Microwave-assisted continuous flow organic synthesis

新化学实体的合成是医药、农化和材料领域发现的支柱。在商界，在这些具有重要社会意义的领域，抢先发现的竞赛至关重要；这将控制来自这些努力的知识产权（即专利空间）和相关财富。因此，化学家们努力开发新的试剂、催化剂、工艺和设备，以便更快地制造更多的化合物，理想情况下，结构更多样化，以满足这些重要的研究领域。为了满足这一重要的需求，本提案概述了一种概念上的新策略的发展，以非常快速和大量地同时制备有机化合物。以流动形式进行反应，而不是在传统的间歇反应装置中静态地进行反应，允许在过程中改变反应条件，例如反应优化和产品的在线处理（分析或纯化）。流动的一个潜在缺点是，反应在流动系统中停留的时间比在标准间歇式反应器中停留的时间短。如果一个反应在动力学上是缓慢的，流动的好处将被不良的反应转化所抵消，导致低产量和净化问题，因为产品混合物被未反应的起始物质污染。众所周知，微波辐射能显著加快化学转化的速度；将微波与流动相结合将使两种技术的全部优势得以实现。初步实验表明，在辐照下，反应通过小直径管（毛细血管）流动，实际上比大直径管的速率提高得更快，我们相信，这为流动合成的广泛接受提供了最大的希望。本提案还提出了进一步的研究进展，将流动微波与毛细管相结合，这些毛细管装载了新的支撑试剂、催化剂和清除剂，反应通过这些试剂流动，从而实现单序列合成和纯化。从本质上讲，这相当于创造了一种自动化的、多步骤的化学合成机器，能够通过平行的毛细血管同时进行多种反应。

The synthesis of new chemical entities is the backbone of discovery in the pharmaceutical, agrochemical, and materials sectors. In the business world, the race to be first to discover is essential in these societally-important areas; this will control the intellectual property (i.e., patent space) and the associated wealth from these efforts. As a result, chemists have strived to develop new reagents, catalysts, processes, and devices in order to make more compounds more quickly, and ideally more structurally diverse to feed into these important research areas. To meet this important demand, this proposal outlines the development of a conceptually new strategy for the simultaneous preparation of organic compounds both very rapidly, and in large numbers. Performing reactions in a flowed format, rather than statically in a conventional batch reaction set up allows for in-process alterations of reaction conditions, such as reaction optimization and in-line processing (analysis or purification) of the products. A potential drawback with flow is that reactions reside in the flow system for a shorter period of time than in a standard batch reactor. If a reaction is kinetically slow, the benefits of flow will be offset by the poor reaction conversion resulting in low yield and purification problems because the product mixture is contaminated with unreacted starting materials. Microwave irradiation is known to dramatically accelerate the rate of chemical transformations; combining microwave with flow will allow the realization of the full benefits of both techniques. Preliminary experiments have shown that reactions flowed through small diameter tubes (capillaries) while being irradiated actually show greater rate enhancement over larger diameter tubes and, we believe, offers the greatest hope for wide acceptance of flow synthesis. This proposal also proposes further advances by combing flow microwave with capillaries loaded with new supported reagents, catalysts, and scavengers through which the reactions flow to allow one-sequence synthesis and purification. Essentially, this amounts to the creation of an automated, multi-step chemical synthesis machine capable of running multiple reactions simultaneously through parallel capillaries.