Water → HCID 58128486, compound

Temperature

-78 °C

Commercially available tert-butyl 4-ethynylpiperidine-1-carboxylate was dissolved in 40 ml of THF and cooled to −78° C. forming a white slurry. Titrated n-BuLi (2.2 M in hexanes, 23.9 ml, 52.6 mmol) was added drop wise with stirring. The clear colorless solution was stirred at −78° C. for 5 minutes. A solution of the R-(+) benzyl glycidyl epoxide (8.63 g, 52.6 mmol) in THF (20 ml) was added drop wise. BF3 etherate (8.43 g, 59.7 mmol) was then added drop wise with a syringe and the solution stirred at −78° C. for 1 hour. Saturated aqueous NH4Cl was added (100 ml), the mixture warmed to RT, diluted with water to dissolve any remaining solids, and extracted with iPrOAc (3×100 ml). The organic fractions were combined, washed with brine, dried over MgSO4, filtered and stripped. Crude product was purified by chromatography on SiO2 eluting with 30% EtOAc:Hexanes. The alcohol was repurified by chromatography on a C18 reversed phase column (12-100% water:acetonitrile 0.1% TFA as two runs.). Product containing fractions were combined, reduced in volume by approximately 50%, made basic by addition of saturated aqueous NaHCO3, water was added to dissolve some white solids, and the mixture extracted with iPrOAc (3×100). The organic fractions were combined, washed with brine, dried over MgSO4, filtered, and stripped to give the titled compound.

1. customforming a white slurry
2. stirringThe clear colorless solution was stirred at −78° C. for 5 minutes
3. stirringthe solution stirred at −78° C. for 1 hour
4. temperaturethe mixture warmed to RT
5. dissolutionto dissolve any remaining solids
6. extractionextracted with iPrOAc (3×100 ml)
7. washwashed with brine
8. dry with materialdried over MgSO4
9. filtrationfiltered
10. customCrude product was purified by chromatography on SiO2 eluting with 30% EtOAc
11. customThe alcohol was repurified by chromatography on a C18 reversed phase column (12-100% water:acetonitrile 0.1% TFA as two runs.)
12. additionProduct containing fractions
13. additionmade basic by addition of saturated aqueous NaHCO3, water
14. additionwas added
15. dissolutionto dissolve some white solids
16. extractionthe mixture extracted with iPrOAc (3×100)
17. washwashed with brine
18. dry with materialdried over MgSO4
19. filtrationfiltered

ORD record

ord-49881834c83043b6b772568642d1e1a0

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08552022B2