Robert L. Woodward

Online quantitative mass spectrometry for the rapid adaptive optimisation of automated flow reactors

An automated continuous reactor for the synthesis of organic compounds, which uses online mass spectrometry (MS) for reaction monitoring and product quantification, is presented. Quantitative and rapid MS monitoring was developed and calibrated using HPLC. The amidation of methyl nicotinate with aqueous MeNH2 was optimised using design of experiments and a self-optimisation algorithm approach to produce >93% yield.

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

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.

Catalytic Enantioselective Desymmetrisation as a Tool for the Synthesis of Hodgkinsine and Hodgkinsine B

Two palladium-catalysed amination protocols are deployed in the desymmetrisation of the complex dimeric alkaloid meso-chimonanthine. The power of these transformations is showcased in an efficient formal and total synthesis of the natural products hodgkinsine and hodgkinsine B, respectively.