AN EFFICIENT METHOD FOR RACEMIZATION OF PREGABALIN INTERMEDIATE
INTRODUCTION

Aspects of the present application relates to an efficient method for racemization of pregabalin intermediate such as 3-(carbamoylmethyl)-5-methylhexanoic acid. Further, the present application relates to the process for the preparation of pregabalin. Pregabalin is a GABA analogue and it's chemically known as (S)-(3)-(amino methyl)-5-methyl hexanoic acid having the following structural Formula I
Pregabalin is also known as (S)-3-isobutyl y-amino butyric acid or (S)-isobutyl GABA. (S)-pregabalin has been found to activate GAD (L-glutamic acid decarboxylase). Pregabalin is an anticonvulsant agent, anxiolytic like and analgesic action and is currently approved for neuropathic pain associated with diabetic peripheral neuropathy, post herpetic neuralgia, as a adjunctive therapy for adult patients with partial onset seizures and for fibromyalgia. (S)-pregabalin is commercially available under the brand name Lyrica in the United States of America.

There are various methods reported in the literature for the racemization of pregabalin intermediate such as 3-(carbamoylmethyl)-5-methylhexanoic acid. Several synthesis of pregabalin reported in the literature.
Organic process Research and Development, 2008, 12, 392-398 discloses a racemization process, i.e. commercially available lipase was employed to resolve racemic 2-carboxyethyl-3-cyano-5-methylhexanoic acid ethyl ester to give (S)-2-carboxyethyl-3-cyano-5-methyl hexanoic acid, followed by decarboxylation and reduction to provide pregabalin. Recycling of unwanted R-enantiomer by reacting it with sodium ethoxide in ethanol in the presence of toluene. The reaction is carried by heating the mixture at 80°C for 8-16 hours, using sodium ethoxide in ethanol results in only partial racemization yielding only 5-10% racemized product in 16 hours.

Organic process Research and Development, 2009, 13, 812-814 discloses a racemization process, i.e. recycling of unwanted S-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid by reacting with piperdine in the presence of toluene to give a cyclic imide, followed by hydrolysis by using a base to give racemic 3-(carbamoylmethyl)-5-methylhexanoic acid.

It is clearly evident that the racemization processes reported in prior art are far from satisfactory as it require number of steps, hazardous reagents and high cost.

There remains a need to provide improved process for the racemization of (S)-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid that are cost-effective and environment friendly.

SUMMARY

In as aspect, the present application provides a simple, cost effective method for synthesis of pregabalin, the present inventors have found that pregabalin could be synthesized from resolution of 3-(carbamoylmethyl)-5-methylhexanoic acid and the undesired S-isomer of 3-(carbamoylmethyl)-5-methyl hexanoic acid could be racemized with a reagent and the resulting racemized product, then resolved to increase the overall yield of for preparation of pregabalin of Formula I.

Typically, pregabalin is synthesized by reacting racemic 3-(carbamoylmethyl) -5- methyl hexanoic acid with (R) -(+)-phenyl ethylamine to obtain R) -(+)-phenyl ethylamine salt of (R)-(-) 3-(carbamoylmethyl)-5-methyl hexanoic acid; and combining the salt with an acid to obtain (R)-isomer of 3-(carbamoylmethyl)-5-methyl hexanoic acid, followed by treatment with Hoffmann reagent (sodium hydroxide and bromine) to obtain (S)-(+)- 3-(carbamoylmethyl)-5-methyl hexanoic acid.

In an aspect, the present application provides a simple method for racemization of (S)-isomer of 3-(carbamoylmethyl)-5-methyl hexanoic acid in reaction mixture is reacted with a reagent to provide a racemic 3-(carbamoylmethyl)-5-methyl hexanoic acid. The said racemic mixture of 3-(carbamoylmethyl)-5-methyl hexanoic acid, then again can be converted to pregabalin by following the above mentioned procedure.

Thus, in one aspect the present invention provides a simple, cost effective process for synthesis of pregabalin.

In another aspect, the present invention provides a cost effective process for racemization of S-3-(carbamoylmethyl)-5-methyl hexanoic acid.

