FIELD OF THE INVENTION
The field of the invention relates to the preparation of highly pure (S)-pregabalin, an anticonvulsant agent.
BACKGROUND OF THE INVENTION
(S)-Pregabalin of formula I is used to activate GAD (L-glutamic acid decarboxylase) enzyme which catalyzes the decarboxylation of glutamate to GABA (Gamma-amino butyric acid) and carbon dioxide. GABA (Gamma-amino butyric acid) is one of the brain's major inhibitory neurotransmitters.

(Formula Removed)

(S)-Pregabalin is useful in anticonvulsant therapy used for neuropathic pain, as an adjunct therapy for partial seizures. It has also been found effective for generalized anxiety disorder. (S)-Pregabalin is marketed by Pfizer under the trade name Lyrica® and is chemically known as (S)-3-(aminomethyl)-5-methylhexanoic acid.
(S)-Pregabalin was first disclosed in US patent 5,563,175 and two routes have been disclosed to prepare (S)-pregabalin. In both the routes, (S)-pregabalin is prepared by initially the condensation of (4R, 5S)-4-methyl-5-phenyl-2-oxazolidinone, chiral auxiliary with 4-methyl-pentanoyl chloride in presence of n-butyl lithium and tetrahydrofuran at a temperature of-78 °C to form an acyloxazolidinone intermediate. The acyloxyoxazolidonone intermediate is then condensed with alkyl or aryl substituted a-bromoacetate followed by removal of chiral auxiliary with lithium hydroxide and hydrogen peroxide to form substituted pentanoic acid intermediate. This intermediate undergo reduction to form an alcohol intermediate which is then treated with tosyl chloride followed by reaction with sodium azide and finally hydrogenation to form (S)-pregabalin. The use of highly moisture and air sensitive
reagent like n-butyllithium and the low temperature (-78 °C) for the condensation reaction to form an acyloxazolidinone intermediate makes the process unsuitable for
large scale production.
Preparation of racemic pregabalin is also reported in an article, Synthesis (1989), (12), 953-5 According to this, racemic pregabalin is prepared by Michael addition of nitromethane to 5-methyl-hex-2-enoic acid ethyl ester mediated by 1,1,3,3-
tetramethylguanidine or 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) to give 5-methyl-3-nitromethyl-hexanoic acid ethyl ester which is then hydrogenated either by hydrogenolysis or by high pressure catalytic hydrogenation to give corresponding amino ester which is further subjected to acid hydrolysis to give racemic pregabalin. Use of potentially unstable and explosive reagent like nitromethane, which is difficult to handle, makes the process unattractive for the industrial scale production.
US patent 5,637,767 discloses a process for the preparation of (S)-pregabalin by condensation of isovaleraldehyde with malonic acid or its diester derivatives of the following formula,

(Formula Removed)
wherein R1 and R2 are the same or different and are hydrogen, C1-C6 alkyl, aryl,
benzyl, substituted benzyl, or C3-C6 cycloalkyl
in presence of catalytic amount of base in refluxing hydrocarbon solvent to give olefinic intermediate of the following formula II.

(Formula Removed)
wherein R1 and R2 are as defined above
The olefinic intermediate of formula II is cyanated with a source of cyanide ion in a polar protic or polar aprotic solvent followed by addition of n-hexane and an acid to give cyano diester intermediate of the formula III,

(Formula Removed)
After completion of cyanation reaction, cyano diester intermediate of formula III is isolated by the addition of water and subsequent layer separation. Aqueous layer is re-extracted with n-hexane; combined hexane layer is washed with water and further concentrated to isolate cyano diester intermediate of formula III.
The cyano diester intermediate of formula III is thereafter decarboxylated with an alkali or alkaline earth metal salt in a solvent and hydrolyzed with an aqueous solution of potassium hydroxide in a polar protic solvent to give carboxylate salt of following formula IV,

(Formula Removed)

where Mis hydrogen, alkali or alkaline earth metal
The carboxylate salt of formula IV is hydrogenated in the presence of sponge nickel catalyst in a mixture of water and polar protic solvent to give carboxylate salt of racemic pregabalin. The carboxylate salt of racemic pregabalin is protonated with mineral acid or carboxylic acid to give racemic pregabalin of following formula V.

(Formula Removed)
Racemic pregabalin of formula V is resolved with selective crystallization with (S)-mandelic acid in a solvent such as water or an alcohol or mixtures thereof to give (S),(S)-mandelate salt of pregabalin of following formula VI.

