Triethylamine → tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

Zinc chloride (1.0 M in Et2O) (8.56 mL, 8.56 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.06 mL, 7.85 mmol) in 1:1 DCE/t-BuOH (10 mL) at 0° C. under nitrogen. The mixture was stirred for 1 hour at 0° C. and then tert-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate (I26) (1.97 g, 7.13 mmol) in 1:1 DCE/tBuOH (30 mL) was added. A solution of triethylamine (600 μL, 0.432 mmol, 1.1 eq) in 1:1 DCE/t-BuOH (10 mL) was next added drop-wise 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 (0-45% EtOAc in petroleum benzine 40-60° C.) to give a pale yellow oil which solidified upon standing. This was triturated sequentially with water, 1:1 water/MeOH and MeOH and the precipitate was filtered to afford a white solid. The solid was recrystallised from water to give the title compound (I34) (0.92 g, 30%) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.01 (s, 1H), 6.86 (dd, J=8.4, 1.7 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 4.25 (s, 2H), 3.91 (s, 3H), 2.81 (t, J=11.8 Hz, 2H), 2.64 (tt, J=12.1, 3.6 Hz, 1H), 1.83 (d, J=13.5 Hz, 2H), 1.69-1.57 (m, 2H), 1.49 (s, 9H). LCMS Method C: rt 7.00 min; m/z=487.0 [M+H]+, 431.0 [M-tButyl+H]+, 485.0 [M−H]−.

Provenance & Evidence