Field of the Invention:

The present invention relates to improved process for the preparation of GABA analogue and its intermediate i.e., 3-(carbamoylmethyl)-5-methylhexanoic acid.

Pregabalin is a GABA analogue and is chemically known as (S)-(+)- (aminomethyl)-5-methylhexanoic acid having the following structural formula-5

Formula

Pregabalin is also known as (S)-3-isobutyl y-amino butyric acid or (S)-3-isobutyl GABA. (S)-pregabalin has been found to activate GAD (L-glutamic acid decarboxylase). (S)-pregabalin has a dose dependent protective effect on-seizure, and is a CNS-active compound. (S)-pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses. (S)-pregabalin has analgesic, anticonvulsant, and anxiolytic activity. (S)-pregabalin is marketed under the trade name LYRICA®.

Background of the Invention:

3-(carbamoylmethyl)-5-methylhexanoic acid is one of the important intermediate in the preparation of GABA analogue such as pregabalin. Several synthesis of pregabalin is reported in the literature. The usage of 3-(carbamoylmethyl)-5-methylhexanoic acid in the preparation of pregabalin synthesis was first disclosed in EP 828704. The disclosed process comprises of reacting ethylcyanoacetate, isovaleraldehyde in presence of di-n-propyl amine in hexane followed by treating the obtained cyano intermediate compound with diethylisocyanate and di-n-propylamine to provide the diester compound, which on hydrolysis with hydrochloric acid at reflux temperature followed by extracting the product into toluene at 70-80°C. The toluene extracts was distilled off under reduced pressure to get on oil 3-isobutylglutraric acid, which is on further crystallized and isolated as a solid. Thus obtained 3-isobutylglutaric acid treated with acetic anhydride to provide the corresponding 3-isobutylglutaric anhydride, which on treating with ammonium hydroxide provides 3-(carbamoylmethyl)-5-methylhexanoic acid. Thus obtained 3-(carbamoylmethyl)-5-methylhexanoic acid is converted into pregabalin by resolving it with (R)-l-phenylethylamine and treatment with an acid, followed by Hoffman degradation with Br2/NaOH to provide (S)-pregabalin. The said process involves the extraction of isobutylglutaric acid at very high temperature of 70-80°C hence difficult to carry out at commercial level. Further it involves the isolation and purification of isobutyl glutaric acid and its conversion amide involves unwanted formation of glutaric anhydride and its isolation, which increases the cost of production. Hence this process is economically not suitable at commercial level.

EP 828704 also disclosed a process for the regeneration of 3-isobutyl glutaric acid from the filtrate obtained after the resolution and isolation of required (R)-3- (carbamoylmethyl)-5-methylhexanoic acid. The other isomer (3S)-3-(carbamoylmethyl)- 5-methylhexanoic acid present in the filtrate is extracted with aqueous sodium hydroxide and then the extracted solution was acidified with hydrochloric acid and heated to reflux for 24 hours, followed by extraction of 3-isobutylglutaric acid with a solvent. The process involves longer reaction time and it requires an additional step to covert the 3-isobutylglutaricacid to 3-(carbamoylmethyl)-5-methylhexanoic acid. Further there is no process disclosed for the recovery of chloroform and phenyl ethylamine involved in the reaction. There is a need in the art for the recovery alternate process for the racemization of other isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid which avoids the said draw backs.

The present invention provides improved economical process for the preparation of pregabalin and its intermediate comprising the recovery and utilization of recovered compound and reagents, which makes the present process economical and commercially viable over the known process.

Summary of the Invention:

Accordingly the first embodiment of the present invention relates to a process for the preparation of pregabalin compound of formula-1 and comprises of the following steps,

a) Reacting the 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2 with R(+)-phenyl ethylamine and isolating the obtained 3-(carbamoylmethyl)-5- methylhexanoic acid (+)-phenylethylamine salt compound of formula-3,

b) recovering solvent and racemization of the other isomer present in the
filtrate directly without isolation,

c) treating the salt compound of formula-3 with a suitable aqueous acid followed by isolating the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-4 from the reaction mixture,

d) recovering phenylethylamine and solvent from the filtrate,

e) reacting the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-4 with bromine in the presence of a suitable base provides the pregabalin compound of formula-1,

f) purifying the pregabalin from a mixture of alcohol and water provides highly pure pregabalin compound of formula-1.

