4-benzylmorpholin-3-one

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To a stirred solution of 2 (5.05 g, 26.4 mmol) in tetrahydrofuran (25 ml) at −78° C. under nitrogen was added lithium diisopropylamide (14.5 ml of a 2M solution, 29.0 mmol) dropwise over 40 minutes. The reaction mixture was stirred at the same temperature over 30 minutes after which time a solution of isobutyraldehyde (2.63 ml, 29.0 mmol) in tetrahydrofuran (15 ml) was added dropwise over 30 minutes. After one hour, the reaction mixture was allowed to warm to room temperature and quenched by addition of saturated ammonium chloride solution. Extraction with dichloromethane and drying over magnesium sulphate gave 53 as a mixture of diastereomers. Upon concentration in vacuo one diastereomer precipitated as a white solid (53a: 0.99 g). The remaining mother liquors were purified by column chromatography (30% ethyl acetate in hexane [v/v]) to give 53 (2.06 g). MW 263.34; C15H21NO3; LCMS (6 min method): m/z 286 [M+Na]+; RT=2.748. was added dropwise over 30 minutes quenched by addition of saturated ammonium chloride solution Extraction with dichloromethane drying over magnesium sulphate

反応条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-benzyl-N-(2-hydroxyethyl) chloroacetamide (627.7 g, 2.76 mol) in tert-butanol (0.9 l) was stirred under nitrogen while warming to 25-30° C. Potassium tert-butoxide (2.897 l of a 1M solution in tert-butanol, 2.90 mol, 1.05 eq) was added over 2 hours. The reaction mixture was then stirred at room temperature for 90 minutes. Ice-cold water (6 l) was added and the resultant cloudy solution extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate and evaporated in vacuo to give a light brown oil (441 g, 84%), which was used in the next stage without further purification; MW 191.23; C11H13NO2; 1H NMR (CDCl3): 7.29-7.40 (5H, m), 4.67 (2H, s), 4.28 (2H, s), 3.87 (2H, t, 5 Hz), 3.31 (2H, t, 5 Hz); LCMS: (12 min method) m/z 192 [M+H]+ @ Rt 1.00 min. the resultant cloudy solution extracted with ethyl acetate The combined organic layers were washed with brine dried over magnesium sulphate evaporated in vacuo

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-benzyl-morpholin-3-one (9.5 g, 50 mmol) in THF (200 mL) is added lithium diisopropylamide (2M solution in THE, 27 mL, 54 mmol, 1.1 eq) dropwise over 20 minutes at −78° C. followed by slow addition of cyclopropyl methylaldehyde (3.85 mL, 55 mmol, 1.1 eq). After stirring at −78° C. for one hour the reaction mixture is allowed to warm to room temperature and stirred for another 6 hours. The reaction is quenched by addition of EtOAc and brine. The aqueous layer is extracted with EtOAc, the combined organic layers are dried over magnesium sulphate and reduced in vacuo. Purification using automated column chromatography (DCM/MeOH, 100/0 to 85/15 [v/v]) gives 75 in 70% purity with 4-benzyl-morpholin-3-one as the major impurity. This product is directly used in the next step. MW 261.32; C15H19NO3; LCMS (6 min method) m/z 261.32 [M+H]+, RT 2.23 to warm to room temperature stirred for another 6 hours The reaction is quenched by addition of EtOAc and brine The aqueous layer is extracted with EtOAc the combined organic layers are dried over magnesium sulphate Purification

