Methyl iodide → HCID 118307937, compound

Participants

Reaction Conditions

Reaction Steps

(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).

Provenance & Evidence