Phosphorus oxychloride → 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-fluoro-3-quinolinecarbonitrile

HRID 1593775Notes

Reaction equation

HRID 1593775 reaction equation
[CH2:1]([O:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]=[C:10]([C:24]#[N:25])[C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([Cl:22])=[CH:16][C:15]=2[Cl:23])=O)=[CH:6][C:5]=1[F:28])[CH3:2].P(Cl)(Cl)(Cl)=O>C(#N)C.CO>[Cl:23][C:15]1[CH:16]=[C:17]([Cl:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=1[NH:13][C:11]1[C:26]2[C:7](=[CH:6][C:5]([F:28])=[C:4]([O:3][CH2:1][CH3:2])[CH:27]=2)[N:8]=[CH:9][C:10]=1[C:24]#[N:25]

Participants

5

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 693122634-ethoxy-3-fluoroanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide

Product 1

HCID 115459364-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-fluoro-3-quinolinecarbonitrileYield 37%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6342AcetonitrileSolvent

Procedure

A suspension of 4-ethoxy-3-fluoroanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (6.28 9, 14.8 mmol) in 54 mL of acetonitrile and 2.0 mL of methanol was heated to reflux and phosphorous oxychloride (8.3 mL, 88.8 mmol) was added dropwise. The mixture was heated at reflux for 17 hours. The resultant solution was concentrated in vacuo and acetonitrile was added to the residue. The solid was collected by filtration, washed with acetonitrile. The solid was suspended in tetrahydrofuran and neutralized with concentrated ammonium hydroxide. After stirring for 30 minutes, water was added and the mixture was stirred for 1 hour. The solid was collected by filtration, washed with water, followed by 1:1 diethyl ether and hexane. The light yellow solid was dried in vacuo to provide 2.2 g (37%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-fluoro-3-quinolinecarbonitrile, mp 185-187° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.95 (t, J=7 Hz, 3H), 3.87 (s, 3H), 4.29 (q, J=7 Hz, 2H), 7.39 (s, 1H), 7.66-7.81 (m, 2H), 8.09 (d, J=9 Hz, 1H), 8.49 (s, 1H), 9.80 (s, 1H); MS (ES) m/z 406.1, 408.2 (M+H)+

Workup

  1. temperaturewas heated
  2. temperatureto reflux
  3. temperatureThe mixture was heated
  4. temperatureat reflux for 17 hours
  5. concentrationThe resultant solution was concentrated in vacuo and acetonitrile
  6. additionwas added to the residue
  7. filtrationThe solid was collected by filtration
  8. washwashed with acetonitrile
  9. additionwater was added
  10. stirringthe mixture was stirred for 1 hour
  11. filtrationThe solid was collected by filtration
  12. washwashed with water
  13. customThe light yellow solid was dried in vacuo

Sources & evidence

ORD record
ord-14fd4a9aa65a4d5ba35d1e375a30f6ef
Source dataset
uspto-grants-2007_11
Patent number
US07297795B2

Reaction notes

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