Acetic Acid → 1,1-Dimethylethyl 4-(3-ethoxy-3-oxo-1-propyn-1-yl)-4-hydroxy-1-piperidinecarboxylate

HRID 747008Notes

Reaction equation

HRID 747008 reaction equation
C([Li])CCC.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(O)(=O)C>O1CCCC1>[CH2:11]([O:10][C:6](=[O:9])[C:7]#[C:8][C:14]1([OH:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]1)[CH3:12]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 12182Ethyl propiolateHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 219552401,1-Dimethylethyl 4-(3-ethoxy-3-oxo-1-propyn-1-yl)-4-hydroxy-1-piperidinecarboxylateYield 105.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-70 °C

Procedure

n-Butyllithium (175 ml, 0.28 mol) was added dropwise over 45 minutes to a stirred, cooled (−70° C.) solution of ethyl propiolate (32 ml, 0.32 mol) in tetrahydrofuran (250 ml). The mixture was stirred at −70° C. for 10 minutes, then a solution of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (18.6 g, 0.093 mol) in tetrahydrofuran (250 ml) was added dropwise over 1 hour maintaining the internal temperature below −70° C. The mixture was stirred at −70° C. for 1 hour and then acetic acid (21 ml) in tetrahydrofuran (50 ml) was added. The mixture was warmed to room temperature and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (300 ml) and ethyl acetate (650 ml) were added and the layers were separated. The aqueous fraction was extracted with ethyl acetate (2×650 ml) and the combined organic fractions were washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a short silica gel column, eluting with 1:1 isohexane:ethyl acetate, to give the title compound (29.2 g, contains trace impurity).

Workup

  1. temperaturemaintaining the internal temperature below −70° C
  2. stirringThe mixture was stirred at −70° C. for 1 hour
  3. temperatureThe mixture was warmed to room temperature
  4. customthe solvent was evaporated under reduced pressure
  5. additionSaturated aqueous sodium hydrogen carbonate (300 ml) and ethyl acetate (650 ml) were added
  6. customthe layers were separated
  7. extractionThe aqueous fraction was extracted with ethyl acetate (2×650 ml)
  8. washthe combined organic fractions were washed with brine
  9. dry with materialdried (Na2SO4)
  10. customthe solvent was evaporated under reduced pressure
  11. customThe residue was purified by chromatography on a short silica gel column
  12. washeluting with 1:1 isohexane

Sources & evidence

ORD record
ord-e951f1ebce4f4ec7873c37144a6a965e
Source dataset
uspto-grants-2008_07
Patent number
US07393858B2

Reaction notes

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