doi:10.16597/j.cnki.issn.1002-154x.2026.01.002
瑞司美替罗的合成方法改进
龙欣怡 范为正∗
（江南大学生命科学与健康工程学院，无锡 214122）
摘 要本研究对甲状腺激素受体β(THR-β)小分子激动剂瑞司美替罗的合成方法进行了改进。以3,6-二氯哒嗪和异丁酸为起始原料,经过自由基取代反应得到3,6-二氯-4-异丙基哒嗪,随后经过偶联反应、亚硝化反应、缩合反应、水解异构反应、分子内取代反应得到目标化合物MGL-3196,总收率为37.2%,纯度为99.36%(HPLC面积归一化法)。目标化合物及关键中间体的结构经质谱、核磁氢谱确证。相较于原研路线,本研究的新工艺路线优化了合成步骤,后处理操作简便,提高了收率,可为MGL-3196及其衍生物的合成提供参考。
关键词非酒精性脂肪肝；甲状腺激素受体β；瑞司美替罗；工艺改进
Improved Synthesis of Resmetirom
LONG Xinyi FAN Weizheng∗
(School of Life Science and Health Engineering, Jiangnan University, Wuxi 214122, China)
Abstract In this paper, the synthesis method of resmetirom( MGL - 3196), a small molecule agonist of thyroid hormone β(THR-β) was improved. Using 3,6 - dichloropyridazine and isobutyric acid as starting materials, 3,6 - dichloro - 4 - isopropylpyridazine was obtained through radical substitution reaction, and then the target compound resmetirom (MGL - 3196) was obtained through coupling reaction, nitrosation reaction, condensation reaction, hydrolytic isomerization reaction and intramolecular substitution reaction. The total yield was 37.2%, and the purity was 99.36% (HPLC area normalization method). The structures of target compound and key intermediates were confirmed by MS and ¹H NMR. Compared with the original research route, the new process route in this study optimizes the synthesis steps, the post - treatment operation is simple and the yield is improved, which can provide a reference for the synthesis of MGL - 3196 and its derivatives.
Keywords nonalcoholic fatty liver disease; thyroid hormone receptor β; resmetirom; process improvement