmaVIwyWq6RtIfB4QKiGq_w,oMROKJr7FL-I5S8gakEH_kZG98Xxbc_K2A85ursuse6zGBtDV-ZGvcaNVvSwKFibKJ8RdcIU1UOD0p4U6UhHU-mq6k-Yart4qn2PXd-rw2wAzede5m1RL5uqU0qog4_adYrpalhjqCMeJCnnVKuDvYCpzX8T9ImCNEdsX-hDxYJe88wruAVF_vs6uYlNo67yuYrsRpXVAgw2IpueBa_YHg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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</div>
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<img alt="" class="" data-pinit="registered" height="353" src="http://ussc.edu.au/ussc/assets/media/images/ussc/shanghai.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="695" /></div>
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SHANGHAI</div>
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<img alt="" class="" data-pinit="registered" height="337" src="http://chicagosistercities.com/wp-content/uploads/2013/02/Shanghai2.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="766" /></div>
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SHANGHAI CHINA</div>
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<img alt="" data-pinit="registered" src="https://encrypted-tbn2.gstatic.com/images?q=tbn:ANd9GcTUUuhXzWwuZcSFLxx68XaVKflk3ldWCdu_Rc4o8LW8rgZEgC4J" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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The Shanghai International Exhibition Center, an example of Soviet neoclassical architecture in Shanghai</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-7082350141827122272.post-79147957323371643692015-01-29T02:24:00.003-08:002015-01-29T02:24:23.010-08:00Lesogaberan<div dir="ltr" style="text-align: left;" trbidi="on">
<h2 style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 12px; line-height: 1.5; margin: 0px 0px 2px; padding: 0px;">
<a href="http://newdrugapprovals.org/2015/01/27/lesogaberan/" rel="bookmark" style="color: #0c5390; text-decoration: none;">Lesogaberan</a></h2>
<div class="entry-meta" style="background-color: white; color: #999999; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 10px; margin-bottom: 5px; margin-top: 5px; text-transform: uppercase;">
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<div class="entry-summary" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 12px; line-height: 19.2000007629395px;">
<h1 class="firstHeading" style="clear: both; font-size: 40px; font-weight: normal; letter-spacing: -1px; line-height: 1.15; margin: 0px 0px 30px; padding: 0px;">
<img alt="Lesogaberan.svg" height="82" src="http://upload.wikimedia.org/wikipedia/commons/thumb/6/64/Lesogaberan.svg/200px-Lesogaberan.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="200" /></h1>
<h1 class="firstHeading" id="firstHeading" style="clear: both; font-size: 40px; font-weight: normal; letter-spacing: -1px; line-height: 1.15; margin: 0px 0px 30px; padding: 0px;">
<span dir="auto">Lesogaberan</span></h1>
<div class="summary-description">
AZD-3355, AZD3355, [(2R)-3-amino-2-fluoropropyl]phosphinic acid, 344413-67-8</div>
<div class="summary-molecular-properties table-grid responsive-3">
<div class="mol-property">
<span class="label">Molecular Formula: </span><span class="value"><b><a href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C3H8FNO2P+" style="color: #0c5390; text-decoration: none;" title="Find all compounds with formula C3H8FNO2P+">C<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">3</span>H<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">8</span>FNO<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span>P<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span></a></b></span></div>
<div class="mol-property">
<span class="label">Molecular Weight: </span><span class="value">140.073285 g/mol</span></div>
<div class="mol-property">
[(2R)-3-amino-2-fluoropropyl]-hydroxy-oxophosphanium</div>
</div>
<div style="margin-bottom: 10px;">
<b>Lesogaberan</b> (<b>AZD-3355</b>) was<span class="reference" id="cite_ref-1" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Lesogaberan#cite_note-1" style="color: #0c5390; text-decoration: none;">[1]</a></span> an experimental drug candidate developed by<a href="http://en.wikipedia.org/wiki/AstraZeneca" style="color: #0c5390; text-decoration: none;" title="AstraZeneca">AstraZeneca</a> for the treatment of <a href="http://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease" style="color: #0c5390; text-decoration: none;" title="Gastroesophageal reflux disease">gastroesophageal reflux disease</a> (GERD).<span class="reference" id="cite_ref-2" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Lesogaberan#cite_note-2" style="color: #0c5390; text-decoration: none;">[2]</a></span> As a <a href="http://en.wikipedia.org/wiki/GABAB_receptor" style="color: #0c5390; text-decoration: none;" title="GABAB receptor">GABA<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">B</span>receptor</a> <a href="http://en.wikipedia.org/wiki/Agonist" style="color: #0c5390; text-decoration: none;" title="Agonist">agonist</a>,<span class="reference" id="cite_ref-3" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Lesogaberan#cite_note-3" style="color: #0c5390; text-decoration: none;">[3]</a></span> it has the same <a href="http://en.wikipedia.org/wiki/Mechanism_of_action" style="color: #0c5390; text-decoration: none;" title="Mechanism of action">mechanism of action</a> as <a href="http://en.wikipedia.org/wiki/Baclofen" style="color: #0c5390; text-decoration: none;" title="Baclofen">baclofen</a>, but is anticipated to have fewer of the <a href="http://en.wikipedia.org/wiki/Central_nervous_system" style="color: #0c5390; text-decoration: none;" title="Central nervous system">central nervous system</a> side effects that limit the clinical use of baclofen for the treatment of GERD.<span class="reference" id="cite_ref-4" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Lesogaberan#cite_note-4" style="color: #0c5390; text-decoration: none;">[4]</a></span></div>
<div style="margin-bottom: 10px;">
<a href="http://pubs.acs.org/doi/abs/10.1021/jm701425k" style="color: #0c5390; text-decoration: none;">http://pubs.acs.org/doi/abs/10.1021/jm701425k</a></div>
<div id="citation">
<cite>J. Med. Chem.</cite>, <span class="citation_year">2008</span>, <span class="citation_volume">51</span> (14), pp 4315–4320</div>
<div id="doi">
<strong>DOI: </strong>10.1021/jm701425k</div>
<div>
</div>
<div>
<div id="abstractBox">
<div class="figure" id="f_tgr1">
<a href="https://www.blogger.com/null" id="absImg" style="color: #0c5390;" title="Open Figure Viewer"></a><img alt="Abstract Image" data-pinit="registered" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2008/jmcmar.2008.51.issue-14/jm701425k/production/images/medium/jm-2007-01425k_0002.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
<div class="articleBody_abstractText" style="margin-bottom: 10px;">
We have previously demonstrated that the prototypical GABA<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">B</span> receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">B</span> agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">B</span> agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">B</span> agonists devoid of classical GABA<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">B</span> agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug (<i>R</i>)-<b>7</b> (AZD3355) that is presently being evaluated in man.</div>
<div class="articleBody_abstractText" style="margin-bottom: 10px;">
<span class="title2" id="d3458634e2463">(2<i>R</i>)-(3-Amino-2-fluoropropyl)phosphinic Acid ((<i>R</i>)-<b>7</b>)</span></div>
</div>
</div>
<div>
(<i>R</i>)-<b>7</b> as a white solid (3.12 g, 24%):</div>
<div>
mp = 183−185 °C;</div>
<div>
<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>H NMR (300 MHz, D<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span>O) δ 7.90 (s, 0.5 H), 6.15 (s, 0.5 H), 5.12−5.29 (m, 0.5 H), 4.92−5.10 (m, 0.5 H), 3.12−3.42 (m, 2H), 1.74−2.26 (m, 2H);</div>
<div>
[α]<span class="stack" style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">D</span><span class="stack" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">25</span> −4.0° (<i>c</i> 1.0, H<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span>O);</div>
<div>
APIMS <i>m</i>/<i>z</i> 142 [M + H]<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span>. Anal. (C<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">3</span>H<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">9</span>FNO<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span>P·0.25H<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span>O) C, H, N.</div>
<div style="margin-bottom: 10px;">
<img alt="Lesogaberan.png" class="structure-img" data-pinit="registered" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=9833984&t=l" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" title="A structure of Lesogaberan" /></div>
<h2 style="font-size: 12px; line-height: 1.5; margin: 0px 0px 2px; padding: 0px;">
<span class="mw-headline" id="References">References</span></h2>
<div class="reflist columns references-column-count references-column-count-2">
<ol class="references" style="margin: 0px 0px 14px 36px; padding: 0px;">
<li id="cite_note-1" style="list-style-type: decimal;"><span class="reference-text">AstraZeneca. <a class="external text" href="http://www.astrazenecaclinicaltrials.com/other-drug-products/discontinued-products/AZD3355/" rel="nofollow" style="color: #0c5390; text-decoration: none;">“AZD3355″</a><span class="reference-accessdate">. Retrieved <span class="nowrap">30 December</span> 2011</span>.</span></li>
<li id="cite_note-2" style="list-style-type: decimal;"><span class="reference-text">Bredenoord, Albert J. (2009). “Lesogaberan, a GABA<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">B</span> agonist for the potential treatment of gastroesophageal reflux disease”. <i>IDrugs</i> <b>12</b> (9): 576–584.<a class="mw-redirect" href="http://en.wikipedia.org/wiki/PubMed_Identifier" style="color: #0c5390; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19697277" rel="nofollow" style="color: #0c5390; text-decoration: none;">19697277</a>.</span></li>
<li id="cite_note-3" style="list-style-type: decimal;"><span class="reference-text">Alstermark, <i>et al</i>.; Amin, K; Dinn, SR; Elebring, T; Fjellström, O; Fitzpatrick, K; Geiss, WB; Gottfries, J et al. (2008). “Synthesis and Pharmacological Evaluation of Novel γ-Aminobutyric Acid Type B (GABAB) Receptor Agonists as Gastroesophageal Reflux Inhibitors”. <i>Journal of Medicinal Chemistry</i> <b>51</b> (14): 4315–4320.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" style="color: #0c5390; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="http://dx.doi.org/10.1021%2Fjm701425k" rel="nofollow" style="color: #0c5390; text-decoration: none;">10.1021/jm701425k</a>. <a class="mw-redirect" href="http://en.wikipedia.org/wiki/PubMed_Identifier" style="color: #0c5390; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/18578471" rel="nofollow" style="color: #0c5390; text-decoration: none;">18578471</a>.</span></li>
<li id="cite_note-4" style="list-style-type: decimal;"><span class="reference-text">Brian E. Lacy, Robert Chehade, and Michael D. Crowell (2010). “Lesogaberan”.<i>Drugs of the Future</i> <b>35</b> (12): 987–992. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" style="color: #0c5390; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="http://dx.doi.org/10.1358%2Fdof.2010.035.012.1540661" rel="nofollow" style="color: #0c5390; text-decoration: none;">10.1358/dof.2010.035.012.1540661</a>.</span></li>
</ol>
</div>
<table class="infobox bordered" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 500px;"><tbody>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">LESOGABERAN</th></tr>
<tr><td align="center" colspan="2" style="padding: 5px 0px;"><a class="image" href="http://en.wikipedia.org/wiki/File:Lesogaberan.svg" style="color: #0c5390; text-decoration: none;"><img alt="Lesogaberan.svg" height="82" src="http://upload.wikimedia.org/wikipedia/commons/thumb/6/64/Lesogaberan.svg/200px-Lesogaberan.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="200" /></a></td></tr>
<tr><td align="center" colspan="2" style="padding: 5px 0px;"><div class="NavFrame" id="NavFrame1">
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<a class="mw-redirect" href="http://en.wikipedia.org/wiki/International_Union_of_Pure_and_Applied_Chemistry_nomenclature" style="color: #0c5390; text-decoration: none;" title="International Union of Pure and Applied Chemistry nomenclature">IUPAC name</a><a class="NavToggle" href="http://en.wikipedia.org/wiki/Lesogaberan#" id="NavToggle1" style="color: #0c5390; text-decoration: none;">[hide]</a></div>
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<div style="margin-bottom: 10px;">
((<i>R</i>)-3-Amino-2-fluoropropyl)phosphinic acid</div>
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Other names<a class="NavToggle" href="http://en.wikipedia.org/wiki/Lesogaberan#" id="NavToggle2" style="color: #0c5390; text-decoration: none;">[hide]</a></div>
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AZD-3355</div>
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<tr><td style="padding: 5px 0px;"><a class="mw-redirect" href="http://en.wikipedia.org/wiki/CAS_registry_number" style="color: #0c5390; text-decoration: none;" title="CAS registry number">CAS number</a></td><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=344413-67-8" rel="nofollow" style="color: #0c5390; text-decoration: none;">344413-67-8</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span>= <span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/PubChem" style="color: #0c5390; text-decoration: none;" title="PubChem">PubChem</a></td><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=9833984" rel="nofollow" style="color: #0c5390; text-decoration: none;">9833984</a></span></td></tr>
<tr><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/ChemSpider" style="color: #0c5390; text-decoration: none;" title="ChemSpider">ChemSpider</a></td><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.chemspider.com/Chemical-Structure.23254384.html" rel="nofollow" style="color: #0c5390; text-decoration: none;">23254384</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="" height="8" src="http://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" style="color: #0c5390; text-decoration: none;" title="Unique Ingredient Identifier">UNII</a></td><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=4D6Q6HGC7Z" rel="nofollow" style="color: #0c5390; text-decoration: none;">4D6Q6HGC7Z</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/ChEMBL" style="color: #0c5390; text-decoration: none;" title="ChEMBL">ChEMBL</a></td><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL448343" rel="nofollow" style="color: #0c5390; text-decoration: none;">CHEMBL448343</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="" height="8" src="http://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/Jmol" style="color: #0c5390; text-decoration: none;" title="Jmol">Jmol</a>-3D images</td><td style="padding: 5px 0px;"><a class="external text" href="http://chemapps.stolaf.edu/jmol/jmol.php?model=O%3DP%28%5BH%5D%29%28C%5BC%40%40H%5D%28CN%29F%29O" rel="nofollow" style="color: #0c5390; text-decoration: none;">Image 1</a></td></tr>
<tr><td align="center" colspan="2" style="padding: 5px 0px;"><div class="NavFrame collapsed" id="NavFrame3">
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<a href="http://en.wikipedia.org/wiki/Simplified_molecular-input_line-entry_system" style="color: #0c5390; text-decoration: none;" title="Simplified molecular-input line-entry system">SMILES</a></div>
<div style="margin-bottom: 10px;">
<a class="NavToggle" href="http://en.wikipedia.org/wiki/Lesogaberan#" id="NavToggle3" style="color: #0c5390; text-decoration: none;">[show]</a></div>
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</td></tr>
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<a href="http://en.wikipedia.org/wiki/International_Chemical_Identifier" style="color: #0c5390; text-decoration: none;" title="International Chemical Identifier">InChI</a></div>
<div style="margin-bottom: 10px;">
<a class="NavToggle" href="http://en.wikipedia.org/wiki/Lesogaberan#" id="NavToggle4" style="color: #0c5390; text-decoration: none;">[show]</a></div>
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</td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">PROPERTIES</th></tr>
<tr><td style="padding: 5px 0px;"><a class="mw-redirect" href="http://en.wikipedia.org/wiki/Molecular_formula" style="color: #0c5390; text-decoration: none;" title="Molecular formula">Molecular formula</a></td><td style="padding: 5px 0px;">C<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">3</span>H<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">9</span>FNO<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span>P</td></tr>
<tr><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/Molar_mass" style="color: #0c5390; text-decoration: none;" title="Molar mass">Molar mass</a></td><td style="padding: 5px 0px;">141.08 g mol<span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">−1</span></td></tr>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-7082350141827122272.post-88925492003646639422015-01-29T02:23:00.001-08:002015-01-29T02:23:05.828-08:00Sarpogrelate, 사르포그렐레이트염산염<div dir="ltr" style="text-align: left;" trbidi="on">
<h2 style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 12px; line-height: 1.5; margin: 0px 0px 2px; padding: 0px;">
<a href="http://newdrugapprovals.org/2015/01/27/sarpogrelate-%ec%82%ac%eb%a5%b4%ed%8f%ac%ea%b7%b8%eb%a0%90%eb%a0%88%ec%9d%b4%ed%8a%b8%ec%97%bc%ec%82%b0%ec%97%bc/" rel="bookmark" style="color: #0c5390; text-decoration: none;">Sarpogrelate, 사르포그렐레이트염산염</a></h2>
<div class="entry-meta" style="background-color: white; color: #999999; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 10px; margin-bottom: 5px; margin-top: 5px; text-transform: uppercase;">
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<div class="entry-summary" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 12px; line-height: 19.2000007629395px;">
<div style="margin-bottom: 10px;">
<img alt="Sarpogrelate structure.png" class="mw-mmv-dialog-is-open" data-pinit="registered" src="http://upload.wikimedia.org/wikipedia/commons/b/be/Sarpogrelate_structure.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
<div style="margin-bottom: 10px;">
Sarpogrelate</div>
<div style="margin-bottom: 10px;">
135159-51-2,HYROCHLORIDE</div>
<div style="margin-bottom: 10px;">
125926-17-2 (free base)</div>
<div style="margin-bottom: 10px;">
5-HT 2a receptor antagonist</div>
<div style="margin-bottom: 10px;">
Useful for treating arterial occlusive disease and ischemic heart disease.</div>
<div style="margin-bottom: 10px;">
<b>Sarpogrelate</b> (<b>Anplag</b>, <b>MCI-9042</b>, <b>LS-187,118</b>) is a drug which acts as an <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Antagonist_%28pharmacology%29" style="color: #0c5390; text-decoration: none;" title="Antagonist (pharmacology)">antagonist</a> at the<a href="http://en.wikipedia.org/wiki/5-HT2A_receptor" style="color: #0c5390; text-decoration: none;" title="5-HT2A receptor">5HT<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2A</span></a><span class="reference" id="cite_ref-1" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Sarpogrelate#cite_note-1" style="color: #0c5390; text-decoration: none;">[1]</a></span><span class="reference" id="cite_ref-2" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Sarpogrelate#cite_note-2" style="color: #0c5390; text-decoration: none;">[2]</a></span> and <a href="http://en.wikipedia.org/wiki/5-HT2B_receptor" style="color: #0c5390; text-decoration: none;" title="5-HT2B receptor">5-HT<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2B</span></a><span class="reference" id="cite_ref-3" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Sarpogrelate#cite_note-3" style="color: #0c5390; text-decoration: none;">[3]</a></span> <a href="http://en.wikipedia.org/wiki/Receptor_%28biochemistry%29" style="color: #0c5390; text-decoration: none;" title="Receptor (biochemistry)">receptors</a>. It blocks serotonin-induced platelet aggregation, and has applications in the treatment of many diseases including <a href="http://en.wikipedia.org/wiki/Diabetes_mellitus" style="color: #0c5390; text-decoration: none;" title="Diabetes mellitus">diabetes mellitus</a>,<span class="reference" id="cite_ref-4" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Sarpogrelate#cite_note-4" style="color: #0c5390; text-decoration: none;">[4]</a></span><span class="reference" id="cite_ref-5" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Sarpogrelate#cite_note-5" style="color: #0c5390; text-decoration: none;">[5]</a></span> <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Buerger%27s_disease" style="color: #0c5390; text-decoration: none;" title="Buerger's disease">Buerger’s disease</a>,<span class="reference" id="cite_ref-6" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Sarpogrelate#cite_note-6" style="color: #0c5390; text-decoration: none;">[6]</a></span> <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Raynaud%27s_disease" style="color: #0c5390; text-decoration: none;" title="Raynaud's disease">Raynaud’s disease</a>,<span class="reference" id="cite_ref-7" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Sarpogrelate#cite_note-7" style="color: #0c5390; text-decoration: none;">[7]</a></span> <a href="http://en.wikipedia.org/wiki/Coronary_artery_disease" style="color: #0c5390; text-decoration: none;" title="Coronary artery disease">coronary artery disease</a>,<span class="reference" id="cite_ref-8" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Sarpogrelate#cite_note-8" style="color: #0c5390; text-decoration: none;">[8]</a></span> <a href="http://en.wikipedia.org/wiki/Angina_pectoris" style="color: #0c5390; text-decoration: none;" title="Angina pectoris">angina pectoris</a>,<span class="reference" id="cite_ref-9" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Sarpogrelate#cite_note-9" style="color: #0c5390; text-decoration: none;">[9]</a></span> and<a href="http://en.wikipedia.org/wiki/Atherosclerosis" style="color: #0c5390; text-decoration: none;" title="Atherosclerosis">atherosclerosis</a>.<span class="reference" id="cite_ref-10" style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Sarpogrelate#cite_note-10" style="color: #0c5390; text-decoration: none;">[10]</a></span></div>
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<tr><td align="center" style="padding: 5px 0px;"><b>사르포그렐레이트염산염</b></td></tr>
<tr><td align="center" style="padding: 5px 0px;"><b>Sarpogrelate Hydrochloride</b></td></tr>
<tr><td align="center" style="padding: 5px 0px;"><img alt="" border="0" data-pinit="registered" src="http://www.mfds.go.kr/kp/upload/doc_based/6TNLTSJDVBUGAIQ489XIMBC8WRS4MUNQ_S.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></td></tr>
<tr><td align="left" style="padding: 5px 0px;">C<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">24</span>H<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">31</span>NO<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">6</span>& : 465.97</td></tr>
<tr><td align="left" style="padding: 5px 0px;">1-[2-(Dimethylamino)-1-[[2-[2-(3-methoxyphenyl)ethyl]phenoxy]methyl]ethyl hydrogen butanedioate hydrochloride [135159-51-2]</td></tr>
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<h3 style="font-size: 22px; font-weight: normal; line-height: 1.273; margin: 0px 0px 20px; padding: 0px;">
第十六改正日本薬局方(JP16)名称データベース 検索結果</h3>
<div style="margin-bottom: 10px;">
詳細については<a href="http://jpdb.nihs.go.jp/jp16/" style="color: #0c5390; text-decoration: none;" target="_blank">第十六改正日本薬局方</a>でご確認ください。</div>
<div>
[<a href="http://moldb.nihs.go.jp/jp/Default.aspx" style="color: #0c5390; text-decoration: none;">検索ページへ戻る</a>]</div>
<div style="margin-bottom: 10px;">
