Field of the invention:
The present invention relates to a novel process for preparation of Pregabalin. The present invention further relates to novel compounds represented by Formula II, III, III A, IV and V and process for preparation thereof. The present invention further relates to the use of these novel compounds in the preparation of Pregabalin.
Background of the invention:
Pregabalin, a calcium channel alpha-2-delta protein ligand, is a structural analogue of gamma-aminobutyric acid (GABA). Pregabalin is chemically described as (S)-3-(aminomethyl)-5-methyl hexanoic acid represented by Formula I below:
Pregabalin was designed as a more potent successor to a related drug, gabapentin. Pregabalin binds with high affinity to the alpha2-delta site, an auxiliary subunit of voltage-gated calcium channels, in the central nervous system tissues. Although the mechanism of action of Pregabalin has not been fully elucidated, results with genetically modified mice and with compounds structurally related to Pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in Pregabalin's anti-nociceptive and antiseizure effects in animal models.
Pregabalin is commercially marketed as LYRICA® by Pfizer Inc. LYRICA® is available as hard-shell capsules containing 25, 50, 75, 100, 150, 200, 225 and 300 mg of Pregabalin. LYRICA® is also available as a 20 mg/ml oral solution. It is an anticonvulsant drug indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy or spinal cord injury and postherpetic neuralgia. It is also used as an adjunctive therapy for adult patients with partial onset seizures, and management of fibromyalgia. For neuropathic pain associated with diabetic peripheral neuropathy, the maximum recommended dose of LYRICA® is 100 mg three times a day in patients with creatinine clearance of atleast 60 ml/min. The recommended dose for postherpetic neuralgia is 75 to 150 mg two times a day or 50 to 100 mg three times a day in patients

with creatinine clearance of atleast 60 ml/min. LYRIC A® at doses of 150 to 600 mg/day has been shown to be effective as adjunctive therapy in the treatment of partial onset seizures in adults. The recommended dose of LYRIC A® for fibromyalgia is 300 to 450 mg/day and for treatment of neuropathic pain associated with spinal cord injury, the recommended dose is 150 to 600 mg/day.
Various processes for preparation of Pregabalin are described in the literature. US5616793 describes a process for preparation of Pregabalin which involves the conversion of 3-isobutyl glutaric acid into its corresponding anhydride. Subsequently, the anhydride reacts with ammonia to produce glutaric acid mono-amide followed by resolution with (R)-l-phenylethylamine yielding the corresponding salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid. This salt is reacted with acid to liberate the R-enantiomer. Finally, Hoffmann degradation with Br2/NaOH provides (S)-Pregabalin. A disadvantage of this method is that it requires separation of enantiomers, thereby resulting in low yield and high cost.
WO2009022839 discloses the synthesis of Pregabalin using a bicyclic lactone compound. This document describes preparing a lactone compound via cyclopropane ring-opening reaction and decarboxylation of the bicyclic lactone compound by nucleophilic addition of isopropylcuprate. The lactone compound is further subjected to sequential reactions of halogenation, azidation and hydrolysis to obtain (S)-3-(azidomethyl)-5-methyl hexanoic acid which is then converted to Pregabalin. This process involves the use of azidation reaction, which requires careful handling. Further this process involves the use of column chromatography, which is not preferable at an industrial scale.
323/MUM/2008 describes a process for the synthesis of Pregabalin by reacting 3-halomethyl-5-methyl-hexanoic acid alkyl ester with potassium phthalimide to obtain alkyl-3-(l-phthalimidomethyl)-5-methyl-hexanoate. The obtained phthalimido methyl compound is subjected to basic hydrolysis and further to acidic hydrolysis to obtain racemic Pregabalin. The racemic Pregabalin thus obtained is subjected to resolution to obtain S- Pregabalin. The disadvantage of this process is that it requires the separation of enantiomers, thereby resulting in low yield and high cost.

WO2009081208 discloses a process for the preparation of pregabalin comprising one or more steps selected from (a) the reaction of 4-methyl-2-pentanone (I) with compound X-G to give the keto intermediate (II);
and/or (b) the reduction of the keto intermediate (II) to the hydroxy intermediate (III);
and/or (c) the displacement of the hydroxyl group of intermediate(III) by a group Y to give the intermediate (IV) or the activation of the hydroxyl group of intermediate (III) to give intermediate(V);
and/or (d) the reaction of intermediate (IV) or (V)with nitromethane in the presence of a base to give the nitro-derivative.
wherein X is a suitable leaving group such as a halo, alkoxy, -O-acyl, thio or sulfonate group, G is a carboxylic acid group or a functional group that is readily converted into a carboxylic acid group, Y is a suitable leaving group such as a halo group, and Z is any group that is capable of enhancing the capacity of a hydroxyl group as a leaving group such as an acyl or sulfonyl group. Subsequently, nitro-derivative is converted to Pregabalin.

There still exists a need to develop a simple, cost-effective and commercially viable process for the preparation of Pregabalin. The present invention provides a novel process for preparation of Pregabalin using novel compounds represented by Formula II, III, III A, IV and V.
Object of the invention:
An object of the present invention is to provide a novel process for preparation of Pregabalin.
Another object of the present invention provides compound selected from Formula II and enantiomers thereof,
where Rl = any activating group such as mesyl, esyl, tosyl, 2-methyl phenyl sulfonyl, 3-methyl phenyl sulfonyl, benzene sulfonyl, trifluoromethane sulfonyl, 2-chlorophenyl sulfonyl, 3-chlorophenyl sulfonyl, 4-chlorophenyl sulfonyl, 2-bromophenyl sulfonyl, 3-bromophenyl sulfonyl, 4-bromophenyl sulfonyl, 2-nitrophenyl sulfonyl, 3-nitrophenyl sulfonyl or 4-nitrophenyl sulfonyl;
compound of Formula III and enantiomers thereof.
compound of Formula IV and enantiomers thereof.
where Rl = -H or any activating group such as mesyl, esyl, tosyl, 2-methyl phenyl sulfonyl, 3-methyl phenyl sulfonyl, benzene sulfonyl, trifluoromethane sulfonyl, 2-chlorophenyl sulfonyl, 3-chlorophenyl sulfonyl, 4-chlorophenyl sulfonyl, 2-bromo

