methyl 3-bromo-2-(bromomethyl)propanoate

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

実験手順: After dissolving 2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (CAS 6969-71-7) (1.0 g) in N,N-dimethylformamide (50 ml), sodium hydride (60% in oil) (355 mg) was added while stirring on ice. After stirring for 20 minutes, methyl 3-bromo-2-(bromomethyl)propionate (2.11 ml) was added dropwise. Stirring was continued for 1 hour and 30 minutes, and then sodium hydride (60% in oil) (200 mg) was added and the mixture was stirred for 3 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (400 mg). was added After stirring for 20 minutes Stirring the mixture was stirred for 3 hours The organic layer was washed with water and brine in that order dried over anhydrous magnesium sulfate After filtration the solvent was distilled off under reduced pressure The residue was purified by NH silica gel column chromatography

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

実験手順: To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (15.2 g, 76.3 mmol) in benzene (200 mL) was added pyrrolidine (13.9 g, 195 mmol). The resulting solution was refluxed with a Dean-Stark trap for 16 h. After removing the solvent by rotary evaporation, the residue was dried on high vacuum and re-dissolved in anhydrous acetonitrile (200 mL). This solution was combined with triethylamine (17.3 g, 170 mmol) and maintained at reflux as methyl 3-bromo-2-(bromomethyl)propanoate (20 g, 77 mmol) was added drop-wise. The reaction was further refluxed for 4 h, cooled to ambient temperature, diluted with water (200 mL) and stirred at ambient temperature for 16 h. The volatile solvents were removed by rotary evaporation, and the residue was partitioned between chloroform and water (200 mL each). The aqueous layer was extracted with chloroform (2×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was purified by flash chromatography, using an ethyl acetate in hexane gradient, to give 15.8 g (69.8% yield) of methyl 3-(tert-butoxycarbonyl)-9-oxo-3-azabicyclo[3.3.1]nonane-7-carboxylate, as a colorless syrup (1H NMR (CDCl3): δ 4.43-4.2 (m, 2H), 3.7 (s, 3H), 3.12-3.0 (m, 2H), 2.55-2.43 (m, 2H), 2.41-2.35 (m, 4H), 1.52 (s, 9H); LC-MS (MH+): 298). The resulting solution was refluxed with a Dean-Stark trap for 16 h After removing the solvent by rotary evaporation the residue was dried on high vacuum re-dissolved in anhydrous acetonitrile (200 mL) maintained was added drop-wise The reaction was further refluxed for 4 h The volatile solvents were removed by rotary evaporation the residue was partitioned between chloroform and water (200 mL each) The aqueous layer was extracted with chloroform (2×100 mL) The combined organic extracts were dried over anhydrous sodium sulfate concentrated by rotary evaporation The residue was purified by flash chromatography

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Bromo-2-bromomethyl-propionic acid methyl ester (30 g, 115 mmol) was added to a stirred solution of freshly distilled 1-cyclohex-1-enyl-pyrrolidine (20.4 mL, 126 mmol) and triethyl amine (35 mL, 252 mmol) in dry CH3CN (400 mL). After the addition, the mixture was heated (100° C.) and stirred for twelve hours before acetic acid (20 mL) and water (100 mL) were added. Then, heating was continued for another three hours. The solvent was evaporated and the residue was partitioned with diethyl ether and water. The organic phase was washed with a NaHCO3 solution until the washes became basic. It was then dried, filtered, and evaporated. The residue was purified over silica gel using 2-30% diethyl ether in hexanes to give the title compound as a clear oil. After the addition were added Then, heating The solvent was evaporated the residue was partitioned with diethyl ether and water The organic phase was washed with a NaHCO3 solution until the washes It was then dried filtered evaporated The residue was purified over silica gel using 2-30% diethyl ether in hexanes

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

実験手順: To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (15.2 g, 76.3 mmol) in benzene (200 mL) was added pyrrolidine (13.9 g, 195 mmol). The resulting solution was refluxed with a Dean-Stark trap for 16 h. After removing the solvent by rotary evaporation, the residue was dried on high vacuum and re-dissolved in anhydrous acetonitrile (200 mL). This solution was combined with triethylamine (17.3 g, 170 mmol) and maintained at reflux as methyl 3-bromo-2-(bromomethyl)propanoate (20 g, 77 mmol) was added drop-wise. The reaction was further refluxed for 4 h, cooled to ambient temperature, diluted with water (200 mL) and stirred at ambient temperature for 16 h. The volatile solvents were removed by rotary evaporation, and the residue was partitioned between chloroform and water (200 mL each). The aqueous layer was extracted with chloroform (2×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was purified by flash chromatography, using an ethyl acetate in hexane gradient, to give 15.8 g (69.8% yield) of methyl 3-(tert-butoxycarbonyl)-9-oxo-3-azabicyclo[3.3.1]nonane-7-carboxylate, as a colorless syrup (1H NMR (CDCl3): δ 4.43-4.2 (m, 2H), 3.7 (s, 3H), 3.12-3.0 (m, 2H), 2.55-2.43 (m, 2H), 2.41-2.35 (m, 4H), 1.52 (s, 9H); LC-MS (MH+): 298). The resulting solution was refluxed with a Dean-Stark trap for 16 h After removing the solvent by rotary evaporation the residue was dried on high vacuum re-dissolved in anhydrous acetonitrile (200 mL) maintained was added drop-wise The reaction was further refluxed for 4 h The volatile solvents were removed by rotary evaporation the residue was partitioned between chloroform and water (200 mL each) The aqueous layer was extracted with chloroform (2×100 mL) The combined organic extracts were dried over anhydrous sodium sulfate concentrated by rotary evaporation The residue was purified by flash chromatography

