FDA Approves Monovisc Injection for Knee Pain

FDA Approves Monovisc Injection for Knee Pain

Sodium Hyaluronate

9067-32-7 (sodium salt)

MF:	C14H22NNaO11
MW:	403.31

26 feb 2014

Anika Therapeutics Inc. announced it has received marketing approval for Monovisc from the U.S. Food and Drug Administration (FDA). Monovisc is a single injection supplement to synovial fluid of the osteoarthritic joint, used to treat pain and improve joint mobility in patients suffering from osteoarthritis (OA) of the knee.

Monovisc is the first FDA-approved, single-injection product with HA from a non-animal source. It is comprised of a sterile, clear, biocompatible, resorbable, viscoelastic fluid composed of partially cross-linked sodium hyaluronate (NaHA) in phosphate buffered saline.

read all at

http://www.dddmag.com/news/2014/02/fda-approves-monovisc-injection-knee-pain

Sodium hyaluronate is the sodium salt of hyaluronic acid, a glycosaminoglycan found in various connective, epithelial, and neural tissues. Sodium hyaluronate, a long-chain polymer containing repeating disaccharide units of Na-glucuronate-N-acetylglucosamine, occurs naturally on the corneal endothelium, bound to specific receptors for which it has a high affinity. The polyanionic form, commonly referred to as hyaluronan, is a visco-elasticpolymer normally found in the aqueous and vitreous humour. As a pharmaceutical, the uses of sodium hyaluronate include:

sodium hyaluronate

Sodium hyaluronate for intra-articular injection (brand names: Euflexxa, Hyalgan, Supartz, Gel-One) is used to treat knee pain in patients withosteoarthritis who have not received relief from other treatments. It is very similar to the lubricating fluid that occurs naturally in the articular capsule of the knee joint. Once injected into the joint capsule, it acts as both a shock absorber and a lubricant for the joint.[1]

Sodium hyaluronate for intraocular viscoelastic injection (brand names: Healon, Provisc, Viscoat) is used as a surgical aid in variety of surgical procedures performed on the eyeball including cataract extraction (intra- and extracapsular), intraocular lens implantation, corneal transplant,glaucoma filtration, and retina attachment surgery. In surgical procedures in the anterior segment of eyeball, instillation of sodium hyaluronate serves to maintain a deep anterior chamber during surgery, allowing for efficient manipulation with less trauma to the corneal endothelium and other surrounding tissues. Its viscoelasticity also helps to push back the vitreous face and prevent formation of a postoperative flat chamber. In posterior segment surgery, sodium hyaluronate serves as a surgical aid to gently separate, maneuver, and hold tissues. It creates a clear field of vision, facilitating intra-operative and post-operative inspection of the retina and photocoagulation.[2]

Sodium hyaluronate is used as a viscosupplement, administered through a series of injections into the knee, increasing the viscosity of the synovial fluid, which helps lubricate, cushion and reduce pain in the joint.[3] It is generally used as a last resort before surgery[4] and provides symptomatic relief, by recovering the viscoelasticity of the articular fluid, and by stimulating new production from synovial fluid.[5] Use of sodium hyaluronate may reduce the need for joint replacement.[6] Injections appear to increase in effectiveness over the course of four weeks, reaching a peak at eight weeks and retaining some effectiveness at six months, with greater benefit for osteoarthritis than oral analgesics.[7] It may also be effective when used with other joints.[8]

Sodium hyaluronate may also be used in plastic surgery to reduce wrinkles on the face or as a filler in other parts of the body.[9] It may be used in ophthalmology to assist in the extraction ofcataracts, the implantation of intraocular lenses, corneal transplants, glaucoma filtration, retinal attachment and in the treatment of dry eyes.[10]

Sodium hyaluronate is also used to coat the bladder lining in treating interstitial cystitis.

hyaluronan

cas 9004-61-9

Sodium hyaluronate functions as a tissue lubricant and is thought to play an important role in modulating the interactions between adjacent tissues. Sodium hyaluronate is a polysaccharide which is distributed widely in the extracellular matrix of connective tissue in man. It forms a viscoelastic solution in water which makes it suitable for aqueous and vitreous humor in ophthalmic surgery. Mechanical protection for tissues (iris, retina) and cell layers (corneal, endothelium, and epithelium) are provided by the high viscosity of the solution. Elasticity of the solution assists in absorbing mechanical stress and providing a protective buffer for tissues. This viscoelasticity enables maintenance of a deep chamber during surgical manipulation since the solution does not flow out of the open anterior chamber. In facilitating wound healing, it is thought that it acts as a protective transport vehicle, taking peptide growth factors and other structural proteins to a site of action. It is then enzymatically degraded and active proteins are released to promote tissue repair.[11] Sodium hyaluronate is being used intra-articularly to treat osteoarthritis.

Sodium hyaluronate is an ophthalmic agent with viscoelastic properties that is used in joints to supplement synovial fluid.

Sodium hyaluronate is absorbed and diffuses slowly out of the injection site. It is eliminated via the canal of Schlemm.

Sodium hyaluronate hyaluronan started to be in use to treat osteoarthritis of the knee in year 1986 with the product Hyalart/Hyalgan by Fidia of Italy, in intra-articular injections.

