反应详情

温度

50 °C

A portion of the resolution methanol mother liquors from Scheme B, step b, is concentrated to a solid (185.6 g of salt). The residue was dissolved in methanol to a concentration of 0.67 g/mL. The methanol solution was then added dropwise to an agitated suspension of toluene (464 g), water (280 g) and potassium carbonate (40.86 g, 0.3 mol). The phases were agitated for a half hour at 50° C. and then allowed to separate. The bottom aqueous phases were extracted a second time with toluene (250 mL). The two organic phases were combined and concentrated on the rotary evaporation to a solid. The solid (82 g, 0.22 mol of (S)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3c) by assay) was then dissolved in isopropanol (382 mL) and water (127 mL). To the solution, 37% HCl (138 g, 1.4 mol) was added. The solution was heated to reflux for a total of 17 hours. The solution was cooled to room temperature and neutralized with 50% NaOH (112.8 g, 1.41 mol). The addition was done slowly to control exotherm. The phases were agitated for 10 minutes before removing the isopropanol on the rotary evaporator. Toluene (500 mL) was added to the residue. The phases were agitated for 10 minutes before being separated. The bottom aqueous phase was extracted a second time with toluene (200 mL). The organic phases were then combined and concentrated on the rotary evaporation until an approximately 30 wt % of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (5) was reached. The slurry was heated to reflux and then slowly cooled to 40° C. where it was seeded. The solution crystallized and was cooled to room temperature. The slurry was chilled in an ice bath for a half an hour before being suction filtered through a coarse sintered glass funnel. The wet cake was washed with 50 mL of chilled isopropanol and then dried to a constant weight. Isolation of the slurry gave 19.96 g of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (5) (23.6% yield, 95% assay). The mother liquor contained 3.3% (4.22 g) α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (5).

1. concentrationA portion of the resolution methanol mother liquors from Scheme B, step b, is concentrated to a solid (185.6 g of salt)
2. dissolutionThe residue was dissolved in methanol to a concentration of 0.67 g/mL
3. customto separate
4. extractionThe bottom aqueous phases were extracted a second time with toluene (250 mL)
5. concentrationconcentrated on the rotary evaporation to a solid
6. temperatureThe solution was heated
7. temperatureto reflux for a total of 17 hours
8. additionThe addition
9. stirringThe phases were agitated for 10 minutes
10. custombefore removing the isopropanol
11. customon the rotary evaporator
12. additionToluene (500 mL) was added to the residue
13. stirringThe phases were agitated for 10 minutes
14. custombefore being separated
15. extractionThe bottom aqueous phase was extracted a second time with toluene (200 mL)
16. concentrationconcentrated on the rotary evaporation until an approximately 30 wt % of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (5)
17. temperatureThe slurry was heated
18. temperatureto reflux
19. temperatureslowly cooled to 40° C. where it
20. customThe solution crystallized
21. temperaturewas cooled to room temperature
22. temperatureThe slurry was chilled in an ice bath for a half an hour
23. filtrationfiltered through a coarse sintered glass funnel
24. washThe wet cake was washed with 50 mL of chilled isopropanol
25. customdried to a constant weight