Department of Chemistry, National University of Singapore, Singapore, Republic of Singapore.
Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore, Republic of Singapore.
Nat Chem. 2021 May;13(5):451-457. doi: 10.1038/s41557-021-00662-w. Epub 2021 Apr 19.
Recent advances in end-to-end continuous-flow synthesis are rapidly expanding the capabilities of automated customized syntheses of small-molecule pharmacophores, resulting in considerable industrial and societal impacts; however, many hurdles persist that limit the number of sequential steps that can be achieved in such systems, including solvent and reagent incompatibility between individual steps, cumulated by-product formation, risk of clogging and mismatch of timescales between steps in a processing chain. To address these limitations, herein we report a strategy that merges solid-phase synthesis and continuous-flow operation, enabling push-button automated multistep syntheses of active pharmaceutical ingredients. We demonstrate our platform with a six-step synthesis of prexasertib in 65% isolated yield after 32 h of continuous execution. As there are no interactions between individual synthetic steps in the sequence, the established chemical recipe file was directly adopted or slightly modified for the synthesis of twenty-three prexasertib derivatives, enabling both automated early and late-stage diversification.
近年来，端到端连续流合成的进展迅速扩展了小分子药效团自动化定制合成的能力，对工业和社会产生了重大影响；然而，仍有许多障碍限制了此类系统中可以实现的连续步骤的数量，包括各个步骤之间的溶剂和试剂不相容性、累积的副产物形成、堵塞风险以及处理链中各步骤之间的时间尺度不匹配。为了解决这些限制，我们在此报告了一种将固相合成和连续流操作相结合的策略，从而实现了活性药物成分的一键式自动化多步合成。我们通过在 32 小时的连续运行后以 65%的分离收率对 prexasertib 进行六步合成来展示我们的平台。由于在该序列中各个合成步骤之间没有相互作用，因此直接采用或对建立的化学配方文件进行了轻微修改，用于合成二十三个 prexasertib 衍生物，从而实现了早期和晚期的自动化多样化。