(Formula Removed)
The (S),(S)-mandelate salt of pregabalin of formula VI is heated with polar protic solvent or mixture thereof with water to give (S)-pregabalin of formula I. (S)-pregabalin is further purified by recrystallization with isopropyl alcohol-water mixture.
The patent does not disclose cyanide ion content of any of the intermediates during the preparation of (S)-pregabalin and the cyanide ion content in final product is also not mentioned. The repetition of the exemplified process to prepare cyano diester intermediate of formula III by the present inventors demonstrates that this cyano diester intermediate has free cyanide ion. Even after treatment with more amount of acid, such as acetic acid, hydrochloric acid, sulfuric acid and the like and aqueous work up, the level of cyanide ion content in the organic layer is not reduced significantly. The patent is silent on the cyanide ion content of this intermediate and of final product.
In our hand we have found significant amount of cyanide ion content at cyano diester intermediate and at different intermediate stages, which is then carried over to the final product during the process. Thus final API synthesized by repeating the above process displays high amount of cyanide ion content which does not comply with the guidelines of regulatory agencies.
US patent application 2005/283023 discloses preparation of (S)-pregabalin by catalytic hydrogenation of the enantiomerically pure 3-cyano-5-methylhexanoic acid
which is obtained by the successive enzymatic kinetic resolution, isolation and hydrolysis of the racemic cyano diester intermediate of formula III..
PCT publication WO 2007/143152 discloses preparation of (S)-pregabalin by decarboxylation of cyano diester intermediate of formula III followed by protonation to give 3-cyano-5-methyl-hexanoic acid which is resolved with a chiral resolving agent to give 3(S)-cyano-5-methyl-hexanoic acid that is further catalytically hydrogenated to give (S)-pregabalin. PCT publication is silent about the preparation of cyano diester intermediate of formula III.
A recently published PCT application WO 2008/062460 discloses a process for the preparation of (S)-pregabalin by using olefinic intermediate of formula II having increased isomeric yield and isomeric olefinic impurity less than 3 % which is prepared by condensation of isovaleraldehyde with malonic acid diester in the presence of morpholine base. Patent application further describes the conversions of the olefinic intermediate of formula II to cyano diester intermediate of formula III by cyanation with a cyanide ion source in ethanol followed by acidic aqueous workup. The cyano diester intermediate of formula HI is decarboxylated by heating with sodium chloride in a mixture of polar aprotic solvent and water followed by hydrolysis with alkali or alkaline metal hydroxide and subsequent hydrogenation to give racemic pregabalin of formula V. Racemic pregabalin is resolved with (S)-mandelic acid in a mixture of alcohol and water followed by hydrolysis with a polar aprotic solvent or mixture thereof with water to give crude (S)-pregabalin, which is further purified by multiple recrystallizations with a mixture of isopropyl alcohol and water. This PCT publication does not provide any data for the cyanide content of different intermediates and (S)-pregabalin.
All the prior art processes are completely silent about the cyanide ion content at the intermediate stages as well as in the final API. Free cyanide ion is highly toxic in nature; it interferes with the cellular system of a body. Therefore before formulating an API, highly toxic compound such as cyanide ion must either be absent in the drug
or present in acceptable amount. According to the regulatory guidelines cyanide ion content must be less than 5 ppm in the final product. Hence there is an urgent need to develop an alternative method to prepare (S)-pregabalin with low or negligible amount of cyanide ion.
In view of the difficulty in completely removing the free cyanide ion along with other impurities from the solution of cyano diester intermediate of formula III in organic solvent by usual working up procedures like washing with water or dilute acid after cyanation of olefinic intermediate of formula II. Thus there is an urgent need for developing a process which will result in the elimination of the free cyanide ion from the intermediates which leads to highly pure (S)-pregabalin. Thus Present invention devises a simple and commercially attractive process to remove cyanide ion and prepare highly pure (S)-pregabalin with very low amount of cyanide ion.
OBJECT OF THE INVENTION
The foremost object of the present invention is to provide highly pure (S)-pregabalin which comply with the guidelines of different regulatory agencies.
Another object of the present invention is to provide (S)-pregabalin having cyanide ion content less than 5 ppm or free from cyanide ion.
Yet another object of the present invention to prepare highly pure (S)-pregabalin by using least number of solvents and achieving better yield and purity to make the process operationally efficient and commercial viable.
SUMMARY OF THE INVENTION
Accordingly, in one embodiment, the present invention provides a process to prepare highly pure (S)-pregabalin having cyanide ion content less than 5 ppm, comprising the steps of:
a) reacting the olefinic intermediate of formula II,

(Formula Removed)
wherein R1 and R2 are the same or different and are hydrogen, C1-C6, alkyl, aryl, benzyl, substituted benzyl, or C3-C6 cycloalkyl
with a source of cyanide ion in a polar solvent or a mixture of water and polar solvent to form cyano diester intermediate of formula III,

