反应详情

温度

35 °C

Place ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate (56.12 g, 0.1064 mol) in a 1-L three necked round-bottom flask and fit the flask with a mechanical stirrer, a Claisen head, a thermometer and a reflux condenser with a nitrogen bubbler on top. Add methanol (300 mL) and turn the stirrer on. Dilute the slurry with water (6 mL) and heat to reflux using a heating mantle controlled by a Therm-O-Watch. When the mixture reaches about 35° C., treat with 50% sodium hydroxide (34.05 g, 0.4256 mol) and rinse in with water (42 mL). Stir at reflux for 2 hours, 15 minutes, cool over 1 hour to 35° C. and then treat with sodium borohydride (2.02 g, 0.0534 mol). Stir for 7.5 hours and allow to stand at room temperature without stirring for 1.75 days. Warm the mixture to 35° C. and quench with acetone (15.5 mL, 0.21 mol) and stir for 2 hours. Add water (60 mL) and adjust the pH to 2.5 with 32% hydrochloric acid (65.22 g). Cool to 40° C. and rinse the pH probe with water (25 mL). Add water over about 30 minutes (192 mL), hold the temperature at 33° C. for 10 minutes and add a few seed crystals. Cool the slurry to -12° C. over about 45 minutes and isolate the solid by filtration (586.2 g). Wash with water (2×100 mL) and then with ethyl acetate (100 mL, prechilled to about -10° C.). Vacuum dry overnight (1 mmHg, 50° C.) to give 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (58.86 g, 98%) as a white solid.

1. temperatureheat
2. temperatureto reflux
3. customreaches about 35° C.
4. washrinse in with water (42 mL)
5. temperatureat reflux for 2 hours, 15 minutes
6. temperaturecool over 1 hour to 35° C.
7. stirringStir for 7.5 hours
8. customto stand at room temperature
9. stirringwithout stirring for 1.75 days
10. stirringstir for 2 hours
11. temperatureCool to 40° C.
12. washrinse the pH probe with water (25 mL)
13. customat 33° C.
14. customfor 10 minutes
15. additionadd a few seed crystals
16. temperatureCool the slurry to -12° C. over about 45 minutes
17. customisolate the solid
18. filtrationby filtration (586.2 g)
19. washWash with water (2×100 mL)
20. customwith ethyl acetate (100 mL, prechilled to about -10° C.)
21. customVacuum dry overnight (1 mmHg, 50° C.)