Flow-oriented synthetic design in the continuous preparation of the aryl piperazine drug flibanserin

An uninterrupted, four-step continuous-flow sequence was developed for the preparation of the aryl piperazine-type serotonin receptor modulator drug, flibanserin. The unprecedented route was designed for efficient operation in flow, consisting of heterogeneously catalyzed reductive amination reactions, benzimidazolone formation using the protecting group as a building block, and biphasic flow deprotection integrated with in-line purification. Gasliquid and liquid-liquid separations facilitate the coupling of the reaction steps and aid removal of excess reagents, which make the system capable of steady-state operation without manual interaction.