新型雄激素受体降解剂关键中间体合成工艺优化  

Optimization of The Synthesis Process of New Androgen Receptor Degraders Key Intermediate

作　　者：吴小珂 孙璐璐 孟昕 杨玉社 王傲 WU Xiaoke;SUN Lulu;MENG Xin;YANG Yushe;WANG Ao(School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing 210023,China;Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China)

机构地区：[1]南京中医药大学新中药学院,江苏南京210023 [2]中国科学院上海药物研究所,上海201203

出　　处：《合成化学》2024年第8期717-722,共6页Chinese Journal of Synthetic Chemistry

基　　金：国家自然科学基金面上项目(82073684)。

摘　　要：YXG-158是具有全新结构的雄激素受体降解剂,有望解决去势抵抗性前列腺癌患者的临床耐药问题,而其放大生产的难点在于关键中间体(3S,10R,13S)-10,13-二甲基-17-(4-甲基-1H-咪唑-1-基)-2,3,4,7,8,9,10,11,12,13,14,15-十二氢-1H-环戊并[a]菲-3-醇(6)的合成。以市售17-碘雄甾-5,16-二烯-3β-醇(7)为原料,仅经一步乌尔曼偶联反应实现中间体6的构建,收率可达30.7%,纯度可达99.72%,产物中区域异构体8仅占比0.28%。采用乌尔曼偶联合成中间体6大大简化了合成路线,提高了反应收率,且利于工业化生产。YXG-158 is an androgen receptor degrader with a new structure which is expected to solve the clinical drug resistance problem in patients in castration-resistant prostate cancer.The difficulty in scaling up its production lies in the key intermediate(3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1 H-cyclopenta[a]phenanthrene-3-ol(6).In this paper,intermediate 6 was synthesized from 17-iodoandrostane-5,16-diene-3-β-ol(7)by one-step Ullmann coupling reaction.The yield was 30.7%,the purity was 99.72%,and the regional isomer 8 only accounted for 0.28% of the product.Ullmann coupling reaction can greatly simplified the synthesis route,increased the reaction yield,and was conductive to industrial production.

关 键 词：前列腺癌 去势抵抗性前列腺癌 雄激素受体降解剂 乌尔曼偶联反应 合成工艺优化 

分 类 号：O622.3[理学—有机化学]