WO2008062460A2 - Crystalline forms of pregabalin - Google Patents

Crystalline forms of pregabalin Download PDF

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WO2008062460A2
WO2008062460A2 PCT/IN2007/000467 IN2007000467W WO2008062460A2 WO 2008062460 A2 WO2008062460 A2 WO 2008062460A2 IN 2007000467 W IN2007000467 W IN 2007000467W WO 2008062460 A2 WO2008062460 A2 WO 2008062460A2
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Prior art keywords
pregabalin
acid
process
crystalline
form
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PCT/IN2007/000467
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French (fr)
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WO2008062460A3 (en
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Dwivedi Shriprakash Dhar
Rajiv Kumar
Tippanu Thirupathi Rao
Doshi Ketan Ambalal
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Cadila Healthcare Limited
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Publication of WO2008062460A3 publication Critical patent/WO2008062460A3/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30Preparation of optical isomers
    • C07C227/34Preparation of optical isomers by separation of optical isomers
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41Preparation of salts of carboxylic acids
    • C07C51/412Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42Separation; Purification; Stabilisation; Use of additives
    • C07C51/43Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40Unsaturated compounds
    • C07C59/42Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/48Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
    • C07C59/50Mandelic acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07Optical isomers
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs

Abstract

The invention relates to crystalline 'forms of Pregabalin and their process o preparation. The invention also relates to a process for preparing 2-carbethoxy-5- methylhex-2-enoic acid ethyl ester, an important intermediat 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 an industrially applicable process for recovery of chiral reagent used for resolution of the (+) (-)Pregabalin; thereby to provide a cost effective and economical process for preparation of Pregabalin.

Description

CRYSTALLINE FORMS OF PREGABALIN Field of invention

The 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-(aminomethyl)-5-methylhexanoic acid (Pregabalin) of Formula (I) substantially 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.

Figure imgf000002_0001

Formula (I)

Background of the invention

Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

3-(aminomethyl)-5-methylhexanoic acid, which is also called /?-isobutyl-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. Pregabalin 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, 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 Al to Burk et al.

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 99/59573, both to A. Aomatsu.

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-propylamine in hexane and glacial acetic acid. The reaction also generates the unwanted olefin isomer (typically 10-13% by GC) i.e. 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]. 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 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 reusability of chiral agent for resolution by its recovery. [See Example-1, Column-11, Line-40-55].

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 malonate 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, the present invention provides the process for preparing 2-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 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.

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).

U.S. Patent Application 2006/0270871 Al discloses the polymorphic Form-I of Pregabalin characterized by DSC thermogram showing a characteristics endothermic peak at 194-2050C and X-ray powder diffraction (XRPD) pattern comprising characteristics 2Θ values at 9.5, 16.62, 18.18, 18.32, 19.06, 19.74, 22.14 and 35.62° 2Θ ±0.2° 2Θ

WO 2006/121557 Al discloses the pregabalin substantially free of lactam containing less than 0.015% area by HPLC of lactam and a process for the preparation thereof. WO '557 Al also provides the HPLC method of analysis for the pregabalin substantially free from lactam.

WO 2006/108151 Al discloses the cyrstalline form of pregabalin. The pregabalin term disclosed in the specification is about racemic pregabalin. Thus, the present invention claims crystalline pregabalin hemihydrate characterized by X-ray powder diffraction peaks at about 5.8, 18.4, 19.2, 20.7, and 23.7° 2Θ ±0.2° 2Θ and by DSC having broad endotherm at about 6O0C to about 1000C and. another endothermic peak at 1810C.

Code 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. LYRICA 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 2Θ (± 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. Based on the XRD pattern of the active ingredient Pregabalin is crystalline anhydrous Form-I.

Thus, the inventors of the present invention thinks that there is still a need to provide a process for the preparation of crystalline pregabalin substantially free from related substances when measured by area percentage of HPLC. Also, there is a need to provide a process for the recyclability of chiral resolving agent thereby reducing the cost of process. Summary of the invention

It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

According to the first aspect of the present invention, there is provided a process for preparing a crystalline compound of formula:

I

^COOH

having the crystal habit such that the ratio between the length and the width of the crystals is between 1:1 to 10:1 wherein a crystalline compound of pregabalin is anhydrous Form I substantially free from impurities comprising the steps of: a. condensing isovaleraldehyde with an dialkyl malonate in presence of base to form a 2-carbalkoxy-5-methylhex-2-enoic acid, alkyl ester (II) substantially free from 2- carbalkoxy-S-methylhex-S-enoic acid, alkyl ester; b. reacting 2-carbalkoxy-5-methylhex-2-enoic acid, alkyl ester (II) with a cyanide source to form a 2-carbalkoxy-3-cyano-5-methylhexanoic acid, alkyl ester (III); c. decarboxylating 2-carbalkoxy-3-cyano-5-methylhexanoic acid, alkyl ester (III) in mixture of water and polar aprotic solvent organic solvent at 1000C to 15O0C temperature to give 3-cyano-5-methylhexanoic acid, alkyl ester (IV); d. hydrolyzing 3-cyano-5-methylhexanoic acid, alkyl ester (IV) with an alkali or alkaline earth metal hydroxide to form an alkali or alkali earth metal carboxylate salt which is hydrogenated to form (±)-3-(aminomethyl)-5-methylhexanoic acid (V); e. treating (±)-3-(aminomethyl)-5-methylhexanoic acid (V) with (L)-(+)-mandelic acid in water, an alcohol, or a mixture of water and an alcohol; f. heating the reaction mixture at about 5O0C to 7O0C and cooled to obtain precipitate of mandelate salt of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (VI); g. treating mandelate salt of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid into a polar aprotic solvent or a mixture of polar aprotic solvent and water to form a slurry at 5O0C to 550C and cooled; and h. isolating (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (I) having crystal habit that the ratio between the length and the width of the crystals is between 1:1 to 10:1 substantially free from impurities.

