BRPI0702883A2 - process for the preparation of r - (+) - 3- (carbamoyl methyl) -5-methylhexanoic acid and its salts - Google Patents

Abstract

PROCESSES FOR THE PREPARATION OF R - (+) - 3- (CARBAMOYLMETHIL) -5-METHYL-HEXANOIC ACID AND ITS SALTS. Processes are provided for the synthesis of R - (+) - 3- (carbamoylmethyl) -5-methylhexanoic acid and its salts, intermediates in the synthesis of S-pregabalin.

Description

PROCESSES FOR PREPARING R- (+) -3- (CARBAMOIL METIL) -5-METHYL-HEXANOIC ACID AND ITS SALTS

Cross-reference to related applicationsThis application claims priority benefit from US provisional applications Serial Nos .: 60 / 808,320, filed May 24, 2006; 60 / 814,245, filed June 15, 2006; 60 / 843,817, filed September 11, 2006; 60 / 850,868, filed October 10, 2006; 60 / 918,177, filed March 14, 2007; 60 / 920,348, filed December 26, 2007, included herein for reference.

Field of the Invention

The invention includes processes for the synthesis of R - (+) - 3- (carbamoylmethyl) -5-methylhexanoic acid ("R-CMH") and its salts, intermediates in the synthesis of S-pregabalin.

Background of the invention

(S) -Preqabalin, (S) - (+) - 3- (Aminomethyl) -5-acidomethylhexanoic, a composition having the chemical structure,

(S) -Pregabalin

is a γ-amino butyric acid or (S) -3-isobutyl analog (GABA). The-Pregabalin. activates GAD (L-glutamic acid carboxylase). (S) -Pregabalin has a dose-dependent protective effect on disease, and is an active compound of CNS. : (S) -Pregabalin is useful in anticonvulsant therapy because of its activation of GAD, promoting the production of GABA, one of the major brain inhibitor neurotransmitters, which is released to 30% of brain synapses. 0 (S) -Pregabalin has analgesic, anticonvulsant and anxiolytic activity.

The preparation of (S) -Pregabalin, as disclosed in U.S. Patent No. 5,616,793, and in DRUGS OF THEFUTURE, 24 (8), 862-870 (1999) is performed to obtain the intermediate, 3- (carbamoylmethyl). -5-methylhexanoic acid ("CMH"), which is optically resolved to produce R-CMH, which is converted to (S) -Pregabalin according to the following scheme:

<formula> formula see original document page 3 </formula>

There is a need in the art for additional processes for the preparation of R-CMH and its salts.

Summary of the Invention In one embodiment, the invention includes a process for the preparation of (R) - (+) -3- (carbamoylmethyl) -5-acidomethylhexanoic acid or its salt, of the formula

<formula> formula see original document page 4 </formula>

characterized by :. a) Isobutylglutaric ring-opening isobutyl 3-anhydride asymmetrically to obtain an ester of the formula

<formula> formula see original document page 4 </formula>

b) amidation of the chiral ester to obtain a (R) - (+) -3- (carbamoylmethyl) -5-methylhexanoic acid salt of the formula

<formula> formula see original document page 4 </formula>

and optionally c): converting the (R) - (+) -3- (carbamoylmethyl) -5-methylhexanoic acid salt to (R) -3- (carbamoylmethyl) -5-methylhexanoic acid salt to wherein R1 and R2 are independently selected from the group consisting of H, C1 to C12 aliphatic, branched or cyclic hydrocarbyl, C6a C9 aromatic hydrocarbyl and CO2H, and M is H or NH4 +. In another embodiment, the invention includes a process for preparation; of (R) - (+) -3- (carbamoylmethyl) -5-acidomethylhexanoic acid or its salt, with the formula

<formula> formula see original document page 5 </formula>

characterized by: (a) a combination of 3-anhydridoisobutylglutaric acid, a chiral alcohol, a selected solvent from the group consisting of Ce-ιο aromatic hydrocarbons, C3-5 ketones, C2-5 ethers, C2_7 esters, C1-2 halogenated hydrocarbons and C1-4 nitriles and a base to obtain a chiral ester of the formula

B). mixture with ammonia to obtain a (R) - (+) -3- (carbamoylmethyl) -5-methylhexanoic acid salt of the formula

<formula> formula see original document page 5 </formula>

and optionally c) adding an acid to obtain R - (+) - 3- (carbamoylmethyl) -5-methyl hexanoic acid, wherein R1 and R2 are independently selected from the group consisting of branched aliphatic H, C1-IL2 hydrocarbons. cyclic, C6-6 aromatic hydrocarbons and CO2H; and M is H or NH 4 +.

In another embodiment, the invention includes a process for preparation. of (R) - (+) -3- (carbamoylmethyl) -5-acidomethylhexanoic acid or its salt, having the formula

<formula> formula see original document page 6 </formula>

characterized by: (a) a combination of 3-anhydridoisobutylglutaric acid, a non-chiral alcohol, a chiral amine and a solvent selected from the group consisting of Ος-ιο aromatic hydrocarbons, C2-5 ethers, C1-2 halogenated hydrocarbons and mixtures thereof to "obtain a chiral ester of formula

<formula> formula see original document page 6 </formula>

b) mixing with ammonia to obtain a (R) - (+) -3- (carbamoylmethyl) -5-methylhexanoic acid salt of the formula

<formula> formula see original document page 6 </formula>

and optionally c) adding an acid to obtain R - (-) - 3- (carbamoylmethyl) -5-methyl hexanoic acid, wherein R1 and R2 are independently selected from the group consisting of H, branched aliphatic hydrocarbons H, C1-12 cyclic, C5-9 aromatic hydrocarbons and CO2H; and M- is H or NH4 +.

In another embodiment, the invention includes a process for preparing (R) - (+) -3- (carbamoylmethyl) -5-methylhexanoic acid or its salt, having the formula

<formula> formula see original document page 7 </formula>

characterized in: a) combination of a chiral ester with formula

<formula> formula see original document page 7 </formula>

with an acid activating agent to form an activated acid derivative of the formula

<formula> formula see original document page 7 </formula>

b) amidation of the activated acid derivative to obtain a carbamoyl ester of the formula <formula> formula see original document page 8 </formula>

c) hydrolysing the carbaraoyl ester with an acid or a base to obtain R- (+) -3- (carbamoylmethyl) -5-methylhexanoic acid or its salt, respectively; and optionally d) converting R- (+) -3- (carbamoylmethyl) -5-methylhexanoic acid salt to R- (+) -3- (carbamoylmethyl) -5-methylhexanoic acid, "wherein R1 and R 2 are independently selected from the group consisting of H, C 1-12 aliphatic, branched or cyclic hydrocarbons, C 6 -g aromatic hydrocarbons and CO 2 H, and LG is a leaving group, wherein the leaving group is derived from the acid activating agent; where X is Hou an alkali metal.

In another embodiment, the invention includes a (S) -prabalin preparation process consisting of the preparation of R - (+) - 3- (carbamoylmethyl) -5-methylhexanoic acid or salts thereof by any of the processes described above and conversion of R - (+) - 3- (carbamoylmethyl) -5-methylhexanoic acid or its salts in (S) -pregabalin.

DETAILED DESCRIPTION OF THE INVENTION The invention includes processes for preparing high yield Ru: CMH without determining the CMH racemate as disclosed in the prior art and thus preventing resolution and recovery of the. enantiomer undesired. In addition, the processes can be easily adapted on an industrial scale.

