4-氟-3-(三氟-磺酰基)苯磺酰胺的合成研究  

Preparation of 4-Fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide

作　　者：王洁[1,2] 庞磊 刘雅莉 李梅彤[1,2] 袁文蛟[1,2] WANG Jie;PAN Lei;LIU Yali;LI Meitong;YUAN Wenjiao(Tianjin Engineering Research Center of Green Chemistry and Waste Reuse,Tianjin University of Technology,Tianjin 300384,China;School of Environmental Science and Safety Engineering,Tianjin University of Technology,Tianjin 300384,China;Tianjin Centralpharm Co.,Ltd.,Tianjin 300400,China;School of Chemical Engineering,Hebei University of Technology,Tianjin 300401,China)

机构地区：[1]天津理工大学天津市绿色化工与废弃物资源化工程研究中心,天津300384 [2]天津理工大学环境科学与安全工程学院,天津300384 [3]天津市中央药业有限公司,天津300400 [4]河北工业大学化工学院,天津300401

出　　处：《天津理工大学学报》2024年第4期104-108,共5页Journal of Tianjin University of Technology

基　　金：国家自然科学基金(21106107)。

摘　　要：Navitoclax(ATB-263)是一种具有抗癌活性的口服小分子Bcl-2抑制剂,也是潜在的硬皮症和老化疾病治疗药物。针对合成Navitoclax的关键中间体4-氟-3-(三氟-甲磺酰基)苯磺酰胺缺少大规模、高效、低成本制备方法的技术难题,文中以邻硝基苯胺为起始原料,经5步反应得到目标产物4-氟-3-(三氟-甲磺酰基)苯磺酰胺,总收率高达48%。此外,文中着重对三氟甲磺酰化反应和氟代反应进行了条件优化,考察了底物、氟代试剂和反应温度对上述反应的影响。该合成方法所涉及中间体和最终产物通过蒸馏和重结晶即可实现分离与纯化,无需柱层析。该合成方法反应条件温和,反应试剂经济易得,具有较强的工业化应用价值。Navitoclax(ATB-263)showed orally anti-cancer activity as a small molecule inhibitor for Bcl-2 protein and was also considered to be a possible therapy for scleroderma and aging diseases.Highly efficient,large-scale and low-cost production of 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,which is a crucial compound to access to Navitoclax,is still a challenge for chemists,even though many methods for preparation of this compound were reported.In this article,2-nitroaniline,as starting material,was transformed into aimed product in five steps with total yield 48%.Additionally,we further investigated the influence of substrate,fluorinated agents,and reaction temperature on trifluoromethanesulfonylation and fluorination to confirm the optimal procedure.More notably,distillation and re-crystallization were involved in purification of intermediates and aimed product without column chromatography.This method we developed demonstrated industrial application prospects,owing to mild reaction conditions and inexpensive and commercially available reaction agents.

关 键 词：4-氟-3-(三氟-甲磺酰基)苯磺酰胺 小分子抑制剂 三氟甲磺酰化反应 氟代反应 细胞凋亡 

分 类 号：R914[医药卫生—药物化学]