WO2009044409A2

WO2009044409A2 - Novel resolution process for pregabalin

Info

Publication number: WO2009044409A2
Application number: PCT/IN2008/000621
Authority: WO
Inventors: Durga Prasad Konakanchi; Ramakrishna Pilli; Subba Rao Pula; Buchappa Gongalla; Kotayya Babu Sikha; Nannapaneni Venkaiah Chowdary
Original assignee: Natco Pharma Limited
Priority date: 2007-10-01
Filing date: 2008-09-26
Publication date: 2009-04-09
Also published as: WO2009044409A3

Abstract

Present invention relates to a novel and improved process for the resolution of racemic pregabalin of formula (I) into (S)-(+)-pregabalin [(S)-(+)-3-aminomethyl-5-methylhexanoic acid] of formula (III) via the novel acid addition salt [(S)-(+) 3-aminomethyl-5-methylhexanoic acid, (-)-O, O'-di-p-toluoyl-L-tartaric acid salt] of formula (II). (S)-(+)-pregabalin of formula-III has analgesic, anticonvulsant and anxiolytic properties and hence is of great therapeutic significance.

Description

NOVEL RESOLUTION PROCESS FOR PREGABALIN

INTRODUCTION

Present invention relates to a novel and improved process for the resolution of racemic pregabalin of formula-I into (S)-(+)-pregabalin [(S)-(+)-3-aminomethyl-5- methylhexanoic acid] of formula-Ill via the novel acid addition salt [(S)-(+) 3- aminomethyl-5-methylhexanoic acid, (-)-O,O'-di-p-toluoyl-L-tartaric acid salt] of formula-II.

(S)-(+)-pregabalin

(S)-(+)-pregabalin of formula-Ill has analgesic, anticonvulsant and anxiolytic properties and hence is of great therapeutic significance.

BACKGROUND OF THE INVENTION (±)-Pregabalin was reported for the first time by Ryszard Andruskiewicz et al. in Synthesis, page 953, 1989. The synthetic route is as shown in scheme-I.

(±)-Pregabalin (I)

Scheme- 1 The synthetic scheme published in the basic patent for pregabalin (US 5563175) using asymmetric Evans alkylation starting from (+)-norephedrin is given below (Scheme- II).

(+)-Norephidrine

S-(+)-PREGABALIN(lll)

Scheme-II The main drawbacks in the synthesis are:

(1) Expensive and hazardous reagents like n-butyl lithium and lithium isopropylamide are used in the process

(2) Low temperatures (-78 ⁰C) are required for the reactions using the reagents n-butyl lithium and lithium isopropylamide in the preparation, which will render the process unviable on commercial scale.

The synthetic process for pregabalin published in the US pat. 5616793 uses (R)- phenylethylamine as resolving agent. The process is given in Scheme-Ill.

Isovaleraldehyde Ethyl cyanoacetate

S(+)Pregabalin (III)

Scheme-Ill

The main drawbacks in this process are: 1) The resolving agent is expensive.

2) Recovery and re-use of resolving agent is tedious.

A process for the resolution of (±)-pregabalin using (S)-(+)-mandelic acid is disclosed in the US pat 5840956. Process disclosed in this patent is shown in Scheme-IV below. Isovaleraldehyde is reacted with diethyl malonate by Knoevenagel condensation to obtain ethyl 2-carboxyethyl-5-methylhex-2-enoate, which on reaction with potassium cyanide afforded ethyl 2-carboxyethyl-3-cyano-5-methylhexanoate. Ethyl 2- carboxyethyl-3-cyano-5-methylhexanoate on heating with sodium chloride in dimethyl sulfoxide under Krapcho conditions yielded ethyl 3-cyano-5-methylhexanoate, which on treatment with

S-(+)-Pregabalin (III)

Scheme- IV potassium hydroxide afforded the corresponding potassium salt. Catalytic hydrogenation of the potassium salt solution using sponge Nickel provided the racemic pregabalin of formula-I. The racemic pregabalin on resolution with S-(+)-Mandelic acid gave S-(+)-pregabalin.

The main drawbacks in this process are: 1) The resolving agent (S- (+)-Mandelic acid) is expensive. 2) The resolving agent is used in large excess.