The second embodiment of the present invention relates to a process for making 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2 which comprises condensing isovaleraldehyde with ethylcyano acetate to provide 2-cyano-5-methylhex-2- enoic acid ethyl ester compound of formula-7, which on in-situ reaction with diethylmalonate to provide cyano triester derivative compound of formula-8, which on in-situ hydrolysis with suitable acid in a suitable solvent at reflux temperature and extracting the 3-isobutylglutaric acid compound of formula-9 into a suitable solvent, which on further treatment with urea to provide 3-isobutylglutraimide compound of formula-10, followed by treating it in-situ with suitable base in a solvent to provide the 3-(carbamoylmethyl)-5-methylhexanoic acid compound, characterized in that the intermediate compounds where not isolated as a solid and extraction of 3-isobutylglutaric acid compound of formula-9 after hydrolysis was carried out at room temperature.

The third embodiment of the present invention relates to a process for the racemization of other isomer and recovery of solvent from the mother liquors obtained by the reaction of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2 with R(+)-phenyl ethylamine.

The fourth embodiment of the present invention relates to a process for the recovery of phenyl ethylamine from the mothers liquors obtained after desaltificaiton of 3-(carbamoylmethyl)-5-methylhexanoic acid (+)-phenylethylamine salt and mother liquors obtained from racemization of other isomer obtained in the resolution of 3- (carbamoylmethyl)-5-methylhexanoic acid compound of formula-2.

The fifth embodiment of the present invention relates to the use of recovered 3- (carbamoylmethyl)-5-methylhexanoic acid, (+)-phenylethylamine and solvent as per the present invention in the preparation of pregabalin and its intermediates.

Brief description of the figures:

Figure-1: Illustrates PXRD of R(+)-phenyl ethylamine salt of 3-(carbamoylmethyl)-5- methylhexanoic acid obtained from the mixture of chloroform and ethanol. Figure-2: Illustrates PXRD of R(+)-phenyl ethylamine salt of 3-(carbamoylmethyl)-5- methylhexanoic acid obtained from chloroform of the present invention.

Detailed Description of the Invention:

As used herein the present invention the term "suitable solvents" refers to solvents selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" like methylene chloride, chloroform and ethylene dichloride; "nitrile solvents" like acetonitrile and propionitrile; polar solvents like water; and mixtures thereof

As used herein the present invention the term "suitable bases" refers to the bases selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like lithium carbonate, sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassiimi bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and their mixtures there of.

Accordingly the present invention provides an improved process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid, pregabalin and process for the racemization of unwanted (3S)-3-(carbamoylmethyl)-5-methylhexanoic acid (other isomer).

Unless otherwise specified the term "3-(carbamoylmethyl)-5-methylhexanoic acid" as used herein the present invention refers to racemic 3-(carbamoylmethyl)-5- methylhexanoic acid.

The first embodiment of the present invention provides a process for the preparation of pregabalin compound of formula-1 comprises of the following steps,

a) Reacting the 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2

Formula 2

with R(+)-phenyl ethylamine in a suitable solvent and isolating obtained 3- (carbamoylmethyl)-5-methylhexanoic acid (+)-phenylethylamine salt compound of formula-3.

Formula 2

b) recovering of the solvent and racemization of the other isomer present in the filtrate directly without isolation,

c) treating the compound of formula-3 with a suitable aqueous acid followed by isolating the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-4 from the reaction mixture,

d) recovering the phenylethylamine from the filtrate,

e) reacting the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-4 with bromine in presence of a suitable base in a suitable solvent provides the pregabalin compound of formula-1,

f) purifying the pregabalin compound of formula-1 from a mixture of alcohol and water provides highly pure pregabalin compound of formula-1.

Wherein in step a) the suitable solvent is selected from chloro solvents, alcohol solvents, ether solvents, ketone solvents, hydrocarbon solvents, ester solvents, polar solvents or mixtures thereof; preferably chloroform.

The prior art process involves the usage of a mixture of chloroform and alcohol solvent and wherein the present invention involves the usage of single solvent i.e., chloroform.

The usage of single solvent chloroform facilitates the easy centrifugation/filtration commercial level there by avoiding the wastage of time and contamination compared to the material obtained from mixture of solvents, hence it is advantageous to use the single solvent.

In step b) of the present embodiment the recovery process is carried out by the direct distillation of the filtrate the solvent is recovered. The compound obtained in the distillation is cooled to 20-30°C and water was added. Acidifying the reaction mixture with a suitable acid provides the other isomer as a precipitated solid. It was further converted into racemic 3-(carbamoylmethyl)-5-methylhexanoic acid.

In step c) the suitable aqueous acid is aqueous hydrochloric acid.

