Trends and Challenges in Multistep Continuous Flow Synthesis

Flow chemistry has become an important tool for manufacturing nowadays, driven by the growing demand for safety, efficiency, scale, and sustainability in chemical industries. Building on basic flow chemistry techniques, multistep continuous flow synthesis has emerged as an attractive synthetic process in pharmaceutical, agricultural, and materials synthesis. In practice, numerous issues need to be addressed in multistep continuous flow processes, such as reaction compatibility, step-connection, material transfer, and flow stability. Aiming to establish an industrially viable multistep flow process for tiadinil, methiadinil, emamectin benzoate and other drug molecules in agricultural and pharmaceutical industry, we cooperated with enterprises in the past few years and encountered nearly all the difficulties that may arise in the process, and these difficulties are also long-standing challenges for industry settings. To tackle these barriers faced, we developed and searched for various solutions to address them. These practices further facilitated the formulation of the common solutions for developing a multistep continuous flow process. This perspective will integrate relevant literature with our research to showcase the key challenges in multistep continuous flow synthesis and discuss corresponding solutions. Additionally, general development of flow process usually begins with extensive screenings of reaction conditions in batch before further optimization in flow. Instead, a more efficient approach called de novo flow, defined as performing reaction optimizations primarily in flow after feasibility has been established in batch, has been emerging as a viable strategy. We also present an outlook on the forthcoming development of multistep continuous flow synthesis and point out the key issues to be addressed in the future.