Allyl bromide → 3-Allyl-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one

Temperature

-78 °C

To a cooled, stirred solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 2.0 mL, 2.0 mmol) in THF (10 mL) at −78° C., was added a solution of (5S,6R & 5R,6S)-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one (0.50 g, 1.54 mmol) in THF (10 mL) dropwise, keeping the internal temperature of the reaction mixture below −65° C. The resulting mixture was stirred at −78° C. for 30 min, then a cold (−78° C.) solution of allyl bromide (0.242 g, 2.0 mmol) in THF (10 mL) was added dropwise, keeping the internal temperature of the reaction mixture below −65° C. The reaction mixture was allowed to warm slowly to ambient temperature and stirred for 18 h. The reaction was quenched by the addition of a saturated solution of sodium chloride (20 mL) and partitioned between water (50 mL) and EtOAc (200 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (50 mL). The combined organic extracts were washed with 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 40:60, to give the title compound. MS: m/z=366.1 (M+1).

1. customthe internal temperature of the reaction mixture below −65° C
2. customthe internal temperature of the reaction mixture below −65° C
3. temperatureto warm slowly to ambient temperature
4. stirringstirred for 18 h
5. customThe reaction was quenched by the addition of a saturated solution of sodium chloride (20 mL)
6. custompartitioned between water (50 mL) and EtOAc (200 mL)
7. customThe organic layer was removed
8. extractionthe aqueous phase was extracted further with EtOAc (50 mL)
9. washThe combined organic extracts were washed with brine
10. dry with materialdried 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 record

ord-354cac64a9354cad92f1af767f45fb31

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09227972B2