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

HRID 1593776Notes

Reaction equation

HRID 1593776 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH:5][CH:6]=[C:7]([C:21]#[N:22])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=1[Cl:20])=O.CO.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:20][C:12]1[CH:13]=[C:14]([Cl:19])[C:15]([O:17][CH3:18])=[CH:16][C:11]=1[NH:10][C:8]1[C:23]2[C:4](=[CH:3][C:2]([F:1])=[C:25]([O:26][CH3:27])[CH:24]=2)[N:5]=[CH:6][C:7]=1[C:21]#[N:22]

Participants

5

Reactant 3

HCID 887MethanolHCID 24813Phosphorus oxychlorideHCID 69313510HCID 69313510, compound

Product 1

HCID 114861534-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrileYield 55%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

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)+

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureto reflux
  3. temperatureThis solution was heated
  4. temperatureat reflux overnight
  5. waitAfter 24 hours
  6. temperaturethe reaction mixture was cooled in an ice-bath
  7. filtrationthe solid was collected by filtration
  8. washwashed with cold acetonitrile (20 mL)
  9. additionTo both the acetonitrile filtrate and the tetrahydrofuran suspension were added concentrated ammonium hydroxide (2×25 mL)
  10. additionWater (2×400 mL) was added
  11. stirringstirring
  12. waitwas continued for 2 hours
  13. washwashed with hot water
  14. customdried under reduced pressure at ˜40° C., overnight

Sources & evidence

ORD record
ord-3caecf5990f948c3af900e3bdba3b6ef
Source dataset
uspto-grants-2007_11
Patent number
US07297795B2

Reaction notes

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