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An Enantioselective Hydrogenation of an Alkenoic Acid as a Key Step in the Synthesis of AZD2716
AstraZeneca, Sweden.
AstraZeneca, Sweden.
AstraZeneca, Sweden.
AstraZeneca, Sweden.
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2016 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 20, no 2, p. 262-269Article in journal (Refereed) Published
Abstract [en]

A classical resolution of a racemic carboxylic acid through salt formation and an asymmetric hydrogenation of an α,β-unsaturated carboxylic acid were investigated in parallel to prepare an enantiomerically pure alkanoic acid used as a key intermediate in the synthesis of an antiplaque candidate drug. After an extensive screening of rhodium- and ruthenium-based catalysts, we developed a rhodium-catalyzed hydrogenation that gave the alkanoic acid with 90% ee, and after a subsequent crystallization with (R)-1-phenylethanamine, the ee was enriched to 97%. The chiral acid was then used in sequential Negishi and Suzuki couplings followed by basic hydrolysis of a nitrile to an amide to give the active pharmaceutical ingredient in 22% overall yield.

Place, publisher, year, edition, pages
2016. Vol. 20, no 2, p. 262-269
Keywords [en]
Carboxylic acids, Rhodium, Active pharmaceutical ingredients, Asymmetric hydrogenation, Basic hydrolysis, Enantioselective hydrogenation, Rhodium-catalyzed, Ruthenium based catalysts, Suzuki couplings, Unsaturated carboxylic acids, Hydrogenation
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:ri:diva-27657DOI: 10.1021/acs.oprd.5b00382Scopus ID: 2-s2.0-84975686952OAI: oai:DiVA.org:ri-27657DiVA, id: diva2:1059475
Available from: 2016-12-22 Created: 2016-12-21 Last updated: 2020-12-01Bibliographically approved

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