DOI: 10.16597/j.cnki.issn.1002-154x.2025.01.003
新型抗结核药德拉马尼的合成
曲书慧1 徐幼桥2 夏卓璐1 季菲1 江峰1∗
(1. 中国药科大学 工学院, 南京 211198; 2. 南京大学医学院附属鼓楼医院, 南京 210008)
摘 要 德拉马尼是一种硝基咪唑衍生物的新型抗结核药物，已成为成人耐多药结核病的重要治疗药物。原始专利和其他文献报道的德拉马尼合成路线存在产率较低等不足，本研究旨在为德拉马尼的合成建立一条优化路线。以低成本的4-(三氟甲氧基)苯酚和N-叔丁氧羰基-4-羟基哌啶为原料，通过Mitsunobu反应、芳构化反应和Sharpless不对称环氧化合成德拉马尼，总收率11%，纯度达99.6%，手性纯度达到100%。该路线提高了德拉马尼的收率和手性纯度，适用于德拉马尼的工业化生产。
关键词 结核病 硝基咪唑衍生物 德拉马尼 工艺优化 手性纯度
Synthesis of Novel Anti-tuberculosis Delamanid
QU Shuhui1 XU Youqiao2 XIA Zhuolu1 JI Fei1 JIANG Feng1∗
(1. School of Engineering, China Pharmaceutical University, Nanjing 211198, China; 2. Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China)
Abstract Delamanid, a novel anti-tuberculosis drug of nitroimidazole derivatives, has become an important therapeutic agent for adult multidrug-resistant tuberculosis. The original patent and other reported synthetic routes for delamanid have certain drawbacks, this study aimed to establish an optimized route for the synthetic process of delamanid. The obtained delamanid in 11% overall yield by Mitsunobu reaction, aromatization reaction, and Sharpless asymmetric epoxidation method using low-cost 4-trifluoromethoxy phenol and N-Boc-4-hydroxypiperidine as raw materials. The obtained delamanid had a purity of 99.6%, and the chiral purity (ee) increased from 99.6% to 100%. The developed route improved the yield and chiral purity of delamanid, which is suitable for the industrial production of delamanid.
Keywords tuberculosis nitroimidazole derivative delamanid process optimization chiral purity