(2S)-2-(2-oxopyrrolidin-1-yl)butanamide

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (45 g, 0.26 mol) in methylene chloride (225 ml) was cooled to 0° C. and triethylamine (53 g, 0.53 mol) and methanesulfonyl chloride (39 g, 0.34 mol) were added dropwise. The mixture was stirred at 0° C. for 30 min., then a stream of ammonia was purged in the solution for 2 hours. The insoluble solids were filtered and the filtrate was concentrated. The product was crystallized from methyl isobutyl ketone to give 36 g (80%) of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. a stream of ammonia was purged in the solution for 2 hours The insoluble solids were filtered the filtrate was concentrated The product was crystallized from methyl isobutyl ketone

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (45 g, 0.26 mol) in methylene chloride (225 ml) was cooled to 0° C. and triethylamine (53 g, 0.53 mol) and methanesulfonyl chloride (39 g, 0.34 mol) were added dropwise. The mixture was stirred at 0° C. for 30 min., then a stream of ammonia was purged in the solution for 2 hours. The insoluble solids were filtered and the filtrate was concentrated. The product was crystallized from methyl isobutyl ketone to give 36 g (80%) of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. a stream of ammonia was purged in the solution for 2 hours The insoluble solids were filtered the filtrate was concentrated The product was crystallized from methyl isobutyl ketone

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The compound (−)-(S)-α-ethyl-2-oxo-1-pyrrolidineacetamide is prepared by suspending 50 grams of (S)-2-aminobutyramide hydrochloride in 500 mL of dichloromethane at room temperature, then cooling to temperatures between −5 and 0° C. and adding 81.2 grams of potassium hydroxide and 23.3 grams of tetrabutylammonium bromide at those temperatures. A 66.4 gram amount of 4-chlorobutyryl chloride is added at the same temperatures. After completion of the reaction, solids are removed by filtration, the solution is adjusted to pH 7-7.5 with acetic acid, and dichloromethane is partially evaporated by the application of a vacuum. 150 mL of ethyl acetate are added to precipitate the product, which is isolated by filtration and washed with ethyl acetate and then with acetone; the product has a chiral purity of 99.8 percent by high performance liquid chromatography. The final product is purified by recrystallization from ethyl acetate, giving a yield of 60-65 percent. at room temperature cooling to temperatures between −5 and 0° C. After completion of the reaction, solids are removed by filtration is partially evaporated by the application of a vacuum 150 mL of ethyl acetate are added to precipitate the product which is isolated by filtration washed with ethyl acetate The final product is purified by recrystallization from ethyl acetate giving a yield of 60-65 percent

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The compound (−)-(S)-α-ethyl-2-oxo-1-pyrrolidineacetamide is prepared by suspending 50 grams of (S)-2-aminobutyramide hydrochloride in 500 mL of dichloromethane at room temperature, then cooling to temperatures between −5 and 0° C. and adding 81.2 grams of potassium hydroxide and 23.3 grams of tetrabutylammonium bromide at those temperatures. A 66.4 gram amount of 4-chlorobutyryl chloride is added at the same temperatures. After completion of the reaction, solids are removed by filtration, the solution is adjusted to pH 7-7.5 with acetic acid, and dichloromethane is partially evaporated by the application of a vacuum. 150 mL of ethyl acetate are added to precipitate the product, which is isolated by filtration and washed with ethyl acetate and then with acetone; the product has a chiral purity of 99.8 percent by high performance liquid chromatography. The final product is purified by recrystallization from ethyl acetate, giving a yield of 60-65 percent. at room temperature cooling to temperatures between −5 and 0° C. After completion of the reaction, solids are removed by filtration is partially evaporated by the application of a vacuum 150 mL of ethyl acetate are added to precipitate the product which is isolated by filtration washed with ethyl acetate The final product is purified by recrystallization from ethyl acetate giving a yield of 60-65 percent

