Development of scalable manufacturing routes to AZD1981. Application of the Semmler-Wolff aromatisation for synthesis of the indole-4-amide Core

Manjunatha Sulur, Parhalad Sharma, Ravi Ramakrishnan, Ravi Naidu, Eric Merifield, Duncan M. Gill, Adrian M. Clarke, Colin Thomson, Michael Butters, Sreekanth Bachu, Colin H. Benison, Nagaraju Dokka, Emily R. Fong, David R.J. Hose, Gareth P. Howell, Siobhan E. Mobberley, Simon C. Morton, Alexander K. Mullen, Jayan Rapai, Bharathi Tejas

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12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1746-1753
Number of pages8
JournalOrganic Process Research and Development
Volume16
Issue number11
Early online date18 Oct 2012
DOIs
Publication statusPublished - 16 Nov 2012
Externally publishedYes

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