A Practical and Chromatography-Free Process for Sabizabulin (VERU-111) via an Acylaminoisoxazole Intermediate

Abstract

Sabizabulin (VERU-111) is an investigational colchicine-binding site microtubule inhibitor under consideration for clinical evaluation in metastatic pancreatic cancer. We report a scalable synthesis of sabizabulin from readily available 3,4,5-trimethoxybenzoic acid. The route was developed to address limitations in step economy, operational complexity, and scalability associated with previously reported approaches. An isoxazole fragment is introduced at an early stage and serves as a masked precursor to the imidazole core, allowing assembly of the target structure without protecting groups. The key transformation involves the two-step conversion of an acylaminoisoxazole to the corresponding acylimidazole by hydrogenation followed by cyclization. The optimized process is operationally simple and does not require chromatographic purification at any stage. The synthesis was demonstrated on a multigram scale, and sabizabulin was obtained in eight steps in 31% overall yield with a final purity of 99.2% by LC–UV.