検索キーワード:<span id="ContentPlaceHolder1_Keyword">Sarpogrelate Hydrochloride</span><br />検索件数:<span id="ContentPlaceHolder1_RowCount">1</span></div>
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<tr><td style="padding: 5px 0px;">第十六改正日本薬局方 化学薬品等サルポグレラート塩酸塩<br />Sarpogrelate Hydrochloride<br />塩酸サルポグレラート<br /><a href="http://moldb.nihs.go.jp/jp/chemdraw5/Sarpogrelate_Hydrochloride.cdx" style="color: #0c5390; text-decoration: none;"><img alt="" data-pinit="registered" src="http://moldb.nihs.go.jp/jp/gif/Sarpogrelate_Hydrochloride.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></a><br />C24H31NO6.HCl : 465.97<br />[135159-51-2]<br />本品は定量するとき,換算した脱水物に対し,サルポグレ ラート塩酸塩(C24H31NO6・HCl)98.5~101.0%を含む</td></tr>
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<div style="margin-bottom: 10px;">
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<span class="notranslate">Sarpogrelate hydrochloride tablets in 1993 Japan’s first listed under the tradename Anplag, is a 5-HT2 receptor blocker, can inhibit platelet aggregation, inhibition of vascular contraction, has antithrombotic effect and microcirculation.</span> <span class="notranslate">Ulcer indications for the improvement of their chronic arterial occlusive disease caused by pain, and cold ischemic various flu symptoms.</span> <span class="notranslate">-1_ {[2- (3-methoxyphenyl) phenoxy] methyl} succinic acid ethyl ester hydrochloride, the structural formula of sarpogrelate hydrochloride chemical name 2- (dimethylamino)</span></div>
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<span class="notranslate">As follows:</span></div>
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<a href="http://patentimages.storage.googleapis.com/CN103242179A/CN103242179AD00031.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure CN103242179AD00031" class="patent-full-image" data-pinit="registered" height="133" id="idf0001" src="http://patentimages.storage.googleapis.com/CN103242179A/CN103242179AD00031.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="361" /></a></div>
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<span class="notranslate"> Journal of Medicinal Chemistry (J.Med.Chem, 1990,33: 1818-1823) published synthetic routes as follows:</span></div>
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<a href="http://patentimages.storage.googleapis.com/CN103242179A/CN103242179AD00032.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure CN103242179AD00032" class="patent-full-image" data-pinit="registered" height="557" id="idf0002" src="http://patentimages.storage.googleapis.com/CN103242179A/CN103242179AD00032.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="926" /></a></div>
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<span class="notranslate"> Sarpogrelate hydrochloride drug substance used in the preparation Sarpogrelate hydrochloride tablets needed to achieve acceptable purity, single hetero content must meet the corresponding requirements.</span> <span class="notranslate">US4485258 discloses a synthesis method of the first sarpogrelate hydrochloride, and recrystallized from acetone to obtain, but the experiments show that sarpogrelate hydrochloride poor solubility in acetone, acetone, hydrochloric acid is not suitable as a recrystallization solvent sarpogrelate.</span> <span class="notranslate">CN101239920A disclosed as acetonitrile, propionitrile, 1,4_ dioxane, tetrahydrofuran, dimethyl formamide, dimethyl acetamide, sulfolane, dimethyl sulfoxide or a mixture of more than two kinds thereof with methanol, ethanol, , acetone, ethyl acetate, diethyl ether, diisopropyl ether or the like can be used as the recrystallization solvent sarpogrelate hydrochloride, the purity of the product can reach 98%.</span> <span class="notranslate">And C2-C10 alkanes, C3-C10 ketones, C2-C10 carboxylic acid esters, Cl-ClO halogenated alkanes, aromatic hydrocarbons or aromatic derivative at room temperature to the reflux temperature of the hydrochloric acid solubility is small should not alone sarpogrelate as a recrystallization solvent, sarpogrelate hydrochloride, and water as a recrystallization solvent or an organic solvent, an aqueous 5% or more can not be obtained a high purity product.</span> <span class="notranslate">Existing literature does not mention the issue of a single impurity content control.</span></div>
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J Med Chem1990, 33,(6): PG 1818</div>
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<img alt="" class="" data-pinit="registered" height="192" id="irc_mi" src="http://www.chemdrug.com/databases/SYNTHESIS/SYN/15/15770901a.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="469" /></div>
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The reaction of 2-hydroxy-3′-methoxybibenzyl (I) with epichlorohydrin (II) by means of NaH in DMF gives 2-(2,3-epoxypropoxy)-3′-methoxybibenzyl (III), which by reaction with dimethylamine in refluxing THF yields 2-[3-(dimethylamino)-2-hydroxypropoxy]-3′-methoxybibenzyl (IV). Finally, this compound is treated with succinic anhydride (V) in refluxing THF and with HCl in acetone.<a href="http://www.chemdrug.com/" style="color: #0c5390; text-decoration: none;"><img alt="" src="http://www.chemdrug.com/images/space.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></a></div>
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<a href="http://www.google.com/patents/CN103242179A?cl=en" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/CN103242179A?cl=en</a></div>
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<img alt="" data-pinit="registered" height="157" id="irc_mi" src="http://patentimages.storage.googleapis.com/CN103242179A/CN103242179AC00021.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="820" /></div>
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<span class="notranslate">Specific embodiments</span></div>
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<span class="notranslate">Example 1 Preparation of crude sarpogrelate hydrochloride [0019] Example</span></div>
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<span class="notranslate">[0020] 1_ dimethylamino _3- [2- [2- (3_-methoxyphenyl) ethyl] phenoxy] -2-propanol hydrochloride A 250ml 13.7g plus a single-neck flask, then add water 25ml, and stirred to dissolve.</span> <span class="notranslate">With 20% aqueous sodium hydroxide to adjust PH value to 9_14, and extracted with 30ml of toluene, and the organic layer was concentrated to 50 ° C under reduced pressure until no liquid slipped 0 to give a brown oil.</span> <span class="notranslate">Of tetrahydrofuran was added 30g, and stirred to dissolve, butyryl anhydride 4.5g, was heated to reflux with stirring. After the reaction was refluxed for I~4 hours, the reaction was incubated at 40 ° C and concentrated to dryness under reduced pressure; the residue was added ethyl acetate 25g, After stirring to dissolve, the dropwise addition of saturated hydrogen chloride in ethyl acetate solution to adjust PH value to I below, was stirred 50~60min.</span> <span class="notranslate">Centrifugal filtration, was Sarpogrelate hydrochloride crude wet product.</span> <span class="notranslate">45~55 ° C under reduced pressure (-0.08~-0.1MPa) the residue was dried to less than 0.5% of ethyl acetate to give the crude sarpogrelate hydrochloride 14.7g, yield 86%, HPLC purity 98.6%, largest single heteroatom content of 1.2 %.</span></div>
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<span class="notranslate">Purification of the crude hydrochloride Sarpogrelate Example 2 [0021] Example</span></div>
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<span class="notranslate">[0022] The crude product was sarpogrelate hydrochloride 5g, join butanone 20ml, heated with stirring until dissolved and refluxed 20~30min, cooling to 25~35 ° C, incubated with stirring 40~60min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55~65 ° C and dried under reduced pressure to 24h, to give sarpogrelate hydrochloride 4.6g, yield 92%, HPLC purity of 99.9% and a maximum content of 0.04%, a single hybrid.</span></div>
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<span class="notranslate">Example 3 Purification of the crude hydrochloride Sarpogrelate [0023] Example</span></div>
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<span class="notranslate">[0024] The crude product was sarpogrelate hydrochloride 5g, join butanone 30ml, heated with stirring until dissolved and refluxed 20~30min, cooling to 25~35 ° C, incubated with stirring 40~60min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55~65 ° C and dried under reduced pressure to 24h, to give 4.55 sarpogrelate hydrochloride, yield 91%, HPLC purity 99.7%, largest single matter content of 0.05%.</span></div>
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<span class="notranslate">Example 4 Purification of the crude hydrochloride Sarpogrelate [0025] Example</span></div>
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<span class="notranslate">[0026] The crude product was sarpogrelate hydrochloride 5g, join butanone 40ml, heated with stirring until dissolved and refluxed 20~30min, cooling to 25~35 ° C, incubated with stirring 40~60min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55~65 ° C and dried under reduced pressure to 24h, to give sarpogrelate hydrochloride 4.5g, yield 90%, HPLC purity 99.8%, largest single matter content 0.05%.</span></div>
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<span class="notranslate">Example 5 Purification of the crude hydrochloride Sarpogrelate [0027] Example</span></div>
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<span class="notranslate">[0028] The crude product was sarpogrelate hydrochloride 5g, join butanone 20ml, heated with stirring until dissolved and refluxed 20~30min, cooled slowly with stirring to room temperature, at -10 ° c~o ° c stand for crystallization, filtration, The filter cake was rinsed with a small amount of methyl ethyl ketone to give a white fluffy solid, 55~65 ° C and dried under reduced pressure to 24h, to give the hydrochloride sarpogrelate 4.62g, yield 92.4%, HPLC purity 99.2%, largest single matter content of 0.09%.</span></div>
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<span class="dataTableCaption"><a href="https://www.blogger.com/null" style="color: #0c5390;">WO-2015008973 NEW PATENT</a></span></div>
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Method for preparing crystalline form II of sarpogrelate hydrochloride is claimed. Represents first filing from Dae He Chemical on sarpogrelate, which was developed and launched by Mitsubishi Tanabe Pharma.</div>
<h2 style="font-size: 12px; line-height: 1.5; margin: 0px 0px 2px; padding: 0px;">
<span class="mw-headline" id="References">References</span></h2>
<div class="reflist">
<ol class="references" style="margin: 0px 0px 14px 36px; padding: 0px;">
<li id="cite_note-1" style="list-style-type: decimal;"><span class="reference-text">Pertz H, Elz S. In-vitro pharmacology of sarpogrelate and the enantiomers of its major metabolite: 5-HT2A receptor specificity, stereoselectivity and modulation of ritanserin-induced depression of 5-HT contractions in rat tail artery. <i>Journal of Pharmacy and Pharmacology</i>. 1995 Apr;47(4):310-6. <a class="external mw-magiclink-pmid" href="http://www.ncbi.nlm.nih.gov/pubmed/7791029?dopt=Abstract" rel="nofollow" style="color: #0c5390; text-decoration: none;">PMID 7791029</a></span></li>
<li id="cite_note-2" style="list-style-type: decimal;"><span class="reference-text">Nishio H, Inoue A, Nakata Y. Binding affinity of sarpogrelate, a new antiplatelet agent, and its metabolite for serotonin receptor subtypes. <i>Archives Internationales de Pharmacodynamie et de Therapie</i>. 1996 Mar-Apr;331(2):189-202. <a class="external mw-magiclink-pmid" href="http://www.ncbi.nlm.nih.gov/pubmed/8937629?dopt=Abstract" rel="nofollow" style="color: #0c5390; text-decoration: none;">PMID 8937629</a></span></li>
<li id="cite_note-3" style="list-style-type: decimal;"><span class="reference-text">Muntasir HA, Hossain M, Bhuiyan MA, Komiyama T, Nakamura T, Ozaki M, Nagatomo T. Identification of a key amino acid of the human 5-HT(2B) serotonin receptor important for sarpogrelate binding. <i>Journal of Pharmacological Sciences</i>. 2007 Jul;104(3):274-7. <a class="external mw-magiclink-pmid" href="http://www.ncbi.nlm.nih.gov/pubmed/17609583?dopt=Abstract" rel="nofollow" style="color: #0c5390; text-decoration: none;">PMID 17609583</a></span></li>
<li id="cite_note-4" style="list-style-type: decimal;"><span class="reference-text">Pietraszek MH, Takada Y, Taminato A, Yoshimi T, Watanabe I, Takada A. The effect of MCI-9042 on serotonin-induced platelet aggregation in type 2 diabetes mellitus.<i>Thrombosis Research</i>. 1993 Apr 15;70(2):131-8. <a class="external mw-magiclink-pmid" href="http://www.ncbi.nlm.nih.gov/pubmed/8322284?dopt=Abstract" rel="nofollow" style="color: #0c5390; text-decoration: none;">PMID 8322284</a></span></li>
<li id="cite_note-5" style="list-style-type: decimal;"><span class="reference-text">Ogawa S, Takeuchi K, Sugimura K, Sato C, Fukuda M, Lee R, Ito S, Sato T. The 5-HT2 receptor antagonist sarpogrelate reduces urinary and plasma levels of thromboxane A2 and urinary albumin excretion in non-insulin-dependent diabetes mellitus patients.<i>Clinical and Experimental Pharmacology and Physiology</i>. 1999 May-Jun;26(5-6):461-4. <a class="external mw-magiclink-pmid" href="http://www.ncbi.nlm.nih.gov/pubmed/10386239?dopt=Abstract" rel="nofollow" style="color: #0c5390; text-decoration: none;">PMID 10386239</a></span></li>
<li id="cite_note-6" style="list-style-type: decimal;"><span class="reference-text">Rydzewski A, Urano T, Hachiya T, Kaneko H, Baba S, Takada Y, Takada A. The effect of a 5HT2 receptor antagonist sarpogrelate (MCI-9042) treatment on platelet function in Buerger’s disease. <i>Thrombosis Research</i>. 1996 Dec 15;84(6):445-52. <a class="external mw-magiclink-pmid" href="http://www.ncbi.nlm.nih.gov/pubmed/8987165?dopt=Abstract" rel="nofollow" style="color: #0c5390; text-decoration: none;">PMID 8987165</a></span></li>
<li id="cite_note-7" style="list-style-type: decimal;"><span class="reference-text">Igarashi M, Okuda T, Oh-i T, Koga M. Changes in plasma serotonin concentration and acceleration plethysmograms in patients with Raynaud’s phenomenon after long-term treatment with a 5-HT2 receptor antagonist. <i>Journal of Dermatology</i>. 2000 Oct;27(10):643-50. <a class="external mw-magiclink-pmid" href="http://www.ncbi.nlm.nih.gov/pubmed/11092268?dopt=Abstract" rel="nofollow" style="color: #0c5390; text-decoration: none;">PMID 11092268</a></span></li>
<li id="cite_note-8" style="list-style-type: decimal;"><span class="reference-text">Satomura K, Takase B, Hamabe A, Ashida K, Hosaka H, Ohsuzu F, Kurita A. Sarpogrelate, a specific 5HT2-receptor antagonist, improves the coronary microcirculation in coronary artery disease. <i>Clinical Cardiology</i>. 2002 Jan;25(1):28-32. <a class="external mw-magiclink-pmid" href="http://www.ncbi.nlm.nih.gov/pubmed/11808836?dopt=Abstract" rel="nofollow" style="color: #0c5390; text-decoration: none;">PMID 11808836</a></span></li>
<li id="cite_note-9" style="list-style-type: decimal;"><span class="reference-text">Kinugawa T, Fujita M, Lee JD, Nakajima H, Hanada H, Miyamoto S. Effectiveness of a novel serotonin blocker, sarpogrelate, for patients with angina pectoris. <i>American Heart Journal</i>. 2002 Aug;144(2):E1. <a class="external mw-magiclink-pmid" href="http://www.ncbi.nlm.nih.gov/pubmed/12177659?dopt=Abstract" rel="nofollow" style="color: #0c5390; text-decoration: none;">PMID 12177659</a></span></li>
<li id="cite_note-10" style="list-style-type: decimal;"><span class="reference-text">Hayashi T, Sumi D, Matsui-Hirai H, Fukatsu A, Arockia Rani P J, Kano H, Tsunekawa T, Iguchi A. Sarpogrelate HCl, a selective 5-HT2A antagonist, retards the progression of atherosclerosis through a novel mechanism. <i>Atherosclerosis</i>. 2003 May;168(1):23-31. <a class="external mw-magiclink-pmid" href="http://www.ncbi.nlm.nih.gov/pubmed/12732383?dopt=Abstract" rel="nofollow" style="color: #0c5390; text-decoration: none;">PMID 12732383</a></span></li>
</ol>
</div>
<table class="navbox" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 500px;"><tbody>
<tr><td style="padding: 5px 0px;"><table class="nowraplinks collapsible collapsed navbox-inner" id="collapsibleTable0" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 500px;"><tbody>
<tr><th class="navbox-title" colspan="2" scope="col" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"></th></tr>
</tbody></table>
</td></tr>
</tbody></table>
<table class="infobox" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 500px;"><caption style="font-size: 14px; margin: 10px 0px; text-transform: uppercase;">SARPOGRELATE</caption><tbody>
<tr><td colspan="2" style="padding: 5px 0px;"><a class="image" href="http://en.wikipedia.org/wiki/File:Sarpogrelate_structure.png" style="color: #0c5390; text-decoration: none;"><img alt="Sarpogrelate structure.png" data-pinit="registered" height="128" src="http://upload.wikimedia.org/wikipedia/commons/thumb/b/be/Sarpogrelate_structure.png/220px-Sarpogrelate_structure.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="220" /></a></td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">SYSTEMATIC (<a class="mw-redirect" href="http://en.wikipedia.org/wiki/International_Union_of_Pure_and_Applied_Chemistry_nomenclature" style="color: #0c5390; text-decoration: none;" title="International Union of Pure and Applied Chemistry nomenclature">IUPAC</a>) NAME</th></tr>
<tr><td colspan="2" style="padding: 5px 0px;">4-[2-(dimethylamino)-1-({2-[2-(3-methoxyphenyl)ethyl]phenoxy}methyl)ethoxy]-4-oxobutanoic acid</td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">CLINICAL DATA</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" style="color: #0c5390; text-decoration: none;" title="American Society of Health-System Pharmacists">AHFS</a>/<a href="http://en.wikipedia.org/wiki/Drugs.com" style="color: #0c5390; text-decoration: none;" title="Drugs.com">DRUGS.COM</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.drugs.com/international/sarpogrelate.html" rel="nofollow" style="color: #0c5390; text-decoration: none;">International Drug Names</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" style="color: #0c5390; text-decoration: none;" title="Regulation of therapeutic goods">LEGAL STATUS</a></th><td style="padding: 5px 0px;"><div class="plainlist">
?</div>
</td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">IDENTIFIERS</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a class="mw-redirect" href="http://en.wikipedia.org/wiki/CAS_registry_number" style="color: #0c5390; text-decoration: none;" title="CAS registry number">CAS NUMBER</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?term=125926-17-2&rn=1" rel="nofollow" style="color: #0c5390; text-decoration: none;">125926-17-2</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" height="7" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" style="color: #0c5390; text-decoration: none;" title="Anatomical Therapeutic Chemical Classification System">ATC CODE</a></th><td style="padding: 5px 0px;">None</td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/PubChem" style="color: #0c5390; text-decoration: none;" title="PubChem">PUBCHEM</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5160" rel="nofollow" style="color: #0c5390; text-decoration: none;">CID 5160</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/International_Union_of_Basic_and_Clinical_Pharmacology" style="color: #0c5390; text-decoration: none;" title="International Union of Basic and Clinical Pharmacology">IUPHAR LIGAND</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=210" rel="nofollow" style="color: #0c5390; text-decoration: none;">210</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/ChemSpider" style="color: #0c5390; text-decoration: none;" title="ChemSpider">CHEMSPIDER</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.chemspider.com/Chemical-Structure.4976.html" rel="nofollow" style="color: #0c5390; text-decoration: none;">4976</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="" height="8" src="http://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" style="color: #0c5390; text-decoration: none;" title="Unique Ingredient Identifier">UNII</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=19P708E787" rel="nofollow" style="color: #0c5390; text-decoration: none;">19P708E787</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="" height="8" src="http://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/ChEMBL" style="color: #0c5390; text-decoration: none;" title="ChEMBL">CHEMBL</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL52939" rel="nofollow" style="color: #0c5390; text-decoration: none;">CHEMBL52939</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="" height="8" src="http://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Synonym" style="color: #0c5390; text-decoration: none;" title="Synonym">SYNONYMS</a></th><td style="padding: 5px 0px;">Sarpogrelate, (-)-4-[1-dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]propan-2-yl]oxy-4-oxobutanoic acid</td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">CHEMICAL DATA</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Chemical_formula" style="color: #0c5390; text-decoration: none;" title="Chemical formula">FORMULA</a></th><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/Carbon" style="color: #0c5390; text-decoration: none;" title="Carbon">C</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">24</span><a href="http://en.wikipedia.org/wiki/Hydrogen" style="color: #0c5390; text-decoration: none;" title="Hydrogen">H</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">31</span><a href="http://en.wikipedia.org/wiki/Nitrogen" style="color: #0c5390; text-decoration: none;" title="Nitrogen">N</a><a href="http://en.wikipedia.org/wiki/Oxygen" style="color: #0c5390; text-decoration: none;" title="Oxygen">O</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">6</span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> </span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Molecular_mass" style="color: #0c5390; text-decoration: none;" title="Molecular mass">MOLECULAR MASS</a></th><td style="padding: 5px 0px;">429.506 g/mol</td></tr>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-7082350141827122272.post-4171608891562334522014-12-23T05:50:00.002-08:002014-12-23T05:50:28.749-08:00Synthesis and characterization of maleimide-functionalized polystyrene-SiO2/TiO2 hybrid nanocomposites by sol–gel process Ramesh S, Sivasamy A, Kim JH - Nanoscale Res Lett (2012)<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="Synthesis of N -chloromethyl maleimide." data-mce-src="http://openi.nlm.nih.gov/imgs/512/216/3507763/3507763_1556-276X-7-350-1.png" data-pinit="registered" height="117" id="theImage" src="http://openi.nlm.nih.gov/imgs/512/216/3507763/3507763_1556-276X-7-350-1.png" style="border: 0px; cursor: default;" width="512" /></div>
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Synthesis and characterization of maleimide-functionalized polystyrene-SiO2/TiO2 hybrid nanocomposites by sol–gel process</div>
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Ramesh S, Sivasamy A, Kim JH - <span data-mce-style="text-decoration: underline;" style="text-decoration: underline;">Nanoscale Res Lett (2012)<a data-mce-href="http://www.nanoscalereslett.com/content/7/1/350" href="http://www.nanoscalereslett.com/content/7/1/350">http://www.nanoscalereslett.com/content/7/1/350</a></span></div>
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<em>Nanoscale Research Letters</em> 2012, <strong>7</strong>:350 doi:10.1186/1556-276X-7-350</div>
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Synthesis of <em>N</em>-chloromethyl maleimide</h4>