(Formula Removed)
wherein R1 and R2 are same as defined above
b) treating the reaction mixture with an acid and water,
c) extracting organic layer with an aqueous solution containing cyanide quenching
agent,
d) optionally repeating step c), and
e) converting the cyano diester intermediate of formula III to (S)-pregabalin
In yet another embodiment, the present invention provides a process for preparing highly pure (S)-pregabalin having cyanide ion content less than 5 ppm or free from cyanide ion, comprising the steps of:
a)
(Formula Removed)
reacting the olefinic intermediate of formula II,
wherein R1 and R2 are the same or different and are hydrogen, C1-C6 alkyl, aryl, benzyl, substituted benzyl, or C3-C6 cycloalkyl
with a source of cyanide ion in a polar solvent or a mixture of water and polar solvent to form cyano diester intermediate of formula III,

(Formula Removed)
wherein R1 and R2 are same as defined above
b) treating the reaction mixture with an acid and water,
c) extracting organic layer with an aqueous solution containing cyanide quenching agent,
d) optionally repeating step c),
e) decarboxylating and hydrolyzing the cyano diester intermediate of formula III to form carboxylate salt of formula IV,

(Formula Removed)
f) hydrogenating the carboxylate salt of formula IV with hydrogenation catalyst in presence of hydrogen to form racemic pregabalin,
g) optionally purifying racemic pregabalin,
h) resolving racemic pregabalin to obtain (S)-pregabalin, and i) optionally, purifying (S)-pregabalin.
DETAILED DESCRIPTION OF THE INVENTION
In one preferred embodiment, the present invention relates to a process for the preparation of (S)-pregabalin having cyanide ion content less than 5 ppm, preferably free from the cyanide ion. According to present invention the reduction in the level of cyanide ion content is achieved at intermediate stage during the preparation of (S)-pregabalin by extracting cyano diester intermediate of formula III with an aqueous solution containing cyanide quenching agent.
Typically, the process involves the reaction of olefinic intermediate of formula II,

(Formula Removed)
wherein R1 and R2 are the same or different and are hydrogen, C1-C6 alkyl, aryl, benzyl, substituted benzyl, or C3-C6 cycloalkyl
C1-C6 alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl; C3-C6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Aryl groups include phenyl and substituted phenyl, naphthyl, pyridinyl, and the like; the aryl moiety may be substituted with one or more substituents, which can be the same or different and includes C1-C6 alkyl, C1-C6 alkoxy and halogen. Preferably, R1 and R2 are ethyl
with a source of cyanide ion in polar solvent or a mixture of water and polar solvent to form cyano diester intermediate of formula III.
Generally, the process involves the treatment of'olefinic intermediate of formula II with a source of cyanide ion followed by stirring at a temperature of 10 to 60 °C for a period of about 4-24 hours, preferably at a temperature of 35 to 45 °C for about 6-8 hours. Suitable source of cyanide ion include, but not limited to, hydrogen cyanide, acetone cyanohydrins or an alkali metal or alkaline earth metal cyanides such as
sodium cyanide, potassium cyanide, or magnesium cyanide and the like. Suitable
polar solvent include, but not limited to C1-C6 alcohols such as methanol, ethanol, n-
propanol, isopropanol and the like; ethers such as tetrahydrofuran, 1,2-dimethoxy
ethane, 1,2-diethoxyethane; dimethylformamide, dimethylacetamide,
dimethylsulfoxide and the like; or mixture thereof in any suitable proportion. The completion of the reaction is monitored by suitable technique such as thin layer chromatography (TLC) or gas chromatography (GC). After completion of reaction, reaction mixture is diluted with a solvent selected from halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and the like; non polar solvent such as n-pentane, n-hexane, n-heptane, cyclohexane and the like; alkyl ethers such as diethyl ether, isopropyl ether, methyl tertiary butyl ether and the like; C3-C6 alkyl ester such as methyl ester, ethyl ester and the like; aromatic solvent such as toluene, xylene and the like; or mixture thereof. Diluted mixture is treated with an aqueous solution of an acid. Suitable acid sources include, but not limited to, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and the like.
The organic layer is separated from the resulting biphasic mixture and extracted with an aqueous solution containing cyanide quenching agent. Cyanide quenching agents include, but not limited to sodium hypochlorite, potassium thiosulfate, sodium thiosulfate or sodium hypo sulfate or compounds which are source of cobalt or trivalent iron. Cyanide ion has a high affinity for metals like cobalt and trivalent iron, and sodium thiosulfate like compounds which contains a sulfur-to-sulfur bond. Suitable trivalent iron sources include, but not limited to, ferric chloride and ferrous sulphate the like.
Preferably an aqueous solution of sodium thiosulfate or sodium hypochlorite is employed. The percentage of the cyanide quenching agent in water may vary from 1 to 50%, preferably 10 to 15% solution is employed.
Multiple extractions can be employed to achieve cyanide ion content below 100 ppm, preferably less than 50 ppm or more preferably less than 5 ppm.
The following tabular data further describes the cyanide ion content before and after the extraction of organic layer with aqueous sodium thiosulfate solution with respect to the prior art processes.
(TABLE REMOVED)
It has been clearly observed by comparative data that working up processes of prior art are not suitable to significantly reduce free cyanide ion content from the reaction mixture. Thus free cyanide ion is carried up to final step during the process and shows its high parts per million values as an impurity in final product. However, extraction of the reaction mixture with an aqueous solution of suitable cyanide quenching agent, as described by the present process, is extremely effective to reduce cyanide ion content from 500 ppm to less than 100 ppm at the intermediate stage, preferably from 50 ppm to less than 5 ppm. When the reaction is preceded with this intermediate having fewer amounts of the cyanide ion content, the final product i.e (S)-pregabalin obtained is having either less than 5 ppm of cyanide ion content or completely free from this toxic impurity.
Alternatively, treatment of aqueous sodium thiosulfate solution, sodium hypochlorite solution can be utilized at any stage during the reaction after the cyanation step to achieve (S)-pregabalin having cyanide ion content less than 5 ppm, It is advantageous to perform the washing process at the intermediate stage just after the cyanation reaction i.e at the stage of cyano diester intermediate of formula III. Moreover, it is always preferred to control the impurities at the initial stages of their formation so that yield loss at the further stages does not occur. The removal of such impurity at the later stage may reduce the yield of the final compound, (S)-pregabalin.
The starting olefinic intermediate of formula II is prepared by the known processes of the prior art such as processes disclosed in US 5,637,767 and WO 2008/062460 or the process mentioned in the present invention.
Generally isovaleraldehyde is condensed with malonic acid or its diester derivatives of the following formula,

