2,2,2-Trifluoroethyl trifluoromethanesulfonate → 5-(2,3-Difluorophenyl)-1-(2,2,2-trifluoroethyl)piperidin-2-one

Temperatur

0 °C

To a stirred solution of 5-(2,3-difluorophenyl)piperidin-2-one (8.88 g, 42 mmol) in THF (250 mL) and NMP (170 mL) at 0° C. was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 48 mL, 48 mmol) over 5 min, keeping the internal temperature of the reaction mixture below 5° C. The resulting mixture was stirred at 0° C. for 15 min, then 2,2,2-trifluoroethyl triflate (11.2 g, 48 mmol) was added dropwise, keeping the internal temperature of the reaction mixture below 5° C. The reaction mixture was allowed to warm slowly to ambient temperature and stirring was continued for 3 h. The resulting mixture was partitioned between saturated aqueous sodium bicarbonate (800 mL) and EtOAc (1 L). The organic layer was removed and the aqueous phase was extracted further with EtOAc (500 mL). The combined organic extracts were washed with water, then brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=293.9 (M+1).

1. customthe internal temperature of the reaction mixture below 5° C
2. customthe internal temperature of the reaction mixture below 5° C
3. temperatureto warm slowly to ambient temperature
4. stirringstirring
5. waitwas continued for 3 h
6. customThe resulting mixture was partitioned between saturated aqueous sodium bicarbonate (800 mL) and EtOAc (1 L)
7. customThe organic layer was removed
8. extractionthe aqueous phase was extracted further with EtOAc (500 mL)
9. washThe combined organic extracts were washed with water
10. dry with materialbrine, then dried over sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated to dryness in vacuo
13. customThe crude product was purified by silica gel chromatography
14. washeluting with a gradient of hexanes

ORD-Eintrag

ord-24475dc1fc3642a78210190b4cd29be5

Quelldatensatz

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08481556B2