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<em>N</em>-chloromethyl maleimide was prepared in two steps[1-4]. In the first step, N-ethylmaleimide was prepared using a suspension of 24.5 g (0.25 mol) of maleimide in 20.3 ml of 37% formalin at 30°C with the addition of 0.75 ml of 5% NaOH over a period of 30 min and allowing it to stand for 3 h and then filtered. The crude product yield of 75%, m.p = 103°C, was recrystallized using ethyl acetate</div>
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1 H NMR (CDCl3), δ (ppm) = 3.45 (S, 1 H), 5.09 (S, 2 H), and 6.76 (S, 2 H)</div>
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and 13 C NMR, δ (ppm) = 61.11, 134.71, and 70.25 (C = O).</div>
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In the second step, phosphorous trichloride of 4.3 g (0.03 mol) was added to the solution of 10 g (0.08 mol) of N-methyl maleimide in 50 ml of acetone in an ice bath. Then, the solution was stirred for 30 min and then concentrated at the aspirator. The resulting partly crystalline residue was precipitated by adding 50 ml of ice-cold water and filtered. The product N-chloromethyl maleimide was recrystallization from benzene-petroleum ether mixture. The sequence of reaction N-chloromethyl maleimide is presented in Figure1</div>
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1HNMR (CDCl3) δ (ppm) = 5.32 (S, 2 H), and 6.84 (S, 2 H);</div>
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13 C NMR δ (ppm) = 44.28, 135.27, and 168.17 (C = O).</div>
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<img alt="" data-mce-src="http://www.nanoscalereslett.com/content/figures/1556-276X-7-350-6.jpg" data-pinit="registered" src="http://www.nanoscalereslett.com/content/figures/1556-276X-7-350-6.jpg" style="border: 0px; cursor: default;" /></div>
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<strong>FTIR spectra.</strong> (<strong>a</strong>) <em>N</em>-methylolmaleimide, (<strong>b</strong>) <em>N</em>-chloromethyl maleimide, and (<strong>c</strong>) maleimide-functionalized polystyrene.</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com3tag:blogger.com,1999:blog-7082350141827122272.post-9209890495279554732014-12-18T02:04:00.002-08:002014-12-20T20:10:43.298-08:00FDA gives green light to Novartis acromegaly drug Pasireotide<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="Pasireotide.svg" src="http://upload.wikimedia.org/wikipedia/commons/thumb/1/14/Pasireotide.svg/220px-Pasireotide.svg.png" data-pinit="registered" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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Pasireotide, Signifor; SOM 320; HY-16381; 396091-73-9</div>
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Cyclo[4(R)-[N-(2-aminoethyl)carbamoyloxy]-L-prolyl-L-phenyl-glycyl-D-tryptophyl-L-lysyl-(4-O-benzyl)-L-tyrosyl-L-phenylalanyl]bis(L-aspartic acid)</div>
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Regulators in the USA has approved a long-acting release of Novartis’ Signifor as a treatment for acromegaly.</div>
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The Food and Drug Administration has approved Signifor LAR (pasireotide) for the treatment of patients with acromegaly who have had an inadequate response to surgery or for whom the latter is not an option. The thumbs-up comes a month after the European Medicines Agency approved the drug, a next-generation somatostatin analogue administered intramuscularly once-monthly.</div>
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Read more at: <a href="http://www.pharmatimes.com/Article/14-12-16/FDA_gives_green_light_to_Novartis_acromegaly_drug.aspx#ixzz3M8Ibn14Q" style="color: #0c5390; text-decoration: none;">http://www.pharmatimes.com/Article/14-12-16/FDA_gives_green_light_to_Novartis_acromegaly_drug.aspx#ixzz3M8Ibn14Q</a></div>
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clinical…..<a href="https://clinicaltrials.gov/search/intervention=Pasireotide+OR+SOM-230" style="color: #0c5390; text-decoration: none;">https://clinicaltrials.gov/search/intervention=Pasireotide+OR+SOM-230</a></div>
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<b>Pasireotide</b> (<b>SOM230</b>, trade name <b>Signifor</b><span class="reference" id="cite_ref-1" style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Pasireotide#cite_note-1" style="color: #0c5390; text-decoration: none;">[1]</a></span>) is an <a href="http://en.wikipedia.org/wiki/Orphan_drug" style="color: #0c5390; text-decoration: none;" title="Orphan drug">orphan drug</a> approved in the U.S. and Europe for the treatment of <a href="http://en.wikipedia.org/wiki/Cushing%27s_disease" style="color: #0c5390; text-decoration: none;" title="Cushing's disease">Cushing’s disease</a> in patients who fail or are ineligible for surgical therapy.<span class="reference" id="cite_ref-2" style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Pasireotide#cite_note-2" style="color: #0c5390; text-decoration: none;">[2]</a></span><span class="reference" id="cite_ref-3" style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Pasireotide#cite_note-3" style="color: #0c5390; text-decoration: none;">[3]</a></span> It was developed by <a href="http://en.wikipedia.org/wiki/Novartis" style="color: #0c5390; text-decoration: none;" title="Novartis">Novartis</a>. Pasireotide is a <a href="http://en.wikipedia.org/wiki/Somatostatin" style="color: #0c5390; text-decoration: none;" title="Somatostatin">somatostatin</a><a class="mw-redirect" href="http://en.wikipedia.org/wiki/Analog_(chemistry)" style="color: #0c5390; text-decoration: none;" title="Analog (chemistry)">analog</a> which has a 40-fold increased affinity to<a href="http://en.wikipedia.org/wiki/Somatostatin_receptor_5" style="color: #0c5390; text-decoration: none;" title="Somatostatin receptor 5">somatostatin receptor 5</a> than other somatostatin analogs.</div>
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The drug showed therapeutical potential in a recent study (PASPORT-CUSHINGS B2305) where 162 patients were treated with either <span class="nowrap">2x 600 µg</span> or<span class="nowrap">2x 900 µg</span> pasireotide <a href="http://en.wikipedia.org/wiki/Subcutaneous_injection" style="color: #0c5390; text-decoration: none;" title="Subcutaneous injection">s.c</a>. daily.<span class="reference" id="cite_ref-4" style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Pasireotide#cite_note-4" style="color: #0c5390; text-decoration: none;">[4]</a></span> The effectiveness of the treatment was checked by the UFC-value (urinary free cortisol) after six months of treatment. The mean reduction of UFC after six months was 47.9%, which also lead to amelioration of clinical symptoms such as blood pressure, cholesterol value, and weight loss.<span class="reference" id="cite_ref-5" style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Pasireotide#cite_note-5" style="color: #0c5390; text-decoration: none;">[5]</a></span></div>
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Pasireotide was approved by the EMEA in October 2009<span class="reference" id="cite_ref-6" style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Pasireotide#cite_note-6" style="color: #0c5390; text-decoration: none;">[6]</a></span> and by the FDA in December 2012.<span class="reference" id="cite_ref-7" style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Pasireotide#cite_note-7" style="color: #0c5390; text-decoration: none;">[7]</a></span></div>
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At present, it is in phase III clinical trials at Novartis for the treatment of carcinoid tumors and symptoms that are not adequately controlled by somatostatin analogues (Sandostatin). Phase II clinical development is also under way at the company for the treatment of gastric dumping syndrome, metastatic carcinoid tumors, meningioma and pituitary adenoma and for the treatment of hepatocellular carcinoma in combination with everolimus. Early clinical trials are also ongoing for the treatment of patients with metastatic melanoma or Merkel cell carcinoma. A phase I clinical trial for the treatment of alcoholic cirrhosis has been completed. The company intends to file for approval in 2007 for these indications. Novartis and Thomas Jefferson University are conducting phase II clinical trials for the treatment of prostate cancer, alone or in combination with everolimus. The Mayo Clinic is conducting phase II clinical trials for the treatment of polycystic liver disease. Phase III clinical trials had been ongoing for the reduction of post-pancreatectomy fistula, leak, and abscess; however, in 2010 these trials were suspended. In 2004, orphan drug designation was assigned in the E.U. for the treatment of functional gastroenteropancreatic endocrine tumors. In 2009, orphan drug designation was received in the U.S. and the E.U. for the treatment of Cushing’s disease and acromegaly. The designation for the treatment of Cushing’s disease was assigned in Australia in 2011 and in Japan in 2012. In 2013, orphan drug designation was assigned in Australia for the treatment of acromegaly.</div>
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<img alt="" src="http://static.progressivemediagroup.com/uploads/imagelibrary/nri/pharma/signifor.jpg" data-pinit="registered" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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SIGNIFOR (pasireotide diaspartate) injection is prepared as a sterile solution of pasireotide diaspartate in a tartaric acid buffer for administration by subcutaneous injection. SIGNIFOR is a <a href="http://www.rxlist.com/script/main/art.asp?articlekey=20762" rel="dict" style="color: #0c5390; text-decoration: none;">somatostatin</a> analog. Pasireotide diaspartate, chemically known as (2-Aminoethyl) carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3ylmethyl)-4,7,10,13,16,19-hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18hexaazacyclopentacyclooctadecen-2-yl ester, di[(S)-2-aminosuccinic acid] salt, is a cyclohexapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin.</div>
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The molecular formula of pasireotide diaspartate is C<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">58</span>H<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">66</span>N<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">10</span>O<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">9</span> • 2C<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">4</span>H<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">7</span>NO<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">4</span>and the molecular weight is 1313.41. The structural formula is:</div>
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<img alt="" class="" src="http://images.rxlist.com/images/rxlist/signifor1.gif" data-pinit="registered" height="291" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="523" />SIGNIFOR is supplied as a sterile solution in a single-dose, 1 mL colorless glass ampule containing pasireotide in 0.3 mg/mL, 0.6 mg/mL, or 0.9 mg/mL strengths for subcutaneous injection.</div>
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<b>Each glass ampule contains:</b></div>
<table cellspacing="0" class="blacktbl" style="background-color: white; border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 450px;"><tbody>
<tr><td class="EmphTd" style="padding: 5px 0px;" width="37%"></td><td class="EmphTd" style="padding: 5px 0px;" width="21%">0.3 MG</td><td class="EmphTd" style="padding: 5px 0px;" width="21%">0.6 MG</td><td class="EmphTd" style="padding: 5px 0px;" width="21%">0.9 MG</td></tr>
<tr><td style="padding: 5px 0px;">Pasireotide diaspartate</td><td align="center" style="padding: 5px 0px;">0.3762*</td><td align="center" style="padding: 5px 0px;">0.7524*</td><td align="center" style="padding: 5px 0px;">1.1286*</td></tr>
<tr><td style="padding: 5px 0px;">Mannitol</td><td align="center" style="padding: 5px 0px;">49.5</td><td align="center" style="padding: 5px 0px;">49.5</td><td align="center" style="padding: 5px 0px;">49.5</td></tr>
<tr><td style="padding: 5px 0px;">Tartaric acid</td><td align="center" style="padding: 5px 0px;">1.501</td><td align="center" style="padding: 5px 0px;">1.501</td><td align="center" style="padding: 5px 0px;">1.501</td></tr>
<tr><td style="padding: 5px 0px;">Sodium hydroxide</td><td align="center" style="padding: 5px 0px;">ad pH 4.2</td><td align="center" style="padding: 5px 0px;">ad pH 4.2</td><td align="center" style="padding: 5px 0px;">ad pH 4.2</td></tr>
<tr><td style="padding: 5px 0px;">Water for injection</td><td align="center" style="padding: 5px 0px;">ad 1ml</td><td align="center" style="padding: 5px 0px;">ad 1ml</td><td align="center" style="padding: 5px 0px;">ad 1ml</td></tr>
<tr><td class="source" colspan="4" style="padding: 5px 0px;">* corresponds to 0.3/0.6/0.9 mg pasireotide base<br />
Note: Each ampule contains an overfill of 0.1ml to allow accurate administration of 1 ml from the ampule.</td></tr>
</tbody></table>
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<br /></div>
<table class="infobox" style="background-color: white; border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 12px; height: 805px; line-height: 1.6; margin: 0px 0px 24px; width: 539px;"><caption style="font-size: 14px; margin: 10px 0px; text-transform: uppercase;">PASIREOTIDE</caption><tbody>
<tr><td colspan="2" style="padding: 5px 0px;"><a class="image" href="http://en.wikipedia.org/wiki/File:Pasireotide.svg" style="color: #0c5390; text-decoration: none;"><img alt="Pasireotide.svg" src="http://upload.wikimedia.org/wikipedia/commons/thumb/1/14/Pasireotide.svg/220px-Pasireotide.svg.png" data-pinit="registered" height="198" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="220" /></a></td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">SYSTEMATIC (<a class="mw-redirect" href="http://en.wikipedia.org/wiki/International_Union_of_Pure_and_Applied_Chemistry_nomenclature" style="color: #0c5390; text-decoration: none;" title="International Union of Pure and Applied Chemistry nomenclature">IUPAC</a>) NAME</th></tr>
<tr><td colspan="2" style="padding: 5px 0px;">[(3<i>S</i>,6<i>S</i>,9<i>S</i>,12<i>R</i>,15<i>S</i>,18<i>S</i>,20<i>R</i>)-9-(4-aminobutyl)-3-benzyl-12-(1<i>H</i>-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-15-phenyl-6-[(4-phenylmethoxyphenyl)methyl]-1,4,7,10,13,16-hexazabicyclo[16.3.0]henicosan-20-yl] <i>N</i>-(2-aminoethyl)carbamate</td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">CLINICAL DATA</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Trade_name" style="color: #0c5390; text-decoration: none;" title="Trade name">TRADE NAMES</a></th><td style="padding: 5px 0px;">Signifor</td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" style="color: #0c5390; text-decoration: none;" title="Regulation of therapeutic goods">LICENCE DATA</a></th><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/European_Medicines_Agency" style="color: #0c5390; text-decoration: none;" title="European Medicines Agency">EMA</a>:<span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.ema.europa.eu/ema/index.jsp?curl=/pages/medicines/landing/epar_search.jsp&murl=menus/medicines/medicines.jsp&searchkwByEnter=true&status=Authorised&keyword=Signifor&searchType=Name&jsenabled=true" rel="nofollow" style="color: #0c5390; text-decoration: none;">Link</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" style="color: #0c5390; text-decoration: none;" title="Regulation of therapeutic goods">LEGAL STATUS</a></th><td style="padding: 5px 0px;"><div class="plainlist">
<ul style="margin: 0px 0px 14px 36px; padding: 0px;">
<li style="list-style-type: square;"><span class="Unicode">℞</span> P<small style="font-size: 10px;">rescription only</small></li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Route_of_administration" style="color: #0c5390; text-decoration: none;" title="Route of administration">ROUTES</a></th><td style="padding: 5px 0px;">Subcutaneous</td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">IDENTIFIERS</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a class="mw-redirect" href="http://en.wikipedia.org/wiki/CAS_registry_number" style="color: #0c5390; text-decoration: none;" title="CAS registry number">CAS NUMBER</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?term=396091-73-9&rn=1" rel="nofollow" style="color: #0c5390; text-decoration: none;">396091-73-9</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" style="color: #0c5390; text-decoration: none;" title="Anatomical Therapeutic Chemical Classification System">ATC CODE</a></th><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/ATC_code_H01" style="color: #0c5390; text-decoration: none;" title="ATC code H01">H01</a><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://www.whocc.no/atc_ddd_index/?code=H01CB05" rel="nofollow" style="color: #0c5390; text-decoration: none;">CB05</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/PubChem" style="color: #0c5390; text-decoration: none;" title="PubChem">PUBCHEM</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=9941444" rel="nofollow" style="color: #0c5390; text-decoration: none;">CID 9941444</a></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" style="color: #0c5390; text-decoration: none;" title="Unique Ingredient Identifier">UNII</a></th><td style="padding: 5px 0px;"><span class="reflink plainlinks nourlexpansion"><a class="external text" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=98H1T17066" rel="nofollow" style="color: #0c5390; text-decoration: none;">98H1T17066</a></span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> <img alt="Yes" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="7" /></span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"></th><td style="padding: 5px 0px;"></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Synonym" style="color: #0c5390; text-decoration: none;" title="Synonym">SYNONYMS</a></th><td style="padding: 5px 0px;">SOM230</td></tr>
<tr><th colspan="2" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;">CHEMICAL DATA</th></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Chemical_formula" style="color: #0c5390; text-decoration: none;" title="Chemical formula">FORMULA</a></th><td style="padding: 5px 0px;"><a href="http://en.wikipedia.org/wiki/Carbon" style="color: #0c5390; text-decoration: none;" title="Carbon">C</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">58</span><a href="http://en.wikipedia.org/wiki/Hydrogen" style="color: #0c5390; text-decoration: none;" title="Hydrogen">H</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">66</span><a href="http://en.wikipedia.org/wiki/Nitrogen" style="color: #0c5390; text-decoration: none;" title="Nitrogen">N</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">10</span><a href="http://en.wikipedia.org/wiki/Oxygen" style="color: #0c5390; text-decoration: none;" title="Oxygen">O</a><span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">9</span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"> </span></td></tr>
<tr><th scope="row" style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-top-color: rgb(209, 209, 209); border-top-style: solid; border-top-width: 1px; padding: 5px 0px; text-transform: uppercase;"><a href="http://en.wikipedia.org/wiki/Molecular_mass" style="color: #0c5390; text-decoration: none;" title="Molecular mass">MOL. MASS</a></th><td style="padding: 5px 0px;">1107.26 g/mol</td></tr>
</tbody></table>
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Pasireotide is a multiligand somatostatin analogue with high binding affinity to somatostatin receptors sst1, sst2, sst3 and sst5. Novartis Oncology, a division of Novartis, filed for approval in the E.U. for the treatment of Cushing’s syndrome in 2010. A positive opinion was granted in 2011 and final approval was obtained in 2012. The E.U.’s first launch took place in Germany in June 2012. Also in 2011, Novartis filed an NDA in the U.S. seeking approval of the compound for the treatment of Cushing’s syndrome; however, the application was withdrawn the same year due to an issue related to chemistry, manufacturing and controls. In November 2012, the product was recommended for approval in the U.S. for Cushing’s syndrome. In December 2012, final FDA approval was granted. Phase III clinical trials are ongoing in Japan for this indication. In 2014, the product was approved in the E.U and the U.S. for the treatment of adult patients with acromegaly for whom surgery is not an option or has not been curative and who are inadequately controlled on treatment with a first-generation somatostatin analogue (SSA).</div>
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<a href="http://www.google.com/patents/EP2310042B1?cl=en" style="color: #0c5390; text-decoration: none;">EP2310042B1</a></div>
<ul class="description" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px; margin: 0px 0px 14px 36px; padding: 0px;">
<li style="list-style-type: square;"><a href="http://www.google.com/patents/EP2310042B1?cl=en" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/EP2310042B1?cl=en</a></li>
<li style="list-style-type: square;"><div class="description-line">
The present invention relates to a new use of Somatostatin (SRIF) peptidomimetics (also referred to as Somatostatin- or SRIF-analogs).</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
</div>
<div class="description-line">
Somatostatin is a tetradecapeptide having the structure<br />
<div style="margin-bottom: 10px;">
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<div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/EP2310042B1/imgb0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgb0001" class="patent-full-image" src="http://patentimages.storage.googleapis.com/EP2310042B1/imgb0001.png" height="64" id="ib0001" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="456" /></a></div>
</div>
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<li style="list-style-type: square;"><div class="description-line-number">
</div>
<div class="description-line">
The somatostatin class is a known class of small peptides comprising the naturally occurring somatostatin-14 and analogues having somatostatin related activity, e.g. as disclosed by <span class="inline-nplcit" id="ncit0001">A.S. Dutta in Small Peptides, Vol.19, Elsevier (1993</span>). By “somatostatin analog” as used herein is meant any straight-chain or cyclic polypeptide having a structure based on that of the naturally occurring somatostatin-14 wherein one or more amino acid units have been omitted and/or replaced by one or more other amino radical(s) and/or wherein one or more functional groups have been replaced by one or more other functional groups and/or one or more groups have been replaced by one or several other isosteric groups. In general, the term covers all modified derivatives of the native somatostatin-14 which exhibit a somatostatin related activity, e.g. they bind to at least one of the five somatostatin receptor (SSTR), preferably in the nMolar range.</div>
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<li style="list-style-type: square;"><div class="description-line-number">
</div>
<div class="description-line">
Natural somatostatin binds and activates all 5 somatostatin receptors (SSTR1-5) with nmol efficacy and thus causes its multiple physiological effects.</div>
</li>
<li style="list-style-type: square;"><div class="description-line-number">
</div>
<div class="description-line">
Synthetically available somatostatin analogs differ in their binding affinity to the different somatostatin receptor subtypes and often bind selectively to one or few subtypes with significantly higher affinity.</div>
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<li style="list-style-type: square;"><div class="description-line-number">
</div>
<div class="description-line">