In one embodiment, the invention includes a process for the preparation of R-CMH or its salt which can be illustrated by Scheme 1 below. Scheme 1. Process for preparing R-CMH or its isobutylglutaric 3-anhydride salt

<formula> formula see original document page 9 </formula>

R-CMH or its salt

wherein R 1 and R 2 are independently selected from the group consisting of H, C 1-12 aliphatic, branched or cyclic hydrocarbons, C 6 -g aromatic hydrocarbons and CO 2 H; and M is H or NH4 +. Preferably R 1 is CO 2 H or H; R 2 is H, a C 8-6 aromatic hydrocarbon or an aliphatic or branched C 1-12 hydrocarbon; or R 1 and R 2 together form a C 1-12 cyclic hydrocarbon.

Preferably, the C 6-9 aromatic hydrocarbon is phenyl. Preferably, the aliphatic or branched C1-12 hydrocarbon is methyl. Preferably the cyclic C1-12 hydrocarbon is 1,3,3-trimethylbicyclo [2.2.1] heptane. Preferred combinations of R 1 and R 2 are CO 2 H and phenyl, H and Η, H and Me, H and phenyl respectively or R 1 and R 2 together form 1,3,3-trimethylbicyclo [2.2.1] heptane of the following formula

<formula> formula see original document page 9 </formula> The asymmetric ring opening step can be performed with (i) a chiral alcohol or (ii) a non-chiral alcohol in combination with a chiral amine acting as a chiral inducer.

When a chiral alcohol is used, the asymmetric ring-opening step generally consists of the combination of isobutylglutaric 3-anhydride ("IBG-anhydride"), a chiral alcohol S-ester, a solvent selected from the group that consists of C6-10 hydrocarbons. aromatic, C3-5 ketones, C2-5 ethers, C2-7 esters, C1-2 halogenated hydrocarbons and C1-4 nitrile and a base.

Preferably, the base is selected from the group consisting of sodium hydride ("NaH") and butyl lithium ("BuLi"). More preferably, the base is NaH inorganic base. Preferably, the NaH is in the form of a 60% w / w oil suspension.

Chiral alcohol opens ΓIBG-anhydride in a stereospecific manner. Therefore, experts in the art would notice that an enantiomer of the. chiral alcohol leads to S-ester formation, while the opposite enantiomer leads to R-ester formation. Examples of suitable chiral alcohols include, among others, (S) -fenchyl alcohol, (S)-mandelic acid, benzylmandelate, ethylmandelate, methylmandelate, 1-phenylethanol, 1-phenyl-2-propanol, 1-phenyl-1-propanol and trifluoromethyl. benzyl alcohol. Preferably, the. alcoholqual is (S) -fenchyl alcohol or (S)-mandelic acid.

Preferably, the C6-10 aromatic hydrocarbon is a Ces hydrocarbon. aromatic, more preferably C 6-7. aromatic hydrocarbon and, at best, toluene. Preferably the C3-5 ketone is a C3-4 ketone, more preferably a C3 ketone and, at best, acetone. A preferred C 2-5 ether is a C 4-5 ether and a more preferred C 2-5 ether is tetrahydrofuran ("THF") or methyl tert-butyl ether ("MTBE"). Preferably, the C2-7 ester is a C2-S ester, more preferably a C2-4 ester, at best a C4 ester. A particularly preferred C 2-7 ester is ethyl acetate. A halogenated C1-4 hydrocarbon is a halogenated C1-3 hydrocarbon, and a more preferred halogenated C1-2 hydrocarbon is dichloromethane ("DCM"). Preferably, C1-4 nitrile is a C1-2 nitrile, more preferably a C2nitrile and more preferably acetonitrile ("ÀCN"). The most preferred solvent is toluene.

Generally, the solvent and alcohol which are first combined are combined to provide a mixture, and the base is then added to the mixture. Preferably, the inorganic base is added to the mixture at a temperature of from about -780 ° C to about 10 ° C, more preferably from about -40 ° C to about 40 ° C and, at best, from about -20 ° C to about 20 ° C.

After addition of the base, IBG-anhydride is added to the mixture. IBG-anhydride may be supplied pure or in solution form. When supplied as a solution, solvent is as described above. IBG-anhydride may be added in drops. When the anhydride is added to stock, the addition is preferably for a period of approximately 0.5. approximately 3 hours, more preferably approximately 0.5 hours to approximately 1 hour.

After the addition of IBG-anhydride, the mixture is preferably maintained. at a temperature of about 0 ° C to about 50 ° C and more preferably from about 200 ° C to about 30 ° C to obtain the S-ester of the following structure. <formula> formula see original document page 12 </formula>

Preferably the mixture is kept for about 1 to about 6 hours and more preferably for about 3 hours.

When a non-chiral alcohol in combination with a chiral amine is used, the asymmetric ring-opening step generally consists of the combination of IBG-anhydride, a chiral amine, a non-chiral alcohol and a solvent selected from the group consisting of C6. -aromatic hydrocarbons, C2-5 ethers, C1-2 halogenated hydrocarbons and mixtures thereof.

Preferably the C6-10 aromatic hydrocarbon is a C6- and aromatic hydrocarbon, more preferably C6-7 aromatic hydrocarbon and, at best, toluene. A C 2-5 ether is a C 4-5 ether and preferably the C 2-5 ether is THF. A halogenated C1-2 hydrocarbon is a halogenated hydrocarbon, and a more preferred C1-2 halogenated hydrocarbon is DCM. The most preferred solvent is toluene.

Chiral amine serves as a chiral inducer for non-chiral alcohol, leading to a stereospecific IBG-anhydride opening. Therefore, those skilled in the art would note that an enantiomer of chiral alcohol leads to S-ester formation, while the opposite enantiomer leads to R-ester formation. Preferably, the chiral amine is an alkaloidalkyl. Preferably, the chiral alkaloid is a quinone alkaloid. Examples of suitable decinchone alkaloids include, but are not limited to, quinidine, cinchonine and their dehydroderivatives. Preferably, chiral amine is quinidine of the following structure:

<formula> formula see original document page 13 </formula>

Preferably, the non-chiral alcohol is a C1-7 alcohol. Preferably the C1-7 alcohol is methanol, ethanol, propanol, n-butanyl and benzyl alcohol. More preferably, the C1-7 alcohol is methanol.

In general, non-chiral alcohol is added to a suspension of IBG-anhydride, and chiral amine in a selected solvent from the group consisting of C6-10 aromatic hydrocarbons, C2-5 ethers, C1-2 halogenated hydrocarbons and their mixtures. Preferably, the alcohol is added to the suspension at a temperature of about 20 ° C to about -78 ° C, more preferably -40 ° C to about -60 ° C. Non-chiral alcohol may be added dropwise to the suspension. When the addition is done, it is preferably made for a period of about 15 minutes to about 45 minutes.

In general, the addition of non-chiral alcohol to the suspension provides a mixture. Preferably, the mixture is stirred for approximately 2 to approximately 96 hours and more preferably from about 2 to approximately 24 hours to obtain the S-ester of the following formula.

<formula> formula see original document page 13 </formula> The above S-ester prepared by one of the above methods may be recovered by any method known to one skilled in the art. These methods include, among others, solvent removal and optionally addition of an acid and drying.

In general, the recovered S-ester is a mixture of two diastereomers, referred to as S-ester and R-ester of the following formulas:

<formula> formula see original document page 14 </formula>

wherein the S-ester is the main diasteromer in the mixture. Preferably, the diastereomeric ratio is from about 80:20 to about 95: 5 area by HPLC of the S-ester to R-ester, respectively.

