N-［4-（2，4-二氨基吡啶并［3，2-d］嘧啶-6-甲氨基）-苯甲酰］-L-谷氨酸二乙酯的合成方法改进
Improved synthesis process of diethyl N-［4-［(2,4-diaminopyrido［3,2-d］pyrimidin-6-yl)methylamino］benzoyl］-L-glutamate

目的：改进抗叶酸类药物关键中间体N-［4-（2，4-二氨基吡啶并［3，2-d］嘧啶-6-甲氨基）-苯甲酰］-L-谷氨酸二乙酯的合成方法。方法：6-乙酰氧基甲基-2,4,二氧代吡啶并［3,2-d］嘧啶（1）经过水解反应、氯代反应、对氨基苯甲酰谷氨酸二乙酯缩合、氨解反应生成N-［4-（2，4-二氨基吡啶并［3，2-d］嘧啶-6-甲氨基）-苯甲酰］-L-谷氨酸二乙酯（5）。结果：改进了N-［4-（2，4-二氨基吡啶并［3，2-d］嘧啶-6-甲氨基）-苯甲酰］-L-谷氨酸二乙酯的合成路线，该合成路线共4步反应，分别为水解反应、氯代反应、对氨基苯甲酰谷氨酸二乙酯缩合反应和氨解反应， 4步反应总收率为36.7%，化合物通过磁共振氢谱、磁共振碳谱和质谱分析法鉴定后结构正确。新路线避免了溴化反应产物的不稳定，改善了氨解反应苛刻的反应条件。结论：新合成路线改善了反应条件和中间体的稳定性，增加了化合物的衍生化范围，对抗叶酸类抗肿瘤抑制剂的合成研究具有重要意义。
Objective：To establish a new approach to synthesis of diethyl N-［4-［(2,4-diaminopyrido［3,2-d］pyrimidin-6-yl)methylamino］benzoyl］-L-glutamate. Methods:Target compound (5) was synthesized by the use of (2,4-dioxo-tetrahydropyridopyrimidin-6-yl)methyl acetate (1) as starting material via hydrolysis, chlorination, condensation with diethyl (paminobenzoyl)glutamate and aminolysis. Results: A new approach to synthesis of diethyl N［4［(2,4diaminopyrido［3,2-d］pyrimidin-6-yl)methylamino］benzoyl］-L-glutamatewas established. This synthetic route has hydrolysis reaction, chlorination, diethyl N-(p-aminobenzoyl)-L-glutamate condensation reaction and ammonolysis reaction. The total yield is 36.7%.The structures of those compounds have identified by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance and mass spectrometry. This synthetic route avoid the unstable brominated re-action product and improves the harsh condition of ammonolysis reaction. Conclusion:The new synthetic route has improved the reaction condition and the stability of the intermediate, and increased the extent of the derivative compounds, which has great significance to anti-folic acid of anti-tumor inhibitor synthesis.