According to the most preferred aspect of the present invention there is provided a process for preparing a crystalline compound of formula:

I

Figure imgf000007_0001

having the crystal habit such that the ratio between the length and the width of the crystals is between 1:1 to 10:1 wherein a crystalline compound of pregabalin is anhydrous Form I substantially free from impurities comprising the steps of: a. condensing isovaleraldehyde with an diethyl malonate in presence of morpholine to form a 2-carbethoxy-5-methylhex-2-enoic acid, ethyl ester (II) substantially free from 2-carbethoxy-5-methylhex-3-enoic acid, ethyl ester; b. reacting 2-carbethoxy-5-methylhex-2-enoic acid, ethyl ester (II) with a cyanide source to form a 2-carbethoxy-3-cyano-5-methylhexanoic acid, ethyl ester (III); c. decarboxylating 2-carbethoxy-3-cyano-5-methylhexanoic acid, ethyl ester (III) in mixture of water and polar aprotic solvent organic solvent at 1000C to 15O0C temperature to give 3-cyano-5-methylhexanoic acid, ethyl ester (IV); d. hydrolyzing 3-cyano-5-methylhexanoic acid, ethyl ester (IV) with an alkali or alkaline earth metal hydroxide to form an alkali or alkali earth metal carboxylate salt which is hydrogenated to form (±)-3-(aminomethyl)-5-methylhexanoic acid (V); e. treating (±)-3-(aminomethyl)-5-methylhexanoic acid (V) with (L)-(+)-mandelic acid in water, an alcohol, or a mixture of water and an alcohol; f. heating the reaction mixture at about 5O0C to 7O0C and cooled to obtain precipitate of mandelate salt of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (VI); g. treating mandelate salt of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid into a polar aprotic solvent or a mixture of polar aprotic solvent and water to form a slurry at 500C to 55°C and cooled; and h. isolating (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (I) having crystal habit that the ratio between the length and the width of the crystals is between 1:1 to 10:1 substantially free from impurities.

Preferred is a resolution method as in step (e), wherein the (±)-3- (aminomethyl)-5-methylhexanoic acid and (S)-mandelic 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)-mandelic acid are combined in methanol or isopropanol. Preferred polar solvents are dimethylsulfoxide and tetrahydrofuran.

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.

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 Fonn I (3S)-

(aminomethyl)-5-methylhexanoic acid

Figure-Ill: XRPD pattern of powder diffractogram of mandelate salt of (3S)- (aminomethyl)-5-methylhexanoic acid

Figure-IV: DSC endotherm of anhydrous Form I of Pregabalin.

Figure-V: A sample chromatogram for purity by GC of PG-Ol

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-IX: 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 Detailed Description of the invention

The term "pregabalin" refers to (S)-Pregabalin in the specification.

The term "Substantially free from impurities" refers to impurities having not in detectable amount at RRT 0.12, 0.25, 0.31, 0.34, 0.50, 0.58, 0.61, 0.78, 1.71, 1.61, 2.28 and 3.04 in (S)-Pregabalin. The term "Substantially free from impurities" also refers to total impurities in (S)-Pregabalin less than about 0.4%, preferably less than about 0.3%.

Also, the individual impurities at RRT 0.20 and 0.23 less than about 0.1%, preferably less than 0.05% when measured by HPLC.

According to another important aspect of the present invention, the term "Substantially free from impurities" also refers to optically purity of pregabalin having

(S)-isomer not less than 99.75% and R-isomer not more than 0.25%, preferably (S)- isomer not less than 99.90% and R-isomer not more than 0.10%, more preferably (S)- isomer 100% and R-isomer is not in detectable amount.

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 dialkylmalonate to form pure compound PG-Ol & having only 1-2% of its olefinic isomer; reacting PG-Ol 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 diethylmalonate to form pure compound PG-Ol, only 1-2% of its olefinic isomer; reacting PG-Ol 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

Figure imgf000010_0001

PG-Ol [II] PG-02 [EI]

Figure imgf000010_0002
Pregabalin

PG-05 [Vl] [I]

According to the most preferred embodiment- of the present invention substantially free from 2-carbalkoxy-5-methylhex-3-enoic acid, alkyl ester means olefmic isomer 2-carbalkoxy-5-methylhex-3-enoic acid, alkyl ester is not more than 3% by area percentage of GC, preferably not more than 2% by area percentage of GC.

The cyanide source can be selected from hydrogen cyanide, acetone cyanohydrin or an alkali metal or alkaline earth metal cyanide, such as sodium cyanide, potassium cyanide, or magnesium cyanide. The reaction is preferably carried out in step (c) in a polar aprotic solvent is dimethyl sulfoxide and the product is hydrolyzed by alkali or alkaline earth metal can be selected from the group of sodium, potassium, lithium, barium, calcium and the like, preferably potassium hydroxide.

