RDEA3170合成工艺优化  

Synthetic Process Optimization of RDEA3170

作　　者：胡旭 尹传奇 杨梦然 傅晶 吴莉 冯权武 HU Xu;YIN Chuan-qi;YANG Meng-ran;FU Jing;WU Li;FENG Quan-wu(School of Chemistry and Environmental Engineering,Wuhan Institute of Technology,Wuhan 430205,Hubei,China)

机构地区：[1]武汉工程大学化学与环境工程学院,湖北武汉430205

出　　处：《精细化工》2019年第1期101-105,共5页Fine Chemicals

基　　金：湖北省教育厅重点项目(D20141510);湖北省教育厅项目(B2017053)~~

摘　　要：以1,4-二溴萘为起始原料,经溴-镁交换、羧基化、酰胺化和脱水反应,优化了4-溴-1-萘甲腈(Ⅳ)合成方法。通过连续反应法,以Pd(PPh3)2Cl2催化实现了4-溴-1-萘甲腈的Miyaura硼烷基化及其产物(4-氰基萘-1-基)硼酸频那醇酯(Ⅴ)与2-((3-溴吡啶-4-基)硫)-2-甲基丙酸乙酯(Ⅰ)的Suzuki偶联,得到2-((3-(4-氰基萘-1-基)吡啶-4-基)硫)-2-甲基丙酸乙酯(Ⅵ)。连续反应的最佳工艺条件为:n(联硼酸频那醇酯)∶n(Ⅳ)∶n(Ⅰ)∶n[Pd(PPh3)2Cl2]∶n(KOAc)∶n(K2CO3)=1.1∶1∶1∶0.06∶3∶3;KOAc和K2CO3分别作为Miyaura硼烷基化和Suzuki偶联反应的碱依次加入,相应的反应温度分别为80和110℃,反应时间分别为2和12 h。化合物Ⅵ水解得到产品RDEA3170[2-((3-(4-氰基萘-1-基)吡啶-4-基)硫)-2-甲基丙酸],其结构经1HNMR和13CNMR表征。该合成工艺RDEA3170的总收率达到42%,适合工业化生产。A new method for the synthesis of 4-bromo-1-naphthonitrile(Ⅳ) from 1,4-dibromonaphthalene was conducted by bromo-magnesium exchange reaction,carboxylation,amidation and dehydration.In the presence of catalyst Pd(PPh3)2Cl2,the Miyaura borylation reaction enabled the synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthonitrile(Ⅴ) by cross-coupling of bis(pinacolato) diboron(BPIN)2 with 4-bromo-1-naphthonitrile and the Suzuki coupling reaction between intermediate Ⅴ with ethyl 2-(3-bromopyridin-4-ylthio)-2-methylpropanoate(Ⅰ) led to ethyl 2-(3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoate(Ⅵ) by continuous reaction process.The optimum conditions were as follows:n[(BPIN)2]∶n(Ⅳ)∶n(Ⅰ)∶n[Pd(PPh3)2 Cl2]∶n(KOAc)∶n(K2 CO3)=1.1∶1∶1∶0.06∶3∶3,for the Miyaura borylation,KOAc used as base,reaction temperature 80 ℃,reaction time 2 h,but for the Suzuki coupling,K2 CO3 used as base,reaction temperature 110 ℃,reaction time 12 h.The final product RDEA3170 [2-(3-(4-cyanonaphthalen-1-yl)pyridin-2-ylthio)-2-methylpropanoic acid] was obtained by hydrolysis of compound Ⅵ and characterized by 1 H NMR and 13 C NMR.The overall yield of RDEA3170 was up to 42%.This synthesis process is suitable for industrial production.

关 键 词：4-溴-1-萘甲腈 溴-镁交换反应 连续反应法 SUZUKI偶联 RDEA3170 合成工艺优化 医药原料 

分 类 号：TQ460.31[化学工程—制药化工]