第 53 卷第 3 期 Vol. 53 No. 3 2023 年 6 月 Jun 2023

所属栏目：医药及中间体 阿加曲班杂质的合成

胡中元，唐旭静，邢 磊，张晓玲，刘彦龙* （正大天晴药业集团股份有限公司研究院，江苏 南京 210000）

摘　要：为有效控制阿加曲班原料药质量并建立质量标准，以4-碘苯胺为起始原料，经与甲基丙烯醛环合、与苄硫醇偶联、氧化、水解制备阿加曲班杂质3-甲基喹啉-6-磺酸，并优化了合成工艺。优化条件下，杂质纯度99.1%（HPLC），总收率49.5%，其结构经1H NMR、13C NMR和HRMS表征确证。合成工艺原料易得，反应条件温和，制备的杂质纯度高，可作为阿加曲班药物质量控制的杂质对照品。

关键词：阿加曲班；4-碘苯胺；杂质

中图分类号：R914　　文献标识码：A　　文章编号：1009-9212（2023）03-0038-03

Synthesis of Impurity in Argatroban

HU Zhong-yuan, TANG Xu-jing, XING Lei, ZHANG Xiao-ling, LIU Yan-long* (Research Institute of Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Nanjing 210000, China)

Abstract：In order to effectively control the quality of Argatroban and establish the quality standard, 4-iodoaniline was used as the starting material, and the intermediate was obtained by cyclization with methacrolein. Argatroban impurity 3-methylquinoline-6-sulfonic acid was synthesized from the intermediate via cross-coupling with benzyl mercaptan, oxidation, hydrolysis, and purification with a purity of 99.1% (HPLC) and an overall yield about 49.5%. The conditions for the synthetic process were optimized. Their structures were confirmed by 1H NMR, 13C NMR and HRMS. This synthetic process is reasonable and feasible, the reaction conditions are mild, and the purity of the impurity is high. It can be used as the impurity reference substance for the quality control of Argatroban.

Key words：Argatroban; 4-iodoaniline; impurity

作者简介：胡中元（1986—），男，安徽蚌埠人，工程师，硕士，研究方向：药物合成工艺（E-mail：164313963@qq.com）。

联 系 人：刘彦龙，高级工程师，研究方向：药物合成工艺。

收稿日期：2023-02-24