他达那非有关杂质制备与结构确证  

Synthesis and identification of related impurities in tadalafil

作　　者：杨超 王清兰 胡诗月 钱玺丞 YANG Chao;WANG Qing-lan;HU Shi-yue;QIAN Xi-cheng(College of Pharmacy,Guzhou College of Health Prodessions,Tongren 554300,China;Key Open Laboratory of traditional Chinese Veterinary Medicine,Tongren Polytechnic College,Tongren 554300,China)

机构地区：[1]贵州健康职业学院药学系,贵州铜仁554300 [2]铜仁职业技术学院民族中兽药重点开放实验室,贵州铜仁554300

出　　处：《中国药物化学杂志》2022年第5期354-357,共4页Chinese Journal of Medicinal Chemistry

基　　金：铜仁市科技局基础科学研究专项基金项目(铜市科研[2020]89号)。

摘　　要：目的 他达那非是新型的治疗男性勃起功能障碍有效的药物之一。为了对他达那非原料药及其制剂进行质量控制,合成了3个他达那非杂质。方法 以他达拉非为原料,经氧化、缩合及重排等反应合成了他达那非有关杂质:(6R,14aR)-6-(苯并[d][1,3]-二噁氧-5-基)-2-甲基-2,3,14,14a-四氢苯并[h]吡嗪[1,2-d][1,4]二偶氮宁-1,4,7,13-(6H,8H)-四酮(EP-H)、(6S)-6-(苯并[d][1,3]二噁氧-5-基)-2-甲基-2,3,7,12b-四氢吡嗪[1′,2′:1,5]吡咯[3,4-]喹啉-1,4,12(6H)-三酮(EP-G)、(6R)-6-(苯并[d][1,3]二噁氧-5-基)-2-甲基-2,3,6,7-四氢吡嗪[1′,2′:1,6]吡啶[3,4-b]吲哚-1,4-二酮(2)。结果 合成的EP-H、EP-G和2的结构均经IR、质谱、^(1)H-NMR和^(13)C-NMR谱确证。结论 3种物质的纯度达到99%以上,可作为他达那非原料药质量控制的杂质对照品。Tadalafil(1) is one of the most effective drugs in the treatment of male erectile dysfunction.In order to improve the quality control of tadalafil API and its preparation, three impurities were synthesized.The impurities 6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,14,14 a-tetrahydrobenzo[h]pyrazino[1,2-d][1,4]diazonine-1,4,7,13(6H,8H)-tetraone(EP-H)、6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,7,12 b-tetrahydropyrazino[1′,2′:1,5]pyrrolo[3,4-b]quinoline-1,4,12(6 H)-trione(EP-G)and 6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,6,7-tetrahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione(impurity 2)were synthesized from tadalafil by oxidation, condensation and rearrangement.The structures of EP-H、EP-G and impurity 2 were characterized by IR、ESI-MS、^(1)H-NMR,and ^(13)C-NMR.The purity of the three substances was more than 99%,which can be used as reference impurities for the quality control strategy of tadalafil.

关 键 词：有关杂质 他达拉非 次氯酸叔丁酯 纯度 质量控制 

分 类 号：R914[医药卫生—药物化学]