Triethylamine → 4-Piperidinol, 4-(p-chlorophenyl)-1-(3-(10,11-dihydro-5H-dibenz(b,f)azepin-5-yl)propyl)-, hydrochloride, hydrate (2:2:1)

Temperature

0 °C

To a stirred solution of the above alcohol (1.01 g, 0.004 mol) and triethylamine (1.02 g, 0.010 mol) in toluene (25 ml) at 0° C., methanesulfonyl chloride (0.6 ml, 0.0077 mol) was added dropwise over 10 minutes. The resulting mixture was stirred at 0° C. for 1.5 h. Water (50 ml) was added and the phases were separated. The aqueous phase was extracted with toluene (50 ml), and the combined organic phases were washed with brine (2×50 ml), dried (MgSO4) and concentrated in vacuo. The crude mesylate was mixed with 4-(4-chlorophenyl)piperidin-4-ol (0.81 g, 0.004 mol) and potassium carbonate (1.08 g, 0.008 mol) in acetonitrile (9 ml) and heated at reflux temperature for 6 h. The reaction mixture was left stirring at room temperature for 2 days. Water (50 ml) was added and the mixture was extracted with ethyl acetate (3×15 ml), washed with brine (2×20 ml), dried (MgSO4) and concentrated in vacuo. Water (50 ml) was added and the mixture was acidified by addition of concentrated hydrochloric acid (3 ml). The aqueous solution was extracted with dichloromethane (2×20 ml), washed with brine (2×20 ml), dried (MgSO4) and concentrated in vacuo. The resulting oil was dissolved in a mixture of ethyl acetate (15 ml) and methanol (2 ml). Heptane was added in small portions, just until the solution turned slightly turbid. After 4 h, crystals were filtered off, washed with heptane and dried, affording 1.1 g (61%) of the title compound as a solid.

1. customthe phases were separated
2. extractionThe aqueous phase was extracted with toluene (50 ml)
3. washthe combined organic phases were washed with brine (2×50 ml)
4. dry with materialdried (MgSO4)
5. concentrationconcentrated in vacuo
6. temperatureheated
7. temperatureat reflux temperature for 6 h
8. waitThe reaction mixture was left
9. stirringstirring at room temperature for 2 days
10. extractionthe mixture was extracted with ethyl acetate (3×15 ml)
11. washwashed with brine (2×20 ml)
12. dry with materialdried (MgSO4)
13. concentrationconcentrated in vacuo
14. additionWater (50 ml) was added
15. additionthe mixture was acidified by addition of concentrated hydrochloric acid (3 ml)
16. extractionThe aqueous solution was extracted with dichloromethane (2×20 ml)
17. washwashed with brine (2×20 ml)
18. dry with materialdried (MgSO4)
19. concentrationconcentrated in vacuo
20. dissolutionThe resulting oil was dissolved in a mixture of ethyl acetate (15 ml) and methanol (2 ml)
21. additionHeptane was added in small portions, just until the solution
22. waitAfter 4 h
23. filtrationcrystals were filtered off
24. washwashed with heptane
25. customdried

ORD record

ord-2290c829f0b64acba1b7e173728340cd

Source dataset

uspto-grants-2001_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06239148B1