Optionally, the diastereomer-coated mixture may be crystallized to increase the ratio of S-ester to R-ester before reacting with ammonia. Crystallization consists of the dissolution of the mixture of diastereomers in a solvent selected from the group consisting of C6-aromatic hydrocarbons, C3-5 ketones, C2-5 ethers, C2-7 esters, C1-2 halogenated hydrocarbons, C1-4 nitriles and their mixtures. precipitation of the S-ester from the solution while the R-ester remains in the solution. Preferably, the mixture of diastereomers is dissolved in a solvent mixture. A mix; Preferred solvent is that of C6-aromatic hydrocarbon and C2-I. ester. The most preferred mixture is toluene and ethyl acetate.

The mixture of diastereomers and solvent may optionally be heated to dissolve the diastereomer mixture to form a solution. Preferably, the combination is heated to a temperature of about 40 ° C to about 150 ° C and more preferably from about 600 ° C to about 120 ° C. Generally, the obtained solution is cooled to precipitate the S-ester. Preferably, a. The solution is cooled to a temperature of about 30 ° C to about 0 ° C and more preferably about 20 ° C to about 2 ° C. The precipitated S-ester may be recovered by filtration.

In general, the crystallized S-ester contains less R-ester than the initial S-ester. Preferably, the ratio of diastereomers is at least 95: 5 area by HPLC of the S-ester to the R-ester, respectively.

The amidation step consists of the mixture of chiral ester S-ester, obtained by any of the above processes, with ammonia and optionally followed by the addition of an acid. The reaction between the S-ester and ammonia leads to the R-CMH deamonium salt of the formula,

<formula> formula see original document page 15 </formula>

which may be reacted with an acid to obtain R-CMH.

Preferably, the ammonia is provided as a solution in a solvent selected from the group consisting of water, an organic solvent and mixtures of water is organic solvent. Preferably, the solvent is selected from the group consisting of: methanol, ethanol, ethylene glycol, isopropanol, ethylacetate and acetonitrile. Ammonia resolution can be obtained by bubbling gas ammonia in the solvent. NH 4 Cl may also be combined with ammonia and S-ester. Preferably, the combination of S-ester and ammonia forms a mixture which is maintained at a temperature of from about -40 ° C to about 110 ° C, more preferably about 40 ° C. C at approximately 110 ° C and, at best, approximately 40 ° C to approximately 80 ° C to obtain the ammonium salt of R-CMH.

Preferably, the mixture is maintained for approximately -2 to approximately 48 hours and more preferably for approximately 6 to 30 hours. Preferably, the mixture is maintained at a pressure of from about 1 to about 6 atmospheres and preferably from about 1 to about 5 atmospheres.

Preferably, the acid is selected from the group consisting of HCl, HBr, H2SO4, H3PO4, acetic acid and formic acid. More preferably, the acid is HCl.

Preferably, the acid is present in an amount sufficient to obtain a pH of from about 0 to about 5 and more preferably from about 2 to about 4. After addition of the acid, cooling is conducted to precipitate the R-CMH. Preferably, cooling is It is made at a temperature of about 10 ° C to about -5 ° C and more preferably about 5 ° C to about 0 ° C.

The R-CMH or salt thereof obtained may be recovered by any method by one skilled in the art. Such methods include, but are not limited to, filtration, extraction of the R-CMH or its salt with a solvent, evaporating the solvent and drying.

Preferably, asymmetric ring opening and amidation may be performed as one-pot processes, ie without isolation of the S-ester.

In another embodiment, the invention includes a process for the preparation of R-CMH and its salts, which can be illustrated by Scheme 2 below.

<formula> formula see original document page 17 </formula>

R-CMH or its salt

wherein R1 and R2 are independently selected from the group consisting of H, C1-4 aliphatic, branched or cyclic hydrocarbons, C9-9 aromatic hydrocarbons and CO2 H; LG is the leaving group, wherein the leaving group is derived from the group. acid activating agent; and X is H or an alkali metal Preferably R 1 is CO2 H or H, R 2 is H, a C 6-9 aromatic hydrocarbon or a C 1-12 hydrocarbon or aliphatic, or R 1 and R 2 together form a C 1-12 hydrocarbon. cyclic.

Preferably, the C 6-9 aromatic hydrocarbon is phenyl. Preferably the aliphatic or branched C1-12 hydrocarbon is methyl. Preferably the cyclic C1-12 hydrocarbon is 1,3,3-trimethylbicyclo [2.2.1] heptane. Preferred combinations of R 1 .. and R 2 are CO 2 H and phenyl, HeH., He Me, H and phenyl, respectively or R 1 and R 2 together form 1,3,3-trimethylbicyclo [2.2.1] heptane of the following formula <formula> see original document page 18 </formula>

The ester half in the acid starting material may be chiral or non-chiral.

The starting R-ester may be provided by the above process using chiral alcohol or the combination of non-chiral alcohol and chiral amine on the condition that the chiral alcohol and chiral amine-enantiomer is used. The opposite enantiomer leads to formation of the R-ester, in ve? of the S-ester as above.

Examples of suitable chiral alcohols include, among others, (R) -phenyl alcohol, (R)-mandelic acid and the opposite enantiomer of the following alcohols. benzylmandelate, ethylmandelate, methylmandelate, 1-phenylethanol, 1-phenyl-2-propanol, 1-phenyl-1-propanol and trifluoromethyl benzyl alcohol. Preferably, chiral alcohol · ··. is (R) -alcoolfenchylic or (R)-mandelic acid.

Preferably, the chiral amine is an alkaloidalkyl. Preferably, the chiral alkaloid is a cinchoná alkaloid. Examples of suitable decinchone alkaloids include, but are not limited to, quinine, cinchonidine and their dehydroderivatives. Preferably, chiral amine is quinine of the following structure:

<formula> formula see original document page 18 </formula>

Activation of the R-ester may be accomplished by the combination of the above R-ester, a base and an acid activating agent in a solvent selected from the group consisting of aromatic C6-5 hydrocarbons, C3-5 ketones, C2-S ethers, C2 -7 esters, C1-2 halogenated hydrocarbons, C1-4 nitriles and their mixtures to obtain an activated acid derivative of the formula

<formula> formula see original document page 19 </formula>

The base may be an organic base or an inorganic base. Preferably the organic base is an amine aliphatic and more preferably an amine aliphatic C2-12. Preferably, the aliphatic C2-12 amine is selected from the group consisting of ethyl amine, diethylamine, propyl amine, dipropyl amine, butyl amine, tributylamine, diisopropyl amine and triethylamine. More preferably, the aliphatic β2-12 amine is triethylamine.

Preferably, the inorganic base is an alkaline hydroxide, an alkaline carbonate or an alkaline bicarbonate. Preferably the alkaline hydroxide is sodium hydroxide or potassium hydroxide. Preferably the alkaline carbonate is sodium carbonate or depotassium carbonate. Preferably the alkaline bicarbonate is sodium bicarbonate or potassium bicarbonate. Most preferably, the base is triethylamine.

Preferably the Ce-aromatic hydrocarbon is a Ce-8 aromatic hydrocarbon, more preferably C6-7 aromatic hydrocarbon and, at best, toluene. Preferably the C3-5 ketone is a C3-4 ketone plus. preferably a C3 ketone and, at best, acetone. A preferred C2-5 ether is a C4-5 ether, more preferably the C2-5 ether is THF or MTBE. Preferably the C2-1 ester is a C2-5 ester, more preferably a C2-4 ester and, at best a C4 ester. Particularly preferred C 2-7 ester is ethyl acetate. Halogenated C1-2 · hydrocarbon is a halogenated hydrocarbon, and a more preferred C1-2 halogenated hydrocarbon is DCM. Preferably, C1-4nitrile is a C1-2 nitrile, more preferably a C2nitrile and more preferably ACN. The most preferred solvent is DCM.

