Title of Invention

PROCESS OF PREPARING CRYSTALLINE PREGABALIN

Abstract

The invention relates to crystalline form of Pregabalin and their process of preparation. The invention also relates to a process for preparing 2-carbethoxy-5-methylhex-2-enoic acid ethyl ester, an important intermediate for synthesis of crystalline Pregabalin, having less than about, 1-2% 2-carbethoxy-5-methylhex-3-enoic acid ethyl ester. Moreover, the present invention provides industrially applicable process for recovery of chiral reagent used for resolution of the (±)-Pregabalin; thereby to provide cost effective and economical process for preparation of Pregabalin.

Full Text

FORM 2 THE PATENTS ACT, 1970 (3.9 of 1970) & The Patent Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION "PROCESS OF PREPARING CRYSTALLINE PREGABALIN AND ITS HIGHLY PURE INTERMEDIATE THEREOF" We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad-380015, Gujarat, India. The following specification describes the invention: Field of Invention: The present invention relates to crystalline forms of Pregabalin and their process of preparation. The invention also relates to a process for preparing pure Pregabalin via 2-carbethoxy-5-methylhex-2-enoic acid ethyl ester, an important intermediate for synthesis of crystalline Pregabalin, having less than about, 1-2% of 2-carbethoxy-5-methylhex-3-enoic acid ethyl ester. The present invention also relates to prepare enantiomerically pure (S)-(+)-3- I ■ :| (aminomethyl)-5-methylhexanoic acid (Pregabalin) of Formula (I) free from (R)-enantiomer, obtained by optionally resolving the racemate (±)-Pregabalin by a standard method of resolution. Thus, process for the recovery of standard resolving agent used for resolution of the (±)-Pregabalin, thereby to provide cost effective and economical process for preparation of (S)-(+)-Pregabalin is also the field of present invention. ij NH2 COOH Formula (I) Background of the Invention: 3-(aminomethyl)-5-methylhexanoic acid, which is also called /Msobutyl-y-aminobutyric acid or isobutyl-GABA, is a potent anticonvulsant. Isobutyl-GABA is related to the endogenous inhibitory neurotransmitter, y-aminobutyric acid or GABA, which is involved in the regulation of brain neuronal activity. Jregabalin may be prepared using known methods. In some of these methods, a racemic mixture of 3-aminomethyl-5-methyl-hexanoic acid is synthesized and subsequently resolved into its R- and S-enantiomers. Such methods are described in U.S. Pat. No. 5,563,175 to R. B. Silverman et. al., U.S. Pat. No. 6,046,353 to T. M. Grote et al, U.S. Pat. No. 5,840,956 to T. M. Grote et. al., U.S. Pat. No. 5,637,767 to T. M. Grote et. al, U.S. Pat. No. 5,629,447 to B. K. Huckabee & D. M. Sobieray, and U.S. Pat. No. 5,616,793 to B. K. Huckabee & D. M. Sobieray. In each of these methods, the racemate is reacted with a chiral acid (a resolving agent) to form a pair of diastereoisomeric salts, which are separated by known techniques, such as fractional crystallization and chromatography. In other methods, Pregabalin is synthesized directly using a chiral auxiliary, (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone. See, e.g., U.S. Pat. Nos. 6,359,169, 6,028,214, 5,847,151, 5,710,304, 1 5,684,189, 5,608,090, and 5,599,973, all to Silverman et. al. In still other methods, Pregabalin is prepared via asymmetric hydrogenation of a cyano-substituted olefin to produce a chiral cyano precursor of (S)-3-aminomethyl-5-methyl hexanoic acid, which is subsequently reduced to yield Pregabalin. See U.S. Patent Application 2003/0212290 A1 to Burk et al. j Furthermore, like Gabapentin, Pregabalin is a gamma-amino acid, which under normal storage conditions and in the presence of water may undergo intramolecular cyclization to form the lactam, 4-isobutyl-pyrrolidin-2-one. See, e.g., WO 99/10186 and WO 99/5957i3, both to A. Aomatsu. Although it is known that the non-active components of the composition may affect lactam formation, it is difficult to predict which excipients or adjuvant may lead to undesirable lactam formation, j The most frequent approach is to design a compound that crosses the blood brain j barrier and then inactivates GABA aminotransferase. The effect is to block the degradation of GABA and thereby increase its concentration. Another approach is to increase GAElA concentrations in the brain by making GABA lipophilic by conversion to hydrophobic GABA amides {Kaplan J. P., et al, G.J. Med. Chem. 1980;23:702-704; Carvajal G., et al, Biochem. Pharmacol 1964;13:1059-1069; Imines: Kaplan J. P., Ibid.; or GABA esters: ShashouaV. K, et al, J., Med. Chem. 1984;27:659-664; and PCT Patent Application WO85/00520, published Feb. 14, 1985). So, that GABA can cross the blood brain barrier. Once inside the brain, these compounds require amidase and esterases to hydrolyze off the carrier group and release GABA. .! I i It has been discovered that the anticonvulsant effect of isobutyl-GABA ^ is stereoselective. That is, the S-stereoisomer of isobutyl-GABA shows better anticonvulsant activity than the R-stereoisomer. See, for example, Yuen, et al, in Bioorganic & Medicinal Chemistry Letters, 1994;4(6):823-826. Thus, it would be beneficial to have an efficient process for the synthesis of the S-stereoisomer of isobutyl-GABA. in Ullmann's Encyclopedia of Industrial Chemistry Vol. 18 A (1991) page 182/183 and in Rompp-Chemie Lexikon Vol. 4 (1991) page 2623 the resolution of certain optically pure enantiomers has been described. These documents, however, do not mention the resolution of y-amino acids. Furthermore the processes disclosed require the protection of the amino acids by additional process steps. >[U.S. Patent No. 5,637,767 discloses the process for preparation of (S)-(+)-Pregabalin via 2-carboyethyl-5-methylhex-2-enoic acid, ethyl ester by reaction of isovaleraldehyde and diethyl malonate in presence of di-n-pfopylamine in hexane and glacial acetic acid. The reaction also generates the unwanted olefin isomer (typically 10-13% by GC) i.e.j-2- 2 carboyethyl-5-methylhex-3-enoic acid, ethyl ester. Thus, GC assay shows 74-76% 2-carboyethyl-5-methylhex-2-enoic acid, ethyl ester; 10-13% 2-carboyethyl-5-methylhex-3-enoic acid, ethyl ester; 87-88% total of both isomers. [See Example-1, Column-11, Line-15- 25]. 