In step d) the recovering of solvent and phenylethylamine is carried out by basifying the filtrate with a suitable aqueous base and followed by extraction with a suitable solvent.

In step e) the suitable base is sodium hydroxide and the suitable solvent is water. The bromine mole ratio is 0.9 to 0.99 moles w.r.to (R)-(-)-3-(carbamoylmethyl)-5- methylhexanoic acid; preferably 0.9 moles. In step f) the suitable alcohol solvent is isopropyl alcohol.

The second aspect of the present invention provides one-pot process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-1,

which comprises of the following steps,

a) condensing isovaleraldehyde compound of formula-5

with ethylcyano acetate compound of formula-6

in presence of di-n-propyl amine in cyclohexane under azeotropic reflux condition provides 2-cyano-5-methylhex-2-enoic acid ethyl ester compound of formula-7,

b) treating the compound of formula-7 obtained in step-a) in-situ with diethylmalonate and di-n-propylamine provides a cyano triester compound of formula-8 ,

c) hydrolyzing the obtained compound of formula-8 in step-b) with conc. hydrochloric acid at reflux temperature provides 3-isobutylglutaric acid compound of formula-9,

d) cooling the reaction mixture and extracting the 3-isobutylglutaric acid compound of formula-9 at 25-25°C,

e) optionally distilling off the solvent to get 3-isobutylgluatric acid residue,

f) treating the 3-isobutylglutaric acid compound of formula-9 obtained in step-d) or step-e) in-situ with urea in presence or absence of a solvent like toluene provides 3- isobutylglutraimide compound of formula-10,

g) hydrolyzing the glutarimide compound of formula-10 in-situ by treating it with a suitable base in a suitable solvent provides the 3-(carbamoylmethyl)-5- methylhexanoic acid compound of formula-2,

characterized in that the intermediate compounds where not isolated as a solid and extraction of final compound from the reaction mixture was carried out at room temperature.

Wherein in step g) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or organic bases; preferably sodium hydroxide and the suitable solvent is selected from alcohol solvents, ester solvents, polar solvents or mixtures thereof; preferably water.

In the prior art process the step c) carried out long time i.e. 72 hours at reflux temperature and extraction is carried out at 70-80°C which is difficult at large scale batches. In the present invention the reaction completed in 48 hours only and the extraction is carried out at 25-35°C. It is more advantage for large scale synthesis.

The third embodiment of the present invention relates to a process for the racemization of other isomer and recovery of the solvent from the mother liquors obtained by the reaction of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2 with R(+)-phenyl ethylamine. The process comprises of the following steps,

a) distilling the chloroform mother liquors obtained by the reaction of 3- (carbamoylmethyl)-5-methylhexanoic acid compound of formula-2 with R(+)-phenyl ethylamine at 60-65°C,

b) collecting the chloroform from the distillate,

c) adding water to the residue and acidifying the reaction mixture with a suitable acid,

d) filtering the precipitated solid and drying the solid,

e) dissolving the compound obtained in step-d) in a suitable solvent and adding Para toluene sulfonic acid,

f) heating the reaction mixture to reflux temperature,

g) cooling the reaction mixture and adding aqueous base solution,

h) stirring the reaction mixture,

i) cooling the reaction mixture to 20-30°C separating the aqueous and organic layers,

j) treating the aqueous layer with carbon,

k) acidifying the filtrate with a suitable acid,

l) stirring the reaction mixture and filtering the compound,

m) purifying the obtained compound from a suitable solvent,

n) drying the compound provides pure racemic 3-(carbamoylmethyl)-5-methylhexanoic acid.

Wherein in step c) and step k) the suitable acid is selected from inorganic acids like hydrochloric acid, hydro bromic acid, sulfuric acid or organic acids like acetic acid, para toluene sulfonic acid, methane sulfonic acid, trifluoro acetic acid preferably hydrochloric acid.

In step e) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, nitrile solvents, polar solvents or mixtures thereof; preferably toluene.

In step g) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or organic bases; preferably sodium hydroxide.

