Self-Optimising Multiphasic Flow Reactor & Work-up Processing

三个关键要素，每个都有自己的重大学术研究挑战和需要回答的问题：i)评估用于从不混溶液体和固体中连续分离液体的系统，使反应器能够与在线HPLC和台式MS和NMR相结合，其使用也可能允许实时光谱校准与IR和UV-Vis。分离方法将被开发，以允许连续的在线测量（即通过半连续或自动制备样品）。这将建立在现有的和经过验证的分离物理原理的基础上，包括使用不同表面能的延伸表面来促进分离[6]。用于在线和在线监测的适当分离系统的开发将取决于反应系统（见iii），并将与这些开发并行进行ii)建立多相流反应器的热和气压控制，以允许更广泛的化学反应。这将与计划于2016年1月开始的博士生密切合作进行iii)范例反应系统如下所示，通过与阿斯利康的讨论，将建立一个可行的工作计划，以开发多相流系统的分层方法。可以评估的条件范围很广，既包括化学反应，也包括这些反应所需的物理形式（多相）a)将演示各种液-液反应的优化。这可能包括典型反应，如与液体氧化剂氧化，有机分子硝化和双相环丙烷化反应。使用自动化系统的快速实验将使机械和统计模型的开发更容易和可扩展的过程开发。将对各种反应器配置进行传质系数的表征，包括塞流和CSTR以及主动和静态混合器的组合。b)将评估各种样例液-液后处理分离系统，尽管每个系统都有一个共同的方面，即需要从两相中可靠地分离和取样。这可以通过使用堆叠的亲水/疏水板来驱动分离来实现——通过使用堆叠的交替激光切割组件，它可以使单元具有与因数相似的占地面积，并避免与加工通道分层相关的成本。此外，这种装置还可以进行小规模的逆流液-液萃取。令人兴奋的是，优化的目标是在双相反应系统之后提供高质量的产品。系统将对其可操作性和可扩展性进行严格评估和基准测试。c)液-固体系可能是最常见的，一个例子是目前在现有的阿斯利康支持的项目中正在评估的连续结晶。这已经在iPRD反应器中成功地进行了测试，并涉及外消旋酸和手性碱的共投喂，以获得非对映体固体。在这种情况下，我们将通过改变溶剂、化学计量、浓度和停留时间来自我优化产量，方法是用在线过滤器分离固体，首先监测母液中的对映体浓度，然后通过转移溶剂流将晶体从过滤器中溶解，然后进入HPLC、MS或ORD检测器。该系统将需要灵活的编程转移溶剂流动的顺序取样和洗涤。一个雄心勃勃的扩展可能是粒度的分析和优化。冷却结晶也可以被评估。对于不溶性固体，可以测试的设计是反洗涤或通过可交换的多平行过滤器直接流动。例子包括氢与Pd/C的转移，铃木交叉偶联或格氏反应。d)范例三相系统活动(i)-(iii)将视情况在第1-3年进行。

Three key elements, each with its own significant academic research challenges & questions to be answered: i) Evaluate systems for continuous separation of liquid from immiscible liquids & solids to allow the reactor to be coupled with at-line HPLC & benchtop MS & NMR, whose use might also allow real-time spectroscopic calibration with IR & UV-Vis. The separation methods will be developed to allow sequential at-line measurement (ie through semi-continuous or automated preparation of samples). This will build on existing & proven physical principles for separation including the use of extended surfaces of differing surface energies to promote separation [6]. The development of appropriate separation systems for in-line & at-line monitoring will depend on the reaction system (see iii) & will be carried out in parallel with these developments ii) Establish thermal & barometric control of the multiphasic flow reactor to allow a wider range of chemistries. This will be carried out in close collaboration with the planned PhD student to start in Jan 2016 iii) Exemplar reaction systems are highlighted below & through discussion with AZ a feasible work programme will be established to develop a hierarchical approach to developing multiphasic flow systems. There are a wide range of conditions that can be evaluated, both in terms of the chemical reactions, but also the physical forms (multiphasic) that such reactions require a) Optimisation of a variety of liquid-liquid reactions will be demonstrated. This could include exemplar reactions such as oxidation with liquid oxidants, nitration of organic molecules & biphasic cyclopropanation reactions. Rapid experimentation using automated systems will enable development of mechanistic & statistical models for facile & scalable process development. Characterisation of mass transfer coefficients will be performed for a variety of reactor configurations including both plug flow & CSTR & combinations of active & static mixers. b) A variety of exemplar liquid-liquid work-up separation systems will be evaluated, though a common aspect each requires reliable separation & sampling from both phases. This could be achieved using stacked hydrophilic/hydrophobic plates to drive separation - by using stacks of alternating laser cut components it may be able to make units that have a similar footprint to the freactor & avoid the cost associated with machining channels into layers. In addition, such devices would also allow for counter-current liquid-liquid extraction at a small scale. Excitingly, optimisation will be targeted to deliver high quality product subsequent to biphasic reaction systems. Systems will be critically evaluated & benchmarked for their operability & scalability. c) Liquid-solid systems are perhaps most common & an exemplar is the continuous crystallisation currently being evaluated in an existing AZ supported project. This has already been tested successfully in the iPRD Freactor & involves co-feeding a racemic acid & chiral base to give diastereomeric solid. In this case we would self-optimise the yield by varying solvent, stoichiometry, concentration & residence time by separating the solid with an in-line filter, monitoring first the enantiomer concentrations in the mother liquors, then by diverting a solvent flow dissolve the crystals off the filter & then to the HPLC, MS or ORD detector. The system would require flexibly programmed diversions of solvent flow for sequences of sampling & washing. An ambitious extension of this might be analysis & optimisation of particle size. Cooling crystallisations could also be evaluated. For insoluble solids, designs that can be tested are reverse washing or flows directed through exchangeable multi-parallel filters. Exemplars could include hydrogen transfer with Pd/C, Suzuki cross-coupling or Grignard reactions. d) Exemplar tri-phasic systems Activities (i)-(iii) will be carried out over years 1-3 as appropriate.