Process for the preparation of an anticonvulsant agent pregabalin hydrochloride

Patent metadata

Field	Value
Publication number	US-9422230-B2
Application number	US-201414890012-A
Country	US
Kind code	B2
Filing date	May 9, 2014
Priority date	May 9, 2013
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

An efficient synthesis of the anticonvulsant drug, Pregabalin hydrochloride is described using simple transformations in high enantiopurity (>99% ee) and overall yield of 44 to 50%.

First claim

We claim:

1. A process for the synthesis of Pregabalin hydrochloride formula S-1

comprising the steps of:
a. subjecting an epoxide of formula (S)-2 to regioselective ring opening with isopropyl magnesium chloride in presence of copper iodide (CuI) to afford a secondary alcohol of formula (R)-3;

b. subjecting the secondary alcohol of formula (R)-3 as obtained in step (a) to its corresponding mesylate using methanesulfonyl chloride and triethyl amine (TEA) in dichloromethane(DCM) at temperature in the range of 0 to 10° C. followed by displacement using trimethylsilyl cyanide (TMSCN) in presence of tetrabutylammonium fluoride (TBAF) in acetonitrile to obtain a cyano derivative of formula (S)-4;

c. subjecting the cyano derivative of formula (S)-4 of step (b) to hydrogenation and concomitant Boc-protection using (Boc) 2 O and Raney-Ni as a catalyst to furnish a amino alcohol of formula (S)-5;

d. oxidizing the amino alcohol of formula (S)-5 of step (c) using sodium chlorite catalyzed by 2,2,6,6-Tetramethyl-1-piperidinyloxy (TEMPO) and bleach at temperature in the range of at 30 to 40° C. to afford a compound of formula (S)-6;

e. subjecting the compound of formula (S)-6 of step (d) for Boc-deprotection using hydrochloride (HCl) and acetone at temperature in the range of 55 to 65° C. to afford Pregabalin hydrochloride of formula (S)-1.

2. The process according to claim 1 , wherein Pregabalin hydrochloride of formula (S)-1 is prepared with yield in the range of 44 to 50%.

3. The process according to claim 1 , wherein the compound of formula (S)-6 is converted to compound of formula (S)-7 for enantiomeric excess (ee) determination of Pregabalin hydrochloride using isobutyl chloroformate and benzylamine

4. The process according to claim 1 , wherein (S)-7 exhibits >99% enantiomeric excess (ee).

Assignees

• Council Scient Ind Res

Inventors

• Murugan Muthukrishnan
• Mohammad Mujahid

Classifications

• C07C227/18 Primary

  by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters · CPC title

• C07C253/30

  by reactions not involving the formation of cyano groups · CPC title

• C07C41/02

  from oxiranes · CPC title

• C07C213/02

  by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups · CPC title