methyl (2S)-5-oxopyrrolidine-2-carboxylate

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

Procedure: (S)-Pyroglutamic acid methyl ester (0.200 g, 1.40 mmol) was dissolved in dry THF (5 ml) and NaH (0.061 g, 1.5 mmol) was added. After gas evolution ceased, 4-nitrobenzyl bromide (0.332 g, 1.54 mmol) was added and the mixture stirred for 1 h. The reaction was quenched with saturated NaHCO3 solution (40 mL) and extracted with EtOAc (2×50 ml). The organic layers were washed with water, brine, dried (MgSO4), filtered, and concentrated to give the title compound as a solid. 1H NMR (CDCl3) δ 8.19 (d, 2H, J=8.6 Hz), 7.40 (d, 2H, J=8.6 Hz), 5.29 (d, 1H, J=15 Hz), 4.19 (d, 1H, J=15 Hz), 4.02 (dd, 1H, J=3,9 Hz), 3.79 (s, 3H), 2.54-2.67 (m, 1H), 2.42-2.51 (m, 1H), 2.27-2.39 (m, 1H), 2.11-2.21 (m, 1H). The reaction was quenched with saturated NaHCO3 solution (40 mL) extracted with EtOAc (2×50 ml) The organic layers were washed with water, brine dried (MgSO4) filtered concentrated

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

Procedure: (S)-Pyroglutamic acid methyl ester (0.200 g, 1.40 mmol) was dissolved in dry THF (5 ml) and NaH (0.061 g, 1.5 mmol) was added. After gas evolution ceased, 4-nitrobenzyl bromide (0.332 g, 1.54 mmol) was added and the mixture stirred for 1 h. The reaction was quenched with saturated NaHCO3 solution (40 mL) and extracted with EtOAc (2×50 ml). The organic layers were washed with water, brine, dried (MgSO4), filtered, and concentrated to give the title compound as a solid. 1H NMR (CDCl3) δ 8.19 (d, 2H, J=8.6 Hz), 7.40 (d, 2H, J=8.6 Hz), 5.29 (d, 1H, J=15 Hz), 4.19 (d, 1H, J=15 Hz), 4.02 (dd, 1H, J=3,9 Hz), 3.79 (s, 3H), 2.54-2.67 (m, 1H), 2.42-2.51 (m, 1H), 2.27-2.39 (m, 1H), 2.11-2.21 (m, 1H). The reaction was quenched with saturated NaHCO3 solution (40 mL) extracted with EtOAc (2×50 ml) The organic layers were washed with water, brine dried (MgSO4) filtered concentrated

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

Procedure: To a solution of commercially available methyl 5-oxo-L-prolinate (20 g, 140 mmol) in DCM (200 ml) were added triethylamine (19.6 ml, 140 mmol), DMAP (17.2 g, 140 mmol) and then dropwise a solution of BOC2O (61 g, 280 mmol) in DCM (100 ml). The resulting red mixture was stirred at room temperature for 2 hours. Then the solvent was removed under reduced pressure and the crude material was purified by chromatography on silica gel eluting with cyclohexane/ethyl acetate (7:3 to 4:6) to afford (after a trituration in hexane/diethylether 1:1) the title compound as a white solid (32.4 g, 96%); Rf (cyclohexanes:ethyl acetate=65:35): 0.21; 1H NMR (300 MHz, CDCl3) δ(ppm): 4.62 (dd, 1H), 3.78 (s, 3H), 2.68-2.58 (m, 1H), 2.52-2.45 (m, 1H), 2.37-2.27 (m, 1H), 2.08-1.97 (m, 1H), 1.48 (s, 9H). Then the solvent was removed under reduced pressure the crude material was purified by chromatography on silica gel eluting with cyclohexane/ethyl acetate (7:3 to 4:6)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl (2S)-5-pyrrolidone-2-carboxylate (80 g) in tetrahydrofuran (900 ml) was added sodium hydride (60% in oil, 23.5 g) by portions. After the addition, the reaction mixture was heated to 60° C., and benzyl bromide (69.8 ml) was added dropwise thereto. After 3 hours, the reaction mixture was cooled to room temperature and water (100 ml) was added dropwise thereto. The reaction mixture was poured into a mixture of ethyl acetate (2 l) and water (800 ml). The organic layer was separated, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (2 l) eluting with a mixture of hexane and ethyl acetate (1:1→1:2, V/V) to give methyl (2S)-1-benzyl-5-pyrrolidone-2-carboxylate (100.8 g). After the addition the reaction mixture was cooled to room temperature The organic layer was separated washed with brine dried over magnesium sulfate Evaporation of the solvent gave an oil, which was chromatographed on silica gel (2 l) eluting with a mixture of hexane and ethyl acetate (1:1→1:2, V/V)