The term "acid activating agent" refers to a substance that contains a group that activates a carbon group, that is, makes the carbon group more susceptible to attack. nucleophilic, when attached to it.

Preferably, the acid activating agent is selected from the group consisting of: alkyl haloformats, anhydrides and sulfonyl halides. Preferably, the alkyl formate is ethyl chloroformate or methyl chloroformate.

Preferably, the anhydride is a symmetrical or mixed anhydride, more preferably acetic anhydride. Preferably the sulfonyl halide is mesyl chloride or tosyl chloride. More preferably, the activating agent is ethyl chloroformate.

In general, the solvent is combined with the initial R-ester base to obtain a mixture. The mixture is cooled prior to the addition of the acid activating agent. Preferably, the mixture is cooled to a temperature of about 20 ° C to about -5 ° C. and most preferably about 50 ° C to about -0 ° C.

After the acid activating agent is added to the mixture, the mixture is heated. Preferably, the mixture is heated to a temperature of about 10 ° C to about 50 ° C, and more preferably about 20 ° C to about 25 ° C. Preferably, the heated mixture is held for about 1 to about 2 hours to obtain the activated acid derivative. of the following formula:

Preferably, R 1 and R 2 are H, and LG is OCO 2 Et, providing an activated acid derivative of the following:

formula:

<formula> formula see original document page 21 </formula>

The activated acid derivative is then subjected to an amidation process consisting of combining the above activated acid with ammonia, followed by the addition of an acid or base to obtain the R-CMH. The reaction of ammonia-activated acid derivative provides a paste with the following amide.

<formula> formula see original document page 21 </formula>

Ammonia may be supplied as described above. Preferably, ammonia is supplied as a gas;

Amide may be recovered from the paste by any method known to a person skilled in the art. These methods include, among others, pulp amide filtration, amide washing and drying of the amide. Alternatively, the amide may react with the acid or base without being isolated, ie in a one-pot reaction.

The above amide ester group is hydrolyzed to R-CMH or its salt by combining the amide with an acid or base. When an acid is used, the above amide is hydrolyzed to R-CMH. When a base is used, the above amide is hydrolyzed to an R-CMH salt. The R-CMH salt can be converted to R-CMH by adding an acid.

The acid may be inorganic acid or an organic acid. Preferably, the inorganic acid is selected from the group consisting of HCl, HBr, H2SO4), HaPO4e, more preferably HCl. Preferably, the organic acid is selected from the group consisting of acetic acid and formic acid. More preferably, the acid is HCl.

The base is an inorganic base. Preferably, the base is an alkali metal base, forming a metal alkali salt of R-CMH during hydrolysis. Preferably, inorganic base is selected from the group consisting of NaOH, KOH and LiOH and more preferably NaOH.

Preferably, the amide is combined with the acid or base to provide a mixture which is stirred at a temperature of from about 10 ° C to about 50 ° C, and more preferably 20 ° C to about 25 ° C. Preferably the mixture is stirred for approximately 1 ° C. approximately 10 hours to obtain the R-CMH or its salt.

The R-CMH or salt thereof thus obtained may be recovered by any method known to one skilled in the art. Preferably, the R-CMH or salt thereof is recovered by adjusting the pH of the stirred mixture to obtain from about 1 to about 5, more preferably from about 2 to about 5, to provide a paste; filtering of R-CMH or its salt from the folder; washing the filtered R-CMH or its salt; and drying the R-CMH or its salt. Preferably, the pH is adjusted by adding a base to the mixture. Preferably, the base is an inorganic base and more preferably the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate. Optionally, an organic base such as ammonia , can be used. In general, the inorganic base may be used as a solid or as an aqueous solution.

R-CMH or its salt prepared by any of the processes described above can be converted to (S) -pregabalin. The conversion may be performed, for example, in accordance with the methods disclosed in US Patent Application No. 2007/0073085, incorporated herein by reference.

Examples

Asymmetric IBG-Anhydride Ring Opening

Example 1: Preparation of Phenyl Ester

A three-necked flask (0.25 l) was charged with toluene (140 ml), phenethyl alcohol (9.26 g) and 60% NaH (2.4 g). The mixture was heated to 80 ° C and then cooled to 5 ° C. A solution of isobutylglutaric 3-anhydride (6.8 g) in toluene (25 ml) was added dropwise to the mixture. The solution was stirred at room temperature for 3 hours. The solvent was evaporated to dryness to obtain the crude ester. The solid was dried at 55 ° C under vacuum.

Example 2: Isolation of (S), (R) -fenchyl ester

The crude ester prepared in the example is added to a mixture of ethyl acetate and toluene and heated to 80 ° C (range 40 ° C to 100 ° C) until dissolved. The solution is cooled to 2 ° C (range 0 to 20 ° C) to obtain a yellowish solid of (S) -3- (1,3,3-trimethylbicyclo [2.2.1] heptan-2-yl) carbonyl) methyl) -5-Acidomethylhexanoic acid (fenchyl ester), which is filtered from the mixture.

Example 3: Preparation and Isolation of (S), (R) -termandelate The · Three-necked flask (0.25L) is charged with toluene (70 ml), S-mandelic acid (3.04 g) and 60% NaH ( 1.6g). The mixture is heated to reflux and then cooled to room temperature. 3-Anhydridoisobutylglutaric acid (3.4 g) is added dropwise.

The solution is stirred at room temperature for 6 hours. The solvent is evaporated, and the residue is crystallized from a mixture of ethyl acetate and toluene to obtain an off-white (S) -4 - (((S) -carboxy (phenyl) methoxy) carbonyl) -3-isobutylbutanoic acid solid (Esther Mandelate)

The solid is dried at 550 ° C / under vacuum.Example 4: Asymmetric ring opening of chiral IBC-chmalcoidal anhydride

A three-necked flask (0.25L) is charged with quinidine (11 mmol), isobutylglutaric 3-anhydride (10 mmol) and toluene (50 mL). The mixture is cooled to -55 ° C. Methanol (30 mmol) is added dropwise over a period of 10 minutes in the cooled suspension. The reaction is stirred for 96 hours. The solution is concentrated to dryness, and the resulting residue is dissolved in diethyl ether (65 ml). The solution is washed with HCl-2N, and the aqueous layer is extracted again with ether. The combined organic layers are dried with MgSO4 and filtered. The filtrate is evaporated to dryness.

Example 5: Opening of asymmetric ring of IBG-chiral comalcaloid anhydride

Methanol (6.2 ml, 153 mmol) was added to a single flame-heated 250 ml round-bottom flask equipped with a magnetic stirrer and loaded with Quinidine (7.1.4 g, 22 mmol), isobutylglutaric 3-anhydride. (3.28g, 19.3mmol) and Toluene (100ml, 30.5vol) at -75 ° C. Sandstone was stirred for 21 hours. The solution was concentrated until drying e.g. The resulting residue was dissolved in diethyl ether (125 ml). The solution was washed with 1N HCl (40ml χ 3), and the aqueous layer was extracted again with ether.

