3-(环丙氨基)丙烯酸乙酯的合成研究

第7卷第5期杭州师范大学学报(自然科学版)Vol 7 No. 52008年9月Journal of Hangzhou Normal University( Natural Science Edition)Sep.2008文章编号:1674-232X(2008)05-0360-033-(环丙氨基)丙烯酸乙酯的合成研究毛建刚,章鹏飞“,顾海宁(1.杭州师范大学材料与化学化工学院,浙江杭州3100362.浙江大学分析中心,浙江杭州310013)报道了3-(环丙氨基)丙烯酸乙酯的环境友好的方便的合成新方法在合成中避免了使用CrO3作为氧化剂,所有的原料都是无毒的,并有很高的产率.该方法具有环境友好的优点关键词:3-(环丙氨基)丙烯酸乙酯;喹喏酮;环境友好;合成中图分类号:O621.3文献标志码:A加替沙星,环丙沙星,司帕沙星等喹喏酮类药物是具有广谱抗菌活性的抗生素7,而3-(环丙氨基)丙烯酸乙酯(3)是合成喹喏酮类药物的关键中间体.作为喹喏酮类药物合成工作的一部分,就需要一种简单的方法来合成3-(环丙氨基)丙烯酸酯.然而,迄今为止现有文献中还没有一种既环境友好又很实用的合成方法杨等通过用CrO3氧化1-丙炔醇9丙炔酸与乙醇的酯化01以及环丙胺对丙炔酸乙酯的Michel加成反应2获得了化合物(3)(见图1),但是反应后生成的铬盐给后处理带来了很大的难度,严重污染了环境,对于药物合成来讲也是极不安全的,并且这条合成路线成本相对较高,因而极大地限制了喹喏酮类药物的产业化1I Cr0OH 4.EtOHCOEt图1反应式现在报道的3-(环丙氨基)丙烯酸乙酯(3)的这种有效的合成方法采用的合成路线(图2)是:首先依据Harkins,H.H的方法合成得到甲酰基乙酸乙酯钠盐(6),随后用环丙胺硫酸盐与化合物(3)反应,再消除水得到所期望的3-(环丙氨基)丙烯酸乙酯(3).该方法除了容易操作、成本低,还有环境友好、高产率总产率高达88%)的优点HCO,Et CH, CO, EtG OE/Na(D-NH )SO,图2反应式二收稿日期:2008-08-18中国煤化工基金项目:国家科技支撑计划项目(2007BA134B05);浙江省绿色化工重HCNMHG作者简介:毛建刚(1980—)男江西玉山人,有机化学专业硕土研究生,主要成和不对称合成研究通讯作者:章鹏飞(1965—),男,安徽绩溪人,教授,博士,主要从事药物合成和不对称合成研究 E-mail: pfzhang@hnu,edu,第5期毛建刚,等:3-(环丙氨基丙烯酸乙酯的合成研究3611实验部分1.1实验条件YanacoMP-S3显微熔点仪(温度计未校正);UV-1型三用紫外分析仪; Agilent5975型质谱仪(EI轰击电压70eV);Av400MH( Bruker)核磁共振仪(TMS为内标,CDCl为溶剂).所用试剂均为分析纯1.2甲酰基乙酸乙酯钠盐(6将2.30g金属钠压成钠丝置于反应瓶中,加入50mL无水乙醚,控制反应液温度为25℃左右,将118g甲酸乙酯与8.2g乙酸乙酯的混合液从恒压滴液漏斗中缓慢滴加到反应瓶中,静置反应,开始反应速度较慢,当反应一段时间后开始加速同时有大量气泡放出,当金属钠完全消失,反应结束过滤得11.6g甲酰基乙酸乙酯钠盐,粗产率为90.3%.HNMR(CDCl2)88.82(1H,s),8.01(1H,s),4.05(2H,q)1.15(3H,t)1.33-(环丙氨基)丙烯酸乙酯(3)在1L的烧瓶中加入30mL的异丙醚,随后在60℃时加入(15.50g,0.073mol)环丙胺硫酸盐,混合物搅拌、回流1h,然后往混合物中逐滴加入50mL甲酰基乙酸乙酯钠盐(6)1(13.80g,0.10mol)的异丙醚溶液滴加时间不短于1h反应混合物另外回流搅拌4.5h.冷却后抽滤滤液在常压下浓缩移去低沸物和大部分溶剂然后减压浓缩得到产物3-环丙胺基丙烯酸乙酯(3)(bp.64~68℃/12Pa,文[11]bp.6568℃/0.012kPa)15.22g,粗产率为98%.HNMR(CDC1):07.44(1H,t),6.76(1H,d),4.19(2H,q),2,70~2.65(1H,m),1.35~1.30(4H,m),0.65~0.31(4H,m)2讨论与结果通过对3(环丙氨基)丙烯酸乙酯(3)合成工艺的改进提供了一种成本低、工艺合理、三废排放量少的合成路线从而为喹喏酮类药物的产业化合成开辟了新途径参考文献:[1] Niki Y, Miyashita N, Kubota Y, et al. 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Analytical Center, Zhejiang University, Hangzhou 310013, China)Abstract: The paper reports an environmentally friendly and convenient synthesis of Ethyl 3-CyclopropylaminoacrylateThe new method avoids using CrO, as oxidant in synthesis and has good yield, all the starting materials are nontoxic. Thenew method has the advantage of being environmental benign.Key words: Ethyl 3-(cyclopropylamine)acrylate: quinolones; environmental benign; synthesis(上接第359页)Existence and Multiplicity of Periodic Solutions forNonautonomous Second Order SystemsYIN Hong-mei, HOU Jing-hua, GUO Dong-xia(School of Mathematical Sciences and Computing Technology, Central South University, Changsha 410083, China)Abstract: By using the least action principle as well as Brezis and Nirenberg,s three critical point theory, thisbtains some existence and multiplicity theorems for periodic solutions of nonautonomous second order systems with atial, partial of which are greater than the product of a convex function and another Lebesgue measurable function, partial haveKey words: periodic solution second order system: Sobolev's inequality subconvex potential; coercivity three-critical-中国煤化工CNMHG