新型降血脂候选药物WS070117杂质合成研究

发布时间：2018-05-25 02:12

本文选题：WS + 杂质合成　；参考：《中国新药杂志》2015年10期

【摘要】：目的:为推进新型降血脂候选药物WS070117的临床前研究,合成其杂质对照品以便对原料药进行质量控制。方法:碳酸钾对原料药直接水解可得到杂质A;水合肼对腺苷中核糖片段的乙酰基进行选择性水解,得到杂质B或者杂质C和D两组分固定比例的混合物;从6-氯腺苷出发,利用三苯基甲基作为保护基,合成杂质E;利用不同位置乙酰化产物1H NMR的酰化位移确定目标产物的结构。结果:合成了杂质A,B,C和D的混合物以及杂质E。结论:确定了腺苷核糖片段乙酰基水解的速率为O-2'O-3'O-5',发现了O-2'和O-3'位之间乙酰基迁移现象,加酸可以减缓乙酰基迁移的速率,同时抑制O-3'向O-2'位的迁移。
[Abstract]:Aim: to promote the preclinical study of WS070117, a new candidate drug for lowering blood lipid, to synthesize its impurity reference substance and to control the quality of the drug. Methods: the impurity A was obtained by direct hydrolysis of potassium carbonate to the raw material, and the acetyl group of ribose fragment in adenosine was selectively hydrolyzed by hydrazine hydrate to obtain impurity B or a mixture of impurity C and D in a fixed proportion. The impurity E was synthesized by using triphenyl methyl as the protective group, and the structure of the target product was determined by the acylation shift of the acetylated product 1H NMR at different positions. Results: the mixture and impurity E were synthesized. Conclusion: the rate of acetyl hydrolysis of adenosine ribose fragment was determined to be O-2O3 (O-5N). The phenomenon of acetyl migration between O-2'and O-3'sites was found. The addition of acid could slow the rate of acetyl migration and inhibit the migration of O-3'to O-2'site.
【作者单位】：中国医学科学院北京协和医学院药物研究所活性物质的发现与适药化研究北京市重点实验室;
【基金】：国家“十二五重大新药创制”科技重大专项:新结构类型调血脂化合物WS070117临床前研究(2012ZX09102101-020)
【分类号】：R914.5

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