Isobutyl iodide → tert-butyl[(3S,5S)-5-(2-fluorophenyl)-1-(2-methylpropyl)-2-oxopiperidin-3-yl]carbamate

HRID 448222Notes

Reaction equation

HRID 448222 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+].I[CH2:34][CH:35]([CH3:37])[CH3:36]>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]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:9]1=[O:21])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 3

HCID 10556Isobutyl iodideHCID 2733832Lithium HexamethyldisilazideHCID 86665197tert-butyl[(3S,5S)-5-(2-fluorophenyl)-2-oxopiperidin-3-yl]carbamate

Product 1

HCID 86665198tert-butyl[(3S,5S)-5-(2-fluorophenyl)-1-(2-methylpropyl)-2-oxopiperidin-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 (0.85 g, 2.76 mmol) in tetrahydrofuran:N-methyl-2-pyrrolidinone (2:1, 18 mL) was added lithium bis(trimethylsilyl)amide (3.58 mL, 3.58 mmol, 1 M in THF) and the mixture was stirred at 0° C. for 30 min. 1-Iodo-2-methylpropane (0.48 mL, 4.13 mmol) was added and the resulting mixture was stirred at 0° C. for 2 h and then warmed to 23° C. and stirred for an additional 18 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→70% ethyl acetate/hexane) was followed by separation of the cis/trans diastereomers using supercritical fluid chromatography with a ChiralPak® AD column and eluting with 20% ethanol in carbon dioxide to afford the title compound as the second diastereomer to elute. MS: m/z=387.2 (M+Na).

Workup

  1. stirringthe resulting mixture was stirred at 0° C. for 2 h
  2. temperaturewarmed to 23° C.
  3. stirringstirred for an additional 18 h
  4. extractionextracted with ethyl acetate (3×)
  5. washThe combined organic extracts were washed with water, brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification by silica gel chromatography (0% ethyl acetate→70% ethyl acetate/hexane)
  10. customwas followed by separation of the cis/trans diastereomers
  11. washeluting with 20% ethanol in carbon dioxide

Sources & evidence

ORD record
ord-736dd5bf36bd4cb0b93c876f4e3f7d8f
Source dataset
uspto-grants-2013_07
Patent number
US08481556B2

Reaction notes

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