The combined organic layers were evaporated to dryness to yield 3.56g of a yellow S-hemiester ((S) -3 - {(methoxycarbonyl) methyl) -5-methylhexanoic acid) yellow oil (90% optical purity, yield - 91%) Example 6: Asymmetrical ring opening of chiral IBG-comalcaloid anhydride

Methanol (6.2 ml, 153 mmol) was added to a 250 ml three-necked round bottom flask equipped with a magnetic stirrer and loaded with quinidine (7.14 g, 22 mmol), isobutylglutaric 3-anhydride (3.28 g, 19.3mmol) and Toluene (100ml, 30.5 vol) at -50 ° C. The reaction was stirred for two hours. The paste was washed with H2SO4-2N (40ml χ 3). The organic layer was evaporated to dryness to yield 3.7 g of yellowish S-Hemiester oil (90% yield - 95% optical purity).

Example 7: Asymmetric ring opening of chiral comalcaloid anhydride IBG-anhydride

Methanol (6.2 ml, 153 mmol) was added to a 250 ml three-necked round bottom flask equipped with a magnetic stirrer and loaded with quinidine (12.5g, 38.6 mmol), isobutylglutaric 3-anhydride (3 28 g, 19.3 mmol) and Toluene (100 ml, 30.5 vol) at -78 ° C. The reaction was stirred 22.5 hours. The paste was washed with HCl-2N (40 mL χ3). The organic layer was evaporated to dryness to yield 3.63 g of yellowish S-Hemiester oil (90% pureza-93% yield).

Example 8: Asymmetric ring opening of chiral comalcaloid anhydride IBG-anhydride

0; methanol (6.2 ml, 153 mmol) was added to a 250 ml three-necked round bottom flask equipped with a magnetic stirrer and loaded with quinidine (7.14 g, 22 mmol), isobutylglutaric 3-anhydride (3, 28 g, 19.3 mmol) and Toluene (33 mL, 30.5 vol) at -78 ° C. The reaction was stirred for 19 hours. The solution was washed with 1N HCl (25ml χ 3). The organic layer was evaporated to dryness to yield 3.38 g of yellowish S-Hemiester oil (90% purity -87% yield).

Example 9: Asymmetric ring opening of chiral comalcaloid anhydride IBG-anhydride

Methanol (6.2 ml, 153 mmol) was added to a 250 ml three-necked round bottom flask equipped with a magnetic stirrer and loaded with quinidine (7.14 g, 22 mmol), isobutylglutaric 3-anhydride (3.28 g, 19.3mmol) and Toluene (100 ml, 30 vol) a The reaction was stirred for two hours. The paste was washed with H2SO4-2N (40ml χ 3). The organic layer was evaporated to dryness to yield 3.4g of yellowish S-Hemiester oil (95% purity -93% yield).

Example 10: Asymmetric ring opening of chiral alkaloid IBG-anhydrid with

To a stirred suspension of 3-anhydridoisobutylglutaric acid (88 mmol) and Quinidine (100 mmol) in Toluene (30 vol). at -50 ° C, methanol (273 mmol) was added dropwise. · The reaction was stirred at -50 ° C for 17 hours.

H. The solution was washed with H2SO4-2N. The organic layer was evaporated to dryness to obtain S-Hemiester. (Purity - 94%, production - 94%).

Example 11: Asymmetric ring opening of chiral alkaloid IBG-anhydrid with

To a stirred suspension of 3-anhydridoisobutylglutaric acid (19.3 mmol) and Quinidine (22 mmol) in Toluene (20 vol) at -50 ° C, Methanol (59.8 mmol) was added. drops. The mixture was stirred at -50 ° C for 17 hours. The solution was washed with H2SO4-2N. The organic layer was evaporated to dryness to obtain S-Hemiester. (Purity.-95%, Yield - 89%.) Example 12: Asymmetric ring opening of chiral alkaloid IBG-anhydrid

To a stirred suspension of 3-anhydridoisobutylglutaric acid (19.3 mmol) and Quinidine (22 mmol) in Toluene (10 vol) at -50 ° C, Methanol (59.8 mmol) was dropwise added. The mixture was stirred at -50 ° C for 4 hours. The solution was washed with H2SO4-2N. The organic layer was evaporated to dryness to obtain S-Hemiester. (Purity - 94%, production - 92%).

Example 13: Asymmetric ring opening of chiral alkaloid IBG-anhydrid with

To a stirred suspension of 3-anhydridoisobutylglutaric acid (19.3 mmol) and Quinidine (22 mmol) in Toluene (30 vol) at -50 ° C, Methanol (193 mmol) was dropwise added. The mixture was stirred at -50 ° C for 16 hours. The solution was washed with H2SO4-2N. The organic layer was. evaporated to dryness to obtain S-Hemiester. (Purity -95%, yield - 83%).

Example 14: Asymmetric ring opening of chiral alkaloid IBG-anhydrid with

To a stirred suspension of 3-anhydridoisobutylglutaric acid (19.3 mmol) and Quinidine (22 mmol) in Toluene (10 vol) at -50 ° C, Methanol (59.8 mmol) was dropwise added. The mixture was stirred at -50 ° C for 22 hours. The solution was washed with H2SO4-2N. The organic layer was evaporated to dryness to obtain S-Hemiester. (Purity -91%, yield - 92%).

Example 15: Opening of asymmetric ring of IBG-chiral alkaloid anhydrid

To a stirred suspension of 3-anhydridoisobutylglutaric acid (270 mmol) and Quinidine (308 mmol) in Toluene (10 vol) at -50 ° C, Methanol (837 mmol) was added dropwise. The mixture was stirred at -50 ° C for 3 hours. The solution was washed with H2SO4-2N. The organic layer was. evaporated to dryness to obtain S-Hemiester. (Purity -95%, yield - 84%).

Example 16: Asymmetric ring opening of chiral alkaloid IBG-anhydrid with

To a stirred suspension of 3-anhydridoisobutylglutaric acid (19.3 mmol) and Cinchonine (22 mmol) in Toluene (30 vol) at -50 ° C, methanol (59.8 mmol) was dropwise added. The mixture was stirred at -50 ° C for 15 hours. The solution was washed with H2SO4-2N. The organic layer was evaporated to dryness to obtain S-Hemiester. (Purity -78%, yield 99%).

Example 17: Asymmetric ring opening of IBG-ano.dridoc with chiral alkaloid

To a stirred suspension of 3-anhydridoisobutylglutaric acid (19.3 mmol) and Cinchonidine (22 mmol) in Toluene (30 vol) at -50 ° C, methanol (59.8 mmol) was added dropwise. The mixture was stirred at -50 ° C for -15 hours. The solution was washed with H2SO4-2N. The organic layer was evaporated to dryness to obtain R-Hemiester. (Purity -68%, yield - 100%).

Example 18: Asymmetric ring opening of chiral alkaloid IBG-anhydrid with

To a stirred suspension of 3-anhydridoisobutylglutaric acid (19.3 mmol) and Cinchonine (22 mmol) in Toluene (30 vol) at -78 ° C, methanol (59.8 mmol) was dropwise added. The mixture was stirred at -50 ° C for 19 hours. The solution was washed with H2SO4-2N. The organic layer was evaporated to dryness to obtain S-Hemiester. (Purity -74%, yield - 90%).

Example 19: Asymmetric ring opening of chiral alkaloid IBG-anhydrid with

Methanol (6.2 mL, 153 mmol) was added dropwise to a 250 mL three-necked round neck flask equipped with a magnetic stirrer and loaded with Quinine (7.14 g, 22 mmol), isobutylglutaric 3-anhydride (3.28 g, 19.3 mmol) and Toluene (100 mL, 30 vol) at -70 ° C. The reaction was stirred 17 hours. The solution was concentrated to dryness and the resulting residue was dissolved in diethyl ether (125ml). The solution was washed with 1N HCl (40 mL χ 3). The organic layer was evaporated to dryness to yield 3.7 g of yellowish R-Hemiester oil (80% yield - 95% optical purity).

