Scalable Subsecond Synthesis of Drug Scaffolds via Aryllithium Intermediates by Numbered-up 3D-Printed Metal Microreactors

Abstract

Continuous-flow microreactors enable ultrafast chemistry; however, their small capacity restricts industrial-level productivity of pharmaceutical compounds. In this work, scale-up subsecond synthesis of drug scaffolds was achieved via a 16 numbered-up printed metal microreactor (16N-PMR) assembly to render high productivity up to 20 g for 10 min operation. Initially, ultrafast synthetic chemistry of unstable lithiated intermediates in the halogen–lithium exchange reactions of three aryl halides and subsequent reactions with diverse electrophiles were carried out using a single microreactor (SMR). Larger production of the ultrafast synthesis was achieved by devising a monolithic module of 4 numbered-up 3D-printed metal microreactor (4N-PMR) that was integrated by laminating four SMRs and four bifurcation flow distributors in a compact manner. Eventually, the 16N-PMR system for the scalable subsecond synthesis of three drug scaffolds was assembled by stacking four monolithic modules of 4N-PMRs.

Chemical-Resistant Green Luminescent Concentrator-Based Photo-Microreactor via One-Touch Assembly of 3D-Printed Modules

“…It was commonly reported from the literature that the experimental MF is higher than the numerical MF, presumably due to nonideal factors in real experiments such as geometric error of the actual structure. 14,28,43 Also, both numerical and experimental MF are obviously lower than the generally acceptable MF value (<5%) for chemical synthesis. 14,28,43 The self-aligning GLC-PMs can be assembled either serially or radially (Figure 5a,c).…”

“…The MF under the flow conditions (total flow rate 60 μL min –1 ) was estimated to be ∼0.92% (numerically) and ∼3.29% (experimentally). It was commonly reported from the literature that the experimental MF is higher than the numerical MF, presumably due to nonideal factors in real experiments such as geometric error of the actual structure. ,, Also, both numerical and experimental MF are obviously lower than the generally acceptable MF value (<5%) for chemical synthesis. ,, …”

“…14,28,43 Also, both numerical and experimental MF are obviously lower than the generally acceptable MF value (<5%) for chemical synthesis. 14,28,43 The self-aligning GLC-PMs can be assembled either serially or radially (Figure 5a,c). It was verified that the reliable pressure resistance of the serial and radial assemblies of GLC-PM was experimentally confirmed without leaking when ACN solvent was injected at a flow rate of up to 20 mL min −1 .…”

“…In general, the concept of numbering-up is the most effective way to increase the synthetic throughput of microreactors while keeping the overall system pressure low. ,− The numbering-up approach maintains the advantages of intrinsic transport phenomena and the use of optimized conditions derived from a single microreactor, as opposed to simply increasing the size of the reactor. However, to minimize the inventory of the pumping system within an efficient installation space, a flow distributor structure is essential for numbering-up production.…”

A field guide to flow chemistry for synthetic organic chemists

“…Kim and co-workers presented a scale-up process of ultrafast sub-second chemistry to synthesize drug scaffolds via 16 numbered-up printed metal microreactors (16N-PMR). 91 As previously mentioned, reactions with organolithium reagents are fast and highly exothermic. To precisely control the lithiated intermediates, an optimal residence time of around 16 ms with a flow rate of 7.5 mL min −1 was used, which created a significant pressure drop in the microreactor.…”