Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor
Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor
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DOI：
10.1039/c6re00059b
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发表时间：
2016-01-01
影响因子：
3.9
通讯作者：
Bourne, Richard A.
中科院分区：
文献类型：
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作者：
Holmes, Nicholas;Akien, Geoffrey R.;Bourne, Richard A.
自优化流动反应器将联合收割机在线分析与进化反馈算法相结合，以快速达到最佳条件。该技术已应用于AZD 9291合成的最后成键步骤，AZD 9291是阿斯利康开发的不可逆表皮生长因子受体激酶抑制剂。采用在线高效液相色谱法实现了一个四参数优化的伸缩酰胺偶联，然后消除反应。最初对模型化合物（2，4-二甲氧基苯胺）进行了优化，并将数据用于跟踪各种杂质的形成，并最终提出其形成机制。然后，我们的方案可以应用于优化2步套叠反应，以89%的产率合成AZD 9291。
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.