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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。
OBJECTIVE: To promote the preclinical study of WS070117, a novel hypolipidemic drug candidate, and synthesize its impurity reference substance for the quality control of APIs. Methods: Potassium carbonate was directly hydrolyzed to obtain impurity A; hydrazine hydrate selectively hydrolyzed the acetyl group of ribose in adenosine to obtain a mixture of impurity B or impurities C and D in a fixed ratio; Adenosine departure, the use of triphenylmethyl as a protective group, the synthesis of impurities E; the use of different positions acetylation product 1H NMR acylation to determine the structure of the target product. Results: Mixtures of impurities A, B, C and D and impurities E were synthesized. CONCLUSION: The rate of acetylation of adenosine ribose segment was determined to be O-2 ’> O-3’> O-5 ’. The acetyl group transfer between O-2’ and O-3 ’ Can slow the rate of acetyl migration while inhibiting the migration of O-3 ’to the O-2’ position.