The cyanide compound is further hydrogenated by a suitable hydrogenating agent is raney nickle in polar organic solvent selected form C1-C4 alcohols like methanol, ethanol, propanol, isopropanol and the like, preferably methanol. It is also one of the aspect of the present invention to provide pregabalin mandelate in pure form by resolution of pregabalin by L-(+)-mandelic acid in alcoholic solvent selected from C1-C4 alcohols like methanol, ethanol, propanol, isopropanol and the like, preferably isopropanol. This pure salt is broken to obtain crude pregabalin (S)- isomer by using mixture of polar aprotic solvent and water wherein the polar aprotic solvent can be selected from acetonitrile, tetrahydrofuran, dimethyl foramide, dimethyl sulfoxide and the like, preferably tetrahydrofuran. The preferred embodiment can also be explained as provided herein after. The present invention is a method for obtaining (S)-3-(aminomethyl)-5-methylhexanoic acid from (±).-3-(ammomethyl)-5-methylhexanoic 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 50C 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 R1 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, Tietze 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, β-alanine, ammonium acetate, di-isoproplylamine, and di-n-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.

In 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.

Examples of such groups include C1-C6 alkyl, C1-C6 alkoxy and halogen. Preferably, R1 and R2 are ethyl. In general, the isovaleraldehyde and

XO2Ri

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,

Figure imgf000012_0001

is reacted with a cyanide source to form

Figure imgf000013_0001

In general,

Figure imgf000013_0002
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.

The

Figure imgf000013_0003

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

Figure imgf000013_0004
can be decarboxylated to form
Figure imgf000014_0001
by heating

Figure imgf000014_0002

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 alkaline earth metal cyanides such as sodium cyanide, magnesium cyanide, and the like. The

Figure imgf000014_0003

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 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 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 are familiar with the reduction of nitrile functional groups. One common method of reducing a nitrile 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.

Figure imgf000015_0001

can be hydrolyzed using an alkali or alkaline earth metal hydroxide such as potassium hydroxide or sodium hydroxide in an alcohol solvent, which promotes decarboxylation. 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-methylhexanoic acid. Racemic 3-(aminomethyl)-5-methylhexanoic acid can be resolved, i.e., the enantiomers separated, by selective crystallization with (S)-mandelic acid. 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 S5S salt precipitates from the solution, and the diastereomers, the R,S salt, stays in solution. Diasteriomeric purity of the S5S salt can be enhanced by further crystallization.

Additional (S)-mandelic acid can be included in the recrystallization to enhance diastereonieric 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 O0C to about 1000C. 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.

The crystalline pregabalin anhydrous Form I having brick shape crystal habit as depicted in Figure- IA and Figure-IB.

It is also one of the aspect of the present invention to provide a crystalline pregabalin mandelate of formula:

IV

Figure imgf000016_0001
characterized by X-ray powder diffraction (XRPD) pattern having peaks at 6.4, 17.9, 20.1 and 26.3° 2θ±0.2° 2Θ and further characterized by X-ray powder diffraction (XRPD) pattern having peaks at 6.4, 12.8, 14.2, 15.2, 17.9, 18.8, 19.3, 20.1, 21.9, 22.7, 24.0, 26.3, 27.9, 28.8, 31.5, 32.2, 34.4, 36.9, 39.3° 2θ±0.2° 2Θ.

According to yet another important aspect of the present invention a crystalline pregabalin anhydrous Form-I is characterized by X-ray powder diffraction (XRPD) pattern having peaks at 9.4, 16.5, 18.1, 18.9, 22.1, 23.4 and 35.5 2θ±0.2° 2Θ and is further characterized by X-ray powder diffraction (XRPD) pattern having peaks at 9.4, 12.1, 16.5, 18.1, 18.9, 19.6, 22.1, 23.4, 23.4, 24.5, 26.4, 28.7, 29.7, 30.8 and 35.5 2θ±0.2° 2Θ and by differential scanning calorimetry (DSC) having endothermic peak at 201.300C.

A crystalline pregabalin anhydrous Form-I according to claim 1-2, having brick shape crystal habit with mean particle size D(0.5) of about 25 μm to about 50 μm, D(0.1) of about 5 μm to about 15 μm and D(0.9) of about 120 μm to about 250 μm, preferably the mean particle size D(0.5) not less than 20 μm, D(0.1) not less than 4 μm and D(0.9) not less than 100 μm.

Also, a crystalline pregabalin anhydrous Form-I according to claim 1-2, having brick shape crystal habit with 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 D(0.5) and the particle size at the 90% quantile D(0.9) is less than 0.25, preferably less than 0.20.

The purity of pregabalin is one of the important aspect of the present invention wherein a crystalline pregabalin anhydrous Form I with brick shape crystal habit having ratio of length and width 1:1 to 10:1 contains less than or of about 0.4% to total impurities, preferably less than or of about 0.3% to total impurities as measured by area percentage of HPLC.