Amidation

Example 20:

A three-necked flask (0.25 l) is charged with aqueous NH 3 (40 ml) and S-Me hemiester (4 g). The mixture is heated at 80 ° C under pressure (5 Atm) for six hours. The solution is cooled to room temperature, and the HCL is added to a pH of 1. The mixture is cooled to 0 ° C, the R-CMH is filtered and dried at 55 ° C under vacuum.

Example 21:

A 50 ml three-neck flask was charged with 22% aqueous NH 3 (25 ml, 8 vol) and S-CMH-methyl ester (MS-1750, 3.16 g). The solution was stirred at room temperature for 92 hours. 37% HCl was added to achieve a pH of 3. The white paste was cooled to 0 ° C, the R-CMH was filtered and dried at 550 ° C under vacuum for 14 hours to obtain 3.65g of white powdered R-CMH. (Optical purity 90%, production - 100%).

Example 22:

An autoclave was charged with 22% aqueous NH 3 (25ml, 12.5 vol.) And S-CMH-methyl ester (MS-1848, 2 g). The solution was stirred at 75 ° C at 2 Atm for 7 hours. 37% HCl was added to obtain a pH of 3.0 Ethyl acetate (200 mL) was added to the white paste, and the precipitate remained in the aqueous phase. Water (20 ml) was added to obtain clear solutions (two phases). The two phases were separated after vigorous stirring for 10 minutes. The organic phase was evaporated to dryness to yield 1.62 g of R-CMH. (Optical purity 80%, yield - 80%).

Example 23:

A 100 ml three-neck flask was charged with 22% aqueous NH 3 (25 ml, 8 vol) and S-CMH-methyl ester (GE-11426, 2 g). The solution was stirred at -40 ° C for 25 hours. 37% HCl was added to obtain a pH = 3. The white paste was vacuum filtered and the filter cake was washed with water (5 ml). The white precipitate was dried at 55 ° C under vacuum for 17 hours to obtain 2.45 g of white, white R7CMH. (Optical purity 87%, yield - 100%).

Example 2.4.

An autoclave (Ò, 1L) was charged with aqueous NH 3 (25ml) and S-Methyl ester (2g). The mixture was heated at 70 ° C under pressure (1.5 bar) for 8 hours. The solution was cooled to room temperature, and 37% HCl was added to obtain p-pH. 3. NH 4 Cl (1.8g) was added to induce precipitation of R-CMH. Precipitated R-CMH was filtered off and dried at 55 ° C under vacuum. (Optical purity. -84%, yield - 60%).

Example 25:

An autoclave (0.1L) was charged with aqueous NH 3 (60ml) and S-Methyl ester (10g). The mixture was heated at 70 ° C under pressure (1.5 bar) for 25 hours. The solution was cooled to room temperature, and 37% HCl was added to obtain pH 3. .NH4Cl (1.8 g) was added to induce precipitation of R-CMH. Precipitated R-CMH was filtered off and dried at 55 ° C under vacuum. (Production - 100%).

Example 26:

A solution of S-methyl ester (20 mmol, GE-1381) emtoluene (10 vol) was extracted with 30% NH 4 OH (2.6 vol χ 2) and stirred at room temperature. environment as clear solution for 16 hours. 30% NH 4 OH (5.2 vol) was added to the solution and stirred at room temperature for 72 hours. The solution was acidified to pH 3 with 75% H 2 SO 4 and evaporated to dryness. The residue was triturated in acetone (20 vol), solids were filtered, and acetone evaporated to dryness. The resulting residue was mixed in water (20 vol) for 17 hours. The precipitate was filtered under vacuum dried in a vacuum oven at 55 ° C for 20 hours.

Example 27:

A one-necked flask (0.1 L) was charged with aqueous NH 3 (18 mL), S-ester (3 g) and ammonium chloride (0.8 g, 1 eg). The solution was heated to 40 ° C and stirred at this temperature for 24 hours and at room temperature for 18.5 hours. The solution was evaporated to dryness. The distilled water (15 vol) was added and the HCl was increased to pH 4. The mixture was stirred overnight; R-CMH was filtered off and dried at 55 ° C under vacuum.

Example 28: Synthesis of R-CMH by "one-pot"

To a stirred suspension of 3-anhydridoisobutylglutaric acid (118 mmol) is Quinidine (134 mmol) in Toluene (10 vol) at -50 ° C, Methanol (365 mmol) has been added dropwise. The reaction was stirred at -50 ° C for 17 hours. The solution was washed with H2SO4-2N. The organic layer was filtered and extracted into 25% NH 4 OH (aq.) (10 vol). The aqueous solution was stirred in a closed flask at 40 ° C for 24 hours and at room temperature for 48 hours. 37% HCl was added to obtain pH 3. The slurry was stirred for 20 hours at room temperature and cooled to 5 ° C. The R-CMH was filtered off and dried at 55 ° C under vacuum.

Example 29: Preparation of (S) -methyl 3- (carbamoylmethyl) -5-methylhexanoate

The round base flask is equipped with a magnetic stirrer and charged with methylene dichloride (100 ml), (S) -3- ((methoxycarbonyl) methyl) -4'-methylhexanoic acid (20 g) and triethylamine (0.77 g ) and cooled to 0-5 ° C followed by the addition of ethyl chloroformate (9 g). The mixture was stirred for 1-2 hours at a temperature of 20 ° C to 25 ° C, followed by quenching with 25% aqueous ammonia (100 mL). The paste is filtered and washed with water and dried to obtain a (R) -methyl 3- (carbamoylmethyl) -5-methylhexanoate solid.

Example 30: Preparation of (R) - (+) - 3- (carbamoylmethyl) -5-acidomethylhexanoic acid (R-CMH)

A flask equipped with a magnetic stirrer is charged with 3N HCl (100 ml) and (R) methyl 3- (carbamoylmethyl) -5-methylhexanoate (20 g). The mixture is stirred for 1-10 hours at 20 ° C to 25 ° C, followed by quenching with 47% NaOH at pH 3. The paste is filtered, washed with water and dried to obtain a white solid of (R) - 3- (carbamoylmethyl) -5-methylhexanoic acid.

Example 31: Conversion of (R) -CMH to (S) -Pregabalin: Example 12 of US Publication No. 20.07 / 0073085

A reactor (0.5 L) was charged with water (165 mL) and NaOH (35.5 g) to obtain a solution. The solution was cooled to 15 ° C, and (R) -CMH (33 g) was added. OBr2 (28.51 g) was added dropwise (15 min) while maintaining the temperature below 25 ° C. The mixture was heated at 60 ° C for 15 minutes and cooled to 15 ° C. Iso-butanol (100 ml) was added and then a solution of H 2 SO 4 (66%) (33 ml) was added. The phases were separated, and the aqueous phase was extracted with isobutanol (83 ml). To the combined organic phases, BU3N (34.2 g) was added, and the mixture was cooled to 2 ° C and stirred for 2 hours. The solid was filtered, washed and dried at 55Â ° C under vacuum, providing (S) -PREGABALIN total purity 99.86% area by HPLC. Example 32: Conversion of (R) -CMH sodium salt to (S) - Pregabalin:

A reactor is charged with water and NaOH to obtain a solution. The solution is cooled to approximately 15 ° C and sodium (R) -CMH salt is added. Br2 is added to the reactor for a period of approximately 15 minutes while the temperature is kept below 25 ° C. The resulting mixture is heated to approximately 60 ° C for approximately 15 minutes and then cooled to approximately 15 ° C. Iso-butanol is added, and then a solution of H2SO4 (66%) is added to form a mixture of two. phases. The two phases are separated, and the aqueous phase is extracted with iso-butanol. The combined organic phases are added to the Bu3N, and the mixture is cooled to approximately 20 ° C and stirred for approximately two hours. The resulting solid is filtered, washed and dried at 550 ° C under vacuum. to provide (S) -pregabalin.