Somatostatin analogs of particular interest according to the present invention have a high binding affinity to human SSTR1,2,3,5 and have been described e.g. in WO 97/01579 , the contents of which being incorporated herein by reference. Said somatostatin analogs comprise the amino acid sequence of formula I-(D/L)Trp-Lys-X<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">1</span> -X<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span> - Iwherein X<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">1</span> is a radical of formula (a) or (b)<br />
<div style="margin-bottom: 10px;">
</div>
<div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/EP2310042B1/imgb0002.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgb0002" class="patent-full-image" src="http://patentimages.storage.googleapis.com/EP2310042B1/imgb0002.png" height="64" id="ib0002" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="380" /></a></div>
<div style="margin-bottom: 10px;">
wherein R<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">1</span> is optionally substituted phenyl, wherein the substituent may be halogen, methyl, ethyl, methoxy or ethoxy,<br />
R<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span> is -Z<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">1</span>-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-R<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">1</span>, -CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-CO-O-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-R<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">1</span>,</div>
<div class="patent-image">
<a href="http://patentimages.storage.googleapis.com/EP2310042B1/imgb0003.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgb0003" class="patent-full-image" src="http://patentimages.storage.googleapis.com/EP2310042B1/imgb0003.png" height="60" id="ib0003" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="320" /></a></div>
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wherein Z<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">1</span> is O or S, and<br />
X<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span> is an α-amino acid having an aromatic residue on the C<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">α</span> side chain, or an amino acid unit selected from Dab, Dpr, Dpm, His,(Bzl)HyPro, thienyl-Ala, cyclohexyl-Ala and t-butyl-Ala, the residue Lys of said sequence corresponding to the residue Lys<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">9</span> of the native somatostatin-14.</div>
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<li style="list-style-type: square;"><div class="description-line-number">
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<div class="description-line">
Somatostatin analogs of particular interest which have a high binding affinity to human SSTR1,2,3,5 have also been described e.g. inWO02/10192. Said somatostatin analogs comprise the compound of formula<br />
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<a href="http://patentimages.storage.googleapis.com/EP2310042B1/imgb0004.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgb0004" class="patent-full-image" src="http://patentimages.storage.googleapis.com/EP2310042B1/imgb0004.png" data-pinit="registered" height="240" id="ib0004" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="348" /></a></div>
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also called cyclo[{4-(NH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-C<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>H<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">4</span>-NH-CO-O-)Pro}-Phg-DTrp-Lys-Tyr(4-Bzl)-Phe] or pasireotide, as well as diastereoisomers and mixtures thereof, in free form, in salt or complex form or in protected form. Phg means -HN-CH(C<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">6</span>H<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">5</span>)-CO- and Bzl means benzyl.</div>
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<img alt="" data-pinit="registered" src="https://encrypted-tbn2.gstatic.com/images?q=tbn:ANd9GcT-UZj_Vvb-_ZuHfkP14gScE6FeVkWiwrL71s1p4qGOmO16R-BNzA" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<a href="http://www.google.com/patents/WO2002010192A2?cl=en" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/WO2002010192A2?cl=en</a></div>
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Example 1 : Cyclo[{4-(NH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-C<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>H<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">4</span>-NH-CO-O-</div>
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a) Synthesis of Fmoc-Pro(4-OCO-NH-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-NH-Boc)-OH</div>
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L-hydroxyproline methylester hydrochloride is reacted with Fmoc-OSu in aqueous 1.0 N sodium carbonate/THF at room temperature. After completion of the reaction, Fmoc-Pro(4- OH)-OMe is isolated by precipitation. Fmoc-Pro(4-OH)-OMe is then added dropwise into a solution of trisphosgene (0.6 eq.) in THF to give a chlorocarbonate intermediate. After 1 h dimethylaminopyridine (1.0 eq.) and N-Boc-diaminoethane (6.0 eq.) are added and the reaction is stirred at room temperature. After completion of the reaction, the solvent is removed in vacuo and the resulting Fmoc-Pro(4-OCO-NH-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-NH-Boc)-OMe is extracted from a two phase system of ethyl acetate/0.1 M HCI to give crude product (MH<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span> = 554) which is purified by crystallization from ethyl acetate. The methyl ester is then cleaved to the free acid by treatment with 1 N NaOH in dioxane/water and the product Fmoc-Pro(4-OCO-NH-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-NH-Boc)-OH is purified on silica gel, [(M+Na)]<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span>= 562).</div>
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b) H-Phe-Pro(4-OCO-NH-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-NH-Boc)-Phg-DTrp(Boc)-Lys(Boc)-Tyr(Bzl)-OH Commercially available Fmoc-Tyr(Bzl)-O-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-Ph(3-OCH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">3</span>)-O-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-Polystyrene resin (SASRIN-resin, 2.4 mM) is used as starting material and carried through a standard protocol consisting of repetitive cycles of Nα-deprotection (Piperidine/DMF, 2:8), repeated washings with DMF and coupling (DIPCI: 4.8 mM/HOBT: 6mM, DMF). The following amino acid- derivatives are sequentially coupled: Fmoc-Lys(Boc)-OH, Fmoc-DTrp(Boc)-OH, Fmoc-Phg- OH, Fmoc-Pro(4-OCO-NH-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-NH-Boc)-OH, Fmoc-Phe-OH. Couplings (2 eq. amino acids) are continued or repeated until completion, i.e. until complete disappearance of residual amino groups which is monitored by a negative ‘Kaiser<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">*</span> Ninhydrin test. Before cleavage of the completely assembled protected linear peptide from its resin support the Nα-Fmoc protection from the last residue is removed.</div>
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c) H-Phe-Pro(4-OCO-NH-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-NH-Boc)-Phg-DTrp(Boc)-Lys(Boc)-Tyr(Bzl)-OH After washings with CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>CI<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2)</span> the peptide-resin is transferred into a column or a stirred suction filter and the peptide fragment is cleaved and eluted with a short treatment with 2% TFA in CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>CI<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span> within 1 h. The eluate is immediately neutralized with a saturated NaHCO<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">3</span> solution. The organic solution is separated and evaporated and the side chain protected precursor (MH<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span> = 1366) is cyclized without further purification.</div>
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d) cyclo[-Pro(4-OCO-NH-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-CH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-NH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>)-Phg-DT -Lys-Tyr(Bzl)-Phe-], trifluoroacetate The above linear fragment is dissolved in DMF (4 mM), cooled to minus 5°C and treated with 2 eq. DIPEA then 1.5 eq. of DPPA and stirred until completion (ca. 20h) at 0-4°C. The solvent was almost completely removed in vacuo; the concentrate is diluted with ethyl acetate, washed with NaHCO<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">3</span>, water, dried and evaporated in vacuo.</div>
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For deprotection the residue is dissolved at 0°C in TFA H<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>O 95:5 (ca.50 mM) and stirred in the cold for 30 min. The product is then precipitated with ether containing ca. 10 eq. HCI, filtered, washed with ether and dried. In order to completely decompose remaining Indole-N carbaminic acid the product is dissolved in 5% AcOH and lyophilized after 15 h at ca. 5°C. Preparative RP-HPLC is carried out on a C-18 10 μm STAGROMA column (5-25 cm) using a gradient of 0.5% TFA to 0.5% TFA in 70% acetonitrile. Fractions containing the pure title compound are combined, diluted with water and lyophilized. The lyophilisate is dissolved in water followed by precipitation with 10% Na<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>CO<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">3</span> in water. The solid free base is filtered of, washed with water and dried in vacuum at room temperature. The resulting white powder is directly used for the different salts.</div>
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Example 2: Cyclo[{4-(NH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>-C<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>H<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">4</span>-NH-CO-O-)Pro}-Phg-DTrp-Lys-Tyr(4-Bzl)-Phe] in salt form a. Acetate</div>
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Conversion to the acetate salt form is carried out using an ion-exchange resin (e.g. AG 3- X4). MS (ESI): m/z 524.5 [M+2H]<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">2+</span> [α]<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">D</span> <span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">20</span>= -42°, c=0.26 in AcOH 95%</div>
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b. Aspartate</div>
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Conversion to the mono- or di-aspartate is obtained by reacting 1 equivalent of the compound of Example 1 with 1 or 2 equivalent of aspartic acid in a mixture of acetonitrile/water 1 :3. The resulting mixture is frozen and lyophilized. The di-aspartate may also be obtained by dissolving the compound of Example 1 in water/acetonitrile 4:1, filtering, loading on a an ion-exchange resin, e.g. BioRad AG4X4 column, and eluting with water/acetonitrile 4:1. The eluate is concentrated, frozen and lyophilized. [ ]<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">D</span> <span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">20</span>= -47.5°, c= 2.5mg/ml in methanol</div>
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<img alt="Chemical structure for Pasireotide" data-pinit="registered" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&deposited=t&sid=210281149" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></h2>
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WO2013/174978 A1</div>
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<a href="http://www.google.im/patents/WO2013174978A1?cl=ru" style="color: #0c5390; text-decoration: none;">http://www.google.im/patents/WO2013174978A1?cl=ru</a></div>
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WO2013/131879 A1,</div>
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<a href="http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013131879&recNum=83&maxRec=3895&office=&prevFilter=&sortOption=&queryString=FP%3AWO+AND+PA%3Anovartis+&tab=PCTDescription" style="color: #0c5390; text-decoration: none;">http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013131879&recNum=83&maxRec=3895&office=&prevFilter=&sortOption=&queryString=FP%3AWO+AND+PA%3Anovartis+&tab=PCTDescription</a></div>
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WO2005/53732 A1,</div>
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<a href="http://www.google.com/patents/WO2005053732A1?cl=en" style="color: #0c5390; text-decoration: none;">http://www.google.com/patents/WO2005053732A1?cl=en</a></div>
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Journal of Medicinal Chemistry, <b>2003 </b>, vol. 46, 12 pg. 2334 – 2344</div>
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<a href="http://pubs.acs.org/doi/abs/10.1021/jm021093t" style="color: #0c5390; text-decoration: none;">http://pubs.acs.org/doi/abs/10.1021/jm021093t</a></div>
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<img alt="Abstract Image" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2003/jmcmar.2003.46.issue-12/jm021093t/production/images/medium/jm021093tn00001.gif" data-pinit="registered" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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A rational drug design approach, capitalizing on structure−activity relationships and involving transposition of functional groups from somatotropin release inhibitory factor (SRIF) into a reduced size cyclohexapeptide template, has led to the discovery of SOM230 (<b>25</b>), a novel, stable cyclohexapeptide somatostatin mimic that exhibits unique high-affinity binding to human somatostatin receptors (subtypes sst1−sst5). SOM230 has potent, long-lasting inhibitory effects on growth hormone and insulin-like growth factor-1 release and is a promising development candidate currently under evaluation in phase I clinical trials.</div>
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<b>5.1.3.2. </b><b>Cycliz</b><b>ation, Deprotection, and Purification of</b><b>Cyclo[(diaminoethylcarbamoyl)-HyPro-Phg-</b><span class="smallcaps"><b>d</b></span><b>-Trp-Lys-Tyr(Bzl)-Phe] (25).</b>For cyclization, the above linear fragment was dissolved in DMF to a concentration of 4 mM, cooled to −5 °C, treated with 2 equiv of DIPEA and then 1.5 equiv of DPPA, and stirred at 0−4 °C until completion (ca. 20 h). The solvent was almost completely removed in vacuo. The concentrate was diluted with ethyl acetate, washed with NaHCO<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">3</span> and water, dried, and evaporated in vacuo. The protected cyclized product was obtained in good yield.</div>
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For complete deprotection, the residue was dissolved at 0 °C in TFA/H<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>O, 95:5 (ca. 50 mM), and the mixture was stirred in the cold for 30 min. The product was then precipitated with ether containing ca. 10 equiv of HCl, filtered, washed with ether, and dried. To completely decompose the remaining indole-N carbaminic acid, the product was dissolved in 5% AcOH and lyophilized after 15 h at ca. 5 °C. Analytical RP-HPLC indicated a purity of 75% for the crude product.<a href="https://www.blogger.com/null" id="jm004601202342" name="jm004601202342" style="color: #0c5390;"></a>Preparative HPLC purification afforded <b>25</b>: 3.1 g, 20% yield, purity 98%, Rt<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">I</span> = 10.70, Rt<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">II</span> = 10.20, Rt<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">IV</span> = 3.90, HRMS 1047.51 (calcd 1047.5014).</div>
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Table 2. <span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>H and <span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">13</span>C NMR Assignments of SOM230, Using Numbering Scheme in NMR Assignment<img alt="" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2003/jmcmar.2003.46.issue-12/jm021093t/production/images/medium/jm021093tu00002a.gif" data-pinit="registered" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
<div class="NLM_p" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px;">
</div>
<div class="NLM_p" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px;">
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;">residue</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">group</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">δ <span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>H [ppm]</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">δ <span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">13</span>C [ppm]</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">residue</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">group</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">δ <span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>H [ppm]</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">δ <span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">13</span>C [ppm]</td></tr>
</tbody></table>
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"><b>1</b></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"><span class="smallcaps">l</span>-phenylglycine</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td></tr>
</tbody></table>
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 1</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">NH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">9.73</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 1</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">α-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">6.47</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">59.3</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 1</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">2/6-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">8.02</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">127.3</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 1</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">CO</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">169.6</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 1</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">3/5-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7.41</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">129.1</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 1</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">1-C</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">141.0</td></tr>
</tbody></table>
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 1</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">4-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7.21</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">128.0</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"><b>2</b></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"><span class="smallcaps">d</span>-tryptophane</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td></tr>
</tbody></table>
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">1‘-NH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">12.20</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">α-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">5.28</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">55.6</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">NH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">10.34</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">β-CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">3.72</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">3.30</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">28.5</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7.65</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">112.0</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">CO</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">173.9</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">4-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7.43</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">119.2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">8-C</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">137.5</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">2-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7.28</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">124.7</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">9-C</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">128.3</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">6-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7.23</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">121.6</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">3-C</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">110.3</td></tr>
</tbody></table>
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">5-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">6.96</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">119.2</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"><b>3</b></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"><span class="smallcaps">l</span>-lysine</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td></tr>
</tbody></table>
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 3</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">NH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">10.10</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 3</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">δ-CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">1.41</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">1.32</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">31.5</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 3</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">α-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">4.62</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">55.2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 3</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">γ-CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">0.89</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">23.5</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 3</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">ε-CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">2.80</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">41.0</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 3</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">CO</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">171.9</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 3</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">β-CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">1.87</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">1.32</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">31.6</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 3</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">NH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">3</span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"><i>a</i></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td></tr>
</tbody></table>
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"><b>4</b></td><td class="colsep2 rowsep2" colspan="2" style="padding: 5px 0px;">(4-<i>O</i>-benzyl)-<span class="smallcaps">l</span>-tyrosine</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td></tr>
</tbody></table>