3) Recovery and re-use of resolving agent is tedious. There are also several asymmetric syntheses published in journals and also in the patent literature. The references are WO 01/55090 (uses chiral catalyst, a rhodium complex of an (R, R)-DuPHOS) or (S, S)-DuPHOS ligands, Mark J. Burk et al., Journal of Medicinal Chemistry, 2003,68,5731-5734 (also uses different rhodium complex DuPHOS ligands, Eric N. Jacobsen et al., J.Am.Chem.Soc. 2003,125,4442-4443 (Uses Chiral aluminium salen complexes) and Garret Hoge, J.Am.Chem.Soc. 2003,125,10219-10227 (Uses P- Chirogenic 1,2-Bisphosphoslanoethane ligands).

These methods need very expensive catalysts and the processes require very sophisticated equipments like high pressure hydrogenator etc.

PROCESS OF THE PRESENT INVENTION

To overcome the disadvantages mentioned above, we have worked extensively in the laboratory and developed a simple process using inexpensive and commercially available resolving agent, (-)-O, O'-di-p-toluoyl-L-tartaric acid [L-DTTA] of formula-IV,

Formula-IV for the resolution of racemic pregabalin. Resolution of racemic pregabalin with (-)-O, O'-di-p-toluyl-L-tartaric acid is hither to not known in the literature. This is a very simple, inexpensive, and commercially available chiral reagent.

The novel synthetic scheme of the present invention is given in the following scheme- V.

S-(+)-Pregabalin (III)

Scheme-V

Scheme- V illustrates a method for making pregabalin, which comprises: 1) heating racemic Pregabalin [(±)-3- (Amino methyl)-5-methylhexanoic acid] of formula-I with (O, O')- di-toluoyl-L-tartaric acid of formula-IV in a suitable solvent mixture to form a novel salt, S-(+)-3-aminomethyl-5-methylhexanoic acid, di-(O,O')-toluyl-L-tartaric acid salt of formula-II; 2) heating the novel salt of formula-II in aqueous tetrahydrofuran to give S- (+)-pregabalin of formula-Ill.

DETAILED DESCRIPTION OF THE PRESENT INVENTION:

The present invention provides a novel resolution process for the preparation of chirally pure S-(+)-pregabalin of formula-Ill,

which comprises,

(i) reaction of racemic pregabalin of formula-I,

I with (-)- (O, O)- di- toluoyl-L-tartaric acid of formula-IV,

Formula-IV in the presence of a solvent medium comprising solvents such as methylene chloride, chloroform, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, isopropyl alcohol, toluene, hexanes including cyclohexane, n-heptane as separately or with a mixture of these solvents and with or with out water at temp ranging 0 - 90 ⁰C to get the novel salt of formula-II,

(ϋ) recrystallization of the crude salt of formula-II from a solvent medium comprising solvents such as methylene chloride, chloroform, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, isopropyl alcohol, toluene, hexanes including cyclohexane, n-heptane as separately or with a mixture of these solvents and with or with out water and isolation of the recrystallized salt at a temperature of 0 - 120 ⁰C. (iii) Liberation of S-(+)-pregabalin of formula-Ill from the purified salt of formula-II using aq solvent at a temperature of 0 - 90 ⁰C

(iv) Recrystallization of crude pregabalin of formula-Ill from a solvent medium comprising solvents such as methylene chloride, chloroform, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, isopropyl alcohol, toluene, hexanes including cyclohexane, n-heptane as separately or with a mixture of these solvents and with or with out water to get pharmaceutically acceptable grade of S- (+)-pregabalin.

The crude salt of formula-II is leached/recrystallized from solvent mixtures aqueous isopropyl alcohol, aqueous acetone, aqueous ethyl alcohol aqueous methanol etc., to improve the chiral purity of the salt. After getting the required purity the salt is treated with aq THF to liberate pregabalin from the salt. The liberated solid pregabalin is filtered and recrystallized from a solvent to get pharmaceutically acceptable grade S- (+)-pregabalin of formula-Ill. Chiral purity of S-(+)-pregabalin prepared according to the present process is >99.90 % with < 0.10% of (R)-pregabalin content.

