Diisopropylethylamine → 6-(3,3-Difluoropyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Participants

Reaction Conditions

Reaction Steps

6-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 223.1, 100 mg, 0.253 mmol) was suspended in iPrOH (0.5 mL). 3,3-Difluoropyrrolidine hydrochloride (72.7 mg, 0.507 mmol) and DIPEA (0.177 mL, 1.013 mmol) were added at RT. The light brown solution was stirred at 140° C. for 23 h. The RM was diluted with EtOAc (50 mL) and washed with a 2 N citric acid solution (20 mL) and water (3×20 mL). The combined aq. phases were extracted with EtOAc and the combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated off under reduced pressure to give the crude material that was purified by flash chromatography (RediSep® Silica gel column, 24 g, DCM/EtOAc 7:3). The resulting product was dissolved in MeOH (2 mL). The resulting white suspension was stirred at RT for 15 min then filtered. The solid was washed with MeOH (5 mL) and dried to afford the title product as a white solid. HPLC (Condition 10) tR=7.017 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=466.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.39 (spt, J=7.04 Hz, 2H) 3.37 (t, J=7.23 Hz, 2H) 3.62 (t, J=13.10 Hz, 2H) 7.37 (d, J=8.99 Hz, 2H) 7.82-7.89 (m, 2H) 8.15-8.19 (m, 1H) 8.82-8.85 (m, 1H) 8.94 (d, J=0.78 Hz, 2H) 9.23 (s, 1H) 10.27 (s, 1H).

Provenance & Evidence