3-甲基-6-氨甲基-喹喔啉-2-甲酸衍生物的合成

Synthesis of 3-Methyl-6-aminomethyl Quinoxaline-2-carboxylic Acid Derivative

通过在3,4-二氨基苯甲腈原有的结构中引入两个活性基团(—NH 2、—COOH),合成新型3-甲基-6-氨甲基-喹喔啉-2-甲酸衍生物,使之与载体蛋白进行偶联,在有机药物中间体方面具有更好的潜在价值。以3,4-二氨基苯甲腈、乙酰乙酸乙酯和N-溴代琥珀酰亚胺(NBS)为原料,通过亲核加成再消除、加氢还原和氢氧化钠水解3步反应,设计并合成了一种3-甲基-6-氨甲基-喹喔啉-2-甲酸衍生物,其结构经^(1)H NMR,^(13)C NMR和MS(ESI)表征,并对关键合成工艺(最佳物质的量之比、加氢还原中溶剂种类、水解试剂种类以及最佳试剂用量)进行优化。结果表明:当3,4-二氨基苯甲腈与乙酰乙酸乙酯的投料比为1∶1时(物质的量之比),反应收率为56%。加氢还原反应中,溶剂为乙醇时收率最高,为44%。在酯化水解为羧酸反应中,当水解催化剂为氢氧化钠,且氢氧化钠与原料的物质的量之比为3∶1时,反应效果最好,产品收率为97%。

Novel 3-methyl-6-aminomethyl-quinoxaline-2-carboxylic acid derivatives were synthesised by introducing two reactive groups(—NH 2,—COOH)into the original structure of 3,4-diaminobenzonitrile to couple with carrier proteins,which have a better potential value in organic drug intermediates.A 3-methyl-6-aminomethyl-quinoxaline-2-carboxylic acid derivative was designed and synthesized using 3,4-diamino benzonitrile,ethyl acetoacetate and N-bromosuccinimide(NBS)as raw materials through three steps of nucleophilic addition and elimination,hydrogenation reduction and sodium hydroxide hydrolysis.Its structure was characterized by ^(1)H NMR,^(13)C NMR and MS(ESI).And optimize the types of hydrolysis reagents for key synthesis processes(as well as the ratio of optimal substance quantity,the type of solvent in hydrogenation reduction,the type of hydrolysis reagent,and the optimal reagent dosage).The results showed that the reaction yield was 56% when the feeding ratio(the ratio of the amount of substances)of 3,4-diaminobenzonitrile to ethyl acetoacetate was 1∶1.In the hydrogenation reduction reaction,ethanol is the solvent with the highest yield of 44%.In the reaction of esterification and hydrolysis to carboxylic acid,when the hydrolysis catalyst is sodium hydroxide,and the ratio of the amount of sodium hydroxide to the amount of raw material is 3∶1,the reaction effect is the best,and the product yield is 97%.