1,2-Dichloroethane → (R)-N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

Participants

Reaction Steps

(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinic acid (Stage 170.1, 57.3 mg, 0.2 mmol), HOBT (43.5, 0.284 mmol) and EDC (42.2 mg, 0.22 mmol) were dissolved in 0.3 M NMM in DMF (0.8 mL) at RT. 4-(Chlorodifluoromethoxy)aniline (36.8 mg, 0.19 mmol) was added and the RM was stirred for 5 h. The RM was then diluted with EtOAc and washed with 10% NaHCO3. The organic layer was dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH, from 2 to 5% MeOH) and treated with Si-Thiol (50 mg) in MeOH to afford the title compound. HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, eluent: EtOH/MeOH (50:50), 0.5 mL/min, UV 210 nm) tR=21.89 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=462.2/464.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.80-1.89 (m, 1H) 2.87 (d, J=11.34 Hz, 1H) 3.21 (m, J=11.10, 4.90 Hz, 2H) 3.33-3.44 (m, 1H) 4.12-4.24 (m, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.77-7.89 (m, 2H) 8.08 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.17 (s, 1H).

Provenance & Evidence