Sustainable flow Oppenauer oxidation of secondary benzylic alcohols with a heterogeneous zirconia catalyst

Sustainable flow Oppenauer oxidation of secondary benzylic alcohols with a heterogeneous zirconia catalyst 

Rajeev Chorghade †, Claudio Battilocchio †, Joel M. Hawkins ‡, and Steven V. Ley *†

Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, U.K., and Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States

Org. Lett., 2013, 15 (22), pp 5698–5701

DOI: 10.1021/ol4027107

http://pubs.acs.org/doi/abs/10.1021/ol4027107

A flow chemistry process for the Oppenauer oxidation of benzylic secondary alcohols using partially hydrated zirconium oxide and a simple carbonyl containing oxidant such as acetone, cyclohexanone, and neopentanal is reported. The heterogeneous oxidative system could be applied to a wide range of functionalized alcohol substrates, allowing clean and fast delivery of ketone products within a few minutes between 40 and 100 °C.

Amiodarone

Amiodarone

CAS : 1951-25-3

 (2-Butyl-3-benzofuranyl)[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone

2-butyl-3-benzofuranyl-4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl ketone; 2-butyl-3-[3,5-diiodo-4-(b-diethylaminoethoxy)benzoyl]benzofuran

Molecular Formula: C25H29I2NO3

Molecular Weight: 645.31

Percent Composition: C 46.53%, H 4.53%, I 39.33%, N 2.17%, O 7.44%

In December 1985, amiodarone was approved by the FDA for the treatment of arrhythmias.[6] This makes amiodarone one of the few drugs approved by the FDA without rigorous randomized clinical trials.

Amiodarone is an antiarrhythmic agent used for various types of cardiac dysrhythmias, both ventricular and atrial. It was discovered in 1961. Despite relatively common side-effects, it is used in arrhythmias that are otherwise difficult to treat with medication.

A more recent synthesis of amiodarone reports the cyclisation of α-phenoxyhexanal 389 under acidic conditions to yield the substituted benzofuran390 (Scheme 76). A Friedel–Crafts acylation next introduces the aryl ring at the 3-position. Demethylation, iodination and a final alkylation with a diethylaminoethane fragment yields amiodarone [115-117].

1. 115   Witczak, M.; Kwiecień, H. Synth. Commun. 2005, 35, 2223–2230.doi:10.1080/00397910500182747
   Return to citation in text: [1]
2. Wang, Z. J. Synthetic Process for 2-Butyl-3-(hydroxy-3,5-diiodobenzoyl)-benzofuran. Chin. Patent 1,858,042, Nov 8, 2006……….116
   Return to citation in text: [1]
3. Ha, H. R.; Stieger, B.; Grassi, G.; Altorfer, H. R.; Follath, F.Eur. J. Clin. Pharmacol. 2000, 55, 807–814.doi:10.1007/s002280050701….117

Scheme 76: Synthesis of amiodarone……….http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-7-57#S76

Literature References:

Benzofuran derivative with multiple electrophysiological effects. Prepn: FR1339389; R. Tondeur, F. Binon,US 3248401 (1963, 1966 to Soc. Belge l’Azote Prod. Chim. Marly).

Physicochemical properties: M. Bonati et al., J. Pharm. Sci. 73,829 (1984).

HPLC determn in plasma: M. De Smet, D. L. Massart, J. Pharm. Biomed. Anal.6, 277 (1988).

Comprehensive description: T. A. Plomp, Anal. Profiles Drug Subs. 20, 1-120 (1991).

Review of pharmacology, clinical efficacy and safety: M. Chow, Ann. Pharmacother. 30, 637-643 (1996); B. N. Singh, Clin. Cardiol. 20, 608-618 (1997).

Clinical trial in cardiac resuscitation: P. J. Kudenchuk et al., N. Engl. J. Med.341, 871 (1999); to prevent atrial fibrillation: D. Roy et al., ibid. 342, 913 (2000).

External links

• Siddoway LA (December 2003). “Amiodarone: guidelines for use and monitoring”. Am Fam Physician 68 (11): 2189–96. PMID 14677664.
• Amiodarone (MedicineNet.com)
• Amiodarone (FamilyPracticeNotebook.com)
• Amiodarone (The WorldWide Intensivist)
• U.S. National Library of Medicine: Drug Information Portal – Amiodarone
• Amiodarone (FDA MedWatch)

SYSTEMATIC (IUPAC) NAME
(2-{4-[(2-butyl-1-benzofuran-3-yl)carbonyl]-2,6-diiodophenoxy}ethyl)diethylamine
CLINICAL DATA
TRADE NAMES	Cordarone, Nexterone
AHFS/DRUGS.COM	monograph
MEDLINEPLUS	a687009
PREGNANCY CAT.	US: D
LEGAL STATUS	℞ Prescription only
ROUTES	oral or intravenous
PHARMACOKINETIC DATA
BIOAVAILABILITY	20–55%
METABOLISM	Liver
HALF-LIFE	58 days (range 15-142 days)
EXCRETION	Primarily Hepatic and Biliary
IDENTIFIERS
CAS NUMBER	1951-25-3
ATC CODE	C01BD01
PUBCHEM	CID 2157
IUPHAR LIGAND	2566
DRUGBANK	DB01118
CHEMSPIDER	2072
UNII	N3RQ532IUT
KEGG	D02910
CHEBI	CHEBI:2663
CHEMBL	CHEMBL633
CHEMICAL DATA
FORMULA	C25H29I2NO3
MOL. MASS	645,31 g/mol

Derivative Type: Hydrochloride

CAS Registry Number: 19774-82-4

Manufacturers’ Codes: L-3428

Trademarks: Amiodar (Sanofi Winthrop); Ancaron (Taisho); Cordarex (Sanofi Winthrop); Cordarone (Wyeth); Ortacrone (Sanofi Winthrop); Pacerone (Upsher-Smith); Tachydaron (AWD); Trangorex (Sanofi Winthrop)

Molecular Formula: C25H29I2NO3.HCl

Molecular Weight: 681.77

Percent Composition: C 44.04%, H 4.44%, I 37.23%, N 2.05%, O 7.04%, Cl 5.20%

Properties: Crystalline powder, mp 156°. Also reported as crystals from acetone, mp 159 ±2° (Bonati). Soly at 25° (g/100ml): chloroform 44.51; methylene chloride 19.20; methanol 9.98; ethanol 1.28; benzene 0.65; tetrahydrofuran 0.60; acetonitrile 0.32; 1-octanol 0.30; ether 0.17; 1-propanol 0.13; water 0.07; hexane 0.03 petroleum ether 0.001. Sparingly sol in isopropanol; slightly sol in acetone, dioxane, and carbon tetrachloride. pH (5% soln) 3.4-3.9. pKa (25°C) 6.56 ±0.06. uv max (methanol): 208, 242 nm (E1%1cm 662 ±8, 623 ±10).

Melting point: mp 156°; mp 159 ±2° (Bonati)

pKa: pKa (25°C) 6.56 ±0.06

Absorption maximum: uv max (methanol): 208, 242 nm (E1%1cm 662 ±8, 623 ±10)

Therap-Cat: Antiarrhythmic (class III).

Keywords: Antiarrhythmic.

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