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

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of (R)-alpha-methylbenzylamine (106 g) and triethylamine (89 g) in toluene (100 ml) was added to a suspension of (RS)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (300 g, 1.75 mol) in toluene (1 L). The mixture was heated until complete dissolution, cooled to room temperature and stirred for 3 hours. The solids were filtered and rinsed with toluene (300 ml) to give 250 g of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-alpha-methylbenzylamine salt. The solids were crystallized from toluene and 205 g (yield 41%) of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-alpha-methylbenzylamine salt was obtained. The isolated solid was treated with hydrochloric acid solution and the enantiomerically pure (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid could be isolated in 90% yield. The mixture was heated until complete dissolution The solids were filtered rinsed with toluene (300 ml)

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

Procedure: A solution of (R)-alpha-methylbenzylamine (106 g) and triethylamine (89 g) in toluene (100 ml) was added to a suspension of (RS)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (300 g, 1.75 mol) in toluene (1 L). The mixture was heated until complete dissolution, cooled to room temperature and stirred for 3 hours. The solids were filtered and rinsed with toluene (300 ml) to give 250 g of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-alpha-methylbenzylamine salt. The solids were crystallized from toluene and 205 g (yield 41%) of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-alpha-methylbenzylamine salt was obtained. The isolated solid was treated with hydrochloric acid solution and the enantiomerically pure (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid could be isolated in 90% yield. The mixture was heated until complete dissolution The solids were filtered rinsed with toluene (300 ml)

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:0.00; pressure:0.00; stir:

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

Procedure: A solution of (R)-alpha-methylbenzylamine (106 g) and triethylamine (89 g) in toluene (100 ml) was added to a suspension of (RS)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (300 g, 1.75 mol) in toluene (1 L). The mixture was heated until complete dissolution, cooled to room temperature and stirred for 3 hours. The solids were filtered and rinsed with toluene (300 ml) to give 250 g of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-alpha-methylbenzylamine salt. The solids were crystallized from toluene and 205 g (yield 41%) of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-alpha-methylbenzylamine salt was obtained. The isolated solid was treated with hydrochloric acid solution and the enantiomerically pure (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid could be isolated in 90% yield. The mixture was heated until complete dissolution The solids were filtered rinsed with toluene (300 ml)

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.