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

吴小珂 ¹孙璐璐 ²孟昕 ²杨玉社 ¹王傲²

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作者信息

1. 南京中医药大学新中药学院,江苏南京 210023;中国科学院上海药物研究所,上海 201203
2. 中国科学院上海药物研究所,上海 201203
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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.

Abstract

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-1H-cyclopenta[a]phenanthrene-3-o1(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 re-gional isomer 8 only accounted for 0.28％of the product.Ullmann coupling reaction can greatly sim-plified 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

Key words

prostate cancer/castration-resistant prostate cancer/androgen receptor degrader/Ullmann coupling reaction/synthesis process optimization

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基金项目

国家自然科学基金面上项目(82073684)

出版年

2024

合成化学

四川省化学化工学会　中国科学院成都有机化学研究所

合成化学

CSTPCD

影响因子：0.42

ISSN：1005-1511

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