Sodium Bicarbonate → (S)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

Participants

Reaction Conditions

Reaction Steps

(S)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 185.1, 116 mg, 0.25 mmol) and pyrimidin-5-ylboronic acid (62 mg, 0.5 mmol) were dissolved in DME (1 mL). A solution of 2 M NaHCO3 (0.375 mL, 0.75 mmol) was added, the mixture was flushed with argon, heated to 100° C. in a pressure safe vial and PdCl2(dppf) (9.15 mg, 0.013 mmol) was added. The RM was stirred under argon at 100° C. for 2 h. The RM was cooled to RT, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (RediSep® Silica gel column, EtOAc/(EtOAc/MeOH 98:2), 50% to 100% (EtOAc/MeOH 98:2) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as a white powder. HPLC (Condition 4) tR=5.03 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, 5 μm, eluent: EtOH/MeOH (50:50), 1 mL/min, UV 220 nm, tR=24.83 min, UPLC-MS (Condition 3) tR=0.99 min, m/z=462.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.80-1.90 (m, 1H) 2.88 (d, J=11.34 Hz, 1H) 3.21 (m, J=10.90, 4.70 Hz, 2H) 3.33-3.43 (m, 1H) 4.20 (d, J=1.96 Hz, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.68 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.99 Hz, 2H) 8.09 (d, J=2.35 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.26 (s, 1H).

Provenance & Evidence