Economical, Practical, and Scalable Synthetic Process Development for the Antiglaucoma Drug Omidenepag Isopropyl

Abstract Omidenepag isopropyl (OMDI) is the only marketed antiglaucoma drug that acts as a prostaglandin E receptor 2 (EP2) agonist. It exhibits high receptor-binding affinity (Ki = 3.6 nM) and potent agonistic activity (EC50 = 8.3 nM). More importantly, OMDI circumvents key limitations commonly associated with prostaglandin analogues, such as periorbital fat atrophy, hyperpigmentation, and drug tolerance, thereby offering greater clinical application value. However, the three previously reported synthetic routes to OMDI suffer from limitations that affect efficiency and scalability; for example, the isolated yields of routes I–III range from 20.5 to 51.2%. All of these routes involve the use of hazardous reagents (e.g., sodium hydride, borane) and often rely on column chromatography purification, which compromises material efficiency and process scalability. To address these issues, we report four new synthetic routes to OMDI developed through iterative optimization that systematically overcome the aforementioned limitations. Among them, route IV (accomplished in only four steps) avoids the use of high-hazard reagents and requires no column chromatography throughout the entire process, ultimately affording an improved overall isolated yield of 64.2% with 99.86% high-performance liquid chromatography (HPLC) purity. Notably, this process has been successfully validated on a hundred-gram scale, providing a reliable foundation for pilot-scale translation and potential industrial application.