Diethyl Malonate → 1-[2-(4-Fluorophenyl)ethyl]-4-methyl-2,6-dioxopiperidine-3-carboxylic Acid Ethyl Ester

HRID 896536Notes

Reaction equation

HRID 896536 reaction equation
[Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:27])/[CH:24]=[CH:25]/[CH3:26])=[CH:16][CH:15]=1>C(O)C.COCCOCCOC>[CH2:7]([O:6][C:4]([CH:3]1[CH:25]([CH3:26])[CH2:24][C:23](=[O:27])[N:22]([CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[C:2]1=[O:10])=[O:5])[CH3:8]

Participants

6

Reactant 3

HCID 7761Diethyl MalonateHCID 5360545SodiumHCID 86591719(2E)-N-[2-(4-Fluorophenyl)ethyl]-2-butenamide

Product 1

HCID 697363791-[2-(4-Fluorophenyl)ethyl]-4-methyl-2,6-dioxopiperidine-3-carboxylic Acid Ethyl Ester

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8150DiglymeSolvent

Procedure

Sodium (1.5 g, 65.1 mmol) was dissolved in ethanol (50 mL) and the solution was concentrated under vacuum. The residue was suspended in toluene (50 mL) and bis(2-methoxyethyl)ether (30 mL). Diethyl malonate (4.0 mL, 26.5 mmol) was added, followed by a suspension of trans-2-butenoic acid [2-(4-fluoro-phenyl)ethyl]amide (5.00 g, 24.1 mmol) in bis(2-methoxyethyl)ether (20 mL). The mixture was heated at reflux for 6 hours. The cooled mixture was washed with 1.0 N aqueous hydrochloric acid, then with water, and dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography, eluting with 25% ethyl acetate in hexane, to provide a pale yellowish oil which slowly crystallized (5.81 g, 75%). This appeared to be a mixture of cis and trans isomers (approximately 15% cis). 1H NMR (300 MHz, CDCl3) δ7.20 (m, 2H), 6.99 (t, J=9 Hz, 2H), 4.28 (m, 2H), 4.00 (m, 2H), 3.66 (d, J=5 Hz, 0.15H), 3.27 (d, J=10 Hz, 0.85H), 2.82 (m, 3H), 2.53 (m, 1H), 2.33 (dd, J=17, 10 Hz, 1H), 1.34 (m, 3H), 1.09 (d, J=7 Hz, 3H). Mass spec (AP+) m/z 322.0 (M+H+, 100%).

Workup

  1. concentrationthe solution was concentrated under vacuum
  2. temperatureThe mixture was heated
  3. temperatureat reflux for 6 hours
  4. washThe cooled mixture was washed with 1.0 N aqueous hydrochloric acid
  5. dry with materialwith water, and dried over sodium sulfate
  6. concentrationconcentrated under vacuum
  7. customThe residue was purified by flash chromatography
  8. washeluting with 25% ethyl acetate in hexane
  9. customto provide a pale yellowish oil which
  10. customslowly crystallized (5.81 g, 75%)
  11. additiona mixture of cis and trans isomers (approximately 15% cis)

Sources & evidence

ORD record
ord-2f81f9ba2ccf41f59eac88fa635762f3
Source dataset
uspto-grants-2005_07
Patent number
US06919356B2

Reaction notes

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