反应详情

温度

50 °C

Crude 4-(3-fluorophenyl)butyric acid ethyl ester (10.5-kg), water (15.8 L) and 50% NaOH (12.0 kg) were charged to a reactor and stirred at 50° C. for 2 hours. The hydrolysis generated a mild exotherm to 55° C. The biphasic mixture became monophasic. Completion of the hydrolysis was confirmed by LC. The reaction mixture was cooled to 20° C. and washed with hexanes 15 kg (containing antistatic agent “ASA 3”) to remove 3′3-difluorobiphenyl impurity generated in the previous step. After phase separation the aqueous layer was acidified with 37% concentrated HCl (16.7 kg), keeping the exotherm below 40° C. Upon cooling the aqueous layer was extracted with MTBE (15 kg in three 5 kg extractions). The solvent was removed by vacuum distillation and excess MTBE removed with a hexane strip. The resulting 4-(3-fluoro-phenyl)-butyric acid (8.83 kg) was removed from the reactor as an oil and used without further purification: MS (M+1)=182; H1 NMR (300 MHz): δ ppm (CDCl3): 1.965 (2H, p, J=4.9, 2.47 hz), 2.37 (2H, t, J=2.47 Hz), 2.66 (2H, t, J=2.45), 6.87 (2H, m), 6.95 (1H, d, J=2.63), 7.22 (1H, m) 11.2(0.2H, bs).

1. customto 55° C
2. temperatureThe reaction mixture was cooled to 20° C.
3. washwashed with hexanes 15 kg (containing antistatic agent “ASA 3”)
4. customto remove 3′3-difluorobiphenyl impurity
5. customAfter phase separation the aqueous layer
6. customthe exotherm below 40° C
7. temperatureUpon cooling the aqueous layer
8. extractionwas extracted with MTBE (15 kg in three 5 kg extractions)
9. customThe solvent was removed by vacuum distillation and excess MTBE
10. customremoved with a hexane strip
11. customThe resulting 4-(3-fluoro-phenyl)-butyric acid (8.83 kg) was removed from the reactor as an oil
12. customused without further purification