Solvent used in salt formation step (i) is selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, or mixture of these solvents. Temperature of reaction during salt formation stage can be in the range of 20°C to boiling point of the solvent used in the process.

Solvent used in recrystallization step (ii) is selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, or mixture of these solvents Isolation temperature of recrystallized salt is preferably 0 - 50 ⁰C Solvent used in pregabalin liberation step (iii) is selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, or mixture of these solvents. Temperature of the reaction during pregabalin liberation is preferably 40⁰C to 90 ⁰C.

Solvent employed in recrystallization step (iv) is selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, or mixture of these solvents Isolation temperature of recrystallized pregabalin is preferably -10 ⁰C to 70 ⁰C.

a) heating racemic Pregabalin [(±)-3- (Amino methyl)-5-methylhexanoic acid] with di- (O, O)-toluoyl-L-tartaric acid of formula-IV affords a mixture of diastereomeric salts from which the desired novel salt, S (+) 3-aminomethyl-5-methylhexanoic acid di- (O, O)-toluoyl-L-tartaric acid of formula-II crystallizes out preferentially with solvents selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, or mixture of these solvents etc.

The temperatures for formation of the salt range from 20 ⁰C to 140 ⁰C and the temperatures for the preferential crystallisation of the desired salt ranges from -10 ⁰C to 70 ⁰C

Formula-II b) heating the novel salt S (+) 3-aminomethyl-5-methylhexanoic acid di- (O, O)-toluoyl- L-tartaric acid salt of formula-II in aqueous tetrahydrofuran gives Pregabalin [S (+) 3- aminomethyl-5-methylhexanoic acid. The mother liquors are recycled for further resolution of fresh racemic pregabalin.

Chiral resolving agent of formula-IV used in the process is recovered from the mother liquor of resolution step (i) by distilling off the solvent form the mother liquors and recrystallised from acetone, methyl ethyl ketone etc,. The resultant crystallized chiral reagent is isolated by filtration to get pure compound of formula-IV.

In a similar way the invention also provides a novel resolution process for the synthesis of other isomer of Pregabalin whose chemical name is (R)-(-)-3-aminomethyl-5-methyl- hexanoic acid of formula-V,

Formula-V

using di- (O, O)-toluoyl-D-tartaric acid of formula- VI,

Formula-VI through the novel salt R (-) 3-aminomethyl-5-methylhexanoic acid di- (O, O)-toluoyl-D- tartaric acid [D-DTTA] of formula-VII.

Formula-VII

The novel compounds of formulae-IV (((S)-(+) 3-aminomethyl-5-methyl-hexanoic acid, (-)-(O,O'-di-p-toluoyl-L-tartaric acid salt) and VII ((R)-(-) 3-aminomethyl-5-methyl- hexanoic acid, (+)-O,O'-di-p-toluoyl-L-tartaric acid salt) are well characterized by ¹H, ¹³C NMR, IR, and Mass spectral analysis.

Advantages of Present invention:

1. Present process uses inexpensive and readily available resolving agent, (-)-O,O'- di-p-toluoyl-L-tartaric acid in the resolution of racemic pregabalin.

2. The resolving agent can be easily recycled making the process economically feasible.

3. Present process is suitable for manufacturing scale operations. The following examples are illustrative of the compounds of the invention and their preparation with out being limiting.

Examples:

1. A. Preparation of S- (+)-3-aminomethyl-5-methylhexanoic acid, di- (O, O')- toluoyl-L-tartaric acid salt of formula-II

10

(±)-3- (Aminomethyl) di- (O, O)-toluoyl- S- (+)-3-aminomethyl-5-methylhexanoic acid, -5-methylhexanoic acid L-tartaric acid di- (O, O')-toluoyl-L-tartaric acid salt

15 Procedure: Step: a)

Into a 5.0 L 4-necked round bottom flask connected to a mechanical stirrer, and equipped with reflux condenser, thermometer socket and addition funnel was charged 100.Og (0.628 moles) of racemic Pregabalin [(±)-3- (Aminomethyl)-5-methylhexanoic acid] and 500.0 ml of methanol while stirring. The temperature of the mass was raised to 60-65 °C and

