Methane → 4-(1-(2-(Pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine trihydrochloride

Temperature

32.5 °C

Charge degassed dimethylsulfoxide (750 mL) to a flask, followed by tert-butyl 4-(4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (150 g, 1.0 equiv), sodium iodide (87.2 g, 1.3 equiv), potassium hydroxide (15 g, 0.6 equiv) and potassium tert-butoxide (95.3 g, 1.9 equiv) while maintaining the temperature between 20° and 35° C. Heat the mixture to 30-35° C. In a separate reactor, dissolve 1-(2-chloroethyl)pyrrolidine hydrochloride (83.7 g, 1.1 equiv) in dimethylsulfoxide (750 mL) and transfer to the first reactor at 30°-35° C. Adjust the temperature to 40°-45° C. and stir for 2-3 h. Cool the mixture to 20°-30° C. and add methyl tert-butyl ether (3 L). Wash the organic phase with water (1.5 L), and back-extract the aqueous layer with methyl tert-butyl ether (3 L). Combine the organic layers, wash with water (1.5 L), separate and treat the organic layer with activated charcoal (7.5 g, 0.05 equiv)) for 1-2 h at 40°-45° C. Filter off the charcoal and wash with methyl tert-butyl ether (150 mL). Concentrate to 3-v volumes in vacuo and add methanol (1.05 L). Concentrate again to 3-4 volumes. Add a solution of 2 N hydrochloric acid in methanol (1.1 L, 5.0 equiv), and heat at 50° C.-60° C. for 2 h. Concentrate to 3-4 volumes in vacuo and add ethyl acetate (1.35 L) drop wise with the temperature at 50° C.-60° C., and stir at that temperature for 1-2 h. Cool the reaction mixture to 20° C.-30° C. and stir at that temperature for 1-2 h. Filter and rinse the cake with 3:1 ethyl acetate:MeOH (300 mL) to give 4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine trihydrochloride as a single regioisomer (130 g, 58%). MS (ES) m/z=333 [M]+.

1. additionCharge
2. customdegassed dimethylsulfoxide (750 mL) to a flask
3. temperaturewhile maintaining the temperature between 20° and 35° C
4. customtransfer to the first reactor at 30°-35° C
5. customto 40°-45° C.
6. temperatureCool the mixture to 20°-30° C.
7. washWash the organic phase with water (1.5 L)
8. extractionback-extract the aqueous layer with methyl tert-butyl ether (3 L)
9. washCombine the organic layers, wash with water (1.5 L)
10. customseparate
11. filtrationFilter off the charcoal
12. washwash with methyl tert-butyl ether (150 mL)
13. concentrationConcentrate to 3-v volumes in vacuo
14. additionadd methanol (1.05 L)
15. concentrationConcentrate again to 3-4 volumes
16. temperatureheat at 50° C.-60° C. for 2 h
17. concentrationConcentrate to 3-4 volumes in vacuo
18. additionadd ethyl acetate (1.35 L) drop wise with the temperature at 50° C.-60° C.
19. stirringstir at that temperature for 1-2 h
20. temperatureCool the reaction mixture to 20° C.-30° C.
21. stirringstir at that temperature for 1-2 h
22. filtrationFilter
23. washrinse the cake with 3:1 ethyl acetate

ORD record

ord-4a3649b472354fae9785476544a27085

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08436002B2