DETAILED DESCRIPTION

The present application provides a simple, economical process for the preparation of pregabalin.

Pregabalin is synthesized by aminolysis of 3-isobutylglutaric anhydride obtained from 3-isobutylglutraric acid, followed by resolution of amide intermediate with (R)-(+)-1-phenylethylamine in chloroform, further converted into pregabalin by using Hoffmann reagent (sodium hydroxide and bromine).

In the above procedure, the R-enantiomer of 3-(carbamoylmethyl)-5-methylhexanoic acid is converted in to pregabalin by using Hoffmann reagent (sodium hydroxide and bromine). But undesired S-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid in the mother liquor. The present inventors were observed that, the mother liquor, after separation of R-enantiomer as a phenylethylaminie salt, approximately contains 15-20% of R-enantiomer and about 80-85% of S-enantiomer of 3-(carbamoylmethyl)-5-methylhexanoic acid.

In an aspect, the present invention provides a method for racemization of S-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid, remaining in the mother liquor. Racemization is carried out by converting the S-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid into a symmetrical cyclic imide, followed by hydrolyzing to afford a racemic compound.

Preferably, S-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid is converted to a symmetrical cyclic imide and then hydrolyzed in situ with an alkali to produce racemic 3-(carbamoylmethyl)-5-methylhexanoic acid.

In Scheme-1 suitable reagent that may be used in step a) include, but are not limited to: acid chlorides, such as for example cyanuric chloride, phosphorous pentachloride, phosphorous oxychloride, or the like; organic acids, such as for example ortho phosphoric acid, acetic acid, succinic acid, or the like;

phosphorous oxides, such as for example phosphorous pentaoxide, or the like; aryl substituted boronic acid, such as for example phenyl boronic acid, or the like.

Step (a) may be carried out in one or more suitable solvents. Suitable solvents that may be used in step a) include, but are not limited to, water; aromatic hydrocarbon solvents such as for example benzene, toluene, ethyl benzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-Ci0aromatic hydrocarbons, or mixtures thereof; ketone solvents; halogenated solvents; ether solvents; aromatic hydrocarbon solvents; ester solvents; nitrile solvents; or mixtures thereof; aliphatic or alicyclic hydrocarbon solvents such as for example n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, C5-C8aliphatic hydrocarbons, petroleum ethers, or mixtures thereof. Ether solvents such as for example, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6ethers, or the like; ester solvent such as for example, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, C3.6esters, or the like.

Suitable temperatures for the reaction of step (a) may be less than about 200°C, less than about 150°C, less than about 120°C, less than about 100°C, less than about 80°C, less than about 40°C, less than about 30°C or any other suitable temperatures.

Preferably, (S)-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid is containing less than about 25% of R-enantiomer, less than about 15% of R-enantiomer, less than about 5% of R-enantiomer or substantially free of R-enantiomer.

Racemization of (S)-3-(carbamoylmethyl)-5-methylhexanoic acid involves reacting (S)- 3-(carbamoylmethyl)-5-methylhexanoic acid with a reagent, such as cyanuric chloride or ortho phosphoric acid or phosphorous pentaoxide or phenyl boronic acid, in the presence of solvent, such as toluene, under reflux for 8-12 hours to give a cyclic imide compound, which upon hydrolysis with aqueous solution of an alkali and then on acidifying with an acid gives racemic 3-(carbamoylmethyl)-5-methylhexanoic acid.

The obtained racemic compound can be further converted in to pregabalin. Preferably, the reaction of racemization is carried out in one pot.

In Scheme-1 suitable base that may be used in step b) include, but are not limited to: alkali metal hydroxides, such as for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, or cesium hydroxide; alkaline metal hydroxides, such as, for example, barium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; or mixtures thereof; or any other suitable reagents.

The cyclic imide compound was then hydrolyzed. Typically hydrolysis is carried out in presence of aqueous solution of strong base such as sodium hydroxide by heating the solution at 60°C for about an hour. This was followed by acidification of the reaction mixture to give racemic 3-(carbamoylmethyl)-5-methylhexanoic acid.

