反应详情

温度

80 °C

Phosphoryl chloride (0.27 ml, 2.94 mmol) was added to a solution of tert-butyl (2R)-2-{[(7-methoxy-4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (0.550 g, 1.47 mmol) and di-iso-propylethylamine (1.02 ml, 5.88 mmol) in 1,2-dichloroethane (20 ml) and the reaction was heated at 80° C. for 1 hour. The mixture was evaporated under reduced pressure and the residue suspended in dimethylacetamide (10 ml) and then 2-(4-amino-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide (0.370 g, 1.47 mmol) was added and the mixture was heated at 90° C. for 1 hour. The mixture was evaporated under reduced pressure and the residue stirred in a 7N solution of ammonia in methanol (100 ml) at ambient temperature for 2 hours. The mixture was evaporated under reduced pressure to leave a yellow solid which was stirred in water (50 ml) for 1 hour and then filtered and the residue purified by silica gel chromatography eluting with a 0 to 10% mixture methanol in dichloromethane to give tert-butyl (2R)-2-[({4-[(1-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]-7-methoxy-3,4-dihydroquinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (0.400 g, 44% yield over 3 steps):

1. customThe mixture was evaporated under reduced pressure
2. temperaturethe mixture was heated at 90° C. for 1 hour
3. customThe mixture was evaporated under reduced pressure
4. customThe mixture was evaporated under reduced pressure
5. customto leave a yellow solid which
6. filtrationfiltered
7. customthe residue purified by silica gel chromatography
8. washeluting with a 0 to 10% mixture methanol in dichloromethane