期刊
NATURE CHEMISTRY
卷 13, 期 5, 页码 451-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41557-021-00662-w
关键词
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资金
- Agency for Science, Technology and Research (A*STAR) of Singapore RIE2020 AME IRG [A1783c0013]
Recent advances in end-to-end continuous-flow synthesis show promising potential for automated small-molecule drug synthesis, but face limitations. A strategy combining solid-phase synthesis and continuous flow operation enables push-button automated multistep synthesis, allowing for both early and late-stage diversification in chemical synthesis.
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.
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