反应详情

A solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (981 mg, 4.52 mmol) in 1:1 tert-butanol:dichloroethane (40 mL) was cooled to 0° C. under nitrogen then 1.0 M zinc(II) chloride in ether (4.52 mL, 4.52 mmol) was added dropwise. After one hour a solution of tert-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate (I26) (1.26 g, 4.11 mmol) and triethylamine (0.860 mL, 6.17 mmol) in 1:1 tert-butanol:dichloroethane (50 mL) was added dropwise at −10° C. then the mixture was stirred for 16 hours allowing the temperature to rise to room temperature. The mixture was concentrated, evaporated onto silica and chromatographed (120 g silica cartridge, 0-10% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I27) (1.277 g, 64% yield) 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=8.3, 1.8 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 4.25 (br s. 2H), 3.91 (s, 3H), 2.87-2.73 (m, 2H), 2.64 (tt, J=12.1, 3.6 Hz, 1H), 1.83 (d, J=12.5 Hz, 2H), 1.69-1.54 (m, overlaps with water), 1.49 (s, 9H). LCMS Method C: rt 7.12 min; m/z 431.0 [M-tBu+2H]+, 387.1 [M-Boc+2H]+; m/z 485.1 [M−H]−.

1. customto rise to room temperature
2. concentrationThe mixture was concentrated
3. customevaporated onto silica
4. customchromatographed (120 g silica cartridge, 0-10% ethyl acetate/petroleum benzine 40-60° C.)