反应详情

温度

20 °C

In 1 gal pressure reactor, a mixture of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (120 g) prepared in accordance with Step C, above, and ammonium hydroxide (28-30%, 2.4 L, 20 vol) was heated in the sealed pressure reactor to 98-103° C. and stirred at this temperature for 2 hours. The reaction was cooled slowly to room temperature (20° C.) and stirred overnight. The solids were filtered and washed with minimum amount of the mother liquor and dried under vacuum. The solids were added to a mixture of EtOAc (15 vol)/water (2 vol) and heated to complete dissolution at 60-70° C. and the aqueous layer was removed and discarded. The EtOAC layer was charged with water (1 vol) and neutralized with aq. HCl to ˜pH 5.4-5.5. and added water (1 vol). The aqueous layer was removed and discarded at 60-70° C. The organic layer was washed with water (1 vol) at 60-70° C. and the aqueous layer was removed and discarded. The organic layer was filtered at 60° C. and concentrated to 3 volumes. EtOAc (6 vol) was charged into the mixture and heated and stirred at 72° C. for 10 min, then cooled to 20° C. and stirred overnight. EtOAc was removed via vacuum distillation to concentrate the reaction mixture to ˜3 volumes. The reaction mixture was maintained at ˜65-70° C. for ˜30 mins. Product crystals having the same crystal form as those prepared in Example 58b (and preparable by the procedure of Example 58b), above, in heptanes slurry were charged. Heptane (9 vol) was slowly added at 65-70° C. The slurry was stirred at 65-70° C. for 2-3 hours and then cooled slowly to 0-5° C. The product was filtered, washed with EtOAc/heptane (3/1 v/v, 4 vol) and dried at 45° C. under vacuum to obtain N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (102.3 g, 88%).

1. customprepared in accordance with Step C
2. stirringstirred overnight
3. filtrationThe solids were filtered
4. washwashed with minimum amount of the mother liquor
5. customdried under vacuum
6. additionThe solids were added to a mixture of EtOAc (15 vol)/water (2 vol)
7. temperatureheated
8. dissolutiondissolution at 60-70° C.
9. customthe aqueous layer was removed
10. additionThe EtOAC layer was charged with water (1 vol)
11. additionand added water (1 vol)
12. customThe aqueous layer was removed
13. customdiscarded at 60-70° C
14. washThe organic layer was washed with water (1 vol) at 60-70° C.
15. customthe aqueous layer was removed
16. filtrationThe organic layer was filtered at 60° C.
17. concentrationconcentrated to 3 volumes
18. additionEtOAc (6 vol) was charged into the mixture
19. temperatureheated
20. stirringstirred at 72° C. for 10 min
21. temperaturecooled to 20° C.
22. stirringstirred overnight
23. customEtOAc was removed via vacuum distillation
24. concentrationto concentrate the reaction mixture to ˜3 volumes
25. temperatureThe reaction mixture was maintained at ˜65-70° C. for ˜30 mins
26. customthose prepared in Example 58b (and preparable by the procedure of Example 58b), above, in heptanes slurry
27. additionwere charged
28. stirringThe slurry was stirred at 65-70° C. for 2-3 hours
29. temperaturecooled slowly to 0-5° C
30. filtrationThe product was filtered
31. washwashed with EtOAc/heptane (3/1 v/v, 4 vol)
32. customdried at 45° C. under vacuum