(Formula Removed)
wherein R1 and R2 are the same or different and are hydrogen, C1-C6 alkyl, aryl, benzyl, substituted benzyl, or C3-C6 cycloalkyl
in refluxing solvent. Condensation can also be achieved by using a catalytic amount of a base such as di-n-propylamine or basic catalyst in combination with an acid such as acetic acid or p-toluene sulfonic acid. Suitable solvent include, but not limited to, aliphatic hydrocarbon solvents such n-hexane, n-heptane; cyclic hydrocarbon solvents such as cyclohexane; ethers such as diethyl ether, isopropyl ether, methyl iso-butyl ether, methyl tert-butyl ether; or chlorinated hydrocarbon solvent such as dichloromethane,l,2-dichloroethane, chloroform; aromatic solvents such as toluene and the like; or mixture thereof. It is advantageous to use chlorinated hydrocarbon solvent to achieve higher ratio of desired olefinic isomer i.e. olefinic intermediate of formula II. During the condensation water is removed azeotropically and
condensation is normally completed in about 2-8 hours. It is advantageous to use another lot of catalytic amount of base and an acid and further refluxed the mixture for another 16-22 hours. The progress of the reaction is monitored by gas chromatography (GC) or thin layer chromatography (TLC) and after the exhaustive aqueous work up the product is isolated as oil. Isolated product can be optionally purified by usual purification procedures known in the prior art. Preferably liquid-liquid extraction is employed by treating the organic layer successively with water, aqueous acidic mixture and aqueous basic solution. Organic layer is separated and solvent is removed by distilling under vacuum below the boiling point of the solvent or without vacuum at the boiling point of the solvent to give olefinic intermediate of formula II.
Olefinic intermediate of formula II undergoes facile Michael addition reaction with a source of cyanide ion to give cyano diester intermediate of formula III. Thereafter, the cyano diester intermediate of formula III is decarboxylated and hydrolyzed by heating in a solvent with a salt or by refluxing it in a solvent with an alkali and alkaline earth metal hydroxide base such as potassium hydroxide, sodium hydroxide, and the like in a solvent to afford carboxylate salt of following formula,