20 maintained at 60-65°C for 10-20min. (-)-(O, O)-Di-toluoyl- L-tartaric acid solution (254.Og, 0.628 moles) was dissolved in 500.0ml of Acetone (lot-I) and was added to the reaction mass at reflux temperature over a period of 20-30minutes. Then 1000.0ml of Acetone was added (lot-II) over a period of 10-15 min to the reaction mass. Maintained the mass under reflux temperature for 60-90 min. The reaction mass was slowly cooled to

25 45±2.5°C in 90-120 min. Further the reaction mass was maintained at 45±2°C for 90- 120min. The solid was filtered on Buchner funnel kept under plant vacuum. The wet cake was washed with 50.0 ml of acetone (lot-Ill). Suck dried thoroughly. Transferred the wet material into dry petri dish and dried in oven at 55-60°C. Weight of the dried material (A): 21O g.

30 Chiral Purity of the dried material A: (+) Isomer salt: 75%. (-) Isomer salt: 25%.

Step: b)

The above (+) isomer crude salt (194.Og) was taken into a 2.0 L 4-necked round bottom flask connected to a mechanical stirrer, and equipped with reflux condenser, thermometer 35 socket, addition funnel. 582.0 ml of acetone and 582.0ml of methanol were charged under stirring. Raised the temperature of the mass to 55-60⁰C. Maintained the mass at reflux temperature for 60-90min. Then slowly cooled the reaction mass to 32.5±2.5°C over a period of 90-120min period. Maintained the reaction mass for 60-90 min at 32.5±2.5°C. Filtered the reaction mass on Buchner funnel and washed with 40.0ml of acetone (lot-II). Suck dried thoroughly. Transferred the wet material into dry petri dish and dried in a oven at 55-60°C. Weight of the dried material: 145.Og

Chiral Purity of the dried material A: (+) Isomer salt: 88%. (-) Isomer salt: 12%. Step: c)

The above (+) isomer once leached salt (140.Og) was taken into a 2.0 L 4-necked round bottom flask connected to a mechanical stirrer, and equipped with reflux condenser, thermometer socket, addition funnel. 350.0 ml of Acetone and 350.0ml of methanol were charged while under stirring. Raised the temperature of the mass to 55-60°C. Maintained the mass at reflux temperature for 60-90min. Then slowly cooled the reaction mass to 32.5±2.5°C over a period of 90-120min period. Maintained the reaction mass for 60-90 min at 32.5±2.5°C. Filtered the reaction mass on Buchner funnel and washed with 30.0ml of Acetone (lot-II). Suck dried thoroughly. Transferred the wet material into dry petri dish and dried in a oven at 55-60⁰C. Weight of the dried material: 125.Og Chiral Purity of the dried material A: (+) Isomer salt: 95.5%. (-) Isomer salt: 4.5%.

This material is sufficiently pure for the next stage for obtaining pharma grade Pregabalin. For the preparation of analytically pure sample the above step c) material is leached twice as per the step c) procedure to obtain chiral purity of the (+) isomer salt - 99.5%

Melting Range: 151.2-152.7

Specific Optical Rotation: -95.8° [C =1% in methanol]

Spectral properties: IR Spectra: 3437.9,2960, 2926, 1727, 1610 cnT¹

¹HNMR (300MHz): 0.83-0.86 dd -CH₃(6H), 1.14-1.22 m -CH₂(CH)₂ (2H), 1.58-1.64 M

-CH (1H),2.O7-2.1O dd -CH₂COOH (IH), 2.19-2.22 dd -CH₂NH₂ (IH), 2.23-2.29 m -

CH(CH₃)₂ (IH), 2.35 s -2 x CH₃ (IH), 3.32-3.35 dd -2 x CH - of tartaric acid (2H), 5.65 b NH₂ (2H), 7.29-7.31 d -4 ArH (4H), 7.80-7.82 d 4 ArH (4H).

