普拉曲沙有关物质的合成

Synthesis of related substances of pralatrexate

目的 加强普拉曲沙的质量控制,合成4个普拉曲沙有关物质,为其质量研究提供对照品。方法 以4-{2-[(2,4-二氨基蝶啶-6-基)甲基]-1-甲氧基-1-氧代-4-戊炔-2-基}苯甲酸甲酯为起始原料,经水解、脱羧、酰化反应,再经水解反应,得到杂质A;以4-{1-[(2,4-二氨基蝶啶-6-基)基]-4-戊炔-2-基}苯甲酸为起始原料,分别与D-谷氨酸二甲酯盐酸盐、L-谷氨酸-1-甲酯盐酸盐、L-谷氨酸-5-甲酯盐酸盐进行酰化缩合,再分别水解或经柱色谱分离,得到杂质B、C及D。结果与结论合成的4种普拉曲沙有关物质的结构均经HR-MS、1H-NMR、13C-NMR谱确证,杂质总收率为8.5%~60.9%,纯度为94.37%~98.33%。4种杂质可用于普拉曲沙原料药的质量控制和质量研究。

Four related substances of pralatrexate were synthesized to strengthen the quality control of pralatrexate and to provide reference for its quality research.Using methyl 4-{2-[(2,4-diaminopteridin-6-yl)methyl]-1-methoxy-1-oxopent-4-yn-2-yl}benzoate as the starting material, impurity A was obtained by hydrolysis, decarboxylation, acylation, and finally hydrolysis.Using 4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoic acid as the starting material, highly pure impurities B,C and D were obtained by acylate and condensation with D-glutamic acid dimethyl carbonate, L-glutamic acid-1-methyl carbonate, L-glutamic acid-5-methyl carbonate, and then hydrolysis or direct column chromatography, respectively.The structures of four impurities were confirmed by HR-MS,1H-NMR and 13C-NMR,which can be used in the quality control of pralatrexate.The syntheses of impurities C and D were reported for the first time and have certain application value.