Methanamine, N-methoxy-, hydrochloride (1:1) → N-methoxy-N-methyl-2-phenylamino-6-trifluoromethyl-nicotinamide

Participants

Reaction Conditions

Reaction Steps

In a 1 L pear-shaped flask, 2-phenylamino-6-trifluoromethyl-nicotinic acid (6.2 g, 22.0 mmol) was combined with DMF (120 mL) to give a dark brown solution. N,O-dimethylhydroxyl-amine hydrochloride (2.79 g, 28.6 mmol) and HBTU (13.3 g, 35.2 mmol) were added. N,N-diisopropylethylamine (8.88 g, 12 mL, 68.7 mmol) was added. The reaction mixture was stirred at 25° C. for 4 hr. The reaction mixture was diluted with methylene chloride (400 mL), washed with saturated NH4Cl (1×300 mL), saturated NaHCO3 (1×300 mL), and brine (1×200 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to give 20.5 g of crude product as a brown oil. The crude material was purified by flash chromatography (silica gel, 250 g, 10% to 35% ethyl acetate-hexanes). Fractions containing the desired product were concentrated, treated with ether and concentrated again to give N-methoxy-N-methyl-2-phenylamino-6-trifluoromethyl-nicotinamide (6.86 g, 96%) as a brown oil which solidified on standing overnight at room temperature. 1H NMR (DMSO-d6) δ ppm 8.85 (s, 1H) 7.93 (d, J=7.5 Hz, 1H) 7.64 (d, J=7.8 Hz, 2H) 7.14-7.48 (m, 3H) 6.78-7.14 (m, 1H) 3.55 (s, 3H) 3.31 (s, 3H). MS calcd. for C15H14F3N3O2 [(M+H)+] 326.0, obsd. 326.0.

Provenance & Evidence