Institute of Process Research and Development, Schools of Chemistry & Chemical and Process Engineering, University of Leeds, Leeds, LS2 9JT, UK.
IBM Research UK, Daresbury Laboratory, Daresbury, WA4 4AD, UK.
Angew Chem Int Ed Engl. 2023 Jan 16;62(3):e202214511. doi: 10.1002/anie.202214511. Epub 2022 Dec 13.
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.
多步化学合成的优化对于新药物的快速发展至关重要。然而，由于步骤之间存在化学相关性，将单独优化的反应串联起来可能导致多步合成效率低下。在此，我们开发了一种自动化连续流动平台，用于同时优化缩合反应。我们的方法应用于 Heck 环化-脱保护反应序列，用于合成 1-甲基四氢异喹啉 C5 官能化的前体。设计了一种使用单个在线 HPLC 仪器进行多点采样的简单方法，能够准确量化每个反应，并深入了解反应途径。值得注意的是，贝叶斯优化技术的集成仅用 14 小时就确定了 81%的总收率，并揭示了形成所需产物的有利竞争途径。
