Rapid flow synthesis of fenofibrate via scalable flash chemistry with in-line Li recovery

Abstract

Flash chemistry controlled organolithium reactions allow redesigning the new economically affordable synthetic routes for life-saving drugs. However, microreactors limit their applications to extend industrial-level productivity. On the other hand, there has been little attention on recycling valuable elements from organic synthesis. In this work, a new compact monolithic metal microreactor was designed to successfully control the lifetime of short-lived organolithium intermediates at a large scale for sub-second scalable synthesis of fenofibrate as an FDA-approved drug for hypertriglyceridemia. Initially, the ultrafast chemistry of highly unstable ArLi intermediate was successfully explored for the synthesis of fenofibrate by its flow-controlled coupling reaction with 4-chlorobenzoyl chloride. As needed, by 3D metal printing of the CAD-CFD simulated works, eight laminated serpentine channels integrated with four flow distributors were constructed in a monolithic metal microreactor, leading to improved productivity up to 1.18 g min−1. At the in-line work-up step, the largely consumed Li was completely recovered for the potential recycling of valuable Li resources in a continuous-flow manner.