1 .i The patent also discloses the process for resolution of racemic Pregabalin with S-(+)-mandelic acid, thereby to obtain enantiomerically pure (S)-(+)-Pregabalin. Thus, there is always a need for the process to obtain (S)-(+)-Pregabalin from 2-carboyethyl-5-methylhex- 2-enoic acid as one of the intermediate having less olefin isomer and high purity by GC. Also, there is a need for the recyclability of the resoluting agent by its recovery. U.S. Patent No. 6,046,353 also discloses the same process for preparation of (S)-(+)- Pregabalin enantiomerically pure free from (R)-(-)-Pregabalin or having LDT (lower i detection limit) less than 0.5%. Thus, it is evident that 2-carboethyl-5-methylhex-2-enoic acid, ethyl ester is the important intermediate for preparation of (S)-(+)-Pregabalin. Also the resolution is achieved in the similar manner as disclosed in U.S. Patent No. 5,637,767. Thus, there is always need to provide simple and cost effective process for the preparation of (S)-(+)-Pregabalin via olefin isomer having less than 1-2% of other olefin isomer and the 40-55]. reusabiliity of chiral agent for resolution by its recovery. [See Example-1, Column-11, Line- Organic Process Research & Development, 1997', 1, 27-38 also showed the same process for the preparation of (S)-(+)-Pregabalin from 2-carboethyl-5-methylhex-2-enoic acid, ethyl ester (40) as the important intermediate formed by reaction, between isovaleraldehyde and diethyl molonate in presence of di-n-propylamine in hexane and glacial acetic acid. The process also results in 10-13% by GC assay in another olefin isomer. The process also follows the classical technique for the resolution with S-(+)-mandelic acid. Thus, in a broad aspect, the present invention provides the process for preparing 2- i carboethyl-5-methylhex-2-enoic acid having less than about 1-2% of 2-carboethyl-5- methylhex-3-enoic acid and recovery of chiral reagent (S)-(+)-mandelic acid form (S)-(+)- mandelate salt of Pregabalin, thereby to provide the industrially applicable, simple and cost effective and economical process for preparing (S)-(+)-Pregabalin enantiomerically pure, having NMT 0.5% of its (R)-enantiomer. In general, crystalline forms of drugs are preferred over amorphous forms of drugs, in part, because of their superior stability. For example, in many situations, an amorphous drug converts to a crystalline drug form upon storage. Because amorphous and crystalline forms of a drug typically have differing physical/chemical properties, potencies and/or 3 bioavailabilities, such interconversion is undesirable for safety reasons in pharmaceutical administration. A key characteristic of any crystalline drug substance is the polymorphic behavior of such a material. i Polymorphs are crystals of the same molecule, which have different physical properties because the crystal lattice contains a different arrangement of molecules. The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density (important in formulation and product manufacturing) and dissolution rates (important in determining bioavailability). Stability differences: may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e. g,, tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e. g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency or are toxic. In addition, the physical properties of the crystalline form may be important in pharmaceutical processing. For example, a. particular crystalline form may form solvates more readily or may be more difficult to filter and wash free of impurities than other forms (i.e., particle shape and size distribution might be different between one crystalline form relative to other forms). WO2005/037784 discloses the crystalline forms of l-{[(a-Isobutanoyloxy ethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid, (1), a prodrug of the GABA analog Gabapentin. WO2002/100347 discloses the method of preparation of prodrug and further discloses the glassy solid material obtained after lyophilization from aqueous acetonitrile. The material obtained by this process is partially or wholly amorphous and certain alkali metal salt forms are hygroscopic. ^ode No. IPCOM000073295D of IP prior art database shows the crystal form of the active ingredient in LYRICA 300 mg hard capsules (3S)-3-(aminomethyl)-5-methylhexanoic acid. ILYRICA 300 mg hard capsules (3S)-3-(aminomethyl)-5-methylhexanoic acid (0617034) was analyzed by XRD. The active ingredient in LYRICA 300 mg hard capsules Pregabalin shows the main XRD peaks of powder diffractogram 29 (± 0.2) 9.5, 12.3, 16.7, 17.8, 18.3, 19.1, 19.9, 20.3, 22.3, 22.8, 23.3, 23.6, 24.8, 26.2, 26.6, 27.0, 27.7, 28.1, 28.7, 29.3, 30.0, 30.4, 31.0, 31.5, 32.1, 33.0, 33.3, 34.1, 34.8, 35.8, 37.5, 38.8. 4 Based on the XRD pattern of the active ingredient Pregabalin is crystalline anhydrous Form-I. Thus, the scope of the present invention relates to crystalline polymorph of Pregabalin i.e. anhydrous Form-I, having brick shape crystal habit as shown in Figure-IA and Figure-IB. J Thus, the invention relates to crystalline form of Pregabalin having brick shape crystal habit and their process of preparation. The invention also relates to a process for preparing pure Pregabalin via 2-carbethoxy-5-methylhex-2-enoic acid ethyl ester, an important intermediate for synthesis of crystalline Pregabalin, having less than about, 1-2% of 2-carbethoxy-5-methylhex-3-enoic acid ethyl ester. The present invention also relates to prepare enantiomerically pure (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin) of Formula (I) free from (R)-enantiomer, obtained by optionally resolving the racemate (±)-Pregabalin by a standard method of resolution. Thus, process for the recovery of standard resolving agent used for resolution of the (±)-PregabaIin, thereby to provide cost effective and economical process for preparation of (S)-(+)-Pregabalin is also the field of present invention. Summary of the Invention: n one aspect, the present invention provides the compounds R102C C02R2 .CN where Ri and R2 are the same or different and are hydrogen, Cj-Ce alkyl, aryl, benzyl or C3 C6 cycloalkyl; where M is hydrogen, an alkali metal, or an alkaline earth metal; -CN ^CC^R! where Ri is defined above; 5 and NH3+ C02H -02C^OH The present invention also provides a method of making (±)-3-(aminomethyl)-5-methylhexanoic acid which comprises condensing isovaleraldehyde with to form [primarily 2-carbethoxy-5-methylhex-2-enoic acid ethyl ester, C02Ri C02R2 having its olefmic isomer 2-carbethoxy-5-methylhex-3-enoic acid ethyl ester less than 1-2% only compared to the other known methods producing the olefmic isomer 2-carbethpxy-5-methylhex-3-enoic acid ethyl