Acetone, oxime → Methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylbenzo[d]isoxazole-5-carboxylate

HRID 558198Notes

Reaction equation

HRID 558198 reaction equation
[CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC([O-])(C)C.[K+].C(C1[C:16](F)=[C:17]([F:33])[C:18]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21])(=O)C>C1COCC1>[F:33][C:17]1[C:16]2[O:5][N:4]=[C:2]([CH3:3])[C:1]=2[CH:24]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[C:18]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32]

Participants

5

Reactant 3

HCID 67180Acetone, oximeHCID 23665647Potassium tert-butoxideHCID 59519431Methyl 5-acetyl-2-(2-fluorophenylamino)-3,4-difluorobenzoate

Product 1

HCID 59519468Methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylbenzo[d]isoxazole-5-carboxylateYield 72%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of acetone oxime (3.17 g, 43.3 mmol) in THF (40 ml) was added t-BuOK (43.3 ml, 1 M in THF, 43.3 mmol). After stirring at room temperature for 30 min, the mixture was cooled to −78° C. To the mixture was added a solution of methyl 5-acetyl-3,4-difluoro-2-(2-fluorophenylamino)benzoate (4.0 g, 12.4 mmol) in THF (70 ml) dropwise. After stirring at −78° C. for 15 min, the reaction was warmed to 0° C. and stirred at the temperature for 4 h. The reaction was quenched with saturated aqueous NH4Cl solution (200 ml) and extracted with EtOAc (2×200 ml). The organic solution was washed with brine (100 ml), dried over MgSO4 and concentrated. To the resulting oil was added a mixture of 5% HCl solution (100 ml) and MeOH (100 ml). The resulting suspension was heated at reflux for 1.5 h. The reaction was cooled to room temperature, concentrated to half volume, and diluted with EtOAc (200 ml). The organic solution was washed with brine (100 ml), dried over Na2SO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=25:75) yielded 2.84 g (72%) of methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylbenzo[d]isoxazole-5-carboxylate as a white solid.

Workup

  1. temperaturethe mixture was cooled to −78° C
  2. stirringAfter stirring at −78° C. for 15 min
  3. temperaturethe reaction was warmed to 0° C.
  4. stirringstirred at the temperature for 4 h
  5. customThe reaction was quenched with saturated aqueous NH4Cl solution (200 ml)
  6. extractionextracted with EtOAc (2×200 ml)
  7. washThe organic solution was washed with brine (100 ml)
  8. dry with materialdried over MgSO4
  9. concentrationconcentrated
  10. additionTo the resulting oil was added
  11. additiona mixture of 5% HCl solution (100 ml) and MeOH (100 ml)
  12. temperatureThe resulting suspension was heated
  13. temperatureat reflux for 1.5 h
  14. temperatureThe reaction was cooled to room temperature
  15. concentrationconcentrated to half volume
  16. additiondiluted with EtOAc (200 ml)
  17. washThe organic solution was washed with brine (100 ml)
  18. dry with materialdried over Na2SO4
  19. concentrationconcentrated

Sources & evidence

ORD record
ord-a0720e024233449ba8b21b78b5bd2695
Source dataset
uspto-grants-2011_11
Patent number
US08063049B2

Reaction notes

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