Triethylamine → tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate

Temperatur

0 °C

Zinc(II) chloride (1.0 M in Et2O; 1.08 mL, 1.08 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.216 g, 0.994 mmol) in 1:1 DCE/t-BuOH (8 mL) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 0° C. then tert-butyl 4-(4-amino-2-fluorophenyl)piperidine-1-carboxylate (A28) (0.266 g, 0.904 mmol) in 1:1 DCE/t-BuOH (8 mL) was added. A solution of Et3N (0.139 mL, 0.994 mmol) in 1:1 DCE/t-BuOH (5 mL) was then added dropwise at 0° C. and the resulting mixture was vigorously stirred for a further 30 minutes at 0° C., then at room temperature for 18 hours. The volatiles removed in vacuo to afford a brown residue which was purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 Cartridge, 0-20% EtOAc in petroleum benzine 40-60° C.) to yield a pale yellow solid. The solid was suspended in MeOH (15 mL) and water (15 mL) and the resulting suspension filtered to afford the title compound A29 as a white solid (0.363 g, 85%); 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.59-7.47 (m, 2H), 7.20-7.14 (m, 1H), 4.37-4.14 (m, 2H), 2.98 (tt, J=12.1, 3.4 Hz, 1H), 2.83 (t, J=11.7 Hz, 2H), 1.80 (d, J=12.8 Hz, 2H), 1.71-1.55 (m, 3H), 1.48 (s, 9H). LCMS-A: rt 6.902 min; m/z 473.1 [M−H]−.

1. stirringthe resulting mixture was vigorously stirred for a further 30 minutes at 0° C.
2. waitat room temperature for 18 hours
3. customThe volatiles removed in vacuo
4. customto afford a brown residue which
5. customwas purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 Cartridge, 0-20% EtOAc in petroleum benzine 40-60° C.)
6. customto yield a pale yellow solid
7. filtrationwater (15 mL) and the resulting suspension filtered

ORD-Eintrag

ord-da3fd6ff60794c369dc11c72cc5e481f

Quelldatensatz

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09266864B2