Chemo- and Bio-Catalysis for the Synthesis of Chiral Amines in Continuous Flow Reactors

The prevalence of chiral amines in pharmaceutical compounds means that efficient synthetic methods are highly desirable. Asymmetric catalysis offers the opportunity for enantioselective synthesis of chiral amines under milder reaction conditions. Chemical and biological catalysts both offer specific advantages and disadvantages that are different to the other catalyst type. Therefore, the combination of catalysts would allow for the advantages of each to be exploited, whilst overcoming the associated disadvantages. This research investigates the combination of chemical and biological catalysts for the production of chiral amines and essential medicines using continuous reactors. Continuous reactors are increasingly seen as a method to improve synthesis routes due to their improved productivity and safety compared to batch reactors. In addition to continuous reactors, immobilised catalysts and design of experiments (DoE) strategies were employed for the development of optimised procedures. Firstly, the enzymatic kinetic resolution of a chiral primary amine was studied in a continuous packed bed reactor (PBR) using an immobilised lipase enzyme. Optimum reaction conditions were determined using a one variable at a time (OVAT) approach to give the maximum 50% conversion with high product ee in only a 6 min residence time (tRes). The PBR system was then applied to an expanded substrate set, including chiral amines and alcohols, to act as a comparison to the standard amine. Secondly, metal catalysed racemisation was investigated as a method to utilise the waste enantiomer from the enzymatic resolution in a dynamic kinetic resolution process (DKR). Homogeneous and heterogeneous Ir, Ru and Pd catalysts were tested for the amine racemisation step. However, the amount of racemisation observed was not sufficient and uncontrolled dimerisation primarily occurred. Next, the enzymatic PBR was applied to the production of essential medicines via enzymatic ammoniolysis. The development of cheaper more efficient methods to produce essential medicines is vital to make them more affordable and accessible to the developing world. In this instance, the reaction conditions were optimised using DoE with the objective being to maximise conversion. Nicotinamide and pyrazinamide were produced in 94% and 100% yields with a tRes of 60 min and 20 min, respectively. The ammoniolysis of a chiral substrate was also tested; however, this was not successful using the experimental conditions described. Finally, metal catalysed N-alkylation using Ir was investigated for the N-alkylation of the chiral primary amine as an alternative method to utilise the waste enantiomer from the continuous resolution. DoE and microwave heating techniques were employed to optimise the reaction conditions and reduce the amount of waste associated with development. In this example, the formation of un-desired dimeric products was problematic and so the optimisation objectives were both maximum conversion and maximum selectivity for the desired product. Overall, the transferal of processes into continuous PBR and optimisation techniques allowed for the intensification of reaction conditions, which led to more productive, efficient routes. However, the difficulties in combining chemical and biological catalysts were also highlighted when the combination of reactions was attempted.