Chiral 3-carbamoylmethyl-5-methyl hexanoic acids, key intermediates for the synthesis of (S)-Pregabalin

A process for the preparation of (S)-Pregabalin, comprising:

• (a) combining a chiral amine of formula 23,
• an organic solvent selected from at least one of aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, esters, alkanes, and ketones, and a base to obtain a mixture;
• (b) cooling the mixture to a temperature of about 10° C. to about −70° C.;
• (c) adding to the mixture 3-isobutyl glutaric anhydride of formula 22;
• to obtain the compound of formula 24;
• (d) recovering the compound of formula 24 from the mixture;
• (e) combining the recovered compound of formula 24, water, an ether, ammonia and an alkali metal, at a temperature of about 10° C. to about −78° C. to obtain a mixture;
• (f) recovering the compound of formula 25 from the mixture;
• (g) combining the recovered compound of formula 25 with bromine, water, and an alkaline hydroxide to obtain a basic mixture;
• (h) heating the basic mixture to a temperature of about 60° C. to about 85° C.;
• (i) adding to the basic mixture a strong mineral acid to obtain an acidic mixture;
• (j) reacting the acidic mixture with a base to obtain (S)-Pregabalin, and
• (l) recovering (S)-Pregabalin;
• wherein Ar is a C6-10 aromatic group selected from the group consisting of naphthyl, phenyl, and substituted phenyl and R is straight or branched C1-4 alkyl, ester or carboxylic acid.

A process for the preparation of (S)-Pregabalin, comprising:

• a) combining a chiral amine of formula 23,
• an organic solvent selected from at least one of aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, esters, alkanes, and ketones, and a base to obtain a mixture;
• b) cooling the mixture to a temperature of about 10° C. to about −70° C.;
• c) adding to the mixture 3-isobutyl glutaric anhydride of formula 22;
• to obtain the compound of formula 24;
• d) recovering the compound of formula 24 from the mixture;
• e) combining the compound of formula 24 with concentrated sulfuric acid to obtain a mixture;
• f) maintaining the mixture at a temperature of about 0° C. to about 50° C., for about 10 hours to about 30 hours;
• g) recovering the compound of formula 25 from the mixture;
• h) combining the recovered compound of formula 25 with bromine, water, and an alkaline hydroxide to obtain a basic mixture;
• i) heating the basic mixture to a temperature of about 60° C. to about 85° C.;
• j) adding to the basic mixture a strong mineral acid to obtain an acidic mixture;
• k) reacting the acidic mixture with a base to obtain (S)-Pregabalin, and
• 1) recovering (S)-Pregabalin;
• wherein Ar is a C6-10 aromatic group selected from the group consisting of naphthyl, phenyl, and substituted phenyl and R is straight or branched C1-4 alkyl, ester or carboxylic acid.