Stereoretentive Etherification of an α‑Aryl-β-amino Alcohol Using a Selective Aziridinium Ring Opening for the Synthesis of AZD7594

A selective aziridinium ring-opening was used to etherify an α-aryl-β-amino alcohol with stereochemical retention. This transformation was achieved in a biphasic system to address phenoxide solubility and the formation of a sulfonate ester impurity. The protecting group strategy was directed by a st...

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Bibliographic Details
Published in:Journal of organic chemistry 2019-04, Vol.84 (8), p.4629-4638
Main Authors: McMillan, Angus E, Steven, Alan, Ashworth, Ian W, Mullen, Alexander K, Chan, Lai C, Galan Espinosa, Maria Rita, Pilling, Michael J, Raw, Steven A, Jones, Martin F
Format: Article
Language:English
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Summary:A selective aziridinium ring-opening was used to etherify an α-aryl-β-amino alcohol with stereochemical retention. This transformation was achieved in a biphasic system to address phenoxide solubility and the formation of a sulfonate ester impurity. The protecting group strategy was directed by a stability study of the activated α-aryl-β-amino alcohol in this system. Process analytical techniques were used to establish reaction understanding, and mixing on large scale was modeled in silico. The process provided a selective and efficient method of preparing the nonsteroidal, inhaled selective glucocorticoid receptor modulator AZD7594.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.8b01062