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学品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利益(例如，最大限度地减少化学废物，避免昂贵或稀缺的试剂/催化剂)。连续流生物催化与间歇式生物催化相比有几个优点。这些优势包括避免从产品流中移除催化剂，最大限度地减少对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动中的应用受到几个因素的限制。这些问题包括固定化载体的不同性能和这些载体与反应器类型的不匹配(例如管式与连续搅拌槽反应器)，以及水/有机流分离方面的问题。目的和目标：在这个项目中，我们将(A)在不同的反应器配置中优化负载型生物催化剂的性能，(B)整合连续分离以促进下游级联反应和/或辅因子回收，(C)展示连续生物和化学催化过程的联合，用于在与我们的工业伙伴合作选择的选定目标上合成样品产品(例如药物中间体)，以及(D)了解催化剂和载体之间的关系，以提高活性和寿命。我们将在两个不同的酶类上举例说明这些方法的健壮性和通用性。应用和好处：这项工作包括EPSRC催化和制造技术(等)领域的研究，将导致更多地采用可持续技术来制造精细化学品(解决制造未来主题)和药品(健康国家主题)，从而为英国带来环境和经济利益。

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.