(2S)-2-[(2,4,6-trichlorophenoxy)methyl]pyrrolidine

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

実験手順: At a temperature of 0° C., a solution of 2-chloro-nicotinoyl chloride (0.313 g; 1.78 mmol) in dichloromethane (5 ml) was added dropwise to a stirred solution of (S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidine (0.30 g; 1.78 mmol), which was prepared as described in example P13, and triethylamine (0.50 ml; 3.56 mmol) in dichloromethane (10 ml). The ice bath was removed and reaction mixture was allowed stirring for 16 hours at ambient temperature. Dichloromethane (40 ml) was added to the mixture. The reaction mixture was washed with 2M HCl (40 ml), 1M NaOH (50 ml) and saturated NaCl (50 ml) and then dried over Na2SO4. After removal of the solvent, the residue (0.21 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1). 0.134 g (17.9% of theory) of (2-chloro-pyridin-3-yl)-[(S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidin-1-yl]-methanone was obtained in form of an oil. 1H NMR (400 MHz, CDCl3): δ 1.88-1.97 (m, 1H), 2.10-2.28 (m, 2H), 2.47-2.54 (m, 1H), 3.30-3.41 (m, 2H), 4.21-4.24 (m, 1H), 4.44 (m, 1H), 4.60-4.65 (m, 1H), 7.26 (s, 2H, Ar—H), 7.30-7.34 (m, 1H, Py-H), 7.68-7.72 (m, 1H, Py-H), 8.42-8.44 (m, 1H, Py-H). MS [M+H]+ 419/421/423/425. was prepared The ice bath was removed reaction mixture The reaction mixture was washed with 2M HCl (40 ml), 1M NaOH (50 ml) and saturated NaCl (50 ml) dried over Na2SO4 After removal of the solvent the residue (0.21 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1)

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

実験手順: At a temperature of 0° C., a solution of 2-chloro-nicotinoyl chloride (0.313 g; 1.78 mmol) in dichloromethane (5 ml) was added dropwise to a stirred solution of (S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidine (0.30 g; 1.78 mmol), which was prepared as described in example P13, and triethylamine (0.50 ml; 3.56 mmol) in dichloromethane (10 ml). The ice bath was removed and reaction mixture was allowed stirring for 16 hours at ambient temperature. Dichloromethane (40 ml) was added to the mixture. The reaction mixture was washed with 2M HCl (40 ml), 1M NaOH (50 ml) and saturated NaCl (50 ml) and then dried over Na2SO4. After removal of the solvent, the residue (0.21 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1). 0.134 g (17.9% of theory) of (2-chloro-pyridin-3-yl)-[(S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidin-1-yl]-methanone was obtained in form of an oil. 1H NMR (400 MHz, CDCl3): δ 1.88-1.97 (m, 1H), 2.10-2.28 (m, 2H), 2.47-2.54 (m, 1H), 3.30-3.41 (m, 2H), 4.21-4.24 (m, 1H), 4.44 (m, 1H), 4.60-4.65 (m, 1H), 7.26 (s, 2H, Ar—H), 7.30-7.34 (m, 1H, Py-H), 7.68-7.72 (m, 1H, Py-H), 8.42-8.44 (m, 1H, Py-H). MS [M+H]+ 419/421/423/425. was prepared The ice bath was removed reaction mixture The reaction mixture was washed with 2M HCl (40 ml), 1M NaOH (50 ml) and saturated NaCl (50 ml) dried over Na2SO4 After removal of the solvent the residue (0.21 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1)

