WO2008117305A2

WO2008117305A2 - A novel process for preparing pregabalin and its acid addition salts

Info

Publication number: WO2008117305A2
Application number: PCT/IN2008/000121
Authority: WO
Inventors: Venkata Siva Kumar Bobba; Srinivas Reddy Sanikommu; Balasaheb Murlidhar More; Dattatray Shamrao Metil; Pravin Bhalchandra Kulkarni; Koilpillai Joseph Prabahar; Mubeen Khan
Original assignee: Glenmark Pharmaceuticals Limited
Priority date: 2007-03-28
Filing date: 2008-03-03
Publication date: 2008-10-02
Also published as: WO2008117305A3

Abstract

The present invention provides process for the preparation of novel intermediates of (S)-Pregabalin. The present invention also provides process for the preparation of (S)-Pregabalin or a pharmaceutically acceptable salt or solvate thereof using the intermediates.

Description

A NOVEL PROCESS FOR PREPARING PREGABALIN AND ITS ACID ADDITION SALTS

FIELD OF THE INVENTION The present invention relates to process for preparing (±)-3-(aminomethyl)-5- methylhexanoic acid and to a method of obtaining (S)-(+)-3-(aminomethyl)-5- methylhexanoic acid from (±)-3-(aminomethyl)-5-methylhexanoic acid. It also encompasses novel intermediate for the preparation of (S)-(+)-3-(aminomethyl)-5- methylhexanoic acid.

BACKGROUND OF THE INVENTION

(S)-Pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, has the empirical formula C₈Hi₇NO₂ and a molecular weight of 159, and is represented by the chemical structure:

Formula I

Pregabalin also known as β-isobutyl-γ-aminobutyric acid; isobutyl-γ-aminobutyric acid or isobutyl-GABA, is a potent anticonvulsant. Isobutyl GABA is related to the endogenous inhibitory neurotransmitter γ-aminobutyric acid or GABA, which is involved in the regulation of brain neuronal activity.

Various methods are known in art for the preparation of (S)- pregabalin.US5563175 discloses a process wherein n-butyl lithium is used under controlled condition to prepare (S)-Pregabalin. The process also involves use of chiral auxiliary to introduce the stereochemical configuration needed in the final product. US5616793 discloses a process wherein (R)-(-)-3-(carbamoyl methyl)-5- methylhexanoic acid is converted to (S)-Pregabalin via Hoffmann degradation with sodium hypobromite followed by precipitation of (S)-pregabalin, after addition of HCl. The product is further purified by crystallization from a mixture of isopropanol and water which can be schematically illustrated as;

Vl VII VIII

US5637767 discloses a process wherein isovaleraldehyde is condensed with diethylmalonate. The condensation product is reacted with a cyanide source, which is followed by decarboxylation and hydrolysis. Pregabalin was finally obtained by hydrogenating the hydrolyzed product.

All these process are either lengthy or involve use of difficult to handle reagents. Thus it was desired to provide a convenient and shorter route for the preparation of (S)- Pregabalin.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of (S)-(+)-3- (aminomethyl)-5-methylhexanoic acid also known as (S)-Pregabalin. The process comprises converting, compound of formula IV,

Formula IV to 5-methyl-3-(nitromethyl)hexanoic acid, compound formula VI,

Formula VI wherein Ri and R₂ are independently selected from the group consisting of hydrogen;Cl-C4 straight, branched or cyclic alkyl; and aralkyl group; (ii) reducing 5-methyl-3-(nitromethyl)hexanoic acid, compound of formula VI, to obtain (±) 3-(aminomethyl)-5-methylhexanoic acid,

FormulaVII

(iii) resolving (±)3-(aminomethyl)-5-methylhexanoic acid to obtain (S)- (+)-3 -(aminomethyl)-5-methylhexanoic acid.

In one of the embodiment, the process of preparing compound of formula IV, comprising reacting a compound of formula II,

Formula II with a compound of formula III,

Formula III is provided.