phenyl sulfonyl, 3-bromophenyl sulfonyl, 4-bromophenyl sulfonyl, 2-nitrophenyl sulfonyl, 3-nitrophenyl sulfonyl or 4-nitrophenyl sulfonyl; R2 and R3 can be same or different and are selected from hydrogen, carboxybenzyl (CBZ), tert-butyloxy carbonyl (BOC), benzoyl, benzyl or acetyl; R2 and R3 can together form a ring structure such as phthalimido group or succinimido group, with the proviso that when Rl=-H, R2 and R3 together represent a phthalimido group; and
where R4 and R5 can be same or different and are selected from -H, methyl, ethyl, propyl, benzyl, tolyl or the like.
Yet another object of the present invention provides a process for conversion of compounds of Formula II, III, IIIA, IV or V to Pregabalin.
Summary of the invention:
One aspect of the present invention provides a process for preparation of Pregabalin or pharmaceutically acceptable salt thereof, comprising the steps of:
a) treating 2(R)-l-cyano-4-methyl-2-pentanol with alkyl sulfonyl halide or aryl sulfonyl halide to obtain the corresponding sulfonate ester;
b) subjecting said sulfonate ester obtained in step a) to nitromethylation or aminomethylation reaction to obtain (3S)-5-methyl-3-(nitromethyl) hexane nitrile or (3S)-5-methyl-3-(aminomethyl) hexane nitrile; and
c) converting said (3S)-5-methyl-3-(nitromethyl) hexane nitrile or (3S)-5- methyl-3-(aminomethyl) hexane nitrile to Pregabalin or pharmaceutically acceptable salt thereof.
OR
a) treating (2S)-l-phthalimido-4-methyl-2-pentanol with alkyl sulfonyl halide or aryl sulfonyl halide to obtain the corresponding sulfonate ester;
b) treating said sulfonate ester obtained in step a) with dialkyl malonate or diaryl malonate to obtain (2S)-l-phthalimido-2-[l,l-(dialkylcarboxy) methyl]-4-methyl

pentane or (2S)-l-phthalimido-2-[1,1-(diarylcarboxy) methyl]-4-methyl pentane; c) converting said (2S)-l-phthalimido-2-[l,l-(dialkylcarboxy)methyl]-4-methyl pentane or (2S)-l-phthalimido-2-[l,l-(diarylcarboxy)methyl]-4-methyl pentane to Pregabalin or pharmaceutically acceptable salt thereof.
Another aspect of the present invention provides a process for conversion of (3S)-5-methyl-3-(nitromethyl) hexane nitrile to Pregabalin or pharmaceutically acceptable salt thereof, comprising the steps of:
a) subjecting (3S)-5-methyl-3-(nitromethyl) hexane nitrile to catalytic hydrogenation to obtain (3S)-5-methyl-3-(aminomethyl)hexane nitrile;
b) subjecting said (3S)-5-methyl-3-(aminomethyl)hexane nitrile to acidic or basic hydrolysis to obtain Pregabalin; and
c) optionally converting said Pregabalin to pharmaceutically acceptable salt thereof.
Another aspect of the present invention provides a process for conversion of (3S)-5-methyl-3-(aminomethyl)hexane nitrile to Pregabalin or pharmaceutically acceptable salt thereof, comprising the steps of:
a) subjecting (3S)-5-methyl-3-(aminomethyl)hexane nitrile to acidic or basic hydrolysis to obtain Pregabalin;
b) optionally converting Pregabalin to pharmaceutically acceptable salt thereof.
Preferably, sulfonate ester is treated with nitromethane or methylamine to obtain (3S)-5-methyl-3-(nitromethyl) hexane nitrile or (3S)-5-methyl-3-(aminomethyl) hexane nitrile.
Another aspect of the present invention provides conversion of (2S)-l-phthalimido-2-[l,l-(dialky lcarboxy )methyl]-4-methyl pentane or (2S)-l-phthalimido-2-[l,l-(diaryl carboxy)methyl]-4-methyl pentane to Pregabalin or pharmaceutically acceptable salt thereof, comprising the steps of:
a) subjecting (2S)-l-phthalimido-2-[l,l-(dialkylcarboxy) methyl]-4-methyl pentane or (2S)-l-phthalimido-2-[l,l-(diarylcarboxy)methyl]-4-methyl pentane to hydrolysis, decarboxylation and deprotection reaction to obtain Pregabalin;
b) optionally converting Pregabalin to pharmaceutically acceptable salt thereof.
Preferably, alkyl sulfonyl halide or aryl sulfonyl halide is selected from methane sulfonyl

chloride, ethane sulfonyl chloride, benzene sulfonyl chloride, p-toluene sulfonyl chloride, 2-methyl phenyl sulfonyl chloride, 3-methyl phenyl sulfonyl chloride, trifluoromethane sulfonyl chloride, 2-chlorophenyl sulfonyl chloride, 3-chlorophenyl sulfonyl chloride, 4-chlorophenyl sulfonyl chloride, 2-bromophenyl sulfonyl chloride, 3-bromophenyl sulfonyl chloride, 4-bromophenyl sulfonyl chloride, 2-nitrophenyl sulfonyl chloride, 3-nitrophenyl sulfonyl chloride or 4-nitrophenyl sulfonyl chloride; and wherein said dialkyl malonate or diaryl malonate is selected from dimethyl malonate, diethyl malonate, dibenzyl malonate or ditosyl malonate.
Preferably, (2S)-l-phthalimido-4-methyl-2-pentanol is prepared by treating (2S)-l-halo-4-methyl-2-pentanol with sodium phthalimide or potassium phthalimide to obtain (2S)-1-phthalimido-4-methyl-2-pentanol.
Another aspect of the present invention provides a compound selected from the group
consisting of,
compound of Formula II and enantiomers thereof,
where Rl = any activating group such as mesyl, esyl, tosyl, 2-methyl phenyl sulfonyl, 3-methyl phenyl sulfonyl, benzene sulfonyl, trifluoromethane sulfonyl, 2-chlorophenyl sulfonyl, 3-chlorophenyl sulfonyl, 4-chlorophenyl sulfonyl, 2-bromophenyl sulfonyl, 3-bromophenyl sulfonyl, 4-bromophenyl sulfonyl, 2-nitrophenyl sulfonyl, 3-nitrophenyl sulfonyl or 4-nitrophenyl sulfonyl; compound of Formula III and enantiomers thereof.
compound of Formula IV and enantiomers thereof.

