合成罗哌卡因中间体S型N-(2,6-二甲苯基)-2-哌啶甲酰胺拆分工艺改进  

Process Improvement for the Separation of Intermediates S-type of N-(2,6-Dimethylphenyl) Piperidine-2-Carboxylic Amide in the Synthesis of Ropivacaine

作　　者：严波 符义刚 李莉娥 

机构地区：[1]宜昌人福药业有限责任公司,湖北宜昌443005 [2]人福医药集团医药研究院,武汉430074

出　　处：《中国药房》2015年第16期2187-2189,共3页China Pharmacy

摘　　要：目的:探讨合成罗哌卡因的关键中间体S型N-(2,6-二甲苯基)-2-哌啶甲酰胺(Pipecoloxylidide)的拆分和消旋新方法,以提高S型Pipecoloxylidide收率。方法:新工艺将拆分后从母液里回收的R型和S型Pipecoloxylidide混合物与偶氮二异丁腈(引发剂)、巯基乙酸乙酯在惰性溶剂甲苯中混合,于80℃进行消旋反应,并再次拆分得到S型Pipecoloxylidide以循环利用。结果:S型Pipecoloxylidide的收率由原工艺的30%左右提高到60%左右,经过拆分后的光学纯度值可达100%。结论:改进后的工艺能耗低(反应温度由原工艺的130℃以上降为80℃),条件温和,减少了副反应发生,工艺操作简单,能有效提高产品收率和纯度。OBJECTIVE： To explore the new method for the separation and racemization of the key intermediates S-type of N- （2, 6-dimethylphenyl） piperidine-2-carboxylic amide （S-type of pipecoloxylidide） in the synthesis of ropivacaine to improve the yield of S-type of pipecoloxylidide. METHODS： New process was used to mix the mixture of R-type and S-type of pipecoloxyli- dide recycled from mother liquor and azobisisobutyronitrile （initiator） and mercaptoacetic ethyl in inert solvent toluene, racemized at 80 ℃ and separated the S-type of pipecoloxylidide again for recycle. RESULTS ： The yield of S-type of pipecoloxylidide was im- proved from around 30% to around 60% and the optical purity value was reached 100%. CONCLUSIONS： The improved process has low energy consumption （the reaction temperature was decreased from over 130 ℃ to 80℃ ）, mild conditions and simple oper- ations. It reduces the incidence of side effects and effectively improves the yield and purity.

关 键 词：罗哌卡因 S型Pipecoloxylidide 合成 拆分 工艺改进 消旋反应 

分 类 号：R914.5[医药卫生—药物化学]