Water → (R)-tert-butyl 3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate

Temperature

0 °C

An oven dried flask was charged with (R)-tert-butyl 3-((R)-hydroxy(phenyl)-methyl)piperidine-1-carboxylate (162 mg, 0.557 mmol) and 60% NaH in mineral oil (112 mg, 5 equiv.). The flask was purged with N2 gas, cooled to 0° C. and anhydrous THF (6 mL) was added slowly. After 5 min, the reaction mixture was allowed to warn to rt slowly. A solution of 3-methoxypropyl methanesulfonate (468 mg, 4 equiv.) in anhydrous THF (5 mL) was added. The mixture was heated at reflux for 4 h. LC-MS indicated the reaction was complete. The reaction mixture was cooled to 0° C. and water was added dropwise. After separation, the aqueous layer was extracted with ether (3×). The combined organic layers were washed with 5% aq HCl, satd aq NaHCO3 and brine, and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 4-g silica gel cartridge eluted with a 0-35% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-((R)-(3-methoxypropoxy)(phenyl)-methyl)piperidine-1-carboxylate (196 mg, 97% yield) as a clear oil. LC-MS (3 min) tR=2.19 min, m/z 386 (M+Na).

1. customAn oven dried flask
2. customThe flask was purged with N2 gas
3. additionanhydrous THF (6 mL) was added slowly
4. customto warn to rt
5. temperatureThe mixture was heated
6. temperatureat reflux for 4 h
7. temperatureThe reaction mixture was cooled to 0° C.
8. customAfter separation
9. extractionthe aqueous layer was extracted with ether (3×)
10. washThe combined organic layers were washed with 5% aq HCl
11. dry with materialdried over Na2SO4
12. concentrationAfter concentration
13. customthe crude product was purified by flash chromatography on a 4-g silica gel cartridge
14. washeluted with a 0-35% EtOAc in hexanes gradient

ORD record

ord-f9eafae37b634ec1b0a0f90b7b0ac941

Source dataset

uspto-grants-2011_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07872028B2