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Using a Johnson‐Claisen Rearrangement Strategy to Construct Azaindoles – A Streamlined and Concise Route for the Commercial Process of Fevipiprant
Author(s) -
Mathes Christian,
Riss Bernard,
Rüegger Ueli,
Hueber Lukas,
Dedic Darija,
Fei Zhongbo,
Reijer Carolien,
Königsberger Kurt,
Napp Matthias,
Schlama Thierry,
Dempsey Glen,
Lustenberger Philipp
Publication year - 2021
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.202100686
Subject(s) - chemistry , claisen rearrangement , indole test , combinatorial chemistry , alkylation , reductive amination , yield (engineering) , organic chemistry , stereochemistry , catalysis , materials science , metallurgy
A novel and concise synthesis of the DP2 receptor antagonist Fevipiprant (NVP‐QAW039) was developed. The initial research route was suffering from a long reaction sequence to the functionalized 7‐aza‐indole core followed by a poorly selective N (1)‐alkylation with the benzyl side chain. These limitations were overcome by introducing the side chain early by reductive amination between the functionalized aldehyde and 2‐amino‐3‐bromopyridine. The 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. The reaction of the advanced propargylic alcohol derivative with trimethyl orthoacetate led to a reactive allene intermediate which spontaneously and selectively cyclizes to the 7‐aza‐indole QAW039‐methyl ester. QAW039 was isolated after ester saponification. Selectivity, yield, and ecological footprint of the new synthesis were significantly improved, and scalability was demonstrated.