Claims (81)

1. A process for the preparation (carbamoylmethyl) -5-methylhexanoic acid or its salt of formula <formula> formula see original document page 34 </formula> characterized in that: a) asymmetrically "ring-opening isobutylglutaric anhydride" obtain a chiral ester of the formula: <formula> formula see original document page 34 </formula> b) chiral ester amidation to obtain a (R) - (+) - 3- (carbamoylmethyl) -5-acid salt formula < formula> formula see original document page 34 </formula> and optionally (c) (R) - (+) - 3- (carbamoylmethyl) -5-methylhexanoic acid conversion to (R) - (+) - 3- (carbamoylmethyl) -5-acidomethylhexanoic acid, wherein R1 and R2 are independently selected from the group consisting of: H, C1 to C12 aliphatic, branched or cyclic hydrocarbyl, C6 to Cg aromatic hydrocarbyl and a) 3-anhydride combination isobutylglutaric, a chiral alcohol, a solvent selected from the group consisting of C6-10 aromatic hydrocarbons, C3-5 ketones, C2-5 ethers, C2-7 ester es, C1-2 halogenated hydrocarbons and C1-4 nitriles and a base to obtain a chiral ester of formula <formula> formula see original document page 35 </formula> (b) mixture with ammonia to obtain a salt of (R) - (+) -3- (carbamoylmethyl) -5-methylhexanoic acid of the formula <formula> formula see original document page 35 </formula> and optionally c) adding an acid to obtain R - (+) - 3- ( carbamoylmethyl) -5-methylhexanoic acid, wherein R 1 and R 2 are independently selected from the group consisting of H, C 1-12 aliphatic, branched or cyclic hydrocarbons, C 6 -g aromatic hydrocarbons and CO 2 H; and M is H or NH4 +. 2. [Claim missing on original document] 3. [Claim missing on original document] 4. [Claim missing on original document] 5. [Claim missing on original document] 6. [Claim missing on original document] 7. [Claim missing on original document] The process of claim 7, characterized in that the bases are selected from the group consisting of sodium butyl lithium hydride. The process of claim 7 or 8, characterized in that the chiral alcohol is selected from the group consisting of (S) -fenchyl alcohol, (S) -mandelic acid, benzylmandelate, ethylmandelate, methylmandelate, 1-phenylethanol, 1-phenyl-2- propanol, 1-phenyl-1-propanol and trifluoromethyl benzyl alcohol. The process of any one of claims 7 to 9, characterized in that the chiral alcohol is (S) -alcoolfenchylic or (S)-mandelic acid. The process of any one of claims 7 to 10, characterized in that the solvent is selected from the group consisting of aromatic hydrocarbons, C 3-4 ketones, C ethers, C 2-5 esters, C 1-4 halogenated hydrocarbons and C 1-2 nitriles. The process of any one of claims 7 to 11, characterized in that the solvent is selected from the group consisting of toluene, acetone, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, dichloromethane and acetonitrile. The process of any one of claims 7 to 12, wherein the solvent and chiral alcohol are combined to form a mixture, and the base of the 3-anhydridoisobutylglutaryr. are added to the mix in sequence. The process of claim 13, characterized in that it is added to the mixture at a temperature of from about -780 ° C to approximately 100 ° C. The process of any one of claims 7 to 14, characterized in that the combination of step a) is maintained at a temperature of from about 0 ° C to about -50 ° C to obtain the chiral ester. The process of any one of claims 7 to 14, characterized in that the chiral ester is crystallized prior to mixing with ammonia. The process of claim 16, characterized in that the chiral ester is crystallized from. a solvent selected from the group consisting of C10-10 aromatic hydrocarbons, C3-5 ketones, C2-5 ethers, C2-10 esters, C1-2 halogenated hydrocarbons, C1-4 nitriles and mixtures thereof; The process of claim 16 or 17, characterized in that the chiral ester is crystallized from a mixture of toluene and ethyl acetate. The process of any one of claims 7 to 18, characterized in that the ammonia is provided in the form of a solution. The process of claim 19, wherein the ammonia is in solution in a solvent selected from the group consisting of water, an organic solvent or mixtures of water and organic solvent. The process of claim 19 or 20, characterized in that the ammonia solution is provided by any of the following methods: a) bubbling of the solvent of ammonia gas; b) adding ammonium chloride to the mixture obtained in step b); or c) a combination of a) and b). The process of any one of claims 7 to 21, characterized in that the mixture of step b) is maintained at a temperature of from about -40 ° C to about-110 ° C to obtain the salt of (R) - (+ *). ) -, - 3- (carbamoylmethyl) -5-methylhexanoic acid. The process of any one of claims 7 to 22, characterized in that the mixture of step b) is maintained at a pressure of approximately 1 to approximately 6 atmospheres to obtain the (R) - (+) - 3- (carbamoylmethyl) - 5-methylhexanoic acid. The process of any one of claims 7 to 23, characterized in that the acid is selected from the group consisting of HCl, HBr> H2SO4, H3PO4, acetic acid and formic acid. The process of any one of claims 7 to 24, characterized in that the acid is present in an amount sufficient to obtain a pH of approximately O to approximately 5. The process of any one of claims 7 to 25, characterized in that step c) further comprises cooling to a temperature of approximately 10 ° C to 27. [Claim missing on original document] 28. [Claim missing on original document] 29. [Claim missing on original document] 30. [Claim missing on original document] 31. [Claim missing on original document] 32. [Claim missing on original document] 33. [Claim missing on original document] 34. [Claim missing on original document] 35. [Claim missing on original document] 36. [Claim missing on original document] The process of any one of claims 28 to 36, wherein the non-chiral alcohol is added to a suspension of isobutylglutaric 3-anhydride, chiral solvent amine. The process of claim 37, wherein the non-chiral alcohol is added to the suspension at a temperature of from about 20 ° C to about -78 ° C. The process of any one of claims 28 to 38, characterized by the chiral ester. be crystallized before mixing with ammonia. The process of claim 39, wherein the chiral ester is crystallized from a solvent selected from the group consisting of C6-10 aromatic hydrocarbons, C3-5 ketones, C2-5 ethers, C2-7 esters, C1-2halogenated hydrocarbons, C1-4 nitriles and their mixtures. 41. The process of claim 39 or 40, characterized in that the chiral ester is crystallized from a solvent that is a mixture of toluene and ethyl acetate. 