反应详情

温度

40 °C

A nitrogen inerted pressure reactor is charged with ((4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-ethyl}-2-phenyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester from OPERATION A (5.0 g), 5% Pd/C (0.45 g; 50% H2O-wet), 2N HCl in MeOH (1.9 mL), toluene (11 mL), and MeOH (3.1 mL). The vessel and its contents are degassed via two cycles of partial evacuation and nitrogen pressurization (25 mm Hg and 50 psi, respectively). The atmosphere is switched to hydrogen via three cycles of partial evacuation and hydrogen pressurization (25 mm Hg and 50 psi, respectively). The reaction is stirred vigorously at 40° C. under a positive pressure of H2 (ca. 50 psi) for ca. 2.5 hours. The reaction is allowed to cool to ambient temperature, and the hydrogen pressure is released and replaced with nitrogen. The reaction is passed through filtering agent to remove the catalyst, rinsing thoroughly with MeOH (2×5 mL). To this solution is added KOH (0.6 g) in water (25 mL). The reaction is stirred vigorously under a nitrogen atmosphere and heated to an internal reaction temperature of ca. 90° C., removing MeOH via distillation. The two-phase mixture is allowed to cool to 70° C. and the upper toluene phase is separated and discarded. The aqueous phase is washed with a second portion of toluene (10 mL) at 70° C. This organic wash is also separated and discarded. To the aqueous phase is added toluene (10 mL), followed by a slow addition of 2N HCl (5 mL). The two-phase mixture is stirred for 10 minutes and the layers are separated. The aqueous phase is extracted with a second portion of toluene (10 mL) and is discarded. The combined organics are heated to reflux under a Dean-Stark water trap for 2.5 hours under argon. The reaction mixture is cooled to 65° C. and seeded with 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide. After 2 hours the reaction mixture is allowed to slowly cool to ambient temperature. The resulting slurry is cooled to ca. 0° C. The product is collected and washed with cold toluene (5 mL). The resulting solid is dissolved in hot toluene (20 mL) and cooled to 65° C. and held for 2 hours. The reaction mixture is slowly cooled to ambient temperature and then to 0° C. The product is collected, washed with cold toluene (5 μL) and dried in vacuo at 70° C. overnight to afford 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide as a white solid.

1. customThe vessel and its contents are degassed via two cycles of partial evacuation and nitrogen pressurization (25 mm Hg and 50 psi
2. temperatureto cool to ambient temperature
3. filtrationthrough filtering agent
4. customto remove the catalyst
5. washrinsing thoroughly with MeOH (2×5 mL)
6. additionTo this solution is added KOH (0.6 g) in water (25 mL)
7. stirringThe reaction is stirred vigorously under a nitrogen atmosphere
8. temperatureheated to an internal reaction temperature of ca. 90° C.
9. customremoving MeOH
10. distillationvia distillation
11. temperatureto cool to 70° C.
12. customthe upper toluene phase is separated
13. washThe aqueous phase is washed with a second portion of toluene (10 mL) at 70° C
14. washThis organic wash
15. customis also separated
16. additionTo the aqueous phase is added toluene (10 mL)
17. additionfollowed by a slow addition of 2N HCl (5 mL)
18. stirringThe two-phase mixture is stirred for 10 minutes
19. customthe layers are separated
20. extractionThe aqueous phase is extracted with a second portion of toluene (10 mL)
21. temperatureThe combined organics are heated
22. temperatureto reflux under a Dean-Stark water trap for 2.5 hours under argon
23. temperatureThe reaction mixture is cooled to 65° C.
24. waitAfter 2 hours the reaction mixture is allowed
25. temperatureto slowly cool to ambient temperature
26. temperatureThe resulting slurry is cooled to ca. 0° C
27. customThe product is collected
28. washwashed with cold toluene (5 mL)
29. dissolutionThe resulting solid is dissolved in hot toluene (20 mL)
30. temperaturecooled to 65° C.
31. waitheld for 2 hours
32. temperatureThe reaction mixture is slowly cooled to ambient temperature
33. customto 0° C
34. customThe product is collected
35. washwashed with cold toluene (5 μL)
36. customdried in vacuo at 70° C. overnight