Acetonitrile → Ethyl 2-methyl-2-(4-oxo-1-piperidinyl)propanoate

HRID 646200Notes

Reaction equation

HRID 646200 reaction equation
Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.Cl.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:8][C:2]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)([CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]

Participants

6

Reactant 4

HCID 6342AcetonitrileHCID 11430Potassium CarbonateHCID 11745Propanoic acid, 2-bromo-2-methyl-, ethyl esterHCID 2723901Piperonylamine

Product 1

HCID 59264612Ethyl 2-methyl-2-(4-oxo-1-piperidinyl)propanoate

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Procedure

A mixture of ethyl 2-bromo-2-methylpropanoate (48.3 ml, 5 equiv), 4-piperidone hydrochloride monohydrate (100 g, 1 equiv), acetonitrile (1216 ml) and potassium carbonate (353 g, 4 equiv) was heated at reflux under nitrogen with mechanical stirring for 20 h then cooled in an ice bath before adding diethyl ether (approx. 1400 ml). The mixture was filtered through celite, evaporated in vacuo, then excess bromoester distilled off (50° C. still head temperature/10 Torr). Flash chromatography (silica, 5-30% ethyl acetate in hexane) and evaporation of the product fractions gave the crude product as a yellow oil. To remove some remaining bromoester contaminant this was partitioned between ethyl acetate and 2M aqueous hydrochloric acid. The organic layer was discarded and the aqueous layer was basified with sodium carbonate, saturated with sodium chloride and extracted with ethyl acetate. Drying and evaporation of the organic extracts gave the desired product as a yellow oil (54.7 g).

Workup

  1. temperaturewas heated
  2. temperatureat reflux under nitrogen
  3. temperaturethen cooled in an ice bath
  4. filtrationThe mixture was filtered through celite
  5. customevaporated in vacuo
  6. distillationexcess bromoester distilled off (50° C. still head temperature/10 Torr)
  7. customFlash chromatography (silica, 5-30% ethyl acetate in hexane) and evaporation of the product fractions
  8. customgave the crude product as a yellow oil
  9. customTo remove some remaining bromoester contaminant
  10. customthis was partitioned between ethyl acetate and 2M aqueous hydrochloric acid
  11. extractionextracted with ethyl acetate
  12. customDrying
  13. customevaporation of the organic extracts

Sources & evidence

ORD record
ord-fec3235d99f54502aec0c46e014be833
Source dataset
uspto-grants-2010_04
Patent number
US07705005B2

Reaction notes

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