Development of a Practical and Scalable Synthesis of a Potent Selective Dual Antagonist for 5-HT2B and 5-HT7 Receptors

Process research and development of a practical and scalable synthetic route toward compound (S)-1 and compound (R)-1, which are potent selective dual antagonists for 5-HT2B and 5-HT7 receptors, respectively, is described. The medicinal chemistry route and second generation route were also unattractive for large-scale use for a variety of reasons. The new synthetic method does not require any purification by column chromatography for all steps and highly exothermic reactions. Additionally, we developed an efficient method of optical resolution in which each carboxylic acid isomer was separated with chiral amine in high yield and high enantiopurity. This highly efficient and scalable process was successfully demonstrated in the large scale synthesis of compound (S)-1 and compound (R)-1 in high enantiopurity.