On the design of complex drug candidate syntheses in the pharmaceutical industry

The overall goal of a process chemistry department within the pharmaceutical industry is to identify and develop a commercially viable approach to a drug candidate. However, the high chemical complexity of many modern pharmaceuticals presents a challenge to process scientists. Delivering disruptive, rather than incremental, change is critical to maximizing synthetic efficiency in complex settings. In this Review, we focus on the importance of synthetic strategy in delivering ‘disruptive innovation’ — innovation that delivers a step change in synthetic efficiency using new chemistry, displacing any prior synthetic route. We argue that achieving this goal requires visionary retrosynthetic strategy and is tightly linked to the discovery and development of new reactions and novel processes. Investing in high-risk innovation during the route design process can ultimately lead to safer, more robust and more efficient manufacturing processes capable of addressing the challenge of high molecular complexity. Routinely delivering such innovation in a time-bound environment requires organizational focus and can be enabled by the concepts of expansive ideation, strategy aggregation and strategy selection. The primary goal of a process chemist is to develop a commercially viable synthetic route to a known drug candidate. The approaches to a synthetic challenge are consequently very different to those used in medicinal chemistry. This Review uses case studies to highlight important considerations, and the tactics used during the design and selection of an efficient drug synthesis.