(Formula Removed)
wherein M is hydrogen, alkali or alkaline earth metal such as sodium, potassium and the like
Suitable solvent for the reaction include, but not limited to polar solvent such as methanol, ethanol, n-propanol, isopropanol, butanol, dimethylsulfoxide, and the like or mixtures thereof with water. Sources of suitable salt include, but not limited to, alkali metal and alkaline earth metal halides such as sodium chloride, sodium bromide, potassium bromide, magnesium chloride, calcium chloride and the like; alkali metal and alkaline earth metal hydroxides such as sodium hydroxide, potassium
hydroxide and the like; alkali metal and alkaline earth metal cyanides such as sodium cyanide, magnesium cyanide, and the like. Generally decarboxylation is completed in about 4 to 24 hours. Carboxylate salt of formula IV so formed is isolated by suitable techniques known in the prior art such as evaporation, filtration or washing etc. Alternatively, it may be used in the next step without isolation.
In one aspect, the carboxylate salt of formula IV is reduced to give alkali or alkaline earth metal salt of racemic pregabalin which is protonated to afford racemic pregabalin of formula V.
Basically nitrile functional group of carboxylate salt is reduced in the reaction that can be done by any common processes known in the prior art. One common method of reduction of nitrile is to use hydrogenation catalyst in polar solvent or a mixture of water and polar solvent, in the presence of hydrogen gas to afford racemic pregabalin or salts thereof.
Typically, the hydrogen gas is applied at a pressure of about 2 to about 8 kg/cm2. Preferably, the hydrogen gas pressure applied is about 4 to about 6 kg/cm2. Normally hydrogenation is completed in about 12 to 120 hours.
Sources of hydrogenation catalysts include, but not limited to, palladium, palladium-on-carbon, palladium hydroxide Pd(OH)2, palladium-on-alumina, palladium-on-carbonate, palladium-on-sulfate, platinum, platinum-on-carbon, platinum-on-alumina, platinum dioxide (PtO2), nickel, Raney nickel, nickel-on-alumina, nickel-on-silica, preferably Raney nickel is used.
Optionally racemic pregabalin of formula V is purified by well known methods, e.g. by trituration with organic solvents, or by standard crystallization and recrystallization procedures. Preferably racemic pregabalin is purified by recrystallization using a mixture of alcoholic solvent or a mixture of alcoholic solvent with water.
Alcoholic solvents can be selected from methanol, ethanol, n-propanol, isopropanol, and the like.
According to present invention cyanide ion content at this stage complies with the guidelines of regulatory agencies and it is less than about 8 ppm, preferably less than 5 ppm or more preferably free from the cyanide ion.
Racemic pregabalin of formula V is then resolved to give (S)-pregabalin of formula I.
Generally, the racemic pregabalin is reacted with an optically active resolving reagent in an alcoholic solvent or a mixture of water and alcoholic solvent or mixture thereof to give diastereomeric mixture. Preferably reaction is conducted at 55-70 °C. Further it is stirred for few minutes to few hours at lower temperature; preferably the reaction mixture is stirred for 10-18 hours at ambient temperature. The diastereomers are separated by ordinary separation methods such as selective crystallization, and the like to obtain desired diastereomer salt. Desired diastereomer salt is subjected to a chemical reaction such as acid hydrolysis, base hydrolysis to remove optically active resolution moiety, whereby the desired optical isomer of pregabalin i.e. (S)-pregabalin is obtained. Sources of optically active resolving reagent include, but not limited to, (S)-mandelic acid, (S)-tartaric acid, (S)-l-phenethylamine, (R)-l-phenethylamine and the like. Alcoholic solvent include, but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like.
Preferably, (S)-mandelic acid is reacted with racemic pregabalin in alcoholic solvent or mixture thereof with water to precipitate (S),(S)-mandelate salt of pregabalin of following formula VI,

