Continuous-Flow Process Intensification for Production of Drugs, Green Hydrogen and Epoxy molding polymer

Abstract

The step-by-step synthesis of functional chemical compounds has been a central task of organic chemistry since the beginning of the study and formed the basis of the fine chemical industry, such as pharmaceuticals, agrochemicals, polymers, etc. Although successful, the industry and academy still face many major challenges in an era of constant resource and environmental demands. On the one hand, the quality of product and efficiency of production may be improved. However, it is necessary to reduce the footprints, energy and labor consumption, high risks and environmental impacts. To solve theabove problems, organic chemists and chemical engineers have been actively seeking alternative synthesis techniques. In this manner, continuous-flow chemistry has emerged as an innovative modern technology. The small sized flow reactors enable dramatically enhanced mass- and heat-transfer, thus providing high efficiency and controllability in the reaction. In comparison with conventional batch process, the continuous flow process can significantly reduce footprints and human intervention. Therefore, for several decades, continuous-flow chemistry has received remarkable attention from academicand industrial communities. However, as for multi-step synthesis of value-added chemicals such as natural products, complex drugs or functional polymer, the transition from the batch process to continuous mode is highly challenging. The traditional batch approach is to convert the starting reagentsinto desired chemicals step-by-step. Usually, after each chemical reactions, the work-up of the reaction mixture, isolation, and purification of the product has to be performed to remove any undesired chemical compounds. These steps maximize the independence of each step: thus it has been successful in realizing even very complex, daunting long step syntheses. However, these approaches have drawbacks on also time- and labor-consuming, significantly lowering the practicality in production of final chemicals. In contrast, the continuous-flow multi-step synthesis would build an integrated syntheticsystem to realize all suitable steps without wasting time and handling the intermediates. In this respect, continuous-flow multi-step synthesis can be considered as innovative solutions. Therefore, besides technical complexity in connecting multi-step reactors and separators, the accumulating effectof upstream reactors on downstream process must be well controlled, either by using appropriatein-line separation/purification technologies. Therefore, the design and optimization of innovative chemical methods and in-line separation process are the keys to successful integrated continuous-flow process.

In Chapter 1, a general introduction of flow reactors, in-line separators were describedand the way for intensification of each flow modules for integrated continuous-flow process was summarized.

In Chapter 2, a numbering-up polyimide microreactor, named compact reaction module on a pad (CRP), for high-throughput production of active pharmaceutical ingredient (API) is described. Here, a newly developed polyimide microreactor is described by modularization of a flow distributor and staticmixers for high productivity of API. The bifurcation typed flow distributor and 3D structuredmicrostatic mixer were designed by computational fluid dynamic (CFD) simulation and manufactured by laser ablation. By assembling each functional module, the CRP was implemented, and it was confirmed thatthe system showed a uniform flow distribution and high mixing efficiency regardless of clogging. Inaddition, the system achieved high-throughput synthesis of -phosphonyloxy ketone, a drug scaffold for anticholinergic under optimized reaction conditions.

In Chapter 3, a numbering-up flow reactor for scalable degradation of chemical warfare agent (CWA) used as biochemical weapons and converting byproducts obtained after degradation of CWA to paracetamol, API for pain reliver, is described. A three-step synthesis of an API from a nerve agent simulant, paraoxon, has been accomplished with a one-flow platform based on a Teflon plate microreactor (TPM). The robust TPM, fabricated by bonding microchannel-patterned Teflon plates with a fluorinated polymer film, provides high chemical andpressure tolerance at elevated temperature and under harsh pH conditions. A three-parallelized TPM platform integrated with heaters delivered complete degradation of paraoxon at a kg-scale detoxification ofthe nerve agent simulant.

In Chapter 4, an integrated continuous-flow process for valorisation of kraftlignin and generation of green hydrogen is described. Individual processes for (1) biomass depolymerization to generate value-added byproducts, electrons, and protons using a redox-activecatalyst PMA: (2) extraction of the byproducts using organic solvents (e.g., chloroform): (3) separation ofthe organic solvent and extracts: and (4) low-voltage hydrogen production upon reactivation(re-oxidation)of the reduced catalysts were designed by CFD and fabricated by CNC milling. Each module was testedto explore the optimal design and operation conditions. Consequently, the integratedmodular system continuously produced hydrogen and value-added byproducts of lignin depolymerization(i.e., vanillin and acetovanillone) more efficiently than its batch and bulk counterparts owing to efficient real-time catalyst recycling and byproduct separation.

In Chapter 5, a graphical neural network combined integrated continuous-flow process is described. One-flow multi-step process for thesynthesis of newly developed Np-C4-Np, which comprises two mesogenic units connected with a flexible spacer, asa monomeric precursor of semiconductor packaging material was implemented. Graphical convolution neural network (GCNN), a deep learning model, predicts a common solvent for three-step reactions, thereby enabling serial esterification-deprotection-epoxidation integrated with in-situ multi-phasic separations. Overall process was designed and integrated the flow modules for (1) operatingthree reaction steps (esterification, deprotection, and epoxidation): (2) extraction of remaining reagents, which can lower the yield of the next reaction step and recover the main product from the crude mixture:and (3)continuous selective solvent remover to remove the extraction solvent (e.g., chloroform) that induces non-polar environment on epoxidation.