PROCESS FOR PREPARING PREGABALIN AND ITS INTERMEDIATE

Related Application:

This application claims the benefit of priority of our Indian patent application numbers 3175/CHE/2009 filed on 24/12/2009 and 3897/CHE/2010 filed on 21/12/2010, which are incorporated herein by reference.

Field of the Invention:

The present invention relates to an improved process for the preparation of GABA analogue such as pregabalin and it's intermediate such as 3-(carbamoylmethyl)-5- methylhexanoic acid. Pregabalin is a GABA analogue and is chemically known as (S)-(3)-(aminomethyl)-5-methylhexanoic acid having the following structural formula- 1.

Formula- 1

Pregabalin is also known as (S)-3-isobutyl γ-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 reported in the literature. The usage of 3-(carbamoylmethyl)-5-methylhexanoic acid in the preparation of pregabalin was disclosed in EP 828704. The disclosed process comprises of reacting ethylcyanoacetate, isovaleraldehyde in the presence of di-n-propyl amine in hexane followed by treating the obtained cyano intermediate compound with diethylmalonate 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 provides 3-isobutylglutraric acid as oil, which is 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 treatment with ammonium hydroxide provides 3-(carbamoylmethyl)-5-methylhexanoic acid. Thus obtained 3 -(carbamoyl methyl)-5-methylhexanoic acid is converted into pregabalin by resolving it with (R)-l-phenylethylamine and treatment with an acid, followed by Hoffman degradation with Br ₂ /NaOH to provide (S)-pregabalin. The said process involves the extraction of isobutylglutaric acid at very high temperature of 70-80°C, which is difficult to carry out at commercial level. Further it involves the isolation and purification of 3-isobutyl glutaric acid and its conversion into 3-(carbamoylmethyl)-5-methylhexanoic acid involves number of steps as well as the isolation of glutaric anhydride, 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 was 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 utilized in the reaction. There is a need in the art for the recovery of chloroform, phenyl ethyl amine and alternate process for the racemization of other isomer of 3-(carbamoylmethyl)-5- methylhexanoic acid which avoids the prior reported. process draw backs.

The present invention provides improved economical process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid and pregabalin comprising the recovery and utilization of recovered compound and reagents, which makes the present process more economical and commercially viable over the reported 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 , which 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 (3R)-3-(carbamoylmethyl)-5- methylhexanoic acid (+)-phenylethylamine salt compound of formula-3,

b) recovering the solvent and racemization of the other isomer (3S)-(carbamoylmethyl)- 5 -methylhexanoic acid) from 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 the 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 to provide highly pure pregabalin compound of formula- 1.

The second embodiment of the present invention relates to a process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2, which comprises of condensing isovaleraldehyde with ethylcyano acetate in a suitable base to provide 2-cyano-5-methylhex-2-enoic acid ethyl ester compound of formula-5, which on in-situ reaction with diethylmalonate in the presence of a suitable base to provide cyano triester derivative compound of formula-6, which on in-situ hydrolysis with suitable acid in a suitable solvent at reflux temperature and extracting the 3- isobutylglutaric acid compound of formula-7 into a suitable solvent, which on further treatment with urea to provide 3-isobutylglutraimide compound of formula-8, followed by treating it in-situ with suitable base in a solvent to provide the 3-(carbamoylmethyl)-5- methylhexanoic acid, characterized in that the intermediate compounds were not isolated as a solid and extraction of 3-isobutylglutaric acid compound of formula-7 after hydrolysis was carried out at room temperature. The third embodiment of. the present invention relates to a process for the recovery & racemization of other isomer .i.e„ (3S)-3-(carbamoylmethyl)-5-methyl hexanoic acid and recovery of solvent from the mother liquors obtained from the reaction of 3-(carbamoylmethyl)-5-methylhexanoic acid 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 (3R)-3-(carbamoylmethyl)-5-methylhexanoic acid (+)-phenylethylamine salt and mother liquors obtained after the isolation of other isomer (3S)-3-(carbamoylmethyl)-5- methylhexanoic acid obtained from the resolution of 3-(carbamoylmethyl)-5- methylhexanoic acid with (+)-phenylethylamine.