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

Procedure: To a solution of (2S)-5-pyrrolidone-2-carboxylic acid (75 g) in methanol (580 ml) was added dropwise thionyl chloride (150 ml) at 0° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for two hours. The solvent was removed in vacuo, and the residue was diluted with a mixture of ethyl acetate (1 l), methanol (50 ml) and water (10 ml). To this mixture was added by portions potassium carbonate (50 g), and the mixture was stirred for two hours. The precipitate was filtered off, and the filtrate was dried over magnesium sulfate. Evaporation of the solvent gave methyl (2S)-5-pyrrolidone-2-carboxylate (82.5 g) as an oil. After the addition The solvent was removed in vacuo the residue was diluted with a mixture of ethyl acetate (1 l), methanol (50 ml) and water (10 ml) To this mixture was added by portions potassium carbonate (50 g) the mixture was stirred for two hours The precipitate was filtered off the filtrate was dried over magnesium sulfate Evaporation of the solvent

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

Procedure: To a solution of (2S)-5-pyrrolidone-2-carboxylic acid (75 g) in methanol (580 ml) was added dropwise thionyl chloride (150 ml) at 0° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for two hours. The solvent was removed in vacuo, and the residue was diluted with a mixture of ethyl acetate (1 l), methanol (50 ml) and water (10 ml). To this mixture was added by portions potassium carbonate (50 g), and the mixture was stirred for two hours. The precipitate was filtered off, and the filtrate was dried over magnesium sulfate. Evaporation of the solvent gave methyl (2S)-5-pyrrolidone-2-carboxylate (82.5 g) as an oil. After the addition The solvent was removed in vacuo the residue was diluted with a mixture of ethyl acetate (1 l), methanol (50 ml) and water (10 ml) To this mixture was added by portions potassium carbonate (50 g) the mixture was stirred for two hours The precipitate was filtered off the filtrate was dried over magnesium sulfate Evaporation of the solvent

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

Procedure: Methyl pyroglutamate (4.3 g) and 7.9 g of 4-benzylpiperidine were dissolved in 20 ml of toluene and the mixture was heated to reflux with stirring for 24 hours. The reaction solution was treated with a silica gel column chromatography to give 7.2 g of the product which was recrystallized from diethyl ether to afford 6.5 g of desired product, m.p. 160°-161° C. the mixture was heated to reflux The reaction solution was treated with a silica gel column chromatography

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

Procedure: L-pyroglutamic acid methyl ester (23.91 g, 177 mmol), morpholine (21.8 g, 250 mmol) and 4-dimethylaminopyridine (0.2 g, 1.64 mmol) are heated under reflux in toluene (130 ml) for 12 hours. The product precipitates as an oil. The oil is separated from the toluene, diluted with dichloromethane (100 ml) and washed successively with 0.1 M HCl, 0.1 M NaOH and water (50 ml each). The dichloromethane phase is concentrated to obtain a suspension, which is filtered yielding the crude product. The crude product is dissolved in THF (200 ml) at 45° C. and, upon cooling in an ice bath, (S)-5-morpholine-4-carbonyl)pyrrolidin-2-one precipitates as white crystals. Enantiopurity (GC) 88.7% (S)-Enantiomer. The product precipitates as an oil The oil is separated from the toluene diluted with dichloromethane (100 ml) washed successively with 0.1 M HCl, 0.1 M NaOH and water (50 ml each) The dichloromethane phase is concentrated to obtain a suspension, which is filtered

