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

Chemistry

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https://doi.org/10.1039/C6RE00059B
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Research output: Contribution to Journal/Magazine › Journal article › peer-review

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Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor. / Holmes, Nicholas; Akien, Geoffrey Richard; Blacker, A. John et al.
In: Reaction Chemistry and Engineering, Vol. 1, No. 4, 01.08.2016, p. 366-371.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Holmes, N, Akien, GR, Blacker, AJ, Woodward, RL, Meadows, RE & Bourne, RA 2016, 'Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor', Reaction Chemistry and Engineering, vol. 1, no. 4, pp. 366-371. https://doi.org/10.1039/C6RE00059B

APA

Holmes, N., Akien, G. R., Blacker, A. J., Woodward, R. L., Meadows, R. E., & Bourne, R. A. (2016). Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor. Reaction Chemistry and Engineering, 1(4), 366-371. https://doi.org/10.1039/C6RE00059B

Vancouver

Holmes N, Akien GR, Blacker AJ, Woodward RL, Meadows RE, Bourne RA. Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor. Reaction Chemistry and Engineering. 2016 Aug 1;1(4):366-371. Epub 2016 May 24. doi: 10.1039/C6RE00059B

Author

Holmes, Nicholas ; Akien, Geoffrey Richard ; Blacker, A. John et al. / Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor. In: Reaction Chemistry and Engineering. 2016 ; Vol. 1, No. 4. pp. 366-371.

Bibtex

@article{71417d3c20174aeb8f77abae42439076,

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

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.",

author = "Nicholas Holmes and Akien, {Geoffrey Richard} and Blacker, {A. John} and Woodward, {Robert L.} and Meadows, {Rebecca E.} and Bourne, {Richard A.}",

year = "2016",

month = aug,

day = "1",

doi = "10.1039/C6RE00059B",

language = "English",

volume = "1",

pages = "366--371",

journal = "Reaction Chemistry and Engineering",

issn = "2058-9883",

publisher = "Royal Society of Chemistry",

number = "4",

}

RIS

TY - JOUR

T1 - Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

AU - Holmes, Nicholas

AU - Akien, Geoffrey Richard

AU - Blacker, A. John

AU - Woodward, Robert L.

AU - Meadows, Rebecca E.

AU - Bourne, Richard A.

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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.

AB - 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.

U2 - 10.1039/C6RE00059B

DO - 10.1039/C6RE00059B

M3 - Journal article

VL - 1

SP - 366

EP - 371

JO - Reaction Chemistry and Engineering

JF - Reaction Chemistry and Engineering

SN - 2058-9883

IS - 4

ER -

Research

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