Sodium Hyaluronate

Brand names of Sodium hyaluronate in Market include (alphabetically):

• AMO Vitrax (ocular)
• AMVISIC Plus (ocular)
• CYSTISTAR, Healon (ocular)
• EYEFILL (ocular)
• HYLO-COMOD (Eye Drop)
• OLIXIA Pure (Eye Drop)
• EUFLEXXA, Bio Technology General (Israel)-Meditrina SA (Rx articular), Molecular weight: 2,400,000-3,600,000 Daltons
• GONILERT/Verisfield (UK) (Rx/articular). Molecular weight:1,800,000-2,000,000 Daltons
• HYALGAN/HYALART- Fidia (Italy)(Medical Device/Rx articular)
• MONOVISC- Anika (USA)(MedicalDevice/articular)
• OSTENIL- TRB Chemedica (Switzerland)(articular injection) [1]
• RECOSYN- Merckle Recordati (Germany) Recosyn info leaflet
• SYNOCROM- Croma Pharma (Austria) (articular injection) . Molecular weight:1,600,000 Daltons
• VISCURE- Cube (UK)(Rx/articular), Molecular weight:1,800,000-2,000,000 Daltons
• VISMED- TRB Chemedica (Switzerland)(eye drop)[2]
• YARDEL- Libytec (Impfstoffwerk Dessau-Tornau/Germany,(Rx/articular), Molecular weight:1,800,000-2,000,000 Daltons

Hyaluronic acid (HA) is a glycosaminoglycan which is present in the hyaline cartilage, synovial joint fluid and skin tissues. More particularly, HA is a linear glycosaminoglycan formed by a mixture of chains of different length constituted by the repetition of a regular disaccharide formed by a glucuronic acid unit and a N- acetyl-glucosamine unit linked beta 1-4. Disaccharides are linked beta 1-3 with an average molecular weight up to 6 Md (6×106 Da). Therefore, each chain in said mixture of chains shows the same repetitive sequence of formula (A)

the corresponding cation generally being hydrogen (hyaluronic acid) or sodium (sodium hyaluronate).

In the tissues, the function of hyaluronic acid is mainly to maintain the structural density allowing in the same time the biochemical actions of the natural products in the specific body districts. In fluids like synovia the action of HA is to keep the right viscosity by a lubricant action. To exert these actions, HA needs to be fully biocompatible including a right metabolic balance. Natural HA is continuously degraded and synthesized by the body enzymes. This homeostasis is deviated when pathological situations occur, therefore increases in the HA catabolism can results in wide range of effects from a severe pathology to simple tissue modifications. The application of HA, as sodium hyaluronate, as filler in cosmetic or in viscoelastic replacement in synovitis, requires that the employed HA polymer has enhanced viscoelastic properties. This rheology has to be balanced with an efficient capability to make the production of the injectable product.

The industrial hyaluronic acid is obtained by extraction from animal tissues or by microorganism fermentation and is commonly available as sodium hyaluronate. Concerning molecular weight, it is generally recognized that low molecular weight HA is a mixture of chains having a mean molecular weight below 250 Kd (2.5×105Da). HA is used, generally as sodium hyaluronate, in many applications in cosmetics, ophthalmology, rheumatology and tissues engineering. In particular HA with a mean molecular weight above 1 Md is used as viscosupplement in joint arthrosis or in wrinkle management. The high molecular weight is required to supplement the synovial fluid or to fill skin connective dead spaces thanks to the viscosity of the resulting solution.

Many medicaments based on the above technology are currently available on the market. They have a high biocompatibility but they are subjected to a rather rapid degradation by the body enzymes, in particular by hyaluronidase, with the consequence of a short half-life.

sodium hyaluronate

References

1.  “Hyaluronate sodium: Indications, Side Effects, Warnings” (Web). Drugs.com. Drugs.com. 5 February 2014. Retrieved 25 February 2014.
2.  “Healon (Sodium Hyaluronate)” [package insert]. (2002). Kalamazo, Michigan: Pharmacia Corporation. (Web). RxList. (Updated 8 December 2004). RxList, Inc. Retrieved 25 February 2014.
3.  Puhl, W.; Scharf, P. (1997). “Intra-articular hyaluronan treatment for osteoarthritis”. Annals of the rheumatic diseases 56 (7): 441. doi:10.1136/ard.56.7.441. PMC 1752402.PMID 9486013. edit
4.  Karlsson, J.; Sjögren, L. S.; Lohmander, L. S. (2002). “Comparison of two hyaluronan drugs and placebo in patients with knee osteoarthritis. A controlled, randomized, double-blind, parallel-design multicentre study”. Rheumatology (Oxford, England) 41 (11): 1240–1248.PMID 12421996. edit
5.  Jubb, R. W.; Piva, S.; Beinat, L.; Dacre, J.; Gishen, P. (2003). “A one-year, randomised, placebo (saline) controlled clinical trial of 500-730 kDa sodium hyaluronate (Hyalgan) on the radiological change in osteoarthritis of the knee”. International journal of clinical practice 57 (6): 467–474. PMID 12918884. edit
6.  Kotz, R.; Kolarz, G. (1999). “Intra-articular hyaluronic acid: Duration of effect and results of repeated treatment cycles”. American journal of orthopedics (Belle Mead, N.J.) 28 (11 Suppl): 5–7. PMID 10587245. edit
7.  Bannuru, R. R.; Natov, N. S.; Dasi, U. R.; Schmid, C. H.; McAlindon, T. E. (2011). “Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis – meta-analysis”. Osteoarthritis and Cartilage 19 (6): 611–619. doi:10.1016/j.joca.2010.09.014.PMID 21443958. edit
8.  Salk, R. S.; Chang, T. J.; d’Costa, W. F.; Soomekh, D. J.; Grogan, K. A. (2006). “Sodium Hyaluronate in the Treatment of Osteoarthritis of the Ankle: A Controlled, Randomized, Double-Blind Pilot Study”. The Journal of Bone and Joint Surgery 88 (2): 295–302.doi:10.2106/JBJS.E.00193. PMID 16452740. edit
9. Beasley, K.; Weiss, M.; Weiss, R. (2009). “Hyaluronic Acid Fillers: A Comprehensive Review”.Facial Plastic Surgery 25 (2): 086–094. doi:10.1055/s-0029-1220647. PMID 19415575. edit
10.  Shimmura, S.; Ono, M.; Shinozaki, K.; Toda, I.; Takamura, E.; Mashima, Y.; Tsubota, K. (1995).“Sodium hyaluronate eyedrops in the treatment of dry eyes”. The British journal of ophthalmology 79 (11): 1007–1011. PMC 505317. PMID 8534643. edit
11.  Boucher, W. S.; Letourneau, R.; Huang, M.; Kempuraj, D.; Green, M.; Sant, G. R.; Theoharides, T. C. (2002). “Intravesical sodium hyaluronate inhibits the rat urinary mast cell mediator increase triggered by acute immobilization stress”. The Journal of Urology 167 (1): 380–384.doi:10.1016/S0022-5347(05)65472-9. PMID 11743360. edit