¹³CNMR (300MHz): 21.06 -2xCH₃ (of L-DTTA) (2C), 22.21 -CH₃ (1C), 22.43 -CH₃ -

CH₂ (C4)

(1C), 24.37 -CH -(CHs)₂ (1C), 30.90 -CH₂ -(CH₂)₃ (1C), 36.16 -jCOOH (1C), 40.28 -

CH₂-(CHa)₂ (1C), 42.13 -CH₂NH₂ (1C), 1.42 - 2 x CH-O- (of L-DTTA) (2C), 126.68 - 2 Ar C -(CH₃ bonded) (2C), 29.2 -8 Ar C -<un substituted) (8C), 143.67 -2 Ar C -(COO bonded) (2C), 164.69 -C=O(Ar COO) (2C), 167.76 -C=O(L-DTTA) (2C), 173.31 -

C=O(Pregabalin) (lC). Mass: 547.43 [M+2], 546.46 [M +1]

B. Preparation of S- (+)-3-aminomethyl-5-methylhexanoic acid: 5

Into a 2.0 L 4-necked round bottom flask connected to a mechanical stirrer, and equipped with reflux condenser, thermometer socket, addition funnel was charged 120.Og (0.628 moles) of S- (+)-3-aminomethyl-5-methylhexanoic acid, di- (O, O')-toluoyl-L-tartaric acid salt of example lA.step c), 720.0ml of tetrahydrofuran and 36.0 ml of demineralised water

10 while stirring. Stirred the mass at 30±5.0°C for 10-20 min. After the dissolution was clear maintained the mass at 30±5.0°C for 90-120 min. The reaction was cooled to 0.0±2.5°C. Further maintained the reaction mass at temperature 0.0±2.5°C for 90-120min. The solid formed was filtered on Buchner funnel kept under plant vacuum. The wet cake was washed with 50.0 ml of chilled tetrahydrofuran. Suck dried thoroughly. Transferred the wet

15 material into dry petri dish and dried in oven at 50-60⁰C. Weight of the dried material (Technical grade): 28 g. Chiral Purity of the dried material A: (+) Isomer: 99.4%. (-) Isomer: 0.6%%.

Recrystallisation procedure:

20

The above technical grade material (25.0 g) was dissolved mixture of Isopropyl alcohol (125.0 ml), demineralised water (125.0 ml) at temperature 70 -75 ⁰C. Activated carbon (1.25 g) was added and maintained for 10-15 min at 70 -75 ⁰C. Filtered the hot solution on hyflow bed and transferred to a particle free 1.0 L three necked RB flask equipped with a

25 condenser and a thermometer socket. Cooled the solution to temperature 30±5.0°C. Then acetone (375.0 ml) was charged in single lot at temperature 30±5.0°C and held at the same temperature for 60-90 min. The cooled to 0.0±2.5°C and further held at that temperature for 4-5 hrs. The crystallized product was filtered and washed with 20.0 ml of chilled isopropyl alcohol. Suck dried thoroughly. Dried the wet material in a oven at temperature

30 60±5.0°C.

Weight of the dried material (pharma grade): 22.5 g.

Melting Range: 186.5-186.8

35 Specific Optical Rotation: (+) 10.5 ° [C =1.08% in Water) spectral properties : IR Spectra: 2955 cm^"1, 2896 cm^'1, 2873 cm^"1, 1645 cm^"1, 1367 cm^'1.

¹HNMR (300MHz): 0.75-0.95 d -CH₃(3H), 0.80-0.90 d -CH₃ (3H), 1.00-1.15 t -CH₂ 40 (2H), 1.45-1.60 m -CH (CH₃)₂ (IH), 1.85-1.90 m -CH (IH), 1.95-

2.10 dd -CH₂EQU (IH), 2.15-2.25 dd -CH₂ axial (IH), 2.55-2.70 dd -CH₂(eq)(lH), 2.75-2.85 dd -CH₂ axial (IH) ¹³CNMR (300MHz): 21.54 -CH₃ (1C), 22.01 -CH₃ (1C), 24.83 -CH₂ (1C), 31.63 -CH (1C), 40.65 -CH (1C), 40.80 -CH₂ C=OOH (1C) 43.75 -CH₂NH₂ (1C), 180.95 -C=O (IC).

