Methyl iodide → 6,8-Difluoro-2-[4-(N,N-dimethylamino)-3-fluorophenyl]-5-(6-methoxyhexylamino)-4H-1-benzopyran-4-one

HRID 1736132Notes

Reaction equation

HRID 1736132 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[C:13]([F:20])[CH:12]=3)=[CH:8][C:7](=[O:21])[C:6]=2[C:22]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].[H-].[Na+].I[CH3:35]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:18])[CH3:19])=[C:13]([F:20])[CH:12]=3)=[CH:8][C:7](=[O:21])[C:6]=2[C:22]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:35]

Participants

5

Reactant 3

HCID 6328Methyl iodide3×HCID 24758Sodium hydrideHCID 19434808HCID 19434808, compound

Product 1

HCID 153470096,8-Difluoro-2-[4-(N,N-dimethylamino)-3-fluorophenyl]-5-(6-methoxyhexylamino)-4H-1-benzopyran-4-oneYield 58%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

500 mg (1.15 mmol) of Compound 60 obtained in Example 60 was dissolved in 20 ml of tetrahydrofuran under argon atmosphere, 92 mg of sodium hydride (60% oil dispersion) and 0.14 ml of iodomethane were added under ice-cooling and the mixture was stirred at room temperature for 1 hour. Thereafter, 0.22 ml of iodomethane was added and the mixture was heated at reflux for 3.5 hours. Additional 0.36 ml of iodomethane was added and the mixture was heated at reflux for 1 hour. The solvent was distilled off under reduced pressure, an aqueous saturated solution of ammonium chloride was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (chloroform:acetone=40:1), followed by recrystallization from n-hexane/ethyl acetate to give 300 mg (58%) of Compound 61.

Workup

  1. temperaturecooling
  2. temperaturethe mixture was heated
  3. temperatureat reflux for 3.5 hours
  4. temperaturethe mixture was heated
  5. temperatureat reflux for 1 hour
  6. distillationThe solvent was distilled off under reduced pressure
  7. additionan aqueous saturated solution of ammonium chloride was added to the residue
  8. extractionthe mixture was extracted with ethyl acetate
  9. washThe organic layer was washed with an aqueous saturated solution of sodium chloride
  10. dry with materialdried over anhydrous sodium sulfate
  11. custompurified by silica gel column chromatography (chloroform:acetone=40:1)
  12. customfollowed by recrystallization from n-hexane/ethyl acetate

Sources & evidence

ORD record
ord-fd2caa3b742e4eb59a691ad26c64827e
Source dataset
uspto-grants-1996_07
Patent number
US05539112

Reaction notes

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