CANGRELOR

Cangrelor, AR-C69931MX Shows Improvement Over Plavix in Phase III Trial

Cangrelor, AR-C69931MX

[dichloro-[[[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-methylsulfanylethylamino)-2-(3,3,3-trifluoropropylsulfanyl)purin-9-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]methyl]phosphonic acid

N-[2-(Methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5¢-adenylic acid monoanhydride with (dichloromethylene)bis[phosphonic acid]

163706-06-7 cas no

Also known as: AR-C69931XX, 163706-06-7, Cangrelor (USAN/INN), Cangrelor [USAN:INN:BAN], UNII-6AQ1Y404U7, cangrelor (AR-C69931MX),

Molecular Formula: C17H25Cl2F3N5O12P3S2

Molecular Weight: 776.359196

Cangrelor

MAR 09, 2013

The Medicines Company said yesterday it will pursue marketing approvals for its anti-clotting drug candidate Cangrelor after it met its primary efficacy endpoint in a Phase III clinical trial of improvement compared with Plavix (clopidogrel).

The intravenous small molecule antiplatelet agent reduced by 22% the likelihood of patients experiencing death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis within 48 hours of taking it—to 4.7% from 5.9% of subjects randomized during CHAMPION PHOENIX. The Phase III trial compared Cangrelor to oral Plavix in 11,145 patients undergoing percutaneous coronary intervention.

Cangrelor also showed a 38% reduction (0.8% compared with 1.4%) over Plavix in the likelihood of patients experiencing the key secondary endpoint, incidence of stent thrombosis at 48 hours.

Cangrelor is designed to prevent platelet activation and aggregation that leads to thrombosis in acute care settings, including in patients undergoing percutaneous coronary intervention. During CHAMPION PHOENIX, Cangrelor made its best showing in patients with Q-wave myocardial infarction (QMI), lowering by 39% (to 0.2% compared with 0.3%) the incidence of QMI. Cangelor’s most disappoint showing was its inability to lower the odds of death compared with Clopidogrel; both drugs showed a likelihood of 0.3%.

“Our next step is to submit for market approvals in the U.S. and Europe. We anticipate submitting these data for a new drug application to the U.S. Food and Drug Administration in the second quarter with findings of prior trials, including the BRIDGE trial in patients awaiting open heart surgery,” Simona Skerjanec, PharmD, senior vp and innovation leader for antiplatelet therapies at The Medicines Company, said in a statement.

Cangrelor is a P2Y12 inhibitor under investigation as an antiplatelet drug[1] for intravenous application. Some P2Y12 inhibitors are used clinically as effective inhibitors of adenosine diphosphate-mediated platelet activation and aggregation.[1] Unlike clopidogrel (Plavix), which is a prodrug, cangrelor is an active drug not requiring metabolic conversion.

Poor interim results led to the abandonment of the two CHAMPION clinical trials in mid 2009.[2] The BRIDGE study, for short term use prior to surgery, continues.[3] The CHAMPION PHOENIX trial was a randomized study of over 11,000 patients published in 2013. It found usefulness of cangrelor in patients getting cardiac stents. Compared with clopidogrel given around the time of stenting, intravenous ADP-receptor blockade with cangrelor significantly reduced the rate of stent thrombosis and myocardial infarction.[4]Reviewers have questioned the methodology of the trial.[5]

One particularly preferred example of a reversible, short-acting P2Y12 inhibitor is cangrelor. Cangrelor is a potent, direct, and reversible antagonist of the platelet P2Y12 receptor. Cangrelor has a half-life of approximately less than 10 minutes, allowing for a return to normal platelet function in a very short period of time upon discontinuation of the drug. By reducing the need for a compound to be metabolized for activity, and by having a relatively short half-life, reversible, short-acting P2Y12 inhibitors are considered “reversible,” meaning that full platelet functionality may return rather quickly as compared to thienopyridines.

