2-(chloromethyl)-2-methyloxirane

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:72.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of N-(2-hydroxyphenyl)benzamide (159 mg, 0.75 mmol), 2-(chloromethyl)-2-methyloxirane (1.60 g, 15 mmol), and benzyltriethylammonium chloride (27 mg, 0.12 mmol) was stirred at 70-75° C. for 6 h. After cooling to room temperature, water (2 ml) was added and the mixture was vigorously shaken. It was extracted with dichloromethane (2×5 ml), and the combined organic extracts were washed with aq. NaOH (2M, 5 ml) and water (10 ml). Drying with Na2SO4, evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 25 to 50%) afforded title compound as yellowish solid (131 mg, 0.46 mmol, 62%). After cooling to room temperature the mixture was vigorously shaken It was extracted with dichloromethane (2×5 ml) the combined organic extracts were washed with aq. NaOH (2M, 5 ml) and water (10 ml) Drying with Na2SO4, evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 25 to 50%)

反応条件: temp:72.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of N-(2-hydroxyphenyl)benzamide (159 mg, 0.75 mmol), 2-(chloromethyl)-2-methyloxirane (1.60 g, 15 mmol), and benzyltriethylammonium chloride (27 mg, 0.12 mmol) was stirred at 70-75° C. for 6 h. After cooling to room temperature, water (2 ml) was added and the mixture was vigorously shaken. It was extracted with dichloromethane (2×5 ml), and the combined organic extracts were washed with aq. NaOH (2M, 5 ml) and water (10 ml). Drying with Na2SO4, evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 25 to 50%) afforded title compound as yellowish solid (131 mg, 0.46 mmol, 62%). After cooling to room temperature the mixture was vigorously shaken It was extracted with dichloromethane (2×5 ml) the combined organic extracts were washed with aq. NaOH (2M, 5 ml) and water (10 ml) Drying with Na2SO4, evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 25 to 50%)

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of (S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide (120 mg, 0.338 mmol), 2-(chloromethyl)-2-methyloxirane (2.88 g, 27.1 mmol and Y(NO3)3×6H2O (3.6 mg, 0.0093 mmol) was stirred under MW at 120° C. for 30 min. After evaporation of oxirane the residue was purified by flash chromatography on silica gel using CH2Cl2-MeOH as a gradient eluent (100:0-99:1) to obtain N-{(S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-[(2-methyloxiran-2-yl)methyl]-1H-imidazole-4-carboxamide as a major product and 1-(3-chloro-2-hydroxy-2-methylpropyl)-N—{(S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide as a minor product. After evaporation of oxirane the residue was purified by flash chromatography on silica gel

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

実験手順: To a solution of 50 g 2-methyl-2-chloromethyloxirane in 23 ml concentrated hydrochloric acid at ice-bath temperature a solution of 27.4 g sodium cyanide in 23 ml hydrochloric acid was added. After stirring for 10 hours at that temperature the reaction mixture was warmed to 40° C. and a solution of 33.8 g potassium cyanide in 50 ml water was added. The resulting mixture was warmed to 50° C. and stirred for 4 hours. After cooling the solution was neutralized and extracted three times with 150 ml ethyl acetate each. The combined organic layers were dried with anhydrous magnesium sulphate. Removal of the solvent afforded 56.4 g (96%) of 1,3-dicyano-2-methyl-2-hydroxypropane. This crude material was sufficiently pure to be submitted directly to the following ring closure. The resulting mixture was warmed to 50° C. stirred for 4 hours After cooling the solution extracted three times with 150 ml ethyl acetate each The combined organic layers were dried with anhydrous magnesium sulphate Removal of the solvent

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

実験手順: To a solution of 50 g 2-methyl-2-chloromethyloxirane in 23 ml concentrated hydrochloric acid at ice-bath temperature a solution of 27.4 g sodium cyanide in 23 ml hydrochloric acid was added. After stirring for 10 hours at that temperature the reaction mixture was warmed to 40° C. and a solution of 33.8 g potassium cyanide in 50 ml water was added. The resulting mixture was warmed to 50° C. and stirred for 4 hours. After cooling the solution was neutralized and extracted three times with 150 ml ethyl acetate each. The combined organic layers were dried with anhydrous magnesium sulphate. Removal of the solvent afforded 56.4 g (96%) of 1,3-dicyano-2-methyl-2-hydroxypropane. This crude material was sufficiently pure to be submitted directly to the following ring closure. The resulting mixture was warmed to 50° C. stirred for 4 hours After cooling the solution extracted three times with 150 ml ethyl acetate each The combined organic layers were dried with anhydrous magnesium sulphate Removal of the solvent

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

実験手順: To a solution of 50 g 2-methyl-2-chloromethyloxirane in 23 ml concentrated hydrochloric acid at ice-bath temperature a solution of 27.4 g sodium cyanide in 23 ml hydrochloric acid was added. After stirring for 10 hours at that temperature the reaction mixture was warmed to 40° C. and a solution of 33.8 g potassium cyanide in 50 ml water was added. The resulting mixture was warmed to 50° C. and stirred for 4 hours. After cooling the solution was neutralized and extracted three times with 150 ml ethyl acetate each. The combined organic layers were dried with anhydrous magnesium sulphate. Removal of the solvent afforded 56.4 g (96%) of 1,3-dicyano-2-methyl-2-hydroxypropane. This crude material was sufficiently pure to be submitted directly to the following ring closure. The resulting mixture was warmed to 50° C. stirred for 4 hours After cooling the solution extracted three times with 150 ml ethyl acetate each The combined organic layers were dried with anhydrous magnesium sulphate Removal of the solvent

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

実験手順: Diphenylmethanamine (68.8 mL, 375 mmol) was added dropwise into a solution of 2-(chloromethyl)-2-methyloxirane (40 g, 375 mmol) in methanol (160 mL) and the reaction was stirred at rt for 72 h and then at reflux for 20 h. The reaction was cooled to ambient temperature, evaporated in vacuo and suspended in acetone (200 mL). The solid was collected by filtration to give 1-benzhydryl-3-methyl-azetidin-3-ol (60 g, 63%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ7.61 (m, 4H), 7.31 (m, 6H), 6.43 (m, 1H), 6.00 (m, 1H), 3.80-4.00 (m, 4H), 1.45 (m, 3H). at reflux for 20 h The reaction was cooled to ambient temperature evaporated in vacuo The solid was collected by filtration

反応条件: temp:72.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of N-(2-hydroxyphenyl)benzamide (159 mg; 0.75 mmol), 2-(chloromethyl)-2-methyloxirane (1.60 g, 15 mmol), and benzyltriethylammonium chloride (27 mg, 0.12 mmol) was stirred at 70-75° C. for 6 h After cooling to room temperature, water (2 ml) was added and the mixture was vigorously shaken. It was extracted with dichloromethane (2×5 ml), and the combined organic extracts were washed with aq. NaOH (2M, 5 ml) and water (10 ml). Drying with Na2SO4, evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 25 to 50%) afforded title compound as yellowish solid (131 mg, 0.46 mmol, 62%). After cooling to room temperature the mixture was vigorously shaken It was extracted with dichloromethane (2×5 ml) the combined organic extracts were washed with aq. NaOH (2M, 5 ml) and water (10 ml) Drying with Na2SO4, evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 25 to 50%)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir: