2,2,2-Trifluoroethyl trifluoromethanesulfonate → tert-Butyl [(3S,5S)-5-(2-fluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]carbamate

HRID 334858Notes

Reaction equation

HRID 334858 reaction equation
[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:11][NH:10][C:9]1=[O:21])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>O1CCCC1.CN1CCCC1=O.O>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:11][N:10]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:9]1=[O:21])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 3

HCID 803662,2,2-Trifluoroethyl trifluoromethanesulfonateHCID 2733832Lithium HexamethyldisilazideHCID 86665197tert-butyl[(3S,5S)-5-(2-fluorophenyl)-2-oxopiperidin-3-yl]carbamate

Product 1

HCID 86707239tert-Butyl [(3S,5S)-5-(2-fluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]carbamate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 22156051tetrahydrofuran N-methylpyrrolidinoneSolvent

Conditions

Temperature
0 °C

Procedure

To a pre-cooled 0° C. solution of tert-butyl[(3S,5S)-5-(2-fluorophenyl)-2-oxopiperidin-3-yl]carbamate (0.59 g, 1.93 mmol) in tetrahydrofuran:N-methyl-2-pyrrolidinone (2:1, 18 mL) was added lithium bis(trimethylsilyl)amide (2.29 mL, 2.29 mmol, 1 M in THF) and the mixture was stirred at 0° C. for 30 min. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.33 mL, 2.29 mmol) was added and the resulting mixture was stirred at 0° C. for 4 h. The mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate→100% ethyl acetate/hexane) was followed by separation of the cis/trans diastereoisomers using normal-phase HPLC using a ChiralPak® AD column, eluting with 60% ethanol in hexanes to afford the title compound as the second diastereomer to elute. MS: m/z=391.2 (M+1).

Workup

  1. stirringthe resulting mixture was stirred at 0° C. for 4 h
  2. extractionextracted with ethyl acetate (3×)
  3. washThe combined organic extracts were washed with water, brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification by silica gel chromatography (0% ethyl acetate→100% ethyl acetate/hexane)
  8. customwas followed by separation of the cis/trans diastereoisomers
  9. washeluting with 60% ethanol in hexanes

Sources & evidence

ORD record
ord-92b8234054cc4b0097f16c0835c706bd
Source dataset
uspto-grants-2014_11
Patent number
US08883807B2

Reaction notes

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