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 4</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">NH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7.99</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 4</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7-CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">4.92</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">69.9</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 4</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">2‘/6‘-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7.46</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">128.0</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 4</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">β-CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">3.46</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">3.10</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">39.7</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 4</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">3‘/5‘-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7.37</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">128.9</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 4</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">CO</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">171.8</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 4</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">4‘-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7.30</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">128.2</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 4</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">4-C</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">157.9</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 4</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">2/6-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7.21</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">131.5</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 4</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">1‘C</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">137.9</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 4</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">3/5-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">6.85</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">114.7</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 4</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">1-C</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">129.8</td></tr>
</tbody></table>
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 4</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">α-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">5.23</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">53.1</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"><b>5</b></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"><span class="smallcaps">l</span>-phenylalanine</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td></tr>
</tbody></table>
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 5</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">NH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">9.82</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 5</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">α-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">4.42</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">53.9</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 5</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">2/6-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7.38</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">130.0</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 5</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">β-CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">3.23</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">3.06</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">37.8</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 5</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">3/5-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7.27</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">129.3</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 5</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">CO</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">171.2</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 5</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">4-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">7.16</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">127.6</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 5</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">1-C</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">136.3</td></tr>
</tbody></table>
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"><b>6</b></td><td class="colsep2 rowsep2" colspan="4" style="padding: 5px 0px;">(γ-<i>O</i>-diaminoethylcarbamate)-l-hydroxyproline</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td></tr>
</tbody></table>
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 6</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">2-NH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">8.04</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 6</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">4-CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">2.95</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">42.4</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 6</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">γ-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">5.23</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">70.9</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 6</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">β-CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">2.63</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">1.25</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">37.0</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 6</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">α-CH</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">4.22</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">60.6</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 6</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">CO</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">170.7</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 6</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">δ-CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">4.12</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">51.4</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 6</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">1-CO</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">156.7</td></tr>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 6</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">3-CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">2</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">3.42</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">44.5</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> 6</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">4-NH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">3</span><span style="font-size: 9px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"><i>a</i></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td></tr>
</tbody></table>
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"><b>A</b></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">acetate</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td></tr>
</tbody></table>
<table class="table " style="border-bottom-color: rgb(209, 209, 209); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-spacing: 0px; font-size: 12px; line-height: 1.6; margin: 0px 0px 24px; width: 100%px;"><colgroup><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col><col></col></colgroup><tbody>
<tr class="colsep2" valign="top"><td class="colsep2 rowsep2" style="padding: 5px 0px;"> A</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">CH<span style="bottom: -0.25em; font-size: 9px; line-height: 0; position: relative; vertical-align: baseline;">3</span></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">2.20</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">22.1</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"> A</td><td class="colsep2 rowsep2" style="padding: 5px 0px;">CO</td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;"></td><td class="colsep2 rowsep2" style="padding: 5px 0px;">174.3</td></tr>
</tbody></table>
<div class="NLM_table-wrap-foot">
<div class="first last" style="margin-bottom: 10px;">
<i><span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">a</span></i> The NH<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">3</span><span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span> protons are part of the water peak at 5.82 ppm.</div>
</div>
</div>
<h2 style="background-color: white; clear: both; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 24px; font-weight: normal; line-height: 1.25; margin: 15px 0px 10px; padding: 0px;">
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<span class="mw-headline" id="References">References</span></h2>
<div class="reflist" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px;">
<ol class="references" style="margin: 0px 0px 14px 36px; padding: 0px;">
<li id="cite_note-1" style="list-style-type: decimal;"> <span class="reference-text">Signifor® (pasireotide) Official Website for healthcare professionals outside the US <a class="external free" href="http://www.signifor.com/" rel="nofollow" style="color: #0c5390; text-decoration: none;">http://www.signifor.com/</a></span></li>
<li id="cite_note-2" style="list-style-type: decimal;"> <span class="reference-text"><a class="external text" href="http://finance.yahoo.com/news/novartis-drug-signifor-approved-eu-051703038.html;_ylt=A2KJ3CQ_5qBPSVwAuzLQtDMD" rel="nofollow" style="color: #0c5390; text-decoration: none;">“Novartis drug Signifor® approved in the EU as the first medication to treat patients with Cushing’s disease”</a><span class="reference-accessdate">. Retrieved <span class="nowrap">2012-07-08</span></span>.</span></li>
<li id="cite_note-3" style="list-style-type: decimal;"> <span class="reference-text">Mancini et al. <a class="new" href="http://en.wikipedia.org/w/index.php?title=Therapeutics_and_Clinical_Risk_Management&action=edit&redlink=1" style="color: #0c5390; text-decoration: none;" title="Therapeutics and Clinical Risk Management (page does not exist)">Therapeutics and Clinical Risk Management</a> 2010;6:505-516</span></li>
<li id="cite_note-4" style="list-style-type: decimal;"> <span class="reference-text">Colao et al. Pasireotide (SOM230) provides clinical benefit in patients with Cushing’s disease: results from a large, 12-month, randomized-dose, double-blind, Phase III study, Abstract OC1.7. European Neuroendocrine Association (ENEA) 14th Congress, 2010:62-63</span></li>
<li id="cite_note-5" style="list-style-type: decimal;"> <span class="reference-text">U.S. National Library of Medicine: Treatment of pituitary-dependent Cushing’s disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial.<a class="external free" href="http://www.ncbi.nlm.nih.gov/pubmed/18957506?dopt=Abstract" rel="nofollow" style="color: #0c5390; text-decoration: none;">http://www.ncbi.nlm.nih.gov/pubmed/18957506?dopt=Abstract</a></span></li>
<li id="cite_note-6" style="list-style-type: decimal;"> <span class="reference-text"><a class="external text" href="http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2009/11/human_orphan_000677.jsp" rel="nofollow" style="color: #0c5390; text-decoration: none;">EMEA Approval for Pasireotide</a></span></li>
<li id="cite_note-7" style="list-style-type: decimal;"> <span class="reference-text"><a class="external text" href="http://www.medscape.com/viewarticle/776273" rel="nofollow" style="color: #0c5390; text-decoration: none;">“FDA Approves Pasireotide for Cushing’s Disease”</a>.</span></li>
</ol>
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<tr><td class="patent-data-table-td citation-patent" style="padding: 5px 0px;"><a href="http://www.google.im/patents/WO2007096055A1?cl=ru" style="color: #0c5390; text-decoration: none;">WO2007096055A1</a><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">7 Feb 2007</td><td class="patent-data-table-td patent-date-value" style="padding: 5px 0px;">30 Aug 2007</td><td class="patent-data-table-td " style="padding: 5px 0px;">Novartis Ag</td><td class="patent-data-table-td " style="padding: 5px 0px;">Combination of somatostatin-analogs with different selectivity for human somatostatin receptor subtypes</td></tr>
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<img alt="" data-pinit="registered" src="http://www.livemint.com/rf/Image-621x414/LiveMint/Period1/2014/08/02/Photos/ranbaxy--621x414.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<span style="color: #454545; font-family: Arial, sans-serif; font-size: 9pt;"><a href="http://cl.s4.exct.net/?qs=7ea2cfbc9768493839b9cc1e8466f54f4b4d9a49626152cae95bdbdfccc39ed3" style="color: #0c5390; text-decoration: none;" target="_blank"><strong><span style="color: #4a3d8a;">Ranbaxy to introduce malarial treatment Synriam in African nations</span></strong></a><br />Ranbaxy Laboratories has obtained regulatory approval to introduce India’s first new chemical entity (NCE) Synriam (arterolane maleate 150mg and piperaquine phosphate 750mg drug) in seven African countries.</span></div>
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read at</div>
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<a href="http://www.pharmaceutical-technology.com/news/newsmalarial-treatment-synriam-4471331?WT.mc_id=DN_News" style="color: #0c5390; text-decoration: none;">http://www.pharmaceutical-technology.com/news/newsmalarial-treatment-synriam-4471331?WT.mc_id=DN_News</a></div>
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Synriam is a new age therapy recommended to treat uncomplicated Plasmodium falciparum malaria in adults. It was launched in India in April 2012.</div>
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The product was also launched in Uganda and is set to be introduced in Nigeria, Senegal, Cameroon, Guinea, Kenya and Ivory Coast by the end of January 2015.</div>
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<img alt="Arterolane.png" data-pinit="registered" src="http://upload.wikimedia.org/wikipedia/commons/thumb/8/86/Arterolane.png/220px-Arterolane.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<b>Arterolane</b></div>
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cas 664338-39-0, UNII-3N1TN351VB, OZ277, RBX-11160, NCGC00274173-01</div>
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<b>Molecular Formula:</b> C<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">22</span>H<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">36</span>N<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2</span>O<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">4</span></div>
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<b>Molecular Weight:</b> 392.53224</div>
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<a href="http://www.google.st/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Medicines+For+Malaria+Venture+Mmv%22" style="color: #0c5390; text-decoration: none;">Medicines For Malaria Venture Mmv</a></div>
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<a href="http://www.google.st/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Ranbaxy+Lab+Ltd%22" style="color: #0c5390; text-decoration: none;">Ranbaxy Lab Ltd</a> innovator</div>
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cis-adamantane-2-spiro-3’-8’-[[[(2’-amino-2’ methylpropyl) amino] carbonyl] methyl] 1’,2’,4’-trioxaspiro [4.5] decane</div>
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cis-adamantane-2-spiro-3′-8′-[[[(2′- amino-2′-methylpropyl)amino]carbonyl]-methyl]- 1 ‘,2′,4′-trioxaspiro[4.5]decane</div>
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<img alt="" data-pinit="registered" src="http://img.naij.com/lifestyle/health/08/f/malaria_mosquito1.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<b>Arterolane</b>, also known as <b>OZ277</b> or <b>RBx 11160</b>,is a substance being tested for <a class="mw-redirect" href="http://en.wikipedia.org/wiki/Antimalarial_drug" style="color: #0c5390; text-decoration: none;" title="Antimalarial drug">antimalarial</a> activity<span class="reference" id="cite_ref-1" style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Arterolane#cite_note-1" style="color: #0c5390; text-decoration: none;">[1]</a></span> by <a href="http://en.wikipedia.org/wiki/Ranbaxy_Laboratories" style="color: #0c5390; text-decoration: none;" title="Ranbaxy Laboratories">Ranbaxy Laboratories</a>.<span class="reference" id="cite_ref-livemint_2-0" style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Arterolane#cite_note-livemint-2" style="color: #0c5390; text-decoration: none;">[2]</a></span> It was discovered by US and European scientists who were coordinated by the <a href="http://en.wikipedia.org/wiki/Medicines_for_Malaria_Venture" style="color: #0c5390; text-decoration: none;" title="Medicines for Malaria Venture">Medicines for Malaria Venture</a> (MMV).<span class="reference" id="cite_ref-3" style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Arterolane#cite_note-3" style="color: #0c5390; text-decoration: none;">[3]</a></span> Its molecular structure is uncommon for pharmacological compounds in that it has both an <a href="http://en.wikipedia.org/wiki/Ozonide" style="color: #0c5390; text-decoration: none;" title="Ozonide">ozonide</a> group and an <a href="http://en.wikipedia.org/wiki/Adamantane" style="color: #0c5390; text-decoration: none;" title="Adamantane">adamantane</a> substituent.<span class="reference" id="cite_ref-4" style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Arterolane#cite_note-4" style="color: #0c5390; text-decoration: none;">[4]</a></span></div>
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<a href="http://en.wikipedia.org/wiki/Clinical_trial#Phase_III" style="color: #0c5390; text-decoration: none;" title="Clinical trial">Phase III clinical trials</a> of arterolane, in combination with <a href="http://en.wikipedia.org/wiki/Piperaquine" style="color: #0c5390; text-decoration: none;" title="Piperaquine">piperaquine</a>, began in India in 2009.<span class="reference" id="cite_ref-5" style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Arterolane#cite_note-5" style="color: #0c5390; text-decoration: none;">[5]</a></span> When clinical trial results were disappointing, the MMV withdrew support<span class="reference" id="cite_ref-livemint_2-1" style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Arterolane#cite_note-livemint-2" style="color: #0c5390; text-decoration: none;">[2]</a></span> and Ranbaxy continued developing the drug combination on its own.</div>
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<strong>Ranbaxy launched India’s first new drug, Synriam<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">TM</span></strong>, treating <em>Plasmodium falciparum</em>malaria in adults. The drug provides quick relief from most malaria-related symptoms, including fever, and has a high cure rate of over 95 %.</div>
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Just one tablet per day is required, for three days, instead of two to four tablets, twice daily, for three or more days with other medicines. The drug is independent of dietary restrictions for fatty foods or milk.</div>
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Ranbaxy developed Synriam as a fixed-dose combination of arterolane maleate and piperaquine phosphate, where arterolane is the new chemical entity (NCE) that was developed as an alternative to artemisinin. It is the first recently developed antimalarial not based on artemisinin, one of the most effective treatments for malaria, which has shown problems with resistance in recent years. Arterolane was discovered by a collaborative drug discovery project funded by the Medicines for Malaria Venture. Since Synriam<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">TM</span> has a synthetic source, unlike artemisinin-based drugs, production can be scaled up whenever required and a consistent supply can be maintained at a low cost.</div>
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The new drug, has been approved by the Drug Controller General of India (DCGI) for marketing in India and conforms to the recommendations of the World Health Organization (WHO) for using combination therapy in malaria. Ranbaxy is also working to make it available in African, Asian and South American markets where Malaria is rampant. Synriam<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">TM</span> trials are ongoing for <em>Plasmodium vivax</em> malaria and a paediatric formulation.</div>
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Derek Lowe of the famous In the Pipeline blog had written about arterolane in 2009. At the time it was in Phase III trial, which I assumed were the trials that Ranbaxy was conducting. But it turned out that arterolane was developed by a collaboration between researchers in the US, the UK, Switzerland and Australia who were funded by the World Health Organization and Medicines for Malaria Venture (a Swiss non-profit).</div>
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They published this work in Nature in 2004 and further SAR (Structure Activity Relationship) studies in J Med Chem in 2010. So Ranbaxy did not develop the drug from scratch? But the press release quotes Arun Sawhney, CEO and Managing Director of Ranbaxy which misleads people to think so: “It is indeed gratifying to see that Ranbaxy’s scientists have been able to gift our great nation its first new drug, to treat malaria, a disease endemic to our part of the world.</div>
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This is a historic day for science and technology in India as well as for the pharmaceutical industry in the country. Today, India joins the elite and exclusive club of nations of the world that have demonstrated the capability of developing a new drug”. So Ranbaxy mixes a known active compound (piperaquine) with a new compound that someone else found to be active (arterolane) and claims that they developed a new drug?</div>
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In an interview in LiveMint, Sawhney says, “Ranbaxy spent around $30 million on Synriam and the contribution from DST [India’s Department of Science & Technology] was Rs.5 crore.</div>
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The drug went through several phases of development since the project began in 2003. We did not look at this as a commercial development. Instead, this is a CSR [Corporate Social Responsibility] venture for us.” That’s a give away because developing a new drug from scratch has to cost more than $30 million + Rs.50 million.</div>
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<li style="list-style-type: square;"><a href="http://www.ranbaxy.com/" style="color: #0c5390; text-decoration: none;" target="_blank">Ranbaxy Laboratories Limited</a> (Ranbaxy), India</li>
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<img alt="Ranbaxy" src="http://www.ranbaxy.com/wp-content/uploads/2012/04/ranbaxy_logo11.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /> now taken over by sun</div>
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Synriam<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">TM</span></div>
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<tr><td style="padding: 5px 0px;"><strong>Generic Name</strong></td></tr>
<tr><td style="padding: 5px 0px;">Arterolane Maleate and Piperaquine Phosphate Tablets</td></tr>
