Optimizing the CHF6523 Isocoumarin Core Scaffold: From the Preclinical Stage to Large-Scale Production

The structure of the new active pharmaceutical ingredient (API) PI3Kδ inhibitor CHF6523.02, identified for the treatment of exacerbating chronic obstructive pulmonary disease (COPD) in patients, is reported. The described molecule bears an isocoumarin core scaffold, whose synthetic route scalability is critical for API process development and the successful establishment of a multikilogram synthesis route. In this paper, we describe the process research and development work for the isocoumarin scaffold synthetic procedure, exploiting a novel and efficient electrophilic cyclization step, to provide large quantities of the product required to support the API candidate’s clinical studies.