GHP June 2017

GHP / June 2017 9 Irish Based Chemical Production Takes Centre Stage g technologies are typically no longer of relevance. Arran’s development chemists are deeply experienced in first time scale-up and incorporating technologies that can present new route options. An excellent example of such a technology is biocatalysis. Biocatalysis is a science whose time has truly come. When correctly applied, it delivers excellent stereocontrol, yield and scalability with superb green credentials. Unlike chemocatalysis, biocatalytic processes do not generate heavy metal waste, often require no protection, or deprotection steps and can often be run in environmentally friendly solvents. The range of chemistry that can be achieved by biocatalysts is wide as is illustrated on a fictional molecule in Figure 1. Effective integration of biocatalysis technology at Arran has opened up new synthetic chemistry possibilities. A good example of this comes from a chiral advanced intermediate synthesis that Arran recently conducted. One step involved preparation of an amino alcohol in high chemical and chiral purity. The existing technology was a diastereomeric salt crystallisation that required 5 cycles to yield the required purity, albeit in poor yield. In parallel with development of this crystallisation, our biocatalysis group screened their selectAZyme TM hydrolase enzyme kit, rapidly finding an enzyme that showed excellent selectivity. This biocatalysed reaction was then developed and successfully scaled-up to yield the desired compound in quadruple the previous yield with no negative effect on the subsequent API delivery timeline (which was conducted at the Almac site), successfully displacing the existing crystallisation technology. The customer received their compound on time, in full and to the required quality. In addition, they received a synthesis method that was high yielding and more readily scalable for future campaigns. Arran has completed this type of technology displacement on multi-projects and for a wide range of functional group interchanges using, for example, carbonyl reductase (CRED) enzymes for ketone to chiral alcohol, transaminase (TAm) for ketone to chiral amine (and racemic amine to chiral amine and ketone), Nitrilase (NIT) for nitrile to chiral acid, P450 mediated unactivated carbon oxidation to ketone and decarboxylase conversion of amino acid to amine, to name but a few. Key to the effective integration of technology to synthesis is using the right technology for the right application. At Arran, we pride ourselves in ‘project pull’ rather than ‘technology push’ enabling us to deliver the most suitable solutions, thus increasing options for decreasing cost and managing project risk for our clients. Enzyme technology can be a game-changer in many situations, but the existing technology and perceived regulatory barriers are often cited as reasons not to change. One of the drivers for growth within the chemical sector is early implementation of the technology; changing mind- sets within the discovery/ early development setting. A biocatalytic transformation included within an early synthetic route transferred into development is more likely to become part of the developed process, or at least sows the seed of possibility for new route evaluation. Getting a technology to become ‘accepted’ in a fast- paced environment is closely linked to ‘ease-of-use’. Having enzyme technology at hand in an accessible format is a key enabler for this. The increase in availability of ready-to-use kits has made a significant difference in this respect. A wide range of different kits are now available, covering a host of synthetic transformations. They are simple- to-use, and contain everything needed for a bench chemist to make that initial evaluation. Interpretation of results are very closely linked, so it is key that the provider of such products can also offer expert evaluation of what the screening results show. A great starting point for further development may not appear so to the untrained eye. Integrated technologies and service areas The Oxford English Dictionary defines ‘integration’ as “the making up or composition of a whole by adding together or combining the separate parts or elements”. It is this act of combining together that is the new paradigm shift in outsourcing. By working with fewer companies that offer more of the full range of services, timelines and costs can be reduced and attrition of weak synthetic routes achieved earlier. This moves the outsourcing model from the collection of a range of ‘a la carte’ services to a ‘table d’hote’ solution model. A key detail of this new model is the integrated services within an organisation as opposed to an accumulation of the same services at various companies across the world. The single organisation of services, Figure 1: Range of chemistries performed by biocatalysts