In step m) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, nitrile solvents, polar solvents or mixtures thereof

The preferred embodiment of the present invention provides a recovery and racemization of other isomer and recovery of solvent from the mother liquors

a) distilling the chloroform mother liquors obtained by the reaction of 3- (carbamoylmethyl)-5-methylhexanoic acid compound of formula-2 with R(+)-phenyl ethylamine at 60-65°C,

b) collecting the chloroform from the distillate,

c) adding water to the residue and acidifying the reaction mixture with a aqueous hydrochloric acid,

d) filtering the precipitated solid and drying the solid,

e) dissolving the compound obtained in step-d) in toluene and adding para toluene sulfonic acid,

f) heating the reaction mixture to reflux temperature,

g) cooling the reaction mixture and adding sodium hydroxide solution to it,

h) stirring the reaction mixture,

i) cooling the reaction mixture to 20-30°C separating the aqueous and organic layers,

j) treating the aqueous layer with carbon,

k) acidifying the filtrate with aqueous hydrochloric acid,

l) stirring the reaction mixture and filtering the compound,

m) purifying the obtained compound from toluene.

n) drying the compound provides pure racemic 3-(carbamoylmethyl)-5-methylhexanoic acid.

The racemic 3-(carbamoylmethyl)-5-methylhexanoic acid obtained by racemization of other isomer is useful in the preparation of (R)-(-)-3-(carbamoylmethyl)- 5-methylhexanoic acid and pregabalin.

The fourth embodiment of the present invention relates to a process for the recovery of phenyl ethylamine from the mothers liquors obtained after desaltificaiton of 3-(carbamoylmethyl)-5-methylhexanoic acid (+)-phenylethylamine salt and mother liquors obtained from racemization of other isomer obtained in the resolution of 3- (carbamoylmethyl)-5-methylhexanoic acid compound of formula-2.

a) collecting the mother liquors from step c) of first embodiment and step d) of third embodiment of the present invention,

b) cooling the mother liquors to 10-15°C,

c) basifying the mother liquors with a suitable aqueous basic solution,

d) extracting the phenyl ethyl amine from the reaction mixture with a suitable solvent,

e) distilling off the solvent completely provides phenyl ethyl amine.

Wherein in step c) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or organic bases; preferably sodium hydroxide.

In step d) the suitable solvent is selected from ester solvents, chloro solvents, ether solvents, ketone solvents, alcohol solvents; preferably methylene chloride.

The recovered phenyl ethyl amine obtained in the present invention is useful in the preparation of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and pregabalin.

The fifth embodiment of the present invention relates to the use of recovered 3- (carbamoylmethyl)-5-methylhexanoic acid, (+)-phenylethylamine and solvent as per the present invention in the preparation of pregabalin and its intermediates.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example-1: Preparation of 3-isobutylpentanedioic acid compound of formula-9

Di-n-propyl amine (0.44 ml) was slowly added to the mixture of ethyl cyanoaceteate (50 grams), isovaleraldehyde (42 grams) and cyclohexane (56 ml) at 25- 30°C. The reaction mixture was heated azeotropically to reflux temperature for 2 hours. After completion of the reaction, the solvent was distilled off completely from the reaction mixture under reduced pressure. The reaction mixture was cooled to 25-30°C and diethyl malonate (78 grams) was added to the reaction mixture at 25-30°C. Di-n- propyl amine (4.5 grams) was slowly added to the reaction mixture at 25-30°C and stirred for 10 minutes. The reaction mixture was heated to 50-55°C and stirred for 5 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C. The reaction mixture was added to the conc. hydrochloric acid (748 ml) at 30-40°C. Heated the reaction mixture to reflux temperature and stirred for 48 hours at same temperature. Cooled the reaction mixture to 25-30°C and extracted with toluene. The organic layer was distilled off under reduced pressure to get the title compound as a residue. Yield: 83 grams

Example-2: Preparation of 3-(carbamoylmetliyl)-5-methylhexanoic acid compound of formuIa-2

The mixture of urea (17.5 grams) and 3-isobutylpentanedioic acid (50 grams) was heated to 130-135°C. Stirred the reaction mixture for 12 hours at same temperature. After completion of the reaction, the reaction mixture was cooled to 80-90°C. Aqueous sodium hydroxide solution (11.7 grams of sodium hydroxide in 175 ml of water) was added to the reaction mixture at 80-90°C and then cooled it to 60-65°C. The reaction mixture was stirred for 3 hours at same temperature and then cooled to 25-30°C. The reaction mixture was washed with toluene. Basic carbon (2.5 grams) was added to the aqueous layer and stirred for 45 minutes. The reaction mixture was filtered through hiflow and washed with water. Acidified the filtrate with conc. Hydrochloric acid at 25-30°C and stirred it for 1 hour. The precipitated solid was filtered and washed with water. Ethyl acetate (200 ml) was added to the wet solid and the reaction mixture was heated to 70-75°C. Stirred the reaction mixture for 30 minutes at same temperature. Cooled the reaction mixture to 0- 5°C slowly and stirred for 90 minutes at same temperature. Filtered the precipitated solid and washed with ethyl acetate. Dried the material to get the title compound. Yield: 37 grams.
Chiral Purity: 49.87% (R-isomer), 50.13% (S-isomer); Purity by HPLC: 96.59%

