Thionyl Chloride → 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Participants

Reaction Conditions

Reaction Steps

A stirred solution of 5-bromo-6-chloro-nicotinic acid (375 g, 1.586 mol) and DMF (37 mL) in toluene (3.1 L) was treated dropwise with SOCl2 (347 mL, 4.758 mol) at RT and then stirred at 85° C. for 2.5 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in THF (3.1 L), cooled to −25° C., treated firstly with DIPEA (543 mL, 3.172 mol) and then by the dropwise addition of a solution of 4-(trifluoromethoxy)aniline (295 g, 1.665 mol) in THF (3.1 L), After 30 min at 10° C. the solvent was evaporated off under reduced pressure and the residue was dissolved in TBME (4 L), washed with 1N HCl (2×1 L), a sat. solution of NaHCO3 (1 L) and brine (2×200 mL) and dried over Na2SO4. The solvent was evaporated off under reduced pressure and the product was crystallized from EtOAc/n-heptane to give the title compound as a beige crystalline solid. UPLC-MS (Condition 3) tR=1.25 min, m/z=393/395/397 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=8.60 Hz, 2H) 7.86 (d, J=8.60 Hz, 2H) 8.73 (d, J=2.20 Hz, 1H) 8.92 (d, J=2.20 Hz, 1H) 10.69 (s, 1H).

Provenance & Evidence