CONDENSATION-REACTIONS OF ACTIVATED PICOLINES WITH ANTHRANILATE ESTERS AND O-NITROBENZALDEHYDE - IMPROVED SYNTHESES OF THE ANTIARRHYTHMIC DRUG ENCAINIDE

Two new and improved syntheses of the antiarrhythmic drug Encainide, 1, are presented. The first approach is based on the condensation of 2-picolyllithium with the p-anisoyl amide of methyl anthranilate, 3, followed by a series of catalytic hydrogenations and methylation. The second route relies on a particularly facile condensation reaction between N-methylpicolinium methyl sulfate and o-nitrobenzaldehyde to produce the alcohol 17c in high yield which is converted to the olefin 18c by a novel dehydration procedure and then to the final molecule, by catalytic hydrogenation over platinum followed by acylation.