反应详情

A mixture of 5-bromo-6-(2-methoxyethoxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 51.1, 50 mg, 0.115 mmol), 1-(tetrahydro-2h-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (49 mg, 0.172 mmol), Pd(Ph3P)4 (13 mg, 0.011 mmol) and toluene (0.5 mL) was stirred for 15 min under an argon atmosphere. K3PO4 (73 mg, 0.345 mmol) was added and the RM was stirred at 110° C. for 6 h. The RM was diluted with MeOH, filtered through a cartridge of PL-Thiol MP-Resin, and the filtrate was evaporated to dryness under reduced pressure to afford 6-(2-methoxyethoxy)-5-(1-(tetrahydro-2h-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, of which (50 mg, 0.099 mmol), TFA (0.25 mL, 3.24 mmol) and DCM (0.4 mL) was stirred at RT for 2 h. The mixture was treated with a solution of Na2CO3 (2 M) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative SFC (Column Diol; gradient 13% to 18% in 6 min.) and lyophilized to afford an off-white powder. UPLC-MS (Condition 2) tR=1.04 min, m/z=423.3 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.34 (s, 3H) 3.73-3.82 (m, 2H) 4.58 (br. s, 2H) 6.90 (d, J=1.88 Hz, 1H) 7.37 (d, J=8.47 Hz, 2H) 7.83-7.87 (m, 1H) 7.89 (d, J=9.03 Hz, 2H) 8.70 (d, J=2.26 Hz, 1H) 8.77-8.90 (m, 1H) 10.55 (br. s, 1H) 13.06-13.22 (m, 1H).

1. stirringthe RM was stirred at 110° C. for 6 h
2. filtrationfiltered through a cartridge of PL-Thiol MP-Resin
3. customthe filtrate was evaporated to dryness under reduced pressure