吉西他滨-13C, 15N2及其代谢产物的合成

吉西他滨-¹³C, ¹⁵N₂及其代谢产物的合成

摘要: 以自制的尿素-¹³C, ¹⁵N₂为前体，与3-乙氧基丙烯腈反应制备胞嘧啶-¹³C, ¹⁵N₂，用BSA保护后，经与2-脱氧-2, 2-二氟-D-赤式-五呋喃糖-3, 5-二苯甲酯-1-甲磺酸酯反应生成2',2'-二氟-2'-脱氧胞嘧啶核苷-3',5'-二苯甲酸酯-¹³C, ¹⁵N₂，分离纯化后经NaOH水解生成吉西他滨-¹³C, ¹⁵N₂，再进一步降解脱氨得到吉西他滨-¹³C, ¹⁵N₂代谢产物。产品经HPLC，LC-MS和¹H NMR表征确定，化学纯度高于98%，¹³C同位素丰度为99%, ¹⁵N同位素丰度为98%。结果表明，合成的吉西他滨-¹³C, ¹⁵N可用于药物代谢研究。

Abstract: Homemade urea-¹³C, ¹⁵N₂ was used to react with 3-methyl acrylonitrile closure to form cytosine-¹³C, ¹⁵N₂ (2),which was protected by trimethylsilylation with BSA and condensed with 2-deoxy-2,2-difluoro-D-erythro-pentofuranose-3,5-dibenzoate-1-methanesulfonate at 120 ℃ to afford blocked gemcitabine-¹³C, ¹⁵N₂. Hydrolytic removal of the blocking groups of gemcitabine-¹³C, ¹⁵N₂ with NaOH gave gemcitabine-¹³C, ¹⁵N₂, and its metabolite was obtained by further hydrolytic deamination of gemcitabine-¹³C, ¹⁵N₂. The final products were characterized and detected by HPLC, LC-MS and NMR, and confirmed that the chemical purities were higher than 98%, isotopic abundances were 99% ¹³C, 98% ¹⁵N, and they were suitable for drug metabolism studies.