Ammonium Chloride → Methyl [(2S)-2-(3,5-difluorophenyl)-2,5,5-trimethyl-6-oxopiperidin-1-yl]acetate

HRID 1866724Notes

Reaction equation

HRID 1866724 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:18])[NH:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:18])[CH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13](=[O:15])[N:14]2[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:5]=[C:6]([F:8])[CH:7]=1

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 60984Methyl bromoacetateHCID 82127Potassium hydride2×HCID 57974084(6S)-6-(3,5-difluorophenyl)-3,3,6-trimethylpiperidin-2-one

Product 1

HCID 57974130Methyl [(2S)-2-(3,5-difluorophenyl)-2,5,5-trimethyl-6-oxopiperidin-1-yl]acetate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (6S)-6-(3,5-difluorophenyl)-3,3,6-trimethylpiperidin-2-one (540. mg, 2.13 mmol) in THF (20 mL), chilled to 0° C. was added potassium hydride (approximately 86 mg, 2.13 mmol, as a 30% suspension in oil) under a constant stream of nitrogen. The reaction was allowed to stir for 30 minutes at which time methyl bromoacetate (391 mg, 2.56 mmol) was added at 0° C. An LCMS after one hour indicated that the reaction was incomplete, thus more potassium hydride was added (approximately 43 mg, 1.06 mmol, as a 30% suspension in oil) at 0° C. The reaction was sealed well and was stirred for an additional 16 hours, during which time the bath temperature warmed to ambient temperature. The reaction was judged to be 46% complete by LCMS analysis. The reaction was chilled to 0° C. and saturated aqueous ammonium chloride (5 mL) was added to quench the potassium hydride. To the reaction was added 1M aqueous HCl (5 mL) and the reaction was diluted with ethyl acetate. The organic layer was washed once with brine and then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of EtOAc:Hexanes—10:90 to 75:25, to give the title compound. MS: m/z=326 (M+1).

Workup

  1. additionwas added at 0° C
  2. customat 0° C
  3. customThe reaction was sealed well
  4. temperatureThe reaction was chilled to 0° C.
  5. customto quench the potassium hydride
  6. additionTo the reaction was added 1M aqueous HCl (5 mL)
  7. additionthe reaction was diluted with ethyl acetate
  8. washThe organic layer was washed once with brine
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customto give a residue that
  13. customwas purified by silica gel chromatography
  14. washeluting with a gradient of EtOAc

Sources & evidence

ORD record
ord-0b4564a601d3444989bf45862218c1ac
Source dataset
uspto-grants-2009_12
Patent number
US07629338B2

Reaction notes

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