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.

通常通过一个接一个地运行一系列反应来实现药物分子的制备。当制备药物的活性成分时，将准备和隔离第一个中间体，然后将其带到第二步，然后进行额外的转换。使用几个单独的步骤来制备最终化合物，在每个阶段，可能会损失材料以及这种方法的效率。但是，自然可以在单个物种中产生令人难以置信的复杂分子 - 抗癌药物紫杉醇是紫杉树形成化合物的一个例子，这是对实验室中化学家的巨大合成挑战。紫杉醇是由一系列反应自然综合的，这些反应在不隔离中间体的情况下进行了依次发生的反应 - 通过设计和开发流动反应器，实验室化学家通常无法使用的奢侈品，该项目将允许在不常规的隔离过程的情况下预先形成化学反应，直到准备了所需的最终结构。该项目将开发出允许化学物质在流经管道而不是标准实验室设备时反应的方法。随着反应化合物的流通，它们将被转换为合成序列中的下一个化合物，然后直到下一个化合物直到整个合成完成。连续流动设备的潜在缺陷之一是，单个反应可能需要彼此之间的条件非常不同 - 非常冷的步骤遵循，遵循的热门步骤可能会更改中间人的浓度，甚至需要变化。这些问题将通过仔细设计反应器模块来解决，例如，可能涉及微波加热。我们将为一系列有机反应开发连续的流动反应，然后开发方式将各个步骤搭配在一起。然后将开发这些耦合步骤，以提供一些知名药物的案例研究准备。特别是，我们将准备他莫昔芬，这是治疗乳腺癌的领先药物，以及Effexor，这是抑郁症治疗的领先药物，以及贝纳德里尔（NYTOL）（NYTOL），这是一种众所周知的苯胺和镇静剂。

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.

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.

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

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

Copper-catalyzed rearrangement of oximes into primary amides

• DOI: 10.1016/j.tetlet.2011.05.129
• 发表时间: 2011-08-17
• 期刊: TETRAHEDRON LETTERS
• 影响因子: 1.8
• 作者: Sharma, Sumeet K.;Bishopp, Simon D.;Williams, Jonathan M. J.
• 通讯作者: Williams, Jonathan M. J.