Also, the crystalline pregabalin anhydrous Form I with brick shape crystal habit having ratio of length and width 1:1 to 10:1, preferably 1:1 to 5:1 does not have detectable level of impurities when measured by HPLC at RRT 0.12, 0.25, 0.31, 0.34, 0.50, 0.58, 0.61, 0.78, 1.71, 1.61, 2.28 and 3.04.

Further, the crystalline pregabalin anhydrous Form I with brick shape crystal habit having ratio of length and width 1:1 to 10:1, preferably 1:1 to 5:1 having impurity at RRT 0.20 and RRT 0.23 is less than about 0.1%, preferably is less than about 0.05% by area percentage of HPLC. The another 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)-(+)-pregablin.

Thus, according to the another embodiment of the present invention there is provided a process for obtaining L-(+)-mandelic acid from the mother liquor comprising the steps of: a. concentrating the mother liquor under vacuum at 7O0C after resolution of pregabalin; b. cooling the reaction mixture at 6O0C to 650C; c. treating the residue with suitable organic solvent at 6O0C to 650C and cooling to room temperature; d. concentrating the reaction mixture under vacuum at 7O0C to obtain white solid residue; e. treatment of the solid residue with suitable organic solvent at 370C to 420C and cooling to room temperature; and f. filtering and isolating L-(+)-mandelic acid.

According to the process in step (c), wherein suitable organic solvent can be selected from aromatic hydrocarbons like toluene, xylene, halogenated solvents like methylene dichloride, chloroform, esters like ethyl acetate, isopropyl acetate, ethers like diethyl ether, isopropyl ether etc, preferably ethyl acetate and in step (e) is methylene dichloride.

Throughout the description and claims the word "comprise" and variations of the word are not intended to exclude other technical features, additives, components, or steps. The content of the abstract of the present application is incorporated herein as reference. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and is not intended to be limiting of the present invention.

Example-1:

Preparation of 2-carbethoxy-5-methyl hex-2-enoic acid ethyl ester

Figure imgf000018_0001
To a solution of 100 g of Isovaleraldehyde in 450 mL methylene dichloride was added 180 g of diethyl malonate at 250C to 350C in round bottom flask fitted with a dean-stark. 11.8 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 was again heated at reflux for 4 hours till azeotropic removal of water. The reaction mixture was cooled to 25°C-35°C. 225 mL of water was added to the reaction mixture, stirred and settled for 15 minutes. Separated organic layer was treated with 150 mL of 10% HCl 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% NaHCO3 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) : sp3 C-H stretch : 2980, 2960, 2935; CO : 1724; C=C stretch : 1649

1H NMR (CDCl3, 300 MHz): δ 0.90-1.01 (m, 6H), 1.24-1.35 (m, 6H), 1.77-1.84 (m, IH), 2.16-2.22 (m, 2H), 4.17-4.34 (m, 4H), 6.99-7.04 (t, IH, J = 7.9 Hz) MS: m/z = 228.28 (M+ 1).

2-carbethoxy-5-methyl hex-2-enoic 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 μm

Injector Temperature : 210°C Detector Temperature : 23O0C

Oven temperature Time (min) Temperature

Initial 0 1000C

Final 44 22O0C

Temp Programme rate: 20°C/minute

Equlibrium time : 1.0 minute

Injection Volume : 0.5 μl

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

Figure imgf000019_0001

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 niL of ethanol over a period of 2-3 hours at 250C to 350C. 91.0 mL of hexane was added at 250C to 350C 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 250C to 350C. Separated organic layer were combined and treated with 91.2 mL of water. The Separated hexane layer was filtered through hyflowbed and washed with hexane. The filtrate was subjected to distillation under vacuum by hot water below 6O0C to remove excess of hexane, cooled to 250C to 350C. [% 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. 1H NMR (CDCl3, 300 MHz): δ 0.96-0.99 (t, 6H, J = 4.5 Hz), 1.20-1.29 (m, 6H), 1.30- 1.33 (m, IH), 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). 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 μm Injector Temperature : 21O0C Detector Temperature : 23O0C

Oven temperature Time (min) Temperature Initial 0 1000C

Final 44 22O0C

Temp Programme rate: 20°C/minute Equlibrium 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- VI

Example-3:

Preparation of 3-Cyano-S-methyl-hexanoic acid ethyl ester

Figure imgf000021_0001

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 niL DMSO and 13.6 mL of R.O. water at 25°C to 350C. The reaction mixture was slowly heated to get 14O0C to 1450C temperature within 1-2 hour. The reaction mixture was stirred for 9-10 hours and gradually cooled to 250C to 350C. 210 mL of methyl tert-butyl ether was added to the reaction mixture followed by addition of 180 mL of water is slowly added in 1-2 hour below 350C, stirred and settled for 30 minutes. The separated aqueous layer was treated with 210 mL methyl tert-butyl ether, stirred and 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 6O0C to remove excess methyl tert-butyl ether. [% Yield = 94%, G.C purity = 94-96%] IR (Nujol-mull, v cm4) : sp3 C-H stretch : 2960, 2935, 2902; CN : 2243, CO : 1739. 1H NMR (CDCl3, 300 MHz): δ 0.89-0.98 (m, 6H), 1.19-1.36 (m, 4H), 1.61-1.64 (m, IH), 3.30-3.33 (m, IH), 2.50-2.57 (dd, IH, J = 7.78 Hz, J = 17.94 Hz), 2.65-2.73 (dd , IH, J = 7.8 Hz, J = 17.8 Hz), 3.03-3.21 (m, IH), 4.16-4.23 (q, 2H, J - 7.13 Hz). MS: m/z = 184.2 (M+l).

