3-(環(huán)丙氨基)丙烯酸乙酯的合成研究

第7卷第5期杭州師范大學(xué)學(xué)報(自然科學(xué)版)Vol 7 No. 52008年9月Journal of Hangzhou Normal University( Natural Science Edition)Sep.2008文章編號:1674-232X(2008)05-0360-033-(環(huán)丙氨基)丙烯酸乙酯的合成研究毛建剛,章鵬飛“,顧海寧(1.杭州師范大學(xué)材料與化學(xué)化工學(xué)院,浙江杭州3100362.浙江大學(xué)分析中心,浙江杭州310013)報道了3-(環(huán)丙氨基)丙烯酸乙酯的環(huán)境友好的方便的合成新方法在合成中避免了使用CrO3作為氧化劑,所有的原料都是無(wú)毒的,并有很高的產(chǎn)率.該方法具有環(huán)境友好的優(yōu)點(diǎn)關(guān)鍵詞:3-(環(huán)丙氨基)丙烯酸乙酯;喹喏酮;環(huán)境友好;合成中圖分類(lèi)號:O621.3文獻標志碼:A加替沙星,環(huán)丙沙星,司帕沙星等喹喏酮類(lèi)藥物是具有廣譜抗菌活性的抗生素7,而3-(環(huán)丙氨基)丙烯酸乙酯(3)是合成喹喏酮類(lèi)藥物的關(guān)鍵中間體.作為喹喏酮類(lèi)藥物合成工作的一部分,就需要一種簡(jiǎn)單的方法來(lái)合成3-(環(huán)丙氨基)丙烯酸酯.然而,迄今為止現有文獻中還沒(méi)有一種既環(huán)境友好又很實(shí)用的合成方法楊等通過(guò)用CrO3氧化1-丙炔醇9丙炔酸與乙醇的酯化01以及環(huán)丙胺對丙炔酸乙酯的Michel加成反應2獲得了化合物(3)(見(jiàn)圖1),但是反應后生成的鉻鹽給后處理帶來(lái)了很大的難度,嚴重污染了環(huán)境,對于藥物合成來(lái)講也是極不安全的,并且這條合成路線(xiàn)成本相對較高,因而極大地限制了喹喏酮類(lèi)藥物的產(chǎn)業(yè)化1I Cr0OH 4.EtOHCOEt圖1反應式現在報道的3-(環(huán)丙氨基)丙烯酸乙酯(3)的這種有效的合成方法采用的合成路線(xiàn)(圖2)是:首先依據Harkins,H.H的方法合成得到甲?；宜嵋阴モc鹽(6),隨后用環(huán)丙胺硫酸鹽與化合物(3)反應,再消除水得到所期望的3-(環(huán)丙氨基)丙烯酸乙酯(3).該方法除了容易操作、成本低,還有環(huán)境友好、高產(chǎn)率總產(chǎn)率高達88%)的優(yōu)點(diǎn)HCO,Et CH, CO, EtG OE/Na(D-NH )SO,圖2反應式二收稿日期:2008-08-18中國煤化工基金項目:國家科技支撐計劃項目(2007BA134B05);浙江省綠色化工重HCNMHG作者簡(jiǎn)介:毛建剛(1980—)男江西玉山人,有機化學(xué)專(zhuān)業(yè)碩土研究生,主要成和不對稱(chēng)合成研究通訊作者:章鵬飛(1965—),男,安徽績(jì)溪人,教授,博士,主要從事藥物合成和不對稱(chēng)合成研究 E-mail: pfzhang@hnu,edu,第5期毛建剛,等:3-(環(huán)丙氨基丙烯酸乙酯的合成研究3611實(shí)驗部分1.1實(shí)驗條件YanacoMP-S3顯微熔點(diǎn)儀(溫度計未校正);UV-1型三用紫外分析儀; Agilent5975型質(zhì)譜儀(EI轟擊電壓70eV);Av400MH( Bruker)核磁共振儀(TMS為內標,CDCl為溶劑).所用試劑均為分析純1.2甲?；宜嵋阴モc鹽(6將2.30g金屬鈉壓成鈉絲置于反應瓶中,加入50mL無(wú)水乙醚,控制反應液溫度為25℃左右,將118g甲酸乙酯與8.2g乙酸乙酯的混合液從恒壓滴液漏斗中緩慢滴加到反應瓶中,靜置反應,開(kāi)始反應速度較慢,當反應一段時(shí)間后開(kāi)始加速同時(shí)有大量氣泡放出,當金屬鈉完全消失,反應結束過(guò)濾得11.6g甲?；宜嵋阴モc鹽,粗產(chǎn)率為90.3%.HNMR(CDCl2)88.82(1H,s),8.01(1H,s),4.05(2H,q)1.15(3H,t)1.33-(環(huán)丙氨基)丙烯酸乙酯(3)在1L的燒瓶中加入30mL的異丙醚,隨后在60℃時(shí)加入(15.50g,0.073mol)環(huán)丙胺硫酸鹽,混合物攪拌、回流1h,然后往混合物中逐滴加入50mL甲?；宜嵋阴モc鹽(6)1(13.80g,0.10mol)的異丙醚溶液滴加時(shí)間不短于1h反應混合物另外回流攪拌4.5h.冷卻后抽濾濾液在常壓下濃縮移去低沸物和大部分溶劑然后減壓濃縮得到產(chǎn)物3-環(huán)丙胺基丙烯酸乙酯(3)(bp.64~68℃/12Pa,文[11]bp.6568℃/0.012kPa)15.22g,粗產(chǎn)率為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討論與結果通過(guò)對3(環(huán)丙氨基)丙烯酸乙酯(3)合成工藝的改進(jìn)提供了一種成本低、工藝合理、三廢排放量少的合成路線(xiàn)從而為喹喏酮類(lèi)藥物的產(chǎn)業(yè)化合成開(kāi)辟了新途徑參考文獻:[1] Niki Y, Miyashita N, Kubota Y, et al. In vitro and in vivo antichlamydial activities of HSR-903, a new fluoroquinolone antibioticlJJ.Antimicrob Agents Chemother., 1997. 