Diethyl Ether → 4-(3,5-Bis-trifluoromethylphenyl)-piperidine-4-carbonitrile

Temperature

70 °C

To a solution of (3,5-bis-trifluoromethylphenyl)-acetonitrile (25 mmol; 6.33 g) and bis-(2-chloroethyl)-carbamic acid tert-butyl ester (28 mmol; 6.73 g) in N,N-dimethylformamide (50 mL) under Argon was added sodium hydride (75 mmol; 1.90 g) in small portions over a 30 min period. When the addition was complete, the resulting mixture was heated at 70° C. for 1 hour, then stirred for 2½ days at room temperature. Diethyl ether (250 mL) was added, followed by water (20 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and evaporated. The resulting residue was dissolved in a 4N hydrochloric acid solution (20 mL) and the mixture was stirred for 1 hour at room temperature. The resulting mixture was evaporated and triturated with diethyl ether (50 mL). The solid was separated via centrifugation and purified via reverse phase HPLC. The desired fractions were combined and lyophilized. The resulting residue was dissolved in ethyl acetate (50 mL) and washed with a 1N sodium hydroxide solution (20 mL). The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in diethyl ether, and a 1N HCl solution in diethyl ether (10 mL) was added dropwise. A white precipitate formed that was separated via centrifugation and dried under vacuum to yield 4-(3,5-bis-trifluoromethylphenyl)-piperidine-4-carbonitrile as a hydrochloride salt. MS (ESI) m/z 323.1 [M+H]+.

1. additionWhen the addition
2. customThe organic layer was separated
3. washwashed with brine
4. dry with materialdried over magnesium sulfate
5. filtrationfiltered
6. customevaporated
7. dissolutionThe resulting residue was dissolved in a 4N hydrochloric acid solution (20 mL)
8. stirringthe mixture was stirred for 1 hour at room temperature
9. customThe resulting mixture was evaporated
10. customtriturated with diethyl ether (50 mL)
11. customThe solid was separated via centrifugation
12. custompurified via reverse phase HPLC
13. dissolutionThe resulting residue was dissolved in ethyl acetate (50 mL)
14. washwashed with a 1N sodium hydroxide solution (20 mL)
15. dry with materialThe organic phase was dried over magnesium sulfate
16. filtrationfiltered
17. customevaporated
18. dissolutionThe residue was dissolved in diethyl ether
19. additiona 1N HCl solution in diethyl ether (10 mL) was added dropwise
20. customA white precipitate formed
21. customthat was separated via centrifugation
22. customdried under vacuum

ORD record

ord-641b7c96ab2544ed8672b6cbdff6a487

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08686152B2