1,2-Dimethoxyethane → (R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1H-pyrrol-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Participants

Reaction Conditions

Reaction Steps

A mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.1, 100 mg, 0.224 mmol), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (131 mg, 0.448 mmol), Pd(PPh3)2Cl2 (15.73 mg, 0.022 mmol), Na2CO3 (95 mg, 0.896 mmol), DME (951 μL), water (272 μL) and EtOH (136 μL) in a MW vial was sealed, evacuated/purged 3 times with argon and stirred at 80° C. for 16 h. MeOH (0.5 mL) was added and the RM was subjected to MW irradiation at 150° C. for 5 min, diluted with DME (3 mL) and treated with Si-Thiol (Silicycle, 1.44 mmol/g, 93 mg, 0.134 mmol) overnight. The RM was centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 20% to 25% in 6 min) to afford the title compound as a grey solid. UPLC-MS (Condition 3) tR 1.02 min, m/z=433.4 [M+H]+, m/z=477.3 [M+formic acid-H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.77 (m, 1H) 1.77-1.88 (m, 1H) 2.97 (d, J=11.80 Hz, 1H) 3.23-3.32 (m, 2H) 3.39-3.49 (m, 1H) 4.15-4.24 (m, 1H) 4.79-4.89 (m, 1H) 6.06-6.13 (m, 2H) 6.76-6.84 (m, 1H) 7.34 (d, J=8.28 Hz, 2H) 7.82-7.92 (m, 2H) 8.02 (d, J=2.51 Hz, 1H) 8.69 (d, J=2.51 Hz, 1H) 10.17 (s, 1H) 11.14 (d, J=1.76 Hz, 1H).

Provenance & Evidence