Diethyl (ethoxymethylene)malonate → 1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydro-cycloocta[b]pyridine-3-carboxylic acid

HRID 1925616Notes

Reaction equation

HRID 1925616 reaction equation
[C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]1([CH2:16][NH2:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25]CC)=[O:24])C>C1(C)C=CC=CC=1>[CH:10]1([CH2:16][N:17]2[C:21](=[O:20])[C:22]([C:23]([OH:25])=[O:24])=[CH:28][C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]2=3)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1

Participants

5

Reactant 3

HCID 6871Diethyl (ethoxymethylene)malonateHCID 10403CyclooctanoneHCID 76688Cyclohexanemethylamine

Product 1

HCID 597188051-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydro-cycloocta[b]pyridine-3-carboxylic acid

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

Under the nitrogen gas atmosphere, a solution of cyclooctanone (15 g, 118 mmol) and cyclohexylmethylamine (16.1 g, 142 mmol) in toluene (300 mL) was refluxed under azeotropic dehydration for 6 hours. After that, diethyl ethoxymethylenemalonate (24 mL, 142 mmol) was added, and the mixture was further refluxed for 2 hours. After the reaction mixture had been removed by distillation under reduced pressure, the residue was dissolved in the mixed solvent of THF (200 mL) and methanol (200 mL), then a 2M sodium hydroxide aqueous solution was added and the mixture was stirred for 2 hours at room temperature. The reaction mixture was removed by distillation under reduced pressure, water was added to the residue and the water layer was washed with diethyl ether one time. Then, after 2 M hydrochloric acid was added to the water layer to acidify it, the water layer was extracted with ethyl acetate. The organic layer was washed with water and then dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and a pale yellow solid (AA01, 21.5 g, 57%, mp: 162-163° C.) was obtained.

Workup

  1. temperaturethe mixture was further refluxed for 2 hours
  2. customAfter the reaction mixture had been removed by distillation under reduced pressure
  3. dissolutionthe residue was dissolved in the mixed solvent of THF (200 mL) and methanol (200 mL)
  4. additiona 2M sodium hydroxide aqueous solution was added
  5. customThe reaction mixture was removed by distillation under reduced pressure, water
  6. additionwas added to the residue
  7. washthe water layer was washed with diethyl ether one time
  8. additionThen, after 2 M hydrochloric acid was added to the water layer
  9. extractionthe water layer was extracted with ethyl acetate
  10. washThe organic layer was washed with water
  11. dry with materialdried with anhydrous sodium sulfate
  12. customThe solvent was removed by distillation under reduced pressure
  13. customa pale yellow solid (AA01, 21.5 g, 57%, mp: 162-163° C.) was obtained

Sources & evidence

ORD record
ord-e445822d165043d19908200ff6fe5dbf
Source dataset
uspto-grants-2012_05
Patent number
US08178681B2

Reaction notes

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