In yet another embodiment, patent relates to novel intermediate of the formula IV,

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of the present invention provides a process for preparation of (S)-Pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid as depicted schematically: Methanol/NaOH

Isovaleraldehyde Nitromethane

Formula II

TEA/ MDC ormula III

Formula IV

Reduction

Resolution

Formula VII Formula I

wherein Ri and R₂ independently are hydrogen; C1-C4 straight, branched or cyclic alkyl; and aralkyl group.For example alkyl denotes methyl, ethyl, isopropyl, tert- butyl. Cyclic alkyl denotes cyclobutyl, cyclopentyl, cyclohexyl and the likes thereof. Aralkyl denotes benzyl and substituted benzyl, like p-methoxybenzyl, nitrobenzyl 2, 4-dimethoxybenzyl, and triphenylmethyl.

In one of the embodiment, isovaleraldehyde is condensed with nitromethane to obtain 4-methyl-l-nitropent-l-ene, compound of formula II,

Formula II.

The solvent used in the condensation step may be selected from polar solvents or non-polar solvents. Advantageously, polar solvents may be selected from the group consisting of alcohols, ketones, acetonitrile, THF, DMSO or DMF and mixtures thereof, preferably methanol; the non polar solvent used in the above condensation step may be selected from the group consisting of chloroform, dichloromethane, ■ diethyl ether, benzene, toluene, hexane and mixtures thereof.

The base used in condensation step may be selected from a group consisting of organic and inorganic bases which include but are not limited to Ci-C₆ mono-, di- or tri- alkyl amines wherein the alkyl groups may be the same or different such as triethylamine

(TEA), C₃-C₅ cyclic amines, such as pyridine; alkali metal carbonate and bicarbonates such as sodium, potassium or lithium carbonates or bicarbonates, and the like and mixtures thereof; hydroxides such as sodium hydroxide, potassium hydroxide, preferably sodium hydroxide.

The condensation reaction is advantageously carried out between -15⁰C to 30°C, preferably between 0⁰C to 5°C.

In one of the embodiment, the above obtained compound of formula II is further converted to a novel intermediate, compound of formula IV, by reacting with a cyclic anhydride of formula III,

Formula IV Formula III wherein Ri and R₂ independently are hydrogen; C1-C4 straight, branched or cyclic alkyl; and aralkyl group. For example alkyl denotes methyl, ethyl, isopropyl, tert-butyl. Cyclic alkyl denotes cyclobutyl, cyclopentyl, cyclohexyl and the likes thereof. Aralkyl denotes benzyl and substituted benzyl, like p-methoxybenzyl, nitrobenzyl 2, 4-dimethoxybenzyl, and triphenylmethyl.

Thus 4-methyl-l-nitropent-l-ene compound of formula II reacts with a compound of formula III wherein Rl and R2 are both methyl (a compound of formula III A also known as Meldrum's acid),

Formula II Formula HIA to obtain 2,2-dimethyl-5-[3-methyl- 1 -(nitromethyl)butyl]- 1 ,3-dioxane-4,6-dione, compound of formula IVA,

Formula IVA. Advantageously, the reaction between compound of formula II and III can be carried out in a solvent which may be selected from a group consisting of toluene, cyclohexane, benzene, diethyl ether, tetrahydrofuran, MTBE, ethylene dichloride, methylenedichloride, preferably methylene dichloride.

The base used for reaction between compound of formula II and III is either an inorganic base or an organic base. Advantageously, inorganic base may be selected from a group consisting of alkali hydroxides such as sodium hydroxide or potassium hydroxide and carbonates or bicarbonates such as sodium carbonate, potassium carbonate, potassium bicarbonate, or sodium bicarbonate; organic base may be selected from a group consisting of mono alkyl, diakyl and trialkyl amines, wherein alkyl denotes Ci-C₄ branched or straight chain, preferably TEA.

The reaction is advantageously carried out between -10 C to about 40⁰C, more preferably between 10⁰C to about 15⁰C.

