Trifluoroacetic acid → (R)-N-(4-(Chlorodifluoromethoxy)phenyl)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Participants

Reaction Conditions

Reaction Steps

2M Na2CO3 (0.375 mL, 0.75 mmol) was added to a solution of (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2, 116 mg, 0.25 mmol) and 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (161 mg, 0.5 mmol) in DME (1.0 mL). under an argon atmosphere. PdCl2(dppf) (9.15 mg, 0.013 mmol) was then added and the RM mixture was stirred at 100° C. for 2 h. After cooling at RT, the RM was dissolved in EtOAc and washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude product was dissolved in DCM (1.4 mL) cooled to 0° C., then treated with TFA (0.77 mL, 10 mmol) and stirred at RT for 3 h. The RM was poured into aq. Na2CO3 10% (15 mL) 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 flash chromatography (RediSep® Silica gel column, DCM/MeOH, from 2% to 10% MeOH) to afford an off-white powder. HPLC (Condition 4) tR=4.33 min, UPLC-MS (Condition 3) tR=0.88 min, m/z=494 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.88 (m, 2H) 2.96 (d, J=11.73 Hz, 0H) 3.24-3.37 (m, 2H) 3.41-3.53 (m, 1H) 3.75 (q, J=5.73 Hz, 2H) 4.04-4.25 (m, 4H) 4.81 (d, J=3.52 Hz, 1H) 4.86-4.94 (m, 1H) 7.31 (d, J=8.21 Hz, 2H) 7.53-7.59 (m, 1H) 7.79-7.89 (m, 3H) 7.93 (d, J=2.35 Hz, 1H) 8.65 (dd, J=2.35, 0.78 Hz, 1H) 10.15 (s, 1H).

Provenance & Evidence