3-Cyano-S-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 μm Injector Temperature : 21O0C

Detector Temperature : 23O0C

Oven temperature Time (min) Temperature

Initial 0 1000C Final 44 22O0C

Temp Programme rate: 20°C/minute

Equlibrium time : 1.0 minute

Injection Volume : 0.5 μl

Carrier gas : Nitrogen Split Flow : 60 ml/min.

Detector : FID

A sample Chromatogram is shown in Figure- VII

Example-4

Preparation of 3-Amino-5-methyl-hexanoic acid ethyl ester

Figure imgf000022_0001

100.0 g of 3-Cyano-5-methyl-liexanoic acid ethyl ester and 133 mL of methanol were taken in autoclave at 250C to 350C and cooled to 2O0C to 350C. 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 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 hyflowbed and washed with mixture of 111.6 mL of water and 48.0 mL of methanol at 250C to 350C. 62 mL of acetic acid was added to filtrate to 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 550C to 6O0C to get clear solution and cooled to 250C to 350C. It was further cooled to O0C to 50C and stirred for 4 hours. The content was filtered at O0C to 50C, washed with chilled isopropyl alcohol. The product was dried at 5O0C to 550C for 8 hours. [% Yield = 58.98%].

3-Amino-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 : Synergi Hydro-RP 80 A (250 mm x 4.6 mm, 4μ) Mobile Phase : Water/ACN-95/05 Flow rate : 1.0 ml/minute

Column oven temp : 250C Run Time : 15 minutes Detector : dual wavelength UV-VIS Diluent : mobile phase Wavelength : 220 nm Injection Volume : 50 /d

Mobile phase composition and flow rate may be varied in order to achieve the required system suitability. Example-5 Preparation of Pregabalin mandelate salt

Figure imgf000023_0001

To the solution of 130 g of L(+)-mandelic acid in 1000 mL of isopropyl alcohol, 30 mL of water was added at 250C to 350C. The reaction mixture was heated to get clear solution at 550C to 650C. 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 250C. 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 7O0C to get clear solution. Previously obtained wet product 90.24 g was added to above reaction mixture at 650C to 7O0C and stirred to get clear solution. Cooled to 500C to 550C and stirred for 15 minutes. Further it was cooled to 250C to 350C and then to O0C to 50C and stirred for 4 hours. The reaction mixture was filtered, washed with chilled isopropyl alcohol at O0C to 50C and dried at 500C to 550C for 8 hours. [% Yield = 52.96 %]. Recovery of L (+)-Mandelic acid: Stage-I : (For the input of IKg of PG-04)

The combined filtrate obtained during filtration was distilled out completely under vacuum at 710C to obtain oily liquid. The concentrated mass was treated with 7.2 L of ethyl acetate at 65°C-70°C. Cooled to 20°C-25°C and stirred for 2 hours or till separation of product by gradually cooling and continuos 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 370C- 420C 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 50°C-55°C for 8 hours to obtain L(+)-mandelic acid. Stage-II

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-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 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 7O0C 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 7O0C 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 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. Example-6

Preparation of Pregabalin [(S)-3-amino methyI-5-hexanoic acid (Semi-Crude)]

Figure imgf000025_0001

PG-06

44 mL of water was added to the solution of 100 g of pregabalin mandelate salt in 833 mL of THF at 250C to 35°C. The reaction mixture was heated upto 5O0C to 550C, stirred and cooled to 250C to 350C. Gradually the reaction mixture was cooled to O0C to 50C and stirred 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:

The combined filtrate obtained was distilled out completely under vacuum upto 7O0C 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 700C 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 0°C-5°C and stirred for 1 hour. The product thus obtained was filtered and washed with chilled methylene dichloride, dried at 5 O0C- 550C for 8 hours to obtain L(+)-mandelic acid. Example-7 Preparation of Pregabalin [(S)-3-amino methyl-5-hexanoic acid (Crude)]

Figure imgf000025_0002
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 780C to 820C and stirred to get clear solution. The reaction mixture was filtered on hyflowbed and washed with hot isopropyl alcohol. The filtrate was taken at 65°C to 820C and gradually cooled to 250C to 350C and then to O0C to 50C, stirred for 5 hours, filtered, and washed with chilled isopropyl alcohol. The product was dried at 5O0C to 550C for 8 hours. [% Yield = 83%].

Example-8

Preparation of Pregabalin [(S)-3-amino methyl-5-hexanoic acid (Pure)]

Figure imgf000026_0001

440 niL 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 780C to 820C and stirred to get clear solution. The reaction mixture was filtered on hyflowbed and washed with hot isopropyl alcohol. The filtrate was taken at 650C to 820C and gradually cooled to 250C to 35°C and then to O0C to 5°C, stirred for 5 hours, filtered, and washed with chilled isopropyl alcohol. The product was dried at 5O0C to 550C for 8 hours. [% Yield = 90%]. IR (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.

