Diethyl (2-chloro-4,5-difluorobenzoyl)propanedioate → Ethyl 3-(2-chloro-4,5-difluorophenyl)-3-oxopropanoate

HRID 1762733Notes

Reaction equation

HRID 1762733 reaction equation
[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:11](=[O:21])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[Cl:20])C(OCC)=O)[CH3:2]>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:11](=[O:21])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[Cl:20])[CH3:2]

Participants

4

Reactant 1

HCID 14425827Diethyl (2-chloro-4,5-difluorobenzoyl)propanedioate

Product 1

HCID 14423850Ethyl 3-(2-chloro-4,5-difluorophenyl)-3-oxopropanoate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

In accordance with the above reaction scheme, a solution of 2-chloro-4,5-difluorobenzoic acid (V) in acetonitrile containing a catalytic amount of dimethylformamide is reacted under an inert atmosphere with the dropwise addition of oxalyl chloride, giving 2-chloro-4,5-difluorobenzoic acid chloride (VI) which is dissolved in diethyl ether and slowly added to a cold solution of magnesium diethylmalonate, followed by the addition to ice water and acidification to pH 2.5, giving (2-chloro-4,5-difluorobenzoyl)propanedioic acid diethyl ester (VII). A solution of compound (VII) in p-dioxane and water is heated at reflux, then evaporated and distilled, giving 2-chloro-4,5-difluoro-β-oxobenzenepropanoic acid ethyl ester (VIII). A solution of compound (VIII) and triethyl orthoformate in acetic anhydride is heated at 150° C. for 2 hours, giving 2-chloro-α-(ethoxymethylene)-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester (IX). Cyclopropylamine is added to a solution of compound (IX) in ethanol, giving 2-chloro-α-[(cyclopropylamino)methylene]-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester (X). Compound (X) is reacted with sodium hydride in dry dimethylformamide under an inert atmosphere with heat, giving 1-cyclopropyl-6,7-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester (XI). Ester (XI) is then refluxed with acid, giving the desired 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (XII).

Workup

  1. temperatureat reflux
  2. customevaporated
  3. distillationdistilled

Sources & evidence

ORD record
ord-6adef49d8f014185a349c510e40210b7
Source dataset
uspto-grants-1989_05
Patent number
US04833270

Reaction notes

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