Synthesis of Arylpiperazine-Based CNS Ligands: Batch Disconnections and Their Continuous-Flow Implementation.
Jeong Daeun D, Han Ji Myoung JM, Lee Ji Hoo JH, Oh In Young IY et al.
The 1-arylpiperazine unit recurs throughout centrally acting drugs, particularly ligands of serotonin and dopamine receptors, where its modular architecture-aryl group, piperazine core, linker, terminal fragment-has made it a durable design template. Three principal intermodule disconnections-the aryl-nitrogen bond, the piperazine-linker bond, and the linker-terminal bond-provide an organizing framework for the routes reviewed here. This review compares representative batch routes with reported continuous-flow implementations, distinguishing related methodological precedents, individual transformations in drug-specific routes, and linked multistep sequences. Three observations emerge from the reviewed examples. First, the drug-directed flow routes examined use preformed arylpiperazine building blocks. Second, dechlorination reported during cariprazine reductive amination highlights the importance of catalyst and solvent selection for that substrate. Third, the reported flow implementations address selected process challenges, while the multistep examples highlight the importance of compatibility between reaction and work-up operations. These observations inform a practical framework for evaluating batch and flow options for individual routes.