The binding of cangrelor to the P2Y12 receptor inhibits platelet activation as well as aggregation when mediated in whole or in part via this receptor. Cangrelor can be derived completely from synthetic materials, and is an analogue of adenosine triphosphate (ATP). ATP is a natural antagonist of the P2Y12 receptor sites and is found in humans.

The chemical structure for cangrelor is depicted below as Formula I.

Cangrelor is clinically well tolerated and safe and has no drug-drug interaction with aspirin, heparin or nitroglycerin. Unlike orally dosed thienopyridines, cangrelor can be administered intravenously and binds directly to P2Y12 receptor sites of platelets. In each of the embodiments of the present invention, the term “cangrelor” encompasses the compound of Formula I as well as tautomeric, enantiomeric and diastereomeric forms thereof, and racemic mixtures thereof, other chemically active forms thereof, and pharmaceutically acceptable salts of these compounds, including a tetrasodium salt. These alternative forms and salts, processes for their production, and pharmaceutical compositions comprising them, are well known in the art and set forth, for example, in U.S. Pat. No. 5,721,219. Additional disclosure relevant to the production and use of cangrelor may be found in U.S. Pat. Nos. 5,955,447, 6,130,208 and 6,114,313, as well as in U.S. Appln. Publication Nos. 2006/0270607 and 2011/0112030.

Invasive procedures means any technique where entry to a body cavity is required or where the normal function of the body is in some way interrupted by a medical procedure and/or treatment that invades (enters) the body, usually by cutting or puncturing the skin and/or by inserting instruments into the body. Invasive procedures can include coronary artery bypass grafting (CABG), orthopedic surgeries, urological surgeries, percutaneous coronary intervention (PCI), other general invasive procedures, such as endarterectomy, renal dialysis, cardio-pulmonary bypass, endoscopic procedures or any medical, surgical, or dental procedure that could result in excessive bleeding or hemorrhage to the patient.

Perioperative means the period of a patient’s invasive procedure which can occur in hospitals, surgical centers or health care providers’ offices. Perioperative includes admission, anesthesia, surgery, to recovery.

Thrombosis is the formation of a blood clot (thrombus) inside a blood vessel obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss. Some examples of the types of thrombosis include venous thrombosis which includes deep vein thrombosis, portal vein thrombosis, renal vein thrombosis, jugular vein thrombosis, Budd-Chiari syndrome, Paget-Schroetter disease, cerebral venous sinus thrombosis, cerebral venous sinus thrombosis and arterial thrombosis which includes stroke and myocardial infarction.

The compound cangrelor from the Medicines Company is represented by the structure

TETRASODIUM SALT

             OR

Cangrelor sodium, AR-C69931MX

Cangrelor Tetrasodium [USAN]
RN: 163706-36-3

Platelet P(2T) receptor antagonist.

5′-O-[[[Dichloro(phosphono)methyl](hydroxy)phosphoryloxy](hydroxy)phosphoryl]-N-[2-(methylsulfanyl)ethyl]-2-(3,3,3-trifluoropropylsulfanyl)adenosine tetrasodium salt

C17-H21-Cl2-F3-N5-O12-P3-S2.4-Na,

864.2899

The Medicines Co. (Proprietary), AstraZeneca Charnwood (Originator)

CARDIOVASCULAR DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, P2Y12 (P2T) Antagonists

2-Mercaptoadenosine (I) was S-alkylated with 1-chloro-3,3,3-trifluoropropane (II) in the presence of NaH to give trifluoropropyl sulfide (III). Subsequent acetylation of (III) with Ac2O at 80 C provided (IV), which was N-alkylated with methylthioethyl iodide (V) and NaH yielding (VI).

Further hydrolysis of the resulting (VI) with 0.1 M NaOH in refluxing MeOH furnished adenosine derivative (VII). The 5′-hydroxyl group of (VII) was then phosphorylated by reaction with phosphoryl chloride in cold triethyl phosphate followed by aqueous work-up.

The resulting 5′-monophosphate (VIII) was treated with carbonyl diimidazole and tri-n-butylamine to produce the phosphoryl imidazole intermediate (IX), which was finally condensed with dichloromethylenebis(phosphonic acid) (X).

The target compound was isolated as the tetrasodium salt upon treatment with NaI in methanol-acetone.

Alkylation of mercaptopurine (I) with 3-chloro-1,1,1-trifluoropropane (II) in the presence of NaH gave thioether (III).

After protection of the amino group of (III) as the acetamide (IV) by means of Ac2O and NaOAc, N-alkylation with 2-(methylthio)ethyl iodide (V) yielded (VI),

which was deacetylated by hydrolysis with NaOH in refluxing MeOH. Subsequent treatment with POCl3 produced the intermediate phosphoryl chloride (VIII).

Then, condensation of this acid chloride with dichloromethylene bisphosphonic acid (IX) in the presence of tributylamine in triethyl phosphate yielded the title compound, which was isolated as the tetrasodium salt.

Alternatively, hydrolysis of acid chloride (VIII) in the presence of ammonium bicarbonate gave phosphate salt (X), which was treated with carbonyldiimidazole, and the activated intermediate (XI) was then condensed with bisphosphonate (IX) to furnish the target compound.

