Rebecca E. Meadows

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.

Role of the Base in Buchwald–Hartwig Amination

The Buchwald-Hartwig amination has been investigated theoretically and experimentally to examine the scope of possible bases under different reaction conditions. Nonpolar solvents resist the formation of new charges. Therefore, the base should be anionic to be able to deprotonate the neutral palladium-amine complex and/or expel the anionic leaving group (bromide). The calculated barrier for the organic base DBU was found to be prohibitively high. In polar solvent, dissociation of bromide becomes possible, but here the base will instead form a complex with palladium, creating an overly stable resting state. The conclusions for both solvent classes hold for both a hindered monodentate phosphine and the labile bidentate ligand BINAP. The computational studies were supported by experimental testing of a range of bases using BINAP in two different solvents, toluene and DMF.

A microfluidic approach for flexible and efficient operation of a cross-coupling reactive flow

In this work, a flexible and efficient flow microreactor has been developed for the synthesis of an aromatic amine via a Buchwald–Hartwig reaction, a key bond-forming reaction in the synthesis of a wide range of naturally-occurring and pharmaceutically active targets. The microreactor, coupled with a highly active palladium N-heterocyclic carbene (NHC) catalyst, enabled the full conversion of the reagents within twenty minutes, even at very low catalyst concentrations. In addition to the classical two-feed design, a novel, more flexible four-feed flow system was developed with a configuration optimised to avoid clogging, which is one of the main problems in microreactors and in continuous flow reactive systems in general. We report the effect of flow rate, temperature and catalyst loading on conversion degree. In particular, a slight increase in temperature allowed faster conversion even at low catalyst loadings, likely due to the highly efficient heat transfer provided by the confined microreactor geometry.

Towards environmentally friendlier Suzuki–Miyaura reactions with precursors of Pd-NHC (NHC = N-heterocyclic carbene) complexes

The preparation of [NHC·H][Pd(η3-R-allyl)Cl2] complexes is disclosed and represents a facile, atom-economical, environmentally friendly and rapid synthesis. These palladates are immediate synthetic precursors to the well-known [Pd(NHC)(η3-R-allyl)Cl] complexes. Their activation leading to catalytically relevant species has been studied in the Suzuki–Miyaura reaction. The need for an activation step prior to the catalysis was examined. The reaction scope showcases its ease and breadth in terms of functional group tolerance. Electron-donating and electron-withdrawing aryl chlorides and bromides were coupled effectively as well as heteroatom-containing and sterically hindered aryl halides. The catalytic reaction was conducted in ethanol with a weak and inexpensive inorganic base.

A General Liquid–Liquid Partitioning Equation and Its Consequences: Learning from the pH Dependent Extraction of a Pharmaceutical Intermediate

We observed that the product of a Buchwald-Hartwig coupling reaction extracted from the organic phase easily, relative to the starting aryl bromide as the pH was lowered. This was surprising given the similarity of their p Kas. The products extraction curve was also significantly steeper than expected. A consideration of the relevant equilibria, including all three of the products p Kas, led to a general model for the liquid-liquid extraction behavior of ionizable molecules. This model predicts the observed, useful extraction behavior.