where Rl = -H or any activating group such as mesyl, esyl, tosyl, 2-methyl phenyl sulfonyl, 3-methyl phenyl sulfonyl, benzene sulfonyl, trifluoromethane sulfonyl, 2-chlorophenyl sulfonyl, 3-chlorophenyl sulfonyl, 4-chlorophenyl sulfonyl, 2-bromo phenyl sulfonyl, 3-bromophenyl sulfonyl, 4-bromophenyl sulfonyl, 2-nitrophenyl sulfonyl, 3-nitrophenyl sulfonyl or 4-nitrophenyl sulfonyl; R2 and R3 can be same or different and are selected from hydrogen, carboxybenzyl (CBZ), tert-butyloxy carbonyl (BOC), benzoyl, benzyl or acetyl; R2 and R3 can together form a ring structure such as phthalimido group or succinimido group, with the proviso that when Rl=-H, R2 and R3 together represent a phthalimido group; and
compound of formula V and enantiomers thereof,
where R4 and R5 can be same or different and are selected from -H, methyl, ethyl, propyl, benzyl, tolyl or the like.
Preferably, compound of Formula III is (3S)-5-methyl-3-(nitromethyl) hexane nitrile, reperesented as formula IIIA
Preferably, in compound of formula II, Rl is selected from mesyl, esyl or tosyl and in compound of formula IV, Rl is selected from mesyl, esyl or tosyl and R2 and R3 together represent a phthalimido group.
Yet another aspect of the present invention provides a process for conversion of

compound selected from compounds of Formula II, III, III A, IV and V to Pregabalin.
Description of the invention:
The present invention provides a novel process for preparation of Pregabalin or pharmaceutically acceptable salt thereof.
According to one embodiment of the present invention, there is provided a process for preparation of Pregabalin, comprising the steps of,
a) treating (2R)-l-cyano-4-methyl-2-pentanol with alkyl sulfonyl halide or aryl sulfonyl halide to obtain the corresponding sulfonate ester;
b) subjecting said sulfonate ester obtained in step a) to nitromethylation or aminomethylation reaction to obtain (3S)-5-methyl-3-(nitromethyl) hexane nitrile or (3S)-5-methyl-3-(aminomethyl)hexane nitrile; and
c) converting said (3S)-5-methyl-3-(nitromethyl) hexane nitrile or (3S)-5-methyl-3-(aminomethyl) hexane nitrile to Pregabalin or pharmaceutically acceptable salt thereof.
. Alkyl sulfonyl halide or aryl sulfonyl halide is selected from methane sulfonyl chloride, ethane sulfonyl chloride, benzene sulfonyl chloride, p-toluene sulfonyl chloride, 2-methyl phenyl sulfonyl chloride, 3-methyl phenyl sulfonyl chloride, trifluoromethane sulfonyl chloride, 2-chlorophenyl sulfonyl chloride, 3-chlorophenyl sulfonyl chloride, 4-chlorophenyl sulfonyl chloride, 2-bromophenyl sulfonyl chloride, 3-bromophenyl sulfonyl chloride, 4-bromophenyl sulfonyl chloride, 2-nitrophenyl sulfonyl chloride, 3-nitrophenyl sulfonyl chloride or 4-nitrophenyl sulfonyl chloride. Preferably, methane sulfonyl chloride or p-toluene sulfonyl chloride is used.
Alternatively, sulfonyl bromide or sulfonyl iodide may be used.
Another embodiment of the present invention provides a process for preparation of Pregabalin, comprising the steps of:
a) reacting (2R)-l-halo-4-methyl-2-pentanol with a cyanide source to obtain (2R)-1-cyano-4-methyl-2-pentanol;
b) treating said (2R)-l-cyano-4-methyl-2-pentanol with alkyl sulfonyl halide or aryl sulfonyl halide to obtain the corresponding sulfonate ester;

c) subjecting said sulfonate ester obtained in step b) to nitromethylation or amino methylation reaction to obtain (3S)-5-methyl-3-(nitromethyl) hexane nitrile or (3 S)-5 -methy 1-3 -(aminomethyl)hexane nitrile; and
d) converting said (3S)-5-methyl-3-(nitromethyl) hexane nitrile or (3S)-5-methyl-3-(aminomethyl) hexane nitrile to Pregabalin or pharmaceutically acceptable salt thereof.
Cyanide source is selected from alkali metal cyanide or alkaline earth metal cyanide, such as sodium cyanide, potassium cyanide, lithium cyanide, rubidium cyanide, cesium cyanide, magnesium cyanide and calcium cyanide, preferred being sodium cyanide or potassium cyanide.
Preferably, (2R)-1 -halo-4-methyl-2-pentanol is (2R)-1 -chloro-4-methyl-2-pentanol.
In a preferred embodiment, the process for preparation of Pregabalin comprises the steps
of,
Step 1: To an aqueous solution of sodium cyanide is added (2R)-l-chloro-4-methyl-2-pentanol at room temperature. The temperature of the mixture is raised to 60 to 100°C, preferably to 80°C and the mixture is maintained under stirring at the same temperature for about 2 to 6 hours, preferably for 4 hours. After the completion of reaction, the mixture is cooled to room temperature. This mixture is then treated with a solvent selected from dichloromethane, dichloroethane, chloroform or carbon tetrachloride, preferably dichloromethane. The layers are separated. Aqueous layer is subjected to repeated solvent extractions. The organic layers are combined and washed with water. The combined organic layers are then dried and concentrated to obtain (2R)-l-cyano-4-methyl-2-pentanol.
Step 2: (2R)-l-cyano-4-methyl-2-pentanol is treated with a solvent selected from dichloromethane, dichloroethane, chloroform or carbon tetrachloride, preferably dichloromethane at room temperature to obtain a solution. To this solution, a base such as triethylamine and a catalyst selected from 4-dimethylamino pyridine, DABCO or DBU, preferably 4-dimethylamino pyridine are added to obtain a mixture. The mixture is cooled to -10 to 10°C, preferably to 0 to 5°C. This mixture is further treated with methane sulfonyl chloride or p-toluene sulfonyl chloride at the same temperature. The mixture is

maintained under stirring at 0 to 10°C, preferably at 5 to 10°C for about 30 min. The temperature of the mixture is raised to room temperature and the mixture is maintained under stirring at the same temperature for about 1 hour. The reaction mixture is then cooled to 0 to 10°C, preferably 5°C. The mixture is then treated with water and solvent selected from dichloromethane, dichloroethane, chloroform or carbon tetrachloride, preferably dichloromethane. The layers are separated. The organic layer is washed with aqueous bicarbonate solution, water and further dried over sodium sulphate. The organic layer thus obtained is concentrated under vacuum to obtain mesylate or tosylate of (2R)-1 -cyano-4-methyl-2-pentanol.
Step 3: To a cold solution of nitromethane in a solvent selected from tetrahydrofuran (THF), acetone, acetonitrile, ethyl acetate, methyl acetate, dimethylformamide (DMF), dimethylacetamide, dimethyl sulfoxide (DMSO), methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), 1,4-dioxane or methyl tetrahydrofuran, preferably THF is added a base selected from sodium hydride, potassium hydride, ammonia, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide or cesium hydroxide, preferably sodium hydride in a lot-wise manner at about 0 to 5°C. This reaction mixture is maintained under stirring at the same temperature for 1 to 3 hours, preferably for 2 hours. A solution of mesylate or tosylate of (2R)-1 -cyano-4-methyl-2-pentanol in a solvent selected from THF, acetone, acetonitrile, ethyl acetate, methyl acetate, dimethyl formamide, dimethylacetamide, DMSO, MTBE, DIPE, 1,4-dioxane or methyl tetrahydrofuran, preferably THF is added to the obtained reaction mixture in a drop wise manner at 0 to 5°C, preferably at 3 to 4°C. The reaction mixture is maintained under stirring at the same temperature for 1 to 3 hours, preferably for 2 hours. The temperature of the reaction mixture is then raised to room temperature and the mixture is maintained at the same temperature for 15 to 24 hours, preferably for 20 hours. After completion of reaction, the reaction mixture is treated with Ci-C4 alcohol such as methanol, ethanol, n-propanol or isopropanol, preferably methanol at the same temperature. The reaction mixture is then maintained under stirring for about 30 min. The mixture is concentrated to obtain an oily residue. The obtained oily residue is treated with water and solvent selected from ethyl acetate, methyl acetate, toluene or hexane preferably ethyl acetate. The layers are

