The preparation of two, preclinical amino-quinazolinediones as antibacterial agents
The preparation of two, preclinical amino-quinazolinediones as antibacterial agents
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DOI：
10.1021/op7000639
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发表时间：
2007-05-01
影响因子：
3.4
通讯作者：
Vrieze, Derek
中科院分区：
文献类型：
--
作者：
Beylin, Vladimir;Boyles, David C.;Vrieze, Derek
本文报道了两种有效的旋转酶/拓扑异构酶抑制剂和抗菌剂氨基喹唑二酮的合成。详细介绍了制备多克尺度的手性侧链和两个不同的氨基喹唑二酮核的早期放大工作。侧链的使能合成采用了先前报道的MeNO2与富含对映体的三角洲-氨基-烯酸酯的Michael加成和内酰胺的两步脱氧。制备和完成氨基喹唑二酮的关键合成步骤包括分子内双阴离子促进环化、亲核芳香族取代、亲电胺化、侧链亲核芳香取代核、去保护和以可接受的产率分离盐酸盐。
This paper describes the synthesis of two amino-quinazolinediones which are potent gyrase/topoisomerase inhibitors and useful as antibacterial agents. The early scale-up work to prepare a chiral side chain on multigram scale and two different amino-quinazolinedione cores is detailed. The enabling synthesis for the side chain employed a previously reported Michael addition of MeNO2 to an enantiomerically enriched delta-amino-enoate and a two-step de-oxygenation of a lactam. Key synthetic steps for core preparation and completion of the amino-quinazolinediones include dianion-promoted cyclization via intramolecular, nucleophilic aromatic substitution, electrophilic amination, nucleophilic aromatic substitution of the side chain to the core, deprotection and isolation of the hydrochloride salt in acceptable yield.