Optionally, compound of formula IV can be purified using organic solvent. Advantageously, the organic solvent may be selected from a group consisting of ketone, C1-C4 alcohols, ethers, hydrocarbons, chlorinated solvents, water and mixtures thereof. More preferably purification is carried out using a mixture of IPA and water. In one of the embodiment, compound of formula IV is converted to a compound of formula VI using an aqueous mineral acid, non aqueous mineral acid or an organic acid to obtain, 5-methyl-3-(nitromethyl)hexanoic acid, compound of formula VI,

Formula VI. Thus 2,2-dimethyl-5-[3-methyl-l-(nitromethyl)butyl]-l,3-dioxane-4,6-dione, compound of formula IVA,

Formula IVA is converted to compound of formula VI,

Formula VI.

The solvent used for the conversion of compound of formula IV to compound of formula VI may be selected from a group consisting of hydrocarbon, chlorinated solvents, C1-C4 alcoholic solvents, water and mixtures thereof. Advantageously, chlorinated solvent may be selected from a group consisting of ethylene dichloride, methylene dichloride; C1-C4 alcoholic solvents may be selected from a group consisting of methanol,ethanol, isopropanol; hydrocarbon solvent may be selected from ^sa group consisting of benzene, toluene, cyclohexane, preferably toluene. The Aqueous or non-aqueous mineral acid is selected from a group consisting of hydrochloric acid, sulphuric acid, ortho phosphoric acid and their mixtures thereof; or organic acid selected from the group consisting Of C₁-C₄ alkyl acids like formic, acetic, propanoic, butanoic acids and their mixtures thereof, alkyl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and their mixtures thereof, aryl sulfonic acid such as p-toluenesulfonic acid, benzenesulfonic acid and mixture thereof, preferably p- toluenesulfonic acid.

Advantageously, the reaction is carried out at elevated temperature, preferably at reflux temperature.

In one of the embodiment, racemic Pregabalin can be obtained by catalytic hydrogenation of compound of Formula VI with an appropriate hydrogenating agent selected from the group consisting of Raney Nickel, Pd/C, Pt/C, hydrazine hydrate, tin chloride or mixtures thereof. Preferably, the reducing agent is Raney Ni.

The solvent used in the reduction step may be selected from a group consisting of C1-C4 straight or branched chain alcohols, toluene, acetonitrile and mixtures thereof. Advantageously, the solvent used is methanol. Advantageously, the reduction is carried out at hydrogen pressure of about 1 Kg/cm² to about 20 kg/cm², preferably between 4 Kg/cm² -12 Kg/cm².

In yet another embodiment, the racemic pregabalin can be resolved to (S)- pregabalin substantially free of (R)-Pregabalin, by using appropriate resolving reagents selected from the group consisting of acids such as Di-p-Toluoyl-D- Tartaric acid, Di-p- Toluoyl-L-Tartaric acid, Dibenzoyl-D-Tartaric acid monohydrate, Dibenzoyl-L-Tartaric acid monohydrate, Di-p-Anisoyl-D-Tartaric acid , Di-p-Anisoyl-L-Tartaric acid, D- Tartaric acid mono-p-chloroanilide , L-Tartaric acid mono-p-chloroanilide, Dibenzoyl- D-Tartaric acid monodimethylamide, Dibenzoyl-L-Tartaric acid, mono dimethy lamide, Malic acid, 10-camphorsulfonic acid, 3-bromocamphor-lO-sulfonic acid, -Chloro mandelic acid, para-Methylmandelic acid, Isobutyl lactate, 2-Hydroxymethyl hexanoic acid, 2-Hydroxymethylbutanoic acid, 2-Hydroxymethylpropanoic acid, Lysine hydrochloride, (1 S,2 R,4 R)-(-)-2,10-camphorsultam, 2-methoxy-2-(l- naphthyl) propionic acid; and amines such as 1 -phenyl propanamine, Amphetamine, 1 -phenyl ethylthiuronium, Tyrosinamide, Threo-l-(4-Nitrophenyl)-2-amino- 1,3 -propanediol, N- methyl-D-glucamine, l-(4-Nitrophenyl)ethylamine, 1-phenylethylamine, 2-phenyl glycinol, α - fenchylamine, 2-Amino-l-butanol, L-Leucinamide, Galactamine, Brucine, Quinine. Yohimbine, Cinchoniine, Ephedrine, strychnine, 1-Phenylbutylamine, 1-(1- Naphthyl)ethylamine, 1-Aminotetraline, 1-Aminoindane, l-(2-Naphthyl)ethylamine, 1- Phenylethylhydroxylamine, Bis-(l-phenylethyl)amine, 1-Phenylethylisocyanate, N- Benzyl-l-phenylethylamine,2-(Phenylmethoxy)cyclohexaneamine,2-(Phenylmethoxy) cyclopentaneamine, 1 -Methoxy-2-aminopropane, galanthamine, morphine, codeine, Nicotine, Nornicotine, Sparteine, veratraman, tubulosan, Vobasan, Spirosolane, tubocuraran, pancracine, rodiasine, Matridine, lythran, Lythrancine, Hasubanan, Kopsan, Formosana, R (+)-l -phenyl ethyl amine. Preferably, the resolving agent is Mandelic acid.