Thus, the present invention provides a method for the preparation of pregabalin, comprising the steps of:
a) reacting racemic 3-(carbamoylmethyl)-5-methylhexanoic acid with R-(+)-

phenyl ethylamine to obtain (R)-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid;

b) reacting (R)-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid with

Hoffmann reagent (sodium hydroxide and bromine) to form pregabalin; and

c) recovering the solvent and racemization of the other isomer (S)-isomer of 3- (carbamoylmethyl)-5-methylhexanoic acid obtained in step a) is reacting with a suitable reagent to provide a racemic 3-(carbamoylmethyl)-5-methylhexanoic acid.

The term "mother liquors" refers the filtrate obtained after the isolation of required compound, after the completion of the required reaction.

The terms "about," "generally," "substantially,", and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art.

This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.

EXAMPLES
EXAMPLE 1: Racemization process of (S)-3-(Carbamoylmethyl)-5-methylhexanoic acid.
(S)-3-(Carbamoylmethyl)-5-methylhexanoic acid (50 g; containing 20 % R-enantiomer), toluene (250 mL) are charged in to a clean round bottom flask at 25°C and stirred for 5-10 minutes. Ortho phosphoric acid (2.61 g) is added to the reaction mixture at 25°C. The resultant reaction mixture is heated its reflux temperature (110°C) and maintained for 12 hours. The reaction mixture is cooled to 60°C. 10% aqueous NaOH solution (125 mL) is added to the reaction mixture at 60°C and maintained for 60 minutes. The reaction mixture is cooled to 25°C. The organic layer is separated; the pH of the aqueous layer is adjusted to 1.5 to 2.0 by the addition of Con. Hydrochloric acid (15 mL) at 25°C and stirred for 10 minutes. The reaction mass is cooled to 0-5°C and maintained for 60 minutes. The obtained solid is filtered, washed with water (50 mL) and dried at 45-50°C for 12 hours to afford 45.0 g of the 3-(Carbamoylmethyl)-5-methylhexanoic acid. Chiral HPLC: R- isomer: 49.49%; S-isomer: 50.51%

EXAMPLE 2: Racemization process of (S)-3-(Carbamoylmethyl)-5-methylhexanoic acid.

(S)-3-(Carbamoylmethyl)-5-methylhexanoic acid (100 g; containing 20 % R-enantiomer), toluene (500 ml_) are charged in to a clean round bottom flask at 25°C and stirred for 5-10 minutes. P205 (7.58 g) is added to the reaction mixture at 25°C. The resultant reaction mixture is heated its reflux temperature (110°C) and maintained for 4 hours. The reaction mixture is cooled to 60°C. Water (200 mL) is added to the reaction mixture at 60°C and two layers are separated.

The organic layer is charged in to another round bottom flask at 60°C. 10% aqueous NaOH solution (250 mL) is added to the organic layer at 60°C and maintained for 60 minutes. The reaction mixture is cooled to 25°C. The organic layer is separated; the pH of the aqueous layer is adjusted to 1.5 to 2.0 by the addition of Con. Hydrochloric acid (32 mL) at 25°C and stirred for 10 minutes. The reaction mass is cooled to 0-5°C and maintained for 60 minutes. The obtained solid is filtered, washed with water (100 mL) and dried at 45-50°C for 16 hours to afford 60.0 g of the 3-(Carbamoylmethyl)-5-methylhexanoic acid. Chiral HPLC: R- isomer: 49.81%; S-isomer: 50.19%