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This example illustrates a varient of the process of Example 3, in which the intermediate 4-chlorobutanamide obtained in situ is not isolated. 84 g of anhydrous sodium sulfate are added to a suspension of 69.25 g (0.5 mole) of (S)-2-amino-butanamide hydrochloride in 600 ml of dichloromethane at ambient temperature. The mixture is cooled to 0° C. and 115 g of ground potassium hydroxide are added, followed by 8.1 g (0.025 mole) of tetrabutylammonium bromide dissolved in 100 ml of dichloromethane. A solution of 77.5 g of 4-chlorobutyryl chloride in 100 ml of dichloromethane is added dropwise at 0° C., with vigorous stirring. After 5 hours' reaction, a further 29 g of ground potassium hydroxide are added. Two hours later, the reaction mixture is filtered over Hyflo-cel and the filtrate evaporated under reduced pressure. The residue (93.5 g) is dispersed in 130 ml of hot toluene for 45 minutes. The resultant mixture is filtered and the filtrate evaporated under reduced pressure. The residue (71.3 g) is dissolved hot in 380 ml of ethyl acetate to which 23 g of 0.4 nm molecular sieve in powder form are added. This mixture is heated to reflux temperature and filtered hot. After cooling the filtrate, the desired product crystallizes to give 63 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. is not isolated After 5 hours' reaction Two hours later, the reaction mixture is filtered over Hyflo-cel the filtrate evaporated under reduced pressure The residue (93.5 g) is dispersed in 130 ml of hot toluene for 45 minutes The resultant mixture is filtered the filtrate evaporated under reduced pressure The residue (71.3 g) is dissolved hot in 380 ml of ethyl acetate to which 23 g of 0.4 nm molecular sieve in powder form are added This mixture is heated to reflux temperature filtered hot After cooling the filtrate the desired product crystallizes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 6.2 g (0.03 mole) of (S)-N-[1-(aminocarbonyl)propyl]-4-chlorobutanamide and 0.484 g (0.0015 mole) of tetrabutylammonium bromide are mixed in 45 ml of dichloromethane at 0° C. under a nitrogen atmosphere. 2.02 g (0.036 mole) of potassium hydroxide powder are added over 30 minutes, at such a rate that the temperature of the reaction mixture does not exceed +2° C. The mixture is then stirred for one hour, after which a further 0.1 g (0.0018 mole) of ground potassium hydroxide is added and stirring continued for 30 minutes at 0° C. The mixture is allowed to return to ambient temperature. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The residue obtained is recrystallized from 40 ml of ethyl acetate in the presence of 1.9 g of 0,4 nm molecular sieve. The latter is removed by hot filtration to give 3.10 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. does not exceed +2° C stirring continued for 30 minutes at 0° C to return to ambient temperature The insoluble matter is filtered off the filtrate is concentrated under reduced pressure The residue obtained is recrystallized from 40 ml of ethyl acetate in the presence of 1.9 g of 0,4 nm molecular sieve The latter is removed by hot filtration

反応条件: temp:92.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the crude methyl-(S)-4-(1-carbamoylpropylamino)butyrate (VIg) in toluene (25 ml) is added hydroxypyrridine (0.7 g, 30 mol %). The mixture is heated to 92° C. until complete conversion. After 17 hours the mixture is concentrated to dryness to yield (S)-2-(2-oxopyrrolidin-1-yl)butyramide. After 17 hours the mixture is concentrated to dryness

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Hydrochloride salt of methyl-4-(1-carbamoylpropylamino)butyrate (VId) (0.7 g, 2.9 mmol) is dissolved in a mixture of tetrahydrofuran (10 ml) and triethylamine (0.6 g, 2 equiv.). The suspension is filtered and filtrates are concentrated to dryness to afford an oil. The resulting residue is dissolved in toluene (15 ml) and 2-hydroxypyridine (53 mg, 0.56 mmol, 20 mol %) is added. The mixture is heated to 80° C. until complete conversion. After 3 days (GC: 100% conversion) the mixture is concentrated to dryness under reduced pressure. The suspension is filtered filtrates are concentrated to dryness to afford an oil After 3 days (GC: 100% conversion) the mixture is concentrated to dryness under reduced pressure

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of pyrrolidine-2-one (85 mg, 1 mmol) in 6 ml of toluene is added sodium methoxide (0. 19 ml of a 30% solution in MeOH, 1 mmol, 1 equiv.). The mixture is heated to 40° C. and concentrated to dryness under reduced pressure. The solid residue is taken up in 3 ml of tetrahydrofuran, cooled to 0° C. and (R)-2-bromobutyramide (IId) (optical purity >98%) (166 mg, 1 mmol, 1 equiv.) is added. The mixture is stirred for 1 h at 0° C. and further 16 h at room temperature. The mixture is then concentrated to dryness under reduce pressure. concentrated to dryness under reduced pressure cooled to 0° C. The mixture is then concentrated to dryness