The reaction between pregabalin and resolving agent may be carried out in a solvent selected from a group consisting of C1-C4 straight or branched alcohols and water and a mixtures thereof. The examples of C1-C4 straight or branched alcohols include ethanol, methanol isopropyl alcohol, n-butanol. Advantageously, the solvent used is ethanol. In an embodiment, the resultant salt thus obtained is converted to (S) - pregabalin using solvent which may be selected from a group consisting of THF, MTBE, water, DMSO. Preferably the solvent used is a mixture of THF and water.

The resolution of racemic pregabalin prepared by present invention can be carried out by any method known in the art, for example, US5637767, incorporated herein by reference.

(S)-Pregabalin obtained by this process is substantially free of (R)-Pregabalin.

The following examples are intended to illustrate particular embodiments of the invention, and are not intended to limit the specification, in any manner.

EXAMPLE l

PREPARATION OF 4-METHYL -1- NITROPENT-1-ENE (FORMULA II)

Isovaleraldehyde (200 g) and nitromethane (89gm) were added in methanol (1600 ml) and the reaction mixture was cooled to 0 to 5°C. Aqueous sodium hydroxide solution (12O g sodium hydroxide flakes dissolved in 240 ml water) was added slowly into the reaction mass at 0 to 5°C over a period of 1 h. Thereafter the reaction was stirred for 2h at 0 - 5°C. The reaction mass was quenched slowly into dilute aqueous hydrochloric acid (1500 ml) and the product was extracted in methylene chloride (1000ml). The organic layer was evaporated to obtain the title compound (300 g).

EXAMPLE-2

PREPARATION OF 2,2-DIMETHYL-S-[S-METHYL-I-(NITROMETHYL) BUTYL]-l,3-DIOXANE-4,6-DIONE (FORMULA IV) Meldrum's acid (335 g) was added to a solution of 4-methyl-l- nitropent-1-ene (300 g) in methylene chloride (1500 ml ) at room temperature and the reaction mass was cooled to 10 -15°C. Thereafter, triethylamine (260 g) was added slowly at 10-15°C and the reaction mass was stirred at room temperature for 2 hours. The reaction mass was washed with water and ~5%w/w aqueous hydrochloric acid .The organic layer was concentrated under reduced pressure to obtain a solid residue. The residue was further triturated with isopropyl alcohol (300 ml) to obtain the product as slurry mass. The solid was filtered and dried to get 2,2-dimethyl-5-[3-methyl-l-(nitromethyl)butyl]-l,3-dioxane-4,6-dione (32Og). IR (KBr) cm^"1: 1749.15 (C=O), 1550.77 [C-NO_2, (S) asymmetric]. 1H NMR (300 MHz, CDCl₃) δ: 0.96(m, 6H), 1.15(m, IH), 1.6(m, 2H), 1.72(m, 6H), 3.3(m, IH), 3.87(m, IH), 4.5(dd, IH), 4.97(dd, IH). EXAMPLE-3

PREPARATION OF 5-METHYL-3-(NITROMETHYL)HEXANOIC ACID (FORMULA VI):

2,2-Dimethyl-5-[3-methyl-l-(nitromethyl)butyl]-l,3-dioxane-4,6-dione (250 g), p- toluenesulphonic acid (43.5 g) and water (16.5 ml) were taken in toluene ( 750ml) and the reaction mixture was stirred at reflux temperature for about 20 hours. Thereafter, the reaction mass was cooled to 20⁰C -25°C. The organic layer was extracted with aqueous sodium carbonate solution (1000 ml). The aqueous layer was acidified with dilute hydrochloric acid and extracted in toluene. The organic layer was concentrated to get 5- methyl-3-(nitromethyl)hexanoic acid ( 150 g).