EXAMPLE 3: Racemization process of (S)-3-(Carbamoylmethyl)-5-methylhexanoic acid.
(S)-3-(Carbamoylmethyl)-5-methylhexanoic acid (10 g; containing 20 % R-enantiomer), toluene (50 mL) are charged in to a clean round bottom flask at 25°C and stirred for 5-10 minutes. Phenyl boronic acid (646 mg) is added to the reaction mixture at 25°C. The resultant reaction mixture is heated its reflux temperature (110°C) and maintained for 12 hours. The reaction mixture is cooled to 60°C. 10% aqueous NaOH solution (25 mL) is added to the reaction mixture at 60°C and maintained for 60 minutes. The reaction mixture is cooled to 25°C. The organic layer is separated; the pH of the aqueous layer is adjusted to 1.5 to 2.0 by the addition of Con. Hydrochloric acid (4.9 mL) at 25°C and stirred for 10 minutes. The reaction mass is cooled to 0-5°C and maintained for 60 minutes. The obtained solid is filtered, washed with water (5 mL) and dried at 45-50°C for 12 hours to afford 7.0 g of the 3-(Carbamoylmethyl)-5-methylhexanoic acid. Chiral HPLC: R- isomer: 49.65%; S-isomer: 50.35%

EXAMPLE 4: Racemization process of (S)-3-(Carbamoylmethyl)-5-methylhexanoic acid.
(S)-3-(Carbamoylmethyl)-5-methylhexanoic acid (100 g; containing 20 % R-enantiomer), toluene (500 mL) are charged in to a clean round bottom flask at 25°C and stirred for 5-10 minutes. Cyanuric chloride (9.8 g) is added to the reaction mixture at 25°C. The resultant reaction mixture is heated its reflux temperature (110°C) and maintained for 12 hours. The reaction mixture is cooled to 60°C. 10% aqueous NaOH solution (250 mL) is added to the reaction mixture at 60°C and maintained for 60 minutes. The reaction mixture is cooled to 25°C. The organic layer is separated; the pH of the aqueous layer is adjusted to 1.0 to 2.0 by the addition of Con. Hydrochloric acid (4.9 mL) at 25°C and stirred for 10 minutes. The reaction mass is cooled to 0-5°C and maintained for 60 minutes. The obtained solid is filtered, washed with water (50 mL) and dried at 45-50°C for 12 hours to afford 65.0 g of the 3-(Carbamoylmethyl)-5-methylhexanoic acid. Chiral HPLC: R- isomer: 50.20%; S-isomer: 49.8%

EXAMPLE 5: Racemization process of (S)-3-(Carbamoylmethyl)-5-methylhexanoic acid.
(S)-3-(Carbamoylmethyl)-5-methylhexanoic acid (20 g), toluene (100 mL) are charged in to a clean round bottom flask at 25°C and stirred for 5-10 minutes. Ortho phosphoric acid (1.04 g) is added to the reaction mixture at 25°C. The resultant reaction mixture is heated its reflux temperature (110°C) and maintained for 12 hours. The reaction mixture is cooled to 60°C. 10% aqueous NaOH solution (50 mL) is added to the reaction mixture at 60°C and maintained for 60 minutes. The reaction mixture is cooled to 25°C. The organic layer is separated; the pH of the aqueous layer is adjusted to 1.4 to 2.0 by the addition of Con. Hydrochloric acid (3.9 mL) at 25°C and stirred for 10 minutes. The reaction mass is cooled to 0-5°C and maintained for 60 minutes. The obtained solid is filtered, washed with water (20 mL) and dried at 45-50°C for 12 hours to afford 17.0 g of the 3-(Carbamoylmethyl)-5-methylhexanoic acid. Chiral HPLC: R- isomer: 49.96%; S-isomer: 50.04%

EXAMPLE 6: Racemization process of (S)-3-(Carbamoylmethyl)-5-methylhexanoic acid.
(S)-3-(Carbamoylmethyl)-5-methylhexanoic acid (20 g), toluene (100 ml_) are charged in to a clean round bottom flask at 25°C and stirred for 5-10 minutes. Phenyl boronic acid (1.29 g) is added to the reaction mixture at 25°C. The resultant reaction mixture is heated its reflux temperature (110°C) and maintained for 12 hours. The reaction mixture is cooled to 60°C. 10% aqueous NaOH solution (50 ml_) is added to the reaction mixture at 60°C and maintained for 60 minutes. The reaction mixture is cooled to 25°C. The organic layer is separated; the pH of the aqueous layer is adjusted to 1.6 to 2.0 by the addition of Con. Hydrochloric acid (4.0 ml_) at 25°C and stirred for 10 minutes. The reaction mass is cooled to 0-5°C and maintained for 60 minutes. The obtained solid is filtered, washed with water (20 ml_) and dried at 45-50°C for 12 hours to afford 14.0 g of the 3-(Carbamoylmethyl)-5-methylhexanoic acid. Chiral HPLC: R- isomer: 49.88%; S-isomer: 50.12%

