Ultrafast Flow Synthesis of Drug Scaffolds via Lithiated Chemistry and Practical Extension

Abstract

Flow chemistry based on microreactors has significantly improved various organic synthetic chemistry performed in traditional batch reactors such as flasks in terms of reaction selectivity and process efficiency, thanks to the high mass and heat transfer efficiency resulting from the small scale of the reactors. As microreactor-based flow chemistry has emerged as an innovative alternative methodology for conducting organic synthetic chemistry, its application area is gradually expanding not only to academia but also to the industrial sector. In particular, the unique advantages of microreactors, such as the ability to precisely control residence times in less than a second, high mixing efficiency to uniformly mix reactants within a shorter time, and high heat dissipation ability, have paved the way for exploring a distinctive research area of effective control and utilization of highly reactive short-lived reaction intermediates. Consequently, this synthetic methodology, ‘ultrafast chemistry’, has contributed to the advancement of organic synthetic chemistry in many aspects, 20162063 including the development of new synthetic pathways, the development of synthetic processes under mild temperature conditions, high reaction selectivity, innovative reduction in reaction times, and elucidation of reaction mechanisms, by making reactions considered very challenging in batch reactors accessible. However, despite the unique advantages of ultrafast synthetic chemistry, several major limitations keep its practical application still in its early stages compared to conventional flow chemistry. To delve more specifically into these major limitations, the following points can be highlighted. First, one key limitation is that the field where ultrafast synthetic chemistry is being applied is restricted. Ultrafast synthetic chemistry is a methodology used in the field of organic synthesis, and even when considering expansion of the applicable field, it is primarily utilized in areas such as drug development and materials science. Additional chemical transformations after ultrafast synthetic chemistry typically occur only in the organic solvent, and orthogonality of functional groups is often lacking. Highly reactive reaction intermediates, especially organolithium-based intermediates, are very sensitive and tend to be primarily applied to specific reactions rather than a broad range of chemical transformations. Second, ultrafast synthetic chemistry has low accessibility and optimization efficiency. Highly reactive reaction intermediates are very sensitive and easily decompose, so they must be carefully controlled by maintaining an anhydrous environment, and often cause fire hazards, necessitating skilled experts for handling. Additionally, the optimization process of ultrafast synthetic chemistry is a time- consuming and labor-intensive complex procedure involving extensive reaction condition screening experiments because it requires fine-tuning of reaction conditions. Third, there is a lack of productivity to meet the demands at an industrial scale. The small scale of microreactors itself that enabled precise control of reaction intermediates becomes an inherent limitation in terms of productivity. To increase productivity by increasing the number of precisely controlled reaction intermediates per unit time, the reaction volume must be increased, while maintaining the advantages of microreactors such as precise residence time control and high mixing efficiency. Therefore, an appropriate scale-up approach is required for ultrafast synthetic chemistry. Recognizing the limitations in the practical application of ultrafast synthetic chemistry described above, each chapter of this doctoral research addresses these limitations by proposing methodologies to overcome them, thereby expanding the applications of ultrafast synthetic chemistry while maintaining its excellent characteristics. First, to broaden the scope of areas where ultrafast synthetic chemistry can be applied, aryllithium intermediates bearing a sulfonyl fluoride (–SO2F) group were controlled, and useful compounds were synthesized through intramolecular SuFEx (Sulfur fluoride exchange) cyclization reactions or SuFEx connections with various organolithium reactants following functionalization. Second, to improve the accessibility and optimization efficiency of ultrafast synthetic chemistry, an automated microreactor platform was developed to perform reactions automatically, and a Bayesian algorithm was applied to suggest the next optimization reaction conditions instead of users, thereby establishing an efficient synthesis system with minimized user intervention. Lastly, to overcome low productivity, a numbering-up strategy was employed to parallelize multiple reactors, allowing precise control of a large amount of reaction intermediates in a large reaction volume, and a monolithic microreactor was used to ensure highly uniform fluid distribution, enabling the synthesis of three drug scaffolds on a larger scale. In more detail, in Chapter 1, a brief overview was provided on the characteristics of flow chemistry based on microreactors and ultrafast synthetic chemistry, distinct from traditional batch reactor-based organic synthesis chemistry. Then, the chapter discussed the limitations that have posed challenges to the practical application of ultrafast synthetic chemistry until now. It also explained the introduction of click chemistry, the numbering-up strategy for microreactors, and autonomous systems as means to