反应详情

温度

2.5 °C

To a suspension of (5.13 g, 11 mmol) of 4-bromo-3-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide in 400 mL of acetonitrile was added 1.5 mL of methanol. The mixture was heated to reflux and phosphorous oxychloride (4.10 mL, 44.0 mmol) was added dropwise. The resulting mixture was heated at reflux for 26 hours. Additional phosphorous oxychloride (2.1 mL) and methanol (0.75 mL) were added and the mixture was heated at reflux for 21 hours. After cooling to 0-5° C. in an ice-bath, the solid was collected by filtration, washed with cold acetonitrile (100 mL) and then suspended in tetrahydrofuran (100 mL). To the tetrahydrofuran suspension was added concentrated ammonium hydroxide and the mixtures were stirred for 1 hour. Water (300 mL) was added and stirring was continued for 1 hour. The solid was collected by filtration, washed with hot water (46° C.), acetonitrile and dried in vacuo overnight to recover 2.1 g of 4-bromo-3-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide. The acetonitrile filtrate and washing were combined and concentrated aqueous ammonium hydroxide was added. The resulting acetonitrile mixture was stirred for 1 hour. Water was added and stirring was continued for 1 hour. The solid was collected by filtration, washed with water, ethyl acetate and ether, then dried in vacuo to provide 1.92 g (39%) of 6-bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-methoxy-3-quinolinecarbonitrile as a yellow solid, mp 256-257° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3H), 4.04 (s, 3H), 7.37 (s, 1H), 7.46 (s, 1H), 7.75 (s, 1H), 8.56(s, 1H), 8.89 (s, 1H), 9.93 (s, 1H); MS (ES) m/z451.9, 454.0 (M+H)+

1. temperatureThe mixture was heated
2. temperatureto reflux
3. temperatureThe resulting mixture was heated
4. temperatureat reflux for 26 hours
5. temperaturethe mixture was heated
6. temperatureat reflux for 21 hours
7. filtrationthe solid was collected by filtration
8. washwashed with cold acetonitrile (100 mL)
9. additionTo the tetrahydrofuran suspension was added concentrated ammonium hydroxide
10. additionWater (300 mL) was added
11. stirringstirring
12. waitwas continued for 1 hour
13. filtrationThe solid was collected by filtration
14. washwashed with hot water (46° C.), acetonitrile
15. customdried in vacuo overnight
16. customto recover 2.1 g of 4-bromo-3-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide
17. washThe acetonitrile filtrate and washing
18. additionconcentrated aqueous ammonium hydroxide was added
19. stirringThe resulting acetonitrile mixture was stirred for 1 hour
20. additionWater was added
21. stirringstirring
22. waitwas continued for 1 hour
23. filtrationThe solid was collected by filtration
24. washwashed with water, ethyl acetate and ether
25. customdried in vacuo