ester 10-13%. further reacting the R1O2C C02R2 6 with a cyanide source to form decarboxylating the to form CN hydrolyzing the C02Ri .CN XX)2R- with an alkali or alkaline earth metal hydroxide to form an alkali or alkaline earth metal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate salt to form (±)-3-(aminomethyl)-5-methylhexanoic acid, wherein Ri and R2 are the same or different and are hydrogen, CpQ, alkyl, aryl, benzyl, or C3-C6cycloalkyl, and optionally resolving the obtained (±)-3-(aminomethyl)-5-methylhexanoic acid to obtain (S)-3-(aminomethyl)-5-methylhexanoic acid by standard method of resolution. to form The n a preferred method decarboxylating and hydrolyzing steps d) and e) are combined the carboxylate salt. present invention also provides for a method wherein the resolution step comprises: a) combining (±)-3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelic acid in water, an alcohol, or a mixture of water and an alcohol; b) heating the reaction mixture and stirring to get clear solution; c) gradual cooling, filtration and washing with alcohol to get wet cake; d) combining the wet cake, (S)-mandelic acid in water, an alcohol, or a mixture of water and an alcohol at higher temperature and stirring to get clear solution; and e) gradual cooling, filtration, washing with alcohol below 5°C and drying at higher temperature. I Preferred is a resolution method wherein the (±)-3-(aminomethyl)-5-methylhexanoic acid and (S)pmandelic acid are combined in a 3% v/v solution of water in isopropyl alcohol. Also preferred is a method wherein the (±)-3-(aminomethyl)-5-methylhexanoic acid and (S)- 7 mandelic acid are combined in methanol or isopropanol. Preferred polar solvents are dimethylsulfoxide and tetrahydrofuran. The (invention further provides a compound having the formula -CN R102C C02R2 wherein R, and R2 are the same or different and are hydrogen, C1-C6 alkyl, aryl, benzyl or C3-Cs cycloalkyl, preferably a compound wherein R| and R2 are ethyl. 'he invention further provides a compound having the formula ^Y^V^^NHa wherein M is hydrogen, an alkali metal, or an alkaline earth metal an Ri and R2 are the same or different and are hydrogen, Ci-Cg alkyl, aryl, benzyl, or C3-C6 cycloalkyl, preferred is a compound wherein M is sodium or potassium. Preferred are the mandelic acid salts of 3-(amino ethyl)-5-methylhexanoic acid wherein the mandelic acid is (S)-mandelic acid and the 3-(aminomethyl)-5-methylhexanoic acid is (S)-3-(aminomethyl)-5-methylhexanoic acid. The first embodiment of the present invention is to provide a method for obtaining (S)-3-(aminomethyl)-5-rnethylhexanoic acid from (±)-3-(aminomethyl)-5-methyl hexanoic acid which comprises combining (±)-3-(aminomethyl)-5-methyl hexanoic acid and S-mandelic acid in water, an alcohol or a mixture of water and an alcohol; heating the reaction mixture and stirring to get clear solution; gradual cooling, filtration and washing with alcohol to get wet cake. Again combining the wet cake, S-mandelic acid in water, an alcohol, or a mixture of water and an alcohol at higher temperature and stirring to get clear solution; and gradual cooling, filtration, washing with alcohol below 5°C and drying at higher temperature. The second embodiment of the present invention is the recovery of standard resoluting agent i.e. (S)-(+)-Mandelic acid, thereby providing cost effective and economical process for preparation of (S)-(+)-Pregabalin. The third embodiment of the present invention is crystallizing (S)-(+)-Pregabalin in a suitable organic solvent, thereby to obtain Pregabaliri in new crystalline forms having brick shape crystal habit as shown in Figure-IA and Figure-IB. The fourth embodiment of the present invention is to obtain (S)-(+)-Pregabalin in crystalline anhydrous Form - I as being the active ingredient in LYRJCA 300 mg hard capsules and showing the main XRD peaks of powder diffractogram 29 (± 0.2) 9.5, 12.3, 16.7, 17i.8, 18.3, 19.1, 19.9, 20.3, 22.3, 22.8, 23.3, 23.6, 24.8, 26.2, 26.6, 27.0, 27.7, 28.1, 28.7, 29 3, 30.0, 30.4, 31.0, 31.5, 32.1, 33.0, 33.3, 34.1, 34.8, 35.8, 37.5, 38.8 as shown in Figure-H. Pregabalin also exists in novel crystalline Form of its mandelate salt as shown in Figure-Ill. Pure Pregabalin obtained by crystallizing Pregabalin yields highly pure crystalline Pregabalin anhydrous Form I having DSC exotherm at 201.30°C Figure-1V. One of the aspect of the present invention is to obtain (S)-(+)-Pregabalin having brick shape crystal habit and having median particle size D(0.5) atleast 20 um, preferably in the range of 25-50 urn. "Median particle size" "D50 refer, corresponding, each to the median or 50% quantile of said particle size distribution. "D(0.10)" and "D(0.90)" refer, corresponding, the 10% respectively and 90% quantile. "D50/D90" refer to the ratio between D50 and D90. Brief description of the accompanying Drawings: Figure-IA: Electron polarizing microscopic image of brick habit of crystals of Pregabalin having ratio between length and width 1:1 to 10:1, preferably 1:1 to 5:1. Figure-IB: Electron polarizing microscopic image of brick habit of crystals of Pregabalin having ratio between length and width 1:1 to 10:1, preferably 1:1 to 5:1. Figure-II: XRPD pattern of powder diffractogram of anhydrous Form I (3S)-(aminomethyl)-5-methylhexanoic acid Figure-Ill: XRPD pattern of powder diffractogram of mandelate salt of (3S)-(aminomethyl)- 5-methylhexanoic acid I Figure-IV: DSC endotherm of anhydrous Form I of Pregabalin. Figure-V: A sample chromatogram for purity by GC of PG-01 Figure-VI: A sample chromatogram for purity by GC of PG-02 Figure-VII: A sample chromatogram for purity by GC of PG-03 Figure-VIII: A sample chromatogram for separation of S and R-isomers of pregabalin by chiral HPLC Figure- X: A sample chromatogram for chiral HPLC of pregabalin with 100% S-isomer and R-isomer not detected Figure-'X: A sample chromatogram for purity by chiral HPLC of pregabalin 9 Detailed Description of the Invention: In accordance with scheme 1 below, the present invention provides an efficient synthesis of racemic isobutyl-GABA and a method for obtaining (S)-isobutyl-GABA from racemic isobutyl-GABA wherein Ri and R2 are the same or different and are hydrogen, Ci-Ce alkyl, aryl, benzyl or C3-C6 cycloalkyl; and M is hydrogen, and alkali metal, or an alkaline earth metal. Scheme-I illustrates a method of making (+)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin) or racemic (+)-3-(aminomethyl)-5-methylhexanoic