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

• Published in: Chemical engineering journal (Lausanne, Switzerland : 1996) Vol. 477; p. 147033
• Main Authors: Kawale, Sanket A., Kang, Dong-Chang, Ahn, Gwang-Noh, Mottafegh, Amirreza, Kang, Ji-Ho, Na, Gi-Su, Kim, Dong-Pyo
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.12.2023
• Subjects: 3D Printing; Flash chemistry; Li-recovery; Monolithic; Numbered-up; Numbered-up; 3D Printing; Flash chemistry; Li-recovery; Monolithic
• ISSN: 1385-8947; 1873-3212
• DOI: 10.1016/j.cej.2023.147033

[Display omitted] •Rapid flow synthesis of Fenofibrate, an FDA-approved hypertriglyceridemia drug.•Scalable sub-second synthesis using numbered-up monolithic microreactor.•Potential recycling of valuable Li resources (LiCl or Li3PO4). 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.