Diethyl Ether → tert-Butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

Temperature

0 °C

2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.355 g, 1.64 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (30 mL) at 0° C. and a 1.0 M ZnCl2 solution in diethyl ether (1.87 mL, 1.87 mmol) was added cautiously over 20 minutes and the reaction was left stirring at 0° C. for 30 minutes. A solution of tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate (I23) (0.431 g, 1.56 mmol) in 1:1 t-BuOH:1,2-dichloroethane (10 mL) was added drop-wise over 15 minutes at 0° C. followed by a solution of triethylamine (0.261 μL, 1.871 mmol) in 1:1 t-BuOH:1,2-dichloroethane (10 mL). The reaction was allowed to warm to room temperature and was stirred for 60 hours. Volatiles were evaporated in vacuo and the resulting oily residue was suspended in water (200 mL), the suspension was sonicated for 30 minutes and the product was collected by filtration, the solid was washed with water (5×10 mL) and dried under a high vacuum to give the title compound (I24) (0.638 g, 90% yield) as a pale pink solid; 1H NMR (400 MHz, d6-DMSO) δ 10.62 (s, 1H), 8.78 (s, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.6 Hz, 2H), 4.05-3.87 (m, 2H), 2.94-2.63 (m, 2H), 2.57 (ddd, J=11.2, 7.7, 3.7 Hz, 1H), 1.87 (d, J=12.8 Hz, 1H), 1.75-1.54 (m, 2H), 1.51-1.35 (m, 10H). LCMS Method C: rt 6.89 min; m/z 455.3 [M+H]−

1. waitthe reaction was left
2. temperatureto warm to room temperature
3. stirringwas stirred for 60 hours
4. customVolatiles were evaporated in vacuo
5. customthe suspension was sonicated for 30 minutes
6. filtrationthe product was collected by filtration
7. washthe solid was washed with water (5×10 mL)
8. customdried under a high vacuum

ORD record

ord-dc7fa9f630484ae0886b36aaaaf3cce5

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09012461B2