acid),-the method comprising condensing isovaleraldehyde with dialkylmalonatea to form pure compound PG-01 & having only 1-2% of its olefinic isomer; reacting PG-01 with a cyanide source to form PG-02; decarboxylating PG-02 to form PG-03; hydrolyzing PG-03 with an alkali metal or alkaline earth metal hydroxide to form PG-04; and hydrogenating & resolving the racemic PG-04 with the standard resolving agent to form S-(+)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin). In a preferred embodiment of the present method, (+)-3-(aminomethyl)-5-methylhexanoic acid can be made by condensing isovaleraldehyde with dialkylmalonate preferably diethyl malonate to form pure compound PG-01, only 1-2% of its olefinic isomer; reacting PG-01 with a cyanide source to form PG-02; hydrolyzing and decarboxylating PG-02 to form PG-03; and hydrogenating PG-03 to form (±)-3-(aminomethyl)-5-methylhexanoic acid. Scheme-I CN ^~^^\^'v' -° ♦ I 1 Ri02C C02R2 PG-02 PG-01 COjR! a T v 'C02R2 b Also provided by the present invention is a method for obtaining (S)-3-(aminomethyl)-5-methylhexanoic acid from (±)-3-(aminomethyl)-5-rhethylhexanoic acid PG-04, the method comprising combining (+)-3-(amino methyl)-5-methylhexanoic acid and (S)-mandelic acid in water, an alcohol or a mixture of water and an alcohol; heating the reaction mixture and stirring to get clear solution; gradual cooling, filtration and washing with alcohol to get wet cake. Again combining the wet cake, S-mandelic acid in water, an alcohol, or a mixture of water and an alcohol at higher temperature and stirring to get clear solution; and gradual cooling, filtration, washing with alcohol below 5°C and drying at higher temperature. In one step of the present method for making (±)-3-(aminomethyl)-5-methylhexanoic acid, isovaleraldehyde is condensed with diethylmalonate, wherein Ri and R2 are the same or different and are hydrogen C1-C6 alkyl, aryl, benzyl, or C3-C6 cycloalkyl. This type of reaction is known to those skilled in the art as a Knoevenagel Condensation, and the conditions under which a Knoevenagel Condensation can be carried out are well known to those skilled in the art. For example, the condensation can be achieved using a catalytic amount of a base such as di-n-propylamine. Other suitable catalysts are known in the literature. See for example, Tietzea L.F., and Beifuss U. in Comprehensive Organic Synthesis, 1991;2:341-394 (Trost B.M., ed.), Pergamon Press. Representative examples of suitable catalysts include pyrrolidine, (3-alanine, ammonium acetate, di-isoproplylamine, and di-propylamine. These basic catalysts can also be used in combination with an acid such as p-toluene sulfonic acid or acetic acid. A preferred catalyst system in the present method is di-n-propylamine and acetic acid. n general, the reaction is run in a refluxing hydrocarbon solvent including, but not limited to, toluene, hexane, heptane, methyl tert-butyl ether or cyclohexane, with the azeotropic removal of water. A preferred solvent is hexane. It is noted that olefin regioisomers can also be formed in the reaction, but are converted to the desired product in a. subsequent step in the reaction sequence. Representative examples of C1-C6 alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl. Representative examples of C3-C6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Representative examples of aryl groups. include phenyl and substituted phenyl, naphthyl, pridinyl, and the like. The aryl moiety may be substituted with one or more substituents, which can be the same or different. 11 Examples of such groups include C1-C6 alkyl, Ci-Ce alkoxy and halogen. Preferably, Ri and R2 are ethyl. In general, the isovaleraldehyde and C02Ri CO2R2 are added to the solvent along with the catalyst, and refluxed with azeotropic removal of water. It is also contemplated that additional catalyst may be added when the rate of azeotropic water collection slows. The progress of the condensation reaction may be monitored by methods well known in the art. In another step of the present method, is reacted with a cyanide source to form CN R2 O2 C C02R2 In general, is reacted with a cyanide source in a polar protic solvent such as ethanol, methanol, n-propanol, isopropanol, a mixture of water and alcohols, or polar aprotic solvents such as dimethylsulfoxide (DMSO) or DMSO/water, and then treated with any of C3-C6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl followed by addition of an acid and then water. Examples of suitable cyanide sources include, but are not limited to, hydrogen cyanide, acetone cyanohydrin or an alkali metal or alkaline earth metal cyanide, such as sodium cyanide, potassium cyanide, or magnesium cyanide. 12 The CN R1G2C CQ2R2 in this step may be used in the next step without purification, i.e. in crude form, or it may be purified. Examples of suitable acids are acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, benzoic acid, mandelic acid, p-toluenesulfonic acid, and the like. The -CN RiOzC "C02R2 can be decarboxylated to form by heating Ri02C C02R2 in a solvent with a salt. Examples of suitable solvents include mixtures of water and a polar solvent such as ethanol or dimethylsulfoxide (DMSO). Examples of suitable salts include alkali metal and alkaline earth metal halides such as sodium chloride and alkali metal and j alkaline earth metal cyanides such as sodium cyanide, magnesium cyanide, and the like. The ~C02R be hydrolyzed with an alkali metal hydroxide or an alkaline earth metal hydroxide to form an alkali or alkaline earth metal carboxylate salt. The alkali or alkaline earth metal hydroxide can be any alkali or alkaline earth metal hydroxide known to those skilled in the art. Examples of suitable alkali metal hydroxides include sodium hydroxide, lithium hydroxide, and potassium hydroxide. Examples of suitable alkaline earth metal hydroxides include i calcium hydroxide and magnesium hydroxide. The reaction is usually run in a suitable protic solvent such as water or a mixture of water and a polar protic solvent such as methanol, ethanol, or isopropanol. The carboxylate salt can be reduced to give the alkali or alkaline earth metal salt of (±)-3-(aminomethyl)-5-methylhexanoic acid. The carboxylate salt can be protonated with mineral acids or carboxylic acids to give the carboxylic acid and then the nitrile group of the i carboxylic acid can be reduced. Conversely, the nitrile group of the carboxylate salt can be reduced, and subsequently