Novel flow devices and development of process automation for H2-driven biocatalysis

在制药工业中，超过90%的合成过程至少需要一个催化步骤。在实践中，这通常意味着昂贵的重金属，如钯，正在高压和高温下使用，以提高反应速度。除了明显的安全和环境成本外，传统的金属催化剂也存在选择性问题，特别是在用于制备手性中心时。在制药行业，手性中心是关键--沙利度胺的案例证明了这一点。相比之下，生物催化剂在室温下工作，并由于其独特的活性中心而显示出良好的选择性。然而，这些需要昂贵的额外辅助因子，如NADH，才能发挥作用。为了使这一过程具有成本效益，必须回收辅因子，但目前的回收系统会产生大量的碳基废物。该项目研究了一种生物催化系统，该系统由NADH依赖的酶进行手性还原，并与固定在固体载体上的无浪费的NADH循环系统配对。氢被用来为酶提供动力，该系统将被改造成流动化学。流经反应器的试剂已被证明比类似的间歇过程更安全、更节能。该项目的重点是提高对流动条件下的酶NADH循环系统的理解，并演示商业流动反应器的放大。

In the pharmaceutical industry, over 90% of synthesis proceeds using at least one catalytic step. In practise, this often means that expensive heavy metals such as palladium are being used at high pressures and temperatures to improve the rate of reactions. As well as the obvious safety and environmental costs, traditional metal catalysts can have selectivity issues, especially when used to make chiral centres. In the pharmaceutical industry, chiral centres are key - demonstrated by the case of thalidomide. By contrast, biocatalysts operate at room temperature and exhibit excellent selectivity due to their unique active sites. However, these require expensive additional cofactors, such as NADH, to function. To make the process cost efficient, the cofactors must be recycled, but current recycling systems create large amounts of carbon based waste. This project investigates a biocatalytic system made from an NADH-dependent enzyme carrying out a chiral reduction paired with a wasteless NADH recycling system, immobilised onto a solid support. Hydrogen is used to power the enzymes and the system will be adapted to flow chemistry. Flowing reagents through a reactor has proven to be safer and more energy efficient than similar batch processes. The focus of this project is to improve understanding of the enzyme NADH recycling system under flow conditions as well as demonstrating scale up in commercially available flow reactors.