EXAMPLE 7: Racemization process of (S)-3-(Carbamoylmethyl)-5-methylhexanoic acid.
(S)-3-(Carbamoylmethyl)-5-methylhexanoic acid (20 g), toluene (100 mL) are charged in to a clean round bottom flask at 25°C and stirred for 5-10 minutes. Cyanuric chloride (1.96 g) is added to the reaction mixture at 25°C. The resultant reaction mixture is heated its reflux temperature (110°C) and maintained for 12 hours. The reaction mixture is cooled to 60°C. 10% aqueous NaOH solution (50 mL) is added to the reaction mixture at 60°C and maintained for 60 minutes. The reaction mixture is cooled to 25°C. The organic layer is separated; the pH of the aqueous layer is adjusted to 1.2 to 2.0 by the addition of Con. Hydrochloric acid (3.9 mL) at 25°C and stirred for 10 minutes. The reaction mass is cooled to 0-5°C and maintained for 60 minutes. The obtained solid is filtered, washed with water (20 mL) and dried at 45-50°C for 12 hours to afford 13.7 g of the 3-(Carbamoylmethyl)-5-methylhexanoicacid. Chiral HPLC: R- isomer: 49.97%; S-isomer: 50.03%

EXAMPLE 8: Racemization process of (S)-3-(Carbamoylmethyl)-5-methylhexanoic acid.
(S)-3-(Carbamoylmethyl)-5-methylhexanoic acid (20 g), toluene (100 mL) are charged in to a clean round bottom flask at 25°C and stirred for 5-10 minutes. P2O5 (1.50 g) is added to the reaction mixture at 25°C.

The resultant reaction mixture is heated its reflux temperature (110°C) and maintained for 12 hours. The reaction mixture is cooled to 60°C. Water (50 mL) is added to the reaction mixture at 60°C and two layers are separated.

The organic layer is charged in to another round bottom flask at 60°C. 10% aqueous NaOH solution (50 mL) is added to the organic layer at 60°C and maintained for 60 minutes. The reaction mixture is cooled to 25°C. The organic layer is separated; the pH of the aqueous layer is adjusted to 1.1 to 2.0 by the addition of Con. Hydrochloric acid (4.1 mL) at 25°C and stirred for 10 minutes. The reaction mass is cooled to 0-5°C and maintained for 60 minutes. The obtained solid is filtered, washed with water (100 mL) and dried at 45-50°C for 16 hours to afford 14.2 g of the 3-(Carbamoylmethyl)-5-methylhexanoic acid. Chiral HPLC: R- isomer: 49.93%; S-isomer: 50.07%

EXAMPLE 9: Preparation of (3R)-3-(carbamoylmethyl)-5-methylhexanoic acid phenyl ethylamine salt.
3-(carbamoylmethyl)-5-methylhexanoic acid (100 g) and a mixture of chloroform (1400 mL), ethanol (23.8 mL) are charged in to the round bottom flask at 25°C and stirred for 10 minutes. The reaction mixture is heated to 55-60°C. (R)-1-phenyl ethylamine (47.2 g) is added drop wise to the reaction mixture at same temperature and maintained for 30 minutes. The reaction mass is cooled to 30-32°C and stirred for 30 minutes. The obtained solid is filtered, washed with chloroform (170 mL) and dried under room temperature, to afford 64.0 g of the title compound.

EXAMPLE 10: Preparation of (3R)-3-(carbamoylmethyl)-5-methylhexanoic acid.

