反应详情

温度

15 °C

Methyl 3-amino-2-fluorobenzoate (50 g, 1 eq) was charged to reactor followed by dichloromethane (250 mL, 5 vol). The contents were stirred and cooled to ˜15° C. and pyridine (26.2 mL, 1.1 eq) was added. After addition of the pyridine, the reactor contents were adjusted to ˜15° C. and the addition of 2,6-difluorobenzenesulfonyl chloride (39.7 mL, 1.0 eq) was started via addition funnel. The temperature during addition was kept <25° C. After complete addition, the reactor contents were warmed to 20-25° C. and held overnight. Ethyl acetate (150 mL) was added and dichloromethane was removed by distillation. Once distillation was complete, the reaction mixture was then diluted once more with ethyl acetate (5 vol) and concentrated. The reaction mixture was diluted with ethyl acetate (10 vol) and water (4 vol) and the contents heated to 50-55° C. with stirring until all solids dissolve. The layers were settled and separated. The organic layer was diluted with water (4 vol) and the contents heated to 50-55° for 20-30 min. The layers were settled and then separated and the ethyl acetate layer was evaporated under reduced pressure to ˜3 volumes. Ethyl Acetate (5 vol.) was added and again evaporated under reduced pressure to ˜3 volumes. Cyclohexane (9 vol) was then added to the reactor and the contents were heated to reflux for 30 min then cooled to 0° C. The solids were filtered and rinsed with cyclohexane (2×100 mL). The solids were air dried overnight to obtain methyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (94.1 g, 91%).

1. customwere adjusted to ˜15° C.
2. additionwas started via addition funnel
3. additionThe temperature during addition
4. customwas kept <25° C
5. additionAfter complete addition
6. temperaturethe reactor contents were warmed to 20-25° C.
7. customdichloromethane was removed by distillation
8. distillationOnce distillation
9. additionthe reaction mixture was then diluted once more with ethyl acetate (5 vol)
10. concentrationconcentrated
11. additionThe reaction mixture was diluted with ethyl acetate (10 vol) and water (4 vol)
12. temperaturethe contents heated to 50-55° C.
13. stirringwith stirring until all solids
14. dissolutiondissolve
15. customseparated
16. additionThe organic layer was diluted with water (4 vol)
17. temperaturethe contents heated to 50-55° for 20-30 min
18. customseparated
19. customthe ethyl acetate layer was evaporated under reduced pressure to ˜3 volumes
20. additionEthyl Acetate (5 vol.) was added
21. customagain evaporated under reduced pressure to ˜3 volumes
22. additionCyclohexane (9 vol) was then added to the reactor
23. temperaturethe contents were heated
24. temperatureto reflux for 30 min
25. temperaturethen cooled to 0° C
26. filtrationThe solids were filtered
27. washrinsed with cyclohexane (2×100 mL)
28. customdried overnight