Development of Scalable Manufacturing Routes to AZD1981. Application of the Semmler鈥揥olff Aromatisation for Synthesis of the Indole-4-amide Core
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- 作者：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
- 刊名：Organic Process Research & Development
- 出版年：2012
- 出版时间：November 16, 2012
- 年：2012
- 卷：16
- 期：11
- 页码：1746-1753
- 全文大小：294K
- 年卷期：v.16,no.11(November 16, 2012)
- ISSN：1520-586X
文摘
A safe and efficient synthesis of AZD1981 is described in which the indole 4-amide core is formed by a Semmler鈥揥olff aromatisation of a cyclohexenone oxime fused to a pyrrole ring. The substrate was obtained via Paal鈥揔norr 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.