Title : Scalable Subsecond Synthesis of Drug Scaffolds by Numbering-up 3D-Printed Metal Microreactor
Abstract:
Continuous-flow microreactors enable ultrafast chemistry impossible in conventional batch reactor through the subsecond reaction time control. However, the small capacity of microreactors has restricted the synthesis of pharmaceutical compounds with industrial level productivity. In this work, a scalable subsecond synthesis of drug scaffolds was achieved by a new numbering-up strategy. The compact monolithic 4 numbering-up metal microreactor (4N-PMR) that is embedded with built-in reactors and flow distributors was fabricated by high-resolution 3D SLM printing method. And the 4N-PMR verified successful controlling of highly reactive short-lived aryllithium intermediates at optimal residence time (~16 ms) over a wide range of temperatures and furnished the increased productivity of 12 aryl products in very good to excellent yields (86-98 %). The excellent symmetry of built-in flow distributors of monolithic 4N-PMR afforded nearly same yields as single microreactor within experimental error range. Moreover, 16 numbering-up printed metal microreactor (16N-PMR) was assembled with four 4N-PMRs and external flow distributors (EFDs) to render high productivity of 3 drug scaffolds without significant loss of yield, including precursor of letrozole as an aromatase inhibitor. Highly uniform flow distribution in EFD and 16N-PMR was numerically and experimentally demonstrated for successful scalable subsecond synthesis that is less tolerable to the change of flow rates. The actual isolation of 10 to 20 grams of drug scaffolds for 10 minutes enables the production up to nearly 3 kilograms per day in a single 16N-PMR set. Facile multiple sets in virtue of 3D printing method can meet various scales of drug scaffolds in pharmaceutical industry. Moreover, the modular system would be readily reconfigurable for a variety of scale-up purposes on demand synthesis.
