WO2017019791A1

WO2017019791A1 - Synthesis of (s)-pregabalin

Info

Publication number: WO2017019791A1
Application number: PCT/US2016/044302
Authority: WO
Inventors: Satyanarayana Janagani
Original assignee: Teva Pharmaceuticals International Gmbh
Priority date: 2015-07-27
Filing date: 2016-07-27
Publication date: 2017-02-02

Abstract

Provided is a process for preparing (S)-Pregabalin

Description

SYNTHESIS OF (S)-PREGABALIN

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Patent Application No.

62/197,182, which is incorporated by reference herein.

FIELD OF THE INVENTION

The disclosure encompasses syntheses of (S)-(+)-3-(aminomethyl)-5-methylh acid, (S)-Pregabalin.

BACKGROUND OF THE INVENTION

(S)-Pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, a compound having the chemical structure,

is also known as pregabalin, γ-amino butyric acid or (S)-3-isobutyl GABA. (S)- Pregabalin, marketed under the name LYRICA®, has been found to activate GAD (L- glutamic acid decarboxylase). (S)-Pregabalin has a dose dependent protective effect on seizure, and is a CNS-active compound. (S)-Pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses. (S)- Pregabalin has analgesic, anticonvulsant, and anxiolytic activity.

Several processes for the synthesis of (S)-Pregabalin are known. For example, U.S. Patent No. 5,599,973 ("'973 patent") discloses the preparation of (S)-Pregabalin using a stoichiometric amount of (4R,5S)-(+) 4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary that may be recycled. See, e.g., '973 patent, col. 14, 1. 29 to col. 18, 1. 23 (example 1). In general, however, the route disclosed in the '973 patent is of limited use on an industrial scale, principally due to the low temperature required for the reaction (e.g., -78°C), the use of pyrophoric reagent (e.g., butyl lithium), and a low overall yield (e.g. , 59%, 65%). U.S. Publication No. 2003/0212290 ("'290 publication") discloses the synthesis of (S)-Pregabalin by an asymmetric hydrogenation of a cyano-substituted olefin of formula 7, to produce a cyano precursor of (S)-3-(aminomethyl)-5-methyl hexanoic acid of formula 8, which i btain (S)-Pregabalin, as described in the following scheme.

[(R,R)-MeD PHOS]Rh(COD)⁺BF4-

However, the disclosed method requires the use of carbon monoxide under high pressure, raising serious problems in adapting this process for production scale.

Another process is disclosed by G.M. Sammis, et al, J. Am. Chem. Soc , 125(15): 4442-43 (2003), in which an aluminum salen catalyst is used in the conjugate addition of hydrogen cyanide to a, β-unsaturated imides.

10

Pregabalin

This process is also not practical for large scale production due to the use of highly poisonous reagents. In addition, the last reduction step requires high hydrogen pressure, which only adds to the difficulties required for adapting this process for use on an industrial scale.

International Publication WO 2006/110783 reports several processes for preparing (S)-Pregabalin via the following intermediate and its analogues.

R^OC "COOR₂ wherein Ri and R2 are independently H, a straight or branched Ci-10 alkyl, C6-10 aryl, or C3-6 allyl.

U.S. Publication Nos. 2007/0191636 and 2007/0197827 also disclose processes for preparing (S)-Pregabalin.

Thus, there is a need in the art for additional process for the preparation of (S)- Pregabalin that provide (S)-Pregabalin in high quality and high yield, and that can be adapted to large (industrial) scale production.

SUMMARY OF THE INVENTION

The present disclosure provides processes for preparing pregabalin, which enables high yields and purity. Moreover, the present provides processes for preparing pregabalin which enables recycling of diastereomeric side products.

In a first aspect, the present disclosure provides processes comprising:

(a) providing a compound of formula (Ilia):

(Ilia)

converting the compound of formula (Ilia) into a compound of formula:

(HI)

wherein Ar is an aromatic group and R is a straight or branched Ci

ester, or carboxylic acid; and

(d) converting the compound of formula (III) into (S)-pregabalin.

Also provided is a compound having the formula:

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof; wherein R⁵ is 1-phenylethyl. A preferred compound of the above formula is:

(IVa)

These compounds can be used in the preparation of (S)-pregabalin. In particular, these compounds can be used as a convenient intermediate for recycling enantiomeric byproducts, particularly the compound of formula (Ilia), in the preparation of (S)-pregabalin. The compound of formula (Ilia) is an enantiomeric by-product, which is typically formed in certain processes for preparing (S)-pregabalin. A facile process for the recycling of this unwanted isomer into a useful intermediate for preparing (S)-pregabalin is therefore highly desirable. Preferably, the recycling process enables a fast method of transforming the by-product, in simple synthetic steps, and avoids complex, time consuming reactions, and multiple crystallization or isolation procedures.

The above process enables the undesired by-product of formula (Ilia) to be readily transformed to the desired isomer of formula (III), which is a useful intermediate for preparing (S)-pregabalin.

The compound of formula (III) can be prepared in the above process with high enantiomeric excess and in good yields, and can be converted to (S)-pregabalin.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with a process of present disclosure, (S)-pregabalin may be prepared from a compound of formula (Ilia) comprising :

(a) providing a compound of formula (Ilia):

(Ilia)

converting the compound of formula (Ilia) into a compound of formula: (IV):

(IV)

converting the compound of formula (IV) into a compound of formula (III):

(HI)

wherein Ar is an aromatic group and R is a straight or branched C_1-6 alkyl, an ester, or carboxylic acid; and

(d) converting the compound of formula (III) into (S)-pregabalin.

The above process therefore provides a way of converting the unwanted isomer (Ilia) into the desired isomer (III), which is useful for the preparation of (S)-pregabalin.

The conversion of the compound of formula (Ilia) into the compound of formula (IV) can be readily carried out by activating the carboxylic acid into a suitable leaving group, in order to enable intramolecular cyclisation to form the cyclic amide compound of formula (IV). Suitable reagents for activating the carboxylic acid group in the compound of formula (Ilia) include acid anhydrides or acid chlorides. Preferably, when an acid anhydride is used, the acid anhydride may be a C4 to Cg acid anhydride, preferably a C4 to Ce acid anhydride. Acetic anhydride is a preferred anhydride reagent. Suitable acid halides include a C2 to Cg acid halide, preferably a C2 to Ce acid halide, more preferably a C2-C4 acid halide, preferably wherein the halide can be chloro or bromo. Acetyl chloride is a preferred reagent for carrying out the transformation of compound (Ilia) to compound (IV).

