<p>This study reports the development of novel intermediates and an improved synthetic process for the preparation of edoxaban, an orally active anticoagulant. The work focuses on the identification, synthesis, and control of process-related impurities formed during the manufacture of edoxaban. A holistic and systematic approach was employed to optimize the synthetic route, with particular emphasis on minimizing impurity formation and enhancing process robustness. This work reports an industrially scalable process that preserves the chiral integrity of edoxaban and avoids the isolation of intermediates. Process development was based on an empirically optimized synthetic pathway, and related substances were identified and characterized using reverse-phase high-performance liquid chromatography and spectroscopic techniques. Comprehensive strategies were implemented to monitor, evaluate, and control impurity formation at each stage of the synthesis. Optimization of key reaction parameters led to a substantial improvement in overall yield, increasing from 24% as reported in the literature to 68%, while significantly reducing the formation of undesirable impurities.</p> Graphical abstract <p></p>