一锅法合成5-取代异唑-3-羧酸甲酯类化合物  

One pot synthesis of 5-substituted isoxazole-3-carboxylic acid methyl ester series compounds

作　　者：靳清贤 张广慧 刘冬 杜星辰 毛文静 方少明 JIN Qingxian;ZHANG Guanghui;LIU Dong;DU Xingchen;MAO Wenjing;FANG Shaoming(School of Materials and Chemical Engineering,Zhengzhou University of Light Industry,Zhengzhou 450002,Henan,China)

机构地区：[1]郑州轻工业大学材料与化学工程学院,河南郑州450002

出　　处：《精细化工》2024年第12期2777-2784,共8页Fine Chemicals

基　　金：国家自然科学基金项目(21544011)。

摘　　要：以甲醇钠为碱催化剂,取代甲基酮与草酸二甲酯经Claisen缩合反应合成了β-二羰基化合物,再经浓硫酸中和后与盐酸羟胺反应成肟,最后高温成环,合成了不同取代基的5-取代异唑-3-羧酸甲酯类化合物。通过^(1)HNMR、^(13)CNMR、MS确证了产物结构,对合成过程中的碱催化剂、溶剂、酸中和的条件进行了优化,对不同取代基的5-取代异唑-3-羧酸甲酯化合物合成工艺差异进行了探讨。结果表明,用一锅法成功合成了26个5-取代异唑-3-羧酸甲酯。其中,23个可在单一溶剂甲醇中制备,避免了中间产物的分离和纯化处理,操作流程简捷,单一溶剂易于回收处理;5-叔丁基异唑-3-羧酸甲酯(Ⅳc)、5-(4-氨基苯基)异唑-3-羧酸甲酯(Ⅳm)和5-(3-氨基苯基)异唑-3-羧酸甲酯(Ⅳn)的合成需要用叔丁醇钾作碱催化剂,并在四氢呋喃中进行;5-三氟甲基异唑-3-羧酸甲酯(Ⅳv)的合成未成功,需要设计新的合成方法和条件。A series of 5-substituted isoxazol-3-carboxylate methyl esters with different substituents were synthesized from β-dicarbonyl compounds,which were prepared firstly from Claisen condensation reaction of substituted methyl ketones and dimethyl oxalate using sodium methanol as base catalyst,then neutralized by concentrated sulfuric acid,reacted with hydroxylamine hydrochloride to obtain oximes,and finally formed a ring at high temperature.The structure of the products was confirmed by 1HNMR,13CNMR and MS,while the reaction conditions of alkali catalyst,solvent and acid neutralization in the synthesis process were optimized,with the differences among synthesis processes of 5-substituted isoxazol-3-methyl carboxylate compounds with different substituents discussed.The results showed that 26 5-substituted isoxazol-3-carboxylate methyl esters were successfully synthesized by one-pot method,of which 23 could be prepared in a single solvent methanol.Without separation and purification of intermediate products,it was simple and carried out only in a single solvent,which could be easily recovered.Among the products,5-tert-butylisooxazol-3-carboxylate methyl ester(Ⅳc),5-(4-aminophenyl)isooxazol-3-carboxylate methyl ester( Ⅳ m) and 5-(3-aminophenyl)isooxazol-3-carboxylate methyl ester( Ⅳ n) required potassium tert-butoxide as base catalyst and tetrahydrofuran as solvent for synthesis,while the synthesis of 5-trifluoromethylisooxazol-3-carboxylate methyl ester(Ⅳv) was unsuccessful,and further development of synthesis technology and optimization conditions were needed.

关 键 词：一锅法 异?唑-3-羧酸酯 异?唑 合成 羧酸 精细化工中间体 

分 类 号：O626[理学—有机化学]