The reaction is preferably conducted in the presence of an organic solvent, preferably wherein the organic solvent comprises: a C6-10 aromatic hydrocarbon, a substituted aromatic hydrocarbon, a C3-8 ether, a halogenated hydrocarbon, C3-8 esters, straight, branched or cyclic C6-io alkanes, or C3-8 ketones. The reaction is more preferably conducted in a C6-10 aromatic hydrocarbon solvent, more preferably toluene. The reaction is preferably conducted at elevated temperature. In particular the reaction can be conducted at a temperature of about 50°C to about 100°C, about 60°C to about 90°C, about 70°C to about 85°C. The final step in the process of recycling the compound of formula (Ilia) comprises converting the cyclic amide (IV) by ring opening, to generate the desired isomer of formula (III). As mentioned above, the compound of formula (III) is a useful intermediate for the preparation of pregabalin. In this step, the compound of formula (IV) is ring opened in order to generate the compound of formula (III). The ring opening is preferably conducted by reaction with a base. Particularly suitable bases include metal hydroxides or a metal alkoxides. The metal hydroxide can be an alkali metal or alkaline earth metal hydroxide, and is preferably sodium hydroxide or potassium hydroxide. The metal alkoxide is preferably an alkali metal or alkaline earth metal alkoxide. A sodium, or potassium alkoxide base is preferred. In particular sodium methoxide or sodium ethoxide. In particularly preferred embodiments, the conversion of the compound of formula (IV) to (III) is effected using sodium hydroxide.

The ring opening reaction to form the compound of formula (III) is preferably conducted at elevated temperature, at about 50°C to about 100°C, about 60°C to about 90°C, about 70°C to about 85°C. Advantageously, the conversion of the compound of formula (Ilia) into the compound of formula (IV) and the conversion of the compound of formula (IV) into a compound of formula (III) can be carried out in one pot, i.e. without isolating the compound of formula (IV). For example if a water-immiscible organic solvent is employed in the cyclisation reaction, water can be added to the reaction mixture containing (IV), and the resulting organic phase can be directly reacted with a base to form compound (III). The compound of formula (III) can be prepared in high yield and high enantiomeric excess by the above recycling process. The compound (III) may be further purified prior to its conversion to (S)-pregabalin.

As discussed above, the compound of formula (Ilia) can be a by-product in the synthesis of pregabalin. The compound of formula (Ilia) can be formed in a diastereomeric mixture with the compound of formula (III) in the synthesis of (S)-pregabalin. The desired isomer, i.e. compound (III), can be preferentially precipitated or crystallised from the mixture, leaving a mother liquor or filtrate that contains a mixture of compound (Ilia) and compound (III), which is enriched in compound (Ilia). Advantageously, the recycling process of the present disclosure can be carried out directly on the mother liquor or filtrate containing the compound (Ilia), thus avoiding the need to further work up, or isolate compound (Ilia) prior to its recycling.

Typically, the compound of formula (Ilia) is prepared in a process for preparing (S)- pregabalin, whereby a chiral amine of formula A:

(A) wherein Ar is a Ce-ιο aromatic group, and R is a straight or branched C_1-4 alkyl, ester, or carboxylic acid, is reacted with 3-isobutyl glutaric anhydride, in the presence of a base. This reaction typically produces a reaction mixture that can contain the compound (Ilia) in an enantiomeric excess (ee) of about 20-30%.

In one preferred embodiment, the compound of formula (Ilia) is prepared by a process comprising: (i) combining 3-isobutyl glutaric anhydride and the chiral amine of formula (A) in an organic solvent, in the presence of a base to obtain a diastereomeric mixture comprising a compound of formula (Ilia) and a compound of formula (III):

(Il ia) (III) and

(ii) recovering the compound of formula (Ilia), from the mixture. The recovered compound of formula (Ilia) is preferably in the form of a mixture comprising the compound of formula (Ilia) and the compound of formula (III), wherein the mixture is enriched in the compound of formula (Ilia).

In another preferred embodiment, the compound of formula (Ilia) can be prepared by a process comprising:

(i) combining the chiral amine of formula (A) with an organic solvent selected from at least one of: Ce-w aromatic hydrocarbons, substituted aromatic hydrocarbons, C2-8 ethers, halogenated hydrocarbons, straight or branched C_1-4 alcohols, C3-8 esters, straight, branched or cyclic C_1-6 alkanes, or C3-8 ketones,, and at least one base to obtain a mixture;

(ii) cooling the mixture to a temperature of about -70°C to about 10°C;

(iii) adding 3-isobutyl glutaric anhydride to the mixture;

(iv) maintaining the mixture at a temperature of about -70°C to about 10°C, preferably for at least about one hour to obtain a diastereomeric mixture comprising the compound

(Il ia) (III) ; and (v) recovering the compound of formula (Ilia) from the mixture. The recovered compound of formula (Ilia) is preferably in the form of a mixture comprising the compound of formula (Ilia) and the compound of formula (III), wherein the mixture is enriched in the compound of formula (Ilia).

The reaction of the chiral amine (A) with 3-isobutyl glutaric anhydride is preferably carried out in the presence of a base, preferably an organic base, preferably wherein the base is diethyl amine, triethyl amine, di-n-propyl amine, di-isopropyl amine, tertbutylamine, morpholine, piperidine, pyridine, or 4-dimethyl aminopyridine, or more preferably wherein the base is 4-dimethyl aminopyridine.

The reaction of 3-isobutyl glutaric anhydride and the chiral amine of formula (A) is preferably conducted in an organic solvent. The organic solvent is preferably at least one of: toluene, tert-butyl methyl ether tetrahydrofuran, diisopropyl ether, diethyl ether,

dichloromethane, ethyl acetate, isopropyl acetate, isobutyl acetate, hexane, cyclohexane, acetone, methyl isobutyl ketone, and methyl ethyl ketone. Alternatively, the organic solvent can be selected from the group consisting of esters, nitriles, ethers, C4-6 straight, branched or cyclic hydrocarbons, and C6-10 substituted or unsubstituted aromatic hydrocarbons, preferably the organic solvent is ethyl acetate, acetonitrile, methyl t-butyl ether, toluene, xylene, hexane, or cyclohexane, or a mixture of toluene and ethyl acetate, and most preferably toluene.