¹H NMR (300 MHz, CDCl₃) δ: 0.94 (m, 6H), 1.28 (t, 2H), 1.7 (m, IH), 2.5 (d, 2H), 2.67 (m, IH), 4.4 (dd, IH), 4.7 (dd, IH), 8.3 (bs, IH).

EXAMPLE-4 PREPARATION OF RACEMIC 3-(AMINOMETHYL)-5-METHYLHEXANOIC ACID (FORMULA VII):

A solution of 5-methyl-3-(nitromethyl)hexanoic acid (150 g) in methanol (1500 ml) was taken in an autoclave. Raney Nickel (30 g) was added to the reaction mass and hydrogenated with 4.0 kg/cm² hydrogen pressure for -12 hours. After completion of reaction, the reaction mass was filtered to remove catalyst and the filtrate was concentrated. The residue mass was triturated with ethyl acetate to obtain racemic 3- (aminomethyl)-5-methyl hexanoic acid (65 g).

EXAMPLE-5 PREPARATION OF (S)-S-(AMINOMETHYL)-S-METHYLHEXANOIC ACID ((S)-PREGABALIN)

(S)-(+)-Mandelic acid (65 g) is suspended in 200 ml of ethyl alcohol and temperature of reaction mass was raised to 55-65°C. Racemic 3-(aminomethyl)-5-methylhexanoic acid (50 g) was added at 55-65°C till it becomes a clear solution. Thereafter, reaction mass cooled to 25-30°C and stirred for 2 h. The precipitated mandelic acid salt of (S)-Pregabalin was isolated by filtration. The mandelic acid salt of (S)-Pregabalin was stirred with a mixture of tetrahydrofuran (530 ml) and water at 50-55°C for 1 hour and further at 0-5°C. The solid was filtered to get (S)-3-(aminomethyl)-5-methylhexanoic acid (S)-Pregabalin which was purified using isopropyl alcohol and water mixture to get (S)-3- (aminomethyl)-5-methylhexanoic acid (12 g) with >99.8% e.e by HPLC.

Claims

Claims:

1. A process for preparing (S)-(+)-3-(Aminomethyl)-5-methylhexanoic acid, compound of formula I,

Formula I comprising;

(i) converting, compound of formula IV,

Formula IV to 5-methyl-3-(nitromethyl)hexanoic acid, compound formula VI,

Formula VII

2. The process of claim 1, wherein 5-methyl-3-(nitromethyl)hexanoic acid, compound formula VI,

Formula VI is obtained by a process comprising reacting compound of formula IV,

Formula IV with an acid ,wherein Rj and R₂ are as defined above.

3. The process of claim 1, wherein compound of formula IV is obtained by a process comprising reacting 4-methyl -1- nitropent-1-ene, compound of Formula II,

Formula II with a compound of Formula III,

Formula III in the presence of a base, wherein Ri and R₂ are as defined above.

4. The process of claim 3, wherein 4-methyl -1- nitropent-1-ene, compound of Formula II,

Formula II is prepared by a process comprising condensing isovaleraldehyde with nitromethane in the presence of base.

5. The process of claim 2, wherein the acid used is selected from a group consisting of mineral acids, organic acids and mixtures thereof.

6. The process of claim 5, wherein the organic acid is an alkyl sulphonic acid, aryl sulphonic acid or mixtures thereof.

7. The process of claim 6, wherein the organic acid is p- toluenesulfonic acid.

8. The process of claim 2, wherein the reaction of compound of formula IV with an acid is carried out in presence of a solvent selected from a group consisting of hydrocarbon, chlorinated solvents, Ci-C₄ alcoholic solvents, water and mixtures thereof.

