2-(bromomethyl)-1-chloro-3-(trifluoromethyl)benzene

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: 20% palladium hydroxide (75.8 mg) was added to a solution of tert-butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-[(2,6-dichlorophenyl)methyl]-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 5b (a chiral form corresponding to the peak with a shorter retention time) (758 mg, 1.29 mmol) in methanol (20 ml), followed by stirring at 40° C. for three hours under a hydrogen atmosphere. The reaction liquid was filtered, and the filtrate was concentrated to give a crude product (501 mg). 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (145 mg, 0.532 mmol) and potassium carbonate (53.2 mg) were added to a solution of this crude product (174 mg) in N,N-dimethylformamide (dehydrated) (6 mL), followed by stirring overnight. 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (145 mg, 0.532 mmol) and potassium carbonate (106 mg) were further added, followed by stirring for four hours. Ethyl acetate was added to the reaction liquid, which was washed with a 1N aqueous sodium hydroxide solution and brine. This was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to give the title compound (82 mg, yield: 32.4%). The reaction liquid was filtered the filtrate was concentrated to give a crude product (501 mg) by stirring overnight by stirring for four hours was washed with a 1N aqueous sodium hydroxide solution and brine This was dried over anhydrous magnesium sulfate concentrated The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate)

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

実験手順: 20% palladium hydroxide (75.8 mg) was added to a solution of tert-butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-[(2,6-dichlorophenyl)methyl]-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 5b (a chiral form corresponding to the peak with a shorter retention time) (758 mg, 1.29 mmol) in methanol (20 ml), followed by stirring at 40° C. for three hours under a hydrogen atmosphere. The reaction liquid was filtered, and the filtrate was concentrated to give a crude product (501 mg). 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (145 mg, 0.532 mmol) and potassium carbonate (53.2 mg) were added to a solution of this crude product (174 mg) in N,N-dimethylformamide (dehydrated) (6 mL), followed by stirring overnight. 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (145 mg, 0.532 mmol) and potassium carbonate (106 mg) were further added, followed by stirring for four hours. Ethyl acetate was added to the reaction liquid, which was washed with a 1N aqueous sodium hydroxide solution and brine. This was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to give the title compound (82 mg, yield: 32.4%). The reaction liquid was filtered the filtrate was concentrated to give a crude product (501 mg) by stirring overnight by stirring for four hours was washed with a 1N aqueous sodium hydroxide solution and brine This was dried over anhydrous magnesium sulfate concentrated The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate)

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(Cyclohex-1-en-1-ylmethyl)piperidin-4-amine obtained in Example 4b (240 mg, 1.24 mmol), N,N-dimethylformamide (3 ml), triethylamine (344 μl, 2.47 mmol) and PyBOP (856 mg, 1.64 mmol) were added to (3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Example 4h (200 mg, 0.822 mmol), followed by stirring with heating in a 45° C. oil bath for 1.5 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (247 mg, 0.903 mmol), potassium carbonate (170 mg, 1.23 mmol) and N,N-dimethylformamide (1 ml) were added thereto, followed by heating with stirring in a 45° C. oil bath for three hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over magnesium sulfate. The resulting crude product was purified by column chromatography twice (NH silica gel, elution solvent: ethyl acetate/heptane and silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (353 mg, yield 70.1%). was extracted with ethyl acetate The organic layer was dried over magnesium sulfate concentrated by heating with stirring in a 45° C. oil bath for three hours was extracted with ethyl acetate The organic layer was washed with water and brine dried over magnesium sulfate The resulting crude product was purified by column chromatography twice (NH silica gel, elution solvent: ethyl acetate/heptane and silica gel, elution solvent: ethyl acetate/heptane)

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(Cyclohex-1-en-1-ylmethyl)piperidin-4-amine obtained in Example 4b (240 mg, 1.24 mmol), N,N-dimethylformamide (3 ml), triethylamine (344 μl, 2.47 mmol) and PyBOP (856 mg, 1.64 mmol) were added to (3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Example 4h (200 mg, 0.822 mmol), followed by stirring with heating in a 45° C. oil bath for 1.5 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (247 mg, 0.903 mmol), potassium carbonate (170 mg, 1.23 mmol) and N,N-dimethylformamide (1 ml) were added thereto, followed by heating with stirring in a 45° C. oil bath for three hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over magnesium sulfate. The resulting crude product was purified by column chromatography twice (NH silica gel, elution solvent: ethyl acetate/heptane and silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (353 mg, yield 70.1%). was extracted with ethyl acetate The organic layer was dried over magnesium sulfate concentrated by heating with stirring in a 45° C. oil bath for three hours was extracted with ethyl acetate The organic layer was washed with water and brine dried over magnesium sulfate The resulting crude product was purified by column chromatography twice (NH silica gel, elution solvent: ethyl acetate/heptane and silica gel, elution solvent: ethyl acetate/heptane)

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

実験手順: 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (443 mg, 1.62 mmol) and potassium carbonate (244 mg) were added to a solution of tert-butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 3b (345 mg, 0.811 mmol) in N,N-dimethylformamide (dehydrated) (10 mL), which was stirred at 45° C. for six hours and at 40° C. for two days. Ethyl acetate was added to the reaction liquid, which was washed with a 1N aqueous sodium hydroxide solution and brine. This was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to give the title compound (320 mg, yield: 63.8%). was washed with a 1N aqueous sodium hydroxide solution and brine This was dried over anhydrous magnesium sulfate concentrated The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate)