Toluene is a particularly preferred solvent for the reaction of chiral amine (A) with 3- isobutyl glutaric anhydride.

The order of combining the reacting substances may influence the purity and the yield of the final product. Preferably, the chiral amine of formula (A) is combined with the base, followed by the addition of the 3-isobutylglutaric anhydride. More preferably, the isobutyl glutaric anhydride is added to the mixture of the chiral amine in the organic solvent. More preferably, the mixture is cooled to a temperature of about -70°C to about 10°C before adding the 3-isobutyl glutaric anhydride.

The reaction is typically maintained at a temperature of about -70°C to about 10°C, about 0°C to about -50°C or at a temperature of about -40°C to -30°C. The reaction mixture is maintained for about an hour to about six hours, preferably wherein the mixture is maintained for about one hour to about two hours. Following the reaction, the compound of formula (III), which is the desired isomer can be recovered from the reaction mixture, which is a diastereomeric mixture comprising (III) and (Ilia). For example, the compound of formula (III) may be recovered by any method known in the art, such as extracting the organic phase with an aqueous basic solution to convert the acidic product to a salt, and acidifying the aqueous phase with a mineral acid to obtain back the acid product.

The compound of formula (III) which is isolated from the reaction mixture can be converted to (S)-pregabalin by any suitable procedure, including the procedures discussed herein. Typically, the compound of formula (III) can be recovered from the reaction mixture by precipitation or crystallization. The compound of formula (III) may optionally be further purified by a crystallization from an organic solvent selected from at least one of esters, nitriles, ethers, C4-6 straight, branched, or cyclic hydrocarbons, and Ce-ιο substituted aromatic hydrocarbons. A preferred ester is ethyl acetate. Preferably, the nitrile is acetonitrile. A preferred ether is methyl t-butyl ether. A preferred Ces substituted aromatic group is either toluene or xylene. Preferred mixtures are that of xylene and ethyl acetate, hexane and ethyl acetate, cyclohexane and ethyl acetate, and toluene and ethyl acetate. The most preferred solvent mixture for the crystallisation of compound (III) toluene and ethyl acetate. The compound of formula (III) isolated from this reaction may have an optical purity of at least about 80% area by HPLC, preferably of at least about 93% area by HPLC, more preferably of about 98% to about 100% area by HPLC, and most preferably of about 99% to about 100% area by HPLC.

The compound of formula (Ilia), which is formed as a by-product in this reaction is the undesired isomer of (III) and may be recovered from the reaction mixture as a mixture with the compound of formula (III), wherein the mixture is enriched in the compound of formula (Ilia).

Typically, the reaction of 3-isobutyl glutaric anhydride with the chiral amine (A) leads to ratio of III (S-enantiomer) to Ilia (R-enantiomer, undesired isomer) of about 75:25. Following isolation of the desired enantiomer (III) from the reaction mixture, e.g. by crystallization or precipitation, the resulting mother liquor or filtrate containing the enantiomeric mixture is then recycled in accordance with the above described process (i.e. conversion of Ilia to IV and IV to III), leading to ratio III: Ilia of around 90: 10 or better. The resulting compound (III), after further re-crystallization can contain not more than 1.5% of the compound of formula Ilia (R-enantiomer, unwanted). Thus, the compound of formula (III) obtained from the recycling process is eminently suitable for conversion to (S)- pregabalin, thereby increasing the overall yield of the API.

In a preferred embodiment, the compound of formula (Ilia) is recovered by a process comprising firstly precipitating or crystallising the compound of formula (III) from the reaction mixture [whereby the compound of formula (III) is further reacted to form (S)- pregabalin] to obtain a mother liquor or filtrate comprising the compounds of formulae (Ilia) and (III) which is enriched in the compound of formula (Ilia).

Advantageously, the present disclosure enables the recycling of the compound of formula (Ilia) by conversion of the compound of formula (Ilia) to (IV) [and subsequently to compound (III)] without isolating the compound of formula (Ilia) from the mother liquor or filtrate obtained following the crystallisation or precipitation of compound (III) from the reaction mixture.

A yet further advantage of the present process is that the recycling of (Ilia) by conversion to (III) can be carried out in one pot, i.e. the conversion of the compound of formula (Ilia) from the mother liquor or filtrate to compound (IV) and (IV) to (III) can be carried out sequentially and without isolating the compound of formula (IV). The compound of formula (III) obtained from the compound of formula (IV) can be further purified by recrystallization preferably from toluene. The resulting compound of formula (III), with or without further purification, can be recycled to the (S)-pregabalin synthesis process.

The compound of formula (III), obtained from the reaction of 3-isobutyl glutaric anhydride and the chiral amine of formula (A), or by the recycling step [i.e. reaction of the undesired isomer (Ilia) to form the cyclic amide (IV) followed by ring opening of the cyclic amide (IV)], can be converted into (S)-pregabalin by any suitable process. Suitable processes include those disclosed in WO2008/118427 and WO2007/035890.

The 3-isobutyl glutaric anhydride employed in the above process may be prepared according to the process disclosed in US. Patent No. 5,616,793. The chiral amines of formula (A) are commercially available, and is used as a chiral auxiliary. Preferably, the chiral amine of formula (A) is methylbenzylamine, and more preferably the chiral amine of formula (A) is (S)- methylbenzylamine. In a particularly preferred embodiment, the preparation of (S)-pregabalin from the compound of formula (III), which is obtained from the reaction of 3-isobutyl glutaric anhydride and the chiral amine of formula (A), as well as the recycling step discussed above [i.e. reaction of the undesired isomer (Ilia) to form the cyclic amide (IV) followed by ring opening of the cyclic amide (IV)], comprises:

(a) converting the hydroxyl group of the compound of formula (III) to a leaving group to form a com ound of formula III-X:

(III-X) wherein X is a leaving group; reacting the compound of formula (III-X) with an azide nucleophile to obtain a compound of

(V) reacting the compound of formula (V) with an alcohol, R^-OH, wherein R¹ represents a Ci-8 straight chain, branched or cyclic alkyl group, preferably a Ci-6 straight chain, branched or cyclic alkyl group, more preferably a Ci to C4 straight chain or branched alkyl group, and most preferably a methyl group, to obtain a compound of formula (VI):

(VI)

; and

(d) hydrolyzing the compound of formula (VI) to form (S)-pregabalin.