protonated to form the carboxylic acid. The salt can be treated with mineral acids or carboxylic acids to give (±)-3-(aminomethyl)5-methylhexanoic acid. Those skilled in the art I- are familiar with the reduction of nitrile functional groups. One common method of reducing i a nitrilel uses a hydrogenation catalyst, such as sponge nickel, in the presence of hydrogen. Other catalysts include palladium, platinum, rhodium, cobalt, and nickel. In general, the reaction^ is run in a solvent system such as a mixture of water and a polar protic solvent.. The amino carboxylate formed after nitrile reduction can be obtained in the acid form by treating the amino carboxylate with an acid. The mineral acids such as hydrochloric acid can be used. Carboxylic acids, such as acetic acid, can also be used. Preferably, the acid is acetic acid, as a byproduct formed by the reaction is MOAc where M is an alkali metal ion (Na, K, and the like), and OAc is an acetate ion. The salt MOAc is more soluble in aqueous alcoholic solvents than inorganic salts such as sodium chloride, potassium chloride, and the like. Thus, isolation of the product is simplified, and the need for ion exchange treatment to remove excess salts is avoided. The cyano acid may also be reduced using a suitable hydrogenation catalyst, such as sponge nickel and hydrogen, in a polar solvent such as methanol, ethanol, or isopropanol in combination with ammonia or a mixture of ammonia and water. Examples of other suitable hydrogenation catalysts include palladium, platinum, rhodium, cobalt, and nickel. Ri02C C02R2 14 can be hydrolyzed using an alkali or alkaline earth metal hydroxide such as potassium hydroxide or sodium hydroxide in an alcohol solvent, which promotes decarboxylating. Further hydrolysis using an alkali or alkaline earth metal hydroxide in water, an alcohol, or a mixture of water and an alcohol, gives carboxylate PG-03, which can be reduced with a hydrogenation catalyst followed by treatment with a mineral acid to give racemic 3- (aminomethyl)-5-methylhexanoicacid. Racemic 3-(aminomethyl)-5-methylhexanoic . acid can be resolved, i.e., the enantiomers separated, by selective crystallization with (S)-mandelic acid. -i Racemic 3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelic acid can be combined in a solvent such as water or an alcohol or a mixture of water and an alcohol to form a salt. Examples of suitable alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and the like. In general, the S,S salt precipitates from the solution, and the diastereomer, the R,S salt, stays in solution. Diasteriomeric purity of the S,S salt can be enhanced by further crystallization. Additional (S)-mandelic acid can. be included in the recrystallization to enhance diastereomeric enrichment. In general, an excess of mandelic acid is used. It is also noted that mandelic acid can be used in combination with another acid in accordance with the "Pope-Peachy? method known in the art. Removal of (S)-mandelic acid from the salt to give enriched (S)-3-(aminomethyl)-5-methylhexanoic acid can be done using a polar aprotic solvent such as dimethylsulfoxide or mixtures of dimethylsulfoxide and water or tetrahydrofuran and water, at temperatures typically in the range of about 0°C to about 100°C. (Trituration to obtain the S-enantiomer has the advantage that it is operationally simple and more economical than traditional acid/base or ion exchange methods. Also provided by the present invention are the novel compounds -CN R102C' "C02R2 where Ri and R2 are the same or different and are hydrogen, Ci-Q alkyl, aryl, benzyl or C3-Ce cycloalkyl; C02M 15 where M is hydrogen, an alkali metal, or an alkaline earth metal; .CN C02R where Ri is a defined above; and NH3+ C02H -02Cx^OH The first embodiment of the present invention is to provide a method for obtaining (S)-3-(aminomethyl)-5-methylhexanoic acid from (±)-3-(aminomethyl)-5-methyl hexanoic acid which comprises combining (±)-3-(aminomethyl)-5-methyl hexanoic acid and S-mandelic acid in water, an alcohol or a mixture of water and an alcohol; heating the reaction mixture and stirring to get clear solution; gradual cooling, filtration and washing with alcohol to get wet cake. Again combining the wet cake, S-mandelic acid in water, an alcohol, or a mixture of water and an alcohol at higher temperature and stirring to get clear solution; and gradual cooling, filtration, washing with alcohol below 5°C and drying at higher temperature. The second embodiment of the present invention is the recovery of standard resoluting agent i.e. (S)-(+)-Mandelic acid, thereby providing cost effective and economical process1 for preparation of (S)-(+)-pregablin, The third embodiment of the present invention is crystallizing (S)-(+)-pregabalin in a suitable organic solvent, thereby to obtain pregabalin in new crystalline forms having brick shape crystal habit as shown in Figure-IA and Figure-IB. Also, the ratio between length and width falls within the range i.e. 1:1 to 10:1, preferably 1:1 to 5:1. The third embodiment of the present invention is crystallizing (S)-(+)-pregabalin in a suitable organic solvent, thereby to obtain pregabalin in new crystalline forms having brick shape crystal habit as shown in Figure-IA and Figure-IB. 16 The fourth embodiment of the present invention is to obtain (S)-(+)-pregabalin in crystalline anhydrous Form - I as being the active ingredient in LYRICA 300 mg hard capsules and showing the main XRD peaks of powder diffractogram 20 (± 0.2) 9.5, 12.3, 16.7, 17»8, 18.3, 19.1, 19.9, 20.3, 22.3, 22.8, 23.3, 23.6, 24.8, 26.2, 26.6, 27.0, 27.7, 28.1, i 28.7, 29J.3, 30.0, 30.4, 31.0, 31.5, 32.1, 33.0, 33.3, 34.1, 34.8, 35.8, 37.5, 38.8 as shown in i Figure-II The (S)-(+)-pregabalin also exists in the novel crystalline form in its mandelate salt form and having XRD peaks of powder diffractogram 20 (±0.2) 6.44, 12.85, 14.26, 15.20, 17.06, 1|8.88, 19.36, 20.16, 21.94, 22.76, 24.01, 26.33, 27.94, 28.87, 31.52, 32.21, 34.47, 36.95* 39.31 as shown in Figure-Ill. Pure pregabalin obtained by crystallizing pregabalin yields highly pure crystalline pregabalin anhydrous Form 1 having onset at 199.06°C and DSC exotherm at 201.30°C Figure-l One of the aspect of the present invention is to obtain (S)-(+)-pregabalin having brick shape crystal habit and having meadian particle size D(0.5) atleast 20 jam, preferably in the range of 25-50 u.m. Also the particle size distribution of D(0.1) is atleast 4 um, preferably in the range