Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor
| Autor: | Nicholas Holmes, Rebecca E. Meadows, Robert L. Woodward, Richard A. Bourne, A. John Blacker, Geoffrey R. Akien |
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| Rok vydání: | 2016 |
| Předmět: |
Fluid Flow and Transfer Processes
Materials science 010405 organic chemistry Process Chemistry and Technology Continuous reactor Flow (psychology) 010402 general chemistry 01 natural sciences High-performance liquid chromatography Combinatorial chemistry Catalysis 0104 chemical sciences Online analysis Elimination reaction Epidermal Growth Factor Receptor Kinase Chemistry (miscellaneous) Yield (chemistry) Chemical Engineering (miscellaneous) Simulation |
| Zdroj: | Reaction Chemistry & Engineering. 1:366-371 |
| ISSN: | 2058-9883 |
| DOI: | 10.1039/c6re00059b |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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