8-Hydroxyquinoline → Ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate

HRID 408033Notes

Reaction equation

HRID 408033 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2.[F:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][NH:32][C:31](=[O:35])[C:30]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:27]>CN(C=O)C.[Cu](I)I>[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][N:32]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:31](=[O:35])[C:30]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:27]

Participants

7

Reactant 4

HCID 19238-HydroxyquinolineHCID 96054-FluoroiodobenzeneHCID 10796Cesium carbonateHCID 53393185Ethyl 4-Ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate

Product 1

HCID 68735913Ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylateYield 76.1%

Reagents, catalysts & solvents 2

HCID 83717Copper iodideCatalystHCID 6228DimethylformamideSolvent2×

Procedure

DMF (9 L) and cesium carbonate (3.1 kg) were charged under nitrogen to a reactor and stirred for 10 min at room temperature. To this mixture, a solution of 8-hydroxyquinoline (0.275 kg) in DMF (1 L), copper iodide (0.27 kg) and 1-fluoro-4-iodobenzene (1.576 kg) were added under nitrogen. Then, ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (1 kg) was added and the reaction mixture was heated to 100° C. for 20 hrs under nitrogen. After completion of the reaction, the mixture was filtered through celite. To the filtrate, water (100 L) was added and the mixture was extracted three times with DCM (25 L). The combined DCM layers were washed two times with water (20 L), two times with 1.5 N HCl (5 L), and one time with brine (10 L), and then dried over sodium sulfate and concentrated to dryness. Petroleum ether (5 L) was added to the concentrate and the resulting slurry was stirred for 30 min. The solids were filtered and dried at room temperature in vacuum to give 1.1 kg crude ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate.

Workup

  1. temperaturethe reaction mixture was heated to 100° C. for 20 hrs under nitrogen
  2. customAfter completion of the reaction
  3. filtrationthe mixture was filtered through celite
  4. additionTo the filtrate, water (100 L) was added
  5. extractionthe mixture was extracted three times with DCM (25 L)
  6. washThe combined DCM layers were washed two times with water (20 L), two times with 1.5 N HCl (5 L), and one time with brine (10 L)
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated to dryness
  9. additionPetroleum ether (5 L) was added to the
  10. concentrationconcentrate
  11. stirringthe resulting slurry was stirred for 30 min
  12. filtrationThe solids were filtered
  13. customdried at room temperature in vacuum

Sources & evidence

ORD record
ord-d5b1d462ff2b418a8c9d459b1d17f7bf
Source dataset
uspto-grants-2014_06
Patent number
US08754230B2

Reaction notes

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