Hydrochloric Acid → (6R)-3,5,5-Trifluoro-6-(2-fluorophenyl)-6-methylpiperidin-2-one

Participants

Reaction Steps

(R)-Ethyl 5-((R)-1,1-dimethylethylsulfinamido)-2,4,4-trifluoro-5-(2-fluorophenyl)hex-2-enoate (5.1 g, 12.5 mmol) was dissolved in ethyl acetate (200 mmol) and placed in a Parr-flask. Palladium on carbon (2.65 g, 2.49 mmol, 10%) was added and the Parr-flask was placed in a Parr-shaker (H2-pressure=2.8 bar initially). After 16 h in the Parr shaker at room temperature the reaction mixture was filtered through a plug of celite using ethyl acetate for elution. The filtrate was concentrated under reduced pressure. This material was dissolved in ethyl acetate (200 ml, 3494 mmol) and the reaction mixture was split equally into two Parr-flasks. Palladium on carbon (2.65 g, 2.49 mmol, 10%) was split in two equal partitions and added to the two Parr-flasks. The flasks were placed in two different Parr-shakers (H2-pressure=2.8 bar initially) and run in parallel. After 16 h in the Parr-shaker at room temperature the two suspensions were combined and filtered through a plug of celite using ethyl acetate for elution. The filtrate was concentrated under reduced pressure. The material thus obtained was dissolved in methanol (330 ml). HCl (4.7 ml, 19 mmol, 4 M in 1,4-dioxane) was added and the reaction was stirred at room temperature for 1 h 30 min. K2CO3 (5.16 g, 37.4 mmol) was added and the reaction was stirred at room temperature for another 1 h 30 min. The reaction was concentrated to dryness under reduced pressure and the residue was partitioned between water (200 mL) and ethyl acetate (250 mL). 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. The crude material was purified using a CombiFlash system (120 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→45:55) to afford (6R)-3,5,5-trifluoro-6-(2-fluorophenyl)-6-methylpiperidin-2-one (1.86 g, 57.2% yield) as a semi-solid/foam (1:1 mixture of diastereomers) LC-MS (m/z) 262.2 (MH+) tR=0.57 minutes (Method B).

Provenance & Evidence