Sodium hydride → HCID 71244864, compound

Temperature

2.5 °C

To a solution of above crude cis and trans mixture of 1-benzyl-3-(hydroxymethyl)piperidin-4-ol (2.69 g, 12.16 mmol) in DCM (60 mL) was added DIPEA (3.39 mL, 24.31 mmol) and MsCl (0.947 mL, 12.2 mmol) dropwise at 0° C. The reaction mixture was further stirred for 1.5 h at 0-5° C. and then quenched with saturated aqueous NaHCO3. The aqueous phase was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated to afford a mixture of mono- and bi-mesylated compounds. The crude was then dissolved in THF (250 mL) and added NaH (1.05 g, 43.8 mmol, 60% in mineral oil) portionwise at room temperature. After being stirred for 40 min at room temperature, the reaction mixture was then heated to 65° C. for 4.5 h. The reaction mixture was cooled to room temperature, then quenched with water and concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (0-100% EtOAc/heptanes) to provide racemic (cis)-3-benzyl-7-oxa-3-azabicyclo[4.2.0]octane as a colorless oil. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.32-7.41 (m, 5H), 4.97 (ddd, J=3.03, 4.42, 6.19 Hz, 1H), 4.68 (t, J=5.68 Hz, 1H), 4.07-4.13 (m, 1H), 3.53-3.60 (m, 2H), 2.90-2.98 (m, 1H), 2.82-2.90 (m, 1H), 2.52-2.59 (m, 2H), 2.49 (dd, J=6.32, 11.37 Hz, 1H), 1.83-1.87 (m, 2H).

1. customquenched with saturated aqueous NaHCO3
2. extractionThe aqueous phase was extracted with DCM
3. dry with materialThe combined organic phases were dried over Na2SO4
4. filtrationfiltered
5. concentrationconcentrated
6. customto afford
7. additiona mixture of mono- and bi-mesylated compounds
8. stirringAfter being stirred for 40 min at room temperature
9. temperaturethe reaction mixture was then heated to 65° C. for 4.5 h
10. temperatureThe reaction mixture was cooled to room temperature
11. customquenched with water
12. concentrationconcentrated in vacuo
13. dissolutionThe residue was dissolved in EtOAc
14. washwashed with saturated aqueous NH4Cl
15. dry with materialdried over Na2SO4
16. filtrationfiltered
17. concentrationconcentrated
18. customThe resulting residue was purified by silica gel flash chromatography (0-100% EtOAc/heptanes)

ORD record

ord-aa237f3953ed4059aa6e7458638fc8ee

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08846656B2