Process Development, Manufacture, and Understanding of the Atropisomerism and Polymorphism of Verinurad

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 desi...

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Bibliographic Details
Published in:Organic process research & development 2022-03, Vol.26 (3), p.936-948
Main Authors: Ring, Oliver T, Hayter, Barry R, Ronson, Thomas O, Agnew, Lauren R, Ashworth, Ian W, Cherryman, Janette, Gall, Malcolm A. Y, Hamilton, Peter R, Inglesby, Phillip A, Jones, Martin F, Lamacraft, Alex L, Leahy, Adam J, McKinney, David, Miller-Potucka, Lucie, Powell, Lyn, Putra, Okky D, Robbins, Andrew J, Tomasi, Simone, Wordsworth, Rosemary A
Format: Article
Language:English
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Summary: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.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.1c00284