A Convenient, Pd-Free Approach to the Synthesis of Risdiplam

Abstract

Several approaches to the synthesis of risdiplam, a pharmacologically relevant pyridopyrimidinone derivative, have been recently reported. However, most of these routes rely exclusively on palladium-catalyzed, cross-coupling reactions and involve low-yielding intermediates, which limit their scalability and complicate impurity control. In this work, we present a five-step, straightforward route to risdiplam, utilizing ethyl 2,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylate—an accessible and cost-effective building block previously developed by our research group—as a starting material. The key step involves construction of the 4H-pyrido[1,2-a]pyrimidin-4-one scaffold via a copper(I)-catalyzed heterocyclization reaction. This represents a novel and convenient protocol for the synthesis of 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one, which serves as a crucial intermediate in the final stages of risdiplam synthesis. The overall process allows us to obtain the target compound with a 20% total yield (from abovementioned starting material) and high purity (99.86%, by HPLC-UV), with a maximum level of unidentified impurities not exceeding 0.046%. The developed approach eliminates the use of palladium catalysis and chromatographic purification, offering a practical and scalable alternative for risdiplam production.