Example-3: Preparation of 3-(carbamoylmethyl)-5-methyIhexanoic acid compound of formula-2 in one pot process:

Di-n-propyl amine (0.44 ml) was slowly added to the mixture of ethyl cyanoaceteate (50 grams), isovaleraldehyde (42 grams) and cyclohexane (56 ml) at 25- 30°C. Heated the reaction mixture azeotropically to reflux temperature for 2 hours. After completion of the reaction, the solvent was distilled off completely from the reaction mixture under reduced pressure. Cooled the reaction mixture to 25-30°C and diethyl malonate (78 grams) was added to the reaction mixture at 25-30°C. Di-n-propyl amine (4.5 grams) was slowly added to the reaction mixture at 25-30°C and stirred for 10 minutes. Heated the reaction mixture to 50-55°C and stirred for 5 hours at same temperature. After completion of the reaction, the reaction mixture was cooled to 25- 30°C. The reaction mixture was added to conc. hydrochloric acid (748 ml) at 30-40°C. Heated the reaction mixture to reflux temperature and stirred for 48 hours at same temperature. Cooled the reaction mixture to 25-30°C and extracted with toluene. The organic layer was distilled off under reduced pressure to get 3-isobutylglutaric acid as residue. Urea (26 grams) was added to the obtained residue and then heated to 130- 135°C. Stirred the reaction mixture for 12 hours at same temperature. After completion of the reaction, the reaction mixture was cooled to 80-90°C. Aqueous sodium hydroxide solution (17,6 grams of sodium hydroxide in 290 ml of water) was added to the reaction mixture at 80-90°C and then cooled it to 60-65°C. The reaction mixture was stirred for 3 hours and then cooled to 25-30°C. The reaction mixture was washed with toluene. Basic carbon (4.2 grams) was added to the aqueous layer and the reaction mixture was stirred for 45 minutes. The reaction mixture was filtered through hiflow and washed with water. Acidified the reaction mixture with conc. hydrochloric acid at 25-30°C and stirred it for 1 hour. The obtained solid was filtered and washed with water. Ethyl acetate (332 ml) was added to the wet solid and the reaction mixture was heated to 70-75°C. Stirred the reaction mixture for 30 minutes at same temperature. Cooled the reaction mixture to 0- 5°C slowly and stirred for 90 minutes at 0-5°C. Filtered the precipitated solid and washed with ethyl acetate and dried to get the title compound. Yield: 61 grams.

Exainple-4: Preparation of (3R)-3-(CarbamoyImethyl)-5-methyIhexanoie acid phenylethylamine salt compound of formula-3

3-(carbamoylmethyl)-5-methylhexanoic acid (50 grams) in chloroform (675 ml) was heated to 50-55°C. (R)-l-phenyl ethylamine (23.9 grams) was added to the reaction mixture at same temperature. Stirred the reaction mixture for 30 minutes at 50-55°C. Cooled the reaction mixture slowly to 20-25°C and stirred for 45 minutes at same temperature. Filtered the precipitated compound and washed with chloroform. Dried the material to get the title compound as a crystalline solid.
Yield: 36 grams.
M.P: 110-118°C
Chiral Purity: 92.66% (R-isomer), 7.34% (S-isomer); Purity by HPLC: 99.66%

Example-5: Recovery of 3-(carbamoylmethyl)-5-methylhexanoic acid from the filtrate obtained in the resolution process