Mass: 160.1 ( M+l)

Recoveries of solvent, salt rich in the desired isomer and the resolving agent:

C. The mother liquors of example- 1 -A step a), b) and c) are mixed together and the solvent mixture was desolvated by distillation and analysed for the ratio of the solvent mixture by GC, and then recycled after adjusting to required ratio of the solvent mixture. The residue was collected and dried. Into a 2.0 L 4-necked round bottom flask connected to a mechanical stirrer, stopper, socket and condenser is charged 120.0 g of the above residue , 720.0 ml of tetrahydrofuran and 36.0 ml of DM water while under stirring. Stirred the mass at 30 +5°C for 20-30 min. Maintained the mass temperature at 30±5°C for 90-120 min. Cooled the mass temperature to 0±2.5°C over a period of 20- 30min. Maintained the mass temperature at 0±2.5°C for 120-150 min. Filtered the compound and washed with 50.0ml of chilled tetrahydrofuran, suck dried thoroughly. Dried the compound at 55 ±5⁰C in drier till LOD was not more thanl .0%w/w. The dried material, which is rich in unwanted isomer goes for racemisation. The tetrahydrofuran mother liquors was taken and distilled to recover the tetrahydrofuran and water mixture, then recycled after adjusting to required percentage of moisture content in the salt breaking step. The residue obtained from the distillation of tetrahydrofuran mother liquors was taken in acetone and the undissolved material was removed by filteration. Then the crude resolving agent, di- (O, O)-toluoyl- L-tartaric acid, was obtained after distilling the solvent. The recovered crude di- (O, O)-toluoyl- L-tartaric acid was recrystallised from water and analysed for complete analysis and recycled in the resolution step.

D. The mother liquors of example- 1 -B and from recrystallisation step was distilled separeately and the recovered solvent mixture was analyzed the ratio of the solvent mixture and moisture content and then recycled after adjusting to required ratio of the solvent mixture and the moisture contents in the respective steps. The dried residue was collected slurried in acetone and filtered. The filtrate goes for recovery of acetone and the resolving agent as mentioned in method C. The chiral purity of the dried salt was about 88.0% (+) isomer and was directly mixed in the input of stage A- step C.

The product obtained by recycling the solvent, salt rich in the desired isomer and the resolving agent matches with pharma specifications, making the process economically and commercially feasible.

2. A. Preparation of R- (-)-3-aminomethyl-5-methylhexanoic acid, di- (O, O')- toluoyl-D-tartaric acid salt of formula- VII

solvent resolution

(±)-3- (Aminomethyl) di- (O, O)-toluoyl- R- (-)-3-aminomethyl-5-methylhexanoic acid, -5-methylhexanoic acid D-tartaric acid di- (O, O')-toluoyl-D-tartaric acid salt

Procedure: Step: a)

Into a 5.0 L 4-necked round bottom flask connected to a mechanical stirrer, and equipped with reflux condenser, thermometer socket addition funnel and stopper were charged 100.Og (0.628 moles) of racemic pregabalin [(±)-3- (Aminomethyl)-5-methylhexanoic acid] and 500.0mlof methanol while stirring. The temperature of the mass was raised to 60- 65°C and maintained at 60-65°C for 10-20min. (+)-(O, O)- Di- toluoyl- D-tartaric acid (254.Og (0.628 moles) was dissolved in 500.0ml of acetone (lot-I) and was added to the reaction mass at reflux temperature over a period of 20-30 min. Then 1000.0ml of Acetone was added (lot-II) over a period of 10-15 min to the reaction mass. Maintained the mass under reflux temperature for 60-90 min. The reaction mass was slowly cooled to 45±2.5°C in 90-120 min, and further maintained at 45±2°C for 90-120min. The solid was filtered on Buchner funnel kept under plant vacuum. The wet cake was washed with 50.0 ml of acetone (lot-Ill). Suck dried thoroughly. Transferred the wet material into dry petri dish and dried in oven at 55-60°C. Weight of the dried material (A): 200.O g. Chiral Purity of the dried material A: (-) Isomer salt: 75%. (+) Isomer salt: 25%.

