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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.

3-Aminoimidazo[1,2-a]pyrazine is an important scaffold that is found in many drugs. This scaffold is rapidly accessible through a Groebke–Blackburn–Bienayme cyclisation starting from an aminopyrazine, an aldehyde and an isocyanide. A scale-up process of this multicomponent reaction has been achieved in high yield and with excellent purity. The scope and limitations of this process leading to various 3-aminoimidazo[1,2-a]pyrazines are disclosed.

The preparation of various 2-(7-azaindolyl)carboxylic esters by Pd-catalyzed coupling of Reformatsky reagents with TBDMS-protected 3-bromo-7-azaindoles leading to a wide range of arylated ester derivatives is reported. After removal of the protecting group, the corresponding free 2-(7-azaindolyl)carboxylic esters are obtained in satisfactory yields.