Thermodynamically Controlled and Industrially Viable Telescopic Process for the Synthesis of Fluazuron

Abstract

Fluazuron N-[(4-chloro-3-[3-chloro-5-(trifluoromethyl)pyridine-2-yl]oxy phenyl]carbamoyl]-2,6-difluorobenzamide (14) is a noteworthy antiparasitic veterinary medicine belonging to the class of benzoyl phenyl urea derivatives, a class of chitin synthesis inhibitors. The commercial-scale synthesis, which is compliant with current regulatory requirements, particularly purity and impurity profiles, is not well established. Therefore, a robust and sustainable manufacturing process is essential to manufacture and supply fluazuron or any drug substance, for that matter, meeting all criteria. In this work, a safe, scalable, economic, and sustainable process was described through a robust in situ protocol for the bottleneck isocyanate intermediate (20) to manufacture a substantially pure fluazuron active pharmaceutical ingredient (API) with >99.5% HPLC purity and a yield of >78% overall. This large-scale GMP manufacturing process was established by implementing DoE tools and principles of green chemistry like process mass intensity assessment (PMI) and the “3Rs” principle (reduce/reuse/recycle) to attain the “3Ps” sustainability target (profit/people/planet). The developed process technology was successfully validated under cGMP plant conditions on a scale of 600 kg batch size to supply the fluazuron API (14) across the globe for veterinary use. This process is commercially friendly and environmentally benign. Furthermore, several process-related impurities were identified, synthesized, characterized, and studied for their purging capability. According to the SciFinder database, there are two new impurities (23 and 24), which are structurally similar to the fluazuron API, that could lead to the discovery of new biological applications in both animal and human drug development.