In step (a) of the above process, the leaving group X in the compound of formula (III- X) is preferably selected from the group consisting of a halogen or a mixed anhydride. For example, the leaving group X is preferably selected from the group consisting of: CI, Br, - OCOR? wherein -OCOR² is derived from a haloformate, an acid halide or an acid anhydride.

Preferably, the leaving group is -OCOR², wherein R² is an alkyl group, preferably a Ci to Ce alkyl group, more preferably a Ci to C3 alkyl group and most preferably ethyl.

In a preferred embodiment, step (a) comprises reacting the compound of formula (III) with a reagent selected from the group consisting of: a haloformate, an acid halide or an acid anhydride, preferably acetic anhydride, di-t-butyl dicarbonate or ethyl chloroformate. Ethyl chloroformate is a particularly preferred reagent. The reaction is preferably carried out in the presence of a base. The base may be added to the compound of formula (III) before the addition of the reagent.

Step (b) of the above process involves reacting the compound (III-X) with an azide nucleophile in order to produce the corresponding azide of formula (V). Typically, the azide nucleophile is a substance containing a nucleophilic "N₃" group. Examples of such substances include, but are not limited to, NaN₃, diphenylphosphoryl azide, trialkyl silyl azide, trialkyl tin azide, and like metal azides. More preferably, the azide nucleophile is NaN₃.

The azide nucleophile can be provided in the form of a solid or in an aqueous or organic solution. Typically, the compound of formula (III-X) is combined with the azide nucleophile at a low temperature. Preferably, the compound of formula (III-X) is combined with the azide nucleophile at a temperature of about 30°C to about -30°C, and more preferably at about -10°C to about -20°C.

The reaction between the azide nucleophile and the compound of formula 3 typically leads to a slurry. The slurry, usually, further comprises an organic solvent. This organic solvent is either the solvent from the reaction used to produce the compound of formula (III- X) when the reaction is one-pot, or a new solvent used to dissolve the compound of formula (III-X).

Preferably, the organic solvent is selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, ethers and ketones. Preferably, the aromatic hydrocarbon is a C6-io aromatic hydrocarbon, and more preferably toluene, xylene or ethyl benzene. Preferably, the aliphatic hydrocarbon is a Ce-ιο aliphatic hydrocarbon, and more preferably either hexane or heptane. Preferably, the ether is a C3-9 ether, and more preferably diethylether, diisopropylether or t-butylmethyl ether. Preferably, the ketone is a C3-6 ketone, and more preferably acetone, methylethyl ketone or methylisobutyl ketone. The more preferred solvent is acetone or toluene.

The above slurry is typically maintained for a sufficient time to provide the compound of formula (V). Preferably, the slurry is maintained for about 0.5 hour to about 4 hours, more preferably for about 0.5 hour to about 2 hours, and most preferably for about 1 hour to about 2 hours.

The slurry of the compound of formula (V) may be used to synthesize the compound of formula (VI) directly, without isolation of the compound of formula (V) from the slurry. Alternatively, the compound of formula (V) can be separated from the slurry by addition of water and an organic solvent prior to its use in the synthesis of the compound of formula (VI). Preferably, the organic solvent is the same as described above. The water dissolves the inorganic salts while the compound of formula (V) is transferred into the organic phase. Optionally, the aqueous phase can be further extracted with the organic solvent to increase the yield of the compound of formula 5.

Thus, advantageously, in a preferred embodiment, steps (a) and (b) may be carried out in one-pot, i.e. without isolation of compound (III-X). Conversion of the compound (III-X) to form compound (VI) is carried out in the presence of an alcohol R^-OH is preferably carried out at elevated temperature, preferably at a temperature of about 50°C to about 100°C, about 60°C to about 90°C, about 70 to about 90°C, or about 80 to about 90°C. In one embodiment, steps (b) and (c) are carried out without isolation of compound

(V). Thus, the organic phase comprising the compound of formula (V) is combined with an alcohol to obtain the compound of formula (VI). Preferably, the organic phase is added slowly to the alcohol, more preferably the organic phase is added over a period of about 0.5 to about 10 hours, and most preferably over a period of about 0.5 hour to about 4 hours. Preferably, the combination is done while heating the alcohol, more preferably while heating the alcohol to a temperature of about 50°C to about 110°C, and most preferably while heating the alcohol to a temperature of about 50°C to about 70°C. Preferably, the alcohol is in the form of a solution of the alcohol in an organic solvent. Preferably, the solvent is the same as mentioned above. Preferably, the alcohol is a C1-5 alcohol, and more preferably methanol, ethanol, isopropanol, t-butanol, n-butanol, isobutanol, or neopentylalcohol. More preferably, the alcohol is either methanol or ethanol. The heated combination is then maintained, preferably, for about 0.5 to about 6 hours to provide the compound of formula 4. More preferably, the heated combination is maintained for about 0.5 to about 4 hours, and most preferably for about 2 to about 4 hours, to provide the compound of formula (VI). In one embodiment, (a), (b) and (c) are carried out without isolation of compounds

(III-X) and (V).

The compound of formula (VI) may be recovered prior to being hydrolyzed to obtain (S)-Pregabalin. The compound of formula (VI) may be recovered, for example, by evaporating the solvents. The recovered compound of formula (VI) may have a purity of at least about 85% area by HPLC, preferably about 92% to about 100% area by HPLC, and more preferably about 95% to about 100% area by HPLC.

The compound of formula (VI) can then be converted to (S)-Pregabalin, for example, by the process disclosed in U.S. Publication No. 2007/0197827 and its international counterpart International Publication No. WO 2007/035890. The compound of formula (VI) is then converted to pregabalin by hydrolysis in step (d). In a preferred embodiment, step (d) comprises reacting the compound of formula (VI) with an acid and a phenol, wherein the phenol may be substituted or unsubstituted.

Typically, the conversion of the compound of formula (VI) to (S)-Pregabalin can be carried out by hydrolyzing both the amide and amine group in a single hydrolysis step. The hydrolysis of the compound of formula (VI) to give (S)-pregabalin can be carried out without isolating the compound of formula (VI), i.e. , a one-pot process.

Preferably, the hydrolysis comprises combining the compound of formula (VI), with an acid and a substituted or unsubstituted phenol, and recovering the (S)-Pregabalin.

