4-Bromophenol → 2-(4-Bromophenoxy)-4-fluoro-5-methoxybenzoic acid

HRID 335916Notes

Reaction equation

HRID 335916 reaction equation
Br[C:2]1[CH:10]=[C:9]([F:11])[C:8]([O:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:10]=[C:9]([F:11])[C:8]([O:12][CH3:13])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:17][CH:16]=1

Participants

5

Reactant 3

HCID 78084-BromophenolHCID 10796Cesium carbonateHCID 534357102-Bromo-4-fluoro-5-methoxybenzoic acid

Product 1

HCID 673830322-(4-Bromophenoxy)-4-fluoro-5-methoxybenzoic acidYield 95%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 2-bromo-4-fluoro-5-methoxybenzoic acid 1 (1.0 kg, 4.02 mol), 4-bromophenol (4.41 mol, 1.05 equiv, 729.5 g) and Cs2CO3 (12.06 mol, 3 equiv. 3.92 kg) in anhydrous DMF (12 L) was degassed with N2 for 30 min. To this mixture was added copper (I) triflate toluene complex (2:1) (0.04 equiv. 83.12 g) and the mixture was further degassed again with N2 for 15 min. The resulting mixture was heated at 110° C. for 4 days. The reaction mixture was cooled to ambient temperature and poured onto 5 L of ice water. The pH was adjusted to 1 with concentrated HCl and the aqueous layer was extracted with EtOAc (3×4 L). The combined extracts were washed with brine (2×2 L). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to provide a thick brown oil. The brown oil was triturated with a 5% IPA/water mixture (5 L) at ambient temp to obtain a brown solid. The solid was filtered, washed with water and hexane and dried overnight under vacuum to afford 2-(4-bromophenoxy)-4-fluoro-5-methoxybenzoic acid (1.3 kg, 95% yield) as a brown solid.

Workup

  1. customwas degassed with N2 for 30 min
  2. additionTo this mixture was added copper (I) triflate toluene complex (2:1) (0.04 equiv. 83.12 g)
  3. customthe mixture was further degassed again with N2 for 15 min
  4. temperatureThe reaction mixture was cooled to ambient temperature
  5. additionpoured onto 5 L of ice water
  6. extractionthe aqueous layer was extracted with EtOAc (3×4 L)
  7. washThe combined extracts were washed with brine (2×2 L)
  8. customThe organic layer was separated
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customto provide a thick brown oil
  13. customThe brown oil was triturated with a 5% IPA/water mixture (5 L) at ambient temp
  14. customto obtain a brown solid
  15. filtrationThe solid was filtered
  16. washwashed with water and hexane
  17. customdried overnight under vacuum

Sources & evidence

ORD record
ord-0b7f031498c244a19dd32cd20e06bfcc
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Reaction notes

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