Isonicotinic Acid → Pyridine-4-carbonyl chloride

Participants

Reaction Conditions

Reaction Steps

Isonicotinic acid N (15 g, 121.8 mmol, obtained from Aldrich Chemical Co.) was added to about 100 mL of thionyl chloride and the reaction mixture was stirred for about 17 h at about 25° C. After this period, excess SOCl2 was removed under reduced pressure to provide a white solid. About 400 mL of THF was added to the resulting solid and the solvent was removed under reduced pressure to provide isonicotinic acid chloride as a white powder. The white powder was dissolved in about 400 mL of THF. The solution was cooled to about 0° C. and 4-trifluoromethyl-aniline (21.6 g, 134.0 mmol, 1.1 eq., obtained from Aldrich Chemical Co.) and sodium bicarbonate (30 g, 365.4 mmol, 3.0 eq.) were added. The reaction mixture was stirred for about 5 min at about 0° C., warmed to about 25° C. over about 30 min, then heated to about 65° C. and kept at that temperature for about 1 h. After this period, the reaction mixture was cooled to about 25° C. and the THF was removed under reduced pressure. The residue was suspended in about 800 mL of ethyl acetate and washed with about 600 mL of aqueous 3N HCl. Separate aqueous and organic layers formed. The layers were separated and the aqueous layer was extracted three times with about 600 mL of ethyl acetate per extraction. The organic layer was combined with the post-extraction ethyl acetate aliquots. The combination was dried with Na2SO4 and the solvent was removed under reduced pressure to provide 32 g of the Compound of Formula O as a white solid (99% yield).

Provenance & Evidence