N-methyl-2-pyrrolidone → HCID 66615669, compound

Temperature

67 °C

4-Hydroxypiperidine (32.5 g) and potassium tert-butoxide (62.7 g) were added to a 1 L jacketed vessel. Tetrahydrofuran (275 mL) was added followed by N-methylpyrrolidone (25 mL). 1,2-Dichloro-4-fluoro-3-methylbenzene (50 g) in tetrahydrofuran (100 mL) was then added, followed by tetrahydrofuran (100 mL). The mixture was heated to 67° C. overnight then cooled to 50° C. Water (250 mL) was added and the mixture was stirred for 10 min at 50° C. The layers were separated and the heating was removed. The organic layer was washed with twice with 10% w/w brine (250 mL). The organic layer was heated to remove solvent by distillation firstly at atmospheric pressure and then under vacuum (400 mbar) whilst isopropanol (950 mL) was added until the tetrahydrofuran was replaced by isopropanol. The solution was then heated to 50° C. Hydrogen chloride in isopropanol (5.5M, 125 mL) was added, an exotherm to 60° C. was observed and the solution was cooled to 50° C. The mixture was cooled from 50° C. to 10° C. over 1 h and then stirred overnight at 10° C. The product was collected by filtration, washed with isopropanol (50 mL) and dried under vacuum at 40° C. to give 4-(3,4-dichloro-2-methyl-phenoxy)-piperidine hydrochloride as an off-white solid (62.3 g).

1. temperaturethen cooled to 50° C
2. customThe layers were separated
3. customthe heating was removed
4. washThe organic layer was washed with twice with 10% w/w brine (250 mL)
5. temperatureThe organic layer was heated
6. customto remove solvent
7. distillationby distillation firstly at atmospheric pressure
8. additionunder vacuum (400 mbar) whilst isopropanol (950 mL) was added until the tetrahydrofuran
9. temperatureThe solution was then heated to 50° C
10. additionHydrogen chloride in isopropanol (5.5M, 125 mL) was added
11. customto 60° C.
12. temperaturethe solution was cooled to 50° C
13. temperatureThe mixture was cooled from 50° C. to 10° C. over 1 h
14. stirringstirred overnight at 10° C
15. filtrationThe product was collected by filtration
16. washwashed with isopropanol (50 mL)
17. customdried under vacuum at 40° C.

ORD record

ord-b3a7a86333f8402c806c7632a1bdd947

Source dataset

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08314127B2