基于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反应条件优化

发布时间：2018-02-27 23:49

本文关键词： 叶酸拮抗剂叶酸二乙酯类似物水解反应　出处：《北京大学学报(医学版)》2017年04期 　论文类型：期刊论文

【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。
[Abstract]:Objective: to improve the hydrolysis conditions of the side chain of 4-amino-5-formyl-8-diaza-tetrahydrofolate, the key intermediate of classical folic acid drugs. Ester 1) is used as raw material for the reaction. The reaction conditions of sodium hydroxide sodium hydroxide (NaOH) and potassium hydroxide (Koh) and potassium hydroxide (Koh) were studied. The reaction conditions of 5 kinds of reaction time and 0.175 mol/L were used to determine the target product and by-product by high performance liquid chromatography. The by-products were determined to be monoester hydrolysates and amide-bond hydrolysates. Based on this, the hydrolysis conditions of 4-amino-5-formyl-810-diaza-tetrahydrofolate diethyl folate were optimized. Results: the improved hydrolysis conditions of 4-amino-5-formyl-8-diaza-tetrahydrofolate diethyl ester were improved. In the solution of 0.3 mol/L KOH at room temperature for 60 minutes. The yield of hydrolysis reaction was 95.6.The product was characterized by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance 13C NMRs and electrospray ionization time of flight mass spectroscopy ESI-MS. The purity of the product was determined to be 96 by HPLC. The new hydrolysis conditions avoided the by-product formation and increased the yield of the reaction. Conclusion: the new hydrolysis condition is simple and convenient. The hydrolysis of diethyl 4-amino-5-formyl-8-diaza-tetrahydrofolate is highly effective. This condition is also of great significance for the synthesis of classical folic acid antagonist and the improvement of production process.
【作者单位】：北京大学药学院化学生物学系;北京大学天然药物与仿生药物国家重点实验室;
【基金】：国家自然科学基金(21172014)资助~~
【分类号】：R914.5

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