New Generic Synthetic Protocols for Pharmaceutical Intermediates Based on Continuous Flow Multifunctional Platforms

基于连续流多功能平台的新型医药中间体通用合成方案

• 批准号: EP/G028141/1
• 负责人: Jonathan Williams
• 金额: $ 72.41万
• 依托单位: University of Bath
• 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%2FG028141%2F1
• 关键词: New; Generic; Synthetic; Protocols; Pharmaceutical

The preparation of drug molecules is usually achieved by running a series of reactions one after the other. When the active ingredient of a drug is prepared, the first intermediate is prepared and isolated, and then taken on to a second step, where an additional conversion takes place. Several separate steps are used to prepare the final compound, and at each stage there is likely to be a loss of material as well as the lack of efficiency of this approach. However, Nature can create incredibly complex molecules within a single species - the anti-cancer drug Taxol is an example where the Yew tree makes a compound which is a formidable synthetic challenge to chemists in the laboratory. The taxol is naturally synthesised by a series of reactions which take place sequentially without the isolation of intermediates - a luxury that the laboratory chemist doesn't normally have available to them.By designing and developing flow reactors, this project will allow chemical reactions to be preformed without a conventional isolation procedure until the desired final structure has been prepared. The project will develop methods for allowing chemicals to react as they flow through pipes rather than in standard laboratory apparatus. As the reacting compounds flow through they will be converted into the next compound in the synthetic sequence, and then on to the next until the entire synthesis has been completed.One of the potential drawbacks of the continuous flow apparatus is that the individual reactions may require very different conditions from each other - very cold steps followed by hot steps, changes to the concentration of intermediates may be required, or even a change in solvent. These problems will be addressed by careful design of the reactor modules, and can involve microwave heating for example. We will develop continuous flow reactions for a series of organic reactions and then develop ways to couple the individual steps together. These coupled steps will then be developed to provide case study preparations of some well know pharmaceutical drugs. In particular, we will prepare Tamoxifen, which the leading drug for the treatment of breast cancer, as well as Effexor which a leading pharmaceutical for the treatment of depression, along with Benadryl (Nytol) which is a well-known anihistamine and sedative.

药物分子的制备通常是通过一个接一个地进行一系列反应来实现的。当制备药物的活性成分时，制备并分离第一中间体，然后进行第二步，在第二步中发生额外的转化。使用几个单独的步骤来制备最终化合物，并且在每个阶段都可能存在材料损失以及这种方法缺乏效率。然而，大自然可以在一个物种中创造出令人难以置信的复杂分子-抗癌药物紫杉醇就是一个例子，紫杉树制造的化合物对实验室的化学家来说是一个巨大的合成挑战。紫杉醇是通过一系列反应自然合成的，这些反应顺序进行，中间体不需要分离--这是实验室化学家通常没有的奢侈品。通过设计和开发流动反应器，该项目将允许化学反应在没有传统分离程序的情况下进行，直到制备出所需的最终结构。该项目将开发方法，使化学品在流经管道而不是标准实验室设备时发生反应。当反应化合物流过时，它们将转化为合成序列中的下一个化合物，然后转化为下一个化合物，直到整个合成完成。连续流动装置的潜在缺点之一是各个反应可能需要彼此非常不同的条件-非常冷的步骤，然后是热的步骤，可能需要改变中间体的浓度，或者甚至溶剂的变化。这些问题将通过仔细设计反应器模块来解决，并且可以涉及例如微波加热。我们将为一系列有机反应开发连续流反应，然后开发将各个步骤耦合在一起的方法。然后将开发这些耦合步骤，以提供一些众所周知的药物的案例研究制剂。特别是，我们将准备他莫昔芬，这是治疗乳腺癌的主要药物，以及Effexor，这是治疗抑郁症的主要药物，沿着Benadryl（Nytol），这是一种众所周知的抗组胺剂和镇静剂。

项目成果

Pt/C catalysed direct reductive amination of nitriles with primary amines in a continuous flow multichannel microreactor

• DOI: 10.1039/c2cy20431b
• 发表时间: 2013-01-01
• 期刊: CATALYSIS SCIENCE & TECHNOLOGY
• 影响因子: 5
• 作者: Sharma, Sumeet K.;Lynch, James;Williams, Jonathan M. J.
• 通讯作者: Williams, Jonathan M. J.

Conversion of nitroalkanes into carboxylic acids via iodide catalysis in water.

• DOI: 10.1039/c5cc08681g
• 发表时间: 2016-01
• 期刊: Chemical communications
• 影响因子: 4.9
• 作者: P. Marcé;James Lynch;A. Blacker;Jonathan M. J. Williams

Iridium-catalyzed formylation of amines with paraformaldehyde

• DOI: 10.1016/j.tetlet.2010.08.106
• 发表时间: 2010-11
• 期刊: Tetrahedron Letters
• 影响因子: 1.8
• 作者: O. Saidi;M. Bamford;A. Blacker;James Lynch;S. Marsden;P. Plucinski;R. Watson;Jonathan M. J. Williams-Jonathan-M.-J.

Hydrophosphonylation of nanoparticle Schiff bases as a mean for preparation of aminophosphonate-functionalized nanoparticles.

纳米粒子席夫碱的氢膦酰化作为制备氨基膦酸酯官能化纳米粒子的方法。

• DOI: 10.3390/molecules18078473
• 发表时间: 2013
• 期刊: Molecules (Basel, Switzerland)
• 作者: Siemieniec J

Mechanistic Studies into Metal-Catalyzed Aldoxime to Amide Rearrangements

• DOI: 10.1002/adsc.201100650
• 发表时间: 2011-12-01
• 期刊: ADVANCED SYNTHESIS & CATALYSIS
• 影响因子: 5.4
• 作者: Allen, C. Liana;Lawrence, Ruth;Williams, Jonathan M. J.
• 通讯作者: Williams, Jonathan M. J.