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 143 g of pyroglutamic acid methyl ester (1 mol) and 139 g morpholine (1.60 mol) in 900 ml of xylene is heated to 140° C. for 20 h. The xylene is evaporated to a volume of 500 ml. From the suspension obtained, the precipitate is filtered off, washed with THF to yield the desired compound after drying in vacuo. From the filtrate the solvent is evaporated completely. This crude product [(R/S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one] is filtered over 800 g silica gel with THF as the solvent and evaporated to dryness to yield a second crop of the desired compound. This compound is used directly in the next step. HPLC analysis shows the material to be in an enantiomeric ratio: 55.8:44.2 [(4-a, R1=H; R4=morpholine): (4-b, R1=H; R4=morpholine), respectively]. The xylene is evaporated to a volume of 500 ml From the suspension obtained the precipitate is filtered off washed with THF

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 143 g of pyroglutamic acid methyl ester (1 mol) and 139 g morpholine (1.60 mol) in 900 ml of xylene is heated to 140° C. for 20 h. The xylene is evaporated to a volume of 500 ml. From the suspension obtained, the precipitate is filtered off, washed with THF to yield the desired compound after drying in vacuo. From the filtrate the solvent is evaporated completely. This crude product [(R/S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one] is filtered over 800 g silica gel with THF as the solvent and evaporated to dryness to yield a second crop of the desired compound. This compound is used directly in the next step. HPLC analysis shows the material to be in an enantiomeric ratio: 55.8:44.2 [(4-a, R1=H; R4=morpholine): (4-b, R1=H; R4=morpholine), respectively]. The xylene is evaporated to a volume of 500 ml From the suspension obtained the precipitate is filtered off washed with THF

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

Procedure: L-pyroglutamic acid methyl ester (23.91 g, 177 mmol), morpholine (21.8 g, 250 mmol) and 4-dimethylaminopyridine (0.2 g, 1.64 mmol) are heated under reflux in toluene (130 ml) for 12 hours. The product precipitates as an oil. The oil is separated from the toluene, diluted with dichloromethane (100 ml) and washed successively with 0.1 M HCl, 0.1 M NaOH and water (50 ml each). The dichloromethane phase is concentrated to obtain a suspension, which is filtered yielding the crude product. The crude product is dissolved in THF (200 ml) at 45° C. and, upon cooling in an ice bath, (S)-5-morpholine-4-carbonyl)pyrrolidin-2-one precipitates as white crystals. Enantiopurity (GC) 88.7% (S)-Enantiomer. The product precipitates as an oil The oil is separated from the toluene diluted with dichloromethane (100 ml) washed successively with 0.1 M HCl, 0.1 M NaOH and water (50 ml each) The dichloromethane phase is concentrated to obtain a suspension, which is filtered

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 143 g of pyroglutamic acid methyl ester (1 mol) and 139 g morpholine (1.60 mol) in 900 ml of xylene is heated to 140° C. for 20 h. The xylene is evaporated to a volume of 500 ml. From the suspension obtained, the precipitate is filtered off, washed with THF to yield the desired compound after drying in vacuo. From the filtrate the solvent is evaporated completely. This crude product [(R/S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one] is filtered over 800 g silica gel with THF as the solvent and evaporated to dryness to yield a second crop of the desired compound. This compound is used directly in the next step. HPLC analysis shows the material to be in an enantiomeric ratio: 55.8:44.2 [(4-a, R1=H; R4=morpholine): (4-b, R1=H; R4=morpholine), respectively]. The xylene is evaporated to a volume of 500 ml From the suspension obtained the precipitate is filtered off washed with THF