新型降血脂候选药物WS070117杂质合成研究  

Synthesis of impurities of the novel cholesterol-lowering drug candidate WS070117

作　　者：张文轩[1] 李波[1] 武红娜 王冬梅[1] 吴松[1] 

机构地区：[1]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,北京100050

出　　处：《中国新药杂志》2015年第10期1166-1170,共5页Chinese Journal of New Drugs

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)

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。Objective： To synthesize impurities of the novel cholesterol-lowering drug candidate WS070117 for its quality control. Methods： Complete hydrolysis of WS070117 by potassium carbonate afforded impurity A; selective hydrolysis of acetyl ribose fragments in the adenosine by hydrazine hydrate afforded impurity B or the im- purities C and D were mixed with fixed ratio of two components. The synthesis of the impurity E was started from 6- chloroadenosine with triphenylmethyl proteeting group. Corresponding signals of acetyl migration in ~H NMR were used to determine the structure of the target products with aeetyl substitutions in different hydroxyl groups. Results ： We synthesized mixed impurities A - D and impurity E. Conclusion： The hydrolysis rate of acetyl ribose fragment in adenosine was O-2＇ 〉 O-3＇ 〉 O-5＇, acetyl migration between O-2＇ and O-3＇ hydroxyl groups was detected, and acid slowed the acetyl migration rate and inhibited the migration from O-3＇ to O-2＇ hydroxyl group.

关 键 词：WS070117 杂质合成 水合肼 乙酰基迁移 

分 类 号：R914.5[医药卫生—药物化学]