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

将导致下一代治疗药物的复杂化合物的合成目前使用传统的基于批处理的实验室方法进行。这种方法在一定程度上可以自动化，通常在合成过程中的许多潜在步骤期间遭受低效和不可控的化学转化，这反过来导致差的产物产率和缺乏产物选择性。目前，这些实验困难可以通过在该过程中应用许多补救清理步骤来解决，但是尽管这些程序产生纯产物的最终目标，但它们仍然是低效和浪费的。在试图评估当前化学过程的效率时，可以计算E因子，其是每千克所生产的期望产品从过程产生的不需要的副产品的千克数的量度。对于散装化学品，该E因子可以低至1-5，但在制药工业中，该值通常高得多，为25-100，这主要是由于增加的复杂性和基于批量的处理。显然，出于环境和安全的原因，开发更有效的方法来清洁生产仍然涉及复杂的多步反应的制药化学品将有很大的好处。在这里提出的研究中，申请人计划将他们在化学合成方面的经验，包括固定化催化剂和微波加热在小的中（？m）和微米级流动反应器，其已被证明与传统的间歇化学相比对化学反应提供更有效的控制。这项工作将利用独特的高表面积：体积化学和优异的热传递特性，可在介/微流系统中，创造可控的，不均匀的和时间依赖性的局部浓度的反应物，中间体和产品，这将创造一个新的维度反应控制有点类似于生物系统中的化学控制。使用这种方法可能的高水平的局部反应控制几乎肯定需要在涉及多功能试剂的复杂的多步骤有机反应的控制中实现阶跃变化。选择用于证明拟定实验方法的化学物质来自药学相关反应类型，包括Curtius重排和Knoevenagel、Suzuki和Heck反应。为了实现产物生产的可扩展性（即毫克至克），可以使支持催化过程的流动系统中的整料在物理上更大而不损失其完整的小孔几何形状，然后可以增加体积流量以产生更多的材料。据估计，假设上述反应的产物产率理想，产物的量将在每小时0.06至2克的范围内。申请人非常清楚，拟议的研究将需要以一种行业能够随时利用的形式进行。因此，在这个项目中，学术团队将与一家领先的流通式微波仪器供应商合作，创造出既能满足制药行业所需产品质量又能满足其数量的设备。我们估计，所提出的方法不仅将目前药物生产的E因子降低10倍，而且将为新型和更可控的合成化学提供新的和令人兴奋的路线。

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.