胆固醇-3,4-^(13)C_(2)的合成  

Synthesis of Isotope-labeled Cholesterol-3,4-^(13)C_(2)

作　　者：白少飞 孙雯 刘前 BAI Shaofei;SUN Wen;LIU Qian(Shanghai Research Institute of Chemical Industry CO.,LTD.,Shanghai 200062,China;National Isotope Engineering Technology Research Center-Shanghai-Sub-Center,Shanghai 200062,China)

机构地区：[1]上海化工研究院有限公司生物医药检测中心,上海200062 [2]国家同位素工程技术研究中心上海分中心,上海200062

出　　处：《同位素》2024年第3期227-236,共10页Journal of Isotopes

基　　金：国家重点研发计划项目(2021YFF0701900)。

摘　　要：针对我国胆固醇-3,4-^(13)C_(2)产品制备方法空白,以乙酸苯酯-1,2-^(13)C_(2)和4-胆甾烯-3-酮为起始原料,合成胆固醇-3,4-^(13)C_(2)。总体标记合成路线采用胆固醇基础结构拆分后引入标记砌块再重构目标化合物结构的方案,其中4-胆甾烯-3-酮通过开环氧化、合环得到标记前体,乙酸苯酯-1,2-^(13)C_(2)作为^(13)C标记引入砌块与标记前体通过乙酰化反应得到乙酰化标记中间体,最后乙酰化标记中间体再经过碳环重构、酯化、还原反应得到^(13)C二标记的类固醇激素类化合物胆固醇-3,4-^(13)C_(2)。其中还原反应显示出一定的不对称合成现象。以投入的乙酸苯酯-1,2-^(13)C_(2)的物质的量计算反应总产率为16.2%。所得终产品经MS、NMR和HPLC表征确认,液相色谱纯度≥96%,液相质谱检测丰度≥98 atom%^(13)C,该产品可用于临床质谱、生物医药等领域检测用稳定同位素内标试剂以及临床质谱用疾病筛查试剂盒原料。The^(13)C-labeled synthesis of cholesterol-3,4-^(13)C_(2)was based on phenyl acetate-1,2-^(13)C_(2)and 4-cholesten-3-one.4-Cholesten-3-one was reacted in a certain proportion solvent mixed by isopropanol and water to obtain the carboxylic acid intermediate through ring opening oxidation reaction using potassium permanganate and sodium periodate as oxidant,and then reacted with acetate under heat and reflux in nitrogen protection to produce the ring-closure carbonyl intermediate.The acetylation labeled intermediate was synthesized with the ring-closure carbonyl intermediate and phenyl acetate-1,2-^(13)C_(2)in tetrahydrofuran as solvent,using sodium hydride as catalyzer through acetylation reaction.Finally the cholesterol-3,4-^(13)C_(2)was obtained sequentially by carbon ring reconstruction reaction,esterification and reduction reaction with the acetylation labeled intermediate as raw material.The reduction reaction showed a certain degree of asymmetric synthesis phenomenon.The yield based on the amount of substance of acetate-1,2-^(13)C_(2)was 16.2%.The structure of target product was confirmed by MS,NMR and HPLC.Its chemical purity(HPLC)was higher than 96%,and isotopic abundance was higher than 98%(atom^(13)C).This product can be used as the stable isotope internal standard reagent for detection in the field of clinical mass spectrometry and biomedical.It can also be used as a raw material of the test kit for clinical mass spectrometry disease detection.

关 键 词：胆固醇-3 4-^(13)C_(2) 稳定同位素标记化合物 类固醇激素 内标试剂 试剂盒 

分 类 号：O628.21[理学—有机化学]