1H NMR (CDCl3, 300 MHz): δ 0.73-0.76 (m, 6H), 1.05-1.09 (t, 2H, J = 6.98 Hz), 1.49-

1.53 (m, IH), 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, 5μ) or equivalent

Mobile Phase n-Hexane/Isopropyl alcohol/Formic acid-80/20/0.1 Flow Rate l.O ml/min. Column oven temp 25°C Run Time 30 mintues Detector dual wavelength UV-VIS Wavelength 264 nm Injection Volume 10 /d Diluent n-Hexane/Isopropyl 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 0.1 % and total impurity NMT 0.4%.

A sample Chromatogram is shown in Figure- VII, IX and X.

Example 9: Table of Impurity profile of pregabalin with present invention and Lyrica®

Figure imgf000027_0001

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 pure (S)-(+)-pregabalin via pregabalin mandelate 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 10:1, preferably 1:1 to 5:1.

4) The present invention also provides the process for preparation of novel crystalline form of pregabalin mandelate salt. 5) The present invention also provides pure (S)-(+)-pregabalin with HPLC purity 99.5% having R-isomer content NMT 0.5%, unknown impurity NMT 0.1% and total impurity NMT 0.4%.

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 brick shape crystal habit and having median particle size D(0.5) atleast 20 μm, preferably in the range of 25-50 μm. Also the particle size distribution of D(0.1) is atleast 4 μm, preferably in the range of 5-15 μm and D(0.90) is atleast 100 μm, preferably in the range of 120-250 μm.

8) The present invention provides (S)-(+)-pregabalin with crystalline particles having brick habit and the ratio of length and width 1:1 to 10:1, preferably 1:1 to 5:1, characterised 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.

9) The present invention provides the process which is environment friendly, cost effective and easily applicable for industrial large scale production.

