Process Development of the PDE IV Inhibitor 3-(Cyclopentyloxy)-<i>N</i>-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide

Abstract

Development of an industrial process for 3-(cyclopentyloxy)-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide, a potent PDE IV type inhibitor, is described. The rapid identification of scalable reaction conditions allowed pilot-scale synthesis of kilogramme quantities for early clinical evaluation. However, as more compound was demanded, better reaction conditions were required in the interests of safety, economics, and environmental impact. This led to the derivation of a high-yielding and very robust procedure which included various safeguards to ensure that high-quality product was obtained and that new trace impurities were effectively removed. The large-scale oxidation of a benzaldehyde derivative to the corresponding benzoic acid using hydrogen peroxide under aqueous alkaline conditions is described.