The mother liquors (700 ml) obtained in example-4 was distilled off atmospherically. Water (50 ml) was added to obtained residue. Adjusted the pH of the reaction mixture to 2.0 to 3.0 using conc. hydrochloric acid (10 ml) at 20-30°C and stirred for 1 hour at same temperature. Filtered the precipitated solid (filtrate kept a side for recovery of phenyl ethylamine) and dried. Toluene (80 ml) and para-toluene sulphonic acid (1.4 grams) were added to the obtained solid and heated to reflux temperature. Stirred the reaction mixture for 10-12 hours azeotropically. The reaction mixture was cooled to 80-90°C. Aqueous sodium hydroxide solution (6.3 grams of sodium hydroxide in 95 ml of water) was added to the reaction mixture at 80-90°C and then cooled to 60-65°C. The reaction mixture was stirred for 3 hovirs at same temperature and then cooled to 25-30°C. Separated the both aqueous and organic layers. Basic carbon (1.4 grams) was added to the aqueous layer and the reaction mixture was stirred for 30 minutes. Filtered the reaction mixture through hiflow and washed with water. Adjusted the pH of the filtrate to 2.0 to 3.0 using conc. hydrochloric acid at 20-30°C and stirred for 90 minutes. Filtered the precipitated compound and washed with water. Ethyl acetate (100 ml) was added to the obtained compound and heated the reaction mixture to 70- 75 °C. Stirred the reaction mixture for 30 minutes at same temperature. Cooled the reaction mixture to 0-5°C slowly and stirred for 90 minutes at same temperature. Filtered the precipitated compound and washed with ethyl acetate. Dried the material to get the title compound.
Yield: 21 grams
Purity by HPLC: 98.81%

ExampIe-6: Preparation of (3R)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-4

Water (140 ml) was added to the (3R)-3-(Carbamoylmethyl)-5-methylhexanoic acid phenylethylamine salt compound of formula-4 (70 grams) at 20-25°C and stirred for 10 minutes. Acidified the reaction mixture with conc, hydrochloric acid (18 ml) at 20-25°C. Stirred the reaction mixture for 1 hour 30 minutes at same temperature. Filtered the reaction mixture and washed with 10% aqueous hydrochloric acid solution. Dried the obtained material to get the title compound.
Yield: 36,8 grams
M.P: 118-121°C
Chiral Purity: 94.22% (R-isomer), 5.78% (S-isomer); Purity by HPLC: 98.52%

Example-7: Recovery of Phenylethylamine from filtrate obtained from Example-5 and Example-6

Cooled the filtrates (220 ml) obtained from example-6 and of example-5 to 10- 15°C. Adjusted the pH of the reaction mixture to 10-11 using aqueous sodium hydroxide (20 grams of sodium hydroxide in 20 ml of water) and the reaction mixture was extracted with methylene chloride. Washed the methylene chloride layer with water. Distilled off the solvent completely to get the title compound.
Yield: 30 grams
Purity by GC: 99.64%

Example-8: Preparation of Pregabalin compound of formula-1

Bromine (23 grams) was added to a solution of aqueous sodium hydroxide (31.9 grams of sodium hydroxide in 150 ml of water) at -5 to 5°C and the reaction mixture was stirred for 45 minutes at same temperature. (3R)-3-(Carbamoylmethyl)-5-methylhexanoic acid (30 grams) was added to the reaction mixture at -5 to 5°C and stirred it for 45 minutes. The temperature of the reaction mixture was raised to 20-25°C and then heated to 50-55°C. The reaction mixture was stirred for 30 minutes at 50-55°C. After completion of the reaction, the reaction mixture was cooled to 20-25°C and the pH of the reaction mixture was adjusted to 6.5-7.0 by using conc. hydrochloric acid (36 ml). The reaction mixture was cooled to 0-5°C and stirred for 1 hour at same temperature. The precipitated compound was filtered and washed with water. The obtained compound was added to a solution of aqueous sodium hydroxide (6 grams of sodium hydroxide in 45 ml of water) at 20-25°C and stirred for 10 minutes. Filtered the above reaction mixture through hiflow bed and the pH of the filtrate was adjusted to 6.5-7.0 using conc. hydrochloric acid (7.2 ml) at 20-30°C. Cooled the reaction mixture to 0-5°C and stirred for 1 hour 30 minutes at same temperature. Filtered the precipitated compound and dried to get the title compound. Yield: 14 grams Purity by HPLC: 97.25%

Example-9: Preparation of Pregabalin compound of formula-1

3.8 ml of bromine was added to the aqueous sodium hydroxide solution (14.5 grams of sodium hydroxide dissolved in 60 ml of water) at 0-5°C. In another flask sodium hydroxide (3.2 g) was dissolved in water (25 ml) and added (3R)-3-(Carbamoylmethyl)- 5-methylhexanoic acid phenylethylamine salt (25 g) at 25-30°C and stirred for 30 minutes. The reaction mixture was washed with dichloromethane. The aqueous layer was added to the above prepared sodium hypobromide solution at 0-5 °C and stirred for 1 hour. The temperature of the reaction mixture was raised to 20-30°C and then further heated to 55°C. Stirred the reaction mixture for 30 minutes. Cooled the reaction mixture to 20-30°C and adjusted the pH of the reaction mixture to 6.5-7.0 using conc. hydrochloric acid. The reaction mixture was cooled to 0-5 °C and stirred for 1 hour. Filtered the precipitated solid, washed with water (10 ml) and dried to get the title compound. Yield: 7 grams

