No abstract

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-3bromopyridine. 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.