9. The process of claim 8, wherein the solvent is a hydrocarbon solvent.

10. The process of claim 9, wherein the hydrocarbon solvent is toluene.

11. The process of claim 10, wherein the reaction is maintained at a temperature of about O⁰C to about 120⁰C.

12. The process of claim 11, wherein the reaction is maintained at a temperature of about

105⁰C to about 120⁰C.

13. The process of claim 11, wherein the reaction is maintained for about 5 hour to about 35 hour.

14. The process of claim 1, wherein in step (ii) reduction is carried out in presence of a reducing agent which is selected from a group consisting of Raney Nickel, Pd/C,

Pt/C, hydrazine hydrate, tin chloride and mixtures thereof.

15. The process of claim 14, wherein the reducing agent is Raney Nickel and the reaction is carried out in the presence of a polar solvent.

16. The process of claim 1, wherein step (ii) reduction is carried out at hydrogen pressure of about 1 kg/cm²- 20kg/cm².

17. The process of claim 16, wherein step (ii) the reaction mixture is maintained for about 5hour to about 20 hour.

18. The process of claim 3, wherein the base is an organic or an inorganic base.

19. The process of claim 18, wherein the organic base is TEA.

20. The process of claim 3, wherein reaction between compound of formula II and III is carried out in presence of an organic solvent selected from group consisting of toluene, cyclohexane, benzene, diethyl ether, tetrahydrofuran, MTBE, ethylene dichloride, methylenedichloride.

21. The process of claim 20, wherein the organic solvent is dichloromethane.

22. The process of claim 3, wherein the reaction is carried out at a temperature of about - 10⁰C to about 40⁰C.

23. The process of claim 22, wherein the reaction is carried out at a temperature of about 10⁰C to about 15⁰C.

24. The process of claim 3, wherein the reaction is maintained for about 1 to about 10 hours.

25. The process of claim 3, wherein compound of formula IV is optionally purified using organic solvent selected from the group consisting of ketone, Ci-C₄ alcohols, ether, hydrocarbon, chlorinated solvents, water and mixture thereof.

26. The process of claim 25, wherein the organic solvent for purification is a mixture of IPA and water.

27. The process of claim 4, wherein the base is an organic or inorganic base.

28. The process of claim 27, wherein the inorganic base is sodium hydroxide.

29. The process of claim 4, wherein the reaction between isovaleraldehyde and nitromethane is carried out in the presence of a polar solvent.

30. The process of claim 29, wherein the polar solvent is selected from a group consisting of C 1 -C4 alcohol, water and mixture thereof .

31. The process of claim 30, wherein the polar solvent is methanol.

32. The process of claim 4, wherein the reaction is done at a temperature of about -10⁰C to about 40⁰C.

33. The process of claim 32, wherein reaction is done at a temperature of about O⁰C to about 5⁰C.

34. The process of claim 1, comprising (i) converting, the compound of formula IV, wherein Rl and R2 are both methyl (a compound of formula IVa),

Formula IVA to 5-methyl-3-(nitromethyl)hexanoic acid, a compound of formula VI.

35. The process of claim 34, wherein 2, 2-dimethyl-5-[3-methyl-l-(nitromethyl)butyl]- l,3-dioxane-4,6-dione, compound of Formula IVA,

Formula IVA is obtained by a process comprising reacting 4-methyl -1- nitropent-1-ene, compound of formula II,

Formula II with meldrum acid of formula,

Meldrum acid.

36. The compound of formula IV,

Formula IV wherein Rj and R₂ are independently selected from the group consisting of hydrogen;Cl- C4 straight ,branched or cyclic alkyl; and aralkyl group.

37. The compound 2, 2-dimethyl-5-[3-methyl-l-(nitromethyl)butyl]-l,3-dioxane-4,6- dione of Formula IVA,

Formula IVA.

38. Use of the compound of formula IV,

Formula IV wherein Rj and R₂ are independently selected from the group consisting of hydrogen;Cl- C4 straight ,branched or cyclic alkyl; and aralkyl group, in the preparation of (S)- (+)-3- (aminomethyl)-5-methylhexanoic acid, a compound of formula I.

39. Use of the compound of formula IVA,

Formula IVA in the preparation of (S)- (+)-3-(aminomethyl)-5-methylhexanoic acid, a compound of formula I.