of 5-15 um and D(0.90) is atleast 100 urn, preferably in the range of 120-250 urn. I "Median particle size" "D50 refer, corresponding, each to the median or 50% quantile of said particle size distribution. "D(0.10)" and "D(0.90)" refer, corresponding, the 10% respectively and 90% quantile. "D50/D90" refer to the ratio between D50 and D90. Particle size distributions may be unimodel, i.e. the density volume size distribution contains only one peak, bimodal, i.e. the density volume size distribution contains two peaks or polymodal, i.e. the density volume size distribution contains more than two peaks. Particle size distributions may be unimodel or bimodel if the crystalline particles are a mixture of single crystals and aggregates or agglomerates. i Crystalline particles of Pregabalin having brick habit and the ratio of length and width 1:1 to 10:1, preferably 1:1 to 5:1, characterized in that the ratio between the median particle size and the particle size at the 90% quantile is less than 0.25, preferably less than 0.20. The examples below are intended to illustrate specific embodiments of the invention and are not intended to limit the scope of the specification, including the claims, in any manner1. 17 Examples Example-1: Preparation of 2-carbethoxy-5-methyl hex-2-enoic acid ethyl ester CHO + C02Et / PG-01 to a solution of 100 g of Isovaleraldehyde in 450 mL methylene dichloride was added 180 g of diethyl malonate at 25°C to 35°C in round bottom flask fitted with a dean-stark. 11.8 i g of morpholine and 8.3 gm of acetic acid were added. The reaction mixture was heated at reflux temperature 45°C-50°C for 5 hours till azeotropic removal of water and was cooled to 25°C-30°C. 11.7 g of morpholine and 8.3 g of acetic acid were added and the reaction mixture i was again heated at reflux for 4 hours till azeotropic removal of water. The reaction mixture was cooled to 25oC-350C. 225 mL of water was added to the reaction mixture, stirred & J I settled for 15 minutes. Separated organic layer was treated with 150 mL of 10% HCI Solution (freshly prepared), stirred and settled for 15 minutes at 25°C-35°C. The organic layer thus separated is treated with 225 mL of, stirred and settled for 15 minutes. The aqueous layer and organic layer are separated. The above procedure is repeated twice with the organic layer. The separated organic layer is then treated with 100 mL 2% NaHCOj solution, stirred for 15 Minutes and settled for 15 minutes. The separated organic layer was treated with 225 mL of water, stirred and settled. Finally separated organic layer is filtered through hyflow bed, washed with methylene dichloride. The excess of methylene dichloride is distilled under vacuum by hot water below 40°C-50°C. [% Yield = 87%; G.C purity = 84-86%, isomer = 1- 2%]. IR (Nujol-mull, v cm"1): sp3C-H stretch : 2980, 2960, 2935; CO : 1724; C=C stretch : 1649 'H NMR (CDCI3, 300 MHz): 8 0.90-1.01 (m, 6H), 1.24-1.35 (m, 6H), 1.77-1.84 (m, 1H), i 2.16-2.22 (m, 2H), 4.17-4.34 (m, 4H), 6.99-7.04 (t, 1H, J = 7.9 Hz) MS: m/z = 228.28 (M+l). 2-carbethoxy-S-methyl hex-2-enpic acid ethyl ester purity may be determined by using the following gas chromatography apparatus and procedures: Column & Packing : Fused silica capillary column Elite-5 of Perkin Elmer j or equivalent Length : 30 m 18 Diameter; 0.53 mm Film thickness : 5 /mi Injector Temperature :210°C Detector Temperature: 230°C Oven temperature Time (min) Temperature Initiali 0 100°C i Final 44 220°C Temp Programme rate: 20°C/minute Equilibrium time 1.0 minute Injection Volume 0.5/*l Carrier gas Nitrogen Split Flow 60 ml/min. Detector FID A sample Chromatogram is shown in Figure-V Example-2: Preparation of 2-carbethoxy-3-cyano-5-methyl hexanoic acid ethyl ester CN Et02C C02Et | PG-02 100.0 g of 2-carbethoxy-5-methyl hex-2-enoic acid ethyl ester prepared above was added slowly to the solution of 21.0 g of sodium cyanide in 100 mL of ethanol over, a period of 2-3 hours at 25°C to 35°C. 91.0 mL of hexane was added at 25°C to 35°C and 27.0 mL of acetic acid was added in 30 minutes which resulted in thick slurry. 81.8 mL of water was added to the reaction mixture and was stirred and settled for 30 minutes resulted in a clear solution. Separated aqueous layer was treated with 91.0 mL of hexane, stirred and settled for 15 minutes at 25°C to 35°C. Separated organic layer were combined and treated with 91.2 mL of water. The Separated hexane layer was filtered through hyflow bed and washed with hexane The filtrate was subjected to distillation under vacuum by hot water below 60°C to remove! excess of hexane, cooled to 25°C to 35°C. [% Yield = 97.97%; GC purity = 92-95%]. IR (Nujol-mull, v cm"1): sp3 C-H stretch : 2981, 2962, 2937; CN : 2245, CO : 1755, 1739. . 'H NMR (CDCI3, 300 MHz): 5 0.96-0.99 (t, 6H, J = 4.5 Hz), 1.20-1.29 (m, 6H), 1.30-1.33 (m, lH)j 1.60-1.68 (m, 2H), 3.30-3.33 (m, IH), 3.53-3.56 (d, IH, J - 8.19 Hz), 4.22-4.32 (m, 4H). I MS: m/z = 256.31 (M+l). 2-carbethoxy-3-cyano-5-methyl hexanoic acid ethyl ester purity may be determined by using the following gas chromatography apparatus and procedures: Column & Packing : Fused silica capillary column Elite-5 of Perkin Elmer or equivalent. Length : 30 m Diameter: 0.53 mm ! Film thickness : 5 fim Injector Temperature :210°C Detector Temperature: 230°C Oven temperature Time (min) Temperature Initial 0 100°C iFinal1 44 220°C Temp Programme rate: 20°C/minute 1 Equilibrium time 1.0 minute Injection Volume 0.5//l 1Carrier gas Nitrogen Split Flowj 60 ml/min. 1-Detector FID A sample Chromatogram is shown in Figure-VI Example-3: Preparation of 3-Cyano-5-methyl-hexanoic acid ethyl ester Et02C C02Et ^ C02Et 20 PG-03 100 g of 2-carbethoxy-3-cyano-5-methyl hexanoic acid ethyl ester above and 27.0 g of sodium chloride IP were treated with 270 mL DMSO and 13.6 mL of R.O. water at 25°C ( to 35°CJ The reaction mixture was slowly heated to get 140°C to 145°C temperature within 1- [ 2 hour. The reaction mixture was stirred for 9-10 hours and gradually cooled to 25°C to 35°C. i 210 mL of methyl tert-butyl ether was added to the reaction mixture followed by addition of i 180 mL of water is slowly added in 1-2 hour below 35°C, stirred and settled for 30 minutes. The separated aqueous layer was treated with 210 mL methyl tert-butyl ether, stirred and j i settled for 30 minutes. The separated organic layer was combined and treated with 200 mL of water, stirred and settled for 30 minutes. The separated organic layer was distilled under vacuum below 60°C to remove excess methyl tert-butyl ether. [% Yield = 94%, G.C purity = 94-96%] IR (Nujol-mull, v cm"1): sp3 C-H stretch : 2960, 2935, 2902; CN : 2243, CO : 1739. 