超声辐射下合成盐酸罗哌卡因

在超声辐射下,以(S)-2-哌啶甲酸(Ⅱ)为原料,依次与氯化亚砜、2,6-二甲基苯胺反应制得(S)-N-(2,6-二甲基苯基)-2-哌啶甲酰胺(Ⅴ),而后,Ⅴ与溴丙烷发生N-丙基化反应,经盐酸成盐得到目标化合物手性纯的盐酸盐罗哌卡因(Ⅰ)。该文考察了超声辐射条件下反应溶剂、反应温度和反应时间等因素对反应收率的影响。优化后的工艺条件与传统加热方法相比,具有条件温和、反应时间短、收率高等优点。得到的最佳反应条件为:以甲苯为酰氯和酰胺反应溶剂,酰氯化反应条件为40℃超声反应1.5 h,丙基化反应条件为40℃超声反应1 h,盐酸罗哌卡因的收率为57.8%,[α]2D5=-6.7°(c2,H2O)。部分中间体和目标产物的结构通过熔点和核磁共振波谱进行了表征。

Synthesis of Ropivacaine hydrochloride under ultrasonic irradiation

Ropivacaine hydrochloride was synthesized from(S)-2-pipecolic acid by successive reaction with SOCl2 and 2,6-dimethylaniline under ultrasonic irradiation to yield(S)-N-(2,6-dimethylphenyl)-piperidin-2-carboxamide(Ⅴ),which went through a subsequent reaction with 1-bromopropane under ultrasonic irradiation.The effects of reaction solvent,temperature and duration under ultrasonic irradiation were investigated.Compared with conventional methods,the present procedures have the advantages of milder conditions,shorter reaction duration and higher yields.The optimal conditions of the synthesis of ropivacaine hydrochloride were as follows:toluene being used as solvent in acylation and amidation reaction,acylation reaction conditions of 40 ℃ for 1.5 h,propyl reaction conditions of 40 ℃ for 1 h.Under such optimum reaction conditions,the total yield was 57.8%,and [α]25D=-6.7°(c2,H2O).Some of the intermediates and the target product were characterized by means of melting point and 1HNMR.