期刊
REACTION CHEMISTRY & ENGINEERING
卷 1, 期 4, 页码 366-371出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c6re00059b
关键词
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资金
- EPSRC
- AstraZeneca
- University of Leeds for a DTG CASE
- Royal Academy of Engineering
- EPSRC [EP/K039202/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/K039202/1, 1232745] Funding Source: researchfish
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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