Reductive Aminations and Amidations, a Self-Optimising Reactor

项目背景（确定问题及其重要性和与可持续性的相关性）在制药工业中，超过90%的产品含有氮基官能团，其中许多是以胺和酰胺的形式存在的。还原性酰胺化和直接酰胺化通常需要几种化学计量量的添加剂，从而降低整体原子经济性。减少所涉及的废物是英国化学工业的重大利益。近年来，通过将经典的酮和醛交换为羧酸，在减少废物的C-N成键反应中进行了大量的工作。这些酸的优点是更丰富，可以持续来源，但反应性较低。近年来，在这一领域的工作已经利用硅烷作为一种有效的试剂，在直接酰胺化和还原性胺化。最近Stoll等人展示了一种使用苯基硅烷和醋酸锌的还原性胺化工艺，虽然它确实显示出优异的效果，但其性能受到无法固定用于流动的限制Morisset等人在室温下仅使用苯基硅烷开发了一种直接酰胺化反应，该反应显示出显著的结果，并有进一步发展为流动平台的潜力。2 E. L. Stoll， T. Tongue， K. G. Andrews， D. Valette， D. J. Hirst和R. M. Denton，化学。科学。[2]刘建军，刘建军，刘建军，等。化学。浙江农业学报，2020,2020,388-392。建议的解决方案和方法建议的解决方案我们建议开发还原胺化和直接酰胺化方案，利用硅烷的双重功能作为直接酰胺化的偶联剂和还原胺化的还原剂。我们打算在批处理和自优化流动反应器中部署这些协议。为了开发流动平台的工艺，我们将探索更可持续的聚合物基支架来支持和固定硅烷，以及研究如何再生和再利用这些支持的硅烷。我们还希望采用机器学习技术，围绕反应条件进行预测，从而进一步理解和控制反应。此外，我们希望将我们的机器学习过程应用于流动反应器。我们打算通过以下步骤实现我们提出的解决方案。利用聚合物支撑的硅烷开发还原性胺化和直接酰胺化方案2。通过经验和机器学习技术探索反应的范围和局限性。进一步开发聚合物支架，优化孔隙度和保留时间4。建立自优化流程平台，使用还原胺化和直接酰胺化协议5。将还原胺化和直接修饰协议应用于示例api

Project background (identification of the problem and its importance and relevance to sustainability)In the pharmaceutical industry over 90% of products contain nitrogen based functional groups, many of these are in the form of amines and amides. Reductive amidations and direct amidations often require several additives in stoichiometric amounts that reduce overall atom economy. Reducing the waste involved is of significant interest to the chemical industry in the UK.In recent years there has been significant work in developing C-N bond forming reactions with reduced waste by exchanging the classical ketones and aldehydes for carboxylic acids. These acids have the advantage of being more abundant and can be sustainably sourced however are less reactive.Recent work in this area has made use of silanes as an efficient reagent in both direct amidations and reductive aminations. Recently Stoll et al. demonstrated a reductive amination process using phenyl silane and zinc acetate, and while it did show excellent results its performance is limited by an inability to be immobilised for use in flow.1 Morisset et al. developed a direct amidation reaction using only phenyl silane at room temperature which showed significant results and the potential for further development into a flow platform.2 1 E. L. Stoll, T. Tongue, K. G. Andrews, D. Valette, D. J. Hirst and R. M. Denton, Chem. Sci., 2020, 11, 9494-9500.2 E. Morisset, A. Chardon, J. Rouden and J. Blanchet, European J. Org. Chem., 2020, 2020, 388-392.Proposed solution and methodologyProposed solution We propose to develop reductive amination and direct amidation protocols that make use of the dual functionality of silanes as both a coupling agent in direct amidations, and as a reductant in reductive aminations. We intend to deploy these protocols for both as a batch process and in a self-optimising flow reactor. To develop the process for the flow platform we will explore more sustainable polymer-based scaffolds to support and immobilise the silanes, as well as looking at how to regenerate and reuse these supported silanes. We also wish to employ machine learning techniques in order to make predictions around the reaction conditions to gain further understanding and control of the reaction. In addition, we wish to employ our machine learning process to the flow reactor. Methodology We intend to realise our preposed solution by the following steps 1. Develop reductive amination and direct amidation protocols using silanes supported on a polymer2. Explore the scope and limitations of the reactions through empirical and machine learning techniques 3. Further develop polymer scaffold to optimise porosity and retention times4. Build a self-optimising flow platform to use reductive amination and direct amidation protocols5. Apply the reductive amination and direct amidation protocols to exemplar APIs