Hydrochloric Acid → N-(4-(Chlorodifluoromethoxy)phenyl)-6-(trans-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

Participants

Reaction Steps

A suspension of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide (Stage 247.1, 80 mg, 0.195 mmol), trans-4-(hydroxymethyl)pyrrolidin-3-ol (+/−), hydrochloride (80 mg, 0.521 mmol) in a mixture of DIPEA (136 μL, 0.778 mmol) and iPrOH (389 μL) was subjected to MW irradiation at 140° C. for 1.5 h. The RM was treated with water (10 mL) and extracted with EtOAc. The combined extracts were washed with sat. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product that was purified by preparative SFC (Column DEAP, from 22% to 27% in 10 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=0.86 min, m/z=492.1 [M+H]+, m/z=536.2 [M+ formic acid-H]; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.04-2.14 (m, 1H) 2.89 (dd, J=11.13, 3.91 Hz, 1H) 3.10 (dd, J=11.13, 5.26 Hz, 1H) 3.20-3.29 (m, 2H) 3.34-3.48 (m, 2H) 3.92-4.01 (m, 1H) 4.63 (t, J=5.26 Hz, 1H) 4.98 (d, J=4.40 Hz, 1H) 7.35 (d, J=9.05 Hz, 2H) 7.81-7.90 (m, 2H) 8.10 (d, J=2.45 Hz, 1H) 8.80 (d, J=2.32 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.19 (s, 1H).

Provenance & Evidence