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

実験手順: 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (443 mg, 1.62 mmol) and potassium carbonate (244 mg) were added to a solution of tert-butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 3b (345 mg, 0.811 mmol) in N,N-dimethylformamide (dehydrated) (10 mL), which was stirred at 45° C. for six hours and at 40° C. for two days. Ethyl acetate was added to the reaction liquid, which was washed with a 1N aqueous sodium hydroxide solution and brine. This was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to give the title compound (320 mg, yield: 63.8%). was washed with a 1N aqueous sodium hydroxide solution and brine This was dried over anhydrous magnesium sulfate concentrated The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate)

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of the chiral form of tert-butyl 2-[(3R*,4S*)-1-benzyl-3-{[1-(2-fluoropentyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3-yl]acetate obtained in Example 1k (161 mg, 0.32 mmol), 20% palladium hydroxide (135 mg) and methanol (5 ml) was stirred at mom temperature for 15 hours under a hydrogen atmosphere. The atmosphere in the reaction vessel was replaced with nitrogen, 20% palladium hydroxide was filtered off, and the solvent was distilled off. 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (159 mg, 0.581 mmol), potassium carbonate (97 mg, 0.702 mmol) and N,N-dimethylformamide (2 ml) were added to the resulting residue, which was heated at 45° C. for three hours and 15 minutes. Water was added to the reaction mixture, which was extracted with ethyl acetate twice. The organic layer was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (153 mg, yield 78.9%). was filtered off the solvent was distilled off was extracted with ethyl acetate twice The organic layer was washed with a saturated aqueous ammonium chloride solution dried over anhydrous magnesium sulfate the solvent was distilled off The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/heptane)

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of the chiral form of tert-butyl 2-[(3R*,4S*)-1-benzyl-3-{[1-(2-fluoropentyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3-yl]acetate obtained in Example 1k (161 mg, 0.32 mmol), 20% palladium hydroxide (135 mg) and methanol (5 ml) was stirred at mom temperature for 15 hours under a hydrogen atmosphere. The atmosphere in the reaction vessel was replaced with nitrogen, 20% palladium hydroxide was filtered off, and the solvent was distilled off. 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (159 mg, 0.581 mmol), potassium carbonate (97 mg, 0.702 mmol) and N,N-dimethylformamide (2 ml) were added to the resulting residue, which was heated at 45° C. for three hours and 15 minutes. Water was added to the reaction mixture, which was extracted with ethyl acetate twice. The organic layer was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (153 mg, yield 78.9%). was filtered off the solvent was distilled off was extracted with ethyl acetate twice The organic layer was washed with a saturated aqueous ammonium chloride solution dried over anhydrous magnesium sulfate the solvent was distilled off The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/heptane)

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: 20% palladium hydroxide (75.8 mg) was added to a solution of tert-butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-[(2,6-dichlorophenyl)methyl]-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 5b (a chiral form corresponding to the peak with a shorter retention time) (758 mg, 1.29 mmol) in methanol (20 ml), followed by stirring at 40° C. for three hours under a hydrogen atmosphere. The reaction liquid was filtered, and the filtrate was concentrated to give a crude product (501 mg). 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (145 mg, 0.532 mmol) and potassium carbonate (53.2 mg) were added to a solution of this crude product (174 mg) in N,N-dimethylformamide (dehydrated) (6 mL), followed by stirring overnight. 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (145 mg, 0.532 mmol) and potassium carbonate (106 mg) were further added, followed by stirring for four hours. Ethyl acetate was added to the reaction liquid, which was washed with a 1N aqueous sodium hydroxide solution and brine. This was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to give the title compound (82 mg, yield: 32.4%). The reaction liquid was filtered the filtrate was concentrated to give a crude product (501 mg) by stirring overnight by stirring for four hours was washed with a 1N aqueous sodium hydroxide solution and brine This was dried over anhydrous magnesium sulfate concentrated The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate)

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(Cyclohex-1-en-1-ylmethyl)piperidin-4-amine obtained in Example 4b (240 mg, 1.24 mmol), N,N-dimethylformamide (3 ml), triethylamine (344 μl, 2.47 mmol) and PyBOP (856 mg, 1.64 mmol) were added to (3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Example 4h (200 mg, 0.822 mmol), followed by stirring with heating in a 45° C. oil bath for 1.5 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (247 mg, 0.903 mmol), potassium carbonate (170 mg, 1.23 mmol) and N,N-dimethylformamide (1 ml) were added thereto, followed by heating with stirring in a 45° C. oil bath for three hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over magnesium sulfate. The resulting crude product was purified by column chromatography twice (NH silica gel, elution solvent: ethyl acetate/heptane and silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (353 mg, yield 70.1%). was extracted with ethyl acetate The organic layer was dried over magnesium sulfate concentrated by heating with stirring in a 45° C. oil bath for three hours was extracted with ethyl acetate The organic layer was washed with water and brine dried over magnesium sulfate The resulting crude product was purified by column chromatography twice (NH silica gel, elution solvent: ethyl acetate/heptane and silica gel, elution solvent: ethyl acetate/heptane)