(2R)-2-(2-oxopyrrolidin-1-yl)butanoic acid

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (35 g, 0.20 mol) in methylene chloride (225 ml) was cooled to 0° C. and triethylamine (41 g, 0.40 mol) and methanesulfonyl chloride (29 g, 0.26 mol) were added dropwise. The mixture was stirred at 0° C. for 30 min., then a stream of ammonia was purged in the solution at 0° C. for 2 hours. The insoluble solids were filtered and the filtrate was concentrated. The product was recrystallized from methyl isobutyl ketone to give 27.5 g (78%) of (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. a stream of ammonia was purged in the solution at 0° C. for 2 hours The insoluble solids were filtered the filtrate was concentrated The product was recrystallized from methyl isobutyl ketone

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The enantioselective synthesis of both the (S)— and (R) enantiomers of 1 were disclosed in the U.S. Pat. No. 4,696,942 and U.S. Pat. No. 4,696,943 by the following processes respectively: a) optical resolution of alpha-ethyl-2-oxo-1-pyrrolidineacetic acid, activation of the chiral alpha-ethyl-2-oxo-1-pyrrolidineacetic acid with an alkylhaloformate and subsequent reaction with ammonia; b) cyclizing the chiral S or R amino-butanamide. In the former process, although optical resolution of racemic alpha-ethyl-2-oxo-1-pyrrolidineacetic acid gave (S) or (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid with satisfactory optical purity, this resolution provides less than 50% yield of the desired enantiomer, with the remaining (more than 50%) isomer mixture being discarded as a waste. Also, the amide formation step has to be performed at a very low temperature, normally between −30 to −40° C. to prevent epimerization, which is not convenient for large scale preparation. The latter process presents a drawback with the fact that the required enantiomeric precursors, (S)— and (R)-4-[[1-aminocarbonyl)propyl]amino]butyrate or (S)— and (R)—N-[1-(aminocarbonyl)propyl]4-halobutanamide, for the cyclization are not readily available.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (35 g, 0.20 mol) in methylene chloride (225 ml) was cooled to 0° C. and triethylamine (41 g, 0.40 mol) and methanesulfonyl chloride (29 g, 0.26 mol) were added dropwise. The mixture was stirred at 0° C. for 30 min., then a stream of ammonia was purged in the solution at 0° C. for 2 hours. The insoluble solids were filtered and the filtrate was concentrated. The product was recrystallized from methyl isobutyl ketone to give 27.5 g (78%) of (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. a stream of ammonia was purged in the solution at 0° C. for 2 hours The insoluble solids were filtered the filtrate was concentrated The product was recrystallized from methyl isobutyl ketone

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The enantioselective synthesis of both the (S)— and (R) enantiomers of 1 were disclosed in the U.S. Pat. No. 4,696,942 and U.S. Pat. No. 4,696,943 by the following processes respectively: a) optical resolution of alpha-ethyl-2-oxo-1-pyrrolidineacetic acid, activation of the chiral alpha-ethyl-2-oxo-1-pyrrolidineacetic acid with an alkylhaloformate and subsequent reaction with ammonia; b) cyclizing the chiral S or R amino-butanamide. In the former process, although optical resolution of racemic alpha-ethyl-2-oxo-1-pyrrolidineacetic acid gave (S) or (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid with satisfactory optical purity, this resolution provides less than 50% yield of the desired enantiomer, with the remaining (more than 50%) isomer mixture being discarded as a waste. Also, the amide formation step has to be performed at a very low temperature, normally between −30 to −40° C. to prevent epimerization, which is not convenient for large scale preparation. The latter process presents a drawback with the fact that the required enantiomeric precursors, (S)— and (R)-4-[[1-aminocarbonyl)propyl]amino]butyrate or (S)— and (R)—N-[1-(aminocarbonyl)propyl]4-halobutanamide, for the cyclization are not readily available.