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<tr><td style="padding: 5px 0px;"><strong>Composition</strong></td></tr>
<tr><td style="padding: 5px 0px;">Each film coated tablet contains: Arterolane maleate equivalent to Arterolane ……………………………150 mg Piperaquinephosphate……………750 mg</td></tr>
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<tr><td style="padding: 5px 0px;"><strong>Dosage Form</strong></td></tr>
<tr><td style="padding: 5px 0px;">Tablets</td></tr>
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<tr><td style="padding: 5px 0px;"><strong>Inactive ingredients:</strong></td></tr>
<tr><td style="padding: 5px 0px;">Microcrystalline cellulose, Crospovidone, Magnesium stearate, Hydroxypropyl methyl cellulose/Hypromellose, Titanium dioxide, Macrogol/ Polyethylene glycol, Talc, Ferric Oxide (Yellow), Ferric Oxide (Red)</td></tr>
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<strong>Description</strong> Synriam<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">TM</span> is a fixed dose combination of two antimalarial active ingredients arterolane maleate and piperaquine phosphate.</div>
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Arterolane maleate is a synthetic trioxolane compound. The chemical name of arterolane maleate is cis-adamantane-2-spiro-3’-8’-[[[(2’-amino-2’ methylpropyl) amino] carbonyl] methyl] 1’,2’,4’-trioxaspiro [4.5] decane hydrogen maleate. The molecular formula is C26H40N2O8 and molecular weight is 508.61. The structural formula is as follows:</div>
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<tr><td colspan="1" rowspan="1" style="padding: 5px 0px;"><big><big>MALARIA</big></big></td></tr>
<tr><td colspan="1" rowspan="1" style="padding: 5px 0px;">Malaria is one of the most prevalent and deadly parasitic diseases in the world. Up to 289 million cases of malaria may have occurred in 2010, causing between 660,000 and 1.25 million deaths, mainly in Africa and mostly of children younger than 5 years.</td></tr>
<tr><td colspan="1" rowspan="1" style="padding: 5px 0px;">(WHO: <a href="http://www.who.int/malaria/publications/world_malaria_report_2012/en/index.html" rel="nofollow" style="color: #0c5390; text-decoration: none;">http://www.who.int/malaria/publications/world_malaria_report_2012/en/index.html</a>; Fidock, D. A. Eliminating Malaria. Science 2013, 340, 1531-1533.)</td></tr>
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<tr><td align="justify" colspan="1" rowspan="1" style="padding: 5px 0px;"><blockquote style="border-left-color: rgb(170, 170, 170); border-left-style: dotted; border-left-width: 2px; font-style: italic; margin: 14px 20px; padding-left: 20px;">
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The most serious problem in malaria treatment is that the parasites causing the disease, particularly the deadly Plasmodium falciparum, have developed resistance to widely used drugs, particularly chloroquine (CQ). Currently, the most efficacious therapies are combinations of an artemisinin-type compound with a long-lasting partner drug like lumefantrine, amodiaquine or mefloquine.</div>
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<img alt="" data-pinit="registered" height="332" src="http://academic.brooklyn.cuny.edu/chem/howell/facultyWebPages/Sanchez-Delgado/DATA/bp_p1.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="352" /></div>
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Malaria, the most common parasitic disease of humans, remains a major health and economic burden in most tropical countries. Large areas of Central and South America, Hispaniola (Haiti and the Dominican Republic), Africa, the Middle East, the Indian subcontinent, Southeast Asia, and Oceania are considered as malaria-risk areas. It leads to a heavy toll of illness and death, especially amongst children and pregnant women.</div>
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According to the World Health Organization, it is estimated that the disease infects about 400 million people each year, and around two to three million people die from malaria every year. There are four kinds of malaria parasites that infect human: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.</div>
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Malaria spreads from one person to another by the bite of mosquito, Anopheles gambiae, which serves as vector. When a mosquito sucks the blood of human, sporozoites are transfused into the human body together with saliva of the mosquito. The sporozoites enter into the hepatocytes, reproduce asexually and finally enter into the blood stream. The parasites continue to multiply inside the red blood cells, until they burst and release large number of merozoites.</div>
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This process continues, destroying a significant number of blood cells and causing the characteristic paroxysm (“chills and fever”) associated with the disease. In the red blood cells, some of the merozoites become male or female gametocytes. These gametocytes are ingested by the mosquito when it feeds on blood. The gametocytes fuse in the vector’s gut; sporozoites are produced and are migrated to the vector’s salivary glands.</div>
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The clinical symptoms of malaria are generally associated with the bursting of red blood cells causing an intense fever associated with chills that can leave the infected individual exhausted and bedridden. More severe symptoms associated with repeat infections and/or infection by Plasmodium falciparum include anaemia, severe headaches, convulsions, delirium and, in some instances, death.</div>
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Quinine, an antimalarial compound that is extracted from the bark of cinchona tree, is one of the oldest and most effective drugs in existence. Chloroquine and mefloquine are the synthetic analogs of quinine developed in 1940’s, which due to their effectiveness, ease of manufacture, and general lack of side effects, became the drugs of choice. The downside to quinine and its derivatives is that they are short-acting and have bitter taste.</div>
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Further, they fail to prevent disease relapses and are also associated with side effects commonly known as “Chinchonism syndrome” characterized by nausea, vomiting, dizziness, vertigo and deafness. However, in recent years, with the emergence of drug- resistant strains of parasite and insecticide-resistant strains of vector, the treatment and/or control of malaria is becoming difficult with these conventional drugs.</div>
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Malarial treatment further progressed with the discovery of Artemisinin</div>
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(qinghaosu), a naturally occurring endoperoxide sesquiterpene lactone isolated from the plant Artemisia annua (Meshnick et al., Microbiol. Rev. 1996, 60, p. 301-315; Vroman et al., Curr. Pharm. Design, 1999, 5, p. 101-138; Dhingra et al., 2000, 66, p. 279-300), and a number of its precursors, metabolites and semi-synthetic derivatives which have shown to possess antimalarial properties. The antimalarial action of artemisinin is due to its reaction with iron in free heme molecules of the malaria parasite, with the generation of free radicals leading to cellular destruction. This initiated a substantial effort to elucidate its molecular mechanism of action (Jefford, dv. Drug Res. 1997, 29, p. 271-325; Cumming et al., Adv. Pharmacol. 1997, 37, p. 254-297) and to identify novel antimalarial peroxides (Dong and Vennerstrom, Expert Opin. Ther. Patents 2001, 1 1, p. 1753-1760).</div>
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Although the clinically useful artemisinin derivatives are rapid acting and potent antimalarial drugs, they have several disadvantages including recrudescence,</div>
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neurotoxicity, (Wesche et al., Antimicrob. Agents. Chemother. 1994, 38, p. 1813-1819) and metabolic instability (White, Trans. R. Soc. Trop. Med. Hyg., 1994, 88, p. 41-43). A fair number of these compounds are quite active in vitro, but most suffer from low oral activity (White, Trans. R. Soc. Trop. Med. Hyg., 1994, 88, p. 41-43 and van Agtmael et al., Trends Pharmacol. Sci., 1999, 20, p. 199-205). Further all these artemisinin derivatives are conventionally obtained from plant source and are therefore expensive.</div>
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As the cultivation of the plant material is dependent on many factors including the weather conditions, the supply source thus becomes finite and there are chances of varying yield and potency. This leads to quality inconsistencies and supply constraints. As malaria is more prevalent in developing countries, a switch to cheaper and effective medicine is highly desirable.</div>
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Thus there exists a need in the art to identify new peroxide antimalarial agents, especially those which are not dependent on plant source and can be easily synthesized, are devoid of neurotoxicity, and which possess improved solubility, stability and pharmacokinetic properties.</div>
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Following that, many synthetic antimalarial 1 ,2,4-trioxanes (Jefford, Adv. Drug Res. 1997, 29, p. 271-325; Cumming et al., Adv. Pharmacol. 1997, 37, p. 254-297), 1,2,4,5-tetraoxanes (Vennerstrom et al., J. Med. Chem., 2000, 43, p. 2753-2758), and other endoperoxides have been prepared. Various patents/applications disclose means and method for treating malaria using Spiro or dispiro 1,2,4-trioxolanes for example, U.S.</div>
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Patent Application No. 2004/0186168 and U.S. Patent Nos. 6,486, 199 and 6,825,230. The present invention relates to solid dosage forms of the various spiro or dispiro 1 ,2,4- trioxolanes antimalarial compounds disclosed in these patents/applications and are incorporated herein by reference.</div>
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Active compounds representing various Spiro and dispiro 1 ,2,4-trioxolane derivatives possess excellent potency, efficacy against Plasmodium parasites, and a lower degree of neurotoxicity, in addition to their structural simplicity and ease of synthesis. Furthermore, these compounds have half-lives which are believed to permit short-term treatment regimens comparing favorably to other artemisinin-like drugs. In general, the therapeutic dose of trioxolane derivative may range between about 0.1-1000 mg/kg/day, in particular between about 1-100 mg/kg/day. The foregoing dose may be administered as a single dose or may be divided into multiple doses. For malaria prevention, a typical dosing schedule could be, for example, 2.0-1000 mg/kg weekly beginning 1-2 weeks prior to malaria exposure, continued up to 1-2 weeks post-exposure.</div>
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Monotherapy with artemisinin (natural or synthetic) class of drugs might cure the patients within 3 days, however perceiving the potential threat of the malarial parasite developing resistance towards otherwise very potent artemisinin class of drugs, WHO had strictly called for an immediate halt to the provision of single-drug artemisinin malaria pills. Combination therapy in case of malaria retards the development of resistance, improve efficacy by lowering recrudescence rate, provides synergistic effect, and increase exposure of the parasite to the drugs.</div>
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Artemsinin based combinations are available in the market for a long time.</div>
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Artemether-lumafentrine (Co-artem®) was the first fixed dose antimalarial combination containing an artemisinin derivative and has been known since 1999. This combination has passed extensive safety and efficacy trials and has been approved by more than 70 regulatory agencies. Co-artem® is recommended by WHO as the first line treatment for uncomplicated malaria.</div>
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Other artemisinin based combinations include artesunate and amodiaquine (Coarsucam®), and dihydroartemisin and piperaquine (Eurartesim®). Unfortunately, all the available artemisinin based combinations have complicated dosage regimens making it difficult and inconvenient for a patient to comply completely with the total prescribed duration. For example, the dosage regimen of Co-artem®for an adult having body weight of more than 35 kg includes 6 doses over three days.</div>
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The first dose comprises four tablets initially, the second dose comprises four tablets after eight hours, the third to sixth doses comprise four tablets twice for another two days; making it a total of 24 tablets. The dosage regimen of Coarsucam® for an adult having body weight of more than 36 kg or age above 14 years includes three doses over three days; each dose comprises two tablets; making it a total of six tablets. The dosage regimen of Eurartesim® for an adult having body weight between 36 kg – 75 kg includes 3 doses over three days, each dose comprises of three tablets, making it a total of nine tablets.</div>
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It is evident that the available artemisinin-based combinations have a high pill burden on patients as they need to consume too many tablets. As noted above, this may increase the possibility of missing a few doses, and, consequently, could result in reduced efficacy due to non-compliance and may even lead to development of resistance for the drug. Therefore, there is an urgent and unmet need for anti-malarial combinations with a simplified daily dosing regimen that reduces the pill burden and would increase patient compliance.</div>
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Apart from simplifying the regimen, there are certain limitations for formulators developing formulations with trioxolones, the first being their susceptibility to degradation in presence of moisture that results in reduced shelf lives. Another is their bitter taste, which can result in poor compliance of the regimen or selection of another, possibly less effective, therapeutic agent.</div>
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PATENT</div>
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<a href="http://www.google.st/patents/US6906205" rel="nofollow" style="color: #0c5390; text-decoration: none;">http://www.google.st/patents/US6906205</a></div>
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<img alt="Figure US06906205-20050614-C00051" data-pinit="registered" height="1563" src="http://patentimages.storage.googleapis.com/US6906205B2/US06906205-20050614-C00051.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="333" /></div>
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PATENT</div>
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<a href="http://www.google.st/patents/WO2013008218A1?cl=en" rel="nofollow" style="color: #0c5390; text-decoration: none;">http://www.google.st/patents/WO2013008218A1?cl=en</a></div>
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structural Formula II.</div>
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<br /></div>
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<a href="http://patentimages.storage.googleapis.com/WO2013008218A1/imgf000013_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000013_0001" class="patent-full-image" data-pinit="registered" height="128" id="imgf000013_0001" src="http://patentimages.storage.googleapis.com/WO2013008218A1/imgf000013_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="388" /></a></div>
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Formula II</div>
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Active compound includes one or more of the various spiro and dispiro trioxolane derivatives disclosed in U.S. Application No. 2004/0186168 and U.S. Patent Nos.</div>
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6,486,199 and 6,825,230, which are incorporated herein by reference. These trioxolanes are relatively sterically hindered on at least one side of the trioxolane heterocycle which provides better in vivo activity, especially with respect to oral administration. Particularly, spiro and dispiro 1,2,4-trioxolanes derivatives possess excellent potency and efficacy against Plasmodium parasites, and a lower degree of neurotoxicity.</div>
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The term “Active compound I” herein means cis-adamantane-2-spiro-3′-8′-[[[(2′- amino-2′-methylpropyl)amino]carbonyl]-methyl]- 1 ‘,2′,4′-trioxaspiro[4.5]decane hydrogen maleate. The Active compound I may be present in an amount of from about 5% to about 25%, w/w based on the total dosage form.</div>
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<br /></div>
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<img alt="" data-pinit="registered" src="http://www.rsc.org/images/artemisin-u3_tcm18-57431.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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PATENT</div>
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<a href="http://www.google.st/patents/WO2007138435A2?cl=en" rel="nofollow" style="color: #0c5390; text-decoration: none;">http://www.google.st/patents/WO2007138435A2?cl=en</a></div>
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A synthetic procedure for preparing compounds of Formula I, salts of the free base c«-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methyl propyl) amino] carbonyl] methyl]- 1 ‘, 2′, 4′-trioxaspiro [4.5] decane has been disclosed in U.S. 6,906,205.</div>
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<img alt="Figure imgf000002_0001" data-pinit="registered" height="167" src="http://patentimages.storage.googleapis.com/WO2007138435A2/imgf000002_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="464" /></div>
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The process for the preparation of compounds of Formula I wherein a compound of Formula II (wherein R is lower alkyl) is reacted with a compound of Formula III (wherein R is lower alkyl) to obtain compound of Formula IV;</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007138435A2/imgf000005_0001.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000005_0001" class="patent-full-image" height="84" id="imgf000005_0001" src="http://patentimages.storage.googleapis.com/WO2007138435A2/imgf000005_0001.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="396" /></a></div>
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<a href="http://patentimages.storage.googleapis.com/WO2007138435A2/imgf000005_0002.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000005_0002" class="patent-full-image" height="104" id="imgf000005_0002" src="http://patentimages.storage.googleapis.com/WO2007138435A2/imgf000005_0002.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="136" /></a></div>
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Formula Formula IV</div>
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followed by hydrolysis of the compounds of Formula IV to give a compound of Formula V;</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007138435A2/imgf000005_0003.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000005_0003" class="patent-full-image" height="84" id="imgf000005_0003" src="http://patentimages.storage.googleapis.com/WO2007138435A2/imgf000005_0003.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="192" /></a></div>
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Formula V followed by the reaction of the compound of Formula V with an activating agent, for example, methyl chloroformate, ethyl chloroformate, propyl chloro formate, n-butyl chloro formate, isobutyl chloroformate or pivaloyl chloride leads to the formation of mixed anhydride, which is reacted in situ reaction with 1 ,2-diamino-2-methyl propane to give a compound of Formula VI; and</div>
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<a href="http://patentimages.storage.googleapis.com/WO2007138435A2/imgf000005_0004.png" style="color: #0c5390; text-decoration: none;"><img alt="Figure imgf000005_0004" class="patent-full-image" data-pinit="registered" height="104" id="imgf000005_0004" src="http://patentimages.storage.googleapis.com/WO2007138435A2/imgf000005_0004.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="232" /></a></div>
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Formula Vl reacting the compound of Formula VI with an acid of Formula HX (wherein X can be the same as defined earlier) to give compounds of Formula I.</div>
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Example 1 : Preparation of O-methyl-2-adamantanone oxime</div>
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To a solution of 2-adamantanone (50 g, 0.3328 mol, 1 equiv.) in methanol (0.25 lit), sodium hydroxide solution (15 g, 0.3761mol, 1.13 equiv, in 50 mL water) was added followed by methoxylamine hydrochloride (37.5 g x 81.59% Purity= 30.596 g, 0.366 mol, 1.1 equiv) at room temperature under stirring. The reaction mixture was stirred at room temperature for 1 to 2 h. The reaction was monitored by HPLC. The reaction mixture was concentrated at 40- 45°C under vacuum to get a thick residue. Water (250 mL) was added at room temperature and the reaction mixture was stirred for half an hour. The white solid was filtered, washed with water (50 mL), and dried at 40 to 45°C under reduced pressure. O-methyl 2- adamantanone oxime (57 g, 95 % yield) was obtained as a white solid.</div>
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(M<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span>+l) 180, <span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>HNMR (400 MHz, CDCl<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">3</span> ): δ 1.98 – 1.79 (m, 12H), 2.53 (s, IH), 3.46 ( s, IH), 3.81 (s, 3H).</div>
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Example 2: Preparation of 4-(methoxycarbonvmethvPcvclohexanone A high pressure autoclave was charged with a mixture of methyl (4- hydroxyphenyl)acetate (50 g, 0.30 mol), palladium ( 5g) (10 %) on carbon (50 % wet) and O- xylene (250 mL). The reaction mixture was stirred under 110 to 115 psi of hydrogen pressure for 7 to 8 h at 140<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C. The reaction was monitored by HPLC. The reaction mixture was then cooled to room temperature, and the catalyst was filtered off. Filtrate was concentrated under reduced pressure to get 4-(methoxycarbonylmethyl)cyclohexanone as light yellow to colorless oily liquid (48.7 g, 97.4 %).</div>
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(M<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span>+!) 171, ‘ HNMR (400 MHz, CDCl <span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">3</span>): δ 1.48 – 1.51 ( m, 2H), 2.1 1-2.07 (m, 2H), 2.4- 2.23 (m, 7H), 3.7 (s, 3H).</div>
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Example 3: Preparation of methyl (Is, 4s)-dispiro [cyclohexane-l, 3′-f 1,2,4] trioxolane-5′, 2″-tricvclor3.3.1.1<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">3</span>-<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">7</span>1decan1-4-ylacetate</div>
