Potassium Phosphate, Tribasic → (R)-N-(4-(Chlorodifluoromethoxy)phenyl)-5-(5-cyano-2-fluorophenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Participants

Reaction Conditions

Reaction Steps

5-Cyano-2-fluorophenylboronic acid (53.5 mg, 0.324 mmol), K3PO4 (138 mg, 0.648 mmol) and PdCl2(dppf)-(CH2Cl2) (17.65 mg, 0.022 mmol) were added to (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1,) in dioxane (1.5 mL) in a vial at RT. The vial was evacuated/purged with argon, sealed and stirred at 130° C. for 2.5 h. The RM was diluted with EtOAc (60 mL), washed with an aq. sat. solution of NaHCO3 (20 mL) and brine (2×20 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated off under reduced pressure. The residue was dissolved in MeOH (3 mL), filtered through a SPE PL-Thiol cartridge (StratoSpheres™, 500 mg, nominal:1.5 mmol), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 18% to 23% in 6 min) to afford the title product as a white solid. HPLC (Condition 10) tR=6.31 min, UPLC-MS (Condition 3) tR=1.12 min, m/z=503.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-2.01 (m, 2H) 2.93 (br. s, 1H) 3.19 (dd, J=11.14, 4.11 Hz, 1H) 3.23-3.43 (m, 2H) 4.21 (br. s, 1H) 4.84 (br. s, 1H) 7.34 (d, J=8.99 Hz, 3H) 7.57 (br. s, 1H) 7.80-7.91 (m, 3H) 7.94-8.24 (m, 4H) 8.79 (d, J=1.96 Hz, 1H) 10.16 (s, 1H).

Provenance & Evidence