Water → (R)-2-(3-Hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-5'-(trifluoromethyl)-[3,3'-bipyridine]-5-carboxamide

Participants

Reaction Conditions

Reaction Steps

A mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 112 mg, 0.25 mmol), (5-(trifluoromethyl)pyridin-3-yl)boronic acid (71.6 mg, 0.375 mmol) and Cs2CO3 (163 mg, 0.5 mmol) in degassed dioxane (3 mL) in a MW vial was evacuated/purged with argon. PdCl2(dppf)-(CH2Cl2) (20.42 mg, 0.025 mmol) was added and the vial sealed. Water (0.6 mL) was added and the RM was stirred at 65° C. for 3.5 h. The solvent was evaporated off under reduced pressure to give a residue that was treated with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4/charcoal, filtered and the filtrate was evaporated off under reduced pressure to give a residue that was purified by flash chromatography (Silica gel column, 25 g, EtOAc). Palladium was removed using a SPE PL-Thiol MP cartridge (StratoSpheres™). The residue was dissolved in EtOAc and n-heptane was added. The solution was concentrated under reduced and the resulting suspension was stirred and filtered. The solid was washed with n-hexane then dried under HV at 45° C. to afford the title product as an amorphous white powder. UPLC-MS (Condition 3), tR=1.09 min, m/z=513.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.69-1.78 (m, 1H) 1.80-1.89 (m, 1H) 2.85 (d, J=10.92 Hz, 1H) 3.13-3.26 (m, 2H) 3.27-3.40 (m, 1H) 4.20 (br. s, 1H) 4.88 (br. s, 1H) 7.36 (d, J=8.66 Hz, 2H) 7.85 (d, J=8.85 Hz, 2H) 8.11 (s, 1H) 8.27 (br. s, 1H) 8.79 (s, 1H) 8.93 (s, 1H) 8.99 (s, 1H) 10.19 (s, 1H).

Provenance & Evidence