Using a Johnson‐Claisen Rearrangement Strategy to Construct Azaindoles – A Streamlined and Concise Route for the Commercial Process of Fevipiprant

Autor: Fei Zhongbo, Darija Dedic, Philipp Lustenberger, Ueli Rüegger, Christian Mathes, Matthias Napp, Kurt Königsberger, Bernard Riss, Thierry Schlama, Glen Dempsey, Carolien den Reijer, Lukas Hueber
Rok vydání: 2021
Předmět:
Zdroj: European Journal of Organic Chemistry. 2021:4490-4494
ISSN: 1099-0690
1434-193X
DOI: 10.1002/ejoc.202100686
Popis: A novel and concise synthesis towards DP2 receptor antagonist Fevipiprant (NVS-QAW039) was developed. The initial research route was suffering from lengthy access to the functionalized 7-aza-indole core followed by a low selective N(1)-alkylation with the benzyl side chain. These limitations were overcome by introducing the side chain early via reductive amination between the functionalized aldehyde and 2-amino-3-bromopyridine. Sonogashira coupling with prop-2-yn-1-ol introduces the 3 missing carbon atoms to build the 7-aza-indole core and sets the stage for the innovative Johnson-Claisen key step. Reaction of the advanced propargylic alcohol derivative with trimethyl orthoacetate leads to a reactive allene intermediate that spontaneously and selectively cyclizes to the 7-aza-indole QAW039-methly ester. QAW039 is isolated after ester saponification. Selectivity, yield, and ecological footprint of the new synthesis were significantly improved, and scalability was demonstrated.
Databáze: OpenAIRE
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