'H NMR (CDCI3, 300 MHz): 8 0.89-0.98 (m, 6H), 1.19-1.36 (m, 4H), 1.61-1.64 (m, 1H), 3.30-3.33 (m, 1H), 2.50-2.57 (dd, 1H, J - 7.78 Hz, J = 17.94 Hz), 2.65-2.73 (dd , 1H, J = 7.8 Hz, J■= 17.8 Hz), 3.03-3.21 (m, 1H), 4.16-4.23 (q, 2H, J = 7.13 Hz). MS: m/z = 184.2 (M+l). 3-Cyano-5-methyl-hexanoic acid ethyl ester purity may be determined by using the following gas chromatography apparatus and procedures: Column & Packing : Fused silica capillary column Elite-5 of Perkin Elmer I or equivalent j Length : 30 m ! Diameter : 0.53 mm j Film thickness : 5 ftm ■ Injector Temperature :210°C i rime (min) Temperature 0 100°C 44' 220°C input1.0 minute 0.5//l Nitrogen 60 ml/min. FID Detector Temperature: 230°C Oven temperature .Initial I: 1 Final Temp Programme rate: 20°C/minute Equilibrium time Injection Volume Carrier; gas Split Flow ! Detector 21 A sample Chromatogram is shown in Figure-VII Example-4 Preparation of 3-Amino-5-methyl-hexanoic acid ethyl ester -CN *C02Ri CN C02M NH2 C02M PG-04 00.0 g of 3-Cyano-5-methyl-hexanoic acid ethyl ester and 133 mL of methanol were taken in autoclave at 25°C to 35°C and cooled to 20°C to 35°C. Potassium hydroxide solution (58.2 g in 161.2 mL water) was added in autoclave within 1 hour and stirred for 1.5 hour. 10.0 g of raney nickel and 66.6 mL of methanol was added in autoclave under N2 pressure t upto 4.0, to 4.5 kg for about 20-24 hour and was maintained until the consumption of H2 was stopped; The reaction mixture was filtered in hyflow bed and washed with mixture of 111.6 mL of water and 48.0 mL of methanol at 25°C to 35°C. 62 mL of acetic acid was added to ] filtrate lb adjust the pH from 4.5 to 5.0 with stirring. 23.3 mL of liq. ammonia was added slowly to adjust the pH 7.5 to 8.0 with stirring. The reaction mixture was heated at 55°C to 60°C to get clear solution and. cooled to 25°C to 35°C. It was further cooled to 0°C to 5°C and stirred for 4 hours. The content was filtered at 0°C to 5°C, washed with chilled isopropyl alcohol. The product was dried at 50°C to 55°C for 8 hours. [% Yield = 5.8.98%]. 3-Amin'o-5-methyl-hexanoic acid ethyl ester purity can be established by the following HPLC method: High-performance liquid chromatography was performed using a Shimadzu LC2010C HPLC system. Column 1 Mobile Phase 1 Flow rate Column' oven temp Run Time Detector Diluent! Wavelength Injection Volume : Synergi Hydro-RP 80 A (250 mm x 4.6 mm, 4u.) Water/ACN-95/05 1.0 ml/minute 25°C 15 minutes dual wavelength UV-VIS mobile phase : 220 nm :50/d Mobile phase composition and flow rate may be varied in order to achieve the required system suitability. i Example-5 I Preparation of Pregabalin mandelate salt -02C. -OH NH3+ ^ C02H PG-05 To the solution of 130 g of L(+)-mandelic acid in 1000 mL of isopropyl alcohol, 30 mL of water was added at 25°C to 35°C. The reaction mixture was heated to get clear solution at 55°C!to 65°C. 100 g of 3-Amino-5-methyl-hexanoic acid ethyl ester was added and stirred to get clear solution. The reaction mixture was cooled to 40°C to 45°C and stirred for 5 hours. The reaction mixture was filtered and washed with isopropyl alcohol at 20°C to 25°C. The wet product was obtained. The reaction mixture of 400 mL of isopropyl, 12.5 mL of water and 20 g of L (+)-mandelic acid was added was heated at 65°C to 70°C to get clear solution. Previously obtained wet product 90.24 g was added to above reaction mixture at 65°C to 70°C and stirred to get clear solution. Cooled to 50°C to 55°C and stirred for 15 minutes. Further it I was cooled to 25°C to 35°C and then to 0°C to 5°C and stirred for 4 hours. The reaction mixture, was filtered, washed with chilled isopropyl alcohol at 0°C to 5°C and dried at 50°C to 55°C for 8 hours. [% Yield = 52.96 %]. Recovery of L (+)-Mandelic acid: I Stage-I!: (For the input of 1Kg of PG-04) The combined filtrate obtained during filtration was distilled out completely under vacuum at 71°C to obtain oily liquid. The concentrated mass was treated with 7.2 L of ethyl acetate at 65°C-70CC. Cooled to 20°C-25°C and stirred for 2 hours or till separation of product by gradually cooling and continues stirring. The product thus obtained was filtered, washed with ethyl acetate and spin dried for 30 minutes. The wet cake was dried at 50°C-55°C for 10-12 hours. The dry solid contains R-isomer, S-isomer and Mandelic acid. [The ethyl acetate filtrate obtained above was treated with sodium sulphate at 20°C-40°C, stirred for 30 minutes and filtered. The ethyl acetate filtrate is distilled out under vacuum upto 70°C to obtain white solid. Cooled to 25°C-30°C. The solid thus obtained was treated with 3.6 L of methylene dichloride and heated to reflux at 37°C-42°C for 1 hour. The 23 reaction mixture was cooled to 0°C-5°C and stirred for 1 hour. The product thus obtained was filtered and washed with chilled methylene dichloride, dried at 50°C-55°C for 8 hours to obtain L(+)-mandelic acid. Stage-H ! 5.53 L of THF was added to the product mixture of R-isomer, S-isomer and mandelic acid at 25°C-30°C. 0.29 L of water was added to the reaction mixture and heated to 50°C- -i 55°C. The reaction mixture was stirred for 30 minutes and cooled to 25°C-35°C and further to 0°C-5°C. The reaction mixture was filtered and washed with chilled THF. The product thus i obtained was dried at 50°C-55°C for 8 hours to obtain mixture of R-isomer and S-isomer. The combined filtrate obtained above was distilled under vacuum upto 70°C to obtain white solid. 