When the hydrolysis is done in one-pot, the phenol and the acid are mixed with a mixture having the compound of formula (VI). Optionally, the mixture having the compound of formula (VI) can be cooled prior to the addition of the acid and phenol. Preferably, the mixture is cooled to a temperature of about 50°C to about 0°C, and more preferably to about 30°C to about 25°C.

The combination of the compound of formula (VI), the phenol, and the acid provides a second mixture, wherein the phenol preferably plays the role of a scavenger of impurities such as N-benzylated pregabalin of the following formula.

Preferably, the acid is a strong mineral acid. As used herein, unless otherwise defined, a "strong" mineral acid is one that, when dissolved in aqueous media, produces a pH of less than about 1.5.

The second mixture also comprises an inorganic salt, such as sodium chloride, potassium chloride, magnesium sulfate, and sodium sulfate. The use of such a salt allows one to heat the second mixture to high temperatures, leading to a shorter reaction time. Preferably, second mixture is heated to a temperature of about 60°C to about 130°C, and more preferably about 80°C to about 110°C.

Typically, the second mixture is heated for a period of time sufficient to obtain an (S)- pregabalin salt. Preferably, the mixture is heated for about 5 to about 24 hours. The reaction time is also related to the kind of mineral acid that is used. Preferably, the mixture is heated for about 18 to about 24 hours when the mineral acid is hydrochloric acid and for about 5 to about 10 hours when the mineral acid is sulfuric acid.

Typically, the acid protonates the amine group of (S)-Pregabalin, thus providing an acid salt of (S)-Pregabalin, from which free (S)-Pregabalin is recovered by extractions and reaction with a base. The recovery typically comprises: adding an inorganic base to the second mixture; extracting the acid salt of (S)-Pregabalin from the mixture with a C4-8 alcohol; adjusting the pH of the extract to about 4 to about 7 and thereby precipitate (S)- Pregabalin. The precipitated (S)-Pregabalin is then collected. Preferably, the inorganic base is added to the second mixture in an amount sufficient to adjust the pH of the combination to about 1 to about 3. Preferably, the inorganic base is sodium hydroxide. Preferably, the pH of the extract is adjusted to about 4 to about 7 by adding a base. Preferably, the base is an organic base and more preferably tributylamine. Preferably, the C4-8 alcohol is iso-butanol.

The strong mineral acid which is preferably employed in the hydrolysis reaction is preferably selected from hydrobromic acid, hydrochloric acid, sulfuric acid or

polyphosphoric acid, and most preferably hydrobromic acid or sulfuric acid.

The substituted or unsubstituted henol may have the formula:

wherein, R is H, alkyl, alkoxy, halogen, or mercapto, R⁴ is H, alkyl or halogen, and the ring Z is a 5-8-membered ring containing carbon and optionally at least one nitrogen, sulfur or oxygen. Preferably, the phenol has the formula:

Preferably, R³ is alkyl (preferably Ci to C3 alkyl), alkoxy (preferably Ci to C3 alkoxy), or halogen (preferably chlorine, bromine or iodine).

More preferably the phenol employed in step (d) is unsubstituted.

In any aspect or embodiment of the present disclosure, in compounds (Ilia), (III), (IV), (A), (III-X), (V) and (VI), the group Ar is preferably a C6-1₀ aryl group, more preferably phenyl. In any aspect or embodiment of the present disclosure, in the compounds (Ilia), (III), (IV), (A), (III-X), (V) and (VI), the group R is preferably a straight or branched Ci-6 alkyl group, or a C3-C8 ester group, or a C2-C6 carboxylic acid group, more preferably R is a straight or branched C1-4 alkyl group, and most preferably R is methyl.

In any aspect or embodiment of the present disclosure, in compounds (Ilia), (III), (IV), (A), (III-X), (V) and (VI), it is preferred that R is methyl and Ar is phenyl.

The (S)-Pregabalin obtained by the above-described process has a purity of at least about 80% area by HPLC, preferably at least about 98% area by HPLC, and more preferably about 99% to about 100% area by HPLC. The (S)-Pregabalin obtained by the above- described process also has less than 0.15%, preferably, less than 0.1%, more preferably less than 0.06%, even more preferably less than 0.02% and most preferably less than 0.01% area by HPLC of the N-benzylated pregabalin impurity. Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES Example 1: Preparation of (3S)-5-methyl-3-(2-oxo-2{[(lS)-l-phenylethyllamino} ethyl) hexanoic acid (III, wherein Ar = phenyl and R = methyl) with recycling of compound (Ilia)

A. 3-isobutylglutaric acid (700g) and acetic anhydride (420g) were heated to 130- 140°C and maintained for about 3 hrs. At the end of the reaction, the reaction mixture was cooled to 70-80°C and acetic acid and acetic anhydride were distilled off under vacuum. Toluene (700 mL) was added to the reaction mixture and further evaporated=for 1.5-2 hrs at 90-95°C. Another 700mL of toluene were added and the resulting 4-isobutylglutaric anhydride (IBG anhydride) solution was cooled to 25-30°C.

B. A different reactor was charged with toluene (4L), S-phenylethylamine (1.05 mol equivalent) and 4-dimethylaminopyridine (DMAP) (4.5g) and the mixture was cooled to

-25 to -15°C. The IBG anhydride solution was added and stirred at -25 to -15°C for 2-3 hrs. The mixture was heated to 25-30°C, 180 mL of aq. HC1 (30%) and water (180 mL) were added and the mixture was heated to 70-75°C. The phases were separated and the organic phase was cooled to 15-30°C and stirred for 2-2.5 hrs. The mixture was filtered and washed twice with toluene (2 vol.).

C. The toluene mother liquor, contained 226 g of the compound of formula Ilia (Ar = phenyl and R = methyl) (ee 76.7 %). The toluene was distilled off to 3 vol and 136 g acetylchloride were added. The mixture was heated to 78-82°C and stirred for 5-6 hrs. At the end of the reaction time, 1130 mL water was added at 50-60°C and the phases were separated. 47.39 g NaOH in 474 mL of water were added to the organic phase and the reaction mixture was heated to 78-82°C and stirred for 8-10 hrs. Then, the reaction mixture was cooled to 25-30°C and the pH was adjusted to 1-3 with 30% HC1. Toluene (8 vol.) was added to the mixture and the phases were separated at 80°C. The organic phase was cooled to 25-30°C and filtered. The filtrate was washed with toluene (2 vol.) and re-crystallized from toluene. Yield 44.94%, purity 97.5%, ee 99.88%.

