Structural elucidation and mechanism study for Hofmann-Martius-like rearrangement products in duloxetine hydrochloride under the process condition
10.11665/j.issn.1000-5048.2023022102
- VernacularTitle:盐酸度洛西汀工艺中类Hofmann-Martius重排产物的确证与产生机制
- Author:
Keke ZHANG
1
;
Jinsheng LIN
;
Lewei ZHENG
;
Jichao WANG
;
Min LI
;
Weiyang SHEN
Author Information
1. .浙江华海药业股份有限公司高等分析技术中心
- Publication Type:Journal Article
- Keywords:
duloxetine hydrochloride;
Hofmann-Martius-like rearrangement;
LC-MS;
mechanism study
- From:
Journal of China Pharmaceutical University
2023;54(4):474-482
- CountryChina
- Language:Chinese
-
Abstract:
Two Hofmann-Martius-like rearrangement products generated in the production of duloxetine hydrochloride 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 °C, as well as the nonprotic solvent acetone is chosen to avoid generation of the two isomers.
