Solid-phase synthesis of 1,4-benzodiazepine-2,5-diones. Library preparation and demonstration of synthesis generality
Solid-phase synthesis of 1,4-benzodiazepine-2,5-diones. Library preparation and demonstration of synthesis generality
复制标题
DOI：
10.1021/jo9622845
复制
发表时间：
1997-03-07
影响因子：
3.6
通讯作者：
Ellman, JA
中科院分区：
文献类型：
--
作者：
Boojamra, CG;Burow, KM;Ellman, JA
本文提出了一种从邻氨基苯甲酸、α-氨基酯和烷基化剂三种市售组分固相合成1，4-苯并二氮杂-2，5-二酮的通用方法。已经开发了反应条件以制备用于先导物鉴定工作的外消旋化合物或用于先导物优化工作的光学纯化合物。还证明了在苯并二氮杂产品中掺入不同的官能团。基于合成顺序的范围和一般性，从11种烷基化剂、12种邻氨基苯甲酸和19种α-氨基酯（9组对映体对和甘氨酸甲酯盐酸盐）制备了1，4-苯并二氮杂-2，5-二酮的文库。该库是使用基于微量滴定仪的装置以空间分离的格式制备的，该装置是廉价的并且直接从有机或生物有机实验室中发现的普通物品构建。通过HPLC分析和H-1 NMR评价代表性化合物，证明了1，4-苯并二氮杂卓-2，5-二酮库的高质量。
A general and expedient method has been developed for the solid-phase synthesis of 1,4-benzodiazepine-2,5-diones 1 from three commercially available components; anthranilic acids, alpha-amino esters, and alkylating agents. Reaction conditions have been developed to prepare either racemic compounds for lead identification efforts or optically pure compounds for lead optimization efforts. The incorporation of diverse functionality into the benzodiazepine products has also been demonstrated. On the basis of the scope and generality of the synthesis sequence, a library of 1,4-benzodiazepine-2,5-diones has been prepared from 11 alkylating agents, 12 anthranilic acids, and 19 alpha-amino esters (nine sets of enantiomeric pairs and glycine methyl ester hydrochloride). The library was prepared in a spatially separate format using a microtiter-based apparatus that is inexpensive and straightforward to construct from ordinary items found in an organic or bioorganic laboratory. The high quality of the 1,4-benzodiazepine-2,5-dione library has been demonstrated by evaluating representative compounds by HPLC analysis and H-1 NMR.