反応条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-benzyl-N-(2-hydroxyethyl)chloroacetamide (627.7 g, 2.76 mol) in tert-butanol (0.9 L) is stirred under nitrogen while warming to 25-30° C. Potassium tert-butoxide (2.897 L of a 1M solution in tert-butanol, 2.90 mol, 1.05 eq) is added over 2 hours. The reaction mixture is then stirred at room temperature for 90 minutes. Ice-cold water (6 L) is added and the resultant cloudy solution extracted with ethyl acetate. The combined organic layers are washed with brine, dried over magnesium sulphate and evaporated in vacuo to give a light brown oil (441 g, 84%), which is used in the next stage without further purification; MW 191.23; C11H13NO2; 1H NMR (CDCl3): 7.29-7.40 (5H, m), 4.67 (2H, s), 4.28 (2H, s), 3.87 (2H, t, 5 Hz), 3.31 (2H, t, 5 Hz); LCMS: (12 min method) m/z 192 [M+H]+RT 1.00 min. the resultant cloudy solution extracted with ethyl acetate The combined organic layers are washed with brine dried over magnesium sulphate evaporated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To a stirred solution of 2 (5.05 g, 26.4 mmol) in tetrahydrofuran (25 ml) at −78° C. under nitrogen was added lithium diisopropylamide (14.5 ml of a 2M solution, 29.0 mmol) dropwise over 40 minutes. The reaction mixture was stirred at the same temperature over 30 minutes after which time a solution of isobutyraldehyde (2.63 ml, 29.0 mmol) in tetrahydrofuran (15 ml) was added dropwise over 30 minutes. After one hour, the reaction mixture was allowed to warm to room temperature and quenched by addition of saturated ammonium chloride solution. Extraction with dichloromethane and drying over magnesium sulphate gave 53 as a mixture of diastereomers. Upon concentration in vacuo one diastereomer precipitated as a white solid (53a: 0.99 g). The remaining mother liquors were purified by column chromatography (30% ethyl acetate in hexane [v/v]) to give 53 (2.06 g). MW 263.34; C15H21NO3; LCMS (6 min method): m/z 286 [M+Na]+; RT=2.748. was added dropwise over 30 minutes quenched by addition of saturated ammonium chloride solution Extraction with dichloromethane drying over magnesium sulphate

反応条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-benzyl-N-(2-hydroxyethyl) chloroacetamide (627.7 g, 2.76 mol) in tert-butanol (0.9 l) was stirred under nitrogen while warming to 25-30° C. Potassium tert-butoxide (2.897 l of a 1M solution in tert-butanol, 2.90 mol, 1.05 eq) was added over 2 hours. The reaction mixture was then stirred at room temperature for 90 minutes. Ice-cold water (6 l) was added and the resultant cloudy solution extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate and evaporated in vacuo to give a light brown oil (441 g, 84%), which was used in the next stage without further purification; MW 191.23; C11H13NO2; 1H NMR (CDCl3): 7.29-7.40 (5H, m), 4.67 (2H, s), 4.28 (2H, s), 3.87 (2H, t, 5 Hz), 3.31 (2H, t, 5 Hz); LCMS: (12 min method) m/z 192 [M+H]+ @ Rt 1.00 min. the resultant cloudy solution extracted with ethyl acetate The combined organic layers were washed with brine dried over magnesium sulphate evaporated in vacuo

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-benzyl-morpholin-3-one (9.5 g, 50 mmol) in THF (200 mL) is added lithium diisopropylamide (2M solution in THE, 27 mL, 54 mmol, 1.1 eq) dropwise over 20 minutes at −78° C. followed by slow addition of cyclopropyl methylaldehyde (3.85 mL, 55 mmol, 1.1 eq). After stirring at −78° C. for one hour the reaction mixture is allowed to warm to room temperature and stirred for another 6 hours. The reaction is quenched by addition of EtOAc and brine. The aqueous layer is extracted with EtOAc, the combined organic layers are dried over magnesium sulphate and reduced in vacuo. Purification using automated column chromatography (DCM/MeOH, 100/0 to 85/15 [v/v]) gives 75 in 70% purity with 4-benzyl-morpholin-3-one as the major impurity. This product is directly used in the next step. MW 261.32; C15H19NO3; LCMS (6 min method) m/z 261.32 [M+H]+, RT 2.23 to warm to room temperature stirred for another 6 hours The reaction is quenched by addition of EtOAc and brine The aqueous layer is extracted with EtOAc the combined organic layers are dried over magnesium sulphate Purification

反応条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-benzyl-N-(2-hydroxyethyl)chloroacetamide (627.7 g, 2.76 mol) in tert-butanol (0.9 L) is stirred under nitrogen while warming to 25-30° C. Potassium tert-butoxide (2.897 L of a 1M solution in tert-butanol, 2.90 mol, 1.05 eq) is added over 2 hours. The reaction mixture is then stirred at room temperature for 90 minutes. Ice-cold water (6 L) is added and the resultant cloudy solution extracted with ethyl acetate. The combined organic layers are washed with brine, dried over magnesium sulphate and evaporated in vacuo to give a light brown oil (441 g, 84%), which is used in the next stage without further purification; MW 191.23; C11H13NO2; 1H NMR (CDCl3): 7.29-7.40 (5H, m), 4.67 (2H, s), 4.28 (2H, s), 3.87 (2H, t, 5 Hz), 3.31 (2H, t, 5 Hz); LCMS: (12 min method) m/z 192 [M+H]+RT 1.00 min. the resultant cloudy solution extracted with ethyl acetate The combined organic layers are washed with brine dried over magnesium sulphate evaporated in vacuo