Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

React. Chem. Eng., 2016, Advance Article
DOI: 10.1039/C6RE00059B, Paper

Open Access

  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.

Nicholas Holmes, Geoffrey R. Akien, A. John Blacker, Robert L. Woodward, Rebecca E. Meadows, Richard A. Bourne
Self-optimising flow reactors combine online analysis with evolutionary feedback algorithms to rapidly achieve optimum conditions.

Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

Self-optimising flow reactors combine online analysis with evolutionary feedback algorithms to rapidly achieve optimum conditions. This technique has been applied to the final bond-forming step in the synthesis of AZD9291, an irreversible epidermal growth factor receptor kinase inhibitor developed by AstraZeneca. A four parameter optimisation of a telescoped amide coupling followed by an elimination reaction was achieved using at-line high performance liquid chromatography. Optimisations were initially carried out on a model compound (2,4-dimethoxyaniline) and the data used to track the formation of various impurities and ultimately propose a mechanism for their formation. Our protocol could then be applied to the optimisation of the 2-step telescoped reaction to synthesise AZD9291 in 89% yield.

Paper

Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

Nicholas Holmes,^a   Geoffrey R. Akien,^ab   A. John Blacker,^ac  Robert L. Woodward,^d   Rebecca E. Meadows^d and  Richard A. Bourne*^acd  

*Corresponding authors

^aInstitute of Process Research and Development, School of Chemistry, University of Leeds, Leeds, UK
E-mail: r.a.bourne@leeds.ac.uk

^bDepartment of Chemistry, Faraday Building, Lancaster University, Lancaster, UK

^cSchool of Chemical and Process Engineering, University of Leeds, Leeds, UK

^dAstraZeneca Pharmaceutical Development, Silk Road Business Park, Macclesfield, UK

React. Chem. Eng., 2016, Advance Article

DOI: 10.1039/C6RE00059B

http://pubs.rsc.org/en/Content/ArticleLanding/2016/RE/C6RE00059B#!divAbstract

Scheme 1 Synthesis of the model acrylamide 6 via the β-chloroamide 5 intermediate.

Scheme 2 Proposed mechanisms to dimers 8a and 8b. The observation of a peak corresponding to 7suggested a Rauhut–Currier mechanism to 8b but subsequent LC-MS-MS analysis showed the major dimer to most likely be 8a. All observed peaks from offline LC-MS are displayed.

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