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 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.

Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, 08901, New Jersey, USA

Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, 06877, Connecticut, USA

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.

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.

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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