Herein, we disclose the unique physical properties of diethanolamine (DEA) boronic esters that have facilitated the development of a simple and standard process for their synthesis and isolation using environmentally sustainable solvents. Moreover, their preparation is facile, robust, and scalable and can be telescoped from a solution of boronic acid or boronic ester via esterification/transesterification with DEA, therefore providing wide access from a plethora of reaction types. To date, AstraZeneca has successfully manufactured three DEA boronic esters at the kilogram scale (5, 50, and 100 kg batches), with plans to expand this to more examples in 2020.
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.
Analysis of progeny from single‐pair matings by starch gel electrophoresis confirms simple Mendelian inheritance at the polymorphic LDH‐A*, mMEP‐2* and sMEP* loci in European grayling (Thymallus thymallus L.). Of the duplicated LDH‐A loci found in most salmonid species, only one locus is expressed in the European grayling.
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