前列腺素D_(2)受体拮抗剂关键中间体的工艺改进  

Process Improvement on Synthesis of Prostaglandin D_(2)Receptor Antagonists Key Intermediate

作　　者：李延顺 孙仕芹 矫鲁振 王世潇 曹国锐[2] LI Yanshun;SUN Shiqin;JIAO Luzhen;WANG Shixiao;CAO Guorui(Department of Biological&Chemical engineering,Shandong Vocational College of Science and Technology,Weifang 261053,China;College of Chemical Engineering,Qingdao University of Science and Technology,Qingdao 266042,China;School of Medicine and Pharmacy,Ocean University of China,Qingdao 266100,China)

机构地区：[1]山东科技职业学院生物与化学工程系,山东潍坊261053 [2]青岛科技大学化工学院,山东青岛266042 [3]中国海洋大学医药学院,山东青岛266100

出　　处：《合成化学》2024年第9期779-786,共8页Chinese Journal of Synthetic Chemistry

基　　金：潍坊市科学技术发展计划项目(2022GX044)。

摘　　要：前列腺素D2受体拮抗剂是治疗哮喘和过敏性疾病的潜在药物,其关键中间体合成方法尚不成熟。以N-乙酸叔丁酯吲哚和环状苯并磺酰醛亚胺为底物,自制的新型螺环噁唑啉为配体,路易斯酸为催化剂,通过催化的傅克烷基化反应制备了前列腺素D2受体拮抗剂的关键中间体。配体筛选结果表明:不同的配体对反应的收率起到关键作用,其中螺环喹啉噁唑啉配体和三氟甲磺酸锌复合物催化的反应收率最高,且未产生开环结构的双吲哚副产物。通过对反应溶剂、底物物质的量之比和反应温度等反应条件的研究,确定了最佳的反应条件:以二氯甲烷为反应溶剂,N-乙酸叔丁酯吲哚和环状苯并磺酰醛亚胺物质的量之比为1∶1, 0℃反应时,收率最高可达97%。该工艺反应条件温和,使用了廉价且环境友好的催化剂,避免使用传统工艺中腐蚀性和易制爆物料。Prostaglandin D_(2)receptor antagonists are potential agents for the treatment of asthma and related allergic diseases,and the synthesis of key intermediate has only been rarely reported.tert-Butyl 2-(1 H-indol-1-yl)acetate and cyclic N-sulfonyl aldimine were used as substrates through Friedel-Crafts alkylation reaction by using spiro oxazoline ligand and Lewis acid to give prostaglandin D_(2)receptor antagonists key intermediate.In the ligand screening process,we found ligand was the critical factor to get the high yield.The zinc complex of a new spiroQuinox ligand was proved to be a suitable catalyst,the reaction gave high yield and without the by-product.The Friedel-Crafts alkylation reaction was studied by exploring reaction solvent,substrate equivalent and temperature to found the optimized reaction conditions.The dichloromethane as the solvent at 0℃,and tert-butyl 2-(1 H-indol-1-yl)acetate:cyclic N-sulfonyl aldimine=1∶1(n∶n),the highest yield of the target product was 97%.The highlights of this method include mild reaction conditions,and the use of cheap and environmentally friendly metal catalyst,avoiding the corrosive and explosive materials in traditional methods.

关 键 词：螺环噁唑啉配体 工艺改进 前列腺素D_(2) 关键中间体 副产物 

分 类 号：O621.25[理学—有机化学]