摘要
对盐酸度洛西汀生产过程中产生的两个类Hofmann-Martius重排产物进行了研究。通过不同反应条件的考察并结合LC-MS和NMR技术对两个类Hofmann-Martius重排产物进行了结构解析与产生机制的分析。结果表明:这两个类Hofmann-Martius重排产物为在强酸性条件下,度洛西汀中萘酚醚键发生断裂产生一个萘酚中间态和一个烷基噻吩正离子中间态,接着烷基噻吩正离子会分别与萘酚中间态在邻位和对位发生亲核取代而产生的一对同分异构体,二者的产生与强酸性和质子性溶剂环境有关,因而在盐酸度洛西汀的生产过程中要有效控制度洛西汀成盐过程中的pH至3~7以及保持反应温度低于50℃,并结合溶剂筛选实验最终得到合适的非质子性结晶溶剂丙酮,以避免这两种同分异构体杂质的产生。
Two Hofmann-Martius-like rearrangement products generated in the production of duloxetine hydro⁃chloride were studied.The structures and generation mechanism of the two Hofmann-Martius rearrangement products were analyzed by LC-MS and NMR.The results showed that under the acidic conditions,the naphthol ether bond of duloxetine would break down and the intermediates of naphthol and the alkyl thiophene cation was generated;the two Hofmann-Martius-like rearrangement products were proven to be a pair of isomers produced by nucleophilic substitution between the naphthol intermediate state and the alkyl thiophene cation intermediate state at the ortho or the para position,respectively.The production of two isomers was related to the strong acidic and protic solvent environment.Therefore,in the salting process of duloxetine hydrochloride,the pH value should be controlled in the range of 3-7 and temperature should be maintained below 50℃,as well as the non⁃protic solvent acetone is chosen to avoid generation of the two isomers.
作者
张可可
林金生
郑乐伟
王吉超
李敏
沈卫阳
ZHANG Keke;LIN Jinsheng;ZHENG Lewei;WANG Jichao;LI Min;SHEN Weiyang(Center of Excellence For Modern Analytical Technologies,Zhejiang Huahai Pharmaceutical Co.,Ltd.,Linhai 317024;School of Science,China Pharmaceutical University,Nanjing 211198,China)
出处
《中国药科大学学报》
CAS
CSCD
北大核心
2023年第4期474-482,共9页
Journal of China Pharmaceutical University
