Sodium hydride → 6-Methoxy-7-(3-morpholinopropoxy)-4-(6-trifluoromethyloxindol-3-yl)quinazoline

HRID 1386334Notes

Reaction equation

HRID 1386334 reaction equation
[H-].[Na+].[F:3][C:4]([F:16])([F:15])[C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1)[N:21]=[CH:20][N:19]=[C:18]2[CH:9]1[C:8]2[C:12](=[CH:13][C:5]([C:4]([F:3])([F:15])[F:16])=[CH:6][CH:7]=2)[NH:11][C:10]1=[O:14]

Participants

4

Reactant 3

HCID 24758Sodium hydrideHCID 6084876-TrifluoromethyloxindoleHCID 118239414-Chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline

Product 1

HCID 217172946-Methoxy-7-(3-morpholinopropoxy)-4-(6-trifluoromethyloxindol-3-yl)quinazolineYield 31%

Procedure

Sodium hydride (53 mg, 1.33 mmol) was added to a solution of 6-trifluoromethyloxindole (200 mg, 0.995 mmol), (prepared as described for the starting material in Example 49), in dry, degassed DMF and the suspension stirred for 15 minutes at ambient temperature. A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (111 mg, 0.332 mmol), (prepared as described for the starting material in Example 5), in a dry, degassed mixture of DMF (5 ml) and THF (2 ml) was added dropwise and the reaction mixture was heated at 60° C. for 3 hours. The mixture was allowed to cool, the DMF was removed by evaporation, 1M hydrochloric acid was added until the aqueous phase was pH8 and ethyl acetate was added to dissolve the resulting precipitate. The organic phase was separated and the aqueous phase re-extracted with ethyl acetate (50 ml×3). The ethyl acetate fractions were combined, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash column chromatography eluting with methylene chloride/methanol (10/1). The purified product was triturated with boiling ether and collected by filtration to give 6-methoxy-7-(3-morpholinopropoxy)-4-(6-trifluoromethyloxindol-3-yl)quinazoline (51 mg, 31%).

Workup

  1. custom(prepared
  2. customin dry
  3. customdegassed DMF
  4. customdegassed
  5. additionmixture of DMF (5 ml) and THF (2 ml)
  6. additionwas added dropwise
  7. temperaturethe reaction mixture was heated at 60° C. for 3 hours
  8. temperatureto cool
  9. customthe DMF was removed by evaporation, 1M hydrochloric acid
  10. additionwas added until the aqueous phase
  11. additionwas added
  12. dissolutionto dissolve the resulting precipitate
  13. customThe organic phase was separated
  14. extractionthe aqueous phase re-extracted with ethyl acetate (50 ml×3)
  15. dry with materialdried (MgSO4)
  16. customthe solvent removed by evaporation
  17. customThe residue was purified by flash column chromatography
  18. washeluting with methylene chloride/methanol (10/1)
  19. customThe purified product was triturated with boiling ether
  20. filtrationcollected by filtration

Sources & evidence

ORD record
ord-578f215233e945719f2fa5f58aa49a31
Source dataset
uspto-grants-2001_07
Patent number
US06265411B1

Reaction notes

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