Patent ID: 8791273
Filing Date: 2014-07-29
Classification: A61K,A61P,C07D

Abstract:
1. A process of preparation of 2-(5S-Methyl-2-oxo-4R-phenyl-pyrrolidin-1-yl)-acetamide of Formula I comprising the following steps: a) addition of 2-nitroprop-1-enylbenzene to diethyl malonate in the presence of complex catalysts consisting of a chiral 2,2′-cyclopropylidene-bis-oxazoline, magnesium triflate and an organic base; b) conversion of diethyl 2-(2-nitro-1R-phenylpropyl)malonate obtained in step a) into enantiomeric 5S-methyl-4R-phenylpyrrolidin-2-one via hydrogenation of diethyl 2-(2-nitro-1R-phenylpropyl)malonate in the presence of Raney Ni at a hydrogen pressure between 3 and 60 atm to obtain a diastereoisomeric mixture of ethyl 5-methyl-2-oxo-4(R)-phenylpyrrolidin-3(S)-carboxylate, resolution of the diastereoisomeric mixture of ethyl 5-methyl-2-oxo-4(R)-phenylpyrrolidin-3(S)-carboxylate thus obtained into separate 5S,4R- and 5R,4-enantiomers, and decarboxylation of ethyl 5(S)-methyl-2-oxo-4(R)-phenylpyrrolidin-3(S)-carboxylate; c) substitution of hydrogen in the amide group of 5S-methyl-4R-phenylpyrrolidin-2-one obtained in step b) with sodium on in a suitable organic solvent; d) alkylation of N-metalated 5S-methyl-4R-phenylpyrrolidin-2-one obtained in step c) with a haloacetic acid ester in a suitable organic solvent; and e) amidation of ethyl 2-(5S-methyl-2-oxo-4R-phenyl-pyrrolidin-1-yl)-acetate obtained in step d) with ammonia in a suitable solvent.