中文摘要：

目的：改进经典抗叶酸类药物关键中间体4-氨基-5-甲酰基-8,10-二去氮杂四氢叶酸二乙酯侧链的水解条件。方法：以经典叶酸拮抗剂侧链N-（4-氨基苯甲酰）-L-谷氨酸二乙酯（1）为反应原料,尝试了氢氧化钠（Na OH）和氢氧化钾（KOH）2种碱催化、20~180 min 5种反应时间和0.175~1 mol/L 3种碱浓度的反应条件,用高效液相色谱法检测目标产物和副产物,最终确定副产物为单酯水解产物以及酰胺键水解产物,并以此为依据完成了4-氨基-5-甲酰基-8,10-二去氮杂四氢叶酸二乙酯（5）水解条件的优化。结果：改进后的4-氨基-5-甲酰基-8,10-二去氮杂四氢叶酸二乙酯侧链的水解条件为0.3 mol/L KOH溶液中室温条件反应60 min,在该反应条件下,水解反应收率为95.6%。反应产物通过磁共振氢谱（1H nuclear magnetic resonance,1H NMR）、磁共振碳谱（13C nuclear magnetic resonance,13C NMR）和电喷雾飞行时间质谱（electrospray ionization time of flight mass spectrometry,ESI-MS）分析鉴定后结构正确,并通过高效液相色谱法确定其纯度为96%。新的水解反应条件避免了副产物的生成,提高了反应收率。结论：利用新的水解条件可以简便、高效地完成4-氨基-5-甲酰基-8,10-二去氮杂四氢叶酸二乙酯的水解反应,该条件对经典叶酸拮抗剂的合成和生产工艺的改进也有重要的意义。

英文摘要：

Objective： To optimize and establish the best hydrolysis method of diethyl ester 4-aminoN5-formyl-N8,N10-dideazatetrahydrofolate through the optimization of simple compound of diethyl N-（4-aminobenzoyl）-L-glutamate. Methods： To increase the low yield of hydrolysis reaction of diethyl ester 4-amino-N5-formyl-N8,N10-dideazatetrahydrofolate due to the by-products and difficult purification,we studied the effect of Na OH and KOH,two kinds of alkalis,three concentrations between 0. 175-1 mol/L and five types of reaction time involved in 20,30,60,120 and 180 min on the common side chain diethyl N-（4-aminobenzoyl）-L-glutamate. A high performance liquid chromatography was established for measuring the target product and the by-products in reaction liquid in different reaction conditions. Finally,on the basis of the best hydrolysis method of diethyl ester 4-amino-N5-formyl-N8,N10-dideazatetrahydrofolate,we completed the optimization of the hydrolysis reaction conditions of diethyl ester 4-aminoN5-formyl-N8,N10-dideazatetrahydrofolate. Results： We developed the best reaction condition for the hydrolysis of diethyl ester 4-amino-N5-formyl-N8,N10-dideazatetrahydrofolate,which could be carried out easily and efficiently. The results indicated that treated with the optimized condition of 0. 3 mol/L KOH in 60 min at the room temperature,diethyl ester 4-amino-N5-formyl-N8,N10-dideazatetrahydrofolate was converted into its diacid derivative in 95. 6 % yield,which turned to be a better reaction condition compared with the previous reaction condition. The structures of those compounds were identified to be correct by1 H nuclear magnetic resonance（1H NMR）,13 C nuclear magnetic resonance（13C NMR） and electrospray ionization time of flight mass spectrometry（ESI-MS）. The purity of the diacid derivative of the compound was determined to be 96% by high performance liquid chromatography（HPLC）. The new hydrolysis reaction condition could not only avoid the formation of single ester hydrolysis product and amide