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

実験手順: Sodium hydride 55% in oil (1.4 g; 29.8 mmol) was added portionwise over 10 minutes to a stirred solution of 2,4,6-trichlorophenol (5.89 g; 29.8 mmol) in dry dimethylformamide (90 ml) at a temperature of 10° C. under nitrogen. The reaction mixture was stirred for 20 minutes at ambient temperature followed by the addition of (S)-tetrahydro-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (5.0 g; 30.6 mmol), which was prepared as described in example P14, in dimethylformamide (25 ml). The reaction mixture was stirred for 4 hours at ambient temperature then poured onto 1M HCl (400 ml) and extracted with ethyl acetate (2×200 ml). The combined ethyl acetate layers are washed with water (2×100 ml), saturated NaCl (100 ml) and then dried over Na2SO4. After removal of the solvent the residue (11.1 g oil) was dissolved in dioxane (150 ml) and treated with sulphuric acid (2.9 ml) and water (2.9 ml). The reaction mixture was stirred at ambient temperature for 15 hours. The reaction mixture was poured on sat. NaHCO3 (300 ml) and extracted with dichloromethane (3×200 ml). The organic layers are washed with saturated NaCl (100 ml) and then dried over Na2SO4. After evaporation of the solvent, the crude product (7.16 g in the form of a orange oil) was purified by flash chromatography over silica gel (eluent:dichloromethane/methanol 9:1) to afford 3.53 g (42.0% of theory) of (S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidine as a oil. was prepared The reaction mixture was stirred for 4 hours at ambient temperature extracted with ethyl acetate (2×200 ml) The combined ethyl acetate layers are washed with water (2×100 ml), saturated NaCl (100 ml) dried over Na2SO4 After removal of the solvent the residue (11.1 g oil) was dissolved in dioxane (150 ml) treated with sulphuric acid (2.9 ml) and water (2.9 ml) The reaction mixture was stirred at ambient temperature for 15 hours The reaction mixture was poured on sat. NaHCO3 (300 ml) extracted with dichloromethane (3×200 ml) The organic layers are washed with saturated NaCl (100 ml) dried over Na2SO4 After evaporation of the solvent the crude product (7.16 g in the form of a orange oil) was purified by flash chromatography over silica gel (eluent:dichloromethane/methanol 9:1)

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

実験手順: Sodium hydride 55% in oil (1.4 g; 29.8 mmol) was added portionwise over 10 minutes to a stirred solution of 2,4,6-trichlorophenol (5.89 g; 29.8 mmol) in dry dimethylformamide (90 ml) at a temperature of 10° C. under nitrogen. The reaction mixture was stirred for 20 minutes at ambient temperature followed by the addition of (S)-tetrahydro-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (5.0 g; 30.6 mmol), which was prepared as described in example P14, in dimethylformamide (25 ml). The reaction mixture was stirred for 4 hours at ambient temperature then poured onto 1M HCl (400 ml) and extracted with ethyl acetate (2×200 ml). The combined ethyl acetate layers are washed with water (2×100 ml), saturated NaCl (100 ml) and then dried over Na2SO4. After removal of the solvent the residue (11.1 g oil) was dissolved in dioxane (150 ml) and treated with sulphuric acid (2.9 ml) and water (2.9 ml). The reaction mixture was stirred at ambient temperature for 15 hours. The reaction mixture was poured on sat. NaHCO3 (300 ml) and extracted with dichloromethane (3×200 ml). The organic layers are washed with saturated NaCl (100 ml) and then dried over Na2SO4. After evaporation of the solvent, the crude product (7.16 g in the form of a orange oil) was purified by flash chromatography over silica gel (eluent:dichloromethane/methanol 9:1) to afford 3.53 g (42.0% of theory) of (S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidine as a oil. was prepared The reaction mixture was stirred for 4 hours at ambient temperature extracted with ethyl acetate (2×200 ml) The combined ethyl acetate layers are washed with water (2×100 ml), saturated NaCl (100 ml) dried over Na2SO4 After removal of the solvent the residue (11.1 g oil) was dissolved in dioxane (150 ml) treated with sulphuric acid (2.9 ml) and water (2.9 ml) The reaction mixture was stirred at ambient temperature for 15 hours The reaction mixture was poured on sat. NaHCO3 (300 ml) extracted with dichloromethane (3×200 ml) The organic layers are washed with saturated NaCl (100 ml) dried over Na2SO4 After evaporation of the solvent the crude product (7.16 g in the form of a orange oil) was purified by flash chromatography over silica gel (eluent:dichloromethane/methanol 9:1)

