Ethyl Acetate → 5-Bromo-2-(6-chloropyridin-3-yloxy)-4-fluorobenzoic acid

HRID 335895Notes

Reaction equation

HRID 335895 reaction equation
[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5](I)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:13][C:14]1[N:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O.CCOCC>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([O:20][C:17]2[CH:18]=[N:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 10796Cesium carbonateHCID 8198212-Chloro-5-hydroxypyridineHCID 673830505-Bromo-4-fluoro-2-iodobenzoic acid

Product 1

HCID 866584825-Bromo-2-(6-chloropyridin-3-yloxy)-4-fluorobenzoic acid

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3283Diethyl EtherSolvent

Conditions

Temperature
115 °C

Procedure

A flask was charged with 5-bromo-4-fluoro-2-iodobenzoic acid (4.00 g, 11.60 mmol), 6-chloropyridin-3-ol (1.803 g, 13.92 mmol), and cesium carbonate (7.56 g, 23.19 mmol). The flask was evacuated and flushed with nitrogen twice before copper (I) trifluoromethanesulfonate toluene complex (0.156 g, 0.302 mmol) was added. Toluene (58.0 mL) (degassed 10 minutes by bubbling nitrogen through the solution prior to use) and ethyl acetate (0.084 mL, 0.858 mmol) were added and the mixture was heated at 115° C. After 2 hours, the reaction was allowed to cool to RT and the mixture was diluted with water (50 mL) and stirred vigorously for 15 minutes. After diluting with ether (200 mL), the layers were separated and the organic layer was extracted with 10% sodium carbonate. The pH of the combined aqueous layers was adjusted to pH ˜2 and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated to afford 5-bromo-2-(6-chloropyridin-3-yloxy)-4-fluorobenzoic acid as a solid. MS m/z=347.9 [M+H].

Workup

  1. customThe flask was evacuated
  2. customflushed with nitrogen twice before copper (I) trifluoromethanesulfonate toluene complex (0.156 g, 0.302 mmol)
  3. additionwas added
  4. customToluene (58.0 mL) (degassed 10 minutes
  5. customby bubbling nitrogen through the solution
  6. additionwere added
  7. temperatureto cool to RT
  8. customthe layers were separated
  9. extractionthe organic layer was extracted with 10% sodium carbonate
  10. extractionextracted with ethyl acetate
  11. washThe combined organic layers were washed with saturated sodium chloride
  12. dry with materialdried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-59e6e3642fd54fb7b213c648158b221a
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Reaction notes

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