Claims

Claims:
1. A process for preparing a crystalline compound of formula:
Figure imgf000029_0001
having the crystal habit such that the ratio between the length and the width of the crystals is between 1:1 to 10:1 wherein a crystalline compound is pregabalin in anhydrous Form I substantially free from impurities comprising the steps of: a. condensing isovaleraldehyde with an dialkyl malonate in presence of base to form a 2-carbalkoxy-5-methylhex-2-enoic acid, alkyl ester (II) substantially free from 2- carbalkoxy-S-methylhex-S-enoic acid, alkyl ester; b. reacting said 2-carbalkoxy-5-methylhex-2-enoic acid, alkyl ester (II) with a cyanide source to form a 2-carbalkoxy-3-cyano-5-methylhexanoic acid, alkyl ester (III); c. decarboxylating said 2-carbalkoxy-3-cyano-5-methylhexanoic acid, alkyl ester (III) in mixture of water and polar aprotic solvent organic solvent at 1000C to 150°C temperature to give 3-cyano-5-methylhexanoic acid, alkyl ester (IV); d. hydrolyzing said 3-cyano-5-methylhexanoic acid, alkyl ester (IV) with an alkali or alkaline earth metal hydroxide to form an alkali or alkali earth metal carboxylate salt which is hydrogenated to form (±)-3-(aminomethyl)-5-methylhexanoic acid (V); e. treating said (±)-3-(aminomethyl)-5-methylhexanoic acid (V) with (L)-(+)-mandelic acid in water, an alcohol, or a mixture of water and an alcohol; f. heating the reaction mixture at 5O0C to 7O0C and cooling it to obtain precipitate of mandelate salt of (S)-(+)-3-(ammomethyl)-5-methylhexanoic acid (VI); g. treating said mandelate salt of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid into a polar aprotic solvent or a mixture of polar aprotic solvent and water to form a slurry at 5O0C to 550C and cooled; and h. isolating (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (I) having crystal habit such that the ratio between the length and the width of the crystals is between 1 : 1 to 10:1 substantially free from impurities.
2. A process for preparing a crystalline compound of formula: ^COOH I having the crystal habit such that the ratio between the length and the width of the crystals is between 1:1 to 10:1 wherein said crystalline compound is pregabalin in anhydrous Form I substantially free from impurities comprising the steps of: a. condensing isovaleraldehyde with an diethyl malonate in presence of morpholine to form a 2-carbethoxy-5-methylhex-2-enoic acid, ethyl ester (II) substantially free from 2-carbethoxy-5-methylhex-3-enoic acid, ethyl ester; b. reacting said 2-carbethoxy-5-methylhex-2-enoic acid, ethyl ester (II) with a cyanide source to foπn a 2-carbethoxy-3-cyano-5-methylhexanoic acid, ethyl ester (III); c. decarboxylating said 2-carbethoxy-3-cyano-5-rnethylhexanoic acid, ethyl ester (III) in mixture of water and polar aprotic solvent organic solvent at 1000C to 150°C temperature to give 3-cyano-5-methylhexanoic acid, ethyl ester (IV); d. hydrolyzing said 3-cyano-5-methylhexanoic acid, ethyl ester (IV) with an alkali or alkaline earth metal hydroxide to foπn an alkali or alkali earth metal carboxylate salt which is hydrogenated to form (±)-3-(aminomethyl)-5-methylhexanoic acid (V); e. treating said (±)-3-(aminomethyl)-5-methylhexanoic acid (V) with (L)-(+)-mandelic acid in water, an alcohol, or a mixture of water and an alcohol; f. heating the reaction mixture at about 500C to 7O0C and cooled to obtain precipitate of mandelate salt of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (VI); g. treating said mandelate salt of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid into a polar aprotic solvent or a mixture of polar aprotic solvent and water to form a slurry at 5O0C to 550C and followed by cooling; and h. isolating (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (I) having crystal habit that the ratio between the length and the width of the crystals is between 1:1 to 10:1 substantially free from impurities.
3. A process as claimed in claim 1 or 2 wherein in step (a) said 2-carbalkoxy-5- methylhex-3-enoic acid, alkyl ester comprises olefinic isomer 2-carbalkoxy-5- methylhex-3-enoic acid, alkyl ester present in an amount of not more than 3%, preferablty 2% by area percentage of GC.
4. A process as claimed in claim 1 or 2 wherein in step (b) said cyanide source is selected from hydrogen cyanide, acetone cyanohydrin or an alkali metal or alkaline earth metal cyanide, such as sodium cyanide, potassium cyanide, or magnesium cyanide.
5. A process as claimed in claim 1 or 2 wherein in step (c), said polar aprotic solvent is dimethyl sulfoxide.
6. A process as claimed in claim 1 or 2 wherein in step (d) said alkali or alkaline earth metal is selected from the group consisting of sodium, potassium, lithium, barium, calcium and the like, preferably potassium hydroxide.
7. A process as claimed in claim 1 or 2 wherein step (d), said hydrogenating agent is raney nickle in polar organic solvent.
8. A process as claimed in claim 8, wherein said polar organic solvent is selected form C1-C4 alcohols like methanol, ethanol, propanol, isopropanol and the like, preferably methanol.
9. A process as claimed in claim 1 or 2 wherein in step (e), said alcohol is selected from C1-C4 alcohols like methanol, ethanol, propanol, isopropanol and the like, preferably isopropanol.
10. A process as claimed in claim 1 or 2 wherein in step (g), said polar aprotic solvent is selected from Acetonitrile, tetrahydrofuran, dimethyl foramide, dimethyl sulfoxide and the like, preferably tetrahydrofuran.
11. A process as claimed in claim 1 or 2, wherein said crystalline pregabalin anhydrous Form-I has a brick shape crystal habit as depicted in Figure- IA and Figure- IB.
12. A crystalline pregabalin mandelate of formula:
IV
Figure imgf000031_0001
characterized by X-ray powder diffraction (XRPD) pattern having peaks at 6.4, 17.9, 20.1 and 26.3° 2θ±0.2° 20.
13. A crystalline pregabalin mandelate as claimed in claim 12 characterized by X-ray powder diffraction (XRPD) pattern having peaks at 6.4, 12.8, 14.2, 15.2, 17.9, 18.8,
19.3, 20.1, 21.9, 22.7, 24.0, 26.3, 27.9, 28.8, 31.5, 32.2, 34.4, 36.9, 39.3° 2θ±0.2° 2Θ.
14. A crystalline pregabalin mandelate as claimed in claim 12 having the characteristic
X-ray powder diffraction (XRPD) patterns as substantially depicted in Figure III.
15. A crystalline pregabalin anhydrous Form-I as claimed in claim 1 or 2 characterized by X-ray powder diffraction (XRPD) pattern having peaks at 9.4, 16.5, 18.1, 18.9, 22.1, 23.4 and 35.5 2θ±0.2° 2Θ.
16. A crystalline pregabalin anhydrous Form-I as claimed in claim 16 further characterized by X-ray powder diffraction (XRPD) pattern having peaks at 9.4, 12.1, 16.5, 18.1, 18.9, 19.6, 22.1, 23.4, 23.4, 24.5, 26.4, 28.7, 29.7, 30.8 and 35.5
2θ±0.2° 2Θ.
17. A crystalline pregabalin anhydrous Form-I as claimed in claim 15 or 16 having the characteristic X-ray powder diffraction (XRPD) patterns as substantially depicted in Figure II.
18. A crystalline pregabalin anhydrous Form-I as claimed in claim 1 or 2 characterized by differential scanning calorimetry (DSC) having endothermic peak at 201.3O0C.
19. A crystalline pregabalin anhydrous Form-I as claimed in claim 18 having the characteristic DSC thermogram as substantially depicted in Figure IV.
20. A crystalline pregabalin anhydrous Form-I as claimed in claim 1 or 2, having brick shape crystal habit with mean particle size D(0.5) of about 25 μm to about 50 μm,
D(0.1) of about 5 μm to about 15 μm and D(0.9) of about 120 μm to about 250 μm.
21. A crystalline pregabalin anhydrous Form-I as claimed in claim 20, having brick shape crystal habit with mean particle size D(0.5) not less than 20 μm, D(0.1) not less than 4 μm and D(0.9) not less than 100 μm.
22. A crystalline pregabalin anhydrous Form-I as claimed in claim 1 or 2, having brick shape crystal habit with 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 D(0.5) and the particle size at the 90% quantile D(0.9) is less than 0.25, preferably less than 0.20.
23. A process as claimed in claim 1 or 2, wherein said crystalline pregabalin anhydrous Form I with brick shape crystal habit having ratio of length and width 1 : 1 to 10:1 contains less than or of about 0.4% to total impurities as measured by area percentage of HPLC.
24. A process as claimed in claim 24, wherein crystalline pregabalin anhydrous Form I with brick shape crystal habit having ratio of length and width 1:1 to 10:1, preferably 1:1 to 5:1 contains less than or of about 0.3% to total impurities as measured by area percentage of HPLC.
25. A process as claimed in claim 1 or 2, wherein, crystalline pregabalin anhydrous Form I with brick shape crystal habit having ratio of length and width 1 :1 to 10:1, preferably 1 :1 to 5:1 does not have detectable level of impurities when measured by
HPLC at RRT 0.12, 0.25, 0.31, 0.34, 0.50, 0.58, 0.61, 0.78, 1.71, 1.61, 2.28 and 3.04.
26. A process according to claim 1 or 2, wherein crystalline pregabalin anhydrous Form I with brick shape crystal habit having ratio of length and width 1:1 to 10:1, preferably 1 :1 to 5:1 having impurity at RRT 0.20 and RRT 0.23 is less than about
0.1% by area percentage of HPLC.
27. A process as claimed in claim 1 or 2, wherein crystalline pregabalin anhydrous Form I with brick shape crystal habit having ratio of length and width 1:1 to 10:1, preferably 1 :1 to 5:1 having impurity at RRT 0.20 and RRT 0.23 is less than about 0.05% by area percentage of HPLC.
28. A process for obtaining L-(+)-mandelic acid from the mother liquor comprising the steps of: a. concentrating the mother liquor under vacuum at 7O0C after resolution of pregabalin; b. cooling the reaction mixture at 6O0C to 650C; c. treating the residue with suitable organic solvent at 6O0C to 650C and cooling to room temperature; d. concentrating the reaction mixture under vacuum at 70°C to obtain white solid residue; e. treatment of the solid residue with suitable organic solvent at 370C to 420C and cooling to room temperature; and f. filtering and isolating L-(+)-mandelic acid.
29. A process as claimed in claim 29 wherein in step said suitable organic solvent is selected from aromatic hydrocarbons like toluene, xylene, halogenated solvents like methylene dichloride, chloroform, esters like ethyl acetate, isopropyl acetate, ethers like diethyl ether, isopropyl ether etc, preferably ethyl acetate.
30. A process as claimed in claim 29 wherein in step (e), said suitable organic solvent can be selected from aromatic hydrocarbons like toluene, xylene, halogenated solvents like methylene dichloride, chloroform, esters like ethyl acetate, isopropyl acetate, ethers like diethyl ether, isopropyl ether etc, preferably methylene dichloride.
31. A process of preparing crystalline pregabalin anhydrous Form I with brick shape crystal habit having ratio of length and width 1:1 to 10:1 substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompaying drawings and/or examples.
32. A crystalline pregabalin anhydrous Form I having impurity at RRT 0.20 less than 0.05% by area percentage of HPLC.
33. A crystalline pregabalin anhydrous Form I having impurity at RRT 0.23 less than 0.05% by area percentage of HPLC.
PCT/IN2007/000467 2006-10-06 2007-10-05 Crystalline forms of pregabalin WO2008062460A2 (en)

