Diethyl (ethoxymethylene)malonate → Diethyl [(3-chloro-4-fluoroanilino)methylidene]propanedioate

Participants

Reaction Steps

3-Chloro-4-fluoroaniline (30.08 kg) in 8 L ethanol was heated at 40-50° C until a clear solution was obtained. Said solution was added to a 100 gallon glass-lined unit charged with 196 L ethanol. Diethyl ethoxymethylenemalonate (49.1 kg) was then added over an 80 minute period with stirring. The mixture was brought to reflux for one hour and then cooled to near 0° C. with stirring. Crystallization was initiated with seeding when the temperature had reached 27° C. during the cooling process. Stirring was continued for another hour, the solid product was filtered on a ceramic filter, and the filter cake was washed with 3×16 L cold (1°-5° C.) ethanol. The product was dried at 40° C. in vacuo for 19 hours to give 55.4 kg diethyl (3-chloro-4-fluorophenyl)aminomethylenepropanedioate, m.p. 71.5°-72.5° C. (85% yield). The combined filtrate and washes were concentrated to 54 L and a second crop was isolated and dried as before to give 5.6 kg additional product, m.p. 71.5°-72.5° C. for a combined yield of 93.5%.

Provenance & Evidence