42. The process of claim 40 or 41, characterized in that the crystallization consists in the combination of solvent and chiral ester; heating the combination to a temperature of about 40 ° C to about 150 ° C to form a solution; and cooling the solution to a temperature of approximately 30 ° C a. approximately 0 ° C to precipitate the chiral ester. The process of any one of claims 28 to 42, characterized in that the ammonia is provided in the form of a solution. The process of claim 43, characterized in that the ammonia is in solution in a solvent selected from the group consisting of water, an organic solvent or mixtures thereof of water is an organic solvent. The process of claim 44, wherein the ammonia solution is provided by any of the following methods: a) bubbling of the solvent of ammonia gas; b) adding ammonium chloride to the mixture obtained in step b); or c) a combination of a) and b). The process of any one of claims 28 to 45, characterized in that the mixture of step b) is maintained at a temperature of from about -40 ° C to about 10 ° C to obtain the salt of (R) - (+) - 3- ( carbamoylmethyl) -5-methylhexanoic acid. The process of any one of claims 28 to 46, characterized in that the mixture of step b) is maintained at a pressure of approximately 1 to approximately 6 atmospheres to obtain the (R) - (+) - 3- (carbamoylmethyl) salt. 5-methylhexanoic acid. The process of any one of claims 28 to 47, wherein the acid is selected from the group consisting of. HCl. HBr, H2SO4, H3PO4, acetic acid and formic acid. The process of any one of claims 28 to 48, characterized in that the acid is present in a sufficient amount to obtain a pH of from about 0 to about 5. The process of any one of claims 28 to 49, characterized in that step c) further comprises cooling to a temperature of approximately 10 ° C to about -5 ° C to precipitate R - (+) - 3- (carbamoylmethyl) -5. -methylhexanoic acid. A process for the preparation of (S) -Working characterized by: a) preparing R - (+) - 3- (carbamoylmethyl) -5-acidomethylhexanoic acid or its salt by the process of any one of claims 28 to 50. ; and b) conversion of R- (+) -3- (carbamoylmethyl) -5-acidomethylhexanoic acid or its salt to (S) -pregabalin. 52. A process for the preparation of R- (+) -3- (carbamoylmethyl) -5-methylhexanoic acid or its salt of formula <formula> formula see original document page 40 </formula> characterized by: a) combination of a chiral ester of the formula with an acid activating agent and a base to obtain an activated acid derivative of the formula) amidation of the activated acid derivative to obtain a carbamoyl ester of the formula <formula> formula see original document page 41 </ formula c) hydrolysing carbamoyl ester with an acid or base to give R- (+) -3- (carbamoylmethyl) -5-methylhexanoic acid or its salt, and optionally c) converting the (R) salt - (+} - 3- (carbamoylmethyl) -5-methylhexanoic acid in (R) - (+) - 3- (carbamoylmethyl) -5-acidomethylhexanoic acid, wherein R1 and R2 are independently selected from the group consisting of: H, C1-I2 aliphatic, branched or cyclic hydrocarbons, C6-9 aromatic hydrocarbons and -CO2H-, and LG is the leaving group, wherein the leaving group is derived from the acid activating agent, wherein X is an alkali metal. The process of claim 52, wherein the aromatic C6-9 hydrocarbon is benzyl, the aliphatic or branched Cw2 hydrocarbon is methyl, and the hydrocarbonetocyclic Cw2 is 1,3,3-trimethylbicyclo [2.2.1] heptane. The process of claim 52 or 53, characterized in that the combinations of R1 and R2 are CO2H and benzyl, He H, HeMe, H and benzyl respectively or R1 and R2 together form '-1,3,3-trimethylbicyclo [2.2.1 ]heptane. The process of any one of claims 52 to 54, wherein the chiral ester is prepared by: a) combining isobutylglutaric 3-anhydride, a chiral alcohol, a solvent selected from the group consisting of C6-10 aromatic hydrocarbons, 5 ketones, C2-S ethers, C2-7 esters, C2 halogenated hydrocarbons and C1-4 nitriles and an inorganic base; or b) a combination of isobutylglutaric 3-anhydride, a non-chiral alcohol, a chiral amine and a selected solvent from the group consisting of C6-10 aromatic hydrocarbons, C2-5 ethers, C1-2 halogenated hydrocarbons and their mixtures. The process of claim 55 or 8, characterized in that the chiral alcohol is selected from the group consisting of (S) -phenyl alcohol, (S)-mandelic acid, benzylmandelate, ethylmandelate, methylmandelate, 1-phenylethanol, 1-phenyl-2- propanol, 1-phenyl-1-proparlol, trifluoromethyl-benzyl. alcohol. The processes of claim 55 or 56, wherein the chiral alcohol is (R) -phenyl alcohol or (R) -mandelic acid. The process of any one of claims 55 to 57, characterized in that the chiral amine is an alkaloid alkali. The process of claim 58, wherein the chiral alkaloid is a cinchona alkaloid. The process of claim 59, wherein the cinchone alkaloid is selected from the group consisting of quinine, cinchonidine and their dehydroderivatives. The process of claim 59 or 60, characterized in that the cinchone alkaloid is quinine. The process of any one of claims 52 to 61, characterized in that the base of step a) is an aliphatic amine, an alkaline hydroxide, an alkaline carbonate or an alkaline bicarbonate. The process of any one of claims 52 to 62, wherein the base of step a) is ethyl amine, diethyl amine, propyl amine, dipropyl amine, butyl amine, tributylamine, diisopropyl amine, triethylamine, sodium hydroxide, potassium, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. The process of any one of claims 52 to 63, characterized in that the chiral ester, the acid activating agent and the base are combined in the presence of a selected solvent from a group consisting of aromatic C6-10 hydrocarbons, C3-5 ketones, C2 -5 ethers, C 2-7 esters, C 1-2 halogenated hydrocarbons, C 1-4 nitriles and their mixtures. The process of claim 64, wherein the solvent is selected from the group consisting of aromatic C6-hydrocarbons, C3-4 ketones, C4-5 ethers, C2-esters, halogenated hydrocarbons and C1-2 nitriles. The process of claim 64 or 65, wherein the solvent is selected from the group consisting of toluene, acetone, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, dichloromethane and acetonitrile. 67. The process of any one of claims 64 to 66, wherein the solvent is combined with the ester and base to obtain a mixture and the acid-activating agent is added to the mixture. The process of claim 67, wherein the solvent, acid and base mixture is cooled to a temperature of from about 20 ° C to about -5 ° C prior to the addition of the acid activating agent. The process of claim 68, wherein, upon addition of the acid activating agent, the mixture is heated to a temperature of from about 10 ° C to about 50 ° C. The process of any one of claims 52 to 69, characterized by the selected acid activating agent of the group consisting of alkyl haloformats, anhydrides and sulfonyl halides. The process of any one of claims 52 to 70, characterized in that the acid activating agent is ethylchloroformate, methyl chloroformate, acetic anhydride, mesylchloride or tosyl chloride. The process of any one of claims 52 to 71, wherein R 1 and R 2 are. H and LG is OCO2Et. The process of any one of claims 52 to 72, characterized in that the activated acid derivative is amidated by mixing with ammonia. The process of claim 73, characterized in that the ammonia is provided in the form of a solution. 75. The process of claim 74, wherein the ammonia is in solution in a solvent selected from the group consisting of water, an organic solvent or mixtures of water and organic solvent. The process of claim 74 or 75, characterized in that the ammonia solution is provided by any of the following methods: a) bubbling of ammonia gas; b) adding ammonium chloride to the mixture obtained in step b); or c) a combination of a) and b) bubbling of ammonia in the solvent or adding ammonium chloride to the mixture obtained in step b). The process of any one of claims 52 to 76, characterized in that the acid is selected from the group consisting of HCl, HBr, H2SO4, H3PO4, acetic acid and formic acid. The process of any one of claims 52 to 77, wherein the base of step c) is an inorganic base. The process of claim 78, wherein the inorganic base is selected from the group consisting of NaOH, KOH and LiOH. The process of any one of claims 52 to 79, characterized in that step c) further comprises agitation at a temperature of about 10 ° C to about 50 ° C. 81. A process for the preparation of (S) -Purabale characterized by: a) preparation of R - (+) - 3- (carbamoylmethyl) -5-acidomethylhexanoic acid or its salt by the process of any one of claims 52 to 80; and b) conversion of R - (+) - 3- (carbamoylmethyl) -5-acidomethylhexanoic acid or its salt to (S) -pregabalin.