第 48 卷第 2 期 Vol. 48 No. 2 2018 年 4 月 Apr 2018

所属栏目：医药及中间体 2-氰基-4-吡啶羧酸甲酯的合成工艺改进

门 靖，丁志新，曹卫凯，安 敏 （西安万隆制药股份有限公司，陕西 西安 710119）

摘　要：对2-氰基-4-吡啶羧酸甲酯的合成工艺进行了优化。以2-甲基-4-吡啶羧酸甲酯（2）为起始原料，经氧化、酰胺化、脱水3步反应制备了目标化合物，其结构经1H NMR和MS确证，总收率为53.0%。通过单因素实验的方法研究了投料比、析晶温度、反应时间等因素对产物的影响，优化工艺条件：n（2）∶n（高锰酸钾）= 1.0∶2.5，析晶温度为0 ~5℃；n（2-羧基-4-吡啶羧酸甲酯）∶n（二氯亚砜）= 1.0∶1.4，反应时间为5~6 h；脱水反应选择三氟乙酸酐-三乙胺体系作为脱水剂。工艺过程操作简单、反应条件温和，易于放大生产，具有较好的实际应用价值。

关键词：2-甲基-4-吡啶羧酸甲酯；2-氰基-4-吡啶羧酸甲酯；三氟乙酸酐-三乙胺

中图分类号：R914　　文献标识码：A　　文章编号：1009-9212（2018）02-0055-04

An Improved Process for the Preparation of 2-Cyano-4-pyridinecarboxylic Acid Methyl Ester

MEN Jing, DING Zhi-xin, CAO Wei-kai, AN Min (Xi'an WanLong Pharmaceutical Co., Ltd., Xi'an 710119, China)

Abstract：2-Cyano-4-pyridinecarboxylic acid methyl ester was synthesized from the 2-methyl-4-pyridinecarboxylic acid methyl ester (2) through a series of reactions including oxidation, amidation and dehydration reaction. The structure was confirmed by 1H NMR and MS. The overall yield was up to 53.0%. The factors including material ratio, crystallization temperature and reaction time were studied by single factor experiment. The preferential experimental results showed that the optimal reaction condition as follows: the ratio of compound 2 to potassium permanganate was 1.0∶2.5; the crystallization temperature was 0~5℃; the ratio of compound 3 to thionyl chloride was 1.0∶1.4; and the reaction time was 5~6 h. Trifluoroacetic anhydride-triethylamine system could play a good part in the dehydration reaction. This improved synthetic route had the advantages of easy preparation and mild reaction conditions, which was suitable for further application and good for practical application values.

Key words：2-methyl-4-pyridinecarboxylic acid methyl ester; 2-cyano-4-pyridinecarboxylic acid methyl ester; trifluoroacetic anhydride-triethylamine

作者简介：门 靖（1986-），男，陕西西安人，工程师，主要从事原料药开发及申报资料撰写工作（E-mail：1257391857@qq.com）。

收稿日期：2018-04-06