2-oxo-1-pyrrolidine derivatives, process for preparing them and their uses

#The invention concerns 2-oxo-1-pyrrolidine derivatives and a process for preparing them and their uses. The invention also concerns a process for preparing α-ethyl-2-oxo-1-pyrrolidine acetamide derivatives from unsaturated 2-oxo-1-pyrrolidine derivatives.

#Particularly the invention concerns novel intermediates and their use in methods for the preparation of (S)-(−)-α-ethyl-2-oxo-1-pyrrolidine acetamide, which is referred under the International Nonproprietary Name of Levetiracetam, its dextrorotatory enantiomer and related compounds. Levetiracetam is shown as having the following structure:

#Levetiracetam, a laevorotary compound is disclosed as a protective agent for the treatment and the prevention of hypoxic and ischemic type aggressions of the central nervous system in the European patent No. 162036. This compound is also effective in the treatment of epilepsy, a therapeutic indication for which it has been demonstrated that its dextrorotatory enantiomer (R)-(+)-α-ethyl-2-oxo-1-pyrrolidine acetamide completely lacks activity (A. J. GOWER et al., Eur. J. Pharmacol., 222, (1992), 193-203). Finally, in the European patent application No. 0 645 139 this compound has been disclosed for its axiolytic activity.

#The preparation of precursor Al was carried out in 70% crude yield by reacting α-ketobutyric acid and pyrrolidinone in refluxing toluene, see Scheme 7. By Z:E, we mean the ratio of Z isomer amount on E isomer amount.

#The crude product was recrystallised from acetone in 70% yield. The geometry of the double bond was assigned to be Z on the basis of correlation with the 1H-NMR (Nuclear Magnetic Resonance) spectral data for known compounds with similar structure.

#Precursor A2 was prepared from Al with diazomethane in THF. It was observed that the Z-E ratio changes from 80:1 to 29:1 during distillation (see Scheme 8).