…………

J. Med. Chem., 1999, 42 (2), pp 213–220

http://pubs.acs.org/doi/full/10.1021/jm981072s

10l (AR-C69931MX)

N6-(2-Methylthioethyl)-2-(3,3,3-trifluoropropylthio)-5‘-adenylic Acid, Monoanhydride withDichloromethylenebis(phosphonic acid) (10l). Prepared as the triammonium salt in 4% yield from 3l:  1H NMR δ(D2O) 8.30 (1H, s, H8), 5.97 (1H, d, J = 5.5 Hz, H1‘), 4.65 (1H, m, H2‘), 4.47 (1H, m, H3‘), 4.28 (1H, m, H4‘), 4.17 (2H, m, H5‘a and H5‘b), 3.67 (br s, NHCH2), 3.21 (2H, t, J = 7.6 Hz, SCH2), 2.72 (2H, t, J = 6.6 Hz, SCH2CH2CF3), 2.58 (2H, m, NCH2CH2), 2.04 (3H, s, SCH3);31P NMR δ(D2O) 8.80 (d, 1P, J = 18.6 Hz, Pγ), 0.42 (dd, 1P, J1 = 18.9 Hz, J2 = 28.9 Hz, Pβ), −9.41 (d, 1P, J = 29.0 Hz, Pα). Anal. (C17H34Cl2F3N8O12P3S2·3H2O) H, N, S; C:  calcd, 23.16; found, 23.66.

References

1.  Cangrelor Attenuates Coated-Platelet Formation
2.  CHAMPION Trials With Cangrelor Stopped for Lack of Efficacy
3. What Cangrelor Failure Means to Medicines
4.  Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events (2013) Bhatt, DL etal. New England Journal of Medicine March 10, 2013 DOI: 10.1056/NEJMoa1300815 (published initially online).
5. The Duel between Dual Antiplatelet Therapies (2013) Lange, RA and Hillis, LD. New England Journal of Medicine March 10, 2013 DOI: 10.1056/NEJMe1302504
6. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh)1998,:Abst P.281
7.  Specific P2Y12 purinoceptor antagonist; inhibits ADP-induced platelet aggregation. Prepn: A. H. Ingall et al., WO 9418216 (1994 to Fisons); eidem, US 5721219 (1998 to Astra); and in vivo antithrombotic activity: idem et al., J. Med. Chem. 42, 213 (1999).
8. In vivo antithrombotic effects in canine arterial thrombosis: J. Huang et al., J. Pharmacol. Exp. Ther. 295, 492 (2000).
9. Mechanism of action study: A. Ishii-Watabe et al., Biochem. Pharmacol. 59, 1345 (2000).
10. Clinical safety assessment and evaluation in acute coronary syndromes: R. F. Storey et al., Thromb. Haemostasis 85, 401 (2001); in angina pectoris and non-Q-wave myocardial infarction: F. Jacobsson et al., Clin. Ther. 24, 752 (2002).
11. Clinical pharmacodynamics compared with clopidogrel: R. F. Storey et al., Platelets 13, 407 (2002).
12. Review of clinical development: S. C. Chattaraj, Curr. Opin. Invest. Drugs2, 250-255 (2001).
13. WO2013/103567 A2,
14. Journal of Medicinal Chemistry, 1999 ,  vol. 42,  2  p. 213 – 220

A REVIEW AND METHODS TO HANDLE PHOSGENE, TRIPHOSGENE SAFELY DURING DRUG SYNTHESIS

Phosgene

Phosgene is the chemical compound with the formula COCl₂. This colorless gas gained infamy as a chemical weapon during World War I. It is also a valued industrial reagent and building block in synthesis of pharmaceuticals and other organic compounds. In low concentrations, its odor resembles freshly cut hay or grass.^[3] In addition to its industrial production, small amounts occur naturally from the breakdown and the combustion oforganochlorine compounds, such as those used in refrigeration systems.^[4] The chemical was named by combining the Greek words 'phos' (meaning light) and genesis (birth); it does not mean it contains any phosphorus (cf. phosphine).

TRIPHOSGENE

Triphosgene (bis(trichloromethyl) carbonate (BTC), C₃Cl₆O₃) is a chemical compound that is used as a safer substitute for phosgene, because at room temperature it is a solid crystal, as opposed to phosgene which is a gas.Triphosgene crystals decompose above 200 °C  READ .......http://www.buss-ct.com/e/company/publications/reaction_technology/eckert_reprint_CO6_2011-hr2.pdf

This compound is commercially available. It is prepared by exhaustive free radical chlorination of dimethyl carbonate:

CH₃OCO₂CH₃ + 3 Cl₂ → CCl₃OCO₂CCl₃ + 6 HCl

Triphosgene can be easily recrystallized from boiling hexanes to yield pure white crystals.

Triphosgene is used as a reagent in organic synthesis for a variety of chemical transformations including to bond one carbonyl group to two alcohols, and to convert an amine group into isocyanate.

The toxicity of triphosgene is the same as phosgene since it decomposes to phosgene on heating and upon reaction with nucleophiles. Even trace moisture leads to formation of phosgene. Therefore this reagent can be safely handled if one takes all the precautions as for phosgene.

Structure and basic properties

Phosgene is a planar molecule as predicted by VSEPR theory. The C=O distance is 1.18 Å, the C—Cl distance is 1.74 Å and the Cl—C—Cl angle is 111.8°.^[5] It is one of the simplest acid chlorides, being formally derived from carbonic acid.

