苯磺酸贝他斯汀的合成新方法  

A New Method for the Synthesis of Bepotastine Besilate

作　　者：胡鑫欣 赖月琴 王浩宇 陈宇 张世明 袁伟成 周鸣强 HU Xin-xin;LAI Yue-qin;WANG Hao-yu;CHEN Yu;ZHANG Shi-ming;YUAN Wei-cheng;ZHOU Ming-qiang(Key Laboratory of Biocatalysis and Chiral Drug Synthesis of Guizhou Province, College of Pharmacy, Zunyi Medical University, Zunyi 563000, China;National Engineering Research Center of Chiral Drugs, Chengdu Likai Chiral Tech Co.,Ltd., Chengdu 610000, China;Zhejiang Jinhua Conba Bio-Pharm Co., Ltd., Jinhua, 321016, China)

机构地区：[1]遵义医科大学药学院贵州省生物催化与手性药物合成重点实验室,贵州遵义563000 [2]成都丽凯手性技术有限公司手性药物国家工程研究中心,四川成都610000 [3]浙江金华康恩贝生物制药有限公司,浙江金华321016

出　　处：《合成化学》2022年第2期140-145,共6页Chinese Journal of Synthetic Chemistry

基　　金：国家自然科学基金资助项目(21871252)。

摘　　要：探索了一条合成苯磺酸贝他斯汀的新路线。以2-吡啶甲酸、氯苯为原料,经过9步反应合成苯磺酸贝他斯汀,其中关键消旋中间体(4-氯苯基)(2-吡啶基)甲氧基哌啶,经过D-DBTA拆分可得到光活性(S)-(4-氯苯基)(2-吡啶基)甲氧基哌啶(>99%ee)。同时,(R)-(4-氯苯基)(2-吡啶基)甲氧基哌啶经过消旋化后再次拆分得到(S)-构型产物。该合成方法反应条件温和,具有工业化生产前景。最终产物结构由^(1)H NMR,^(13)C NMR和HR-MS(ESI)确证。In this paper,a new method for the synthesis of bepotastine besilate was reported.Optically active bepotastine besilate could be successfully prepared via nine steps by using 2-picolinic acid and chlorobenzene as the raw materials.Thereinto,the key racemic intermediate 2-((4-chlorophenyl)(piperidin-4-yloxy)methyl)pyridine could be resolved by D-DBTA to give(S)-2-((4-chlorophenyl)(piperidin-4-yloxy)methyl)pyridine in>99%ee,and the(R)-enantiomer could be recycled for racemization and resolution again.This method features mild reaction conditions and potential of industrial production.The final product was confirmed by ^(1)H NMR,^(13)C NMR and HR-MS(ESI).

关 键 词：苯磺酸贝他斯汀 抗过敏药 手性拆分 药物合成 

分 类 号：R914.5[医药卫生—药物化学]