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

(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).

1. customplaced in a Parr-flask
2. filtrationAfter 16 h in the Parr shaker at room temperature the reaction mixture was filtered through a plug of celite
3. washfor elution
4. concentrationThe filtrate was concentrated under reduced pressure
5. customthe reaction mixture was split equally into two Parr-flasks
6. additionadded to the two Parr-flasks
7. filtrationfiltered through a plug of celite
8. washfor elution
9. concentrationThe filtrate was concentrated under reduced pressure
10. customThe material thus obtained
11. stirringthe reaction was stirred at room temperature for another 1 h 30 min
12. concentrationThe reaction was concentrated to dryness under reduced pressure
13. customthe residue was partitioned between water (200 mL) and ethyl acetate (250 mL)
14. customThe phases were separated
15. extractionthe aqueous layer was extracted with ethyl acetate (2×100 mL)
16. washThe combined organics were washed with brine
17. dry with materialdried over MgSO4
18. filtrationfiltered
19. concentrationconcentrated under reduced pressure
20. customThe crude material was purified
21. washa CombiFlash system (120 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→45:55)
22. customto afford

ORD 기록

ord-a461106e50b24d09b899441d32b9fd81

출처 데이터셋

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09353084B2