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US7763749B2 (en) 2005-05-10 2010-07-27 Teva Pharmaceutical Industries Ltd. Method for the preparation of Pregabalin and salts thereof
US7619112B2 (en) 2005-05-10 2009-11-17 Teva Pharmaceutical Industries Ltd. Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid
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WO2009125427A3 (en) * 2008-02-18 2010-06-03 Matrix Laboratories Limited Process for preparing (s)-3-(aminomethyl)-5-methylhexanoic acid
WO2009125427A2 (en) * 2008-02-18 2009-10-15 Matrix Laboratories Limited Process for preparing (s)-3-(aminomethyl)-5-methylhexanoic acid
WO2010061403A2 (en) * 2008-11-26 2010-06-03 Ind-Swift Laboratories Limited Process to prepare highly pure (s)-pregabalin
WO2010061403A3 (en) * 2008-11-26 2012-05-18 Ind-Swift Laboratories Limited Process to prepare highly pure (s)-pregabalin
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WO2011076915A1 (en) 2009-12-24 2011-06-30 Moehs Iberica S.L. Novel method for the preparation of (s)-pregabalin field of the invention
WO2011141923A3 (en) * 2010-05-14 2012-01-19 Lupin Limited Improved synthesis of optically pure (s) - 3-cyano-5-methyl-hexanoic acid alkyl ester, an intermediate of (s)- pregabalin
WO2012059797A1 (en) * 2010-11-04 2012-05-10 Lupin Limited Process for synthesis of (s) - pregabalin
WO2014072785A2 (en) 2012-11-07 2014-05-15 Hikal Limited A process for the preparation of pregabalin
CN103145571A (en) * 2013-03-27 2013-06-12 李兴惠 Crystal form of derivative of aminomethyl caproic acid
CN103450045A (en) * 2013-08-22 2013-12-18 河北诚信有限责任公司 Synthetic method of pregabalin intermediate 2-carboxethyl-3-cyano-5-methylethyl caproate
CN104649919A (en) * 2015-02-10 2015-05-27 浙江华海药业股份有限公司 Preparation method of small-particle pregabalin
CN105367434A (en) * 2015-11-26 2016-03-02 太仓运通生物化工有限公司 Method for synthesizing pregabalin from isobutyraldehyde

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