Industrially, phosgene is produced by passing purified carbon monoxide and chlorine gas through a bed of porous activated carbon, which serves as acatalyst:^[4]

CO + Cl₂ → COCl₂ (ΔH_rxn = −107.6kJ/mol)

The reaction is exothermic, therefore the reactor must be cooled. Typically, the reaction is conducted between 50 and 150 °C. Above 200 °C, phosgene reverts to carbon monoxide and chlorine, K_eq (300K) = 0.05. World production of this compound was estimated to be 2.74 million tonnes in 1989.^[4]

Because of safety issues, phosgene is often produced and consumed within the same plant, and extraordinary measures are made to contain this toxic gas. It is listed on schedule 3 of the Chemical Weapons Convention: All production sites manufacturing more than 30 tonnes per year must be declared to the OPCW.^[6] Although less dangerous than many other chemical weapons, such as sarin, phosgene is still regarded as a viablechemical warfare agent because it is so easy to manufacture when compared to the production requirements of more technically advanced chemical weapons such as the first-generation nerve agent tabun.^[7]

Upon ultraviolet (UV) radiation in the presence of oxygen, chloroform slowly converts into phosgene by a radical reaction. To suppress thisphotodegradation, chloroform is often stored in brown-tinted glass containers. Chlorinated compounds used to remove oil from metals, such as automotive brake cleaners, are converted to phosgene by the UV rays of arc welding processes.^[8]

Phosgene may also be produced during testing for leaks of older-style refrigerant gases. Chloromethanes (R12, R22 and others) were formerly leak-tested in situ by employing a small gas torch (propane, butane or propylene gas) with a sniffer tube and a copper reaction plate in the flame nozzle of the torch. If any refrigerant gas was leaking from a pipe or joint, the gas would be sucked into the flame via the sniffer tube and would cause a colour change of the gas flame to a bright greenish blue. In the process, phosgene gas would be created due to the thermal reaction. No valid statistics are available, but anecdotal reports suggest that numerous refrigeration technicians suffered the effects of phosgene poisoning due to their ignorance of the toxicity of phosgene, produced during such leak testing.^{[citation needed]} Electronic sensing of refrigerant gases phased out the use of flame testing for leaks in the 1980s. Similarly, phosgene poisoning is a consideration for people fighting fires that are occurring in the vicinity of freon refrigeration equipment, smoking in the vicinity of a freon leak, or fighting fires using halon or halotron.

The great majority of phosgene is used in the production of isocyanates, the most important being toluene diisocyanate (TDI) and methylene diphenyl diisocyanate (MDI). These two isocyanates are precursors to polyurethanes.

Synthesis of carbonates

Significant amounts are also used in the production of polycarbonates by its reaction with bisphenol A.^[4] Polycarbonates are an important class of engineering thermoplastic found, for example, in lenses in eye glasses. Diols react with phosgene to give either linear or cyclic carbonates (R = H, alkyl, aryl):

HOCR₂-X-CR₂OH + COCl₂ → 1/n [OCR₂-X-CR₂OC(O)-]_n + 2 HCl

Synthesis of isocyanates

The synthesis of isocyanates from amines illustrates the electrophilic character of this reagent and its use in introducing the equivalent of "CO²⁺":^[9]

RNH₂ + COCl₂ → RN=C=O + 2 HCl (R = alkyl, aryl)

Such reactions are conducted in the presence of a base such as pyridine that absorbs the hydrogen chloride.

Laboratory uses

In the research laboratory phosgene still finds limited use in organic synthesis. A variety of substitutes have been developed, notably trichloromethyl chloroformate ("diphosgene"), a liquid at room temperature, and bis(trichloromethyl) carbonate ("triphosgene"), a crystalline substance.^[10] Aside from the above reactions that are widely practiced industrially, phosgene is also used to produceacid chlorides and carbon dioxide from carboxylic acids:

RCO₂H + COCl₂ → RC(O)Cl + HCl + CO₂

Such acid chlorides react with amines and alcohols to give, respectively, amides and esters, which are commonly used intermediates. Thionyl chloride is more commonly and more safely employed for this application. A specific application for phosgene is the production of chloroformic esters:

ROH + COCl₂ → ROC(O)Cl + HCl

Although it is somewhat hydrophobic, phosgene reacts with water to release hydrogen chloride and carbon dioxide:

COCl₂ + H₂O → CO₂ + 2 HCl

Analogously, with ammonia, one obtains urea:

COCl₂ + 4 NH₃ → CO(NH₂)₂ + 2 NH₄Cl

Halide exchange with nitrogen trifluoride and aluminium tribromide gives COF₂ and COBr₂, respectively.^[4]

History

Phosgene was synthesized by the British chemist John Davy (1790–1868) in 1812 by exposing a mixture of carbon monoxide and chlorine to sunlight. He named it "phosgene" in reference of the use of light to promote the reaction; from Greek, phos (light) and gene (born).^[11] It gradually became important in the chemical industry as the 19th century progressed, particularly in dye manufacturing.