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This example illustrates a variant of the process of Example 3, in which the intermediate 4-chlorobutanamide obtained in situ is not isolated. 84 g of anhydrous sodium sulfate are added to a suspension of 69.25 g (0.5 mole) of (S)-2-amino-butanamide hydrochloride in 600 ml of dichloromethane at ambient temperature. The mixture is cooled to 0° C. and 115 g of ground potassium hydroxide are added, followed by 8.1 g (0.025 mole) of tetrabutylammonium bromide dissolved in 100 ml of dichloromethane. A solution of 77.5 g of 4-chlorobutyryl chloride in 100 ml of dichlorometha is added dropwise at 0° C., wih vigorous stirring. After 5 hours' reaction, a further 29 g of ground potassium hydroxide are added. Two hours later, the reaction mixture is filtered over Hyflo-cel and the filtrate evaporated under reduced pressure. The residue (93.5 g) is dispersed in 130 ml of hot toluene for 45 minutes. The resultant mixture is filtered and the filtrate evaporated under reduced pressure. The residue (71.3 g) is dissolved hot in 380 ml of ethyl acetate to which 23 g of 0,4 nm molecular sieve in powder form are added. This mixture is heated to reflux temperature and filtered hot. After cooling the filtrate, the desired product crystallizes to give 63 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. is not isolated After 5 hours' reaction Two hours later, the reaction mixture is filtered over Hyflo-cel the filtrate evaporated under reduced pressure The residue (93.5 g) is dispersed in 130 ml of hot toluene for 45 minutes The resultant mixture is filtered the filtrate evaporated under reduced pressure The residue (71.3 g) is dissolved hot in 380 ml of ethyl acetate to which 23 g of 0,4 nm molecular sieve in powder form are added This mixture is heated to reflux temperature filtered hot After cooling the filtrate the desired product crystallizes

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This example illustrates a variant of the process of Example 3, in which the intermediate 4-chlorobutanamide obtained in situ is not isolated. 84 g of anhydrous sodium sulfate are added to a suspension of 69.25 g (0.5 mole) of (S)-2-amino-butanamide hydrochloride in 600 ml of dichloromethane at ambient temperature. The mixture is cooled to 0° C. and 115 g of ground potassium hydroxide are added, followed by 8.1 g (0.025 mole) of tetrabutylammonium bromide dissolved in 100 ml of dichloromethane. A solution of 77.5 g of 4-chlorobutyryl chloride in 100 ml of dichloromethane is added dropwise at 0° C., with vigorous stirring. After 5 hours' reaction, a further 29 g of ground potassium hydroxide are added. Two hours later, the reaction mixture is filtered over Hyflo-cel and the filtrate evaporated under reduced pressure. The residue (93.5 g) is dispersed in 130 ml of hot toluene for 45 minutes. The resultant mixture is filtered and the filtrate evaporated under reduced pressure. The residue (71.3 g) is dissolved hot in 380 ml of ethyl acetate to which 23 g of 0,4 nm molecular sieve in powder form are added. This mixture is heated to reflux temperature and filtered hot. After cooling the filtrate, the desired product crystallizes to give 63 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. is not isolated After 5 hours' reaction Two hours later, the reaction mixture is filtered over Hyflo-cel the filtrate evaporated under reduced pressure The residue (93.5 g) is dispersed in 130 ml of hot toluene for 45 minutes The resultant mixture is filtered the filtrate evaporated under reduced pressure The residue (71.3 g) is dissolved hot in 380 ml of ethyl acetate to which 23 g of 0,4 nm molecular sieve in powder form are added This mixture is heated to reflux temperature filtered hot After cooling the filtrate the desired product crystallizes

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (45 g, 0.26 mol) in methylene chloride (225 ml) was cooled to 0° C. and triethylamine (53 g, 0.53 mol) and methanesulfonyl chloride (39 g, 0.34 mol) were added dropwise. The mixture was stirred at 0° C. for 30 min., then a stream of ammonia was purged in the solution for 2 hours. The insoluble solids were filtered and the filtrate was concentrated. The product was crystallized from methyl isobutyl ketone to give 36 g (80%) of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. a stream of ammonia was purged in the solution for 2 hours The insoluble solids were filtered the filtrate was concentrated The product was crystallized from methyl isobutyl ketone