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A solution of O-methyl-2-adamantanone oxime (example 1) (11.06 g, 61.7 mmol, 1.5 equiv.) and 4-(methoxycarbonymethyl)cyclohexanone (example 2) (7.0 g, 41.1 mmol, 1 equiv.) in cyclohexane ( 200ml) and dichloromethane (40 mL) was treated with ozone (ozone was produced with an OREC ozone generator [0.6 L/min. O<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">2,</span> 60 V] passed through an empty gas washing bottle that was cooled to -78<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C). The solvent was removed after the reaction was complete. After removal of solvents, the crude product was purified by crystallization from 80% aqueous ethanol (200 mL) to afford the title compound as a colorless solid. Yield: 10.83 g, 78%, mp: 96-98<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C; <span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>HNMR (500 Hz<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">3</span>CDCl<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">3</span>): δ 1.20-1.33 (m, 2H), 1.61-2.09 (m, 5 21H), 2.22 (d, J = 6.8Hz, 2H), 3.67(s,3H).</div>
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Example 4: Preparation of (Is, 4s)-dispiro [cyclohexane-1, 3′-[l,2,4] trioxolane-5′, 2″- tricvclo [3.3.1.1<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">3</span>‘<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">7</span>] decanl-4-ylacetic acid</div>
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Sodium hydroxide (3.86 g, 96.57 mmol, 3 equiv.) in water (80 mL) was added to a solution of methyl (\s, 4s)-dispiro [cyclohexane-1, 3′-[l,2,4] trioxolane-5′, 2″-tricyclo</div>
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10 [3.3.1.I<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">3</span>‘<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">7</span>] decan]-4-ylacetate (example 3) (10.83 g, 32.19 mmol, 1 equiv.) in 95% ethanol (150 mL). The mixture was stirred at 50<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C for about 4 h, cooled to O<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C, and treated with IM hydrochloric acid (129ml, 4 equiv). The precipitate was collected by filtration, washed with 50 % aqueous ethanol (150 mL) and dried in vacuum at 40 <span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C to give the title compound as colorless solid. Yield: 9.952 g, 96%, mp: 146-148<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C ( 95% ethanol), <span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>HNMR (500 Hz,</div>
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15 CDCl<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">3</span>): δ 1.19-1.41 (m,2H), 1.60-2.05 (m,21H), 2.27 (d, J=6.8 Hz,2H).</div>
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Example 5: Preparation of c?s-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methyl propyl) amino] carbonyl] methyl]-! ‘, T , 4′-trioxaspiro [4.5] decane</div>
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Method A:</div>
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(Is, 4s)-dispiro[cyclohexane- 1 ,3 ‘-[ 1 ,2,4]trioxolane-5 ‘,2 ‘ ‘-tricyclo[3.3.1.1<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">3</span>‘<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">7</span>]decan]-4-</div>
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.0 ylacetic acid (example 4) (5 g ,15.5mmol, 1 equiv) was mixed with triethylamine (2.5 g , 24.8 mmol, 1.6 equiv) in 100ml of dichloromethane. The reaction mixture was cooled to – 1O<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C to 0<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C. Ethyl chloro formate (1.68 g, 17 mmol, 1.0 equiv) in 15 mL dichloromethane was charged to the above reaction mixture at – 10<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C to 0<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C. The reaction mixture was stirred at the same temperature for 10 to 30 minutes. The resulting mixed anhydride reaction mixture</div>
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15 was added dropwise to a previously prepared solution of l,2-diamino-2-methylpropane (1.64 g, 18.6 mmol, 1.2 equiv), in 100 mL dichloromethane at -10<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C to O<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the same temperature till the reaction was complete. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. The reaction was complete</div>
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>0 within 2 h. Nitrogen atmosphere was maintained throughout the reaction. Water (50 mL) was charged, organic layer was separated and washed with 10% sodium bicarbonate solution (50 mL) and water (50 mL) at room temperature. The organic layer was dried over sodium sulphate and the solvent was removed at 25 to 4O<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C under reduced pressure. Hexane (50ml) was added to obtain residue under stirring at room temperature. The mixture was filtered and washed with 5 mL of chilled hexane. The solid was dried under reduced pressure at room 5 temperature.</div>
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Yield: 5.2 g (85.4 %), (M<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span>+l) 393, <span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>HNMR (400 MHz, DMSO-J<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">6</span> ): δ 0.929 ( s, 6H), 1.105 – 1.079 (m, 2H), 1.887-1.641 (m, 21H), 2.030-2.017 (d, 2H), 2.928 (d, 2H).</div>
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Method B:</div>
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(Is, 4s)-dispiro [cyclohexane-1, 3′-[l,2,4] trioxolane-5′, 2″-tricyclo [3.3.1.I<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">3</span>‘<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">7</span>]</div>
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10 decan]-4-ylacetic acid (example 4) (10 g, 31mmol, 1 equiv) was treated with isobutyl chloroformate (4.5 g, 33mmol, 1.1 equiv) in presence of organic base like triethyl amine (5 g, 49.6mmol, 1.6 equiv) at 0<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C to 7°C in 250ml of dichloromethane. The solution was stirred at O<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C to 7°C for aboutlO to 30 minutes. To the above reaction mixture, previously prepared solution of l,2-diamino-2-methylpropane (3.27 g, 37 mmol, 1.2 equiv), in 50 mL of</div>
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15 dichloromethane was added at O<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C to 7°C in one lot. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the room temperature till reaction was over. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. Reaction was complete within 2 h. The reaction nitrogen atmosphere was maintained throughout the reaction. Water (250 mL) was charged, organic</div>
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20 layer was separated and washed with 10% sodium bicarbonate solution (200 mL) and water (100 mL) at room temperature and the solvent was removed at 25 to 4O<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C under reduced pressure. Hexane (100ml) was added to the residue, under stirring, at room temperature. The mixture was filtered and washed with chilled hexane (10 mL). The resultant solid was dried under reduced pressure at room temperature. Yield: 10.63 g (87%), (M<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span>+l) 393, <span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>HNMR</div>
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>5 (400 MHz, DMSO-J<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">6</span> ) :δ 0.928 ( s, 6H), 1.102 – 1.074 (m, 2H), 1.859-1.616 (m, 21H), 2.031- 2.013 (d, 2H), 2.94-2.925 (d, 2H). Method C:</div>
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(\s, 4s)-dispiro[cyclohexane-l,3′-[l,2,4]trioxolane-5′,2″-tricyclo[3.3.1.1<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">3>7</span>]decan]-4- ylacetic acid (example 4) (5 g, 15.5mmol, 1 equiv) was treated with pivaloyl chloride (1.87 g, 15.5 mmol, 1 equiv) and triethylamine (2.5gm, 24.8mmol, 1.6 equiv) at -15°C to -10<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C in dichloromethane (125 mL). The solution was stirred at -15<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C to -10<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C for aboutlO to 30 minutes. It resulted in the formation of mixed anydride. To the above reaction mixture, previously prepared solution of 1 ,2-diamino-2-methylpropane (1.64 g, 18.6 mmol, 1.2 equiv) in 25 mL dichloromethane was added at -15°C to -10<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the room temperature till reaction was over. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. The reaction was complete within 2 h. Nitrogen atmosphere was maintained throughout the reaction. Water (125 mL) was charged, organic layer was separated and washed with 50 mL of 10% sodium bicarbonate solution and 125 mL of water, respectively at room temperature. Finally solvent was removed at 25 to 4O<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C under reduced pressure. 50 mL of 5% Ethyl acetate – hexane solvent mixture was added to the residue under stirring at room temperature. The mixture was filtered and washed with 5 mL of chilled hexane. Solid was dried under reduced pressure at room temperature. Yield: 5.03 g (83 %), (M<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span>+l) 393, <span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>JINMR (400 MHz, OMSO-d<span style="bottom: -0.25em; font-size: 11px; line-height: 0; position: relative; vertical-align: baseline;">6</span> ):δ 0.93 ( s, 6H), 1.113 – 1.069 (m, 2H), 1.861-1.644 (m, 21H), 2.033-2.015 (d, 2H), 2.948-2.933 (d, 2H).</div>
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Example 6: Preparation of c/s-adamantane-2-spiro-3′ -8 ‘-πT(2′-amino-2′ -methyl propyl) amino! carbonyl] methyli-l ‘, 2\ 4′-U-JoXaSpJrQ [4.51 decane maleate To a solution of c/s-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methyl propyl) amino] carbonyl] methyl]-! ‘, 2′, 4′-trioxaspiro [4.5] decane (example 5) (60 g, 0.153 moles) in ethanol (150 mL) was added a solution of maleic acid (17.3 g, 0.15 moles, 0.98 equiv. in ethanol 90 mL) and the reaction mixture was stirred for about 1 h. To this clear solution, n- heptane (720 mL) was added at room temperature in 1 h and the reaction mixture was stirred for 3 h. It was then cooled to 0 to 10<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C and filtered. The cake was washed with n-heptane (60 mL) and dried under vacuum at 40-45<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C.</div>
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Yield: 67 g, 77.4%, mp: 149<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">0</span>C (decomp), (M<span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">+</span>+l) 393.5, <span style="font-size: 11px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span>HNMR (300 MHz, DMSO-^ ): δ 1.05-1.11 (2H,m), 1.18 (6H,s), 1.64-1.89 (21H,m), 2.07(2H,d), 3.21 (2H,d), 6.06 (2H,d), 7.797 (2H, bs), 8.07 (IH, t).</div>
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<img alt="" data-pinit="registered" src="http://upload.wikimedia.org/wikipedia/commons/8/86/Arterolane.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<img alt="" data-pinit="registered" src="http://www.york.ac.uk/media/chemistry/news/malaria2.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<img alt="" data-pinit="registered" height="553" src="http://www.bayerpharma.com/static/media/images/content/BHC_00076239_810.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="725" /></div>
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References</div>
<div class="reflist" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; line-height: 22.3999996185303px;">
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<li id="cite_note-livemint-2" style="list-style-type: decimal;"> <span class="reference-text"><a class="external text" href="http://www.livemint.com/2007/09/21011423/Blow-to-Ranbaxy-drugresearch.html" rel="nofollow" style="color: #0c5390; text-decoration: none;">Blow to Ranbaxy drug research plans</a> at LiveMint.com, Sep 21 2007</span></li>
<li id="cite_note-3" style="list-style-type: decimal;"> <span class="reference-text">Vennerstrom, Jonathan L.; Arbe-Barnes, Sarah; Brun, Reto; Charman, Susan A.; Chiu, Francis C. K.; Chollet, Jacques; Dong, Yuxiang; Dorn, Arnulf et al. (2004). “Identification of an antimalarial synthetic trioxolane drug development candidate”. <i>Nature</i> <b>430</b> (7002): 900–4.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" style="color: #0c5390; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="http://dx.doi.org/10.1038%2Fnature02779" rel="nofollow" style="color: #0c5390; text-decoration: none;">10.1038/nature02779</a>. <a class="mw-redirect" href="http://en.wikipedia.org/wiki/PubMed_Identifier" style="color: #0c5390; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/15318224" rel="nofollow" style="color: #0c5390; text-decoration: none;">15318224</a>.</span></li>
<li id="cite_note-4" style="list-style-type: decimal;"> <span class="reference-text"><a class="external text" href="http://pipeline.corante.com/archives/2009/11/23/ozonides_as_drugs_what_will_they_think_of_next.php" rel="nofollow" style="color: #0c5390; text-decoration: none;"><i>In the Pipeline</i>: “Ozonides As Drugs: What Will They Think Of Next?”</a>, by Derek Lowe, November 23, 2009, at Corante.com</span></li>
<li id="cite_note-5" style="list-style-type: decimal;"> <span class="reference-text"><a class="external text" href="http://www.wwarn.org/node/95" rel="nofollow" style="color: #0c5390; text-decoration: none;">Indian company starts Phase III trials of synthetic artemisinin</a>, May 4 2009, at the WorldWide Antimalarial Resistance Network</span></li>
<li style="list-style-type: decimal;"><a href="http://www.nature.com/nature/journal/v430/n7002/full/nature02779.html" rel="nofollow" style="color: #0c5390; text-decoration: none;">http://www.nature.com/nature/journal/v430/n7002/full/nature02779.html</a></li>
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PROCESS FOR THE PREPARATION OF DISPIRO 1,2,4-TRIOXOLANE ANTIMALARIALS (OZ277)</div>
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<a href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6906205.PN.&OS=PN/6906205&RS=PN/6906205" style="color: #0c5390; text-decoration: none;">US6906205</a></div>
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6-15-2005</div>
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Spiro and dispiro 1,2,4-trioxolane antimalarials</div>
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<a href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6825230.PN.&OS=PN/6825230&RS=PN/6825230" style="color: #0c5390; text-decoration: none;">US6825230</a></div>
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11-31-2004</div>
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Spiro and dispiro 1,2,4-trixolane antimalarials</div>
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ANTIMALARIALS</div>
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<img alt="" data-pinit="registered" src="http://www.rsc.org/images/FEATURE-malaria-395-A_tcm18-116236.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<img alt="" class="" data-pinit="registered" height="471" src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/Articleimage/2014/MD/c4md00011k/c4md00011k-f5_hi-res.gif" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" width="603" /></div>
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<img alt="" data-pinit="registered" src="http://www.rsc.org/chemistryworld/sites/default/files/upload/ELQ-structure-with-text_300.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<a href="http://www.rsc.org/chemistryworld/2013/03/new-antimalarial-drug-class-resistance-elq-300-quinolone" rel="nofollow" style="color: #0c5390; text-decoration: none;">http://www.rsc.org/chemistryworld/2013/03/new-antimalarial-drug-class-resistance-elq-300-quinolone</a></div>
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<img alt="Antimalarial drugsSpeeding to a new lead" data-pinit="registered" src="http://www.nature.com/nrd/journal/v9/n11/images/nrd3301-i1.jpg" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></div>
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<a href="http://www.nature.com/nrd/journal/v9/n11/full/nrd3301.html" rel="nofollow" style="color: #0c5390; text-decoration: none;">http://www.nature.com/nrd/journal/v9/n11/full/nrd3301.html</a><br />Structure of NITD609; the 1<span class="i">R</span>,3<span class="i">S</span>configuration is fundamental for its antimalarial activity</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1tag:blogger.com,1999:blog-7082350141827122272.post-65289225398838768332014-12-02T05:34:00.001-08:002014-12-02T05:34:46.560-08:00Pimobendan<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="Pimobendan" data-pinit="registered" src="http://www.druglead.com/cds/structure/Pimobendan.gif" style="border: none; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></div>
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<img alt="Pimobendan" data-pinit="registered" src="http://upload.wikimedia.org/wikipedia/commons/thumb/4/40/Pimobendan_Enantiomers_Structural_Formulae.png/240px-Pimobendan_Enantiomers_Structural_Formulae.png" style="border: none; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></div>
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Pimobendan</div>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">CAS:</b> 74150-27-9</div>
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3-[2-(4-methoxyphenyl)-3H-benzimidazol-5-yl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one</div>
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4,5-Dihydro-6-[2-(4-methoxyphenyl)-1<i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">H</i>-benzimidazol-5-yl]-5-methyl-3(2<i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">H</i>)-pyridazinone</div>
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UD-CG 115; UD-CG 115 BS; 2-(4-methoxyphenyl)-5(6)-(5-methyl-3-oxo-4,5-dihydro-2<i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">H</i>-6-pyridazinyl)benzimidazole</div>
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<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">4,5-dihydro-6-(2-(4-methoxyphenyl)-1H-benzimidazole-5-yl)-5-methyl-3(2H)-pyridazinone</li>
<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">pimobendan</li>
<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">pimobendane</li>
<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">UD CG 115</li>
<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">UD-CG 115</li>
<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">UD-CG115</li>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">MF:</b> C19H18N4O2</div>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">MW:</b> 334.37</div>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Percent Composition:</b> C 68.25%, H 5.43%, N 16.76%, O 9.57%</div>
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Boehringer Ingelheim (Originator)<a href="http://www.chemdrug.com/" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;"><img alt="" src="http://www.chemdrug.com/images/space.gif" style="border: none; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></a></div>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Derivative Type:</b> Hydrochloride</div>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">CAS :</b> 77469-98-8</div>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">MF:</b> C19H18N4O2.HCl</div>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">MW:</b> 370.83</div>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Percent Composition:</b> C 61.54%, H 5.16%, N 15.11%, O 8.63%, Cl 9.56%</div>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Prop:</b> Crystals from methanol and ethereal HCl, mp 311°(dec). LD50 orally in mice: ~600 mg/kg (Austel, 1982).</div>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">MP:</b> mp 311°(dec)</div>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Toxicity data:</b> LD50 orally in mice: ~600 mg/kg (Austel, 1982)</div>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Therap-Cat:</b> Cardiotonic.</div>
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<img alt="pimobendan.png" data-pinit="registered" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=4823&t=l" style="border: none; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></div>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Pimobendan</b> (<a href="http://en.wikipedia.org/wiki/International_Nonproprietary_Name" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="International Nonproprietary Name">INN</a> is a veterinary medication manufactured by <a href="http://en.wikipedia.org/wiki/Boehringer_Ingelheim" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Boehringer Ingelheim">Boehringer Ingelheim</a> under the trade names <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Vetmedin</b> and <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Acardi</b>) or <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">pimobendane</b>. It is a calcium sensitizer with positive <a href="http://en.wikipedia.org/wiki/Inotropic" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Inotropic">inotropic</a> and <a href="http://en.wikipedia.org/wiki/Vasodilator" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Vasodilator">vasodilator</a> effects. It is also a selective <a href="http://en.wikipedia.org/wiki/Phosphodiesterase_inhibitor" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Phosphodiesterase inhibitor">inhibitor</a> of<a href="http://en.wikipedia.org/wiki/Phosphodiesterase" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Phosphodiesterase">phosphodiesterase</a> III (<a href="http://en.wikipedia.org/wiki/PDE3" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PDE3">PDE3</a>).</div>
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Pimobendan is used in the management of <a href="http://en.wikipedia.org/wiki/Heart_failure" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Heart failure">heart failure</a> in dogs, most commonly caused by myxomatous mitral valve disease (also known as <a href="http://en.wikipedia.org/w/index.php?title=Endocardiosis&action=edit&redlink=1" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Endocardiosis (page does not exist)">endocardiosis</a>), or <a href="http://en.wikipedia.org/wiki/Dilated_cardiomyopathy" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Dilated cardiomyopathy">dilated cardiomyopathy</a>.<span id="cite_ref-1" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Pimobendan#cite_note-1" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[1]</a></span> Research has shown that pimobendan increases survival time and improves quality of life in patients with <a href="http://en.wikipedia.org/wiki/Congestive_heart_failure" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Congestive heart failure">congestive heart failure</a> secondary to mitral valve disease when compared with <a href="http://en.wikipedia.org/wiki/Benazepril" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Benazepril">benazepril</a>, an<a href="http://en.wikipedia.org/wiki/ACE_inhibitor" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="ACE inhibitor">angiotensin-converting-enzyme (ACE) inhibitor</a>.<span id="cite_ref-2" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Pimobendan#cite_note-2" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[2]</a></span> Under the trade name Acardi, it is available for human use in <a href="http://en.wikipedia.org/wiki/Japan" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Japan">Japan</a>.<span id="cite_ref-3" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Pimobendan#cite_note-3" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[3]</a></span></div>
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Mechanism of action</h2>