overcome these limitations. In Chapter 2, the control and utilization of aryllithium intermediates bearing a sulfonyl fluoride (–SO2F) functional group, a key reactive moiety in the SuFEx reaction highly regarded as the next-generation click chemistry, using a microreactor is described. Optimization of reaction conditions was performed to maximize the utilization of the highly reactive intermediate, generated through the lithiation of simple and stable 2-bromobenzene sulfonyl fluoride, before its decomposition. Under the selected optimal conditions (tR1 = 0.016 s, T = –18 °C), various electrophiles were introduced, leading to the synthesis of targeted functionalized sulfonyl fluorides in high yields (61–93%). Notably, the intramolecular SuFEx cyclization reaction, previously deemed impractical in batch reactors, was successfully conducted using aldehyde and isocyanate electrophiles. Leveraging this cyclization reaction, the precursor of the neuroprotective drug repinotan was synthesized through a new synthetic pathway within 3 seconds. Furthermore, by integrating the previously developed functionalization reaction and SuFEx reactions with various organolithium reactants, including unstable aryllithium intermediates, a complex sulfone compound capable of diverse chemical transformations was synthesized in one flow within 10 seconds. The developed synthetic methodology in this study extends the applicability of ultrafast synthetic chemistry, encompassing diverse fields such as bioorthogonal chemistry and drug delivery systems. In Chapter 3, the development of an automated platform capable of performing ultrafast synthetic chemistry reactions automatically and the construction of an autonomous platform capable of designing experiments independently in the reaction optimization process by integrating a Bayesian optimization algorithm were described. A platform was constructed to automatically control key reaction conditions in ultrafast synthetic chemistry, such as flow rate, reaction temperature, reaction volume, and type of reagent, and perform real-time analysis of reactions, all under the control of a central computer. The platform was used to carry out ultrafast synthetic chemistry reactions based on 80 sets of reaction conditions designed by the user. Through this process, a reaction space mapping was achieved within a total of 4 hours, allowing to determine the lifespan of the o-lithiophenyl isothiocyanate intermediate, confirming conditions that provided an 88% maximum yield. Furthermore, by combining a Bayesian optimization algorithm, the reaction optimization for three and four variables were completed within 1 hour with 10 experiments and 1.5 hour with 15 experiments, respectively. In addition, a library of drug scaffolds was automatically constructed in 20 minutes using combinatorial chemistry algorithm. This study has made ultrafast synthetic chemistry more accessible and practical, enabling even inexperienced users to perform it easily and efficiently. Chapter 4 describes the precise control of three aryllithium intermediates in a larger reaction volume per unit time for drug scaffold synthesis using a monolithic numbered-up microreactor fabricated using a high-resolution metal 3D printing technique. To maintain the precise controllability of highly reactive intermediates, the mixing efficiency, distribution performance, heat dissipation efficiency, and pressure drop of the numbered-up microreactors were simulated. Then, it was demonstrated that the productivity of sensitive ultrafast synthetic chemistry could be increased fourfold within a yield error of 3% by performing and comparing experiments in which three aryllithium intermediates were reacted with four electrophiles under various reaction temperature conditions using both a single capillary microreactor and a numbered-up microreactor. Furthermore, to showcase the scalability of the numbering-up strategy, four monolithic numbered-up microreactors were integrated with external flow distributors to establish a modular numbered-up system with a total productivity of 16 times. The distribution performance of the external flow distributor was validated through simulation and experimentation. The control of the three aryllithium intermediates was carried out again using this modular system to synthesize drug scaffolds, demonstrating a 16-fold increase in productivity and provisionally producing approximately 3 kg of product per day. The numbering-up strategy implemented in this study demonstrated that the productivity of ultrafast synthetic chemistry could be increased to meet larger demands. The significance of this doctoral thesis is to enable ultrafast synthetic chemistry to be widely used in both academia and industry by presenting an approach to overcome the limitations that hinder the practical application of it that fully utilizes the unique advantages of microreactors. Ultrafast synthetic chemistry, achieving expanded applicability, enhanced accessibility and efficiency, and high productivity is anticipated to significantly contribute to the advancement of science and technology as an innovative and powerful methodology for obtaining target compounds. In a more concrete sense, these improvements are expected to contribute to the ultimate goal of practical extension of ultrafast synthetic chemistry through the integrated use of new reactive intermediates for extension of applicable fields, autonomous platform for rapid optimization in the development of process utilizing those intermediates, and numbered-up microreactor for fulfillment of industrial-scale demand after process development.