ExampIe-10: Purification of Pregabalin compound of formula-1

Pregabalin (20 grams) was added to the mixture of isopropyl alcohol(80 ml) and water (80 ml). Heated the reaction mixture to reflux temperature and stirred for 30 minutes at same temperature. Filtered the reaction mixture through hiflow bed and washed with aqueous isopropyl alcohol. Cooled the filtrate to 0-5°C and stirred for 1 '/z hour at same temperature. Filtered the precipitated compoimd and dried to get pure pregabalin. Yield: 17 grams Purity by HPLC: 99.91%

We claim:

1) An improved process for the preparation of pregabalin compound of formula-1 comprises of the following steps,

a) Reacting the 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2

with R(+)-phenyl ethylamine in a suitable solvent and isolating obtained 3- (carbamoylmethyl)-5-methylhexanoic acid (+)-phenylethylamine salt compound of formula-3,

b) recovering of the solvent and racemization of the other isomer present in the filtrate,

c) treating the compound of formula-3 with a suitable aqueous acid followed by isolating the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-4 from the reaction mixture,

d) recovering phenylethylamine from the filtrate,

e) reacting the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-4 with bromine in presence of a suitable base in a suitable solvent provides the pregabalin compound of formula-1.

f) purifying the pregabalin compound of formula-1 from a mixture of alcohol and water provides highly pure pregabalin compound of formula-1.

2) The process according to claim-1, wherein in step a) the suitable solvent is selected from chloro solvents, alcohol solvents, ether solvents, ketone solvents, hydrocarbon solvents, ester solvents, polar solvents or mixtures thereof; preferably chloroform;

In step b) the recovery process is carried out by the direct distillation of the filtrate obtained in step a) the solvent is recovered, the compound obtained in the distillation is cooled to 20-30°C and water was added, acidifying the reaction mixture with a suitable acid provides the other isomer as a precipitated solid, it was further converted into racemic 3-(carbamoylmethyl)-5-methylhexanoic acid;

In step c) the suitable aqueous acid is aqueous hydrochloric acid;

In step d) the recovering of phenylethylamine is carried out by basifying the filtrate with a suitable aqueous base and followed by extraction with a suitable solvent;

In step e) the suitable base is sodium hydroxide and the suitable solvent is water, preferred mole ratio for bromine is 0.9 moles w.r.to (R)-(-)-3-(carbamoylmethyl)-5- methylhexanoic acid;

In step f) the suitable alcohol solvent is isopropyl alcohol.

3) A process for the preparation of pregabalin compound of formula-1 comprises of the following steps,

a) Reacting the 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2

with R(+)-phenyl ethylamine in chloroform and isolating obtained 3- (carbamoylmethyl)-5-methylhexanoic acid (+)-phenylethylamine salt compound of formula-3,

b) recovering of chloroform and racemization of the other isomer present in the filtrate directly without isolation,

c) treating the salt compound of formula-3 with aqueous hydrochloric acid followed by isolating the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-4 from the reaction mixture,

d) recovering phenylethylamine from the filtrate,

e) reacting the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-4 with 0.9 moles of bromine in presence of sodium hydroxide in water provides the pregabalin compound of formula-1,

f) purifying the pregabalin from a mixture of isopropyl alcohol and water provides highly pure pregabalin compound of formula-1.

4) one-pot process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2.

which comprises of the following steps,

a) condensing isovaleraldehyde compound of formula-5

with ethylcyano acetate compound of formula-6

in presence of di-n-propylamine in cyclohexane under azeotropic reflux condition provides 2-cyano-5-methylhex-2-enoic acid ethyl ester compound of formula-7,

b) treating the compound of formula-7 obtained in step-a) in-situ with diethylmalonate and di-n-propylamine provides a cyano triester compound of formula-8,

c) hydrolyzing the obtained compound of formula-8 in step-b) with conc. hydrochloric acid in toluene at reflux temperature provides 3-isobutylglutaric acid compound of formula-9.

d) cooling the reaction mixture and extracting the 3-isobutylglutaric acid compound of formula-9 at 25-25°C,

e) optionally distilling off the solvent to get 3-isobutylgluatric acid residue,

f) treating the 3-isobutylglutaric acid compound of formula-9 obtained in step-d) or step-e) in-situ with urea in presence or absence of a solvent like toluene at suitable temperature provides 3-isobutylglutraimide compound of formula-10,

g) hydrolyzing the glutarimide compound of formula-10 in-situ by treating it with a suitable base in a suitable solvent provides the 3-(carbamoylmethyl)-5- methylhexanoic acid compound of formula-2.

