Methyl iodide → HCID 118307937, compound

Temperature

-78 °C

(2R)-Tert-butyl 3,3,5-trifluoro-2-(2-fluorophenyl)-2-methyl-6-oxopiperidine-1-carboxylate (1.30 g, 3.60 mmol) (1:1 mixture of diastereomers) was dissolved in tetrahydrofuran (36 mL) (dried over 4 Å MS) and added to a dry round bottom flask. The solution was cooled to −78° C. using a dry ice/acetone bath. LiHMDS (lithium hexamethyldisilazide) (4.50 mL, 4.50 mmol, 1.0 M in tetrahydrofuran) was added in a dropwise manner and the resulting solution was stirred at stirred at −78° C. for 1 h. Methyl iodide (2.55 g, 1.13 mL, 18 mmol) was added in a dropwise manner and the solution was stirred at −78° C. for 45 min then the cooling was removed and the solution was stirred for another 15 min at room temperature. The solution was re-cooled to −78° C. and quenched with saturated aqueous NH4Cl (25 mL). The cooling bath was removed and the reaction was allowed to warm to room temperature. The two reaction mixtures were combined and ethyl acetate (200 mL) and water (50 mL) were added. The phases were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. All of the thus obtained material was dissolved in 1,2-dichloroethane (85 ml) and the solution was cooled to 0° C. using an ice/water bath. TFA (21 ml, 273 mmol) was added and the cooling bath was allowed to slowly expire overnight, with stirring of the reaction mixture. The reaction was diluted with toluene (50 mL) and concentrated to approximately 25 ml-under vacuum. The residue was diluted with ethyl acetate (150 mL) and washed with saturated aqueous NaHCO3 (50 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×75 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified using a CombiFlash system (80 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→50:50) to afford (6R)-3,5,5-trifluoro-6-(2-fluorophenyl)-3,6-dimethylpiperidin-2-one (1.86 g, 6.76 mmol, 94% yield) (1:1.8 mixture of diastereomers) LC-MS (m/z) 276.2 (MH+) tR=0.62 minutes (Method B).

1. additionadded to a dry round bottom flask
2. stirringat stirred at −78° C. for 1 h
3. stirringthe solution was stirred at −78° C. for 45 min
4. customthe cooling was removed
5. stirringthe solution was stirred for another 15 min at room temperature
6. temperatureThe solution was re-cooled to −78° C.
7. customquenched with saturated aqueous NH4Cl (25 mL)
8. customThe cooling bath was removed
9. temperatureto warm to room temperature
10. customThe two reaction mixtures
11. customThe phases were separated
12. extractionthe aqueous layer was extracted with ethyl acetate (2×100 mL)
13. washThe combined organics were washed with brine
14. dry with materialdried over MgSO4
15. filtrationfiltered
16. concentrationconcentrated under reduced pressure
17. dissolutionAll of the thus obtained material was dissolved in 1,2-dichloroethane (85 ml)
18. temperaturethe solution was cooled to 0° C.
19. stirringwith stirring of the reaction mixture
20. concentrationconcentrated to approximately 25 ml-under vacuum
21. additionThe residue was diluted with ethyl acetate (150 mL)
22. washwashed with saturated aqueous NaHCO3 (50 mL)
23. customThe phases were separated
24. extractionthe aqueous layer was extracted with ethyl acetate (2×75 mL)
25. washThe combined organics were washed with brine
26. dry with materialdried over MgSO4
27. filtrationfiltered
28. concentrationconcentrated under reduced pressure
29. customThe crude material was purified
30. washa CombiFlash system (80 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→50:50)

ORD record

ord-2be2115f055e4a60ade32bfc214bdfe4

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09353084B2