In a further embodiment, the present invention relates to an improved process for the preparation of 3 -(carbamoylmethyl)-5 -methylhexanoic acid compound of formula-2, which comprises of the following steps,

a) Reacting the 3-isobutylglutaric acid compound of formula-7 with urea at a suitable temperature with or without using a solvent to provide the 3-isobutylglutarimide compound of formula-8,

b) hydrolyzing the 3-isobutylglutarimide with a suitable base in presence or absence of a solvent provides the compound of formula-2.

In a further embodiment, the present invention relates to a process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2, which comprises of treating (3S)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-9 with suitable acid in a suitable solvent to provide 3-isobutylglutarimide compound of formula-8, which on hydrolysis with a suitable base in presence or absence of a solvent provides the compound of formula-2. In another embodiment, the present invention relates to a process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2, which comprise of heating the (3S)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-9 at a suitable temperature for a sufficient time to provide the 3-isobutylglutarimide compound of formula-8, which on hydrolysis with a suitable base in presence or absence of solvent provides the compound of formula-2.

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.

Advantages of the present invention:

· Provides a simple and improved process for the preparation of 3-(carbamoylmethyl)- 5 -methylhexanoic acid

• Economical and commercially viable process.

• Involves less number of steps compared to prior art.

• Provides an improved process for the racemization of other isomer i.e., (3S)-3- (carbamoylmethyl)-5-methylhexanoic acid.

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 potassium bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and their mixtures there of.

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

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

Formula-2

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

Formula-3

b) recovering the chloroform and other isomer from the filtrate followed by racemizing the other isomer i.e., (3S)-3-(carbamoylmethyl)-5-methylhexanoic acid,

c) treating the 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,

Formula-4 d) recovering the phenylethylamine from the filtrate by basifying it with a suitable aqueous base followed by extracting the phenyl ethylamine with a suitable solvent, e) reacting the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-4 with bromine in the presence of a aqueous sodium hydroxide provides the pregabalin compound of formula- 1 , wherein the bromine is used in the mole ratio of

0.9 to 0.99 moles w.r.to formula-4; preferably 0.9 moles,

f) purifying the pregabalin compound of formula- 1 from aqueous isopropyl alcohol provides highly pure pregabalin compound of formula- 1. In the prior art processes mixture of chloro and alcohol solvents used for the preparation of formula-3, wherein the present invention involves the usage of single solvent i.e., chloroform. The usage of chloroform alone facilitates the easy centrifugation/filtration of formula-3 at commercial level there by avoiding the wastage of time and contamination compared to the prior art process, wherein centrifugation/filtration of formula-3 obtained from mixture of alcohol and chloro solvents takes more time. Hence the present invention is advantageous over the prior art process.

Further the recovery of chloroform as described in step-b has been carried out by direct distillation of the filtrate and collecting the recovered chloroform from distillate. And the other isomer i.e., (3S)-(carbamoylmethyl)-5-methylhexanoic acid and (+)-phenyl ethylamine salt present in the filtrate obtained as a crude after distillation, was cooled and water was added to it followed by acidifying with a suitable acid provides (3S)-(carbamoylmethyl)-5-methylhexanoic acid. This other isomer further racemized by using the present process and can be utilized again in the preparation of pregabalin as a starting material.

As described in step-d, the phenylethyalmine salt was recovered from the filtrate by basifying the filtrate with a suitable aqueous base, followed by extracting the phenyl ethylamine with a suitable solvent selected from hydrocarbon solvents, ether or chlorosolvents, preferably methylene chloride. Further the extracted solvent was distilled off to provide the (+)-phenylethylamine salt. The recovery, racemization and reutihzation of the intermediates, reagents and solvents further reduces the cost of production and makes the present process was more advantageous and economical compared to the prior art.