(Formula Removed)
which is then isolated by filtration. It is advantageous to add additional amount of (S)-mandelic acid to enhance diastereomeric purity of (S),(S)-mandelate salt of pregabalin. (S)-Mandelic acid is removed from the salt by using a polar aprotic solvent such as dimethylsulfoxide or tetrahydrofuran or mixture thereof in presence or absence of water to give (S)-pregabalin.
Optionally, the isolated (S)-pregabalin may be further purified by known methods, e.g. by trituration with alcoholic solvents, or by standard recrystallization procedures using organic solvents. Preferably (S)-pregabalin is purified by recrystallization from an alcoholic solvent or from a mixture of alcoholic solvent and water. Alcoholic solvents can be selected from ethanol, methanol, n-propanol, isopropanol, n-butanol, isobutanol and the like or mixtures thereof.
Before and after purification of (S)-pregabalin cyanide ion content in both cases is found to be very low and usually below the detection limit.
The process of the present invention is highly advantageous in preparing (S)-pregabalin having less than 5 ppm of cyanide ion content or preferably free from the cyanide ion. Another major advantage of the present invention is the utilization of least number of solvents at different stages, hence stages with common solvent can be carried out in one pot. Different stages of the invention are completed almost in similar solvents and solvent is also recycled and hence renders the process cost effective and efficient..
Having described the invention with reference to certain preferred aspects, other aspects will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Preparation of (S)-pregabaHn
Step (I): Preparation of 2-carboxvethyl-5-methylhex-2-enoic acid ethyl ester
To a stirred mixture of diethylmalonate (1.67 kg), isovaleraldehyde (1.0 kg) in dichloromethane (2300 ml), di-n-propylamine (100 g) and acetic acid (200 ml) were added at 25-30 °C. The reaction mixture was refluxed at a temperature of 40-45 °C for 4-6 hours with removal of water azeotropically. A second lot of catalyst di-n-propylamine (100 g) and acetic acid (200 ml) were added and mixture was further refluxed for 18-20 hours with azeotropic removal of water. After completion of reaction, the reaction mixture was cooled to 25-35 °C and demineralized water (4000 ml) was added to the mixture. Reaction mixture was stirred and layers were separated. The organic layer was extracted with IN hydrochloric acid (1000 ml) then washed with demineralized water (4000 ml). The organic layer was successively washed with IN hydrochloric acid (1000 ml) then washed with demineralized water (4000 ml). The organic layer was then treated with 10% sodium bicarbonate solution (1000 ml) and water (4000 ml). Above step of extraction and washing was repeated one more time with the organic layer. The separated organic layer was dried over sodium sulfate, filtered through hyflow bed, washed with dichloromethane and distilled to afford 2.23 kg of title compound having purity of 88.5% by GC.
Step (ID: Preparation of 2-carboxyethyl-3-cyano-5-methyl hexanoic acid ethyl ester
Example 1: To a stirred suspension of potassium cyanide (0.555 kg) in ethanol (2.85 L), 2-carboxyethyl-5-methylhex-2-enoic acid ethyl ester (2.23 kg) was added at 25-30 °C. The reaction mixture was stirred for 7-8 hours at 40-42 °C. After completion of reaction (monitored by gas chromatography), reaction mixture was cooled and dichloromethane (2.85 L), acetic acid (0.56 L) and demineralized water (6.7 L) were added and stirred for 10 minutes. The organic layer was separated and aqueous layer was extracted with dichloromethane (2.85 L). The combined organic layer was
successively washed with 10% sodium thiosulfate solution (1 x 4.5 L) then with demineralized water (2 x 4.5 L). The organic layer was once again successively washed with 10% sodium thiosulfate solution (1 x 4.5 L) then with demineralized water (2 x 4.5 L). The organic layer was separated dried over sodium sulfate, filtered through hyflow bed which was washed with dichloromethane (1.2 L) and distilled to obtain 2.15 kg of title compound having purity 87.01 % by GC. Cyanide ion content: < lOOppm.
Example 2; To a stirred suspension of potassium cyanide (0.250 kg) in ethanol (1.3 L), 2-carboxyethyl-5-methylhex-2-enoic acid ethyl ester (1000 g) was added at 25-30 °C. The reaction mixture was stirred for 1-8 hours at 40-42 °C. After completion of reaction (monitored by gas chromatography), reaction mixture was cooled and dichloromethane (1300 ml), acetic acid (250 ml) and demineralized water (3000 ml) were added and stirred for few minutes. The organic layer was separated and aqueous layer was extracted with dichloromethane (1300 ml). Combined organic layer was extracted with 10% sodium thiosulfate solution (2 x 2000ml) then with demineralized water (2 x 2000ml). The organic layer was separated dried over sodium sulfate and evaporated to obtain title compound having purity of 87% by GC. Cyanide content: < 50ppm.
