利匹韦林中间体4-[(4-羟基-2-嘧啶基)氨基]苯腈的合成  

Synthesis of 4-[(4-Hydroxy-2-Pyrimidine)Amino]Benzonitrile of Ripiverin Intermediate

作　　者：刘彤 陈钒 冷彬爽 陈心慧 肖艳华 LIU Tong;CHEN Fan;LENG Binshuang;CHEN Xinhui;XIAO Yanhua(School of Chemical Engineering and Pharmacy,Wuhan Institute of Technology,Key Laboratory of Green Chemical Process(Wuhan Institute of Technology),Ministry of Education,Hubei Key Laboratory of Novel Chemical Reactor and Green Chemical Technology(Wuhan Institute of Technology),Wuhan 430205,China)

机构地区：[1]武汉工程大学化工与制药学院,绿色化工过程教育部重点实验室(武汉工程大学),新型反应器与绿色化学工艺湖北省重点实验室(武汉工程大学),湖北武汉430205

出　　处：《武汉工程大学学报》2022年第4期390-394,共5页Journal of Wuhan Institute of Technology

基　　金：国家自然科学基金(22004095);武汉工程大学研究生教育创新基金(CX2020009);武汉工程大学校长基金(XZJJ2020018)。

摘　　要：为提高利匹韦林关键中间体4-[(4-羟基-2-嘧啶基)氨基]苯腈(1)的合成收率,设计了以S-甲基异硫脲硫酸盐(2)与乙氧基甲叉丙二酸二乙酯(3)为原料,经缩合、水解、酸化、催化脱羧合成2-甲硫基-4-嘧啶酮,利用其进一步与对氨基苯腈反应合成目标产物1的新工艺,并对该工艺中的缩合反应和脱羧反应进行了优化。由正交实验得到的缩合反应最佳工艺条件为原料2、3和氢氧化钠物质的量之比为1.0∶1.2∶3.2、反应温度为20℃、混合溶剂中乙醇与水的体积比为1.2∶1;脱羧反应的高效催化剂为吡啶,最佳温度为215℃。优化后合成目标产物1的总收率达到61.52%。经核磁共振(1H NMR)鉴定,所有化合物的谱图数据均与文献一致。该路线原料廉价,条件简单,适用于工业化生产。To improve the yield of key intermediate of Ripiverin,4-[(4-hydroxy-2-pyrimidine)amino]benzonitrile(1),a new process was designed,where 2-methylthio-4-pyrimidone was synthesized by condensation,hydrolysis,acidification and decarboxylation with S-methyl isothiourea sulfate(2)and diethyl ethoxymethylenemalonate(3)as raw materials,and was further reacted with 4-aminobenzonitrile to obtain the target product 1.The condensation reaction and decarboxylation reaction were optimized.The optimum process conditions of the condensation reaction are obtained by orthogonal experiment at molar ratio of raw materials 2,3 to NaOH of 1.0∶1.2∶3.2,reaction temperature of 20℃,and volume ratio of ethanol to water of 1.2∶1 in the mixed solvent.The efficient catalyst for the decarboxylation is pyridine,and the optimum temperature is 215℃.The total yield reaches 61.52%after optimizing the process.The data of all compounds identified through hydrogen nuclear magnetic resonance is consistent with the reported data in literature.This route is suitable for industrial production due to cheap raw materials and simple conditions.

关 键 词：利匹韦林 4-[(4-羟基-2-嘧啶基)氨基]苯腈 合成 

分 类 号：R978.7[医药卫生—药品]