The second aspect of the present invention provides one-pot process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2,

Formula-2

which comprises of condensing isovaleraldehyde with ethylcyano acetate in the presence of di-n-propyl amine in cyclohexane under azeotropic reflux condition to provide 2-cyano-5-methylhex-2-enoic acid ethyl ester compound of formula-5,

Formula-5

which on in-situ treatment with diethylmalonate in the presence of di-n-propylamine provides cyano triester compound of formula-6,

Formula-6

which on in-situ hydrolysis with concentrated hydrochloric acid at reflux temperature, followed by extracting the 3-isobutylglutaric acid compound of formula-7 with a suitable solvent after cooling the reaction mixture to 20-25°C, optionally distilling off the solvent from extract to get the 3-iso ,

further treating the extracted 3-isobutylglutaric acid compound of formula-7 or its residue in-situ with urea in presence or absence of a solvent at a suitable temperature provides 3-isobutylglutraimide compound of formula-8,

Formula-8

which on in-situ hydrolysis by treating it with a suitable base in a suitable solvent provides the 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2,

Formula-2

characterized in that the intermediate compounds were not isolated as a solid and extraction of 3-isobutylglutaric acid compound from the reaction mixture was carried out at room temperature after hydrolysis.

In the prior art processes, hydrolysis of formula-8 was carried out at very high temperature for longer hours such as 72 hours at reflux temperature and the extraction of the obtained 3-isobutylglutaric acid was carried out at high temperature such as 70-80°C, which is difficult to carried out at commercial level. In the present invention the reaction completed within in 48 hours at reflux temperature and further the extraction was carried out after cooling the reaction mixture to 25-35°C. Hence the present invention is more advantageous for commercial level production compared to the prior art process.

The third embodiment of the present invention provides a process for the racemization of other isomer i.e., (3S)-(carbamoylmethyl)-5-methylhexanoic acid and recovery of the solvent from the mother liquors obtained by the reaction of 3-(carbamoylmethyl)-5-methylhexanoic acid with R(+)-phenyl ethylamine. The process comprises of the following steps, a) distilling the mother liquors obtained after 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 and separating the aqueous and organic layers,

j) ' subjecting the aqueous layer to carbon treatment,

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.

Wherein in step c) and step k) the suitable acid used 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 and trifluoro aceticacid 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. In a preferred embodiment, the process for the recovery and racemization of other isomer (3S)-(carbamoylmethyl)-5-methylhexanoic acid and recovery of solvent from the mother liquors comprises of;

a) distilling the 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 and separating the aqueous and organic layers,

j) subjecting the aqueous layer to carbon treatment,

k) acidifying the filtrate with aqueous hydrochloric acid,

1) 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.

3-(carbamoylmethyl)-5-methylhexanoic acid obtained by the racemization of recovered (3S)-(carbamoylmethyl)-5-methylhexanoic acid as per the present invention is having purity greater than 98% by HPLC, preferably greater than 99% and further utilized for the preparation of pregabalin and its intermediate. The fourth embodiment of the present invention provides a process for the recovery of phenyl ethylamine from the mothers liquors obtained after desaltification of (3R)-3-(carbamoylmethyl)-5-methylhexanoic acid (+)-phenylethylamine salt and filtrate obtained after the isolation of other isomer i.e.,(3S)-(carbamoylmethyl)-5- methylhexanoic acid from the mother liquors, which obtained from the resolution of 3-(carbamoylmethyl)-5-methylhexanoic acid with R(+)-phenylethylamine, which comprises of

a) cooling the mother liquors containing phenylethylamine to 10-15°C,

b) basifying the mother liquors with a suitable aqueous base selected from inorganic bases like alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or organic bases; preferably aqueous sodium hydroxide ,

c) extracting the phenyl ethyl amine from the reaction mixture with a suitable solvent selected from ester solvents, chloro solvents, ether solvents, ketone solvents, alcohol solvents; preferably methylene chloride,

d) distilling off the solvent completely to get the (+)-phenyl ethyl amine salt.