Example 3: To a stirred suspension of potassium cyanide (44.8 g) in ethanol (257 ml), 2-carboxyethyl-5-methylhex-2-enoic acid ethyl ester (200 g) was added at 25-30 °C. The reaction mixture was stirred for 7-8 hours at 40-42 °C. After completion of reaction (monitored by gas chromatography), reaction mixture was cooled and dichloromethane (259 ml), acetic acid (50.5 ml) and demineralized water (600 ml) were added and stirred for 10 minutes. The organic layer was separated and aqueous layer was extracted with dichloromethane (257 ml). The combined organic layer was successively washed with 10% sodium thiosulfate solution (1 x 400 ml) then with demineralized water (1 x 400 ml). The organic layer was once again successively washed with 10% sodium thiosulfate solution (1 x 400 ml) then with demineralized
water (1 x 400 ml). The organic layer was separated dried over sodium sulfate, filtered through hyflow bed which was washed with dichloromethane (1.2 L) and distilled to obtain 194 g of title compound having purity 87.23 % by GC. Cyanide ion content: < 50 ppm.
Example 4: To a stirred suspension of potassium cyanide (0.497 kg) in ethanol (2.56 L), 2-carboxyethyl-5-methylhex-2-enoic acid ethyl ester (2.0 kg) was added at 25-30 °C. The reaction mixture was stirred for 7-8 hours at 40-42 °C. After completion of reaction (monitored by gas chromatography), reaction mixture was cooled and dichloromethane (2056 L), acetic acid (0.50 L) and demineralized water (6.0 L) were added and stirred for 10 minutes. The organic layer was separated and aqueous layer was extracted with dichloromethane (2.56 L). The combined organic layer was successively washed with 10% sodium thiosulfate solution (1 x 4.0 L) then with demineralized water (2 x 4.0 L). The organic layer was once again successively washed with 10% sodium thiosulfate solution (1 x 4.0 L) then with demineralized water (2 x 4.0 L). The organic layer was separated dried over sodium sulfate, filtered through hyflow bed which was washed with dichloromethane (1.2 L) and distilled to obtain 2.0 kg of title compound having purity 86.79 % by GC. Cyanide ion content: < 5 ppm.
Step III: Preparation of racemic pregabalin
To a stirred solution of 2-carboxyethyl-3-cyano-5-methyl hexanoic acid ethyl ester (2.15 kg) in ethanol (0.75 L), a solution of potassium hydroxide (0.45 kg) in ethanol (2.25 L) was added at ambient temperature. The mixture was refluxed for 4-6 hours at 75-80 °C and then cooled to ambient temperature. A solution of potassium hydroxide (0.91 kg) in demineralized water (1.5 L) was added to the resulting mixture and further stirred for 1 hour at the same temperature. The mixture was hydrogenated under a hydrogen gas pressure (5 kg/cm ) for 48 hours at room temperature in the presence of Raney nickel (0.33 kg). The catalyst was filtered through hyflow bed under nitrogen gas atmosphere and washed with a mixture of ethanol (1.0 L) and
demineralized water (2.0 L). Ethanol was removed by distillation under vacuum. The resulting residue was slowly added to acetic acid (1.6 L) at 50-60 °C. The reaction mixture was cooled to ambient temperature and further stirred for 12 hours. The reaction mixture was further cooled to 0-5 °C and stirred for 3-4 hours. The resulting product was filtered, washed with tetrahydrofuran (1.1 L) and dried under vacuum for 24 hours to obtain 1.03 kg of title compound.
Step IV: Purification of racemic pregabalin
Racemic pregabalin (1.03 kg) was taken in ethanol (6.5 L) and water (2.8 L) and heated at 70-75 °C to afford clear solution. The solution was filtered, slowly cooled to 0-5 °C and stirred for 2 hours at same temperature. The precipitated solid was filtered, washed with ethanol (1.0 L) and dried at 40-45 °C to afford 0.67 kg of title compound having purity 99.62% by HPLC. Cyanide ion content: < 2 ppm
Step V: Preparation of (S)-pregabalin
A suspension of (S)-mandelic acid (0.86 kg) in absolute ethanol (6.0 L) and racemic pregabalin (0.60 kg) was heated to 60-65 °C to afford clear solution. The solution was cooled to ambient temperature and stirred for 16 hours. The resulting precipitated solid was filtered, washed with ethanol (0.30 L) and suck dried for 1 hour. The wet material was again treated with (S)-mandelic acid (0.143 kg) in ethanol (3.0 L) at 65-70 °C to afford a clear solution. The solution was cooled to 0-5 °C and stirred for 4 hours then filtered, washed with ethanol (0.30 L) and suck dried for 1 hour.
The wet material was taken in tetrahydrofuran (2.85 L) and demineralized water (0.15 L) and stirred for 20-25 minutes at 50-55 °C. The solution was then cooled to 0-5 °C and stirred for 4 hours at the same temperature. The precipitated solid was filtered, washed with ethanol (0.30 L) and dried at 40-45 °C under vacuum to obtain title compound.
Step VI: Purification of (S)-pregabalin
(S)-Pregabalin was taken in ethanol (1.75 L) and water (0.75 L) and heated at 70-75 °C to afford clear solution. The solution was filtered, slowly cooled to 0-5 °C and stirred for 4 hours at same temperature. The precipitated solid was filtered, washed with ethanol (0.30 L) and dried at 40-45 °C under vacuum to afford 0.137 kg of title compound having purity 99.92% by HPLC. Cyanide ion content: Not Detected.

