Reductive Aminations and Amidations, a Self-Optimising Reactor

项目背景（确定问题及其对可持续性的重要性和相关性）在制药行业，超过90%的产品含有氮基官能团，其中许多是胺和酰胺的形式。还原酰胺化和直接酰胺化通常需要化学计量量的几种添加剂，这降低了总体原子经济性。在英国，减少所涉及的废物是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，在开发减少废物的C-N键形成反应方面进行了大量工作。这些酸的优点是更丰富，可以持续来源，但反应性较低。最近在这一领域的工作已经利用硅烷作为直接酰胺化和还原胺化的有效试剂。最近Stoll等人证明了使用苯基硅烷和乙酸锌的还原胺化方法，虽然它确实显示出优异的结果，但其性能受到不能固定用于流动的限制。1 Morisset等人开发了在室温下仅使用苯基硅烷的直接酰胺化反应，其显示出显著的结果和进一步开发成流动平台的潜力。2 1 E. L. Stoll，T.舌头，K。G. Andrews，D. Valette，D.赫斯特和R. M.丹顿，化学科学，2020，11，9494-9500.2 E. Morisset，A. Chardon，J. Rouden和J. Blanchet，欧洲有机化学杂志，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，其利用硅烷的双重官能度作为直接酰胺化中的偶联剂和还原胺化中的还原剂。我们打算部署这些协议作为一个批处理和在一个自我优化的流动反应器。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撑和固定硅烷，并研究如何再生和重复使用这些支撑的硅烷。我们还希望采用机器学习技术来预测反应条件，以进一步了解和控制反应。此外，我们希望将我们的机器学习过程应用于流动反应器。方法我们打算通过以下步骤实现我们的预设解决方案1.开发还原胺化和直接酰胺化方案，使用聚合物负载的硅烷2。通过经验和机器学习技术探索反应的范围和局限性3.进一步开发聚合物支架，以优化孔隙率和保留时间4。建立一个自我优化的流程平台，使用还原胺化和直接酰胺化方案5。将还原胺化和直接酰胺化方案应用于示例性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