Sodium Carbonate → Ethyl {4-[4-[(difluoromethyl)oxy]-9-(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetate

HRID 222437Notes

Reaction equation

HRID 222437 reaction equation
[CH2:1]([O:3][C:4]1[C:5]2[C:6](=[O:31])[N:7]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][C:19]=3[F:30])[CH2:8][C:9]=2[C:10]([OH:17])=[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)[CH3:2].Cl[C:33]([F:38])([F:37])C([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:37][CH:33]([F:38])[O:17][C:10]1[C:9]2[CH2:8][N:7]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][C:19]=3[F:30])[C:6](=[O:31])[C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=12

Participants

5

Reactant 3

HCID 10340Sodium CarbonateHCID 2734985Sodium chlorodifluoroacetate2×HCID 58231483Ethyl {4-[9-(ethyloxy)-4-hydroxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetate

Product 1

HCID 58231465Ethyl {4-[4-[(difluoromethyl)oxy]-9-(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetateYield 22.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of ethyl {4-[9-(ethyloxy)-4-hydroxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetate (2.40 g, 5.67 mmols) in DMF (30 ml) was added sodium chlorodifluoroacetate (1.72 g, 11.34 mmol) and sodium carbonate (1.20 g, 11.34 mmol). The mixture was heated to 100° C. for 3 hours. Further sodium chlorodifluoroacetate (1.72 g, 11.34 mmol) was added, heating continued for 1.5 hours, and the same amount added again and heating continued for 30 minutes. The mixture was cooled to room temperature and partitioned between ethyl acetate ×2 and water. The combined organics were washed with water ×3 and brine. This was dried over magnesium sulphate, filtered and evaporated to a brown oil. This was purified by chromatography on silica gel, eluting with ethyl acetate (5-40%) in hexane to give the title compound as a yellow solid (0.60 g, 1.27 mmol).

Workup

  1. temperatureheating
  2. additionthe same amount added again
  3. temperatureheating
  4. waitcontinued for 30 minutes
  5. temperatureThe mixture was cooled to room temperature
  6. custompartitioned between ethyl acetate ×2 and water
  7. washThe combined organics were washed with water ×3 and brine
  8. dry with materialThis was dried over magnesium sulphate
  9. filtrationfiltered
  10. customevaporated to a brown oil
  11. customThis was purified by chromatography on silica gel
  12. washeluting with ethyl acetate (5-40%) in hexane

Sources & evidence

ORD record
ord-79d1ecccce444afab2e61da9a12cb264
Source dataset
uspto-grants-2012_06
Patent number
US08207213B2

Reaction notes

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