反应详情

温度

10 °C

To a reactor vessel was charged N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ˜10° C. and N-bromosuccinimide (“NBS”) (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ˜20° C. and stirred for 45 min. Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to ˜120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to ˜120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ˜10° C. 2,2-Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ˜5 minutes between additions. The reaction was warmed to 20-25° C. After 45 min, the vessel contents were heated to 75° C. and held for 1.75 hours. The reaction mixture was then cooled to 5° C. and water (270 ml) was slowly charged keeping the temperature below 30° C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25° C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50° C. and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0° C. and held for ˜2 hrs. The solids were filtered and rinsed with heptanes (2×2 vol). The solid product was then dried under vacuum at 30° C. to obtain N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (28.8 g, 80%).

1. temperaturethe reaction mixture was warmed to ˜20° C.
2. stirringstirred for 45 min
3. stirringthe mixture was stirred
4. customthe layers separated
5. additionWater (5 vol) was again added to the dichloromethane layer
6. stirringthe mixture was stirred
7. customthe layers separated
8. concentrationThe dichloromethane layers were concentrated to ˜120 mL
9. additionEthyl acetate (7 vol) was added to the reaction mixture
10. concentrationconcentrated to ˜120 mL
11. additionDimethylacetamide (270 mL) was then added to the reaction mixture
12. temperaturecooled to ˜10° C
13. stirringwith stirring for ˜5 minutes between additions
14. temperatureThe reaction was warmed to 20-25° C
15. waitAfter 45 min
16. temperaturethe vessel contents were heated to 75° C.
17. waitheld for 1.75 hours
18. temperatureThe reaction mixture was then cooled to 5° C.
19. customthe temperature below 30° C
20. stirringthe mixture was stirred
21. customlayers separated
22. additionEthyl acetate (7 vol) was again charged to the aqueous layer
23. stirringthe contents were stirred
24. customseparated
25. additionEthyl acetate (7 vol) was charged again to the aqueous layer
26. stirringthe contents were stirred
27. customseparated
28. washwashed with water (4 vol) 4 times
29. stirringstirred overnight at 20-25° C
30. concentrationThe organic layers were then concentrated
31. temperatureunder heat
32. temperatureThe vessel contents were then heated to 50° C.
33. additionheptanes (120 mL) were added slowly
34. additionAfter addition of heptanes
35. temperaturethe vessel contents were heated
36. temperatureto reflux
37. temperaturethen cooled to 0° C.
38. waitheld for ˜2 hrs
39. filtrationThe solids were filtered
40. washrinsed with heptanes (2×2 vol)
41. customThe solid product was then dried under vacuum at 30° C.