Toluene → 5-Bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid

HRID 931542Notes

Reaction equation

HRID 931542 reaction equation
Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1(C)C=CC=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1O.C(=O)([O-])[O-:30].[Cs+].[Cs+]>O.CCOC(C)=O>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([O:30][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][C:25]=2[F:27])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]

Participants

7

Reactant 4

HCID 1140TolueneHCID 10796Cesium carbonateHCID 118912,5-Dibromobenzoic acidHCID 27373684-Fluoro-2-methoxyphenol

Product 1

HCID 574756385-Bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acidYield 78.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

A dry 100 L glass jacketed reactor equipped with an addition funnel, reflux condenser, solids addition system and temperature probe was charged with 2,5-dibromobenzoic acid (2685 g, 9.6 mol) and copper (I) triflate toluene complex (2:1, 50.0 g, 0.2 mol). Toluene (30 L) and EtOAc (20 mL) were then charged, followed by 2-methoxy-4-fluorophenol (1500 g, 10.6 mol). Cesium carbonate (6258 g, 19.2 mol) was added in portions while stirring vigorously. The mixture was heated to 90° C. for 4 hours. The mixture was cooled to 35° C. and water (15 L) was added. After 15 minutes of stirring the phases were separated and the aqueous phase was washed with toluene (7.5 L). With stirring, EtOAc (15.0 L) was added to the aqueous phase, followed by 6 M HCl (5.6 L) keeping the internal temperature below 30° C. The layers were separated and the organics were dried over magnesium sulfate. Filtration through a pad of celite and concentration provided a solid that was reslurried in 915 mL of EtAOc and 9.2 L of heptanes. Stirring was continued for 1 hour before the solids were filtered and washed with heptanes. Drying provided 2560 g of 5-bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid as a cream colored solid.

Workup

  1. customequipped with an addition funnel
  2. temperaturereflux condenser
  3. additionsolids addition system and temperature probe
  4. temperatureThe mixture was cooled to 35° C.
  5. stirringAfter 15 minutes of stirring the phases
  6. customwere separated
  7. washthe aqueous phase was washed with toluene (7.5 L)
  8. stirringWith stirring
  9. additionEtOAc (15.0 L) was added to the aqueous phase
  10. customthe internal temperature below 30° C
  11. customThe layers were separated
  12. dry with materialthe organics were dried over magnesium sulfate
  13. filtrationFiltration
  14. concentrationthrough a pad of celite and concentration
  15. customprovided a solid
  16. stirringStirring
  17. filtrationwere filtered
  18. washwashed with heptanes
  19. customDrying

Sources & evidence

ORD record
ord-436ab4e9dd3d4d50a517d12b01c9d83a
Source dataset
uspto-grants-2016_03
Patent number
US09296759B2

Reaction notes

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