tert-butyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate

tert-butyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate Property

storage temp. 

2-8°C

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H302Harmful if swallowed

H315Causes skin irritation

H319Causes serious eye irritation

H335May cause respiratory irritation

Precautionary statements

P261Avoid breathing dust/fume/gas/mist/vapours/spray.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

tert-butyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate Chemical Properties,Usage,Production

Synthesis

General procedure: tert-butyl-1-piperazinecarboxylate (1.00 g, 5.37 mmol) and pyridine (0.868 mL, 10.7 mmol) were dissolved in dichloromethane (27 mL) and the mixture was cooled to 0 °C. Subsequently, trifluoroacetic anhydride (0.910 mL, 6.44 mmol) was slowly added dropwise and the reaction mixture was gradually warmed up to room temperature with continuous stirring for 1 hour. Upon completion of the reaction, the reaction solution was diluted with ethyl acetate (150 mL) and washed sequentially with aqueous potassium bisulfate (2 x 50 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl 4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylate (1.50 g, 99%) as an oil, which solidified on standing. Tert-butyl 4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylate (0.908 g, 3.22 mmol) was dissolved in tetrahydrofuran (24 mL), borane-tetrahydrofuran complex (8 mmol) was added, and the reaction mixture was heated and refluxed for 2 hours. After cooling, 2N hydrochloric acid (4 mL) was carefully added and stirred until gas release ceased, followed by dilution with ethyl acetate (200 mL). 0.2 M aqueous sodium hydroxide (75 mL) was added and after partitioning, the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (eluent: 20% hexane solution of ethyl acetate) to give tert-butyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate (0.627 g, 73%) as a white solid. Tert-butyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate (0.736 g, 2.74 mmol) was dissolved in dioxane (5 mL), a 4.0 M hydrochloric acid solution of dioxane (10 mL) was added, and the reaction was stirred until thin-layer chromatography analysis showed that the reaction was complete (about 3 hours). The volatiles were evaporated under reduced pressure and the residue was dried under vacuum to give 1-(2,2,2-trifluoroethyl)piperazine (0.631 g, 95%) as a white solid.

References

[1] Patent: WO2005/110996, 2005, A1. Location in patent: Page/Page column 45-46
[2] Patent: CN106187838, 2016, A. Location in patent: Paragraph 0437; 0438; 0439
[3] Patent: WO2006/46031, 2006, A1. Location in patent: Page/Page column 46-47
[4] Patent: CN105461697, 2016, A. Location in patent: Paragraph 0198; 0199