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.
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The authors thank all of the collaborators and researchers who have worked on these fascinating molecules during their development. M.D.E. and M.A.S. are especially grateful to P. Baran for insightful discussions and inspiration, along with S. Tummala, R. Waltermire, A. Ortiz and C. Guerrero for helpful discussions.
The authors declare no competing interests.
Ensuring the robust and expansive evaluation of all key strategic bonds, developing a much fuller retrosynthetic analysis before entering the lab, and using the collective wisdom of multiple researchers to raise and address concerns.
- Strategy aggregation
Taking the multiple synthetic proposals, or proposed disconnections, and collating them into clusters of aligned core disconnection strategies or reactivities, not focusing on any individual technology or precedent. Key experiments can rapidly be explored in the lab to assist in the triaging of strategies.
- Strategy selection
Aligning the team on selecting a strategy, not an individual synthesis proposal. The selected strategy should have multiple related synthetic options (for example, shared reactivity patterns or common intermediates) such that high-risk disruptive approaches can be investigated, while data gained from the exploration can be applied to lower-risk proposals. Appropriate selection can also lead to a more effective staged approach to synthesis development, which is often crucial in aligning work to the risk of the drug progressing to market.
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Eastgate, M., Schmidt, M. & Fandrick, K. On the design of complex drug candidate syntheses in the pharmaceutical industry. Nat Rev Chem 1, 0016 (2017). https://doi.org/10.1038/s41570-017-0016
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