Citric Acid → 2-[4-(N-acetyl-N-ethoxycarbonylmethylamino)-3-fluorophenyl]-6,8-difluoro-5-hexylamino-4H-1-benzopyran-4-one

HRID 1736145Notes

Reaction equation

HRID 1736145 reaction equation
[C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH2:30])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].I[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]

Participants

6

Reactant 4

HCID 311Citric AcidHCID 125271-IodohexaneHCID 24758Sodium hydride2×HCID 19434923HCID 19434923, compound

Product 1

HCID 194349762-[4-(N-acetyl-N-ethoxycarbonylmethylamino)-3-fluorophenyl]-6,8-difluoro-5-hexylamino-4H-1-benzopyran-4-oneYield 28%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

1.20 g (2.76 mmol) of 2-[4-(N-acetyl-N-ethoxycarbonylmethylamino)-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 44 was dissolved in 20 ml of dimethylformamide under argon atmosphere, 111 mg of sodium hydride (60% oil dispersion) and 0.82 ml of 1-iodohexane were added under ice-cooling and the mixture was stirred at room temperature for 1.7 hours. 33 mg of sodium hydride was added and the mixture was stirred for additional 40 minutes. A 10% aqueous solution of citric acid was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetonitrile=10:1) to give 433 mg (28%) of 2-[4-(N-acetyl-N-ethoxycarbonylmethylamino)-3-fluorophenyl]-6,8-difluoro-5-hexylamino-4H-1-benzopyran-4-one.

Workup

  1. temperaturecooling
  2. stirringthe mixture was stirred for additional 40 minutes
  3. extractionthe mixture was extracted with ethyl acetate
  4. washThe organic layer was washed with an aqueous saturated solution of sodium chloride
  5. dry with materialdried over anhydrous sodium sulfate
  6. distillationthe solvent was distilled off under reduced pressure
  7. customThe residue was purified by silica gel column chromatography (chloroform:acetonitrile=10:1)

Sources & evidence

ORD record
ord-48cfd7b05c0f4e5b85f3ce18c930c62b
Source dataset
uspto-grants-1996_07
Patent number
US05539112

Reaction notes

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