Acetic Acid → Ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate

HRID 1601000Notes

Reaction equation

HRID 1601000 reaction equation
[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]2[CH2:11][CH:10]2[CH2:12][CH:13]=O)[C:3]=1[CH3:15].N1CCCCC1.C(O)(=O)C.[C:26]([O:34]CC)(=O)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(O)C.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:31]([O:30][C:28]([C:27]1[C:26](=[O:34])[N:5]2[C:4]([C:3]([CH3:15])=[C:2]([Cl:1])[C:7]([F:8])=[CH:6]2)=[C:9]([CH:10]2[CH2:12][CH2:13]2)[CH:11]=1)=[O:29])[CH3:32]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 7761Diethyl MalonateHCID 8082PiperidineHCID 224748792-(4-Chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropane acetaldehyde

Product 1

HCID 9927245Ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylateYield 51.6%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 246701,1'-Biphenyl, mixt. with 1,1'-oxybis(benzene)Solvent2×

Conditions

Temperature
235 °C

Procedure

A sample of 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropane acetaldehyde (6.37 mmol) was dissolved in 50 mL of ethanol, and to this were added 1.5 mL of piperidine, 1.5 mL of acetic acid, and 5 mL of diethyl malonate (32.9 mmol). The reaction was heated at reflux under nitrogen for 4 hours. The solvents were then removed, and the residue was dissolved in ether. The ether was washed with water and brine, then dried over MgSO4 and concentrated Purification in a kugelrohr apparatus gave 2.4 g of the crude condensation product. This intermediate product was dissolved in 20 ML of of Dowtherm A™, and this solution was added to 100 mL of Dowtherm A™ heated to 235° C. The reaction was then stirred at 220° C. for 45 min. After cooling, the product was separated from the solvent by flash chromatography, eluting with hexane to remove the solvent and then with 1:4 ethyl acetate hexane to remove the product. In this manner 1.065 g of 8-chloro-1- cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester was obtained after removal of the solvent. MS 324, 326 (M+H)+ ; 1H NMR (CDCl3)∂: 0.75 (m, 2H), 1.07 (m, 2H), 1.42 (t, 3H, J=7 Hz), 2.31 (m, 1H), 3.08 (s, 3H), 4.42 (q, 2H, J=7 Hz), 8.40 (s, 1H), 9.44 (d, 1H, J=6 Hz).

Workup

  1. temperatureThe reaction was heated
  2. temperatureat reflux under nitrogen for 4 hours
  3. customThe solvents were then removed
  4. dissolutionthe residue was dissolved in ether
  5. washThe ether was washed with water and brine
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated
  8. customPurification in a kugelrohr apparatus
  9. customgave 2.4 g of the crude
  10. customcondensation product
  11. temperatureAfter cooling
  12. customthe product was separated from the solvent by flash chromatography
  13. washeluting with hexane
  14. customto remove the solvent
  15. customwith 1:4 ethyl acetate hexane to remove the product

Sources & evidence

ORD record
ord-ecacbab753d34860b0d4a5daf5aff46d
Source dataset
uspto-grants-1999_11
Patent number
US05977133

Reaction notes

Loading…