tert-butyl N-[[4-(aminomethyl)phenyl]methyl]carbamate

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

実験手順: A solution of 2,4-dichloro-3-nitroquinoline (11.4 g, 47.1 mmol) in DMF (200 mL) was cooled to 0° C. Triethylamine (19.6 mL, 0.141 mol) and 1-(N-Boc-aminomethyl)-4-(aminomethyl)benzene (13.3 g, 56.5 mmol) were sequentially added, and the reaction was stirred for one hour and cooled again to 0° C. Water (300 mL) was added, and the mixture was stirred for 30 minutes at 0° C. and then extracted with dichloromethane. The dichloromethane fraction was concentrated under reduced pressure to provide 20 g of tert-butyl 4-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}benzylcarbamate as a red oil. the mixture was stirred for 30 minutes at 0° C. extracted with dichloromethane The dichloromethane fraction was 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 2,4-dichloro-3-nitroquinoline (11.4 g, 47.1 mmol) in DMF (200 mL) was cooled to 0° C. Triethylamine (19.6 mL, 0.141 mol) and 1-(N-Boc-aminomethyl)-4-(aminomethyl)benzene (13.3 g, 56.5 mmol) were sequentially added, and the reaction was stirred for one hour and cooled again to 0° C. Water (300 mL) was added, and the mixture was stirred for 30 minutes at 0° C. and then extracted with dichloromethane. The dichloromethane fraction was concentrated under reduced pressure to provide 20 g of tert-butyl 4-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}benzylcarbamate as a red oil. the mixture was stirred for 30 minutes at 0° C. extracted with dichloromethane The dichloromethane fraction was concentrated under reduced pressure

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

実験手順: 2-Chloro-nicotinic acid (2.86 g, 18.2 mmol), 1-hydroxybenzotriazole (3.0 g, 21.8 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.18 g, 21.8 mmol) were dissolved in N,N-dimethylformamide (50 ml) at room temperature and (4-aminomethyl-benzyl)-carbamic acid tert-butyl ester (4.29 g, 18.2 mmol) (see Preparation 1) added followed by addition of N-methyl morpholine (4 ml, 36.3 mmol). The reaction mixture was stirred under an atmosphere of nitrogen at room temperature for 18 hours, then partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic layer separated. The organic layer was then washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulphate and the solvent removed in vacuo. The residue was then triturated with diethylether (2-fold 10 ml) to give (4-{[(2-chloro-pyridine-3-carbonyl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester (6.71 g) as a white solid. partitioned between ethyl acetate (100 ml) and water (100 ml) the organic layer separated The organic layer was then washed with a saturated aqueous solution of sodium chloride (100 ml) dried over anhydrous magnesium sulphate the solvent removed in vacuo The residue was then triturated with diethylether (2-fold 10 ml)

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

実験手順: 2-(4-Fluoro-phenoxy)-nicotinic acid (see reference Patent application WO 98/45268) (6.20 g, 26 mmol), 1-hydroxybenzotriazole (5.39 g, 40 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.62 g, 34 mmol) were disolved in N,N-dimethylformamide (50 ml) at room temperature and (4-aminomethyl-benzyl)-carbamic acid tert-butyl ester (6.28 g, 26 mmol) (see Preparation 1) added followed by addition of N-methyl morpholine (4.4 ml, 40 mmol). The reaction mixture was stirred under an atmosphere of nitrogen at room temperature for 18 hours, and then partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic layer separated. The organic phase was then washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulphate and the solvent removed in vacuo. The residue was triturated with diethylether (15 ml) giving [4-({[2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester (9.52 g) as an off-white solid. partitioned between ethyl acetate (100 ml) and water (100 ml) the organic layer separated The organic phase was then washed with a saturated aqueous solution of sodium chloride (100 ml) dried over anhydrous magnesium sulphate the solvent removed in vacuo The residue was triturated with diethylether (15 ml)

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: At 0° C., 25.0 g (106 mmol) of 4-(tert-butyloxycarbonylaminomethyl)benzylamine in 150 ml of dichloromethane are added dropwise to a solution of 22.4 g (111 mmol) of 4-nitrophenyl chloroformate in 200 ml of dichloromethane, and the mixture is stirred for 10 min. 15.6 ml (111 mmol) of triethylamine are then added dropwise, and the mixture is stirred at RT for 1.5 h. At 0° C., initially 24.5 g (111 mmol) of benzyl piperazine-1-carboxylate in 80 ml of dichloromethane and then 15.6 ml (111 mmol) of triethylamine are added dropwise. The mixture is stirred at RT for 16 h. The solvent is removed from the reaction mixture and the crude product is chromatographed over silica gel (toluene/ethyl acetate=1:1). Crystallization from diisopropyl ether gives 41.7 g of the title compound as a colorless solid of m.p. 108–112° C. the mixture is stirred at RT for 1.5 h The mixture is stirred at RT for 16 h The solvent is removed from the reaction mixture the crude product is chromatographed over silica gel (toluene/ethyl acetate=1:1) Crystallization from diisopropyl ether

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

実験手順: At 0° C., 25.0 g (106 mmol) of 4-(tert-butyloxycarbonylaminomethyl)benzylamine in 150 ml of dichloromethane are added dropwise to a solution of 22.4 g (111 mmol) of 4-nitrophenyl chloroformate in 200 ml of dichloromethane, and the mixture is stirred for 10 min. 15.6 ml (111 mmol) of triethylamine are then added dropwise, and the mixture is stirred at RT for 1.5 h. At 0° C., initially 24.5 g (111 mmol) of benzyl piperazine-1-carboxylate in 80 ml of dichloromethane and then 15.6 ml (111 mmol) of triethylamine are added dropwise. The mixture is stirred at RT for 16 h. The solvent is removed from the reaction mixture and the crude product is chromatographed over silica gel (toluene/ethyl acetate=1:1). Crystallization from diisopropyl ether gives 41.7 g of the title compound as a colorless solid of m.p. 108–112° C. the mixture is stirred at RT for 1.5 h The mixture is stirred at RT for 16 h The solvent is removed from the reaction mixture the crude product is chromatographed over silica gel (toluene/ethyl acetate=1:1) Crystallization from diisopropyl ether