Example 2: Preparation of (3S)-5-methyl-3-(2-oxo-2{[(lS)-l-phenylethyllamino} ethyl) hexanoic acid

A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with toluene (400 ml), (S)-(-)-phenylethylamine (142.35 g,1.1764 mole), and 4-dimethylaminopyridine (0.7176 g, 0.0059 mole). The mixture was cooled to a temperature of -10°C to -15°C, followed by addition of a solution of 3- isobutyl glutaric anhydride (100 g, 0.59 mole) [e.g. obtained in accordance with the process disclosed Drugs of the Future, 24 (8), 862-870 (1999) or according to Example 1 step (A) above] in toluene (100 ml), over a period of 45-60 minutes, and stirring for additional 1.5-2 hours, at a temperature of -10°C to -15°C. The mixture was then extracted with 10% aqueous solution of NaOH (500 ml), and the aqueous phase was washed with toluene (1x250 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a solution of hydrochloric acid (1-12N). The aqueous phase was further extracted with toluene (lx 800 ml) at a temperature of 70-80°C. The toluene layer was washed with 10% sodium chloride solution {700ml) at a temperature of 70-80°C followed by crystallization to get 125 g (73.0% yield) of a white solid of (3S)-5-methyl-3-(2-oxo-2-{[(l S)-l-phenylethyl]amino}ethyl) hexanoic acid with an optical purity of 99.75 %, as measured by chiral HPLC.

The toluene mother liquor obtained from the crystallization, which contains a mixture of diastereomers [i.e. compound (Ilia) and (III) wherein Ar = phenyl and R = methyl) is then further processed in accordance with Example 1, step C, in order to convert the compound of formula (Ilia) to (III).

Example 3; Preparation of (3S)-5-methyl-3-(2-oxo-2{[(l S)-l-phenylethyllamino} ethyl) hexanoic acid

Desired major

To a cooled (0 °C) solution of 4-Isobutylglutaric anhydride (0.1 moles) in toluene is added (lS)-l-phenylethanamine (0.1 moles) slowly during 30 minutes and the mixture is warmed to 70 °C, washed with dilute HC1 followed by brine and cooled to ambient temperature during several hours. The precipitate is filtered, washed with toluene and vacuum dried until constant weight to yield (3S)-5-methyl-3-[2-oxo-2-[[(lS)-l- phenylethyl] amino] ethyl]hexanoic acid. Diastereomeric purity by HPLC = 99.5%. The toluene mother liquor obtained from the precipitation, which contains a mixture of diastereomers [i.e. compound (Ilia) and (III) wherein Ar = phenyl and R = methyl) is then further processed in accordance with Example 1, step C, in order to convert the compound of formula (Ilia) to (III).

Example 4: Preparation of {(S)-4-methyl-2-[((S)-l-phenylethylcarbamoyl)- methyllpentvUcarbamic acid methyl ester A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with acetone (25 ml), (3S)-5-methyl-3-(2-oxo- 2{[(l S)-l-phenylethyl]amino} ethyl) hexanoic acid (5 g, 0.0172 mole), and with

triethylamine (2.17g, 0.0215 mole), and cooled to -10° to -20°C followed by addition of solution of ethyl chloroformate (2.05 g, 0.0189 mole in 5 ml acetone). The mixture was stirred for 1 hour at a temperature of -10° to -20°C, followed by addition of solution of sodium azide (2.8g, 0.0429 mole in water). The resulted slurry was maintained for 1 hour at - 10° to -20°C, quenched over ice water followed by extracting the mass with sufficient amount of toluene. The toluene layer was slowly added over a refluxing mixture of toluene and methyl alcohol, followed by stirring for 2 to 4 hours. The stripping off the solvent results in 4.95 g (89.7% yield) of {(S)-4-methyl-2-[((S)-l-phenylethylcarbamoyl)- methyl]pentylcarbamic acid methyl ester (120) with a purity of 97.4% area, as measured by HPLC.

Example 5: Preparation of (S)-Pregabalin

A 0.2 1 reactor was loaded with 70% sulfuric acid (200 g) containing compound 26 (10 g, 0.031 mole), and was heated to 115-120°C for 5-10 hours, and then cooled to room temperature, i.e., about 20° to about 25°C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 35 ml of iso-butanol, the organic layer was separated, and Β¾Ν was added in an amount sufficient to provide a pH of 4. The (S)-Pregabalin was precipitated, filtered, and washed with 10 ml of iso-butanol. After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 40.4% yield. Purity: 99.95% area by HPLC.

Example 6: Preparation of (S)-Pregabalin

A flask was loaded with 47% HBr (12 ml), water (6 ml), and compound 26 (6 g), and then was heated to reflux for 3 hours. The solution was cooled to room temperature, and water (12 ml) was added. An aqueous 47% sodium hydroxide solution was added to obtain pH of 3. The solution was then extracted twice with isobutanol (15 ml), the combined organic layers were evaporated and fresh isobutanol was added (15 ml). B¾N (3.8 g) was added. The mixture was cooled to 2°C for 1 hour, then (S)-Pregabalin was filtered, and washed with of iso-butanol (3 ml). After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 90% yield.

Example 7: Conversion of the Compound of Formula 4 to (S)-Pregabalin: Example 14 of International Publication No. WO 2007/035890

A 0.2 1 reactor was loaded with 70% sulfuric acid (200 g) containing compound 26 (10 g, 0.031 mole), and was heated to 115-120°C for 5-10 hours, and then cooled to room temperature, i.e., about 20° to about 25°C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 35 ml of iso-butanol, the organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of 4. The (S) Pregabalin was precipitated, filtered, and washed with 10 ml of iso-butanol. After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 40.4% yield. Purity: 99.95% area by HPLC.

Compound 26 has the following chemical structure:

wherein Ar is a C_6-1o aromatic group, and R is a straight or branched C_1-4 alkyl, ester or carboxylic acid.