separated. The organic layer is dried and concentrated under vacuum to obtain (3 S)-5 -methyl-3 -(nitromethyl)hexane nitrile.
Step 4: A solution of (3 S)-5-methyl-3-(nitromethyl)hexane nitrile in a suitable organic solvent is subjected to catalytic hydrogenation (hydrogen pressure of 50 psi) at room temperature for about 2 to 4 hours. After the completion of the reaction, the reaction mixture is filtered and the filtrate is concentrated to obtain (3S)-5-methyl-3-(aminomethyl)hexane nitrile.
Catalytic hydrogenation is carried out in the presence of catalyst selected from Raney-nickel, palladium/carbon, platinum/carbon or Pt02. Suitable solvent is selected from methanol, ethanol, n-propanol, isopropanol, ethyl acetate, methyl acetate, tetrahydrofuran, 1,4-dioxane or the like.

Alternatively, mesylate or tosylate of (2R)-l-cyano-4-methyl-2-pentanol can be treated with methylamine to obtain (3 S)-5-methyl-3-(aminomethyl)hexane nitrile.
Step 5: (3S)-5-methyl-3-(aminomethyl) hexane nitrile is subjected to acidic or basic hydrolysis to obtain Pregabalin. Basic hydrolysis is carried out in the presence of base selected from potassium hydroxide, sodium hydroxide, calcium hydroxide or cesium hydroxide, preferably potassium hydroxide. Acidic hydrolysis is carried out in the presence of dilute acids such as dilute HC1 or dilute H2S04.
Another embodiment of the present invention provides a novel compound of Formula 11 and enantiomers thereof,
where Rl = any activating group such as mesyl, esyl, tosyl, 2-methyl phenyl sulfonyl, 3-methyl phenyl sulfonyl, benzene sulfonyl, trifluoromethane sulfonyl, 2-chlorophenyl sulfonyl, 3-chlorophenyl sulfonyl, 4-chlorophenyl sulfonyl, 2-bromophenyl sulfonyl,

3-bromophenyl sulfonyl, 4-bromophenyl sulfonyl, 2-nitrophenyl sulfonyl, 3-nitrophenyl sulfonyl or 4-nitrophenyl sulfonyl;
In a preferred embodiment, compound of Formula II is in R configuration.
Another embodiment of the present invention provides a novel compound of Formula III, 5-methyl-3-(nitromethyl) hexane nitrile and enantiomers thereof,
Preferably, compound of Formula III is (3S)-5-methyl-3-(nitromethyl)hexane nitrile, represented by Formula IIIA.
In a preferred embodiment, the process for preparation of Pregabalin is as represented in the below Scheme I,

In an alternate embodiment, there is provided a process for preparation of Pregabalin or pharmaceutically acceptable salt thereof, comprising the steps of:
a) treating (2S)-l-phthalimido-4-methyl-2-pentanol with alkyl sulfonyl halide or aryl sulfonyl halide to obtain the corresponding sulfonate ester;
b) treating said sulfonate ester obtained in step a) with dialkyl malonate or diaryl malonate to obtain (2S)-l-phthalimido-2-[l,l-(dialkylcarboxy)methyl]-4-methyl pentane or (2S)-l-phthalimido-2-[l,l-(diarylcarboxy)methyl]-4-methyl pentane;
c) converting said (2S)-l-phthalimido-2-[l,l-(dialkylcarboxy)methyl]-4-methyl pentane or (2S)-l-phthalimido-2-[l,l-(diarylcarboxy)methyl]-4-methyl pentane to Pregabalin or pharmaceutically acceptable salt thereof.
Alkyl sulfonyl halide or aryl sulfonyl halide is selected from methane sulfonyl chloride, ethane sulfonyl chloride, benzene sulfonyl chloride, p-toluene sulfonyl chloride, 2-methyl phenyl sulfonyl chloride, 3-methyl phenyl sulfonyl chloride, trifluoromethane sulfonyl chloride, 2-chlorophenyl sulfonyl chloride, 3-chlorophenyl sulfonyl chloride, 4-chlorophenyl sulfonyl chloride, 2-bromophenyl sulfonyl chloride, 3-bromophenyl sulfonyl chloride, 4-bromophenyl sulfonyl chloride, 2-nitrophenyl sulfonyl chloride, 3-nitrophenyl sulfonyl chloride or 4-nitrophenyl sulfonyl chloride, preferably, methane sulfonyl chloride or p-toluene sulfonyl chloride. Alternatively, sulfonyl bromide or sulfonyl iodide may be used.
Dialkyl malonate or diaryl malonate is selected from dimethyl malonate, diethyl malonate, dibenzyl malonate, ditosyl malonate or the like, preferably diethyl malonate. In an alternate embodiment, there is provided a process for preparation of Pregabalin or pharmaceutically acceptable salt thereof, comprising the steps of,
a) reacting (2S)-l-halo-4-methyl-2-pentanol with phthalimide salt to obtain (2S)-1 -phthalimido-4-methyl-2-pentanol;
b) treating said (2S)-l-phthalimido-4-methyl-2-pentanol with alkyl sulfonyl halide or aryl sulfonyl halide to obtain the corresponding sulfonate ester;
c) treating said sulfonate ester obtained in step b) with dialkyl malonate or diaryl malonate to obtain (2S)-l-phthalimido-2-[l,l-(dialkylcarboxy)methyl]-4-methyl pentane or (2S)-l-phthalimido-2-[l,l-(diarylcarboxy)methyl]-4-methyl pentane ;