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Bromo-2-bromomethyl-propionic acid methyl ester (30 g, 115 mmol) was added to a stirred solution of freshly distilled 1-cyclohex-1-enyl-pyrrolidine (20.4 mL, 126 mmol) and triethyl amine (35 mL, 252 mmol) in dry CH3CN (400 mL). After the addition, the mixture was heated (100° C.) and stirred for twelve hours before acetic acid (20 mL) and water (100 mL) were added. Then, heating was continued for another three hours. The solvent was evaporated and the residue was partitioned with diethyl ether and water. The organic phase was washed with a NaHCO3 solution until the washes became basic. It was then dried, filtered, and evaporated. The residue was purified over silica gel using 2-30% diethyl ether in hexanes to give the title compound as a clear oil. After the addition were added Then, heating The solvent was evaporated the residue was partitioned with diethyl ether and water The organic phase was washed with a NaHCO3 solution until the washes It was then dried filtered evaporated The residue was purified over silica gel using 2-30% diethyl ether in hexanes

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Bromo-2-bromomethyl-propionic acid methyl ester (30 g, 115 mmol) was added to a stirred solution of freshly distilled 1-cyclohex-1-enyl-pyrrolidine (20.4 mL, 126 mmol) and triethyl amine (35 mL, 252 mmol) in dry CH3CN (400 mL). After the addition, the mixture was heated (100° C.) and stirred for twelve hours before acetic acid (20 mL) and water (100 mL) were added. Then, heating was continued for another three hours. The solvent was evaporated and the residue was partitioned with diethyl ether and water. The organic phase was washed with a NaHCO3 solution until the washes became basic. It was then dried, filtered, and evaporated. The residue was purified over silica gel using 2-30% diethyl ether in hexanes to give the title compound as a clear oil. After the addition were added Then, heating The solvent was evaporated the residue was partitioned with diethyl ether and water The organic phase was washed with a NaHCO3 solution until the washes It was then dried filtered evaporated The residue was purified over silica gel using 2-30% diethyl ether in hexanes

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

実験手順: After dissolving 2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (CAS 6969-71-7) (1.0 g) in N,N-dimethylformamide (50 ml), sodium hydride (60% in oil) (355 mg) was added while stirring on ice. After stirring for 20 minutes, methyl 3-bromo-2-(bromomethyl)propionate (2.11 ml) was added dropwise. Stirring was continued for 1 hour and 30 minutes, and then sodium hydride (60% in oil) (200 mg) was added and the mixture was stirred for 3 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (400 mg). was added After stirring for 20 minutes Stirring the mixture was stirred for 3 hours The organic layer was washed with water and brine in that order dried over anhydrous magnesium sulfate After filtration the solvent was distilled off under reduced pressure The residue was purified by NH silica gel column chromatography

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

実験手順: To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (15.2 g, 76.3 mmol) in benzene (200 mL) was added pyrrolidine (13.9 g, 195 mmol). The resulting solution was refluxed with a Dean-Stark trap for 16 h. After removing the solvent by rotary evaporation, the residue was dried on high vacuum and re-dissolved in anhydrous acetonitrile (200 mL). This solution was combined with triethylamine (17.3 g, 170 mmol) and maintained at reflux as methyl 3-bromo-2-(bromomethyl)propanoate (20 g, 77 mmol) was added drop-wise. The reaction was further refluxed for 4 h, cooled to ambient temperature, diluted with water (200 mL) and stirred at ambient temperature for 16 h. The volatile solvents were removed by rotary evaporation, and the residue was partitioned between chloroform and water (200 mL each). The aqueous layer was extracted with chloroform (2×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was purified by flash chromatography, using an ethyl acetate in hexane gradient, to give 15.8 g (69.8% yield) of methyl 3-(tert-butoxycarbonyl)-9-oxo-3-azabicyclo[3.3.1]nonane-7-carboxylate, as a colorless syrup (1H NMR (CDCl3): δ 4.43-4.2 (m, 2H), 3.7 (s, 3H), 3.12-3.0 (m, 2H), 2.55-2.43 (m, 2H), 2.41-2.35 (m, 4H), 1.52 (s, 9H); LC-MS (MH+): 298). The resulting solution was refluxed with a Dean-Stark trap for 16 h After removing the solvent by rotary evaporation the residue was dried on high vacuum re-dissolved in anhydrous acetonitrile (200 mL) maintained was added drop-wise The reaction was further refluxed for 4 h The volatile solvents were removed by rotary evaporation the residue was partitioned between chloroform and water (200 mL each) The aqueous layer was extracted with chloroform (2×100 mL) The combined organic extracts were dried over anhydrous sodium sulfate concentrated by rotary evaporation The residue was purified by flash chromatography

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Bromo-2-bromomethyl-propionic acid methyl ester (30 g, 115 mmol) was added to a stirred solution of freshly distilled 1-cyclohex-1-enyl-pyrrolidine (20.4 mL, 126 mmol) and triethyl amine (35 mL, 252 mmol) in dry CH3CN (400 mL). After the addition, the mixture was heated (100° C.) and stirred for twelve hours before acetic acid (20 mL) and water (100 mL) were added. Then, heating was continued for another three hours. The solvent was evaporated and the residue was partitioned with diethyl ether and water. The organic phase was washed with a NaHCO3 solution until the washes became basic. It was then dried, filtered, and evaporated. The residue was purified over silica gel using 2-30% diethyl ether in hexanes to give the title compound as a clear oil. After the addition were added Then, heating The solvent was evaporated the residue was partitioned with diethyl ether and water The organic phase was washed with a NaHCO3 solution until the washes It was then dried filtered evaporated The residue was purified over silica gel using 2-30% diethyl ether in hexanes