反应详情

Premixed hydrochloric acid solution [cHCl (516.0 g), water (4813 ml)] was charged to a reaction vessel containing 2-{(3S)-3-[(2-{[tert butyl(dimethyl)silyl]oxy}ethyl)amino]pyrrolidin-1-yl}-6-chloro-N-[(1-hydroxycycloheptyl)methyl]quinoline-5-carboxamide (525.0 g) and toluene (5250 ml) at 20° C. to 30° C. The reaction mixture was stirred at 25° C. to 30° C. for 20 hours and filtered. The filter cake was washed with water (525 ml). The filtrate and wash were combined and the layers were separated. The aqueous layer was washed with toluene (2625 ml), and charged to a reaction vessel. Premixed potassium bicarbonate solution [water (1803 ml), potassium bicarbonate (601.3 g)] and n-butanol (5250 ml) were charged at 25° C. to 30° C. and the resulting mixture stirred for 67 minutes. The phases were separated and the aqueous phase extracted with n-butanol (2625 ml). The combined butanol phases were combined and washed with water (2600.0 ml) four times. At this point the butanol solution was combined with the butanol solution from a reaction of identical scale. The solution was filtered and the filter cake washed with n-butanol (1050 ml). The filtrate and wash were combined and concentrated to ca. 9.5 L at 40° C. to 50° C. n-Butanol (1050 ml) was charged and concentrated to ca. 9.5 L at 40° C. to 50° C. n-Butanol (1050 ml) was charged and concentrated to ca. 10.5 L at 40° C. to 50° C. n-Butanol (1050 ml) was charged and concentrated to ca. 10.5 L at 40° C. to 50° C. n-Butanol (1050 ml) was charged and concentrated to ca. 10.5 L at 40° C. to 50° C. The mixture was concentrated to ca 5.3 L at 40° C. to 50° C. The mixture was held at 40° C. to 50° C. for 61 hours and mixed heptanes (5250 ml) were charged at 40° C. to 50° C. The mixture was stirred at 40° C. to 50° C. for 60 minutes, at 20 to 25° C. for 92 minutes and filtered. The filter cake was washed with premixed heptanes and n-butanol [heptanes (2100 ml) n-butanol (2100 ml)]. The filter cake was dried at 40° C. for 30 hours, at 60° C. for 24 hours, at 65° C. for 19 hours and 80° C. for 9 hours to provide the title compound as an off-white solid (524.4 g).

1. additionwas charged to a reaction vessel
2. filtrationfiltered
3. washThe filter cake was washed with water (525 ml)
4. washThe filtrate and wash
5. customthe layers were separated
6. washThe aqueous layer was washed with toluene (2625 ml)
7. additioncharged to a reaction vessel
8. additionPremixed potassium bicarbonate solution [water (1803 ml), potassium bicarbonate (601.3 g)] and n-butanol (5250 ml) were charged at 25° C. to 30° C.
9. stirringthe resulting mixture stirred for 67 minutes
10. customThe phases were separated
11. extractionthe aqueous phase extracted with n-butanol (2625 ml)
12. washwashed with water (2600.0 ml) four times
13. customAt this point the butanol solution was combined with the butanol solution from a reaction of identical scale
14. filtrationThe solution was filtered
15. washthe filter cake washed with n-butanol (1050 ml)
16. washThe filtrate and wash
17. concentrationconcentrated to ca. 9.5 L at 40° C. to 50° C. n-Butanol (1050 ml)
18. additionwas charged
19. concentrationconcentrated to ca. 9.5 L at 40° C. to 50° C. n-Butanol (1050 ml)
20. additionwas charged
21. concentrationconcentrated to ca. 10.5 L at 40° C. to 50° C. n-Butanol (1050 ml)
22. additionwas charged
23. concentrationconcentrated to ca. 10.5 L at 40° C. to 50° C. n-Butanol (1050 ml)
24. additionwas charged
25. concentrationconcentrated to ca. 10.5 L at 40° C. to 50° C
26. concentrationThe mixture was concentrated to ca 5.3 L at 40° C. to 50° C
27. waitThe mixture was held at 40° C. to 50° C. for 61 hours
28. additionmixed heptanes (5250 ml)
29. additionwere charged at 40° C. to 50° C
30. stirringThe mixture was stirred at 40° C. to 50° C. for 60 minutes, at 20 to 25° C. for 92 minutes
31. filtrationfiltered
32. washThe filter cake was washed with premixed heptanes and n-butanol [heptanes (2100 ml) n-butanol (2100 ml)]
33. customThe filter cake was dried at 40° C. for 30 hours, at 60° C. for 24 hours, at 65° C. for 19 hours and 80° C. for 9 hours