川芎嗪中间体2-氯甲基-3,5,6三甲基吡嗪的合成优化

摘要

Objective To compare the synthesis methods of"one-step method"and"four-step method"and explore the key steps of the"four-step method",and finally to determine and optimize the synthesis method of the key intermediate of ligustrazine,2-chlo-romethyl-3,5,6-trimethylpyrazine(TMP-Cl).Methods TMP-Cl was synthesized by free radical halogenation"one-step process"and oxygen generation,acetylation,hydrolysis,mild halogenation"four-step process",combined with HPLC to monitor the reac-tion process,and HRMS,1H-NMR and 13C-NMR were used to confirm the structure of compounds.Results The mild halogena-tion"reaction was firstly carried out in the"four-step method"with TsCl/TEA/DMAP system which had never been reported yet.And the single-step yield was nearly 100%.After comparison,we found that the"four-step method"shared the merits of less by-products and mild reaction conditions.The final product yield was as high as 80%.The"one-step method"was harsh in condi-tion to produce much more by-products than the"four-step method".The main product yield of"one-step method"was about 50%.Conclusion The"four-step method"has the advantages of mild reaction conditions,small stimulus,high yield and simple post-treatment.It is the satisfactory method for the synthesis of TMP-Cl,which could provide a practical reference for the future designing and synthesizing the ligustrazine derivatives.%目的 对比"一步法"与"四步法"的制备方法,同时对"四步法"的关键步骤进行探讨,确定并优化川芎嗪中间体2-氯甲基-3,5,6三甲基吡嗪(TMP-Cl)的合成方法.方法 分别通过自由基卤代的"一步法"以及氧代、乙酰化、水解和温和卤代的"四步法"合成TMP-Cl,结合HPLC监测反应进程,并借助HRMS、1H-NMR和13C-NMR确认化合物结构.结果 本实验"四步法"中首次采用未见报道的TsCl/TEA/DMAP体系进行温和卤代反应,单步产率近100%.综合对比研究发现,"四步法"副产物少且反应条件温和,终产物产率高达80%.而"一步法"反应剧烈,副产物较多,主产物产率在50% 左右.结论 "四步法"反应条件温和、刺激性小、产率高、后处理简单,是TMP-Cl的最佳合成方法,对于川芎嗪衍生物的后期设计、合成具有实际参考意义.