New route development activities toward ceralasertib (AZD6738) have resulted in the discovery of an efficient, acid additive-free, photoredox Minisci reaction. Mechanistic understanding resulting from LED-NMR reaction profiling, quantum yield measurements, and Stern−Volmer quenching studies have enabled optimization of the catalyst system, resulting in a significant enhancement in the rate of reaction. A large-scale continuous photoflow process has been developed, providing encouraging proofof-concept data for the future application of this technology in the clinical manufacture of ceralasertib.

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 kinetics of the esterification of maleic acid in methanol have been investigated following the contamination of a batch of an API maleate salt with the corresponding monomethyl maleate salt. The esterification was found to be catalyzed by H + generated by the ionization of maleic acid, giving rise to an observed rate law with a one-and-a-half-order dependence upon the maleic acid concentration. On the basis of the measured rate constants over a range of temperatures a predictive model has been developed that will estimate the time taken to achieve a given degree of esterification as a function of temperature and maleic acid concentration. Rate constants have also been determined for the maleic acid-catalyzed esterification of monomethyl maleate. Neutralization of maleic acid through salt formation with triethylamine reduces the rate of esterification in a manner that is consistent with the degree of neutralization. The potential for the esterification of maleic acid in other alcohols and for the esterification of other carboxylic acids in alcohols is discussed in the light of these findings.

The manufacturing route toward verinurad, an amphoteric, class II atropisomer that readily forms solvates, has proven to be highly complex. This previously required the isolation of intermediates with challenging physical properties and the application of cryogenic processes. New processes were designed and optimized, enabling the manufacture of 113 kg of verinurad in its desired polymorphic form. An interdisciplinary approach involving the synthesis, high-throughput experimentation, analytical chemistry, crystallization science, in silico modeling, and engineering was employed. Kinetic measurement of enantiomerically enriched verinurad salts confirmed that racemization occurred within the clearance time frame, thus mitigating safety concerns associated with inherent axial chirality in verinurad.

Solid-phase synthesis of oligonucleotides relies on a repeating cycle of rapid and well-defined synthetic steps to generate the target sequence. It is recognized that the underlying skeleton of the nucleotide influences the rates of the coupling reactions when the phosphoramidite coupling method is used. Using both in-line mid-IR spectroscopy and rapid NMR spectroscopy, we studied the rates of activation of traditional deoxyribonucleoside phosphoramidites and their chemically modified constrained ethyl (cEt) ribose locked nucleic acid analogues. This article reports our findings, which demonstrate a striking difference in the kinetics of activation for the two nucleotide structures. It was found that the cEt phosphoramidites required a larger excess of activator to achieve complete activation compared with their deoxyribonucleoside analogues. However, even with double the relative activator charge, the observed rate was over 10 times lower.