反应详情

温度

0 °C

2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.110 g, 0.506 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (10 mL) at 0° C. A 1.0 M ZnCl2 solution in diethyl ether (0.578 mL, 0.578 mmol) was added cautiously, after addition the reaction was left stirring at 0° C. for 30 minutes. A solution of tert-butyl 4-(4-amino-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I47) (impure, ˜80% pure, 0.217 g, 0.482 mmol) in 1:1 t-BuOH:1,2-dichloroethane (5 mL) was added drop-wise at 0° C. followed by a solution of NEt3 (0.081 mL, 0.58 mmol) in 1:1 t-BuOH:1,2-dichloroethane (5 mL) and the reaction was allowed to warm to room temperature and was stirred for 18 hours, then at 60° C. for 24 hours. The organic solvents were evaporated vacuo and the crude gum was purified by silica gel chromatography (40 g Si cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I48) (0.085 g, 33% yield) as a pale yellow oily solid; 1H NMR (400 MHz, d6-DMSO) δ 10.38 (s, 1H), 8.72 (s, 1H), 7.52 (cl, J=8.1 Hz, 1H), 7.33-7.29 (m, 2H), 4.13-4.04 (m, 2H), 2.88-2.72 (m, 3H), 1.79 (d, J=12.1 Hz, 2H), 1.56-1.44 (m, 2H), 1.42 (s, 9H). LCMS Method C: rt 7.02 min; m/z 539.0, 541.0 [M−H]−.

1. customat 0° C
2. additionafter addition the reaction
3. waitwas left
4. temperatureto warm to room temperature
5. stirringwas stirred for 18 hours
6. waitat 60° C. for 24 hours
7. customThe organic solvents were evaporated vacuo
8. customthe crude gum was purified by silica gel chromatography (40 g Si cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.)