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Process For Preparing Darifenacin Hydrobromide

Abstract: The present invention provides novel compound and preparation of this compound. The present invention also provides process for the preparation of Darifenacin hydrobromide or a pharmaceutically acceptable salt or solvate thereof using this novel compound.

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Patent Information

Application #
Filing Date
13 December 2007
Publication Number
29/2010
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

GLENMARK PHARMACEUTICALS LIMITED
GLENMARK HOUSE, HDO-CORPORATE BLDG, WING-A, B.D.SAWANT MARG, CHAKALA, ANDHERI (E), MUMBAI

Inventors

1. K. NAGAN NIRMALAN
GLENMARK PHARMACEUTICLS LIMITED PLOT NO. A-607, T.T.C. INDUSTRIAL AREA, MIDC, MAHAPE, NAVI MUMBAI 400709
2. SACHIN MAHADEO LAD.
GLENMARK PHARMACEUTICLS LIMITED PLOT NO. A-607, T.T.C. INDUSTRIAL AREA, MIDC, MAHAPE, NAVI MUMBAI 400709

Specification

FORM 2 THE PATENTS ACT 1970 (Act 39 of 1970) & THE PATENTS RULE 2003 (SECTION 10 and rule 13) PROVISIONAL SPECIFICATION PROCESS FOR PREPARING DARIFENACIN HYDROBROMIDE" Glenmark Pharmaceuticals Limited an Indian Company, registered under the Indian company's Act 1957 and having its registered office at Glenmark House, HDO - Corporate Bldg, Wing -A, B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099 THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION Process for preparing Darifenacin hydrobromide Field of Invention The invention relates to process for the preparation of Darifenacin, (S)-2-{l-[2-(2, 3-dihydrobenzofuran-5-yl) ethyl]-3-pyrrolidinyl}-2, 2-diphenylacetamide, and pharmaceutically acceptable salts thereof, Darifenacin The present invention also relates to novel intermediate, 3-(l-cyano-l, 1-diphenylmethyl)-tertiarybutoxycarbonyl pyrrolidine of formula IIIa, an individual isomer or racemic mixture thereof. Background of the invention. Darifenacin is administered for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency. Darifenacin is available in the market under the trade name of ENABLEX® and is available as the hydrobromide salt, (S)-2-{ 1-[2-(2, 3-dihydrobenzofuran-5-yl) ethyl]-3-pyrrolidinyl}-2, 2-diphenylacetamide hydrobromide of the formula, Darifenacin was first disclosed in U.S.5,096,890.This patent discloses three routes for the synthesis of darifenacin hydrobromide. All three routes proceed via Mitsunobu reaction, as described below; TOS" -N, TsOMe,Ph,P UH —^ I ^ DEAD.THF N, OH / Tos T^OTs H Accordingly, l-tosyl-3-(R)-pyrrolidinol is reacted with methyl tosylate, and with diethylazodicarboxylate (DEAD), a very dangerous reagent. In such reactions triphenylphophine oxide contamination is unavoidable. US2003/0191176 discloses preparation of darifenacin hydrobromide using BF3, yet another toxic and hazardous reagent. US20070203221 discloses preparation using N-protected-3-(S)-pyrrolidinol of formula, R^X / N H OH wherein X is S, SO2, Si, or CO and R is phenyl,tolyl,ortho,meta, or para-xylyl,linear or branched C1-10 alkyl, H, or CF3. Use of such an intermediate involves undesired byproducts.Cleaved sulfonyl groups react with the phenyl rings of the desired intermediate and result in unwanted byproducts. Hence it was felt necessary to come up with routes which are commercially viable and provide good yields and purity. Summary of the invention. In one embodiment, the invention encompasses N-protected-3 -pyrrolidine of the formula IIIa and optically active isomers thereof, In another embodiment, the invention encompasses a process for preparing darifenacin hydrobromide comprising converting the N- protected-3-(S)-pyrrolidine into darifenacin hydrobromide. In another embodiment invention encompasses a process for preparing a compound of formula IIIa resolving it into a compound of formula III and converting into darifenacin hydrobromide. In another embodiment, the invention encompasses a process for preparing darifenacin hydrobromide comprising: a) combining (S)-3-Hydroxy pyrrolidine, Boc anhydride in presence of an organic solvent and a base to obtain N-tert-butoxycarbonyl-(S)-(+)-3-pyrrolidinol of formula I, y i b) combining the boc protected intermediate, a solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, polar aprotic organic solvent, and mixtures thereof, a sulfonyl halide, and a base to obtain corresponding N-tert-Butoxycarbonyl-(S)-3-X- sulfonyloxypyrrolidine of formula II, o-so,-x y II c) reacting the N-tert-butoxycarbonyl-3-X- sulfonyloxypyrrolidine with diphenylacetonitrile and a base in an organic solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof to obtain 3-S-(+)-(l-cyano-l, 1-diphenylmethyl) tert-butoxycarbonyl) pyrrolidine of formula III, III d) reacting the S-(+)-(l-cyano-l, 1-diphenylmethyl) tert-butoxycarbonyl) pyrrolidine with an acid and combining the resultant product with a Cm alcohol and an optically active acid to obtain 3- (S)-(+)-(l-carbamoyl-1, 1-diphenylmethyl)pyrrolidine salt of formula IV, e) optionally converting the compound of formula IV to a compound of formula V, CONH2 V f) reacting the 3-(S)-(+)-(l-carbamoyl-1,1-diphenylmethyl) pyrrolidine with a compound of the formula VI, ^^ VI and a base in a solvent selected from the group consisting of C6-9 aromatic hydrocarbon, a polar organic solvent, water, and mixtures thereof; and g) admixing HBr with the resultant product in the presence of a water miscible solvent to obtain darifenacin hydrobromide, wherein X is selected from the group consisting of C1-10 alkyl, C6-9 aryl, and Y is a leaving group selected from the group consisting of, mesyloxy, Br, I,C1 tosyloxy, trifluoroacetyloxy, and trifluoromethane- sulfonyloxy. The optically active acid for resolution may be selected from L-(+)-Tartaric acid, Dibenzoyl-D-tartaric acid or its mono hydrate, Di-p-toluoy-D-tartaric acid or its mono hydrate, D-(+)-Tartaric acid-O-O- ditoluoylester, Di-benzoyl-D-tartaric acid anhydride. In another embodiment, the invention encompasses a process for preparing N-tert-butoxycarbonyl-(S)-(+)-3-pyrrolidinol, a compound of formula I, V3H c / I comprising combining 3-(S)-hydroxy pyrrolidine with Boc anhydride in the presence of a solvent or mixtures thereof, and a base. In another embodiment, the invention encompasses a process for preparing Darifenacin hydrobromide comprising, preparing N-tert-butoxycarbonyl-(S)-(+)-3-pyrrolidinol and converting N-tert-butoxycarbonyl-(S)-(+)-3-pyrrolidinol into Darifenacin hydrobromide. In another embodiment, the invention encompasses a process for preparing N-tert-Butoxycarbonyl-(S)-3-X-sulfonyloxypyrrolidine, compound of formula II, >0-SO„-X c ,ss

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