Economical and Practical Process Development for a Novel Multitarget Tyrosine Kinase Inhibitor Vorolanib

Vorolanib (X-82, CM082) is a novel multitarget tyrosine kinase inhibitor that effectively inhibits the activity of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and FMS-like tyrosine kinase-3 (FLT-3) receptors. Vorolanib is currently accessible in the Chinese market, and its approved indication is combined with Everolimus for patients with advanced renal cell carcinoma (RCC) who have previously failed tyrosine kinase inhibitor (TKI) treatment. Here, we have developed an economical and practical process for Vorolanib, which exhibits low cost, high yield, simple post-treatment, and environmental protection based on extensive investigations into synthesis methods (raw materials, temperature, coupling reagent, solvent, reaction time, post-treatment, etc.). This process was successfully used to prepare Vorolanib with a total yield of 67.1% and a purity of 99.97%, and no chiral degradation occurred during the synthesis. All intermediates were confirmed by ESI-MS and 1H NMR, whereas the target compounds were confirmed by ESI-MS, H-1 NMR, and C-13 NMR.