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Pimobendan is a positive <a href="http://en.wikipedia.org/wiki/Inotrope" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Inotrope">inotrope</a>. It sensitizes and increases the binding efficiency of cardiac <a href="http://en.wikipedia.org/wiki/Myofibril" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Myofibril">myofibril</a> to the calcium ions that are already present without increasing the consumption of oxygen and energy. Pimobendan also causes peripheral <a href="http://en.wikipedia.org/wiki/Vasodilation" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Vasodilation">vasodilation</a> by inhibiting the function of <a href="http://en.wikipedia.org/wiki/PDE3" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PDE3">phosphodiesterase III</a>. This results in decreased pressure, translating into smaller cardiac <a href="http://en.wikipedia.org/wiki/Preload_(cardiology)" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Preload (cardiology)">preload</a> and<a href="http://en.wikipedia.org/wiki/Afterload" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Afterload">afterload</a> (decreases the failing heart’s workload).</div>
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Pharmacokinetics</h2>
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Pimobendan is absorbed rapidly when given via the oral route and has a <a href="http://en.wikipedia.org/wiki/Bioavailability" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Bioavailability">bioavailability</a> of 60-65%. It is metabolized into its active form by the <a href="http://en.wikipedia.org/wiki/Liver" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Liver">liver</a>. The <a href="http://en.wikipedia.org/wiki/Half-life" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Half-life">half-life</a> of pimobendan in the blood is 0.4 hours and the half-life of its metabolite is 2 hours. Elimination is by excretion in the bile and then feces. Pimobendan is 90–95% <a href="http://en.wikipedia.org/wiki/Plasma_protein_binding" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Plasma protein binding">bound to plasma proteins</a> in circulation. This has implications in patients suffering from low blood protein levels (<a href="http://en.wikipedia.org/wiki/Hypoproteinemia" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Hypoproteinemia">hypoproteinemia</a>/<a href="http://en.wikipedia.org/wiki/Hypoalbuminemia" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Hypoalbuminemia">hypoalbuminemia</a>) and with patients that are on concurrent therapies that are also highly protein bound.</div>
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Combinations</h2>
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Pimobendan is often used in combination with three other drugs to palliate dogs with heart disease and reduce clinical signs of disease. These are:</div>
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<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><a href="http://en.wikipedia.org/wiki/Furosemide" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Furosemide">Furosemide</a>, a diuretic, to reduce <a href="http://en.wikipedia.org/wiki/Pulmonary_edema" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Pulmonary edema">pulmonary edema</a>. This can be given intravenously if the animal is in respiratory distress (6–8 mg/kg), and then titrated down to the minimum dose required orally.</li>
<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><a href="http://en.wikipedia.org/wiki/Spironolactone" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Spironolactone">Spironolactone</a>, an <a href="http://en.wikipedia.org/wiki/Aldosterone_antagonist" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Aldosterone antagonist">aldosterone antagonist</a>. This has two actions, firstly, as a <a href="http://en.wikipedia.org/wiki/Potassium-sparing_diuretic" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Potassium-sparing diuretic">potassium-sparing diuretic</a>, although its diuretic properties are small compared with those of furosemide. Secondly, it reduces aldosterone-mediated myocardial remodelling and fibrosis, slowing the progression of heart disease.</li>
<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">An <a href="http://en.wikipedia.org/wiki/ACE_inhibitor" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="ACE inhibitor">ACE inhibitor</a>, often <a href="http://en.wikipedia.org/wiki/Enalapril" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Enalapril">enalapril</a> (trade name Enacard) or <a href="http://en.wikipedia.org/wiki/Benazepril" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Benazepril">benazepril</a> (Fortekor). These drugs inhibit the action of <a href="http://en.wikipedia.org/wiki/Angiotensin-converting_enzyme" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Angiotensin-converting enzyme">angiotensin-converting enzyme</a>, producing a balanced vasodilation, along with other favourable effects.</li>
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Other drugs may also be used as required to manage certain <a href="http://en.wikipedia.org/wiki/Arrhythmias" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Arrhythmias">arrhythmias</a> that are often associated with heart disease.</div>
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Synthesis</h2>
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Pimobendan can be synthesized beginning with <a href="http://en.wikipedia.org/wiki/Anisoyl_chloride" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Anisoyl chloride">anisoyl chloride</a>.</div>
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<a href="http://en.wikipedia.org/wiki/File:Pimobendan.png" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;"><img alt="" data-file-height="1167" data-file-width="3461" data-pinit="registered" src="http://upload.wikimedia.org/wikipedia/commons/thumb/5/58/Pimobendan.png/700px-Pimobendan.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/5/58/Pimobendan.png/1050px-Pimobendan.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/5/58/Pimobendan.png/1400px-Pimobendan.png 2x" style="border: none; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="700" /></a><div style="border: 0px; margin-bottom: 1.5em; outline: 0px; padding: 0px;">
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Pimobendan synthesis:<span id="cite_ref-4" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="http://en.wikipedia.org/wiki/Pimobendan#cite_note-4" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[4]</a></span></div>
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<img alt="" data-pinit="registered" src="http://www.chemdrug.com/databases/SYNTHESIS/SYN/09/09050801a.gif" style="border: none; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></div>
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The cyclization of methyl 3- [4- (4-methoxybenzoylamino) -3-nitrobenzoyl] butyrate (I) with hydrazine hydrate in refluxing acetic acid gives 4,5-dihydro-6- [4- (4-methoxybenzoylamino) -3- nitrobenzoyl] -5-methylpyridazin-3 (2H) -one (II), which is reduced with H2 over Pd / C in ethanol yielding the corresponding amino derivative (III). Finally, this compound is cyclized in refluxing acetic acid.<a href="http://www.chemdrug.com/" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;"><img alt="" src="http://www.chemdrug.com/images/space.gif" style="border: none; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></a></div>
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References</h2>
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<li id="cite_note-1" style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"> Gordon SG, Miller MW, Saunders AB (2006). <a href="http://www.jaaha.org/cgi/pmidlookup?view=long&pmid=16527909" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">“Pimobendan in heart failure therapy—a silver bullet?”</a>. <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">J Am Anim Hosp Assoc</i> <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">42</b> (2): 90–3. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PubMed Identifier">PMID</a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/16527909" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">16527909</a>.</li>
<li id="cite_note-2" style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"> Häggström J, Boswood A, O’Grady M, <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">et al.</i> (July 2008). “Effect of Pimobendan or Benazepril Hydrochloride on Survival Times in Dogs with Congestive Heart Failure Caused by Naturally Occurring Myxomatous Mitral Valve Disease: The QUEST Study”. <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">J. Vet. Intern. Med.</i> <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">22</b> (5): 1124–35. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Digital object identifier">doi</a>:<a href="http://dx.doi.org/10.1111%2Fj.1939-1676.2008.0150.x" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">10.1111/j.1939-1676.2008.0150.x</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PubMed Identifier">PMID</a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/18638016" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">18638016</a>.</li>
<li id="cite_note-3" style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"> <a href="http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=54" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">“Kusuri-no-Shiori Drug Information Sheet”</a>. RAD-AR Council, Japan. April 2005. Retrieved 2008-08-06.</li>
<li id="cite_note-4" style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"> Nicolas, C.; Verny, M.; Maurizis, J. C.; Payard, M.; Faurie, M. (1986). “Synthesis of 14C-bucromarone succinate and hydrochloride”. <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Journal of Labelled Compounds and Radiopharmaceuticals</i> <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">23</b> (8): 837. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Digital object identifier">doi</a>:<a href="http://dx.doi.org/10.1002%2Fjlcr.2580230806" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">10.1002/jlcr.2580230806</a>. <a href="http://en.wikipedia.org/w/index.php?title=Template:Cite_doi/10.1002.2Fjlcr.2580230806&action=edit&editintro=Template:Cite_doi/editintro2" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">edit</a></li>
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Further reading</h2>
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<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Lee JA, Allen DG (March 1990). <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1662365" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">“Calcium sensitisers”</a>. <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">BMJ</i> <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">300</b> (6724): 551–2. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Digital object identifier">doi</a>:<a href="http://dx.doi.org/10.1136%2Fbmj.300.6724.551" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">10.1136/bmj.300.6724.551</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PubMed Central">PMC</a> <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1662365" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">1662365</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PubMed Identifier">PMID</a> <a href="http://www.ncbi.nlm.nih.gov/pubmed/2108746" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">2108746</a>.</li>
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External links</h2>
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<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><a href="http://www.vetmedin.com/" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Official Vetmedin Product Website</a></li>
<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><a href="http://www.vetmedin.co.uk/" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">UK Product Website</a></li>
<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><a href="http://www.vetmedin.com.au/" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Australia Product Website</a></li>
<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><a href="http://www.vetmedin.org/" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Russia Product Website</a></li>
<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Website about the QUEST study (reference 2) (<a href="http://www.questtrial.com/" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">http://www.questtrial.com</a>)</li>
<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><a href="http://cavalierhealth.net/mitral_valve_disease.htm#A_Few_Words" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">A Few Words About Pimobendan</a></li>
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<table style="border-collapse: collapse; border: 0px; font-size: 14px; margin: 0px; outline: 0px; padding: 0px; width: 693px;"><caption style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Pimobendan</caption><tbody style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><td colspan="2" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/File:Pimobendan_skeletal.svg" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;"><img alt="Pimobendan skeletal.svg" data-file-height="393" data-file-width="874" src="http://upload.wikimedia.org/wikipedia/commons/thumb/6/6d/Pimobendan_skeletal.svg/200px-Pimobendan_skeletal.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/6/6d/Pimobendan_skeletal.svg/300px-Pimobendan_skeletal.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/6/6d/Pimobendan_skeletal.svg/400px-Pimobendan_skeletal.svg.png 2x" style="border: none; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="200" /></a></td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th colspan="2" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;">Systematic (<a href="http://en.wikipedia.org/wiki/International_Union_of_Pure_and_Applied_Chemistry_nomenclature" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="International Union of Pure and Applied Chemistry nomenclature">IUPAC</a>) name</th></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><td colspan="2" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;">(<i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">RS</i>)-6-[2-(4-methoxyphenyl)-1<i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">H</i>-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2<i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">H</i>)-one</td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th colspan="2" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;">Clinical data</th></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="American Society of Health-System Pharmacists">AHFS</a>/<a href="http://en.wikipedia.org/wiki/Drugs.com" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Drugs.com">Drugs.com</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://www.drugs.com/international/pimobendan.html" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">International Drug Names</a></td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Regulation of therapeutic goods">Legal status</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><div style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">
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<li style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">℞ P<small style="border: 0px; color: #555555; font-size: 13px; margin: 0px; outline: 0px; padding: 0px;">rescription only</small></li>
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<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/Route_of_administration" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Route of administration">Routes</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;">Oral</td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th colspan="2" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;">Pharmacokinetic data</th></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/Bioavailability" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Bioavailability">Bioavailability</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;">60 to 65%</td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/Biological_half-life" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Biological half-life">Half-life</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;">0.4 hours</td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/Excretion" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Excretion">Excretion</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;">In feces</td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th colspan="2" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;">Identifiers</th></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/CAS_registry_number" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="CAS registry number">CAS number</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?term=74150-27-9&rn=1" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">74150-27-9</a><span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"> <img alt="Yes" data-file-height="600" data-file-width="600" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="border: none; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="7" /></span></td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System#ATCvet" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Anatomical Therapeutic Chemical Classification System">ATCvet code</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/ATC_code_C01" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="ATC code C01">QC01</a><a href="http://www.whocc.no/atcvet/atcvet_index/?code=QC01CE90" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">CE90</a></td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/PubChem" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PubChem">PubChem</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4823" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">CID 4823</a></td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/ChemSpider" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="ChemSpider">ChemSpider</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://www.chemspider.com/Chemical-Structure.4657.html" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">4657</a><span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"> <img alt="" data-file-height="600" data-file-width="525" src="http://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/11px-X_mark.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/14px-X_mark.svg.png 2x" style="border: none; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="7" /></span></td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Unique Ingredient Identifier">UNII</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=34AP3BBP9T" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">34AP3BBP9T</a><span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"> <img alt="" data-file-height="600" data-file-width="525" src="http://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/11px-X_mark.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/14px-X_mark.svg.png 2x" style="border: none; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="7" /></span></td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/KEGG" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="KEGG">KEGG</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://www.kegg.jp/entry/D01133" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">D01133</a><span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"> <img alt="Yes" data-file-height="600" data-file-width="600" src="http://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="border: none; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="7" /></span></td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/ChEMBL" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="ChEMBL">ChEMBL</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL24646" rel="nofollow" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">CHEMBL24646</a><span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"> <img alt="" data-file-height="600" data-file-width="525" src="http://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/11px-X_mark.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/14px-X_mark.svg.png 2x" style="border: none; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="7" /></span></td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th colspan="2" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;">Chemical data</th></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/Chemical_formula" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Chemical formula">Formula</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/Carbon" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Carbon">C</a><span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">19</span><a href="http://en.wikipedia.org/wiki/Hydrogen" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Hydrogen">H</a><span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">18</span><a href="http://en.wikipedia.org/wiki/Nitrogen" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nitrogen">N</a><span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">4</span><a href="http://en.wikipedia.org/wiki/Oxygen" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Oxygen">O</a><span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">2</span><span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"> </span></td></tr>
<tr style="border: 0px; margin: 0px; outline: 0px; padding: 0px;"><th scope="row" style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;"><a href="http://en.wikipedia.org/wiki/Molecular_mass" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Molecular mass">Mol. mass</a></th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; margin: 0px; outline: 0px; padding: 6px;">334.37 g/mol</td></tr>
</tbody></table>
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<b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">References:</b> Positive inotropic agent. Prepn: V. Austel <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">et al.,</i> <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">DE</b> <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">2837161</b>; <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">eidem,</i> <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">US</b> <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">4361563</b> (1980, 1982 both to Thomae).</div>
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Cardiovascular effects: J. C. A. von Meel, <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Arzneim.-Forsch.</i> <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">35,</b> 284 (1985); P. D. Verdouw <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">et al.,</i> <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Eur. J. Pharmacol.</i><b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">126,</b> 21 (1986). Comparison of enantiomer activity: K. Fujino <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">et al.,</i> <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">J. Pharmacol. Exp. Ther.</i> <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">247,</b> 519 (1988).</div>
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Clinical trial in congestive heart failure: F. Hagemeijer, <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Am. Heart J.</i> <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">122,</b> 517 (1991); S. D. Katz <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">et al.,</i> <i style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">ibid.</i> <b style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">123,</b> 95 (1992).</div>
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