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Process for the Manufacture of Pregabalin

IP.com Disclosure Number: IPCOM000200645D
Publication Date: 2010-Oct-22

Publishing Venue

The IP.com Prior Art Database

Abstract

We provide a process for the manufacture of a compound of formula (I) using an enzyme catalysed reduction of a compound of formula (IIa) or (IIb). Compounds of formula (I) are useful for preparing Pregabalin (III).

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Process for the Manufacture of Pregabalin

ABSTRACT

We provide a process for the manufacture of a compound of formula (I) using an enzyme catalysed reduction of a compound of formula (IIa) or (IIb).   Compounds of formula (I) are useful for preparing Pregabalin (III).

Pregabalin, or (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid,

is the active agent in Lyrica®, which is approved for the treatment of epilepsy, neuropathic pain, fibromyalgia and generalized anxiety disorder.

It will be recognized that 3-aminomethyl-5-methyl-hexanoic acid has a single chiral centre and so exists as two optical isomers.   As indicated above, pregabalin is the (S)-enantiomer, and a key consideration in the commercial manufacture of pregabalin is the strategy by which optically pure material is obtained.

In the process described herein, a b-cyano-a,b-unsaturated ester is reduced in the presence of an enoate reductase enzyme to provide the desired stereocentre.

In a first aspect, we provide a process for preparing a compound of formula (I)

wherein R1 is selected from hydrogen, C1-C12-alkyl, C3-C12 cycloalkyl, aryl-C1-C6-alkyl and aryl, said alkyl, cycloalkyl and aryl being optionally substituted by one or more groups selected from halo, C1-C6-alkoxy and tri(C1-C3-alkyl)silyl,

comprising the steps of:

a) preparing a compound of formula (IIa) or (IIb)

or a mixture thereof, wherein R1 is as defined for the compound of formula (I); and

b) treating the compound of formula (IIa) or (IIb), or the mixture of compounds, with a suitable reducing agent in the presence of an enoate reductase enzyme.

In a preferred embodiment, R1 is selected from C1-C12-alkyl and benzyl.

In a more preferred embodiment, R1 is selected from C1-C4-alkyl.

In a particularly preferred embodiment, R1 is ethyl.

In this first aspect, we provide a two-step process for preparing a compound of formula (I).

The first step comprises the preparation of a compound of formula (IIa) or (IIb), or a mixture thereof.

The compounds of formula (IIa) and (IIb) can be prepared by any suitable method.   It will be understood that some methods will provide for a specific double bond geometry, other methods will provide a high degree of selectivity, and some methods will be non-selective.   Accordingly, depending on the method selected, the compound of formula (IIa) or the compound of formula (IIb) may be obtained as a pure single isomer, a mixture enriched in one component (such as a 90:10, 80:20, 20:80 or 10:90 mixture), or as a 50:50 mixture.   If the method chosen provides a mixture that is unsuitable for use in the second step of the process then the isomers may be separated by conventional techniques.

Examples of methods suitable for the preparation of compounds of formula (IIa) and (IIb) are set out in Schemes 2 to 6.   These methods provide further aspects of the invention.

Scheme 2

a: diethyl carbonate, NaH; b: Tf2O, LiOTf, iPr2NEt; c: Zn(CN)2, Pd(PPh3)4

4-Methyl-2-pentanone may be reacted with a carbona...