反应详情

温度

30 °C

A solution of 3-[(1S)-2-tert-butoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide (456.32 g of an 11.41% w/w solution in acetonitrile; 103.80 mmol) was charged to a jacketed vessel. The stirred mixture was heated to between 93° C. and 101° C. (jacket temperature) and solvent was removed by distillation under atmospheric pressure until a total of 370 mL of distillate was collected. The mixture was then cooled (jacket temperature 30° C.) and MTBE (500 mL) was added to give a cloudy mixture. The jacket temperature was set to 20° C. and aqueous hydrochloric acid (250 mL of a 2.10M solution) was added when the temperature of the reaction mixture reached 23.6° C. The mixture was stirred for 10 minutes then separated. The upper organic layer washed with water (250 mL) and the layers were separated. The retained organic layer was heated (jacket temperature 68° C.) and solvent removed by distillation under atmospheric pressure until a total of 440 mL of distillate was collected. Isopropyl alcohol (300 mL) was then added to the mixture in the vessel. The jacket temperature was set to 95° C. and solvent removed by distillation under atmospheric pressure until a total of 250 mL of distillate was collected. The mixture was cooled to between 20 and 21° C. and a solution of hydrogen chloride (5.52 M in isopropanol, 616 mL) was added. The mixture was heated to 50° C. over 40 minutes. The mixture was maintained at 50° C. for a further 70 minutes before addition of a seed of 3-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide (66 mg). The mixture was stirred for a further 15 min then seeded once more (53 mg). The mixture was set on a pre-programmed cooling ramp to 15° C. over 400 min. The product started to crystallise approximately 40 minutes after initiation of the cooling profile. After stirring for approximately 20 hours after initiation of the cooling ramp, the crystallised product was collected by filtration. The collected solid was washed with MTBE (150 mL). The product cake was sucked dry on the filter then subjected to further drying in vacuum for approximately 18 hours at 45° C. to give the title product (40.52 g; with a purity of 94.22% w/w by HPLC assay (73.4% yield after correction for assay)).

1. addition103.80 mmol) was charged to a jacketed vessel
2. temperatureThe stirred mixture was heated to between 93° C. and 101° C. (jacket temperature) and solvent
3. customwas removed by distillation under atmospheric pressure until a total of 370 mL of distillate
4. customwas collected
5. additionwas added
6. customto give a cloudy mixture
7. customwas set to 20° C.
8. customreached 23.6° C
9. customthen separated
10. washThe upper organic layer washed with water (250 mL)
11. customthe layers were separated
12. temperatureThe retained organic layer was heated (jacket temperature 68° C.) and solvent
13. customremoved by distillation under atmospheric pressure until a total of 440 mL of distillate
14. customwas collected
15. additionIsopropyl alcohol (300 mL) was then added to the mixture in the vessel
16. customwas set to 95° C.
17. customsolvent removed by distillation under atmospheric pressure until a total of 250 mL of distillate
18. customwas collected
19. temperatureThe mixture was cooled to between 20 and 21° C.
20. additiona solution of hydrogen chloride (5.52 M in isopropanol, 616 mL) was added
21. temperatureThe mixture was heated to 50° C. over 40 minutes
22. temperatureThe mixture was maintained at 50° C. for a further 70 minutes before addition of a seed of 3-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide (66 mg)
23. stirringThe mixture was stirred for a further 15 min
24. temperaturecooling ramp to 15° C. over 400 min
25. customto crystallise approximately 40 minutes after initiation of the cooling profile
26. stirringAfter stirring for approximately 20 hours after initiation of the cooling ramp
27. filtrationthe crystallised product was collected by filtration
28. washThe collected solid was washed with MTBE (150 mL)
29. customThe product cake was sucked dry on the
30. filtrationfilter
31. customto further drying in vacuum for approximately 18 hours at 45° C.