Development of novel catalytic structures and thermal regimes for continuous flow reaction chemistry

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The synthesis of complex chemical compounds that will lead to the next generation of therapeutic drugs is currently carried out using traditional batch based laboratory methodology. This approach, which can to some extent be automated, typically suffers form inefficient and uncontrollable chemical conversions during the many potential steps in a synthetic process, which in turn leads to poor product yields and a lack of product selectivity. At present, these experimental difficulties can be dealt with by applying a number of remedial clean up steps in the process but whilst these procedures produce the final goal of a pure product, they remain inefficient and wasteful. In an attempt to assess the efficiency of current chemical processes, an E-factor can be calculated which is a measure of the number of kilograms of unwanted by-products generated from a process per kilogram of the desired product produced. For bulk chemicals this E-factor can be as low as 1-5 but in the pharmaceutical industry this value is often much higher at 25-100 due mainly to the increased complexity and batch based processing. Clearly for both environmental and safety reasons there will be substantial benefits in developing more effective approaches to the cleaner production of pharmaceutical chemicals which will still involve complex multi-step reactions. In the research proposed here the applicants plan to bring their experiences in chemical synthesis including immobilized catalysts and microwave heating in small meso (?m) and micron scale flow reactors, which has been demonstrated to offer more effective control over chemical reactions compared to traditional batch chemistry. The work will exploit the unique high surface area:volume chemistries and excellent thermal transfer characteristics available in meso/micro flow systems, to create controllable, non-uniform and time-dependent localised concentrations of reactants, intermediates and products, which will create a new dimension in reaction control somewhat akin to the chemical control in biological systems. The high level of localised reaction control possible using this approach is almost certainly required to achieve a step change in the control of complex, multi-step organic reactions involving multi-functional reagents. The chemistries selected to demonstrate the proposed experimental methodology have been drawn from pharmaceutically relevant reaction types and will include the Curtius rearrangement and Knoevenagel, Suzuki and Heck reactions. In order to achieve scalability of product production (i.e. milligrams to grams) the monoliths in the flow system that support the catalytic process can be made physically larger without losing their integral small pore geometries and volumetric flow can then be increased to generate more material. It has been estimated that, assuming an ideal yield of products for the above named reactions, quantities of product will range from 0.06 to 2 g per hour. The applicants are very conscious that the proposed research will need to be delivered in a format that industry will be able to readily exploit. Accordingly in this project the academic team will be working with a leading supplier of flow-through microwave instrumentation to create equipment that will meet both the quality and quantity of product the pharmaceutical industry is are seeking. We estimate the proposed methodology will not only reduce the E-factor for current drug production by a factor of 10, but will offer new and exciting routes to novel and more controllable synthetic chemistries.