Efficient Syntheses of AZD4407 via Thioether Formation by Nucleophilic Attack of Organometallic Species on Sulphur

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• 作者：Marie-Lyne Alcaraz ; Sté ; phanie Atkinson ; Philip Cornwall ; Alison C. Foster ; Duncan M. Gill ; Lesley A. Humphries ; Philip S. Keegan ; Richard Kemp ; Eric Merifield ; Robert A. Nixon ; Allison J. Noble
• 刊名：Organic Process Research & Development
• 出版年：2005
• 出版时间：September 2005
• 年：2005
• 卷：9
• 期：5
• 页码：555 - 569
• 全文大小：198K
• 年卷期：v.9,no.5(September 2005)
• ISSN：1520-586X

文摘

The development of two efficient strategies for the synthesis ofAZD4407 is reported, both of which are considered suitablefor large-scale manufacture. In the first approach, 3-bromothiophene is coupled with (2S)-2-methyltetrahydropyran-4-one using Grignard chemistry. Following hydroxyl protectionand lithiation at thiophene C-2, reaction with a protected5-mercapto-1-methyl-1,3-dihydro-indol-2-one derivative bearinga leaving group on sulphur provides AZD4407 after acid-catalysed deprotection and epimerisation. The second approachstarts from 2,4-dibromothiophene, which undergoes a selectiveGrignard exchange reaction at C-2 followed by reaction withsimilar protected mercapto-oxindole derivatives. Reprotectionof the oxindole ring, followed by a second Grignard exchange,and reaction with (2S)-2-methyltetrahydropyran-4-one providesAZD4407 after acid-catalysed deprotection and epimerisation.