N-{4-{N-甲基-N-[2-羟基-3-(2,4-二氧代-1,2,3,4-四氢嘧啶-5-基)氨基]丙基}氨基-3-溴}苯甲酰基-L-谷氨酸二乙酯及其衍生物的合成

报道了N-{4-{N-甲基-N-2-羟基-3-(2,4-二氧代-1,2,3,4-四氢嘧啶-5-基)氨基]丙基}氨基-3-溴}苯甲酰基-L-谷氨酸二乙酯及其衍生物的简便合成方法. 分别以4-氨基苯甲酸乙酯和4-氨基苯甲酰基-L-谷氨酸二乙酯为起始物, 经甲基化、烯丙基化、溴羟基化、环氧化、开环、脱保护等反应首次合成了6个新型5-取代氨基嘧啶类化合物, 并通过¹H NMR, ¹³C NMR 和MS对其化学结构进行了表征. 初步生物活性结果表明, 苯环侧链的L-谷氨酸酯部分是此类化合物抑制人重组二氢叶酸还原酶的必需结构.

Synthesis of Diethyl N-{4-[N-Methyl-N-(3-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)amino-2-hydroxypropyl)amino]-benzoyl}-L-glutamate and Its Derivatives

A new practical approach to prepare diethyl N-{4-N-methyl-N-(3-(2,4-dioxo-1,2,3,4-tetrahy-dropyrimidin-5-yl)amino-2-hydroxypropyl)amino]benzoyl}-L-glutamate and its derivatives has been realized from ethyl 4-aminobenzoate (4a) and diethyl N-(4-aminobenzoyl)-L-glutamate (4b). Six novel 5-(substituted)amino pyrimidines 9～11 were synthesized via methylation, allylation, bromohydroxylation, epoxidation, ring-opening, deprotection reaction and so on, and were characterized by ¹H NMR, ¹³C NMR and MS techniques. The inhibitory activities against human dihydrofolate reductase of the compounds have been determined. The results showed that the bioactivities of the compounds were related with L-glutamate side chain.