d) converting said (2S)-l-phthalimido-2-[l,l-(dialkylcarboxy)methyl]-4-methyl pentane or (2S)-l-phthalimido-2-[l,l-(diarylcarboxy)methyl]-4-methyl pentane to Pregabalin.
Phthalimide salt is selected from sodium phthalimide, potassium phthalimide or the like.
Preferably, (2S)-l-halo-4-methyl-2-pentanol is (2S)-l-chloro-4-methyl-2-pentanoL
In a preferred embodiment, the process for preparation of Pregabalin comprises the steps of,
Step 1: A mixture of (2S)-l-chloro-4-methyl-2-pentanol, potassium phthalimide and sodium iodide in a solvent selected from dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, acetonitrile, acetone, tetrahydrofiiran, toluene, ethyl acetate, methyl acetate or mixture thereof, preferably dimethyl formamide is heated to 100 to 120°C, preferably 110°C. The reaction mixture is maintained under stirring at the same temperature for 15 to 24 hours, preferably for 21 hours. After the completion of the reaction, the solvent is distilled off under vacuum. The reaction mixture is cooled to room temperature and then treated with water. This mixture is maintained under stirring at the same temperature for about 20 to 40 min, preferably for 30 min. The mixture obtained is filtered and the wet cake is washed with water. The wet cake is further treated with potassium carbonate solution to obtain a suspension. The suspension is stirred for 20 to 40 min, preferably for 30 min. The suspension is filtered and the wet cake is washed with water followed by a solvent selected from hexane, heptane, pentane, cyclopentane, cyclohexane, toluene or xylene, preferably hexane to obtain the desired product, (2S)-1 -phthalimido-4-methyl-2-pentanol.
Step 2: (2S)-l-phthalimido-4-methyl-2-pentanol is treated with a solvent selected from dichloromethane, dichloroethane, chloroform or carbon tetrachloride, preferably dichloromethane at room temperature to obtain a solution. To this solution, a base such as triethylamine and a catalyst selected from 4-dimethylamino pyridine, DABCO or DBU, preferably 4-dimethylamino pyridine are added to obtain a mixture. The mixture is cooled to -15 to 15°C, preferably to 5 to 10°C. This mixture is further treated with methane sulfonyl chloride or p-toluene sulfonyl chloride at the same temperature. The mixture is

maintained under stirring at 0 to 10°C, preferably at 5 to 10°C for about 30 min. The temperature of the mixture is raised to room temperature and the mixture is maintained under stirring at the same temperature. The mixture is then washed with water and aqueous sodium bicarbonate. The organic layer is separated, dried and concentrated under vacuum to obtain mesylate or tosylate of (2S)-l-phthalimido-4-methyl-2-pentanol.
Step 3: To a suspension of a base selected from sodium hydride, potassium hydride, ammonia, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide or cesium hydroxide, preferably sodium hydride in a suitable solvent is slowly added diethyl malonate at room temperature. The reaction mixture is maintained under stirring for about 30 min at the same temperature. A solution of mesylate or tosylate of (2S)-l-phthalimido-4-methyl-2-pentanol in a suitable solvent is added to the obtained mixture and then refluxed for 15 to 20 hours, preferably for 18 hours. The reaction mixture is cooled to room temperature and then treated with an aqueous solution of ammonium chloride. The product (2S)-l-phthalimido-2-[l,l-(diethylcarboxy) methyl] -4-methyl pentane thus obtained is isolated by suitable techniques such as solvent extraction, filtration, crystallization, concentration under vacuum or the like.
Suitable solvent is selected from tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tertiary butyl ether or 1,4-dioxane, preferably tetrahydrofuran.
Step 4: (2S)-l-phthalimido-2-[l,l-(diethylcarboxy)methyl]-4-methyl pentane is subjected to hydrolysis under acidic or alkaline conditions. Preferably, (2S)-1-phthalimido-2-[l,l-(diethylcarboxy)methyl]-4-methyl pentane is treated with an aqueous solution of a base selected from sodium hydroxide, potassium hydroxide or calcium hydroxide at a temperature of 60 to 70°C for 2 to 4 hours. After completion of reaction, the volume of the reaction mixture is reduced. The concentrated solution is cooled to room temperature and is acidified to obtain the corresponding dicarboxylic acid.
The obtained dicarboxylic acid is subjected to decarboxylation reaction to obtain the corresponding chiral 3-phthalimidomethyl-5-methyl hexanoic acid.
The obtained chiral 3-phthalimidomethyl-5-methyl hexanoic acid is further deprotected to

obtain Pregabalin. Deprotection is carried out using acidic or basic agents such as HC1, H2SO4, hydrazine hydrate, methylamine, ethylamine, triethylamine or the like, preferably hydrazine hydrate.
Another embodiment of the present invention provides a novel compound of Formula IV and enantiomers thereof,
where Rl= -H or any activating group such as mesyl, esyl, tosyl, 2-methyl phenyl sulfonyl, 3-methyl phenyl sulfonyl, benzene sulfonyl, trifluoromethane sulfonyl, 2-chlorophenyl sulfonyl, 3-chlorophenyl sulfonyl, 4-chlorophenyl sulfonyl, 2-bromophenyl sulfonyl, 3-bromophenyl sulfonyl, 4-bromophenyl sulfonyl or 2-nitrophenyl sulfonyl, 3-nitrophenyl sulfonyl or 4-nitrophenyl sulfonyl; R2 and R3 can be same or different and are selected from hydrogen, carboxybenzyl (CBZ), tert-butyloxycarbonyl(BOC), benzyl, benzoyl or acetyl; R2 and R3 can together form a ring structure such as phthalimido group or succinimido group, with the proviso that when Rl=-H, R2 and R3 together represent a phthalimido group.
In a preferred embodiment, compound of Formula IV is IVA, where Rl is selected from mesyl, esyl or tosyl; R2 and R3 together represent a phthalimido group.
Preferably, compound of Formula IVA is in S-configuration.
Another embodiment of the present invention provides a novel compound of Formula V,
where R4 and R5 can be same or different and are selected from -H, methyl, ethyl, propyl, benzyl, tolyl or the like.

In a preferred embodiment, the process for preparation of Pregabalin is as represented in the below Scheme II,
Another embodiment of the present invention provides a process for conversion of compound selected from Formula II> Formula III, Formula IIIA, Formula IV, Formula IVA or Formula V to Pregabalin.
Another embodiment of the present invention provides (2S)-l-chloro-4-methyl-2-pentanol and (2R)-l-chloro-4-methyl-2-pentanol. (2S)-l-chloro-4-methyl-2-pentanol or its (2R)-isomer, starting material for Pregabalin, is prepared by the methods known in the art.
In a preferred embodiment, the process for preparation of (2S)-l-chloro-4-methyl-2-pentanol comprises subjecting (S)-Epichlorohydrin to Grignard reaction in the presence of isopropyl magnesium bromide or isopropyl magnesium chloride, copper salt and solvent selected from tetrahydrofuran (THF), methyl tert butyl ether (MTBE), diisopropyl ether (DIPE), 1,4-dioxane or methyl tetrahydrofuran, preferably THF. The addition is carried out at a temperature of-10 to 0°C, After the completion of addition, the reaction mixture is maintained at room temperature for about 15 hours. After the completion of the reaction, the reaction mixture is further cooled and subjected to usual workup. The reaction mixture is filtered through hyflo bed. The residue obtained is subjected to solvent extraction. The organic layer is separated and concentrated to obtain (2S)-l-chloro-4-methyl-2-pentanol.
A similar approach can be followed to obtain the (2R)-isomer.

