反应详情

温度

-10 °C

An argon-purged reactor is charged with 5-(4-fluorophenyl)-2-isopropyl-1-[2-((S)-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide (0.020 mol/>99% ee) and benzyl alcohol (52 mL). The reaction mixture is cooled to −10° C. and NaOH (0.040 mol) is added. After stirring for 19 hours at −10C the reaction is quenched with 37% HCl (0.042 mol) and diluted with water (25 mL) and toluene (25 mL). After the mixture is warmed to ambient temperature, the lower aqueous layer is discarded. The upper organic layer is combined with 20% Pd(OH)2/C (1.0 g) and H2SO4 (0.01 moles) and hydrogenated under 50 psi hydrogen at 50° C. for 16 hours. The reaction mixture is heated to 80° C. and filtered through diatomaceous earth. The reactor and catalyst cake is rinsed with hot toluene (10 mL). The lower aqueous layer is discarded. The upper organic layer is washed with a warm solution of aqueous HCl (0.16 g 37% HCl in 25 mL hot water) and heated to reflux for 2.5 hours under argon, removing water azeotropically. 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 about 0° C. The product is collected and washed with cold toluene (25 mL). The resulting solid is dissolved in hot toluene (95 mL) and cooled to 65° C. and held for 2 hours. The reaction mixture is slowly cooled to ambient temperature and further cooled to 0° C. The product is collected, washed with cold toluene (25 mL) 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 (8.4 g) as a white solid.

1. customAn argon-purged reactor
2. temperatureAfter the mixture is warmed to ambient temperature
3. temperatureThe reaction mixture is heated to 80° C.
4. filtrationfiltered through diatomaceous earth
5. washThe reactor and catalyst cake is rinsed with hot toluene (10 mL)
6. washThe upper organic layer is washed with a warm solution of aqueous HCl (0.16 g 37% HCl in 25 mL hot water)
7. temperatureheated
8. temperatureto reflux for 2.5 hours under argon
9. customremoving water azeotropically
10. temperatureThe reaction mixture is cooled to 65° C.
11. waitAfter 2 hours the reaction mixture is allowed
12. temperatureto slowly cool to ambient temperature
13. temperatureThe resulting slurry is cooled to about 0° C
14. customThe product is collected
15. washwashed with cold toluene (25 mL)
16. dissolutionThe resulting solid is dissolved in hot toluene (95 mL)
17. temperaturecooled to 65° C.
18. waitheld for 2 hours
19. temperatureThe reaction mixture is slowly cooled to ambient temperature
20. temperaturefurther cooled to 0° C
21. customThe product is collected
22. washwashed with cold toluene (25 mL)
23. customdried in vacuo at 70° C. overnight