Dimethylformamide → 2-(Difluoromethoxy)-1-fluoro-4-(trifluoromethyl)benzene

HRID 2118102Notes

Reaction equation

HRID 2118102 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].Cl[C:14]([F:19])([F:18])C([O-])=O.[Na+].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[F:18][CH:14]([F:19])[O:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[F:1]

Participants

6

Reactant 4

HCID 6228Dimethylformamide3×HCID 11430Potassium CarbonateHCID 5188882-Fluoro-5-(trifluoromethyl)phenolHCID 2734985Sodium chlorodifluoroacetate

Product 1

HCID 534037512-(Difluoromethoxy)-1-fluoro-4-(trifluoromethyl)benzene

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

A 100-L round bottom flask equipped with overhead stirrer, thermocouple, nitrogen inlet, condenser and steam bath was charged with 2-fluoro-5-(trifluoromethyl)phenol (5.50 kg), sodium chlorodifluoroacetate (9.31 kg), and DMF (4 L). There was an exotherm to 46.7° C. when the 4 L of DMF was charged to the flask. The temperature of the reaction was immediately reduced to 19° C. by rapid cooling with an ice/water bath. An additional 37.3 L of DMF (total DMF, 41.3 L) was then slowly charged, maintaining the internal temperature below 30° C. After cooling to ambient temperature, water (5.5 L) was charged, resulting in a 10° C. exotherm. Potassium carbonate (5.28 kg) was then added. The ice water bath was removed and the batch was heated to 97° C. using a steam bath. The reaction was complete after aging for 2 h at 97° C., as evidenced by HPLC assay, with <1% starting material remaining. The reaction was cooled to ambient temperature, and water (42 L) was slowly added. The batch was transferred to a 170-L extractor and extracted with MTBE (2×18 L). The organic layers were combined and washed with water (1×11 L) and brine (1×11 L). The MTBE solution was pumped into a 22-L flask equipped with a thermocouple, distillation apparatus, and a heating mantle. The MTBE was distilled off at 55-118° C. and atmospheric pressure. The desired product was purified by distillation at 120-157° C. and atmospheric pressure, and was isolated as a clear oil.

Workup

  1. customA 100-L round bottom flask equipped with overhead stirrer
  2. customto 46.7° C.
  3. additionwas charged to the flask
  4. customwas immediately reduced to 19° C.
  5. temperatureby rapid cooling with an ice/water bath
  6. temperaturemaintaining the internal temperature below 30° C
  7. customresulting in a 10° C. exotherm
  8. customThe ice water bath was removed
  9. temperaturethe batch was heated to 97° C.
  10. temperatureThe reaction was cooled to ambient temperature
  11. additionwater (42 L) was slowly added
  12. extractionextracted with MTBE (2×18 L)
  13. washwashed with water (1×11 L) and brine (1×11 L)
  14. customThe MTBE solution was pumped into a 22-L flask
  15. customequipped with a thermocouple, distillation apparatus
  16. distillationThe MTBE was distilled off at 55-118° C.
  17. distillationThe desired product was purified by distillation at 120-157° C.
  18. customatmospheric pressure, and was isolated as a clear oil

Sources & evidence

ORD record
ord-a13b58b0dd5245e0b60f0bb605602682
Source dataset
uspto-grants-2008_10
Patent number
US07442808B2

Reaction notes

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