Lustenberger, Philipp, Mathes, Christian, Riss, Bernard, Hueber, Lukas, Dedic, Darija, den Reijer, Carolien, Koenigsberger, Kurt, Napp, Matthias, Schlama, Thierry, Rueegger, Ulrich and Fei, Zhongbo (2021) Using a Johnson-Claisen Rearrangement Strategy to Construct Azaindoles – A Streamlined and Concise Route for the Commercial Process of Fevipiprant. European Journal of Organic Chemistry, 2021 (31). pp. 4490-4494. ISSN 1434-193X1099-0690

Abstract

Abstract: 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.

Item Type:	Article
Keywords:	Fevipiprant / QAW039 • allene • hydroamination • 7-aza-indole • commercial process
Date Deposited:	03 Sep 2021 00:45
Last Modified:	03 Sep 2021 00:45
URI:	https://oak.novartis.com/id/eprint/44954