Isopropyl Magnesium Bromide or Isopropyl Magnesium chloride is prepared by the
processes known in the art.
Pregabalin obtained by the process of the present invention is purified by the processes known in the art. The solvent used for purification is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, ethanol, methanol, isopropanol, butanol, ethyl acetate, methyl acetate, water or mixture thereof.
Another embodiment of the present invention provides pharmaceutical compositions comprising Pregabalin, prepared by the process of the present invention. Pregabalin obtained by the process of the present invention may be combined with pharmaceutically acceptable excipients to obtain suitable pharmaceutical compositions.
Unless explicitly excluded, all stereoisomers as well as racemic mixtures of compounds represented by Formula II, III, IV and V mentioned herein are covered within the scope of the invention.
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term "room temperature" means the temperature in the range of 20 to 40°C, preferably 25 to 30°C.
The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for human pharmaceutical use.
The following examples are for illustrative purposes only and are not intended to limit the scope of the invention in any way.
Examples:
Example 1: Preparation of (2S)-l-chloro-4-methyl-2-pentanol
In a 5 litre, RB flask equipped with an overhead stirrer, addition funnel, nitrogen inlet and reflux condenser with calcium chloride guard tube were taken (S)-(+)-Epichlorohydrin (68 gm), copper iodide (14 gm) and THF (340 ml). This mixture was cooled to -10°C and

to this 1 M solution of Isopropyl Magnesium bromide (815 ml) was added under nitrogen atmosphere at -10 to 0°C. After the completion of addition, the temperature of the reaction mixture was raised to room temperature and the mixture was maintained at the same temperature for 15 h. After completion of reaction, the reaction mass was cooled to -10°C and to this aqueous ammonia solution saturated with ammonium chloride was added through addition funnel at -10 to 0°C. The mixture was stirred at the same temperature for 1 hour. The mixture was filtered through hyflo bed. The residue thus obtained was washed with ethyl acetate (680 ml). The ethyl acetate extract was isolated and further washed with aqueous ammonia solution saturated with ammonium chloride. The ethyl acetate layer was concentrated under vacuum to obtain (2S)-l-chloro-4-methyl-2-pentanol. Yield: 86.42%
1H NMR (CDC13 ; δ ppm): 0.91 (d, 6H), 1.27(m, 1H), 1.47(m,. 1H), 1.79 (m, 1H), 3.42-3.62(m, 2H), 3.86 (m, 1H).
Alternatively, (R)-(-)-Epichlorohydrin can be used to synthesize (2R)-l-chloro-4- methyl-2-pentanol.
Example 2: Preparation of (2S)-l-cyano-4-methyI-2-pentanol
In a 1 litre four-neck RB flask equipped with an overhead stirrer, addition funnel and reflux condenser with vent connected to sodium hypochlorite solution trap, were taken water (550 ml) and sodium cyanide (59 gm) at room temperature. To this mixture, was added (2S)-l-chloro-4-methyl-2-pentanol (55 gm) at the same temperature in a drop-wise manner. The temperature of the mixture was raised to 80°C. The mixture was maintained under stirring at the same temperature for 4 hours. After completion of the reaction, the mixture was cooled to room temperature. The mixture was further treated with dichloromethane (400ml) and stirred for 10 min. The layers were separated. The aqueous layer was further extracted with dichloromethane (2x200ml). The combined dichloromethane layers were washed with water (200ml), saturated brine solution (2x200ml) and water (200ml). The dichloromethane layer was dried and then concentrated under vacuum to obtain (2S)-l-cyano-4-methyl-2-pentanol. Yield: 72.6% 1H NMR (CDC13; δ ppm): 0.90 (d, 6H), 1.37(m, 1H), 1.531(m, 1H), 1.748 (m, 1H), 2.409-2.546 (m, 2H), 3.97 (m, 1H). MS (EI): m/z = 128.3(M+H); 150.0 (M+Na)

Alternatively, (2R)-l-chloro-4-methyl-2-pentanol can be used to synthesize (2S)-l-cyano-
4-methyl-2-pentanol.
Alternatively, (2R)-l-chloro-4-methyl-2-pentanol can be used to synthesize
(2R)-l-cyano-4-methyl-2-pentanol.
Example 3: Preparation of Mesylate of (2R)-l-cyano-4-methyl-2-pentanol
In a 100 ml four-neck RB flask equipped with an overhead stirrer, addition funnel, nitrogen inlet and reflux condenser with calcium chloride guard tube were taken (2R)-l-cyano-4-methyl-2-pentanol (1 gm) and dichloromethane (10 ml) at room temperature. To this solution, were added triethylamine (2.2 ml) and 4-dimethyl amino pyridine (0.02 gm). The mixture was cooled to 0°C. To this mixture, was added methane sulfonyl chloride (0.9 ml) through an addition funnel at the same temperature. The mixture was maintained under stirring at 5 to 10°C for 30 min. The temperature of mixture was raised to room temperature. The mixture was maintained at the same temperature for 1 hour. After the completion of reaction, the mixture was cooled to 5°C and further treated with water (20 ml) and dichloromethane (20 ml). The organic layer was separated and was washed with 5 % aqueous bicarbonate solution (2x20ml) and water (2x20ml). The dichloromethane layer was dried over sodium sulphate and concentrated under vacuum to obtain mesylate of (2R)-l-cyano-4-methyl-2-pentanol. Yield: 89.5%
lH NMR (CDC13; δ ppm): 0.96 (d, 6H), 1.52 (m, 1H), 1.76 (m, 1H), 1.83 (m, 1H), 2.94 (dd, 1H, y=5.2Hz, 17.2 Hz), 2.72 (dd, 1H, J-4.8Hz, 17.2Hz), 3.1 (s, 3H), 4.9l(m, 1H). MS (EI): m/z = 228.2(M+Na); 244.2(M+K) Similarly, tosylate of (2R)-l-cyano-4-methyl-2-pentanol can be synthesized.
Example 4: Preparation of (3S)-5-methyl-3-(nitromethyl) hexane nitrile
In a 100 ml four-neck RB flask equipped with an overhead stirrer, addition funnel, nitrogen inlet and reflux condenser with calcium chloride guard tube were taken THF (10 ml) and nitromethane (0.33 gm) at room temperature. The mixture was cooled to 0 - 5°C. To this mixture, 60% sodium hydride (0.48 gm) was added in a lotwise manner at the same temperature. The mixture was maintained under stirring at the same temperature for 2 hours. To this mixture, a solution of mesylate of (2R)-l-cyano-4-

