酒石酸唑吡坦的合成工艺优化  

Synthetic Process Improvement of Zolpidem Tartrate

作　　者：鲍广龙 张乃华 陈庆涛 冯中 张贵民 BAO Guanglong;ZHANG Naihua;CHEN Qingtao;FENG Zhong;ZHANG Guimin(Shandong Engineering Research Center for New Drug Pharmaceuticals R&D in Shandong Province,Lunan Better Pharmaceutical Co.,Ltd.,Linyi 273400;Shandong Pharmaceutical Internationalization Engineering Laboratory,Shandong New Time Pharmaceutical Co.,Ltd.,Linyi 273400)

机构地区：[1]鲁南贝特制药有限公司,药物新制剂研发山东省工程研究中心,山东临沂273400 [2]山东新时代药业有限公司,山东省药物国际化工程实验室,山东临沂273400

出　　处：《中国医药工业杂志》2024年第4期510-514,共5页Chinese Journal of Pharmaceuticals

基　　金：泰山产业创新领军人才项目(tscx202306086)。

摘　　要：文章对酒石酸唑吡坦(1)的合成工艺进行了改进与优化。以乙醛酸(4)为起始原料与乙酸酐反应得到2,2-二乙酰氧基乙酸(5),5经氯化亚砜氯代生成2,2-二乙酰氧基乙酰氯(6),然后6与二甲胺反应制得N,N-二甲基-2,2-二乙酰氧基乙酰胺(7),7经吡啶对甲苯磺酸盐水解得关键侧链中间体N,N-二甲基-2-氧代乙酰胺(8)。以对甲基苯乙酮(2)为另一起始物料,经溴素溴代后与2-氨基-5-甲基吡啶经“一锅法”合成6-甲基-2-(4-甲基苯基)咪唑[1,2-a]吡啶(3),然后3与8亲核加成制得α-羟基唑吡坦(9),9经三甲基氯硅烷/碘化钠体系一步还原生成唑吡坦(10),最后10与L-(+)-酒石酸成盐制得1,纯度>99.89%,总收率52.4%(以2计)。改进后的工艺稳定、操作简便、生产成本低,适合工业化生产。An improved synthetic process of zolpidem tartrate(1)was developed.Glyoxylic acid(4)was reacted with acetic anhydride to obtain 2,2-diacetoxyacetic acid(5),which was chlorinated by thionyl chloride to generate 2,2-diacetoxyacetyl chloride(6).Then,6 reacted with dimethylamine chloride to provide N,N-dimethyl-2,2-diacetoxyacetamide(7).Finally,7 was hydrolyzed by pyridinium 4-toluenesulfonate to afford the key intermediate N,N-dimethyl-2-oxoacetamide(8).p-Methylacetophenone(2)was another starting material,and brominated with bromine,followed by the reaction with 2-amino-5-methylpyridine by“one-pot”method to synthesize 6-methyl-2-(4-methylphenyl)-imidazole[1,2-a]pyridine(3),which was converted intoα-hydroxyzolpidem(9)via nucleophilic addition with 8,and then 9 was subjected to the reduction by chlorotrimethylsilane/NaI system to bring out zolpidem(10).Finally,the target compound 1 was obtained from 10 through salification with L-(+)-tartaric acid with an overall yield of 52.4%(based on 2)and the purity of 99.89%.The process was stable with simple operation and low cost,which was suitable for industrial production.

关 键 词：酒石酸唑吡坦 镇静催眠药 合成工艺 制药工艺 

分 类 号：R971.3[医药卫生—药品] R914.5[医药卫生—药学] TQ460.6[化学工程—制药化工]