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

HRID 1855296Notes

Reaction equation

HRID 1855296 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+]>CCOC(C)=O.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 AcetateSolvent2×

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 added to the reactor, followed by 2-methoxy-4-fluorophenol (1500 g, 10.6 mol). With vigorous stirring cesium carbonate (6258 g, 19.2 mol) was added to the mixture in portions. 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 sping and the aqueous phase was washed with toluene (7.5 L). With stirring, EtOAc (15.0 L) was added to the mixture, 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 MgSO4. Filtration through a pad of celite and concentration provided a solid that was reslurried in 915 mL of EtOAc and 9.2 L of heptanes. Stirring was continued for 1 hour before the solids were filtered and washed with heptanes. The solids were dried to provide 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. additionwas added to the mixture in portions
  5. temperatureThe mixture was cooled to 35° C.
  6. washthe aqueous phase was washed with toluene (7.5 L)
  7. stirringWith stirring
  8. additionEtOAc (15.0 L) was added to the mixture
  9. customthe internal temperature below 30° C
  10. customThe layers were separated
  11. dry with materialthe organics were dried over MgSO4
  12. filtrationFiltration
  13. concentrationthrough a pad of celite and concentration
  14. customprovided a solid
  15. stirringStirring
  16. waitwas continued for 1 hour before the solids
  17. filtrationwere filtered
  18. washwashed with heptanes
  19. customThe solids were dried

Sources & evidence

ORD record
ord-50d7dd9ba34648cdba348c94c30f9360
Source dataset
uspto-grants-2015_02
Patent number
US08962859B2

Reaction notes

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