methyl-2-pentanol (1 gm) in THF (5 ml) was added in a drop-wise manner at the same temperature and the mixture was maintained under stirring for 2 hours. The reaction mixture was then maintained at room temperature for 20 hours. After the completion of reaction, methanol (2ml) was added and the mixture was maintained under stirring at room temperature for 30 min. The mixture was concentrated under vacuum to obtain a oily residue. This oily residue was treated with water (15ml) and this mixture was subjected to extraction using ethyl acetate (2x15ml). The ethyl acetate layer was separated, dried over sodium sulphate and concentrated under vacuum to obtain (3S)-5-methyl-3-(nitromethyl) hexane nitrile. Yield: 74.7% At this stage, olefin impurity is formed along with the desired product.
Example 5: Preparation of (3S)-5-methyl-3-(aminomethyl) hexane nitrile
(3S)-5-methyl-3-(nitromethyl)hexane nitrile in methanol is subjected to hydrogenation in presence of Raney nickel in a hydrogenation apparatus under pressure of about 50 psi and temperature of 40 to 50°C. The completion of reaction is monitored by TLC. After completion of reaction, the reaction mixture is filtered through hyflo bed and the residue is washed with methanol. The filtrate is concentrated to obtain the titled product.
Example 6: Preparation of Pregabalin
(3S)-5-methyl-3-(aminomethyl) hexane nitrile is treated with an aqueous/methanolic solution of potassium hydroxide at reflux. After the completion of reaction, the solution is acidified using dilute HC1 to precipitate out the product. The product thus obtained is filtered, washed and dried to obtain the desired product.
Example 7: Preparation of (2S)-l-phthalimido-4-methyl-2-pentanol
In a 500 ml four-neck RB flask equipped with an overhead stirrer, addition funnel and reflux condenser with calcium chloride guard tube were taken (2S)-l-chloro-4-methyl-2-pentanol (20 gm), N,N-dimethylformamide (200 ml), potassium phthalimide (32.5 gm) and sodium iodide (3.7 gm) at room temperature. The temperature of the reaction mixture was raised to 110°C. The reaction mixture was maintained under stirring at the same temperature for 21 hours. After the completion of reaction, N,N-dimethylformarnide (100ml) was distilled off at 65°C. The reaction mixture was cooled to room temperature. To another 1 lit RB flask equipped with an overhead stirrer was charged water (300 ml).

To this, was slowly added the reaction mixture with stirring at room temperature. The obtained reaction mixture was maintained under stirring at the same temperature for 30 min. The reaction mass obtained was filtered and washed with water (200 ml). The wet cake obtained was treated with 5% potassium carbonate solution (200ml) and the mixture was stirred at room temperature for 30 min. The suspension was filtered and the residue was washed with water (200 ml). The obtained wet cake was further treated with hexane (200ml) under stirring for 30 min. The suspension was filtered and the residue was washed with hexane (140ml). The wet cake obtained was dried to get (2S)-l-phthalimido-4-methyl-2-pentanol. Yield: 89.22%
1H NMR (DMSO; δ ppm): 0.85 (d, 3H), 0.90(d, 3H), 1.47(m, 1H), 1.17 (m, 1H), 1.19 (m, 1H), 1.3 (m, 1H), 3.42-3.6 (m, 2H), 3.83 (m, 1H), 4.80 (d, 1H), 7.83.-7.86 (m, 4H). MS (EI): m/z = 270.2 (M+Na)
Example 8: Preparation of mesylate of (2S)-l-phthalimido-4-methyl-2-pentanol
In a 250 ml four-neck RB flask equipped with an overhead stirrer, addition funnel, nitrogen inlet and reflux condenser with calcium chloride guard tube were taken (2S)-1-phthalimido-4-methyl-2-pentanol (10 gm) and dichloromethane (100ml). To this mixture were added triethylamine (11.2 ml) and 4-dimethyl amino pyridine (0.2 gm). The mixture thus obtained was stirred at room temperature. The mixture was cooled to 5°C. Methane sulfonyl chloride (4.72 gm) was added dropwise to the cold mixture at 5 to 10°C. The mixture was maintained under stirring at the same temperature for 30 min. After the completion of the reaction, the temperature of mixture was raised to room temperature. The reaction mass was washed with water (100 ml), aqueous sodium bicarbonate (100ml) followed by washing with water (2x200 ml). The organic layer was separated, dried and concentrated under vacuum to obtain mesylate of (2S)-l-phthalimido-4-methyl-2-pentanol. Yield: 98%
lH NMR (DMSO; δ ppm): 0.84 (d, 3H), 0.89 (d, 3H), 1.58 (m, 2H), 1.76 (m, 1H), 3.095 (s, 3H), 3.43-3.52 (m, 1H), 3.83 (m, 2H), 7.85 (m, 4H).
Example 9: Preparation of (2S)-l-phthalimido-2-[l,l-(diethyl carboxy) methyl]-4-methyl pentane.
In a four-neck RB flask equipped with an overhead stirrer, addition funnel, nitrogen inlet

and reflux condenser with calcium chloride guard tube are taken sodium hydride and tetrahydrofuran and this mixture is cooled to 0 to 5°C. To this suspension is added diethyl malonate at room temperature. The reaction mixture is stirred for 30 min at the same temperature. A solution of mesylate of (2S)-l-phthalimido-4-methyl-2-pentanol in anhydrous tetrahydrofuran is added and the mixture is heated to reflux. The completion of the reaction is monitored by TLC. The reaction mixture is then cooled to room temperature and then treated with methanol followed by saturated aqueous ammonium chloride. The mixture is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulphate, filtered and concentrated under vacuum to obtain the titled compound.
Example 10: Preparation of Pregabalin
In a four-neck RB flask equipped with an overhead stirrer, addition funnel, nitrogen inlet and reflux condenser with calcium chloride guard tube are taken (2S)-l-phthalimido-2-[l,l-(diethylcarboxy) methyl]-4-methyl pentane and aqueous solution of potassium hydroxide to obtain a mixture. This mixture is heated to 65°C. The mixture is maintained under stirring at the same temperature for 3 hours. After completion of the reaction, the solution is filtered through hyflo bed. The filtrate is concentrated to reduce the volume. The concentrated solution is cooled to room temperature. This solution is further treated with dilute HC1 under stirring. The reaction mixture is maintained under stirring for 30 min. The reaction mass is then extracted using a suitable organic solvent. The organic extracts are washed with sodium bicarbonate solution, water and dried over sodium sulfate. The organic layer is evaporated to obtain chiral 3-phthalimidomethyl-5-methyl hexanoic acid.
The obtained chiral 3-phthalimidomethyl-5-methyl hexanoic acid is further treated with deprotecting agents such as HC1, H2S04, hydrazine hydrate, methylamine, ethylamine, triethylamine or the like, preferably hydrazine hydrate.

