建立了一种合成2-(5-氧-4,5-二氢-1,2,4-恶二唑-3-基)苯甲酸的有效方法

V. Tkachuk, T. Lyubchuk, T. Tkachuk, O. Hordiyenko
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引用次数: 0

摘要

2-(5-氧-4,5-二氢-1,2,4-恶二唑-3-基)苯甲酸是通过与1,1′-羰基二咪唑(CDI)的热杂环化反应合成的,得到的中间体3H,5H-[1,2,4]恶二唑[3,4-a]异吲哚-3,5-二酮。在室温和加热条件下,用碳酸二乙酯在乙醇中乙酸钠存在下直接环化3-(羟基亚胺)异吲哚啉-1- 1是不成功的。当在二氯甲烷中有三乙胺存在的情况下使用三光气时,观察到同样的结果。用氯甲酸甲酯处理3-(羟亚胺)异吲哚-1- 1得到3-((甲氧羰基)氧)亚胺异吲哚-1- 1,该异吲哚-1- 1热稳定,在甲苯和邻二甲苯中煮沸24小时不能环化成所需的酸。多余的CDI用3-(羟亚胺)异吲哚-1- 1在无水乙酸乙酯中回流,随后碱性水解得到所需的2-(5-氧-4,5-二氢-1,2,4-恶二唑-3-基)苯甲酸,总收率为90%。在没有碱的情况下进行反应,试图在中间体3H,5H-[1,2,4]恶二唑[3,4-a]异吲哚-3,5-二酮的形成阶段停止该过程,但失败了。在反应过程中,特别是在分离阶段发生部分水解,形成3H,5H-[1,2,4]恶二唑[3,4-a]异吲哚-3,5-二酮和2-(5-氧-4,5-二氢-1,2,4-恶二唑-3-基)苯甲酸的混合物,比例约为2:3。所得物质与甲醇氢氧化钠溶液混合后,用1M盐酸酸化,定量转化为所需的纯酸。所开发的方法允许使用3-(羟基亚胺)异吲哚-1- 1作为方便的起始材料,用于制备vic-(5-氧-4,5-二氢-1,2,4-恶二唑-3-基)芳香酸及其相关化合物,特别是目前已知的其他方法无法获得的异构体vic-氨基咪甲基(杂)芳香酸。在该方法的发展过程中得到的所有化合物都通过核磁共振光谱进行了研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A DEVELOPMENT OF AN EFFECTIVE METHOD FOR THE SYNTHESIS OF 2-(5-OXO-4,5-DIHYDRO-1,2,4-OXADIAZOL-3-YL)BENZOIC ACID
2-(5-Oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzoic acid was synthesized using a new effective method – thermal heterocyclization of 3-(hydroxyimino)isoindolin-1-one, which occurs as a result of its interaction with 1,1'-carbonyldiimidazole (CDI) and subsequent base-promoted cycleopening of the obtained intermediate 3H,5H-[1,2,4]oxadiazolo[3,4-a]isoindole-3,5-dione. Direct cyclization of 3-(hydroxyimino)isoindolin-1-one by the reaction with diethyl carbonate in the presence of sodium ethylate in ethanol at room temperature and under heating was unsuccessful. The same result was observed when using triphosgene in the presence of triethylamine in dichloromethane. Treating 3-(hydroxyimino)isoindolin-1-one with methyl chloroformate gave 3-(((methoxycarbonyl)oxy)-imino)isoindolin-1-one which was thermally stable and was not cyclized into the desired acid by boiling in toluene and o-xylene for 24 hours. The reflux of the excess of CDI with 3-(hydroxyimino)isoindolin-1-one in anhydrous ethyl acetate and subsequent alkaline hydrolysis gave the desired 2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzoic acid in a total yield of 90%. An attempt to stop the process at the stage of formation of the intermediate 3H,5H-[1,2,4]oxadiazolo[3,4-a]isoindole-3,5-dione by carrying out the reaction in the absence of a base failed. Its partial hydrolysis took place during the reaction, and especially at the stage of isolation, and as a result a mixture of 3H,5H-[1,2,4]oxadiazolo[3,4-a]isoindole-3,5-dione and 2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzoic acid was formed in a ratio of about 2:3. The obtained substance after mixing with aqueousmethanolic NaOH solution and subsequent acidification with 1M HCl was quantitatively converted into the pure desired acid. The developed method allows the use of 3-(hydroxyimino)isoindolin-1-ones as convenient starting materials for the preparation of vic-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)aromatic acids and subsequently related compounds, in particular isomeric vic-carbamimidoyl(hetero)aromatic carboxylic acids, which cannot be obtained by other currently known methods. All the compounds obtained during the development of the method were studied by means of NMR spectroscopy.
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