Further information: Use of poison gas in World War I and Second Italo-Abyssinian War

Following the extensive use of phosgene gas in combat during World War I, it was stockpiled by various countries as part of their secret chemical weapons programs.^[12][13][14]

In May 1928, eleven tons of phosgene escaped from a war surplus store in central Hamburg.^[15] 300 people were poisoned of whom 10 died.^[15]

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US Army phosgene identification poster from World War II

Phosgene was then only frequently used by the Imperial Japanese Army against the Chinese during the Second Sino-Japanese War.^[16] Gas weapons, such as phosgene, were produced by Unit 731 and authorized by specific orders given by Hirohito (Emperor Showa) himself, transmitted by the chief of staff of the army. For example, the Emperor authorized the use of toxic gas on 375 separate occasions during the battle of Wuhan from August to October 1938.^[17]

Phosgene is an insidious poison as the odor may not be noticed and symptoms may be slow to appear.^[18] The odor detection threshold for phosgene is 0.4 ppm, four times the threshold limit value. Its high toxicity arises from the action of the phosgene on the proteins in the pulmonary alveoli, the site of gas exchange: their damage disrupts the blood-air barrier, causing suffocation. It reacts with the amines of the proteins, causing crosslinking by formation of urea-like linkages, in accord with the reactions discussed above. Phosgene detection badges are worn by those at risk of exposure.^[4]

Sodium bicarbonate may be used to neutralise liquid spills of phosgene. Gaseous spills may be mitigated with ammonia.^[19]

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TRIPHOSGENE HANDLING

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Left, reaction vessel with amino acid and triphosgene dissolved in THF; middle, appearance of the reaction mixture after addition of 2,4,6-collidine; and right, appearance of the reaction mixture after microwave irradiation.

Typical glassware standard equipment for the safety phosgenation with phosgene supply from triphosgene: (A) phosgene generator (V = 1 L, T = 85 °C) loaded with 600 g of triphosgene; (B) refluxer (water cooled, T = 15 °C); (C) phosgene line (Viton hose); (D) phosgenation reactor (V = 10 L, T = 110 °C); (E) refluxer (cryostat cooled, T = −30 °C); (F) off-gas line (Viton hose) from the top of the refluxer (E); (G) cooling trap (dry ice cooled, T = −60 °C); (H) off-gas line; (I) cryostat. The assembly of the equipment is somewhat reduced to effect more clarity of the ensemble.

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Phosgene is quantitatively formed from solid triphosgene in a solvent-free and safe process without any reaction heat, catalyzed by planar N-heterocycles with deactivated imino functions.

The rate of phosgene generation is adjustable to the rate of phosgene consumption in the subsequent phosgenation reaction by thermal control, catalyst concentration, and in some cases, specific properties of selected metal phthalocyanines. A thermal runaway reaction of this process is impossible.

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Use a safer process for generating phosgene. 

Decomposition of triphosgene (1a) into carbon tetrachloride, carbon dioxide, and 1 equiv of phosgene (3)

Phosgene (COCl2) is useful in organic synthesis for chlorination, chlorocarbonylation, carbonylation, and dehydration; but its high toxicity discourages its use. Until now, the best substitute for COCl2 has been triphosgene [(CCl3O)2CO], a stable solid that has low vapor pressure. Although (CCl3O)2CO can be used in phosgenation reactions, removing the unreacted reagent from reaction mixtures is difficult because of its high boiling point. In contrast, COCl2 is easily removed by evaporating it.

(CCl3O)2CO reacts with silica gel, metal salts, or Lewis acids to generate 1 equiv of phosgene by an electrocyclic reaction. H. Eckert* and J. Auerweck at the University of Technology, Munich (Germany) report that pyridine and phthalocyanine derivatives catalyze the decomposition of (CCl3O)2CO to generate 3 equiv of COCl2.

The catalysts, phenanthridine , poly(2-vinylpyridine) , and phthalocyanines , convert liquid (CCl3O)2CO to the desired COCl2. The size and structure of the catalysts allow (CCl3O)2CO to react by the mechanism shown. The reaction was run at the 100-g scale to generate 22 L of gaseous COCl2 with an oil bath or an IR heater as the heat source. Because the catalysts are not soluble in (CCl3O)2CO, the process is considered to be heterogeneous catalysis.

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Controlled transformation of triphosgene (1) into 3 equiv of phosgene (3) catalyzed by 4

Compounds 1 and 4a−4 h are commercially available products from Sigma-Aldrich, with the following purities: 1, 98% (IR νC═O 1820 cm−1, 13C NMR δ 108.0, 140.9); 4a, 98%; 4c, n.a.; 4d, 99%;4e, 97%; 4f, 97%; 4g, 90%; 4h, 85%.

Because the reaction is controlled by temperature, turning off the heat source causes the liquid (CCl3O)2CO to crystallize and stops the reaction, making the process safe. The reaction can be used to generate COCl2 externally or to produce it in situ. According to the authors, this method fulfills the goal of “safety phosgenation on demand of consumer”.

ORGANIC PROCESS RESEARCH AND DEVELOPMENT

Heiner Eckert * and Johann Auerweck

Department of Chemistry, Technische Universitaet Muenchen, Lichtenbergstr. 4, Garching 85747, Germany

Org. Process Res. Dev., 2010, 14 (6), pp 1501–1505

DOI: 10.1021/op100239n

READ AT

http://pubs.acs.org/doi/abs/10.1021/op100239n?journalCode=oprdfk&quickLinkVolume=14&quickLinkPage=1501&volume=14

DETECTION

A FRET approach towards potential detection of phosgene is presented, which is based on a selective chemical reaction between phosgene (or triphosgene as a simulant) and donor and acceptor fluorophores.

http://pubs.rsc.org/en/content/articlelanding/2007/cc/b614725a/unauth#!divAbstract

http://www.rsc.org/suppdata/cc/b6/b614725a/b614725a.pdf

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FRET has been applied in an experimental method for the detection of phosgene. In it, phosgene or rather triphosgene as a safe substitute serves as a linker between an acceptor and a donor coumarine (forming urea groups).[3] The presence of phosgene is detected at 5x10-5M with a typical FRET emission at 464 nm.

