Nitrogen → Tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

Zinc chloride (1.0 M in Et2O) (1.97 mL, 1.97 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.384 g, 1.77 mmol) in 1:1 DCE/t-BuOH (10 mL) at 0° C. under a stream of N2 gas. The mixture was stirred for 1 hour at 0° C. and then tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (I44) (0.453 g, 1.64 mmol) in 1:1 DCE/tBuOH (7 mL) was added. A solution of NEt3 (0.251 mL, 1.80 mmol) in 1:1 DCE/t-BuOH (8 mL) was next added dropwise at 0° C. The reaction mixture was vigorously stirred for a further 30 minutes at 0° C. after the final addition and then at room temperature for 24 hours. The solvent was removed in vacuo to afford a brown oily residue which was purified by column chromatography on silica gel (0-20% EtOAc in petroleum benzine 40-60° C.) to yield a pale yellow solid. The solid was suspended in MeOH (10 mL) and water (10 mL). The resulting precipitate was filtered to afford the title compound (I45) (0.658 g, 88%) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.60 (s, 1H), 8.77 (d, J=0.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 4.13-3.98 (m, 2H), 2.80 (bs, 2H), 2.69-2.61 (m, 1H), 1.74 (d, J=12.4 Hz, 2H), 1.53-1.39 (m, 11H). LCMS Method C: rt 6.81 min; m/z 401 [M−tButyl+2H]+, 357 [M-Boc+2H]+.

Provenance & Evidence