Example 8: Conversion of the Compound of Formula 4 to (S)-Pregabalin: Example 16 of International Publication No. WO 2007/035890

A flask was loaded with 47% HBr (12 ml), water (6 ml), and compound 26 (6 g), and then was heated to reflux for 3 hours. The solution was cooled to room temperature, and water (12 ml) was added. An aqueous 47% sodium hydroxide solution was added to obtain pH of 3. The solution was then extracted twice with isobutanol (15 ml), the combined organic layers were evaporated and fresh isobutanol was added (15 ml). Bu3N (3.8 g) was added. The mixture was cooled to 2°C for 1 hour, then (S)-Pregabalin was filtered, and washed with of iso-butanol (3 ml). After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 90% yield.

Claims

A process for preparing (S)-pregabalin comprising:

(a) providing a compound of formula Ilia):

(Ilia)

wherein Ar is an aromatic group and R is a straight or branched C_1-6 alkyl, an ester, or carboxylic acid;

(b) converting the compound of formula (Ilia) into a compound of formula: (IV):

(IV)

(c) converting the compound of formula (IV) into a compound of formula (III):

(III)

; and

converting the compound of formula (III) into (S)-pregabalin.

2. A process according to Claim 1, wherein step (b) comprises reacting the compound of formula (Ilia) with an acid anhydride or an acid halide.

3. A process according to Claim 2, wherein the acid anhydride is a C4 to Cg acid

anhydride, preferably a C4 to Ce acid anhydride, more preferably acetic anhydride.

4. A process according to Claim 2, wherein the acid halide is a C2 to Cg acid halide, preferably a C2 to Ce acid halide, more preferably a C2-C4 acid halide, preferably wherein the halide can be chloro or bromo, and most preferably wherein the acid halide is acetyl chloride.

5. A process according to any of Claims 1-4, wherein the compound of formula (Ilia) is reacted with acetyl chloride.

6. A process according to any of Claims 1-5, wherein step (b) is carried out in the

presence of an organic solvent, preferably wherein the organic solvent comprises: a C6-io aromatic hydrocarbon, a substituted aromatic hydrocarbon, a C3-8 ether, a halogenated hydrocarbon, a C3-8 ester, a straight, branched or cyclic C6-10 alkane, or a C3-8 ketone, preferably wherein the organic solvent is a C6-10 aromatic hydrocarbon, more preferably toluene.

7. A process according to any of Claims 1-6, wherein step (b) comprises heating,

preferably to a temperature of about 50°C to about 100°C, about 60°C to about 90°C, about 70°C to about 85°C.

8. A process according to any preceding claim, wherein step (c) comprises reacting the compound of formula (IV) with a base, preferably selected from a metal hydroxide or a metal alkoxide.

9. A process according to Claim 8, wherein the metal hydroxide is an alkali metal or alkaline earth metal hydroxide, preferably sodium hydroxide or potassium hydroxide.

10. A process according to Claim 8 wherein the metal alkoxide is an alkali metal or alkaline earth metal alkoxide, preferably a sodium, or potassium alkoxide, and more preferably sodium methoxide or sodium ethoxide.

11. A process according to any of Claims 1-10, wherein step (c) comprises reacting the compound of formula (IV) with sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.

12. A process according to any preceding claim wherein step (c) comprises heating, preferably to a temperature of about 50°C to about 100°C, about 60°C to about 90°C, about 70°C to about 85°C.

13. A process according to any preceding claim, wherein after step (b), water is added and the organic phase is reacted with a base in accordance with step (c).

14. A process according to any of Claims 1-13, wherein steps (b) and (c) are carried out in one pot, without isolating the compound of formula (IV).

15. A process according to any of Claims 1-14, wherein the compound of formula (Ilia) is provided as a mixture comprising a compound of formula (Ilia) and formula (III), wherein the mixture is enriched with the compound of formula (Ilia).

16. A process according to any preceding claim, further comprising isolating, and

optionally purifying the compound of formula (III) prior to step (d)

17. A process according to any of Claims 1-16, wherein the compound of formula (Ilia) is prepared by a process comprising reacting a chiral amine of the following formula A:

(A) wherein Ar is a Ce-ιο aromatic group, and R is a straight or branched C_1-4 alkyl, ester, or carboxylic acid, with isobutyl glutaric anhydride, in the presence of a base.

18. A process according to Claim 17, wherein the process comprises:

(i) combining 3-isobutyl glutaric anhydride and the chiral amine of formula (A) in an organic solvent, in the presence of a base to obtain a diastereomeric mixture comprising a compound of formula (Ilia) and a compound of formula (III):

(Il ia) (III) recovering the compound of formula (Ilia) from the mixture.

19. A process according to Claim 17 or Claim 18, wherein the compound of formula (Ilia) is prepared by a process comprising:

(iii) combining the chiral amine of formula (A) with an organic solvent selected from at least one of: C6-io aromatic hydrocarbons, substituted aromatic hydrocarbons, C2-8 ethers, halogenated hydrocarbons, straight or branched C1-4 alcohols, C₃-8 esters, straight, branched or cyclic C_1-6 alkanes, or C₃-8 ketones,, and at least one base to obtain a mixture;

(iv) cooling the mixture, preferably to a temperature of about -70°C to about 10°C;

(v) adding 3-isobutyl glutaric anhydride to the mixture;

(vi) maintaining the mixture, preferably at a temperature of about -70°C to about 10°C, preferably for at least about one hour to obtain a diastereomeric mixture comprising the compound of formula (Ilia) and (III):

(Il ia) (III) recovering the compound of formula (Ilia) from the mixture.

20. A process according to any of Claims 18-19, wherein the base is an organic base, preferably wherein the base is diethyl amine, triethylamine, di-n-propyl amine, di- isopropyl amine, tertbutylamine, morpholine, piperidine, pyridine, or 4-dimethyl aminopyridine, or more preferably wherein the base is 4-dimethyl aminopyridine.

21. A process according to any of Claims 18-20, wherein the compound of formula (III) is recovered from the diastereomeric mixture, and converted to (S)-pregabalin.

22. A process according to any of Claims 18-21, wherein the organic solvent in step (i) is at least one of: toluene, tert-butyl methyl ether tetrahydrofuran, diisopropyl ether, diethyl ether, dichloromethane, ethyl acetate, isopropyl acetate, isobutyl acetate, hexane, cyclohexane, acetone, methyl isobutyl ketone, and methyl ethyl ketone, preferably toluene.

23. A process according to any of Claims 18-22, wherein the mixture is maintained at a temperature of about 0°C to about -50°C.

