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

开发连续流动反应化学的新型催化结构和热机制

• 批准号: EP/G027765/1
• 负责人: Steve Haswell
• 金额: $ 41.83万
• 依托单位: University of Hull
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FG027765%2F1
• 关键词: Development; novel; catalytic; structures; thermal

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.

将导致下一代治疗药物的复杂化合物的合成目前是使用传统的基于批次的实验室方法进行的。这种方法在一定程度上可以自动化，但在合成过程中的许多潜在步骤中，通常会遇到低效和无法控制的化学转化，这反过来又导致产品产量低和缺乏产品选择性。目前，这些实验中的困难可以通过在过程中应用一些补救的清理步骤来解决，但尽管这些程序产生了纯产品的最终目标，但它们仍然效率低下和浪费。为了评估当前化学工艺的效率，可以计算E因数，它是每生产一公斤所需产品的过程中产生的不需要的副产品的公斤数的量度。对于散装化学品，这个E系数可以低到1-5，但在制药行业，这个值通常在25-100之间，这主要是由于增加的复杂性和基于批的处理。显然，出于环境和安全两方面的原因，开发更有效的药物化学品清洁生产方法将会有很大的好处，因为这种方法仍将涉及复杂的多步骤反应。在这里提出的研究中，申请人计划带来他们在化学合成方面的经验，包括固定化催化剂和在小型中微米流动反应器中的微波加热，这已经被证明比传统的间歇化学提供了更有效的化学反应控制。这项工作将利用中/微观流动系统中独特的高表面积：体积化学和良好的热传递特性，创建反应物、中间体和产物的可控、非均匀和随时间变化的局部浓度，这将在反应控制方面创造一个新的维度，在某种程度上类似于生物系统中的化学控制。几乎可以肯定的是，使用这种方法可能实现的高水平的局部反应控制，是实现涉及多功能试剂的复杂的、多步骤的有机反应控制的一步改变。为证明所提出的实验方法学而选择的化学方法取自与药物相关的反应类型，将包括Curtius重排以及Knovenagel、Suzuki和Heck反应。为了实现产品生产的可扩展性(即毫克到克)，支持催化过程的流动系统中的整体可以在物理上变得更大，而不会失去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，假设上述反应的理想产物产率，每小时的产物量将在0.06至2克之间。申请者非常清楚，拟议中的研究将需要以一种行业能够随时利用的格式进行交付。因此，在这个项目中，学术团队将与一家领先的流动微波仪器供应商合作，创造出符合制药行业所需产品质量和数量的设备。我们估计，所提出的方法不仅将使目前药物生产的E因子降低10倍，而且将为新的和更可控的合成化学提供新的和令人兴奋的途径。