Water (211 mL) and (3R)-3-(carbamoylmethyl)-5-methylhexanoic acid phenyl ethylamine salt (64.0 g) are charged in to the round-bottom flask at 25°C and stirred for 10 minutes. The reaction mixture pH is adjusted to 1.2 to 1.4 by the addition of Con. Hydrochloric acid (23 mL) at 25°C and stirred for 10 minutes. The reaction mass is cooled to 0-5°C and maintained for 60 minutes. The obtained solid is filtered, washed with cold water (66 mL) and dried at 45-50°C for 12 hours, to afford 34.1 g of the title compound. Chiral purity: 99.1 %

EXAMPLE 11: Preparation of Pregabalin a compound of Formula (I).
A solution of sodium hydroxide (25.6 g) in water (80 mL) and (3R)-3-(carbamoylmethyl)-5-methylhexanoic acid (60.0 g) are charged in to the round bottom flask at 25°C and stirred for 10 minutes. The reaction mixture is cooled to 0-5°C.

Bromine (51.2 g) is slowly added to a solution of aqueous sodium hydroxide (45.0 grams of sodium hydroxide in 140 mL of water) in another round bottom flask at 5-10°C and the reaction mixture is maintained for 30 minutes. This NaOBr solution is added drop wise to the above reaction mixture at 5-10°C and maintained for 10 minutes. Then reaction mixture is allowed to raise the temperature 30°C gradually. At this point of time self-exothermic reaction is observed, temperature is raised to 48°C. The reaction mass is cooled to 25°C. The reaction mixture pH is adjusted to 5.12 to 5.25 by the addition of Con. Hydrochloric acid (23 mL) at 25°C and stirred for 10 minutes. The reaction mass is heated to 55-60°C and stirred for 15 minutes. The reaction mass is cooled to 5-10°C and maintained for 60 minutes. The obtained solid is filtered, washed with cold water (180 mL) and dried at 50°C for 10 hours, to afford 50 g of the title compound.

Example 12: Purification of pregabalin of Formula (I)
Pregabalin (50 g), mixture of isopropyl alcohol (165 mL) and water (165 mL) are charged in to the round bottom flask at 25°C and stirred for 10 minutes. The reaction mixture is heated 75-80°C and maintained for 15 minutes. The reaction mass is cooled to 0-5°C and maintained for 60 minutes. The obtained
solid is filtered, washed with cold water (50 mL) and dried at 50°C for 14 hours, to afford 36.0 g of the pure pregabalin. Purity by HPLC: 99.8% Chiral HPLC: 99.97%

Claims:

1. A process for racemization of (S)-3-(carbamoylmethyl)-5-methylhexanoic acid comprising the steps of:

a. reacting (S)-3-(carbamoylmethyl)-5-methylhexanoic acid with a reagent in the presence of solvent under reflux for 10-12 hrs;

b. treating the reaction mixture with aqueous alkali solution; and acidifying the reaction mixture to give racemic 3-(carbamoylmethyl)-5- methylhexanoic acid.

2. A process for racemization of (S)-3-(carbamoylmethyl)-5-methylhexanoic acid, as claimed in claim 1, wherein the (S)-3-(carbamoylmethyl)-5-methylhexanoic acid is reacted with a reagent in the presence of solvent to form a cyclic imide compound.

3. A process for racemization as claimed in claim 2 wherein the said reaction is carried out in the presence of a reagent selected from cyanuric chloride, ortho phosphoric acid, phosphorous pentaoxide or phenyl boronic acid.

4. A process for racemization as claimed in claim 3, wherein said reagent is Cyanuric Chloride.

5. A process for the racemization as claimed in claim 3, wherein said reagent is ortho phosphoric acid.

6. A process for racemization as claimed in claim 2, wherein said reaction is carried out in the presence of a solvent selected from toluene, methyl tert-butyl ether, n-hexane, ethyl acetate or chloroform.

7. A process for racemization as claimed in claim 6, wherein said solvent is toluene.

8. A process for racemization as claimed in claim 2 wherein the said (S)-3-(carbamoylmethyl)-5-methylhexanoic acid is present as a mixture along with the corresponding R-isomer or having only (S)-isomer.

9. A process for racemization as claimed in claim 8 wherein the said reaction mixture is enriched
(S)-isomer of 3-carbamoylmethyl)-5-methylhexanoic acid.