1.72 L of ethyl acetate was added to the solid product at.65°C-70°C and the content was stirred, cooled upto 20°C-25°C and further stirred for 2 hours. The reaction mixture was filtered and the solid residue was discarded. The ethyl acetate filtrate was treated with sodium sulphate at 20°C-40°C, stirred for 30 minutes and filtered. The ethyl acetate filtrate is distilled out under vacuum upto 70°C to obtain white solid. Cooled to 25°C-30°C. i The solid thus obtained was treated with 3.6 L of methylene dichloride and heated to reflux at 37°C-42°C for 1 hour. The reaction mixture was cooled to 0°C-5°C and stirred for 1 hour. The product thus obtained was filtered and washed with chilled methylene dichloride, dried at 50oC-55°C for 8 hours to obtain L(+)-mandelic acid. i i Example-6 i Preparation of Pregabalin [(S)-3-amino methyl-5-hexanoic acid (Semi-Crude)] NH3+ , "^ ^COOH C°2H ' II 1 PG-06 -02C r)H N-^N-^NH, 44 mL of water was added to the solution of 100 g of pregabalin mandelate salt in 833 mL of THF at 25°C to 35°C. The reaction mixture was heated upto 50°C to 55°C, stirred and cooled to 25°C to 35°C. Gradually the reaction mixture was cooled to 0°C to 5°C and stirred i for 5 hours. The content was filtered and washed with THF and IPA. The product was dried at 50°C|55°C for 8 hours. [% Yield = 83%] Recovery of L (+)-Mandelic acid: i The combined filtrate obtained was distilled out completely under vacuum upto 70°C and cooled to 60°C-65°C. The solid thus obtained was treated with 1.72 L of ethyl acetate at same temperature and cooled upto 25°C-30°C. The reaction mixture was stirred for 2 hours, filtered and washed with ethyl acetate. The filtrate thus obtained was treated with sodium sulphate'. The ethyl acetate filtrate is distilled out under vacuum upto 70°C to obtain white solid. Cooled to 25°C-30°C. The solid thus obtained was treated with 0.86 L of methylene dichloride and heated to reflux at 37°C-42°C for 1 hour. The reaction mixture was cooled to 0oC-5°Ci and stirred for 1 hour. The product thus obtained was filtered and washed with chilled methylene dichloride, dried at 50°C-55°C for 8 hours to obtain L(+)-mandelic acid. i Example-7 Preparation of Pregabalin [(S)-3-amino niethyl-5-hexanoic acid (Crude)] 440 mL of water was added to the solution of 100 g of semi-crude pregabalin in 1250 isopropyl alcohol at 25°C-35° and was heated at 78°C to 82°C and stirred to get clear solution. The reaction mixture was filtered on hyflow bed and washed with hot isopropyl alcohol. The filtrate Was taken at 65°C to 82°C and gradually cooled to 25°C to 35°C and then to 0°C to 5°C, stirred for 5 hours, filtered, and washed with chilled isopropyl alcohol. The product was dried at 50°C to 55°C for 8 hours. [% Yield = 83%]. Exampie-8 Preparation of Pregabalin [(S)-3-amino methyl-5-hexanoic acid (Pure)] 440 mL of water was added to the solution of 100 g of semi-crude pregabalin in 1250 isopropyl alcohol at 25°C-35° and was heated at 78°C to 82°C and stirred to get clear solution. The reaction mixture was filtered on hyflow bed and washed with hot isopropyl alcohol. The filtrate was taken at 65°C to 82°C and gradually cooled to 25°C to 35°C and then to 0°C to 5°C, stirred for 5 hours, filtered, and washed with chilled isopropyl alcohol. The product was dried at' 50°C to 55°C for 8 hours. [% Yield = 90%]. 1R (KBr, v cm"1): sp3 C-H stretch : 2960, 2935, 2902; N-H stretch : 2818, 2872; C-H bend : 1388 and C-O stretch : 1163.08. 25 'H NMR (CDC13, 300 MHz): 5 0.73-0.76 (m, 6H), 1.05-1.09 (t, 2H, J = 6.98 Hz), 1.49-1.53 (m, 1H)J 1.99-2.19 (m, 3H), 2.78-2.88 (m, 2H). MS: m/z= 181.8 (M+l). Enantiomeric purity can be established by the following chiral HPLC method: High-performance liquid chromatography was performed using a Shimazdu LC2010C HPLC system Column! : Chiralpak AD-H (250 mm X 4.6 mm, 5u) Mobile Phase : Flow Rate Column loven temp Run Time i Detector 1. Wavelength Injection Volume Diluent 1 : j or equivalent n-Hexane/Isopropyl alcohol/Formic acid-80/20/0.1 10ml/min. 25°C 30 mintues dual wavelength UV-VIS 264 nm 10 fA n-Hexane/lsopropyl alcohol-50/50. Mobile phase composition and flow rate may be varied in order to achieve the required system suitability. HPLC shows purity > 99.5% having R-isomer content NMT 0.5%, unknown impurity NMT 0.5% and total impurity NMT 2.0%. A sample Chromatogram is shown in Figure-VII, IX and X. Advantages of the Invention: 1) The present invention provides the process for preparation of important intermediate 2-carbethoxy-5-methyl hex-2-enoic acid ethyl ester having G.C purity = 84-86% and having its isomer 2-carbethoxy-5-methyl hex-3-enoic acid ethyl ester limiting to 1-2%. 2) The present invention also provides the process for recovery of chiral resolution agent mandelic acid thereby providing the efficient and cost effective process for providing j pure (S)-(+)-pregabalin via pregabalin mandelage salt. 3) The present invention provides (S)-(+)-pregabalin in a pure crystalline anhydrous Form-I having brick habit crystals and also having the ratio of length and width in between 1:1 to i 10:1, preferably 1:1 to 5:1. 26 4) The present invention also provides the process for preparation of novel crystalline form of pregabalin mandelate salt. i 5) The present invention also provides pure (S)-(+)-pregabalin with HPLC purity 99.5% having R-isomer content NMT 0.5%, unknown impurity NMT 0.5% and total impurity NMT 2.0%. ■ 6) The present invention relates with (S)-(+)-pregabalin having unimodel or bimodel particle size distribution i.e. the density volume size distribution contains only one peak or two peaks respectively. 7) The present invention relates with the process for preparing (S)-(+)-pregabalin having i brick! shape crystal habit and having median particle size D(0.5) atleast 20 um, preferably in the range of 25-50 urn. Also the particle size distribution of D(0.1) is atleast 4 um, preferably in the range of 5-15 um and D(0.90) is atleast 100 urn, preferably in the range ofl2'0-250um. j 8) The present invention provides (S)-(+)-pregabalin with crystalline particles having brick i habit and the ratio of length and width 1:1 to 10:1, preferably 1:1 to 5:1, characterised in i - that the ratio between the median particle size and the particle size at the 90% quantile is less than 0.25, preferably less than 0.20. 9) The present invention provides the process which is environment friendly, cost effective and easily applicable for industrial large scale production. i i" Dated this the 3rd day of October 2006. [ H. Subramaniam Of Subramaniam, Nataraj & Associates Attorneys for the Applicants Abstract PROCESS OF PREPARING CRYSTALLINE PREGABALIN AND ITS HIGHLY PURE INTERMEDIATE THEREOF The invention relates to crystalline form of Pregabalin and their process of preparation. The invention1 also relates to a process for preparing 2-carbethoxy-5-methylhex-2-enoic acid ethyl ester, an important intermediate for synthesis of crystalline Pregabalin, having less than about, 1-2% 2-carbethoxy-5-methylhex-3-enoic acid ethyl ester. Moreover, the present invention provides industrially applicable process for recovery of chiral reagent used for resolution of the (±)-Pregabalin; thereby to provide cost effective and economical process for preparation of Pregabalin. 28

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