Acetic Acid → tert-Butyl [(3S,5S,6R)-5-(3-chlorophenyl)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]carbamate

Temperature

23 °C

A slurry of methyl 2-[(tert-butoxycarbonyl)amino]-4-(3-chlorophenyl)-5-oxohexanoate as a 1:1 racemic mixture of diastereomers (11.1 g, 30.0 mmol), 2,2,2-trifluoroethylamine (9.59 mL, 120 mmol), acetic acid (10.3 mL, 180 mmol), sodium triacetoxyborohydride (25.4 g, 120 mmol), and flame-dried 4 Å molecular sieves (50 g) in 1,2-dichloroethane (300 mL) was stirred at 23° C. for 8 h. Additional 2,2,2-trifluoroethylamine (9.59 mL, 120 mmol), acetic acid (10.3 mL, 180 mmol), and sodium triacetoxyborohydride (25.4 g, 120 mmol) were added and stirring was continued for 20 h. The reaction mixture was diluted with dichloromethane (200 mL) then poured into water (500 mL). Molecular sieves were removed by filtration, and the organic layer was washed with water (3×500 mL), dried over sodium sulfate, and concentrated. A solution of the residue in ethanol (200 mL) was stirred in the presence of solid potassium carbonate (12.4 g, 90 mmol) at 60° C. for 2 h, then 23° C. for 16 h. The bulk of the ethanol was removed under reduced pressure and the remaining slurry was then partitioned between water (500 mL) and ethyl acetate (300 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was crystallized from a 2:1 mixture of hexane and ethyl ether to give the title compound as a racemate. The enantiomers were separated using normal-phase HPLC using a ChiralPak® AD column, eluting with 40% hexane in ethanol initially, stepping to 20% hexane in ethanol (0.1% diethylamine used as a modifier) to afford the title compound as the second enantiomer to elute. MS: m/z=421.2 (M+1).

1. dry with materialflame-dried 4 Å molecular sieves (50 g) in 1,2-dichloroethane (300 mL)
2. stirringstirring
3. waitwas continued for 20 h
4. customMolecular sieves were removed by filtration
5. washthe organic layer was washed with water (3×500 mL)
6. dry with materialdried over sodium sulfate
7. concentrationconcentrated
8. wait23° C. for 16 h
9. customThe bulk of the ethanol was removed under reduced pressure
10. customthe remaining slurry was then partitioned between water (500 mL) and ethyl acetate (300 mL)
11. washThe organic layer was washed with brine
12. dry with materialdried over sodium sulfate
13. concentrationconcentrated
14. customThe residue was crystallized from a 2:1 mixture of hexane and ethyl ether

ORD record

ord-b13312add3ed49ad90b1d5409e7d21e9

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08912210B2