Practical, Facile, and Efficient Approach to Scalable Synthesis of the Flavonoid Derivative GL-V9

GL-V9, an innovative synthetic flavonoid derivative, has been submitted to Investigational New Drug (IND) application to the National Medical Products Administration (NMPA) in 2023 for the treatment of acute myeloid leukemia. This study details the development of an advanced, efficient synthesis pathway for GL-V9, enabling the production of significant quantities of the drug substance to fulfill the needs for forthcoming clinical trials. Characterized by a five-step process under mild conditions─starting with commercially available chrysin and proceeding through Elbs oxidation, O-alkylation, hydrolysis, methylation, and concluding with N-alkylation, this method achieved GL-V9 with exceptional high-performance liquid chromatography purity (>99.5 area %) and an overall yield of 29.1%. Importantly, the synthesis of GL-V9 introduces a versatile framework for the development of other flavonoid scaffolds, underscoring its wide applicability in the field of medicinal chemistry. This scalable and efficient pathway not only facilitates the production of GL-V9 but also opens avenues for exploring novel flavonoid-based therapies.