Hydrochloric Acid → HCID 10423223, compound

Participants

Reaction Conditions

Reaction Steps

A 3-neck 5-L flask, equipped with a thermometer, reflux condenser, nitrogen inlet and a mechanical stirrer was charged with 4-[(2,6-difluorobenzyl)amino]3-nitropyridine(146g, 0.55mol) and concentrated hydrochloric acid(1.4L, 16.8mol). The solution was heated on a steam bath to 90° C. and stannous chloride dihydrate(659g, 2.92mol) was added portionwise. After heating the suspension at 90° C. for 1.5 hours, the condenser was replaced with a distillation apparatus and approximately 1.5L of H2O removed by distillation at 100mm Hg. The remaining suspension was cooled in an ice bath and neutralized to pH 7 with concentrated ammonium hydroxide. The pasty solid was collected by filtration and dried overnight on a Buechner funnel. The still damp solid was transferred to a 12-L flask equipped with a mechanical stirrer and reflux condenser and charged with ethyl acetate. With rapid stirring, the suspension was heated at reflux for 3.5 hours on a steam bath, cooled slightly, filtered using positive nitrogen pressure, and the filtrate concentrated in vacuo. The resulting oily solid was slurried in ethyl ether, solids collected by filtration and dried overnight on a Buechner funnel to yield 123g (83.1%) of 3-amino-2-chloro-4-[(2,6-difluorobenzyl)amino]pyridine. TLC (silica gel, EtOAc/ether, 1:1) Rf =0.71; mp=221°-2230° C.; 1H NMR (DMSO-d6): 4.36(d,J=5.1 Hz, 2H, CH2), 4.84 (s, 2H, NH2), 6.06(t, J=5.1 Hz, 1H, NH), 6.54(d,J=5.4Hz, 1H, C-5H), 7.01-7.65 (m, 3H, C-3'H, C-4'H, C-5'H), 7.44 (d, J=5.3 Hx, 1H, C-6H).

Provenance & Evidence