反应详情

Alternatively, the following method may be used. In a glass-lined nitrogen purged hydrogenator are charged 1-(4-Benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanol hydrochloride (150 g, 303.7 mmol), demineralized water (352 mL), i-PrOH (375 mL) and 5% Pd/C (30 g, 50% water, Johnson & Matthey type 440). The heterogeneous reaction mixture was then purged 5 times with 25 psi nitrogen then purged 5 times with 50 psi hydrogen, and the hydrogenation was performed at RT. The initial Tmass was 22° C. and the maximum Tmass during the hydrogenation was 23° C. The reactor was stirred vigorously. In-process analysis after 2 hours indicated complete hydrogenolysis. The hydrogenation was stopped after 3 hours. The nitrogen purged reaction mixture was then filtered at RT through an hyflo filter (56 g), impregnated beforehand with 75 mL of a 50/50 v/v isopropanol/water mixture and washed with 300 mL of a 50/50 v/v isopropanol/water mixture. The filtrates were stored overnight at RT. The filtrates were concentrated at 40-50° C. under reduced pressure (typical 622 g distilled). The reaction mixture was cooled to RT and post-agitated. After 3 hours, 1 mL of the solution was taken and cooled to 0° C. to initiate crystallization. These seeds were added to the reaction mixture and precipitation was observed within a few minutes. The mixture was post-agitated at RT for 2 hours. The crystals were filtered and rinsed with H20 (30 mL). Then, the precipitate was dried under reduced pressure (400 mmHg) with a nitrogen flow (0.1 bar) for 4 hours affording the title compound as the hydrate polymorph (103.5 g, 81% yield).

1. customThe heterogeneous reaction mixture was then purged 5 times with 25 psi nitrogen
2. customthen purged 5 times with 50 psi hydrogen
3. customwas performed at RT
4. customwas 22° C.
5. customwas 23° C
6. waitThe hydrogenation was stopped after 3 hours
7. customThe nitrogen purged
8. customreaction mixture
9. filtrationwas then filtered at RT through an hyflo
10. filtrationfilter (56 g)
11. washwashed with 300 mL of a 50/50 v/v isopropanol/water mixture
12. waitThe filtrates were stored overnight at RT
13. concentrationThe filtrates were concentrated at 40-50° C. under reduced pressure (typical 622 g distilled)
14. stirringpost-agitated
15. waitAfter 3 hours
16. temperaturecooled to 0° C.
17. customcrystallization
18. additionThese seeds were added to the reaction mixture and precipitation
19. waitwas observed within a few minutes
20. stirringThe mixture was post-agitated at RT for 2 hours
21. filtrationThe crystals were filtered
22. washrinsed with H20 (30 mL)
23. customThen, the precipitate was dried under reduced pressure (400 mmHg) with a nitrogen flow (0.1 bar) for 4 hours