METHOD OF PRODUCING (S)-3-AMINOMETHYL-5-METHYLHEXANOIC ACID (PREGABALIN) Russian patent published in 2015 - IPC C07C229/08 C07C227/04 C07C227/34 C07B57/00 

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing (S)-(+)-3-aminomethyl-5-methylhexanoic acid (pregabalin) of formula (I) The method includes steps (a)-(g). Step (a) includes reacting alkyl ether of cyanoacetic acid CNCH₂COOR (A) and isobutyraldehyde to obtain alkyl ether of 2-cyano-4-methylpentanoic acid (B) At step (b) the obtained ether (B) reacts with ethyl ether of alpha-haloacetic acid (Hal=Cl, Br, I) in the presence of a base at 10-90°C in a solvent, such as N,N-dimethyl formamide, tetrahydrofuran, 1,4-dioxane, diemthyl sulphoxide and dimethoxyethane, or without a sovent to form 4-ethyl-1-methyl-2-cyano-2-isobutylsuccinate (C) Step (c) includes hydrolysis of compound (C) under the action of a base, such as an alkali metal hydroxide, at 20-80°C, to obtain 2-cyano-2-isobutylsuccinic acid. Step (d) includes decarboxylation of the obtained 2-cyano-2-isobutylsuccinic acid in the presence of a mineral acid, e.g. sulphuric or hydrochloric acid, in an organic solvent, e.g. ethyl acetate, at 70-80°C to obtain (RS)-3-cyano-5-methylhexanoic acid. Step (e) includes separating enantiomers of the obtained (RS)-3-cyano-5-methylhexanoic acid by forming a corresponding salt with cinchonidine in an organic solvent, such as ethanol, methanol, 1,4-dioxane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane and diethylene glycol dimethyl ether, at 20-80°C, separating the cinchonidine salt of (S)-3-cyano-5-methylhexanoic acid and additional purification thereof by repeated salt formation in ethyl acetate. At step (f) the cinchonidine salt of (S)-3-cyano-5-methylhexanoic acid is treated with a mixture of ethyl acetate and diluted hydrochloric acid (1:1) at room temperature and the (S)-3-cyano-5-methylhexanoic acid (II) formed is separated from the organic layer. Step (g) includes hydrogenation of the separated optically pure (S)-3-cyano-5-methylhexanoic acid (II), which is catalysed by Raney nickel, to form (S)-(+)-3-aminomethyl-5-methylhexanoic acid (pregabalin) (I). The method is characterised by that at step (a) reaction of the alkyl ether of cyanoacetic acid CNCH₂COOR, where R=C₁-C₄-alkyl, with isobutyraldehyde is carried out under the action of carbon monoxide at pressure of 1-200 atm and temperature of 20-200°C in a polar solvent, such as methanol, ethanol, water, 1,4-dioxane, tetrahydrofuran, acetonitrile, dimethoxyethane and diethylene glycol dimethyl ether, and the catalyst used is a cobalt, nickel, ruthenium or rhodium compound; at step (b) the base used is sodium hydride.

EFFECT: method reduces the number of steps when producing an intermediate, reduces the amount of wastes and improves environmental safety.

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