We claim,
1. A process for preparation of Pregabalin or pharmaceutically acceptable salt thereof, comprising the steps of:
a) treating 2(R)-l-cyano-4-methyl-2-pentanol with alkyl sulfonyl halide or aryi sulfonyl halide to obtain the corresponding sulfonate ester;
b) subjecting said sulfonate ester obtained in step a) to nitromethylation or aminomethylation reaction to obtain (3S)-5-methyl-3-(nitromethyl) hexane nitrile or (3S)-5-methyl-3-(aminomethyl) hexane nitrile; and
c) converting said (3S)-5-methyl-3-(nitromethyl) hexane nitrile or (3S)-5-methyl-3-(aminomethyl) hexane nitrile to Pregabalin or pharmaceutical^ acceptable salt thereof.
OR
a) treating (2S)-l-phthalimido-4-methyl-2-pentanoi with alkyl sulfonyl halide or aryl sulfonyl halide to obtain the corresponding sulfonate ester;
b) treating said sulfonate ester obtained in step a) with dialkyl malonate or diaryl malonate to obtain (2S)- l-phthalimido-2-[ 1,1 -(dialkylcarboxy) methyl]-4-methyl pentane or (2S)-l-phthalimido-2-[l,l-(diarylcarboxy) methyl]-4-methyl pentane; and
c) converting said (2S)-l-phthalimido-2-[l,l-(dialkylcarboxy)methyl]-4-methyl pentane or (2S)-1 -phthalimido-2- [ 1,1 -(diarylcarboxy)methy 1] -4-methy 1 pentane to Pregabalin or pharmaceutically acceptable salt thereof.
2. The process as claimed in claim 1, wherein said conversion of (3S)-5- methyl-3 (nitromethyl) hexane nitrile to Pregabalin or pharmaceutically acceptable salt thereof, comprises the steps of:
a) subjecting said (3S)-5-methyl-3-(nitromethyl) hexane nitrile to catalytic hydrogenation to obtain (3 S)-5-methyl-3-(aminomethyl)hexane nitrile;
b) subjecting said (3S)-5-methyl-3-(aminomethyI)hexane nitrile to acidic or basic hydrolysis to obtain Pregabalin;
c) optionally converting said Pregabalin to pharmaceutically acceptable salt thereof.

3. The process as claimed in claim 1, wherein said conversion of (3S)-5- methyl-3-
(aminomethyl)hexane nitrile to Pregabalin or pharmaceutically acceptable salt
thereof, comprises the steps of:
a) subjecting said (3S)-5-methyl-3-(aminomethyl)hexane nitrile to acidic or basic hydrolysis to obtain Pregabalin;
b) optionally converting said Pregabalin to pharmaceutically acceptable salt thereof.

4. The process as claimed in claim 1, wherein said sulfonate ester is treated with nitromethane or methylamine to obtain (3S)-5-methyl-3-(nitromethyl) hexane nitrile or (3S)-5-methyl-3-(aminomethyl)hexane nitrile.
5. The process as claimed in claim 1, wherein said conversion of (2S)-1-phthalimido-2-[l,l-(dialkylcarboxy)methyl]-4-methyl pentane or (2S)-1-phthalimido-2-[l,l-(diarylcarboxy)methyl]-4-methyl pentane to Pregabalin or pharmaceutically acceptable salt thereof, comprises the steps of:

a) subjecting said (2S)-l-phthalimido-2-[l,l-(dialkylcarboxy)methyI]-4-methy[ pentane or (2S)-l-phthalimido-2-[l,l-(diarylcarboxy)methyl]-4-methy! pentane to hydrolysis, decarboxylation and deprotection reaction to obtain Pregabalin;
b) optionally converting said Pregabalin to pharmaceutically acceptable salt thereof.
6. The process as claimed in claim 1, wherein said alkyl sulfonyl halide or aryl
sulfonyl halide is selected from methane sulfonyl chloride, ethane sulfonyl
chloride, benzene sulfonyl chloride, 2-methyl phenyl sulfonyl chloride, 3-methyl
phenyl sulfonyl chloride, p-toluene sulfonyl chloride, trifluoromethane sulfonyl
chloride, 2-chlorophenyl sulfonyl chloride, 3-chlorophenyl sulfonyl chloride,
4-chlorophenyl sulfonyl chloride, 2-bromophenyl sulfonyl chloride,
3-bromophenyl sulfonyl chloride, 4-bromophenyl sulfonyl chloride, 2-nitrophenyl
sulfonyl chloride, 3-nitrophenyl sulfonyl chloride or 4-nitrophenyl sulfonyl
chloride; and wherein said dialkyl malonate or diaryl malonate is selected from
dimethyl malonate, diethyl malonate, dibenzyl malonate or ditosyl malonate.

7. The process as claimed in claim 5, wherein said (2S)-l-phthalimido-4-methyl-2-pentanol is prepared by treating (2S)-l-halo-4-methyl-2-pentanoI with sodium phthalimide or potassium phthalimide to obtain (2S)-l-phthalirnido-4-methyt-2-pentanol.
8. A compound selected from the group consisting of,
where Rl= any activating group such as mesyl, esyl, tosyl, 2-methyl phenyl sulfonyl, 3-methyl phenyl sulfonyl, benzene sulfonyl, trifluoromethane sulfonyl, 2-chlorophenyl sulfonyl, 3-chlorophenyl sulfonyl, 4-chlorophenyl sulfonyl, 2-bromophenyl sulfonyl, 3-bromophenyl sulfonyl, 4-bromophenyl sulfonyl, 2-nitrophenyl sulfonyl, 3-nitrophenyl sulfonyl or 4-nitrophenyl sulfonyl;
where Rl= -H or any activating group such as mesyl, esyl, tosyl, 2-methyl phenyl sulfonyl, 3-methyl phenyl sulfonyl, benzene sulfonyl trifluoromethane sulfonyl, 2-chlorophenyl sulfonyl, 3-chlorophenyl sulfonyl, 4-chlorophenyl sulfonyl, 2-bromophenyl sulfonyl, 3-bromophenyl sulfonyl, 4-bromophenyl sulfonyl, 2-nitrophenyl sulfonyl, 3-nitrophenyl sulfonyl or 4-nitrophenyl sulfonyl;

R2 and R3 can be same or different and are selected from hydrogen, carboxybenzyl (CBZ), tert-butyloxycarbonyl(BOC), benzyl, benzoyl or acetyl; R2 and R3 can together form a ring structure such as phthalimido group or succinimido group,
with the proviso that when Rl=-H, R2 and R3 together represent a phthalimido group; and
where R4 and R5 can be same or different and are selected from -H, methyl, ethyl, propyl, benzyl, tolyl or the like.
9. The compound as claimed in claim 8, wherein
in compound of formula II, Rl is selected from mesyl, esyl or tosyl; and
in compound of formula IV, Rl is selected from mesyl, esyl or tosyl, R2 and R3
together represent a phthalimido group.
10. The process as claimed in claim 1, wherein a compound selected from
Formula II, Formula III, Formula III A, Formula IV or Formula V, as defined in
claim 8, is converted to Pregabalin.