tert-butyl 4-(chloromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate

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:

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

実験手順: To a −78° C. solution of oxalyl chloride (5.1 mL, 57 mmol) in dichloromethane (100 mL) in an oven-dried round-bottomed flask was added dimethylsulfoxide (8.2 mL, 114 mmol) in dichloromethane (17 mL). The mixture was stirred for 2 minutes and tert-butyl 4-(chloromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (13.7 g, 52 mmol) in dichloromethane (50 mL) was added over 10 minutes. The solution was stirred for 15 minutes at −78° C. and triethylamine (36 mL, 260 mmol) was added. The mixture was stirred at −78° C. for 15 minutes and was warmed to room temperature. The mixture was stirred for 15 minutes at room temperature and was quenched with saturated aqueous NaHCO3 (200 mL). The aqueous solution was washed with Et2O (2×300 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a yellow oil that solidified upon standing under nitrogen atmosphere at room temperature (13.7 g, 99%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.48-1.60 (m, 2H), 2.00-2.07 (m, 2H), 3.07 (t, 2H), 3.57 (s, 2H), 3.69-3.79 (m, 2H), 9.55 (s, 1H). The solution was stirred for 15 minutes at −78° C. The mixture was stirred at −78° C. for 15 minutes The mixture was stirred for 15 minutes at room temperature was quenched with saturated aqueous NaHCO3 (200 mL) The aqueous solution was washed with Et2O (2×300 mL) The combined organic layers were washed with brine dried (Na2SO4) concentrated under reduced pressure

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

実験手順: To a −78° C. solution of oxalyl chloride (5.1 mL, 57 mmol) in dichloromethane (100 mL) in an oven-dried round-bottomed flask was added dimethylsulfoxide (8.2 mL, 114 mmol) in dichloromethane (17 mL). The mixture was stirred for 2 minutes and tert-butyl 4-(chloromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (13.7 g, 52 mmol) in dichloromethane (50 mL) was added over 10 minutes. The solution was stirred for 15 minutes at −78° C. and triethylamine (36 mL, 260 mmol) was added. The mixture was stirred at −78° C. for 15 minutes and was warmed to room temperature. The mixture was stirred for 15 minutes at room temperature and was quenched with saturated aqueous NaHCO3 (200 mL). The aqueous solution was washed with Et2O (2×300 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a yellow oil that solidified upon standing under nitrogen atmosphere at room temperature (13.7 g, 99%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.48-1.60 (m, 2H), 2.00-2.07 (m, 2H), 3.07 (t, 2H), 3.57 (s, 2H), 3.69-3.79 (m, 2H), 9.55 (s, 1H). The solution was stirred for 15 minutes at −78° C. The mixture was stirred at −78° C. for 15 minutes The mixture was stirred for 15 minutes at room temperature was quenched with saturated aqueous NaHCO3 (200 mL) The aqueous solution was washed with Et2O (2×300 mL) The combined organic layers were washed with brine dried (Na2SO4) concentrated under reduced pressure

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

実験手順: To a −78° C. solution of oxalyl chloride (5.1 mL, 57 mmol) in dichloromethane (100 mL) in an oven-dried round-bottomed flask was added dimethylsulfoxide (8.2 mL, 114 mmol) in dichloromethane (17 mL). The mixture was stirred for 2 minutes and tert-butyl 4-(chloromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (13.7 g, 52 mmol) in dichloromethane (50 mL) was added over 10 minutes. The solution was stirred for 15 minutes at −78° C. and triethylamine (36 mL, 260 mmol) was added. The mixture was stirred at −78° C. for 15 minutes and was warmed to room temperature. The mixture was stirred for 15 minutes at room temperature and was quenched with saturated aqueous NaHCO3 (200 mL). The aqueous solution was washed with Et2O (2×300 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a yellow oil that solidified upon standing under nitrogen atmosphere at room temperature (13.7 g, 99%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.48-1.60 (m, 2H), 2.00-2.07 (m, 2H), 3.07 (t, 2H), 3.57 (s, 2H), 3.69-3.79 (m, 2H), 9.55 (s, 1H). The solution was stirred for 15 minutes at −78° C. The mixture was stirred at −78° C. for 15 minutes The mixture was stirred for 15 minutes at room temperature was quenched with saturated aqueous NaHCO3 (200 mL) The aqueous solution was washed with Et2O (2×300 mL) The combined organic layers were washed with brine dried (Na2SO4) concentrated under reduced pressure

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

実験手順: A solution of 1-tert-butyl 4-methyl 4-(chloromethyl)piperidine-1,4-dicarboxylate (11.7 g, 40.2 mmol) in anhydrous THF (100 mL) was cooled to 0° C. Lithium aluminum hydride (1N in THF, 44.3 mL, 44.3 mmol), was added slowly (15-20 min) and the solution was stirred at 0° C. for 25 minutes. The mixture was quenched by adding water (1.8 mL) dropwise with great caution. Aqueous 1N NaOH (1.8 mL) was added dropwise, and the mixture was stirred for 5 minutes. The cooling bath was removed, the solids were filtered off, and the cake was washed with Et2O (2×100 mL). The filtrate was washed with water (2×100 mL), brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure to give tert-butyl 4-(chloromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate as a solid (9.96 g, 93.8%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.48-1.55 (m, 4H), 3.36-3.41 (m, 4H), 3.57 (s, 2H), 3.59 (br s, 2H). The mixture was quenched by adding water (1.8 mL) dropwise with great caution Aqueous 1N NaOH (1.8 mL) was added dropwise the mixture was stirred for 5 minutes The cooling bath was removed the solids were filtered off the cake was washed with Et2O (2×100 mL) The filtrate was washed with water (2×100 mL), brine (100 mL) dried (Na2SO4) concentrated under reduced pressure

