Development of a Manufacturing Process for S-892216 Part I: A Novel Method for Constructing a Multi-Substituted Barbiturate Skeleton for Scalable Synthesis

S-892216, a second-generation 3CL protease inhibitor, is currently being developed as a clinical drug candidate for the treatment of SARS-CoV-2 infection. This paper outlines the development process and scaling-up of S-892216 for early-phase clinical trials. The developed synthetic route involved a condensation reaction between carboxylic acids and urea with T3P, followed by cyclization in the presence of CDI and DBU to construct a barbiturate core. This novel method facilitated the efficient production of high-quality S-892216 in six steps, with an overall yield of 41.3% from readily available starting materials.