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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。
Aiming at the shortcomings of high polarity, poor solubility and low yield of the compound of 4-amino-8-deaza tetrahydro folic acid diethyl ester in the prior synthesis method, the introduction of the protective group at the 2,4-position amino group is improved. Starting from 6-acetoxy-2,4-dichloropyrido [3,2-d] pyrimidine and introducing benzyl group at 2,4-position, it was connected with diethyl-aminobenzoyl glutamate, After sodium borohydride and nickel chloride reduction and then deprotected to generate the key intermediate of folic acid inhibitors 4-amino-8-deaza tetrahydro folic acid diethyl ester. This method requires a short time, high yield, easy operation and post-processing. The selectivity of 6-acetoxy-2,4-dichloropyrido [3,2-d] pyrimidine benzylation, sodium borohydride and nickel chloride reduction were discussed. This method for the synthesis of tetrahydrofolate has important reference value.