We developed a scalable Suzuki process for the synthesis of lanabecestat (+)-camsylate, an active pharmaceutical ingredient that was recently investigated in a Phase III clinical program for the treatment of early Alzheimer's disease. The evolution of this process culminated with the use of a stable and crystalline diethanolamine boronic ester that rapidly hydrolyses under the reaction conditions. Herein, we report that the liberated diethanolamine plays an important role in the catalytic process, with supporting evidence for an equilibrium between an unbound and bound palladium complex. Additionally, the diethanolamine acts as an internal scavenger during the crystallization of lanabecestat by increasing the solubility of the palladium species, obviating the need for a discrete scavenging step.

The problems of extracting products efficiently from reaction workups are often overlooked. Issues such as emulsions and rag layer formation can cause long separation times and slow production, thus resulting in manufacturing inefficiencies. To better understand science within this area and to support process development, an image processing methodology has been developed that can automatically track the interface between liquid–liquid phases and provide a quantitative measure of the separation rate of two immiscible liquids. The algorithm is automated and has been successfully applied to 29 cases. Its robustness has been demonstrated with a variety of different liquid mixtures that exhibit a wide range of separation behaviormaking such an algorithm suited to high-throughput experimentation. The information gathered from applying the algorithm shows how issues resulting from poor separations can be detected early in process development.

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Rationale Low‐molecular‐weight amines are encountered in pharmaceutical analysis, e.g. as reactants in chemical syntheses, but are challenging to analyse using ultrahigh‐performance liquid chromatography/mass spectrometry (UHPLC/MS) due to their high polarity causing poor retention. Ion chromatography/mass spectrometry (IC/MS) is an emerging technique for polar molecule analysis that offers better separation. A generic IC/MS method would overcome problems associated with using UHPLC/MS in drug discovery and development environments. Methods Amine standards were analysed using IC/MS with gradient elution (variety of column temperatures evaluated). An electrospray ionisation (ESI) quadrupole mass spectrometer was operated in positive ion polarity in scanning mode. The make‐up flow composition was evaluated by assessing the performance of a range of organic modifiers (acetonitrile, ethanol, methanol) and additives (acetic acid, formic acid, methanesulfonic acid). The ESI conditions were optimised to minimise adduct formation and promote generation of protonated molecules. Results The performance attributes were investigated and optimised for low‐molecular‐weight amine analysis. Organic solvents and acidic additives were evaluated as make‐up flow components to promote ESI, with 0.05% acetic acid in ethanol optimal for producing protonated molecules. The hydrogen bonding capability of amines led to abundant protonated molecule–solvent complexes; optimisation of source conditions reduced these, with collision‐induced dissociation voltage having a strong effect. The detection limit was ≤1.78 ng for the amines analysed, which is fit‐for‐purpose for an open‐access chemistry environment. Conclusions This study demonstrates the value of IC/MS for analysing low‐molecular‐weight amines. Good chromatographic separation of mixtures was possible without derivatisation. Ionisation efficiency was greatest using a make‐up flow of 0.05% acetic acid in ethanol, and optimisation of ESI source conditions promoted protonated molecule generation for easy determination of molecular weight.

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