An Efficient and Cost-Effective Synthesis of Pagoclone

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• 作者：Timothy L. Stuk ; Bryce K. Assink ; Ronald C. Bates ; Jr. ; David T. Erdman ; Victor Fedij ; Sandra M. Jennings ; Jennifer A. Lassig ; Randy J. Smith ; and Traci L. Smith
• 刊名：Organic Process Research & Development
• 出版年：2003
• 出版时间：November 2003
• 年：2003
• 卷：7
• 期：6
• 页码：851 - 855
• 全文大小：85K
• 年卷期：v.7,no.6(November 2003)
• ISSN：1520-586X

文摘

The compound (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3S-(5-methyl-2-oxohexyl)-1-isoindolinone (pagoclone) shows anxiolyticactivity due to partial agonism of the benzodiazepine site ofthe GABA_A receptor. We describe the development of aneconomical and practical process for a 100+ kg pilot plantproduction used to supply development needs. For the keyreaction, a mages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-keto phosphonium salt was prepared by selectivelyreacting a primary mages/gifchars/alpha.gif" BORDER=0>-bromo ketone with triphenylphosphinein the presence of a secondary mages/gifchars/alpha.gif" BORDER=0>-bromo ketone. A novel Wittigreaction with a 1-isoindolinone was used to produce racemicpagoclone. The enantiomerically pure drug substance wasprepared by hydrolyzing a mages/gifchars/gamma.gif" BORDER=0 >-lactam and resolving the resultingenantiomeric carboxylic acids with (+)-ephedrine hemihydrate.An alternate resolution, involving chiral multicolumn chromatography (MCC) was also developed. The synthesis was completed by a racemization-free lactam formation to affordpagoclone.