Continous Flow

http://pubs.rsc.org/en/content/articlelanding/2011/cc/c1cc15662d/unauth#!divAbstract

http://www.rsc.org/suppdata/cc/c1/c1cc15662d/c1cc15662d.pdf

Utilizing a flow-reactor, phosgene precursor can be generated in situwith minimal excess (5%). Since the reaction is done in microliter scale,  If the amide is the desired product, immediate amidation, with various amines, will certainly decrease epimerization of the acid chloride. With optimized flow, the reaction can be completed in mere 20 seconds while suppressing generating the other isomer. the results are reproducible. Afterwards, mixture containing the product can be quenched with saturated NH4Cl (aq) in CH2Cl2. Although yield can be slightly lower compared to the batch synthesis, the selectivity is quite strong.

 EXAMPLES OF USE OF TRIPHOSGENE

Chlorination of Aliphatic Primary Alcohols via Triphosgene-Triethylamine Activation
Caitlan E. Ayala, Andres Villalpando, Alex L. Nguyen, Gregory T. McCandless and Rendy Kartika*
*Department of Chemistry, 232 Choppin Hall, Louisiana State University, Baton Rouge, Louisiana 70803, United States, Email: rkartikalsu.edu

C. E. Ayala, A. Villalpando, A. L. Nguyen, G. T. McCandless, R. Kartika, Org. Lett., 2012, 14, 3676-3679.

DOI: 10.1021/ol301520d (free Supporting Information)

Activation of primary aliphatic alcohols with triphosgene and triethylamine mixtures afforded either alkyl chloride or diethylcarbamate products, and the switch in selectivity appeared to be driven by sterics. The reaction conditions to achieve this highly useful transformation were unexceptionally mild and readily tolerated by a wide range of sensitive functionalities.

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ABACAVIR SULPHATE

VESTIPITANT

The following synthetic route was reported by Giuseppe Guercio et al from GlaxoSmithKline:

The initial chemical development synthetic route, derived from the one used by medicinal chemistry, involved several hazardous reagents, gave low yields and produced high levels of waste. Through a targeted process of research and development, application of novel techniques and extensive route scouting, a new synthetic route for GW597599 was developed. This paper reports the optimisation work of the third and last stage in the chemical synthesis of GW597599 and the development of a pilot-plant-suitable process for the manufacturing of optically pure arylpiperazine derivative 1. In particular, the process eliminated the use of triphosgene in the synthesis of an intermediate carbamoyl chloride, substantially enhancing safety, overall yield, and throughput.

source:

 Org. Process Res. Dev., 2009, 13 (6), pp 1100–1110. 

Org. Process Res. Dev., 2009, 13 (3), pp 489–493.

Org. Process Res. Dev., 2008, 12 (6), pp 1188–1194.

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TIVOZANIB

VIAGRA

EFAVIRENZ .........EP2454244A1

Enantiomerically pure hydantoins are prepared from optically pure α-amino amides utilizing triphosgene. A mechanism for the racemization observed with 1,1'-carbonyldiimidazole (CDI) for this type of reaction is proposed.
D. Zhang, X. Xing, G. D. Cuny, J. Org. Chem., 2006, 71, 1750-1753.

Double acylation of a titanaselenide by triphosgene;

4,5-ethylenedithio-1,3-diselenol-2-one

IMINOSTILBENE DERIVATIVES

N-Hydroxysuccimide esters of carboxylic acids have been widely used in organic synthesis as reactive acylating reagents. These active esters are especially useful as intermediates in the synthesis of peptides and proteins since they acylate primary amines to give the amides in high yields. We have developed a new and convenient one-pot procedure for the preparation of N-hydroxysuccinimide esters of carboxylic acids using N-hydroxysuccinimide and triphosgene as an acid activator. A variety of carboxylic acids can be easily and rapidly converted to the corresponding N-hydroxysuccinimido esters at room temperature. The results of this transformation will be presented.

References

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9. The weighing error of this procedure mainly comes from icy condensed humidity at the cool glassware of the cooling trap and is less than 0.5 g, determined by a series of weighings under the same conditions, the same equipment, temperature (T = −78 °C), and handling time <10 s, but without 3. Under these conditions evaporation of 3 (bp 8 °C) hardly ever happens and can be ignored. 
10. Monitox plus gas monitor (COCl2) and phosgene badges from Compurhttp://www.compur.com/gasmessgeraete/front_content.php?idcat=7&changelang=3.

    • Davy's account of his discovery of phosgene
    • International Chemical Safety Card 0007
    • CDC - Phosgene - NIOSH Workplace Safety and Health Topic
    • NIOSH Pocket Guide to Chemical Hazards
    • U.S. CDC Emergency Preparedness & Response
    • U.S. EPA Acute Exposure Guideline Levels
    • Regime For Schedule 3 Chemicals And Facilities Related To Such Chemicals, OPCW website
    • CBWInfo website
    • Use of Phosgene in WWII and in modern-day warfare (Refer to Section 4.C of the article)
    • An experience with accidental poisoning by heated tetrachlorethylene solvent