(+)-phenyl ethyl amine recovered as per the present invention is having purity greater than 99% by GC and further utilized for resolution of racemic compound such as 3-(carbamoylmethyl)-5-methylhexanoic acid.

In a further embodiment, the present invention provides a process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2, which comprises of the following steps,

a) Reacting the 3-isobutylglutari a- 7

Formula-7

with urea in presence or absence of solvent at a suitable temperature ranges from 70- 180°C for a sufficient period of time to provide the 3-isobutylglutarimide compound of formula-8,

Formula-8

b) hydrolyzing the 3-isobutylglutarimide with a suitable base in the presence or absence of a solvent provides the compound of formula-2.

In a further embodiment, the present invention provides a process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2,

Formula-2

which comprises of the following steps,

a) Treating (3S)-3-(carbamoylmeth -5-methylhexanoic acid compound of formula-9

Formula-9

with a suitable acid such as paratoluene sulfonic acid, hydrochloric acid, sulfuric acid, preferably paratoluene sulfonic acid in a suitable solvent selected from toluene, xylene, heptane, hexane and cyclohexane or mixtures thereof to provide 3-isobutylglutarimide compound of formula-8,

b) hydrolyzing the compound of formula-8 with suitable base in presence or absence of a solvent provides the compound of formula-2.

Wherein in the above process the suitable solvent if used is selected from toluene, xylene, heptane, hexane and cyclohexane or mixtures thereof.

In another embodiment, the present invention provides a process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2, which comprises of the following steps, a) Heating the (3S)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-9 at a suitable temperature ranges from 100-200°C for a sufficient period of time to provide the 3-isobutylglutarimide compound of formula-8,

b) hydrolyzing the 3-isobutylglutarimide compound of formula-8 with a suitable base in presence or absence of a solvent provides the compound of formula- 1.

Wherein in the above processes for the preparation of compound of formula-2, the suitable solvent, if used is selected from toluene, xylene, heptane, hexane and cyclohexane or mixtures thereof.

Further the present invention provides the use of recovered 3-(carbamoylmethyl)- 5-methylhexanoic acid, (+)-phenylethylamine and chloroform in the preparation of pregabalin and its intermediates. Pregabalin obtained as per the present invention can be further micronized or milled by the conventional methods known in the art to the get the desired particle size to facilitate the formulation composition needs.

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

XRD analysis of crystalline 3-(carbamoylmethyl)-5-methylhexanoic acid (+)-phenylethylamine salt was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min.

The related substance of pregabalin was analyzed by HPLC using the following conditions: Column: Inertsil ODS-3V 250 x 4.6 mm; 5μηι or equivalent; Flow rate: 0.8 ml/min; wavelength: 210 nm; Temperature: 25°C; Injection volume: 50 μΐ; Run time: 60 min; and using aqueous di-ammonium hydro genphosphate having 6.5 pH, methanol and acetonitrile in the ration of 80: 10:10(v/v) as a mobile phase-A and diluent; acetonitrile and water in 90: 10 ratio(v/v) as mobile phase-B. 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-isobutylglutaric acid compound of formula-7:

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 cone, 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-(carbamoyImethyl)-5-methylhexanoic acid compound of formula-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 (1 1.7 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 arid 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 cone. 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: One-pot preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-2:

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 cone, 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 cone, 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. Example-4: Preparation of (3R)-3-(CarbamoyImethyl)-5-methyIhexanoic 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. ExampIe-5: Racemization process of (S)-3-(carbamoyImethyl)-5-methylhexanoic acid:

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 cone, 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 hours 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 cone, 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%

