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Automated synthesis of prexasertib and derivatives enabled by continuous-flow solid-phase synthesis

Nature Chemistry volume 13, pages 451–457 (2021)Cite this article

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Abstract

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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Fig. 1: Derivatization for molecule optimization.
Fig. 2: Schematic of the development of automated SPS-flow synthesis of APIs and derivatives.
Fig. 3: Development of automated SPS-flow synthesis of prexasertib.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information. A video of the SPS-flow automated synthesis of prexasertib is recorded as Supplementary Video 1.

Code availability

The LabVIEW code for operating the SPS-flow automated synthesis in this study is available at https://github.com/nus-automated-flow-system/auto-SPS-Flow-Supplementary-Software.

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Acknowledgements

This work was supported by the Agency for Science, Technology and Research (A*STAR) of Singapore RIE2020 AME IRG (grant no. A1783c0013). We thank J. T. Njardarson for allowing us to reproduce and modify the poster ‘Top 200 small molecule pharmaceuticals by retail sales in 2018’ (see Supplementary Table 11).

Author information

Authors and Affiliations

  1. Department of Chemistry, National University of Singapore, Singapore, Republic of Singapore

    Chenguang Liu, Wenbin Wu, Mu Wang, Weihao Chen & Jie Wu

  2. Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore, Republic of Singapore

    Jiaxun Xie, Jiawei Rong & Saif A. Khan

  3. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Republic of Singapore

    Shabana Binte Idres & Lih-Wen Deng

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  1. Chenguang Liu
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Contributions

J.W. conceived and designed the experiments. C.L., W.W., M.W. and W.C. performed the experiments. J.W., S.A.K., C.L. and M.W. analysed the experimental data. C.L. and J.R. built the SPS-flow reactor system. J.X. performed the programming for automated control. B.I.S. and L.-W.D. performed the preliminary biological screening. J.W. and S.A.K. wrote the manuscript with input from all authors. All of the authors have approved the final version of the manuscript.

Corresponding authors

Correspondence to Saif A. Khan or Jie Wu.

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Competing interests

J.W., S.A.K., C.L., W.W., W.C., M.W. and J.X. are inventors on International Patent Application PCT/SG2020/050603 filed by the National University of Singapore, which covers the synthesis of non-peptide small-molecules using the strategy of automated SPS-flow synthesis. The authors declare no other competing interests.

Additional information

Peer review information Nature Chemistry thanks Kevin Cole, Christopher Gordon and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Information

Supplementary Figs. 1–64, Tables 1–11, synthetic procedural details, automation development and implementation, high-resolution mass spectrometry, infrared data, NMR data and spectra, HPLC spectra.

Reporting Summary

Supplementary Video 1

Recording of the automated synthesis of prexasertib using the SPS-flow system.

Supplementary Data 1

Raw data for the bioactivity evaluation shown in Supplementary Fig. 23.

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Liu, C., Xie, J., Wu, W. et al. Automated synthesis of prexasertib and derivatives enabled by continuous-flow solid-phase synthesis. Nat. Chem. 13, 451–457 (2021). https://doi.org/10.1038/s41557-021-00662-w

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