One of the most valuable insights from Roche’s recent ChemRxiv preprint is how medicinal chemistry and process chemistry diverge in practice.
By analysing nearly 700,000 reactions recorded in Roche’s electronic lab notebooks over 15 years, the authors show how the types of reactions performed change as molecules move from discovery into development.
- Medicinal chemistry dominates the total number of reactions performed, reflecting its role as the engine of rapid SAR exploration. Speed, reliability, and flexibility matter most here—and the data show this clearly. High‑throughput amide couplings, heteroatom arylations, and deprotections account for a large fraction of discovery workflows, enabling fast iteration with minimal route design risk from failed reactions.
- Process and development chemistry tell a different story. The total number of reactions fell dramatically: a 7-fold reduction in pre-clinical development, and a 10-fold reduction in technical process development. As compounds progress downstream, the reaction mix shifts toward scalable, stereoselective transformations with three reaction type trends highlighted by the authors:
- Reductions increase dramatically in development (from ~4% in Medicinal Chemistry to ~13–15%), reflecting the need for enantioselective, stereodefining steps rather than chromatographic resolution.
- Functional group interconversions rise by ~50%, underlining the importance of protection strategy optimisation and robustness when routes are transferred and scaled.
- Acylation chemistry drops in relative importance, moving from a discovery workhorse to a more selective tool once routes are fixed.
The paper also includes useful commentary on the pitfalls of training machine learning models for process development based on a dataset dominated by chemistry performed to serve medicinal chemistry, as well as insights into trends over time of reaction types, standardized reaction conditions, physicochemical properties, and molecular complexity.
Read the full paper here Charting the evolving chemical synthesis repertoire at Roche | ChemRxiv