Step: b)

The above (-) isomer crude salt (194.Og) was taken into a 2.0 L 4-necked round bottom flask connected to a mechanical stirrer, and equipped with reflux condenser, thermometer socket, addition runnel. A mixture of 582.0 ml of Acetone and 582.0ml of methanol were charged while under stirring. Raised the temperature of the mass to 55-60°C. Maintained the mass at reflux temperature for 60-90min. Then slowly cooled the reaction mass to 32.5±2.5°C over a period of 90-120min period. Maintained the reaction mass for 60-90 min at 32.5±2.5°C. Filtered the reaction mass on Buchner and washed with 40.0ml of Acetone (lot-II). Suck dried thoroughly. Transferred the wet material into dry petri dish and dried in a oven at 55-60°C. Weight of the dried material: 140.Og Chiral Purity of the dried material A: (-) Isomer salt: 88%. (+) Isomer salt: 12%. Step: c)

Once leached salt (140.Og) of the above (-) isomer was taken into a 2.0 L 4-necked round bottom flask connected to a mechanical stirrer, and equipped with reflux condenser, thermometer socket, addition funnel. A mixture of 350.0 ml of Acetone and 350.0ml of methanol were charged while under stirring. Raised the temperature of the mass to 55- 60°C. Maintained the mass at reflux temperature for 60-90min. Then slowly cooled the reaction mass to 32.5±2.5°C over a period of 90-120min period. Maintained the reaction mass for 60-90 min at 32.5±2.5°C. Filtered the reaction mass on Buchner and washed with 30.0ml of Acetone (lot-II). Suck dried thoroughly. Transferred the wet material into dry petri dish and dried in a oven at 55-60⁰C. Weight of the dried material: 125.Og Chiral Purity of the dried material A: (-) Isomer salt: 95.5%. (+) Isomer salt: 4.5%.

For the preparation of analytically pure sample the above step c) material was leached twice as per the step c) procedure to obtain chiral purity of the (-) isomer salt - 99.5%

Melting range: 154.1-154.2

Specific Optical Rotation: (+) 99.58 ° [C = 1% in methanol]

Spectral properties:

IR Spectra: 3437.9,2960, 2926, 1727, 1610 cm-¹

Mass: 547.43 [M+2], 546.46 [M +1]

C. Preparation of R- (-)-3-aminomethyl-5-methylhexanoic acid:

Into a 2.0 L 4-necked round bottom flask connected to a mechanical stirrer, and equipped with reflux condenser, thermometer socket, addition funnel were charged 120.Og (0.628 moles) of S- (-)-3-aminomethyl-5-methylhexanoic acid, di- (O, O')-toluoyl-D-tartaric acid salt of example lA.step c), 720.0ml of tetrahydrofuran and 36.0 ml of demineralised water while stirring. Stirred the mass at 30±5.0°C for 10-20 min. When the dissolution was clear the mass was maintained at 3O±5.O°C for 90-120 min and then was cooled to 0.0±2.5°C. Further maintained the reaction mass at temperature 0.0±2.5°C for 90-120min. The solid formed was filtered on Buchner funnel kept under plant vacuum. The wet cake was washed with 50.0 ml of chilled tetrahydrofuran. Suck dried thoroughly. Transferred the wet material into dry petri dish and dried in oven at 50-60°C. Weight of the dried material (Technical grade): 29.0 g.

Chiral Purity of the dried material A: (-) Isomer: 99.80%. (+) Isomer: 0.20%%.

Recrystallisation procedure: The above technical grade material (25.0 g) was dissolved mixture of Isopropyl alcohol (125.0 ml), demineralised water (125.0 ml) at 70 -75 ⁰C. Activated carbon (1.25 g) was added and maintained for 10-15 min at 70 -75 ⁰C. Filtered the hot solution on hyflow bed and transferred to a particle free 1.0 L three necked RB flask equipped with a condenser and a thermometer socket. Cooled the solution to temperature 30±5.0°C. Acetone (375.0 ml) was charged in single lot at temperature 3O±5.O°C, held at the same temperature for 60- 90 min, and then cooled to 0.0±2.5°C and further held at that temperature for 4-5 hrs. The crystallized product was filtered and washed with 20.0 ml of chilled isopropyl alcohol. Suck dried thoroughly. Dried the wet material in a oven at temperature 60±5.0°C.

Weight of the R(-) Pregabalin : 22.5 g.

