Route Selection and Process Development of a Multikilogram Route to the Inhaled A2a Agonist UK-432,097

Abstract

This article describes the selection, process development, and scale-up of a synthetic route to a complex nucleoside analogue, the A2a agonist UK-432,097 (1), that culminated in the manufacture of over 25 kg of the API. The key steps in the process were (1) a stereoselective glycosidation reaction; (2) a scalable bleach–TEMPO oxidation; and (3) an unusual elevated temperature crystallization process for the final API. The problems that were encountered with the scale-up of the route together with how they were overcome are also presented.