5) A process for the racemization of other isomer into racemic 3-(carbamoylmethyl)-5-methylhexanoic acid, which comprises of the following steps,

a) Distilling the chloroform mother liquors obtained by the reaction of 3- (carbamoylmethyl)-5-methylhexanoic acid compound of formula-2 with R(+)- phenyl ethylamine at 60-65°C,

b) collecting the chloroform from the distillate,

c) adding water to the residue and acidifying the reaction mixture with a suitable acid,

d) filtering the precipitated solid and drying the solid,

e) dissolving the compound obtained in step-d) in a suitable solvent and adding Para toluene sulfonic acid,

f) heating the reaction mixture to reflux temperature,

g) cooling the reaction mixture and adding aqueous base solution,

h) stirring the reaction mixture,

i) cooling the reaction mixture to 20-30°C, separating the aqueous and organic layers,

j) treating the aqueous layer with carbon.

k) acidifying the filtrate with a suitable acid,

1) stirring the reaction mixture and filtering the compound,

m) purifying the obtained compound from a suitable solvent,

n) drying the compound provides pure racemic 3-(carbamoylmethyl)-5-methylhexanoic acid.

6) A process for the recovery of phenyl ethyl amine from the mother liquors, which comprises of the following steps,

a) collecting the mother liquors from step c) of first embodiment and step d) of third embodiment of the present invention,

b) cooling the mother liquors to 10-15°C,

c) basifying the mother liquors with a suitable aqueous basic solution,

d) extracting the phenyl ethyl amine from the reaction mixture with a suitable solvent,

e) distilling off the solvent completely provides phenyl ethyl amine.

7) A process for the racemization of other isomer i.e. (3S)-3-(carbamoylmethyl)-5- methylhexanoic acid, which comprises of the following steps,

a) dissolving the other isomer in a suitable solvent and adding para toluene sulfonic acid,

b) heating the reaction mixture to reflux temperature,

c) cooling the reaction mixture and adding aqueous base solution,

d) stirring the reaction mixture,

e) cooling the reaction mixture to 20-30°C, separating the aqueous and organic layers,

f) treating the aqueous layer with carbon,

g) acidifying the filtrate with a suitable acid,

h) stirring the reaction mixture and filtering the compound,

i) purifying the obtained compound from a suitable solvent,
drying the compound provides pure racemic 3-(carbamoylmethyl)-5- methylhexanoic acid.

8) The process according to claim 1, wherein the step b) the recovering of the solvent and racemization of the other isomer comprises of following steps,

a) Distilling the chloroform mother liquors obtained by the reaction of 3- (carbamoylmethyl)-5-methylhexanoic acid compound of formula-2 with R(+)- phenyl ethylamine at 60-65°C,

b) collecting the chloroform from the distillate,

c) adding water to the residue and acidifying the reaction mixture with a suitable acid,

d) filtering the precipitated solid and drying the solid,

e) dissolving the compound obtained in step-d) in a suitable solvent and adding Para toluene sulfonic acid,

f) heating the reaction mixture to reflux temperature,

g) cooling the reaction mixture and adding aqueous base solution,

h) stirring the reaction mixture,

i) cooling the reaction mixture to 20-30°C, separating the aqueous and organic layers,

j) treating the aqueous layer with carbon,

k) acidifying the filtrate with a suitable acid,

1) stirring the reaction mixture and filtering the compound,

m) purifying the obtained compound from a suitable solvent,

n) drying the compound provides pure racemic 3-(carbamoylmethyl)-5- methylhexanoic acid.

9) The process according to claim 1, wherein the step d) recovering phenylethylamine comprises of the following steps,

a) Collecting the mother liquors from step c) of first embodiment and step d) of third embodiment of the present invention,

b) cooling the mother liquors to 10-15°C,

c) basifying the mother liquors with a suitable aqueous basic solution,

d) extracting the phenyl ethyl amine from the reaction mixture with a suitable solvent,

e) distilling off the solvent completely provides phenyl ethyl amine.

10) Use of (+)-phenyl ethyl amine, 3-(carbamoylmethyl)-5-methylhexanoic acid and solvents obtained according to claims 5 to 7 in the preparation of (R)-(-)-3- (carbamoylmethyl)-5-methylhexanoic acid and pregabalin.