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A novel scalable process to the GSK3β inhibitor AZD8926 based on a heterocyclic ziegler coupling
AstraZeneca, Sweden; Cambrex Karlskoga, Sweden.
AstraZeneca, Sweden.
AstraZeneca, Sweden.
AstraZeneca, Sweden.
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2013 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 17, no 4, p. 672-678Article in journal (Refereed) Published
Abstract [en]

Development of a new, safe, and scalable route to the GSK3β inhibitor, AZD8926, is presented. In brief, the process constitutes of (i) a synthesis of 1-(pyran-4-yl)-2-trifluoromethyl-imidazole, 14; (ii) a Ziegler-type coupling of lithiated 14 with commercially available 2-chloro-5-fluoropyrimidine via 1,2-addition over the 3,4-C-N bond; (iii) a copper-catalyzed dehydrogenative aromatization using oxygen as the stoichiometric oxidant; and (iv) an aromatic C-N bond formation using either a Buchwald-Hartwig coupling or an acid-catalyzed amination. This process circumvents the main issue in the early-phase route, in which serious process safety constraints were associated with the hazardous properties of the structure, formation, and reduction of 5-methyl-4- nitroisoxazole, 2 (4200 J/g). The new process has been demonstrated on a multigram, 2-L scale. The overall yield was improved from 4 to 14%, and the number of steps decreased from 12 to 10.

Place, publisher, year, edition, pages
2013. Vol. 17, no 4, p. 672-678
Keywords [en]
Buchwald-hartwig couplings, C-n bond formations, Hazardous properties, Process safety, Stoichiometric oxidant
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:ri:diva-6534DOI: 10.1021/op300365eScopus ID: 2-s2.0-84876583385Local ID: 23812OAI: oai:DiVA.org:ri-6534DiVA, id: diva2:964372
Available from: 2016-09-08 Created: 2016-09-08 Last updated: 2023-05-09Bibliographically approved

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Minidis, Alexander

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