24. A process according to any of Claims 18-23, wherein the mixture is maintained at a temperature of about -40°C to -30°C.

25. A process according to any of Claims 18-24, wherein the mixture is maintained for about one hour to about six hours, preferably wherein the mixture is maintained for about one hour to about two hours.

26. The process according to any of Claims 18-25, wherein the organic solvent is an ester, nitrile, ether, C4-6 straight, branched or cyclic hydrocarbon, or C6-10 substituted or unsubstituted aromatic hydrocarbon, preferably wherein the organic solvent is ethyl acetate, acetonitrile, methyl t-butyl ether, toluene, xylene, hexane, or cyclohexane, or a mixture of toluene and ethyl acetate, and most preferably toluene.

27. A process according to any of Claims 18-26, wherein the compound of formula (Ilia) is recovered as a mixture with the compound of formula (III), wherein the mixture is enriched in the compound of formula (Ilia).

28. A process according to any of Claim 18-27, wherein the compound of formula (Ilia) is recovered by a process comprising precipitating or crystallising the compound of formula (III) from the reaction mixture to obtain a mother liquor or filtrate comprising the compounds of formulae (Ilia) and (III) which is enriched in the compound of formula (Ilia).

29. A process according to any preceding claim, wherein the conversion of the compound of formula (Ilia) to (IV) is carried out without isolating the compound of formula (Ilia) from the mother liquor or filtrate obtained according to the process of Claim 28.

A process according to Claim 29, wherein the conversion of the compound of formula (Ilia) in the mother liquor or filtrate to (IV) and (IV) to (III) is carried out in one pot.

31. A process according to any preceding claim wherein the compound of formula (III) obtained from the compound of formula (IV) is recrystallised, preferably from toluene.

A process according to any preceding claim wherein the compound of formula (III) i converted into (S)-pregabalin by a process comprising:

(a) converting the hydroxyl group of the compound of formula (III) to a leaving

group to form a compound of formula III-X:

(III-X)

wherein X is a leaving group;

(b) reacting the compound of formula (III-X) with an azide nucleophile to obtain a compound of formula (V):

(V)

reacting the compound of formula (V) with an alcohol, R^-OH, wherein R¹ represents a C_1-8 straight chain, branched or cyclic alkyl group, preferably a Ci-6 straight chain, branched or cyclic alkyl group, more preferably a Ci to C4 straight chain or branched alkyl group, and most preferably a methyl group, to obtain a compound of formula (VI):

(VI)

; and

(d) hydrolyzing the compound of formula (VI) to form (S)-pregabalin.

33. A process according to Claim 32, wherein the leaving group X is halogen or a mixed anhydride.

34. A process according to Claim 33, wherein the leaving group is CI, Br, -OCOR² _, wherein -OCOR² is derived from a haloformate, an acid halide or an acid anhydride.

35. A process according to Claim 34, wherein the leaving group is -OCOR², wherein R² is an alkyl group, preferably a Ci to Ce alkyl group, more preferably a Ci to C3 alkyl group and most preferably ethyl.

36. A process according to any of Claims 32-35, wherein step (a) comprises reacting the compound of formula (III) with a reagent which is a haloformate, an acid halide or an acid anhydride, preferably acetic anhydride, di-t-butyl dicarbonate and ethyl chloroformate, preferably ethyl chloroformate, and preferably wherein the reaction is carried out in the presence of a base.

37. A process according to Claim 36, wherein the base is added to the compound of formula (III) before the addition of the reagent.

38. A process according to any of Claims 32-37, wherein the azide nucleophile in step (b) is a metal azide, diphenylphosphoryl azide, trialkyl silyl azide, or a trialkyl metal azide (preferably trialkyl tin azide)

39. A process according to Claim 38, wherein the azide nucleophile is sodium azide.

40. A process according to any of Claims 32-39, wherein steps (a) and (b) are carried out without isolation of compound (III-X).

41. A process according to any of Claims 32-40, wherein step (c) is carried out at a

temperature of about 50°C to about 100°C, about 60°C to about 90°C, about 70 to about 90°C, or about 80 to about 90°C.

42. A process according to any of Claims 32-41, wherein steps (b) and (c) are carried out without isolation of compound (V).

43. A process according to any of Claims 32-42, wherein steps (a), (b) and (c) are carried out without isolation of compounds (III-X) and (V).

44. A process according to Claim 43, wherein steps (a), (b) and (c) are carried out as a one-pot process.

45. A process according to any of Claims 32-44, wherein step (d) comprises reacting the compound of formula (VI) with an acid and a phenol, which may be substituted or unsubstituted.

46. A process according to Claim 45, wherein the acid is a mineral acid, preferably a strong mineral acid, more preferably selected from hydrobromic acid, hydrochloric acid, sulfuric acid or polyphosphoric acid, and most preferably hydrochloric acid.

A process according to Claim 45 or Claim 46, wherein the phenol has the formula:

wherein, R is H, alkyl, alkoxy, halogen, or mercapto, R⁴ is H, alkyl or halogen, the ring Z is a 5-8-membered ring containing carbon and optionally at least one nitrogen, sulfur or oxygen.

A process according to Claim 47, wherein the phenol has the formula

A process according to Claim 47 or Claim 48, wherein R³ is alkyl (preferably Ci to C₃ alkyl), alkoxy (preferably Ci to C3 alkoxy), or halogen (preferably chlorine, bromine or iodine).

50. A process according to any of Claims 48-49, wherein the phenol is unsubstituted.

51. A process according to any preceding claim, wherein Ar is a C6-1₀ aryl group,

preferably phenyl.

52. A process according to any preceding claim, wherein R is a straight or branched Ci-6 alkyl group, or a C3-C8 ester group, or a C2-C6 carboxylic acid group.

53. A process according to any preceding claim, wherein R is a straight or branched C1-4 alkyl group, preferably methyl. A process according to any preceding claim, wherein R is methyl and Ar is phenyl.

A process according to any preceding claim, further comprising combining the (S)- pregabalin with at least one pharmaceutically acceptable excipient to provide a pharmaceutical composition or dosage form.

A compound having the formula:

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof; wherein R⁵ is 1-phenylethyl.

A compound accordin to Claim 56, having the formula (IV a):

(IVa)

58. The use of a compound of formula as defined in Claim 56 or Claim 57 in the

preparation of (S)-pregabalin.