Diethyl [(3-chloro-4-fluoroanilino)methylidene]propanedioate → Ethyl 7-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

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Reaction Conditions

Reaction Steps

In a 30 gallon stainless steel unit, 55 L of Dowtherm A (a eutectic mixture of diphenyl and diphenyl ether) was stirred and heated at reflux (253°-257° C.) for one hour. To this was added a solution of 31.3 kg diethyl (3-chloro-4-fluorophenyl)aminomethylenepropanedioate in 10 L Dowtherm A held at 94°-98° C. The addition was effected over a period of four hours so that reflux of the reaction mixture was maintained. The reaction mixture was then allowed to cool and crystallization of the product began. After the temperature had reached 28°-30° C., the solid product was collected on a ceramic filter and washed with 2×9 L dimethylformamide (DMF). The damp filter cake was added to 65 L DMF in a 30 gallon kettle. The resulting slurry was heated at 90°-95° C. for 30 minutes and then cooled to 40° C. The solid was collected on a ceramic filter, washed with 2×8 L DMF and dried at 60° C. for 24 hours to give 23.8 kg ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate containing about 10% of the 5-chloro-6-fluoro isomer as indicated by NMR spectra.

Provenance & Evidence