阿那格雷三氯衍生物的合成  

Synthesis of Anagrelide Trichloro Derivative

作　　者：蔡泽宇 胡伟 孟宪华 王正雄 CAI Zeyu;HU Wei;MENG Xianhua;WANG Zhengxiong(Wuhan R&D Center,Hubei Hongyuan Pharmaceutical Technology Co.,Ltd,Wuhan 430206,China)

机构地区：[1]湖北省宏源药业科技股份有限公司武汉研发中心,湖北武汉430206

出　　处：《武汉工程大学学报》2019年第2期121-124,共4页Journal of Wuhan Institute of Technology

摘　　要：以3,4,5-三氯苯胺为起始物料,经过桑德迈尔反应,氧化开环,还原反应,烷基化反应,环合反应得到阿那格雷三氯衍生物。桑德迈尔反应中,反应温度控制在70～80℃范围内,4,5,6-三氯靛红收率为79.7%;氧化开环中,反应温度保持50℃,在6 mol/L氢氧化钠水溶液中滴加过氧化氢,6-氨基-2,3,4-三氯苯甲酸收率64.4%;环合反应时,用氯甲脒盐酸盐替代溴化氰作为环合剂,避免剧毒物对人体的伤害。所得到化合物及中间体经过质谱、核磁共振氢谱等分析手段进行了表征,波谱数据与化合物结构吻合。合成阿那格雷三氯衍生物的方法步骤少、收率高,具有良好的应用前景。Starting from 3,4,5-trichloroaniline,an anagrelide trichloroderivative was synthesized via 5 sequential reaction steps including Sandmeyer reaction,oxidative ring-opening,reduction,alkylation,and cyclization reactions.The reaction temperature was adjusted in the range of 70-80℃in the Sandmeyer reaction,and the yield of 4,5,6-trichloroindigo reached 79.7%.In the oxidative ring-opening process,concentrated H2 O2 solution was added drop by drop into a 6 mol/L NaOH aqueous solution at a constant temperature of 50℃,and the yield of 6-amino-2,3,4-trichloro-benzoic acid was 64.4%.In the cyclization reaction,chloroformamidinehydrochloride was employed as the cyclizing agent instead of the highly toxic cyanogen bromide.The overall products and intermediates in each reaction step were characterized using mass spectroscopy and1 HNMR spectroscopy,and the results are in good agreement with the corresponding molecular structures.This study provides a novel method to synthesize an anagrelide trichloroderivative with relatively less steps and high yield,thus showing a good prospect for industrial application.

关 键 词：阿那格雷 三氯衍生物 合成 

分 类 号：O624.6[理学—有机化学] 0621.3[理学—化学]