Trifluoroacetic acid → 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one

HRID 1472304Notes

Reaction equation

HRID 1472304 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.B(F)(F)F.CCOCC>O>[Br:1][C:2]1[CH:10]=[C:6]2[C:5]([O:11][C:12]3[C:13]([F:20])=[CH:14][C:15]([O:18][CH3:19])=[CH:16][C:17]=3[C:7]2=[O:9])=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 8000Boron trifluoride etherateHCID 9845Trifluoroacetic anhydrideHCID 574756385-Bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid

Product 1

HCID 574756397-bromo-4-fluoro-2-methoxy-9H-xanthen-9-oneYield 58.8%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
0 °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. customwas transferred to another 100 L glass reactor
  4. temperatureto warm to RT
  5. stirringstir for 1 hour
  6. filtrationThe solids were filtered
  7. washwashed with water (4.7 L) and 3 N NaOH (2×3.5 L) and water (7 L)
  8. customThe solids were transferred into a 22 L reactor
  9. additionacetone (4.7 L) was added
  10. waitThe solids were slurried for 1.5 hour
  11. washthe filtered, washing well with acetone (4.7 L)

Sources & evidence

ORD record
ord-3c036e9ee1fb49b49d2b9254fa972b3e
Source dataset
uspto-grants-2015_04
Patent number
US09012446B2

Reaction notes

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