Dimethylamine → 4-Dimethylamino-but-2-enoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1,7]naphthyridin-6-yl]-amide

Participants

Reaction Steps

4-Bromobut-2-enoyl chloride was generated by the reaction of 4-bromobut-2-enoic acid, trimethylsilyl ester (0.63 mL) with oxalyl chloride (0.33 mL) in methylene chloride (6 mL) with one drop of N,N-dimethyl formamide for one hour. The reaction was stripped of solvent and redissolved in 8 mL of anhydrous tetrahydrofuran. An aliquot of 4 mL of this reagent was added to a solution of 500 mg of 6-amino-4-(3-bromo-phenylamino)-[1.7]naphthyridine-3-carbonitrile in 15 mL of tetrahydrofuran containing 315 uL of Hunig's base at 0° C. After 2 hours, an additional 2 mL of acid chloride/tetrahydrofuran was added. After an additional hour, saturated aqueous sodium bicarbonate and chloroform was added and the chloroform phase dried and stripped to give a crude product that was purified by flash chromatography with a gradient of ethyl acetate/chloroform, then methanol/chloroform to give 360 mg of a one-to-one mixture of 4-bromo-but-2-enoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1.7]naphthyridin-6-yl]-amide, and 4-chloro-but-2-enoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1.7]naphthyridin-6-yl]-amide. This material was dissolved in 10 mL of tetrahydrofuran containing 1 mL of N,N-dimethyl formamide and reacted with 200 mg of NaBr for three days. An aliquot of 2 mL of 1 M dimethyl amine in tetrahydrofuran was then added at 0° C. The reaction was diluted with saturated aqueous sodium bicarbonate, ice, and chloroform. The organic phase was dried with sodium sulfate, evaporated, and purified by flash chromatography with a gradient of 5-10% methanol/chloroform to give 190 mg of 4-dimethylamino-but-2-enoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1.7]naphthyridin-6-yl]-amide as an amorphous yellow solid: melting point 180-185° C. (decomposed); mass spectrum (mri/e): M+H 450.9, 452.9.

Provenance & Evidence