Recent Advances in the Multistep Continuous Preparation of APIs and Fine Chemicals

Abstract

Abstract: Over the last two decades, with the advent of continuous flow technologies, continuous processes have emerged as a major area in organic synthesis. In this context, continuous flow proce-sses have been increasing in the preparation of Active Pharmaceutical Ingredients (APIs) and fine chemicals, such as complex synthetic intermediates, agrochemicals, and fragrances. Thus, the deve-lopment of multi-step protocols has attracted special interest from the academic and industrial che-mistry communities. In addition to the beneficial aspects intrinsically associated with continuous processes (e.g., waste reduction, optimal heat transfer, improved safety, and the possibility to work under harsh reaction conditions and with more dangerous reagents), these protocols also allow a ra-pid increase in molecular complexity. Moreover, in telescoped multi-step processes, isolation and purification steps are generally avoided or, if necessary, carried out in-line, presenting an important economy of time, solvents, reagents, and labor. Last, important synthetic strategies such as photo-chemical and electrochemical reactions are compatible with flow processes and are delivering rele-vant advances to the synthetic approaches. In this review, a general overview of the fundamentals of continuous flow processes is presented. Recent examples of multi-step continuous processes for the preparation of fine chemicals, including telescoped and end-to-end processes, are discussed, poin-ting out the possible advantages and/or limitations of each of these methodologies.