Synthesis of entacapone

Entacapone is a catechol-O-methyltransferase inhibitor given together with levodopa in the treatment of Parkinson’s disease, to prolong its effect.

It is made by Knoevenagel condensation of 3,4-dihydroxy-5-nitrobenzaldehyde with N,N-diethyl-2-cyanoacetamide, an active methylene compound, catalysed by piperidine and acetic acid. The reaction gives mainly the E isomer, the one used as the drug, with the aryl group trans to the amide.