Process for preparation of pregabalin and novel intermediates.

Abstract

The invention relates to novel pyrrolidinone derivs. I [R1, R2, R3 are independently H, alkyl, cycloalkyl, aryl, heteroaryl, optionally substituted], which are esp. useful as intermediates for the prepn. of pregabalin. Pyrrolidinones I were prepd. by hydrogenating the corresponding pyrrolinones, which are obtained by cyclizing amides i-BuCH(CHCl2)CH2CONHCR1R2R3. The amides were prepd. by reacting 2,2-dichloro-3-isobutylcyclobutanone with primary amine H2NCR1R2R3. Thus, intermediate 4-isobutyl-1-[(1R)-phenylethyl]-2-pyrrolidinone was treated with methanesulfonic acid in toluene for 14 h at reflux to give (4S)-(+)-isobutyl-2-pyrrolidinone, which was dissolved in 6N HCl and heated at reflux for 12 h to yield pregabalin. [on SciFinder(R)]