Selective Production of Acetonitrile in a Fixed-bed Reactor and Flash Synthesis of Fenofibrate in a 3D-printed Microreactor

Abstract

Microfluidics consists of small-sized flow channels for handling fluidics, with channel dimensions less than 1000 μm and small volumes of working fluid. Microfluidics, which deals with small volumes and dimensions, has many advantages over existing approaches related to various fields, such as chemical synthesis, catalysis, and energy conversion. Microfluidics offers several advantages, including high heat and mass transfer, reduced sample and reagent consumption, shorter reaction times, improved portability, and the ability to integrate multiple functions into a compact system. Therefore, microfluidics has gained significant attention in recent years due to its numerous advantages over conventional reactors. In particular, microfluidic system integration and process diversification have enhanced the system performance for continuous-flow chemistry. 20182619 While microfluidics has numerous advantages, challenges, such as fabrication complexity, clogging issues still need to be addressed. Especially, the substantial difference in size between laboratory and industrial reactors mainly hinder widespread adoption of microfluidics in various industries. As an alternative, the integration of microfluidics with 3D printing technology has opened up new possibilities for designing and manufacturing sophisticated and self-customized microscale devices. The implementation of a self-customized structure could reduce mixing efficiency and time scale during the flash chemistry as well as the catalyst loaded structure could increase the contact between the reactant and the catalyst to achieve high catalytic activity. Therefore, the development of a well-designed numbered-up microreactor with a compact system is important to satisfy the productivity required in the industrial. In this thesis, amination of methanol (MeOH)/dimethyl ether (DME) for the selective production of acetonitrile (ACN) and flash chemistry for the synthesis of fenofibrate, which is FDA-approved drug for hypertriglyceridemia, were investigated. In amination of MeOH/DME, Zn-Al mixed oxide catalysts were synthesized at different synthetic pH and Zn/(Zn + Al) molar ratio. The effect of synthesis conditions into the changes in physical and chemical properties of catalysts was described using the various characterization. Additionally, the catalytic activity in DME amination over 0.33ZA catalyst, which showed the highest yield of ACN, was compared in the 3D printed microreactor and fixed bed reactor to confirm the possibility of application of microreactor in heterogenous catalysis. In flash chemistry, the capillary reactor showed the better yield of fenofibrate than batch reactor due to the increase in the mass transfer. Particularly, the increase in the productivity of fenofibrate was confirmed in numbering-up 3D printed microreactor. Li, which is one of the valuable resources and largely consumed Li during organolithium flash chemistry was recovered in the integration of microreactor and separation system. In Chapter 1, a general introduction of microreactors, 3D printing technology for fabrication of microreactor, and numbering-up of microreactor was summarized. In Chapter 2 and 3, amination of MeOH/DME for the selective synthesis of ACN on Zn-Al mixed oxide synthesized under different synthesis conditions (pH conditions and Zn/(Zn + Al) molar ratio) were investigated. Here, the physical and chemical properties of the samples were characterized using X-ray diffraction (XRD), N2 sorption, and X-ray photoelectron spectroscopy (XPS), as well as temperature- programmed desorption (TPD) with different probe molecules, such as NH3, CO2, iso- propanol (IPA), MeOH, and DME. Particularly, the changes in the acidity and basicity of the catalysts with the different synthesis conditions were mainly influenced by the degree of disorder of the ZnAl2O4 spinel structure. The effect of reaction parameters, such as weight hourly space velocity (WHSV) and reaction temperature, was investigated to maximize the yield of ACN. Especially the activity of 0.33ZA catalyst synthesized at pH = 8.5, which showed the highest activity in DME amination, was compared in fixed-bed reactor and 3D-printed microreactor. In Chapter 4, 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. Initially, the ultrafast chemistry of highly unstable ArLi intermediate was successfully explored and compared for the synthesis of fenofibrate by its flow-controlled coupling reaction with 4-chlorobenzoyl chloride in batch and commercially available capillary microreactor. 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.