Development of a Scalable Route to the SMO Receptor Antagonist SEN794

A practical and scalable route to the SMO receptor antagonist SEN794 1 is described herein. A new and efficient access to the key intermediate 7 via the Krohnke reaction was developed, significantly simplifying the synthesis and reducing costs. The optimized route consists of six chemical steps plus a palladium scavenging step. The intermediates are solids and were isolated by filtrations, except for ester 9, which was telescoped as the crude oil into the subsequent step. In the final amide formation step, target compound 1 was conveniently crystallized from the reaction mixture in high purity.