41(4): 857-859,[2] Takahashi Y, Masuda N, Otsuki M, et al. In vitro activity of HSR-903, a new quinolone[JJ. Antimicrob Agents Chemother., 1997, 41.(6):1326-1330[3] Tomioka H, Sato K, Akaki T, et al. Comparative in vitro antimicrobial activities of the newly synthesized quinolone HSR-903, Sitafloxacin(DU-6859a), Gatifloxacin( AM-1155), and Levofloxacin against Mycobacterium tuberculosis and Mycobacterium avium complex[]. Antimicrob Agents Chemother. 1999. 43(12): 3001-3004[4] Watanabe A, Tokue Y, Takahashi H, et aL. In vitro activity of HSR-903, a new oral quinolone, against bacteria causing respiratory infections[J]. Antimicrob Agents Chemother., 1999, 43(7):1767-1768[5] Yoshizumi S, Domon, H, Miyazaki S, et al. In vivo activity of HSR-903, a new fluoroquinolone, against respiratory pathogensLJJ.Antimicrob Agents Chemother., 1998, 42(4): 785-788[6]Sun J, Deguchi Y, Tauchi Y, et al. Distribution characteristics of orally administered olamufloxacin, a newly synthesized fluoroquinolo-ntibacterial, in lung epithelial lining fluid and alveolar macrophage in rats[J]. Eur. Pharm. Biopharm., 2006. 64(2): 238-45[7] Vancutsem PM, Babish JG, Schwark w S, et al. The fluoroquinolone antimicrobials, structure, antimicrobial activity, pharmacoki-netics and clinical use in domestic animals and toxicity[J3. Cornell Vet., 1990, 80(2):173[8] Wolf V. Notiz uber die Darstellung der Propiolsaure[J].Chem,, Ber,1953,86(6).735-737.[9]楊永正高云,李紹新3環(huán)丙胺基丙烯酸乙酯的合成[.中國醫藥工業(yè)雜[10] Rhinesmith H S. Action of Grignard reagents on the esters of propiolic aci中國煤化工1[11] Jung M E, Buszek KR. The stereochemistry of addition of trialkylammoniCN Galts to activated acety-es. Preparation of novel dienophiles for Diels-Alder reactions[J]. J. Am.1988,110(12);3965-3969[12] Grobe K, Heitzer H, Wiss H, et aL. Cycloaracylierung von Enaminen, I. Synthese von 4-Chinolon-3-carbonsaurenLJJ. Liebigs Ann杭州師范大學(xué)學(xué)報(自然科學(xué)版)2008年der Chem.,1987,1987(1):29-37[13]Maurer F, Grohe K. 2, 4-Dichloro-5-fluorobenzoic acid[P]. Ger Offen.3435392, 1986[14]李眉郭惠元環(huán)丙沙星合成路線(xiàn)圖解[]中國醫藥工業(yè)雜志,1992,23(9):427429[15] Harkins HH, Johnson T B. Researches on pyrimidines, cv. a new test for thymine and 5-methylcytosine in the presence of uracil andcytosine[J].J. Am. Chem. Soc., 1929, 51(4).1237-1242A Practical Synthesis of Ethyl 3-(cyclopropylamine)acrylateMAO Jian-gang, ZHANG Peng-fei, GU Hai-ning2(l College of Material Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, China2. 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頁(yè))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-中國煤化工CNMHG