反应详情

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.

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