Methanol → 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile

Participants

Reaction Steps

To a suspension of 3-fluoro-4-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (360 mg, 0.88 mmol) in 40 mL of acetonitrile was added 0.1 mL of methanol. The reaction mixture was heated to reflux and phosphorous oxychloride (0.65 mL, 7.0 mmol) was added dropwise, via syringe. After 2 hours the mixture became a clear orange solution. This solution was heated at reflux overnight. After 24 hours, the reaction mixture was cooled in an ice-bath and the solid was collected by filtration, washed with cold acetonitrile (20 mL) and then suspended in tetrahydrofuran (50 mL). To both the acetonitrile filtrate and the tetrahydrofuran suspension were added concentrated ammonium hydroxide (2×25 mL) and the mixtures were stirred for 1 hour. Water (2×400 mL) was added and stirring was continued for 2 hours. The resulting solids were combined, washed with hot water and dried under reduced pressure at ˜40° C., overnight, to provide 189 mg (55%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile as orange crystals, mp 219-221° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.87 (s, 3H), 4.02 (s, 3H), 7.36 (s, 1H), 7.65-7.80 (m, 2H), 8.08 (d, J=9 Hz, 1H), 8.48 (s, 1H), 9.85 (s, 1H); MS (ES) m/z392.0, 394.0 (M+H)+

Provenance & Evidence