SYNTHESIS OF AN ORALLY-ACTIVE PAF ANTAGONIST OF THE N-[4-(3-PYRIDINYL) BUTYL]PENTADIENAMIDE CLASS

The PAF antagonist [R-(E,E)]-5-(4-methoxyphenyl)-N-[1-methyl-4-(3-pyridinyl)butyl]-2,4-decadienamide (2) was synthesized from (S)-alpha-methyl-3-pyridinebutanol (14), which was obtained either from ethyl lactate or by enantioselective kinetic hydrolysis of its racemate using the lipase derived from Pseudomonas cepacia (syn. P. fluorescens). Mesylation of 14, followed by azide displacement and hydrogenation, produced amine (7), which was coupled with the p-nitrophenol ester (8) to give 2. The direct coupling of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid (27) with azide (24) in the presence of tri-n-butylphosphine also gave 2. Acid (27) was prepared by a vinylogous Reformatsky reaction between ketone (25) and methyl 4-bromocrotonate.