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

実験手順: A solution of 1-tert-butyl 4-methyl 4-(chloromethyl)piperidine-1,4-dicarboxylate (11.7 g, 40.2 mmol) in anhydrous THF (100 mL) was cooled to 0° C. Lithium aluminum hydride (1N in THF, 44.3 mL, 44.3 mmol), was added slowly (15-20 min) and the solution was stirred at 0° C. for 25 minutes. The mixture was quenched by adding water (1.8 mL) dropwise with great caution. Aqueous 1N NaOH (1.8 mL) was added dropwise, and the mixture was stirred for 5 minutes. The cooling bath was removed, the solids were filtered off, and the cake was washed with Et2O (2×100 mL). The filtrate was washed with water (2×100 mL), brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure to give tert-butyl 4-(chloromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate as a solid (9.96 g, 93.8%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.48-1.55 (m, 4H), 3.36-3.41 (m, 4H), 3.57 (s, 2H), 3.59 (br s, 2H). The mixture was quenched by adding water (1.8 mL) dropwise with great caution Aqueous 1N NaOH (1.8 mL) was added dropwise the mixture was stirred for 5 minutes The cooling bath was removed the solids were filtered off the cake was washed with Et2O (2×100 mL) The filtrate was washed with water (2×100 mL), brine (100 mL) dried (Na2SO4) concentrated under reduced pressure

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

実験手順: A solution of 1-tert-butyl 4-methyl 4-(chloromethyl)piperidine-1,4-dicarboxylate (11.7 g, 40.2 mmol) in anhydrous THF (100 mL) was cooled to 0° C. Lithium aluminum hydride (1N in THF, 44.3 mL, 44.3 mmol), was added slowly (15-20 min) and the solution was stirred at 0° C. for 25 minutes. The mixture was quenched by adding water (1.8 mL) dropwise with great caution. Aqueous 1N NaOH (1.8 mL) was added dropwise, and the mixture was stirred for 5 minutes. The cooling bath was removed, the solids were filtered off, and the cake was washed with Et2O (2×100 mL). The filtrate was washed with water (2×100 mL), brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure to give tert-butyl 4-(chloromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate as a solid (9.96 g, 93.8%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.48-1.55 (m, 4H), 3.36-3.41 (m, 4H), 3.57 (s, 2H), 3.59 (br s, 2H). The mixture was quenched by adding water (1.8 mL) dropwise with great caution Aqueous 1N NaOH (1.8 mL) was added dropwise the mixture was stirred for 5 minutes The cooling bath was removed the solids were filtered off the cake was washed with Et2O (2×100 mL) The filtrate was washed with water (2×100 mL), brine (100 mL) dried (Na2SO4) concentrated under reduced pressure

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

実験手順: To a −78° C. solution of oxalyl chloride (5.1 mL, 57 mmol) in dichloromethane (100 mL) in an oven-dried round-bottomed flask was added dimethylsulfoxide (8.2 mL, 114 mmol) in dichloromethane (17 mL). The mixture was stirred for 2 minutes and tert-butyl 4-(chloromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (13.7 g, 52 mmol) in dichloromethane (50 mL) was added over 10 minutes. The solution was stirred for 15 minutes at −78° C. and triethylamine (36 mL, 260 mmol) was added. The mixture was stirred at −78° C. for 15 minutes and was warmed to room temperature. The mixture was stirred for 15 minutes at room temperature and was quenched with saturated aqueous NaHCO3 (200 mL). The aqueous solution was washed with Et2O (2×300 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give the title compound (SM-3a) as a yellow oil that solidified upon standing under nitrogen atmosphere at room temperature (13.7 g, 99%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.48-1.60 (m, 2H), 2.00-2.07 (m, 2H), 3.07 (t, 2H), 3.57 (s, 2H), 3.69-3.79 (m, 2H), 9.55 (s, 1H). The solution was stirred for 15 minutes at −78° C. The mixture was stirred at −78° C. for 15 minutes The mixture was stirred for 15 minutes at room temperature was quenched with saturated aqueous NaHCO3 (200 mL) The aqueous solution was washed with Et2O (2×300 mL) The combined organic layers were washed with brine dried (Na2SO4) concentrated under reduced pressure

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

実験手順: A solution of 1-tert-butyl 4-methyl 4-(chloromethyl)piperidine-1,4-dicarboxylate (11.7 g, 40.2 mmol) in anhydrous THF (100 mL) was cooled to 0° C. Lithium aluminum hydride (1N in THF, 44.3 mL, 44.3 mmol), was added slowly (15-20 min) and the solution was stirred at 0° C. for 25 minutes. The mixture was quenched by adding water (1.8 mL) dropwise with great caution. Aqueous 1N NaOH (1.8 mL) was added dropwise, and the mixture was stirred for 5 minutes. The cooling bath was removed, the solids were filtered off, and the cake was washed with Et2O (2×100 mL). The filtrate was washed with water (2×100 mL), brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure to give tert-butyl 4-(chloromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate as a solid (9.96 g, 93.8%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.48-1.55 (m, 4H), 3.36-3.41 (m, 4H), 3.57 (s, 2H), 3.59 (br s, 2H). The mixture was quenched by adding water (1.8 mL) dropwise with great caution Aqueous 1N NaOH (1.8 mL) was added dropwise the mixture was stirred for 5 minutes The cooling bath was removed the solids were filtered off the cake was washed with Et2O (2×100 mL) The filtrate was washed with water (2×100 mL), brine (100 mL) dried (Na2SO4) concentrated under reduced pressure