反应详情

温度

55 °C

To a solution of N,N-diisopropylethylamine (187 mL, 1073.6 mmol) in THF (240 mL) at 60-65° C. was added a solution of methyl 3-amino-5-fluoro-4-methylbenzoate sulfuric acid salt (80.0 g, 268.8 mmol) in THF (720 mL), maintaining the temperature in the range 45-65° C. Bromoacetonitrile (56.2 mL, 806.8 mmol) was charged and the solution heated to reflux for 3 d before concentration to 8 rel. vols. by distillation at atmospheric pressure. The solution was cooled to ambient temperature and water (1000 mL) added, maintaining the temperature in the range 18-23° C. The pH was adjusted to 1.2-1.5 with aq. hydrochloric acid (4 M, ˜80 mL) and the resulting slurry stirred at ambient temperature for 2 h before being filtered through 100 μm filter cloth under nitrogen. The filter cake was washed with mixed heptanes (2×320 mL) and dried under nitrogen at up to 45° C. to afford methyl 3-(cyanomethylamino)-5-fluoro-4-methylbenzoate (54.9 g, 99.1% w/w).

1. temperaturethe solution heated
2. temperatureto reflux for 3 d before concentration to 8 rel
3. distillationby distillation at atmospheric pressure
4. temperatureThe solution was cooled to ambient temperature
5. additionwater (1000 mL) added
6. temperaturemaintaining the temperature in the range 18-23° C
7. filtrationbefore being filtered through 100 μm
8. filtrationfilter cloth under nitrogen
9. washThe filter cake was washed with mixed heptanes (2×320 mL)
10. customdried under nitrogen at up to 45° C.