4-氨基-8-去氮杂四氢叶酸二乙酯的新合成方法  

A Novel Synthesis of Diethyl 4-Amino-8-deazatetrafolate

作　　者：周受辛[1] 田超[1] 王孝伟[1] 刘俊义[1,2] 张志丽[1] 

机构地区：[1]北京大学化学生物学系,北京100191 [2]北京大学天然药物与仿生药物国家重点实验室,北京100191

出　　处：《化学通报》2012年第10期897-902,共6页Chemistry

基　　金：国家自然科学基金项目(2097201;2067208);国家博士点基金项目(20070001742)资助

摘　　要：针对4-氨基-8-去氮杂四氢叶酸二乙酯现有合成方法中化合物极性大、溶解度差、收率低的缺点,采用在2,4位氨基引入保护基的方法进行改进。以6-乙酰氧基-2,4-二氯吡啶并[3,2-d]嘧啶为原料,在2,4-位引入苄基后与对氨基苯甲酰谷氨酸二乙酯连接,经硼氢化钠和氯化镍还原后再脱保护,生成叶酸类抑制剂关键中间体4-氨基-8-去氮杂四氢叶酸二乙酯。此方法所需时间短,收率较高,操作及后处理方便。并对6-乙酰氧基-2,4-二氯吡啶并[3,2-d]嘧啶苄基化的选择性、硼氢化钠和氯化镍还原方法进行了讨论。此方法对于四氢叶酸类化合物的合成有重要参考意义。To conquer disadvantages in existing synthetic routes of diethyl 4-amino-8-deazatetrafolate,just as high polarity and poor solubility of some intermediates as well as unsatisfying overall yield,a novel synthesis method with protecting groups introduced for 2,4-diamino groups was reported.Starting from 6-acetoxymethyl-2,4-dichloropyridopyrimidine,diethyl 4-amino-8-deazatetrafolate as a key intermediate of anti-folate inhibitors was obtained by a series of successive reactions including protection,condensation,reduction and debenzylation.Relatively shorter reaction time,higher yield and convenient work-up were achieved using this method.The regioselectivity of benzylation and reduction method of pyridine ring were also investigated.This novel synthesis route is of significance for synthesis of tetrahedronfolate analogues.

关 键 词：4-氨基-8-去氮杂四氢叶酸二乙酯 苄基化 硼氢化钠 氯化镍 合成 

分 类 号：TQ225.242[化学工程—有机化工]