Hydrochloric Acid → 1,1,1,3,3,3-Hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride

Temperature

65 °C

A 1-L pressure vessel was charged with 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (70.8 g, 219 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), tert-butyl piperazine-1-carboxylate (40.0 g, 215 mmol, Sigma-Aldrich, St. Louis, Mo.), 200 mL of toluene, and sodium tert-butoxide (43.3 g, 451 mmol). Nitrogen gas was bubbled through the solution for 5 min then chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (RuPhos Palladacycle) (1.57 g, 2.15 mmol, Strem Chemicals Inc, Newburyport, Mass.) and 2-dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (2.00 g, 4.30 mmol, Strem Chemicals Inc, Newburyport, Mass.) were added. The vessel was sealed and heated at 65° C. for 2 h. The mixture was then diluted with water and extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give an oil. To this material was added 200 mL of EtOAc and 200 mL of 4N HCl in dioxane. The solution was heated at 80° C. for 12 h and the resulting suspension was then allowed to cool to room temperature. The solid precipitate was collected by filtration to give 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (76.2 g) as a white solid.

1. customNitrogen gas was bubbled through the solution for 5 min
2. customThe vessel was sealed
3. extractionextracted with EtOAc
4. dry with materialThe combined organic extracts were dried (MgSO4)
5. filtrationfiltered
6. concentrationconcentrated
7. customto give an oil
8. temperatureThe solution was heated at 80° C. for 12 h
9. temperatureto cool to room temperature
10. filtrationThe solid precipitate was collected by filtration

ORD record

ord-4ecb1a989ccd4558a3a687f42f4779fd

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08431563B2