Development of Scalable Manufacturing Routes to AZD1981. Application of the Semmler–Wolff Aromatisation for Synthesis of the Indole-4-amide Core

Abstract

A safe and efficient synthesis of AZD1981 is described in which the indole 4-amide core is formed by a Semmler–Wolff aromatisation of a cyclohexenone oxime fused to a pyrrole ring. The substrate was obtained via Paal–Knorr pyrrole synthesis, followed by incorporation of the key 3-arylthio substituent by reaction with 4-chlorophenylsulfenyl chloride. In this manner, the 1,2,3,4-substitution pattern of the AZD1981 core was regiospecifically established in a concise and efficient telescoped sequence. Accordingly, AZD1981 was obtained in 40% overall yield in six chemical steps, with two isolated crystalline intermediates.