Flow Chemistry: Towards A More Sustainable Heterocyclic Synthesis

Abstract

Flow Chemistry is a revolutionary field in Organic Chemistry. By changing the conventional methods and apparatus applied in the chemical synthesis, flow chemistry emerges as a game changer for organic synthesis laboratories, in both academia and industries. Considered as a sustainable practice, flow processes play an important role in the development of fine chemical products and in drug discovery development pro- [a] The main advantages of flow chemistry are that it allows the reaction to be carried out safely with high selectivity, high reproducibility and reduced energy consumption/carbon footprint. These features make this emerging technology for organic synthesis desirable for green and sustainable chemical synthesis, giving the chemist time for work planning and design, instead of using it in repetitive tasks, [5b,12] as expressed by the CHEM21 project by awarding a green flag for continuousflow reactions, in opposition to an amber flag for those performed under batch conditions. [13] Pedro Brandão received his MSc in Pharmaceutical Sciences from the Faculty of Pharmacy -University of Porto, in 2011. Pursuing his passion on studies in the field of Drug Discovery and Development, he is currently undergoing his PhD studies in Chemistry, in the field of Catalysis and Sustainability. His main focus of work is the discovery of new drug candidates through sustainable techniques. Marta Pineiro received her Ph.D. in Organic Chemistry in 2003 in the University of Coimbra, Portugal, and since 2002 has been enrolled at the University of Coimbra, being at present Auxiliary Professor. Her research interests are in the area of sustainable organic synthesis, microwave-assisted organic synthesis and synthesis and biological applications of tetrapyrrolic macrocycles. Teresa M. V. D. Pinho e Melo studied Chemistry at the University of Coimbra, where she graduated in 1985, got her M. 7191CPBA) as the oxidizing agent, avoiding the handling of this expensive and explosive reagent. [25] Recently, Morodo et al. explored the synthesis of two very important oxiranes (epichlorohydrin and glycidol) from biobased glycerol, under flow conditions. As depicted in Scheme 1, and using pimelic acid as the catalyst (10 mol-%), a sequential hydrochlorination/dichlorination process allows high conversion of glycerol (> 99 %) into 1,3-dichloro-2-propanol, followed by the quantitative conversion into a separable mixture of glycidol and epichlorohydrin (2:3). The separation of these two products is performed by an in-line membrane separation system, which allows the first product to be collected in the aqueous phase, while the second is collected in MTBE. This heterocycle can be further used as a synthetic precursor to relevant APIs bearing -amino alcohol moieties (e.g., propranolol, alprenolol and naftopidil). [26] Scheme 1. Sequential flow setup for the preparation of glycidol and epichlorohydrin, important APIs synthetic intermediates.Scheme 3. Synthesis and inline purification of a bicyclic aziridine (SGMR = silicon-glass microfluidic react...

Continuous‐Flow Dynamic Kinetic Resolution of Racemic Alcohols by Lipase–Oxovanadium Cocatalysis

“…Due to these improvements, the flow DKR could be conducted for continuous 3 days to produce the desired esters in high yield and with 99% ee by using smaller amounts of CALB and VMPS4 compared to the corresponding batch reactions. Considering the increasing need and importance of continuous‐flow reactions,, [9b], , this study should provide useful information for continuous‐flow systems using a column reactor packed with multiple catalysts where several different reactions proceed simultaneously.…”

“…Flow chemistry has drawn increasing attention in the last few decades . In particular, the application of flow reactors for continuously running processes in the presence of heterogeneous catalysts has emerged with great potential , .…”

“…Flow chemistry has drawn increasing attention in the last few decades . In particular, the application of flow reactors for continuously running processes in the presence of heterogeneous catalysts has emerged with great potential , . The use of packed‐bed reactors, for example, improves the turnover numbers and lifetimes of the catalysts by avoiding their tedious recovery for reuse as in case of batch reactions that requires additional handling to set up the next reaction.…”

“…Additionally, the continuous‐flow processes generally present advantages over batch procedures, such as better mass and heat transfer, improved safety profiles, easier work‐up and as well as the accurate control of temperature, pressure and reaction time. Thus, continuous‐flow processes have higher productivity and reproducibility than the batch reactions, and are also favorable for automation and scale‐up …”

Flow Synthesis of Biologically-Relevant Compound Libraries

“…In particular, this approach has demonstrated to be superior to batch protocols in every case where heat transfer and mixing are important, hazardous or sensitive materials are handled, and high temperatures/pressures are required. Furthermore, this technology is considered a green synthetic approach as it often delivers better product yields than those derived from batch protocols, and also it allows easier product purification leading to minimum waste production [10][11][12]. In the drug discovery field, the need for novel molecules with drug-like structures to be used for high-throughput screening required enabling technologies for their production; in this context, flow chemistry represents the ideal tool for generating compound libraries in a fast and automated fashion [13].…”