2-Methoxybenzaldehyde → 2-Chloro-N-(2-methoxybenzyl)pyridin-3-amine

Participants

Reaction Conditions

Reaction Steps

To a 5 L 3-necked round bottom flask fitted with mechanical stirrer, thermometer, addition funnel, and nitrogen inlet, were added 1.6 L of acetic acid and 80.0 grams (0.62 moles) of 3-amino-2-chloropyridine. The mixture was agitated for approx. 10 minutes at 25° C. for dissolution. To the resulting solution was charged 105.9 grams (119.3 mL/0.78 moles/1.25 equivalents) of o-anisaldehyde (2-methoxybenzaldehyde), upon which was obtained a yellow solution after stirring 10 minutes at 25° C. Over a 30 minute period in portions were added 263.7 grams (1.24 moles, 2.0 equivalents) sodium triacetoxyborohydride, while maintaining a temperature of 20° C. The mixture was stirred for 12-18 hours and concentrated to a semi-solid, which was partitioned between methylene chloride and water (800 mL each). The pH was adjusted to 9.5 with 700 mL 25% sodium hydroxide solution while maintaining a temperature of 25°-30° C. by cooling. The layers were separated, the aqueous layer was washed with methylene chloride (3×300 mL each), and the methylene chloride layers were combined. The organic layer was washed with 300 mL of saturated sodium chloride solution, and then dried with magnesium sulfate for 30 minutes. The magnesium sulfate was removed by filtration, and the methylene chloride filtrate was evaporated and displaced with ethyl acetate, leaving an off white tacky material (174 grams). The product was reslurried in 120 mL of fresh ethyl acetate at 0°-5° C. for 1.5 hours, filtered, washed with cold ethyl acetate and dried, giving 133.2 grams (86.1%) of the title compound. M.P. 121° -125° C. 1H NMR (CDCl3) δ 7.70 (dd, 1H, J=1Hz, 2Hz), 7.25 (m, 2H), 7.05 (m, 1H), 6.90 (m, 3H), 4.95 (t, 1H), 4.40 (d, 2H, J=6), 3.85 (s, 3H).

Provenance & Evidence