Optimising Continuous Flow Biocatalysis Processes for Fine Chemical Manufacturing

背景：将生物催化转化整合到商业精细化工和医药产品的合成中正变得越来越普遍，随之而来的是环境和经济效益（例如，最小化化学废物流，避免昂贵或稀缺的试剂/催化剂）。连续流生物催化与间歇法相比有几个优点。这些优点包括避免了从产品流中去除催化剂的需要，最大限度地减少了产率和变构控制的平衡控制限制。然而，目前生物催化在连续流中的应用受到几个因素的限制。这些问题包括固定支架的可变性能和这些支架与反应器类型的不匹配（例如管式与连续搅拌槽式反应器），以及水/有机流分离中的问题。如果能够克服这些限制，不仅可以改善生物转化步骤，而且还可以扩展上下游化学催化步骤，对该过程的效率和可持续性产生积极影响。宗旨和目标：在这个项目中，我们将(a)在不同的反应器配置中优化支持的生物催化剂的性能，(b)整合连续分离，以促进下游级联反应和/或辅助因子回收，(c)展示连续生物和化学催化过程的结合，在与工业伙伴合作选择的特定目标上合成范例产品（例如药物中间体）。(d)了解催化剂和载体之间的关系，以提高活性和寿命。我们将举例说明两种不同的酶类的方法，以证明鲁棒性和方法的普遍性。应用和效益：这项工作包括EPSRC催化和制造技术（以及其他）领域的研究，将导致更多地采用精细化学品制造（解决未来制造主题）和药品（健康国家主题）的可持续技术，从而为英国带来环境和经济效益。

Background: The integration of biocatalytic transformations into the synthesis of commercial fine chemical and pharmaceutical products is becoming increasingly widespread, with attendant enviromental and economic benefits (e.g. minimisation of chemical waste streams, avoiding expensive or scarce reagents/catalysts). Continuous flow biocatalysis has several advantages over batch alternatives. These advantages include avoiding the need for catalyst removal from the product stream, minimising equilibrium controlled limitations on yield and allosteric control. Current use of biocatalysis in continuous flow is, however, limited by several factors. These include the variable performance of the immobilization supports and the mismatching of these supports to the type of reactor (e.g. tubular vs continuous stirred-tank reactor), as well as issues in the separation of aqueous/organic streams. If these limitations can be overcome, not only will the biotransformation step be improved, but it also opens up possible telescoping with up/downstream chemo-catalytic steps, with positive impact upon the efficiency and sustainability of the process.Aims and objectives: In this project, we will (a) optimise the performance of supported biocatalysts in different reactor configurations, (b) integrate continuous separation with the intention of facilitating downstream cascade reactions and/or co-factor recycling, (c) demonstrate the union of continuous bio- and chemo-catalysis processes for the synthesis of exemplar products (e.g. drug intermediates) on select targets chosen in collaboration with our industrial partners, and (d) understand the relationship between the catalyst and support to improve activity and longevity. We will exemplify the methods on two distinct enzyme classes to demonstrate the robustness and generality of the methods. Applications and benefits: This work, which encompasses research in the EPSRC areas of Catalysis and Manufacturing Technologies (amongst others), will lead to greater uptake of sustainable technologies for the manufacture of fine chemicals (addressing the Manufacturing the Future theme) and medicines (Healthy Nation theme), thus delivering environmental and economic benefits to the UK.