Lithium Hexamethyldisilazide → tert-Butyl {(3S,5S)-5-(2,3-difluorophenyl)-2-oxo-1-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]piperidin-3-yl}carbamate

HRID 448234Notes

Reaction equation

HRID 448234 reaction equation
[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[CH2:11][NH:10][C:9]1=[O:22])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:34][C:35]([F:40])([F:39])[C@@H:36]1[CH2:38][O:37]1>O1CCCC1.CN1CCCC1=O.O>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C@H:12]1[CH2:11][N:10]([CH2:38][C@H:36]([OH:37])[C:35]([F:40])([F:39])[F:34])[C:9](=[O:22])[C@@H:8]([NH:7][C:6](=[O:23])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:13]1

Participants

6

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 7171781(2S)-2-(Trifluoromethyl)oxiraneHCID 69096669tert-butyl[(3S,5S)-5-(2,3-difluorophenyl)-2-oxopiperidin-3-yl]carbamate2×

Product 1

HCID 86665203tert-Butyl {(3S,5S)-5-(2,3-difluorophenyl)-2-oxo-1-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]piperidin-3-yl}carbamate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 22156051tetrahydrofuran N-methylpyrrolidinoneSolvent

Conditions

Temperature
-30 °C

Procedure

To a pre-cooled −30° C. solution of tert-butyl[(3S,5S)-5-(2,3-difluorophenyl)-2-oxopiperidin-3-yl]carbamate (described in Intermediate 11, step B, 56 mg, 0.172 mmol) in tetrahydrofuran:N-methyl-2-pyrrolidinone (2:1, 0.8 mL) was added lithium bis(trimethylsilyl)amide (0.22 mL, 0.22 mmol, 1 M in THF) and the mixture was stirred at −30° C. for 30 min. (2S)-2-(Trifluoromethyl)oxirane (19 mg, 0.172 mmol) was added and the resulting mixture was stirred at −30° C. for 2 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→90% ethyl acetate/hexane) afforded the title compound. MS: m/z=461.2 (M+Na).

Workup

  1. additionwas added
  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→90% ethyl acetate/hexane)

Sources & evidence

ORD record
ord-9c09d843f6e3479182a07bb2d890fac2
Source dataset
uspto-grants-2013_07
Patent number
US08481556B2

Reaction notes

Loading…