WE CLAIM
1) A process for the preparation of highly pure (S)-pregabalin of formula I having cyanide ion content less than 5 ppm or free from cyanide ion

(Formula Removed)
which comprises:
a) reacting the olefinic intermediate of formula II,

(Formula Removed)
wherein R1 and R2 are the same or different and are hydrogen, C1-C6 alkyl, aryl, benzyl, substituted benzyl, or C3-C6 cycloalkyl
C1-C6 alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl; C3-C6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; aryl groups include phenyl and substituted phenyl, naphthyl, pyridinyl, and the like; aryl moiety may be substituted with one or more substituents, which can be the same or different and include C1-C6, alkyl, C1-C6 alkoxy and halogen
with a source of cyanide ion in a polar solvent or a mixture of water and polar solvent to form cyano diester intermediate of formula III,

(Formula Removed)
wherein R1 and R2 are same as defined above
b) treating the reaction mixture with an acid and water,
c) extracting organic layer with an aqueous solution containing cyanide quenching agent,
d) optionally repeating step c), and
e) converting the cyano diester intermediate of formula III to (S)-pregabalin.

2) The process according to claim 1, wherein in step a) source of cyanide ion include hydrogen cyanide, acetone cyanohydrin or an alkali metal or alkaline earth metal cyanide, such as sodium cyanide, potassium cyanide, or magnesium cyanide and the like; and polar solvent include C1-C8 alcohols; ethers; dimethyl formamide, dimethyl acetamide, dimethylsulfoxide and the like; or mixture thereof.
3) The process according to claim 1, wherein in step b) acid is selected from acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like.
4) The process according to claim 1, wherein in step c) cyanide quenching agent include sodium hypochlorite, potassium thiosulfate, sodium thiosulfate or sodium hyposulfate or compounds which are source of cobalt, trivalent iron.
5) A process for the preparation of (S)-pregabalin of formula I having cyanide ion content less than 5 ppm or free from cyanide ion,

(Formula Removed)
a) reacting the olefinic intermediate of formula II,

(Formula Removed)
wherein R1 and R2 are the same or different and are hydrogen, C1-C6 alkyl, aryl, benzyl, substituted benzyl, or C3-C6 cycloalkyl
C1-C6 alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl; C3-C6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; aryl groups include phenyl and substituted phenyl, naphthyl, pyridinyl, and the like; aryl moiety may be substituted with one or more substituents, which can be the same or different and include C1-C6 alkyl, C1-C6 alkoxy and halogens
with a source of cyanide ion in a polar solvent or a mixture of water and polar solvent to form cyano diester intermediate of formula III,

(Formula Removed)
wherein R1 and R2 are same as defined above
b) treating the reaction mixture with an acid and water,
c) extracting organic layer with an aqueous solution containing cyanide quenching agent,
d) optionally repeating step c),
e) decarboxylating and hydrolyzing the cyano diester intermediate of formula III to form carboxylate salt of formula IV,

(Formula Removed)

where M is hydrogen, alkali or alkaline earth metal such as sodium, potassium and the like
f) hydrogenating the carboxylate salt of formula IV with hydrogenation catalyst in presence of hydrogen to form racemic pregabalin,
g) optionally purifying racemic pregabalin,
h) resolving racemic pregabalin to (S)-pregabalin using optically active resolving reagent and,
i) optionally purifying (S)-pregabalin.
6) The process according to claim 4, wherein in step a) source of cyanide ion include hydrogen cyanide, acetone cyanohydrin or an alkali metal or alkaline earth metal cyanide, such as sodium cyanide, potassium cyanide, or magnesium cyanide and the like; and polar solvent include C1-C8 alcohols such as methanol, ethanol, n-propanol, isopropanol; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxy ethane; dimethyl formamide, dimethyl acetamide, dimethylsulfoxide and the like; or mixture thereof.
7) The process according to claim 4, wherein in step b) acid is selected from acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like and in step c) cyanide quenching agent include sodium hypochlorite, potassium thiosulfate, sodium thiosulfate or sodium hyposulfate or compounds which are source of cobalt, trivalent iron.
The process according to claim 4, wherein in step e) decarboxyltion and hydrolysis is carried out with alkali or alkaline earth metal hydroxide base such as sodium hydroxide, potassium hydroxide and the like or in a solvent which
include methanol, ethanol, n-propanol, isopropanol, butanol, dimethyl sulfoxide, and the like or mixtures thereof with water.
9) The process according to claim 4, wherein in step f) hydrogenation catalysts
include palladium, palladium-on-carbon, palladium hydroxide Pd(OH)2,
palladium-on-alumina, palladium-on-carbonate, palladium-on-sulfate, platinum,
platinum-on-carbon, platinum-on-alumina, platinum dioxide (PtCh), nickel.
Raney nickel, nickel-on-alumina, nickel-on-silica and the like.
10) The process according to claim 4, wherein in step g) and i) purification of
racemic and (S)- pregabalin is carried out by crystallization with an alcoholic
solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol,
isobutanol and the like or a mixture of alcoholic solvent and water.