Holmes, N orcid.org/0000-0002-3846-6493, Akien, GR, Blacker, AJ orcid.org/0000-0003-4898-2712 et al. (3 more authors) (2016) Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor. Reaction Chemistry & Engineering, 1 (4). pp. 366-371. ISSN 2058-9883
Abstract
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.
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Copyright, Publisher and Additional Information: | © 2016, The Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. | ||||||
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Institution: | The University of Leeds | ||||||
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemical & Process Engineering (Leeds) > Institute for Particle Science and Engineering (Leeds) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
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Depositing User: | Symplectic Publications | ||||||
Date Deposited: | 25 May 2016 09:08 | ||||||
Last Modified: | 23 Jun 2023 22:06 | ||||||
Published Version: | http://dx.doi.org/10.1039/C6RE00059B | ||||||
Status: | Published | ||||||
Publisher: | Royal Society of Chemistry | ||||||
Identification Number: | https://doi.org/10.1039/C6RE00059B |