Melting range : 187.0-187.5 Specific Optical Rotation : -10.5 ° [C =1.08% in Water] spectral properties :

IR Spectra : 3437.9, 2960, 2926, 1727, 1610 cm^"1. Mass: 160.1 (M+ 1).

Claims

We claim:

LA novel resolution process for the preparation of S-(+)-Pregabalin whose chemical name is (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid of formula-Ill

which comprises,

(i) forming a salt with racemic pregabalin of formula-I,

I with (-)-O,O)- di-(toluoyl-L-tartaric acid of formula-FV,

Formula-I V in the presence of a solvent medium selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, or mixture of these solvents at temp. 0 - 90 ⁰C to get the novel diastereomeric salt of formula-II and more preferably 40 - 65 ⁰C,

(ii) recrystallization of the crude salt of formula-II from a solvent selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, or mixture of these solvents and isolation of the recrystallized salt at a temperature of 0 - 120 ⁰C and more preferably 30 -60 ⁰C.

(iii) Regeneration of S-(+)-pregabalin of formula-Ill from the purified salt of formula-II using mixture of tetrahydrofuran and water at a temperature of 0 -

90 ⁰C and more preferably -5 ⁰C - 35 ⁰C

(iv) Recrystallization of crude S-(+)-pregabalin of formula-Ill from solvents selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate or mixture of these solvents at temp. 0 — 90 ⁰C to get the novel diastereomeric salt of formula-II and more preferably 40 - 65 ⁰C to get pharmaceutically acceptable pregabalin.

2. A novel compound, S- (+)-3-aminomethyl-5-methylhexanoic acid, (O, O')- di- toluoyl-L-tartaric acid salt of formula-II.

Formula-II

3. A process for the preparation of S- (+)-3-aminomethyl-5-methylhexanoic acid, (O, O')- di-toluoyl-L-tartaric acid salt of formula-II.

which comprises,

(i) forming a salt of racemic pregabalin of formula-I,

I with (-)-di-(O,O)-toluoyl-L-tartaric acid of formula-IV,

Formula-IV in the presence of a solvent medium selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, or mixture of these solvents at temp. 0 - 90 ⁰C to get the novel diastereomeric salt of formula-II and more preferably 40 - 65 ⁰C,

(ϋ) recrystallization of the crude salt of formula-II from a solvent is selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene; or mixture of these solvents and isolation of the recrystallized salt at a temperature of 0 - 120 ⁰C and more preferably 30 -60 ⁰C to get compound of formula-II.

4. A novel compound, S- (-)-3-aminomethyl-5-methylhexanoic acid, di- (O, O')- toluoyl-D-tartaric acid salt of formula- VII.

Formula-VII

5. A process for the preparation of S-(-)-3-aminomethyl-5-methylhexanoic acid, (O, O')- di-toluoyl-D-tartaric acid salt of formula- VII.

which comprises, (i) forming a salt of racemic pregabalin of formula-I,

with (+)- (O, O)- di-toluoyl-D-tartaric acid of formula-VI,

Formula-VI in the presence of a solvent medium selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, or mixture of these solvents at temp. 0 - 90 ⁰C to get the novel diastereomeric salt of formula- VII and more preferably 40 - 65 ⁰C, ii) recrystallization of the crude salt of formula- VII from a solvent selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, or mixture of these solvents and isolation of the recrystallized salt at a temperature of 0 — 120 ⁰C and more preferably 30 —60 ⁰C to obtain compound of formula -VII.

6. The solvent medium for formation of salt and for recrystallisation is selected from water, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, esters such as ethyl acetate, isopropyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, or mixture of these solvents .

7. The temperature for salt formation of formula-II is selected from 0 - 90 ⁰C and more preferably 40 - 65 ⁰C.

8. The temperature for recrystallisation of formula-II is selected from 0 - 120 ⁰C and more preferably 30 -60 ⁰C to get the pure compound of formula-II.

9. The solvent used for regeneration of pregabalin of formula-Ill from the purified salt of formula-II is a mixture of tetrahydrofuran and water.

10. The temperature for regeneration of pregabalin of formula-Ill from the purified salt of formula-II is 0 - 90 ⁰C and more preferably -5 ⁰C to 35 ⁰C.