Example-6: Preparation of (3R)-3-(carbamoyImethyl)-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-3 (70 grams) at 20-25 °C and stirred for 10 minutes. Acidified the reaction mixture with cone, 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

Example-7: Recovery of Phenylethylamine:

Cooled the filtrates (220 ml) obtained from example-6 and 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 6.7 by using cone, 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 6.8 using cone, 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

Particle Size Distribution: D(0.1): 1 1.8 μιη; D(0.5): 47.57 μηι; D(0.9): 162.3 μπι; D[4,3]: 71.98 um

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 (3 R)-3 -(carbamoyl methyl)-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 cone. 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

Example-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 ½ hour at same temperature. Filtered the precipitated compound and dried to get pure pregabalin.

Yield: 17 grams

Purity by HPLC: 99.91%

Particle Size Distribution: D(0.1): 6.5 μιη; D(0.5): 49.74 μιη; D(0.9): 191.40 μπι; D[4,3]:

77.20 μιη

Example-ll: Preparation of 3-(carbamoylmethyI)-5-methylhexanoic acid:

A mixture of 3-isobutylglutaric acid (200 grams) and urea (70 grams) was heated to 160°C and stirred upto completion of the reaction. The reaction mixture was cooled to 90-100° C and toluene (400 ml) was added. The reaction mixture was cooled to 25-30°C and water (100 ml) was added then stirred. The precipitated solid was filtered and washed with water. Aqueous sodium hydroxide (48 grams in 700 ml of water) was added to the obtained solid and heated it into 60-65 °C then stirred up to complete of the reaction. The reaction mixture was cooled and washed with toluene. Carbon (5 grams) was added to the aqueous layer, stirred for 30 minutes and then filtered through hyflow. The filtrate was acidified using hydrochloric acid, cooled to 10-15 °C and stirred for an hour. The solid obtained was filtered, washed with water and dried to get the title compound.

Yield: 150 grams Example-12: Preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid:

A mixture of 3-isobutylglutaric acid (50 grams), urea (17.5 grams) and toluene (150 ml) was heated to reflux temperature and stirred upto completion of the reaction under azeotropic mode. The reaction mixture was cooled to 25-30°C and water (25 ml) was added to it, then stirred for an hour. The solid obtained was filtered and washed with water. Aqueous sodium hydroxide (12 grams in 165 ml of water) was added to the obtained solid and heated it into 60-65 °C then stirred upto completion of the reaction. The reaction mixture was cooled and washed with toluene. The reaction mixture was acidified using hydrochloric acid, cooled to 10-15°C and stirred for an hour. The solid obtained was filtered, washed with water and dried to get the title compound.

Yield: 22 grams

Example-13: Preparation of 3-(carbamoylmethyI)-5-methyIhexanoic acid:

A mixture of (S)-3-(carbamoylmethyl)-5-methylhexanoic acid (100 grams), paratoluene sulfonic acid (5 grams) and toluene (300 ml) was heated to reflux temperature and stirred up to completion of the reaction under azeotropic mode. Aqueous sodium hydroxide (30 grams in 300 ml) was added to the reaction mixture at 60-65 °C then stirred. After completion of the reaction it was cooled to 25-30°C and layers was separated. Aqueous layer was acidified with concentrated hydrochloric acid, cooled to 10-15°C and stirred for 90 minutes. The solid obtained was filtered and washed with water and dried to get the title compound.

Yield: 80 grams

Example-14: Preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid:

(S)-3-(carbamoylmethyl)-5-methylhexanoic acid (38 grams) was heated to 150°C and maintained for 4 hours. The reaction mixture was cooled to 60-65°C and aqueous sodium hydroxide (9 grams in 100 ml) was added to it. The reaction mixture was stirred up to the completion of the reaction and then cooled to 10-15°C. Acidified the reaction mixture with hydrochloric acid and stirred for 90 minutes. The solid obtained was filtered and washed with aqueous hydrochloric acid and dried to get the title compound.

Yield: 28 grams