Hydrochloric Acid → HCID 18700426, compound

To a 3-l round bottom flask containing thionyl chloride (21.1 mL, 291 mmole) and dichloromethane (900 mL) is added dimethyl formamide (28 mL, 364 mmole). The solution is stirred for 10 minutes then {4-[5-(4-fluorophenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidin-1-yl} acetonitrile (45.9 g, 145 mmole) is added in one portion. The resulting slurry is stirred for 30 minutes then 2 N aqueous sodium hydroxide (900 mL) is added. The organic layer is separated, washed with saturated aqueous sodium chloride (500 mL), dried over sodium sulfate (100 g), filtered and concentrated to an oil. The oil is dissolved in tetrahydrofuran (120 mL) then a 0° C. solution of 1 N potassium t-butoxide in t-butanol (437 mL, 437 mmole) and 2,2,2-trifluoroethanol (40.2 mL, 582 mmole) is added. The reaction mixture is warmed to room temperature and stirred for 18 hours. The solvent volume is reduced to 100 mL by distillation, then water (700 mL) is added. The aqueous suspension is washed with methyl t-butylether (700 mL). The organic extract is washed with saturated aqueous sodium chloride then concentrated to an oil (50 mL). To the oil is added ethanol (450 mL), water (150 ml), 36% aqueous hydrochloric acid (24.3 mL, 291 mmole) and 35% aqueous hydrazine (26.6 mL, 291 mmole). The resulting solution is warmed to 80° C., stirred for 3 hours, cooled to room temperature and sodium hydroxide (17.4 g, 435 mmole) is added. The solvent volume is reduced to 320 mL by distillation and water (600 mL) is added. The aqueous suspension is washed with dichloromethane (2×500 mL). The dichloromethane extracts are washed with water, then 500 mL of a 3:2:1:1 solution of saturated aqueous sodium chloride:water:36% aqueous hydrochloric acid:ethanol. The aqueous sodium chloride:water:36% aqueous hydrochloric acid:ethanol solution is washed again with dichloromethane (500 mL). The combineed dichloromethane extracts are dried over sodium sulfate (100 g), filtered and concentrated to 250 mL to effect crystallization. To complete the crystallization, methyl t-butylether (500 mL) is added and the resulting slurry is cooled to 0° C. The solids are collected by filtration, washed with methyl t-butylether (100 mL) and dried to constant weight to give {4-[5-(4-fluorophenyl)-4-(2,2,2-trifluoroethoxymethyl)-oxazol-2-yl]-piperidine hydrochloride (47.3 g, 120 mmole). 1H NMR (400 MHz, d6 DMSO) d 1.96 (m, 2H), 2.20 (m, 2H), 3.02 (q, 2H), 3.30 (m, 3H), 4.18 (q, 2H), 4.66 (s, 2H), 7.37 (t, 2H), 7.68 (q, 2H), 9.0 (bs, 1H), 9.20 (bs, 1H).

1. stirringThe resulting slurry is stirred for 30 minutes
2. customThe organic layer is separated
3. washwashed with saturated aqueous sodium chloride (500 mL)
4. dry with materialdried over sodium sulfate (100 g)
5. filtrationfiltered
6. concentrationconcentrated to an oil
7. dissolutionThe oil is dissolved in tetrahydrofuran (120 mL)
8. stirringstirred for 18 hours
9. distillationThe solvent volume is reduced to 100 mL by distillation
10. additionwater (700 mL) is added
11. washThe aqueous suspension is washed with methyl t-butylether (700 mL)
12. extractionThe organic extract
13. washis washed with saturated aqueous sodium chloride
14. concentrationthen concentrated to an oil (50 mL)
15. temperatureThe resulting solution is warmed to 80° C.
16. stirringstirred for 3 hours
17. temperaturecooled to room temperature
18. distillationThe solvent volume is reduced to 320 mL by distillation and water (600 mL)
19. additionis added
20. washThe aqueous suspension is washed with dichloromethane (2×500 mL)
21. washThe dichloromethane extracts are washed with water
22. washThe aqueous sodium chloride:water:36% aqueous hydrochloric acid:ethanol solution is washed again with dichloromethane (500 mL)
23. dry with materialThe combineed dichloromethane extracts are dried over sodium sulfate (100 g)
24. filtrationfiltered
25. concentrationconcentrated to 250 mL
26. customcrystallization
27. customthe crystallization, methyl t-butylether (500 mL)
28. additionis added
29. temperaturethe resulting slurry is cooled to 0° C
30. filtrationThe solids are collected by filtration
31. washwashed with methyl t-butylether (100 mL)
32. customdried to constant weight

ORD record

ord-507d2edddaf24ba7867ed209b4762d98

Source dataset

uspto-grants-2000_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06090825