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

HRID 1593780

Reaction equation

HRID 1593780 reaction equation
[Br:1][C:2]1[CH:25]=[CH:24][C:5]([NH:6][CH:7]=[C:8]([C:22]#[N:23])[C:9]([NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([Cl:20])=[CH:14][C:13]=2[Cl:21])=O)=[CH:4][C:3]=1[O:26][CH3:27].CO.P(Cl)(Cl)(Cl)=O>C(#N)C>[Br:1][C:2]1[CH:25]=[C:24]2[C:5](=[CH:4][C:3]=1[O:26][CH3:27])[N:6]=[CH:7][C:8]([C:22]#[N:23])=[C:9]2[NH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([Cl:20])=[CH:14][C:13]=1[Cl:21]

Participants

5

Reactant 3

HCID 887Methanol2×HCID 24813Phosphorus oxychloride2×HCID 693122584-bromo-3-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide

Product 1

HCID 117121406-Bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-methoxy-3-quinolinecarbonitrileYield 39%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
2.5 °C

Procedure

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)+

Workup

  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

Sources & evidence

ORD record
ord-2059bb4d4cef402886d13161534f2743
Source dataset
uspto-grants-2007_11
Patent number
US07297795B2

Linked notes

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