Diethyl Sulfate → Ethyl (trans)-4-cyano-3-ethoxy-1-piperidine-carboxylate

HRID 1264655Notes

Reaction equation

HRID 1264655 reaction equation
[H-].[Li+].O[C:4]([CH3:8])([CH3:7])[C:5]#[N:6].[H][H].C12OC1C[CH2:14][N:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]2.S(OCC)([O:26][CH2:27][CH3:28])(=O)=O>C1COCC1.O>[C:5]([C@@H:4]1[CH2:8][CH2:12][N:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@H:7]1[O:26][CH2:27][CH3:28])#[N:6]

Participants

8

Reactant 5

HCID 6163Diethyl SulfateHCID 6406Acetone CyanohydrinHCID 62714Lithium hydrideHCID 12414163Ethyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylateHCID 178418361HCID 178418361, compound

Product 1

HCID 86589666Ethyl (trans)-4-cyano-3-ethoxy-1-piperidine-carboxylateYield 63.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

Reaction was carried out under a nitrogen atmosphere. Lithium hydride (95%) (0.036 mol) was suspended in THF (30 ml). A solution of 2-hydroxy-2-methyl-propanenitrile (0.036 mol) in TEF (10 ml) was added dropwise (evolution of hydrogen gas). The mixture was stirred for 90 minutes at room temperature. A solution of 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid, ethyl ester (0.03 mol) in THF (15 ml) for 90 minutes. The reaction mixture was cooled to 15 ° C. Diethyl sulfate (0.039 mol) was added (exothermic temperature rise to 25 ° C.). The reaction mixture was stirred for one hour at room temperature, then stirred and refluxed for 6 hours, cooled and a drop of water was added. The solvent was evaporated. The residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2C]2/CH3OH from 100/0 to 99/1). The pure fractions were collected and the solvent was evaporated, yielding 4.3 g of ethyl (trans)-4-cyano-3-ethoxy-1-piperidine-carboxylate (intermediate 13).

Workup

  1. customReaction
  2. temperatureThe reaction mixture was cooled to 15 ° C
  3. stirringThe reaction mixture was stirred for one hour at room temperature
  4. stirringstirred
  5. temperaturerefluxed for 6 hours
  6. temperaturecooled
  7. customThe solvent was evaporated
  8. customThe residue was partitioned between water and DCM
  9. customThe organic layer was separated
  10. customdried
  11. filtrationfiltered
  12. customthe solvent was evaporated
  13. customThe residue was purified by column chromatography over silica gel (eluent: CH2C]2/CH3OH from 100/0 to 99/1)
  14. customThe pure fractions were collected
  15. customthe solvent was evaporated

Sources & evidence

ORD record
ord-edbb9d380177426581c529ef0d2bdbad
Source dataset
uspto-grants-2003_04
Patent number
US06544997B1

Reaction notes

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