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

HRID 1472303Notes

Reaction equation

HRID 1472303 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). With vigorous stirring cesium carbonate (6258 g, 19.2 mol) was added 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 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. Step 2: A dry 100 L glass jacketed reactor equipped with an addition funnel, reflux condenser and temperature probe was charged with 5-bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid (2340 g, 6.9 mol). TFA (11.7 L) was carefully added followed by TFAA (1144 mL). Boron trifluoride diethyl etherate (85 mL, 0.68 mol) was then carefully added. Stirring was continued to 4 hours at which point the reaction was transferred to another 100 L glass reactor containing 35.1 L of water cooled to 0° C. The resulting slurry was allowed to warm to RT and stir for 1 hour. The solids were filtered and washed with water (4.7 L) and 3 N NaOH (2×3.5 L) and water (7 L). The solids were transferred into a 22 L reactor and acetone (4.7 L) was added. The solids were slurried for 1.5 hour and the filtered, washing well with acetone (4.7 L). An additional slurry with acetone (6.4 L@45° C.) provided 1310 g of 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one as an off white solid.

Workup

  1. customequipped with an addition funnel
  2. temperaturereflux condenser
  3. additionsolids addition system and temperature probe
  4. additionwas added in portions
  5. temperatureThe mixture was cooled to 35° C.
  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. waitwas continued for 1 hour before the solids
  18. filtrationwere filtered
  19. washwashed with heptanes
  20. customDrying

Sources & evidence

ORD record
ord-f94824adc2d94064bf4045912d56b200
Source dataset
uspto-grants-2015_04
Patent number
US09012446B2

Reaction notes

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