Bayesian Self-Optimization for Telescoped Continuous Flow Synthesis.

Autor: Clayton AD; Institute of Process Research and Development, Schools of Chemistry & Chemical and Process Engineering, University of Leeds, Leeds, LS2 9JT, UK., Pyzer-Knapp EO; IBM Research UK, Daresbury Laboratory, Daresbury, WA4 4AD, UK., Purdie M; ISEL, Pharmaceutical Technology and Development, Operations, AstraZeneca, Macclesfield, UK., Jones MF; Chemical Development, Pharmaceutical Technology and Development, Operations, AstraZeneca, Macclesfield, UK., Barthelme A; UCB Pharma SA, All. de la Recherche 60, 1070, Anderlecht, Belgium., Pavey J; UCB Pharma SA, All. de la Recherche 60, 1070, Anderlecht, Belgium., Kapur N; Institute of Process Research and Development, School of Mechanical Engineering, University of Leeds, Leeds, LS2 9JT, UK., Chamberlain TW; Institute of Process Research and Development, Schools of Chemistry & Chemical and Process Engineering, University of Leeds, Leeds, LS2 9JT, UK., Blacker AJ; Institute of Process Research and Development, Schools of Chemistry & Chemical and Process Engineering, University of Leeds, Leeds, LS2 9JT, UK., Bourne RA; Institute of Process Research and Development, Schools of Chemistry & Chemical and Process Engineering, University of Leeds, Leeds, LS2 9JT, UK.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2023 Jan 16; Vol. 62 (3), pp. e202214511. Date of Electronic Publication: 2022 Dec 13.
DOI: 10.1002/anie.202214511
Abstrakt: The optimization of multistep chemical syntheses is critical for the rapid development of new pharmaceuticals. However, concatenating individually optimized reactions can lead to inefficient multistep syntheses, owing to chemical interdependencies between the steps. Herein, we develop an automated continuous flow platform for the simultaneous optimization of telescoped reactions. Our approach is applied to a Heck cyclization-deprotection reaction sequence, used in the synthesis of a precursor for 1-methyltetrahydroisoquinoline C5 functionalization. A simple method for multipoint sampling with a single online HPLC instrument was designed, enabling accurate quantification of each reaction, and an in-depth understanding of the reaction pathways. Notably, integration of Bayesian optimization techniques identified an 81 % overall yield in just 14 h, and revealed a favorable competing pathway for formation of the desired product.
(© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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