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

実験手順: At a temperature of 0° C., a solution of 2-chloro-nicotinoyl chloride (0.313 g; 1.78 mmol) in dichloromethane (5 ml) was added dropwise to a stirred solution of (S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidine (0.30 g; 1.78 mmol), which was prepared as described in example P13, and triethylamine (0.50 ml; 3.56 mmol) in dichloromethane (10 ml). The ice bath was removed and reaction mixture was allowed stirring for 16 hours at ambient temperature. Dichloromethane (40 ml) was added to the mixture. The reaction mixture was washed with 2M HCl (40 ml), 1M NaOH (50 ml) and saturated NaCl (50 ml) and then dried over Na2SO4. After removal of the solvent, the residue (0.21 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1). 0.134 g (17.9% of theory) of (2-chloro-pyridin-3-yl)-[(S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidin-1-yl]-methanone was obtained in form of an oil. 1H NMR (400 MHz, CDCl3): δ 1.88-1.97 (m, 1H), 2.10-2.28 (m, 2H), 2.47-2.54 (m, 1H), 3.30-3.41 (m, 2H), 4.21-4.24 (m, 1H), 4.44 (m, 1H), 4.60-4.65 (m, 1H), 7.26 (s, 2H, Ar—H), 7.30-7.34 (m, 1H, Py-H), 7.68-7.72 (m, 1H, Py-H), 8.42-8.44 (m, 1H, Py-H). MS [M+H]+ 419/421/423/425. was prepared The ice bath was removed reaction mixture The reaction mixture was washed with 2M HCl (40 ml), 1M NaOH (50 ml) and saturated NaCl (50 ml) dried over Na2SO4 After removal of the solvent the residue (0.21 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1)

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

実験手順: Sodium hydride 55% in oil (1.4 g; 29.8 mmol) was added portionwise over 10 minutes to a stirred solution of 2,4,6-trichlorophenol (5.89 g; 29.8 mmol) in dry dimethylformamide (90 ml) at a temperature of 10° C. under nitrogen. The reaction mixture was stirred for 20 minutes at ambient temperature followed by the addition of (S)-tetrahydro-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (5.0 g; 30.6 mmol), which was prepared as described in example P14, in dimethylformamide (25 ml). The reaction mixture was stirred for 4 hours at ambient temperature then poured onto 1M HCl (400 ml) and extracted with ethyl acetate (2×200 ml). The combined ethyl acetate layers are washed with water (2×100 ml), saturated NaCl (100 ml) and then dried over Na2SO4. After removal of the solvent the residue (11.1 g oil) was dissolved in dioxane (150 ml) and treated with sulphuric acid (2.9 ml) and water (2.9 ml). The reaction mixture was stirred at ambient temperature for 15 hours. The reaction mixture was poured on sat. NaHCO3 (300 ml) and extracted with dichloromethane (3×200 ml). The organic layers are washed with saturated NaCl (100 ml) and then dried over Na2SO4. After evaporation of the solvent, the crude product (7.16 g in the form of a orange oil) was purified by flash chromatography over silica gel (eluent:dichloromethane/methanol 9:1) to afford 3.53 g (42.0% of theory) of (S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidine as a oil. was prepared The reaction mixture was stirred for 4 hours at ambient temperature extracted with ethyl acetate (2×200 ml) The combined ethyl acetate layers are washed with water (2×100 ml), saturated NaCl (100 ml) dried over Na2SO4 After removal of the solvent the residue (11.1 g oil) was dissolved in dioxane (150 ml) treated with sulphuric acid (2.9 ml) and water (2.9 ml) The reaction mixture was stirred at ambient temperature for 15 hours The reaction mixture was poured on sat. NaHCO3 (300 ml) extracted with dichloromethane (3×200 ml) The organic layers are washed with saturated NaCl (100 ml) dried over Na2SO4 After evaporation of the solvent the crude product (7.16 g in the form of a orange oil) was purified by flash chromatography over silica gel (eluent:dichloromethane/methanol 9:1)