Suzuki-Miyaura偶联反应在沙丁胺醇合成中的应用  

Application of Suzuki-Miyaura coupling reaction in the synthesis of salbutamol

作　　者：陈丽平 仇中选 李振鹏 王跃兴 黄龙江[1] CHEN Liping;QIU Zhongxuan;LI Zhenpeng;WANG Yuexing;HUANG Longjiang(School of Chemical Engineering,Qingdao University of Science&Technology,Qingdao 266042,Shandong,China;School of Biological&Chemical Engineering,Qingdao Technical College,Qingdao 266555,Shandong,China)

机构地区：[1]青岛科技大学化工学院,山东青岛266042 [2]青岛职业技术学院生物与化工学院,山东青岛266555

出　　处：《精细化工》2022年第8期1716-1721,共6页Fine Chemicals

基　　金：山东省自然科学基金(ZR2020MB104);天然药物活性物质与功能国家重点实验室开放课题(GTZK202105)。

摘　　要：以5-溴水杨醛为起始原料,经还原、苄基保护、Suzuki-Miyaura偶联、双键加成、亲核取代、钯碳还原反应合成了沙丁胺醇,反应总收率为56.0%(以5-溴水杨醛计)。并对关键的Suzuki-Miyaura偶联反应条件进行了优化,获得最优的反应条件为:n[1-苄氧基-2-苄氧甲基-4-溴苯(Ⅱ)]∶n(乙烯基三氟硼酸钾)∶n(氯化钯)∶n(三苯基膦)∶n(碳酸铯)=1∶1.2∶0.02∶0.06∶2,V(四氢呋喃)∶V(水)=9∶1混合液为溶剂,中间体Ⅱ浓度为0.5 mol/L,回流反应12 h,在该条件下1-苄氧基-2-苄氧甲基-4-乙烯基苯(Ⅲ)收率为91%。中间体及产物的结构经HRMS、^(1)HNMR、^(13)CNMR确证。Salbutamol with an overall yield of 56.0%(based on 5-bromosalicylaldehyde)was synthesized from 5-bromosalicylaldehyde via reduction,benzyl protection,Suzuki-Miyaura coupling reaction,addition to double bond,nucleophilic substitution and Pd/C reduction,followed by optimization on key parameters of Suzuki-Miyaura coupling reaction.The optimal reaction conditions were obtained as follows:n[1-benzyloxy-2-benzyloxymethyl-4-bromobenzene(Ⅱ)]∶n(potassium vinyltrifluoroaborate)∶n(palladium chloride)∶n(triphenylphosphine)∶n(cesium carbonate)=1∶1.2∶0.02∶0.06∶2,volume ratio of tetrahydrofuran to water in solvent 9∶1,intermediateⅡconcentration 0.5 mol/L,refluxing time 12 h.Under this condition,the yield of 1-benzyloxy-2-benzyloxymethyl-4-vinyl benzene(Ⅲ)was 91%.Meanwhile,the structure of intermediates and salbutamol were confirmed by HRMS,^(1)HNMR and^(13)CNMR.

关 键 词：沙丁胺醇 Suzuki-Miyaura偶联 5-溴水杨醛 乙烯基三氟硼酸钾 精细化工中间体 

分 类 号：O622[理学—有机化学]