Ammonia → 6-Chloro-5-(1H-imidazol-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Participants

Reaction Conditions

Reaction Steps

A solution of isopropyl magnesium chloride 2 M in THF (2.5 mL, 5 mmol) was added dropwise to a solution of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 32.2, 885 mg, 2 mmol) in THF (15 mL) at a temperature between −70 and −85° C. under an argon atmosphere. The RM was then stirred at between −45 and −40° C. for 30 min, then cooled to −75° C. and treated dropwise with DMF (0.465 mL, 6.00 mmol). The RM allowed to slowly warm to RT, then treated with NH4Cl aq. solution (15 mL) and extracted with EtOAc. The combined extracts were washed with a sat. NH4Cl solution, with water and brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure. The residue was dissolved in MeOH (10 mL), treated with glyoxal 40% in water (0.178 mL, 3.89 mmol) and 25% aq. NH3 (1.462 mL, 19.44 mmol) and the RM was stirred for at RT for 24 h. The solvent was evaporated off under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by column chromatography (Silica gel, 50 g, n-hexane/EtOAc 2:1 and 1:1) and recrystallized from n-hexane/EtOAC to afford the title product as white crystals. UPLC-MS (Condition 3) tR 0.88 min, m/z=383.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 7.19 (s, 1H) 7.41 (d, J=7.72 Hz, 3H) 7.89 (d, J=8.85 Hz, 2H) 8.76 (d, J=2.07 Hz, 1H) 8.94 (d, J=2.07 Hz, 1H) 10.77 (s, 1H) 12.60 (br. s, 1H).

Provenance & Evidence