枸橼酸舒芬太尼绿色合成工艺优化  

Optimization of the Green Synthesis Process of Sufentanil Citrate

作　　者：王辉[1] 曾令高 赵俊豪 谷栩薇 高梓真[1] 杨相平[1] WANG Hui;ZENG Linggao;ZHAO Junhao;GU Xuwei;GAO Zizhen;YANG Xiangping(Pharmaceutical Research Institute of Jiangsu Nhwa Pharmaceutical Co.,Ltd.·Jiangsu Provincial Key Laboratory of Central Nervous System Drugs,Xuzhou,Jiangsu,China 221100;Chongqing Institute for Food and Drug Control·NMPA Key Laboratory for Quality Monitoring of Narcotic Drugs and Psychotropic Substances,Chongqing,China 401121)

机构地区：[1]江苏恩华药业股份有限公司·江苏省中枢神经药物研究重点实验室,江苏徐州221100 [2]重庆市食品药品检验检测研究院·国家药品监督管理局麻醉精神药品质量监测重点实验室,重庆401121

出　　处：《中国药业》2024年第17期11-15,共5页China Pharmaceuticals

基　　金：重庆英才计划“包干制”项目[cstc2021ycjh-bgzxm0315]。

摘　　要：目的优化枸橼酸舒芬太尼的绿色合成工艺。方法以N-叔丁氧羰基-哌啶酮、苯胺及2-(2-噻吩)乙醇为原料,经Bargellini、酯化、还原、甲基化、脱保护、磺酰化、N-烷基化、酰化反应得舒芬太尼,最后经成盐得枸橼酸舒芬太尼。结果优化后的绿色合成工艺避免了使用剧毒试剂氰化物及钯炭加氢脱苄基工艺,终产品的纯度可达99.5%以上。结论优化后的枸橼酸舒芬太尼合成工艺,原料廉价易得,反应条件温和,操作简便,工艺安全性高,可保证药品的质量及安全性,适合绿色工业化生产。Objective To optimize the green synthesis process of sufentanil citrate.Methods With N-Boc-piperidone,aniline,and 2-(2-thiophene)ethanol as active pharmaceutical ingredients(API),sufentanil was obtained through Bargellini,esterification,reduction,methylation,deprotection,sulfonation,N-alkylation,and acylation reactions.Finally,sufentanil citrate was obtained by salt formation.Results The optimal green synthesis process avoided the use of highly toxic reagents cyanides and palladium on carbon hydrogenation debenzylation processes,and the purity of the final product could reach over 99.5%.Conclusion The optimal synthesis process of sufentanil citrate has the advantages of cheap and easily obtainable API,mild reaction conditions,simple operation,and high process safety,which can ensure the quality and safety of the drug and is suitable for green industrial-scale production.

关 键 词：枸橼酸舒芬太尼 绿色合成 工艺优化 

分 类 号：R917.2[医药卫生—药物分析学] TQ460.6[医药卫生—药学]