6,6'-二甲基-2,2'-联吡啶-4,4'-二甲酸甲酯的合成与表征

doi:10.11944/j.issn.1000-0518.2017.02.160163

摘要/Abstract

摘要：

以6-甲基-2-羟基吡啶-4-甲酸甲酯为起始原料,经酯化反应制备2-甲基-6-(对甲苯磺酰氧基)吡啶-4-甲酸甲酯,使其在过渡金属镍络合物催化作用下自身偶联合成6,6'-二甲基-2,2'-联吡啶-4,4'-二甲酸甲酯,通过改变投料比例、反应温度及投料顺序获得最佳反应条件,收率77%。经核磁共振、红外光谱、质谱及差示扫描热量法等对分子结构进行了表征,验证了合成方法的可靠性。该结构能够满足均相时间分辨荧光免疫分析螯合剂中间体的需求。目前,它已成功用于均相时间分辨荧光免疫分析。

关键词: 均相时间分辨荧光免疫分析, 自身偶联, 二甲基-联吡啶-二甲酸甲酯

Abstract:

Dimethyl 6,6'-dimethyl-[2,2'-bipyridine]-4,4'-dicarboxylate was synthesized in two steps from methyl 6-methyl-2-hydroxypyridine-4-carboxylate. The first step was the preparation of methyl 2-methyl-6-[(p-toluenesulfonyl)oxy]pyridine-4-carboxylate by esterification. The second step was to prepare the target product by nickel complex catalyzed homocoupling reaction. Several other factors which affected the reaction such as material proportion, reaction temperature and addition order were investigated. When the reaction was carried out under the optimal conditions, 77% yield was achieved. The products were characterized by nuclear magnetic resonance(NMR), Fourier transform infrared spectrometer(FTIR), mass spectrometry(MS) and differential scanning calorimetry(DSC) to prove the reliability of the synthetic method. This structure can fully satisfy the need of chelating agent intermediate for homogeneous time-resolved fluoroimmunoassay(HTRF), which has been succeeded in prectical applications.

Key words: homogeneous time-resolved fluoroimmunoassay, homocoupling, dimethyl dimethyl-[bipyridine]-dicarboxylate

柴永真, 常宇, 宋蕊琴, 刘巍, 李云辉, 潘利华. 6,6'-二甲基-2,2'-联吡啶-4,4'-二甲酸甲酯的合成与表征[J]. 应用化学, 2017, 34(2): 146-150.

CHAI Yongzhen, CHANG Yu, SONG Ruiqin, LIU Wei, LI Yunhui, PAN Lihua. Synthesis and Characterization of Dimethyl 6,6'-Dimethyl-[2,2'-bipyridine]-4,4'-dicarboxylate[J]. Chinese Journal of Applied Chemistry, 2017, 34(2): 146-150.

参考文献

[1]	Cordaro J G, McCusker J K, Bergman R G. Synthesis of Mono-substituted 2,2'-Bipyridines[J]. Chem Commun,2002,14:1496-1497.
[2]	Bass P,Purdon R A,Patterson M A,et al.Gastric Antisecretory and Other Pharmacologic Studies on 2,2'-Bipyridine[J]. J Pharmacol Exp Ther,1966,152(152):104-115.
[3]	Kaes C,Katz A,Hosseini M W. Bipyridine: The Most Widely Used Ligand. A Review of Molecules Comprising at Least Two 2,2'-Bipyridine Units[J]. Chem Rev,2000,100(10):3553-3590.
[4]	LI Haiyan,LI Yunhui,PAN Lihua,et al.Preparation and Characterization of a Novel Type Complex[J]. Chinese J Appl Chem,2010,27(9):1008-1011(in Chinese). 李海燕,李云辉,潘利华,等. 一种新型化合物的合成与表征[J]. 应用化学,2010,27(9):1008-1011.
[5]	Alpha B,Anklam E,Deschenaux R,et al.Synthesis and Characterisation of the Sodium and Lithium Cryptates of Macrobicyclic Ligands Incorporating Pyridine, Bipyridine, and Biisoquinoline Units[J]. Helv Chim Acta,1988,71:1042-1052.
[6]	Penalva V,Hassan J,Lavenot L,et al.Direct Homocoupling of Aryl Halides Catalyzed by Palladium[J]. Tetrahedron Lett,1998,39:2559-2560.
[7]	Tiecco M,Testaferri L,Tingoli M,et al.A Convenient Synthesis of Bipyridines by Nickel-phosphine Complex-Mediated Homo Coupling of Halopyridines[J]. Synthesis,1984,16(9):736-738.
[8]	Vanderesse R,Lourak M,Fort Y,et al.Activation of Reducing Agents. Sodium Hydride Containing Complex Reducing Agents 23.Symmetrical Coupling of Nitrogen-containing Heterocyclic Halides[J]. Tetrahedron Lett,1986,27(45):5483-5486.
[9]	Fort Y,Becker S,Caubere P. A Convenient Synthetic Route to Bis-heteroaromatic and Bis-heterocyclic Compounds Promoted by Liganded Nickel Complex Reducing Agents[J]. Tetrahedron,1994,50(41):11893-11902.
[10]	HONG Ran. Nickel Catalyst Ullmann Coupling Reaction of the Preliminary Study and Crystal Morphology Effect of the Hydrogen Acceptor in the Catalytic Transfer Hydrogenation[D]. Shanghai:Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,2001(in Chinese). 洪然. 镍催化的Ullmann偶联反应的初步研究以及氢转移化中氢受体的晶体形态效应[D]. 上海:中国科学院上海有机化学研究所,2001.
[11]	QIAN Yanlong,WANG Chen,TAO Xiaochun,et al.Synthesis of 2,2'-Bipyridine Through Catalitic Coupling Reaction of α-Brompyridine Using Nickel Complex[J]. J Org Chem,2003,23(11):1264-1266(in Chinese). 钱延龙,王晨,陶晓春,等. 镍络合物催化条件下2,2'-联吡啶的偶联合成[J]. 有机化学,2003,23(11):1264-1266.
[12]	Cornella J,Gómez-Bengoa E,Martin R. Combined Experimental and Theoretical Study on the Reductive Cleavage of Inert C—O Bonds with Silanes:Ruling out a Classical Ni(0)/Ni(Ⅱ) Catalytic Couple and Evidence for Ni(Ⅰ) Intermediates[J]. J Am Chem Soc,2013,135(5):1997-2009.
[13]	Lanni E L, McNeil A J. Mechanistic Studies on Ni(dppe)Cl2-catalyzed Chain-growth Polymerizations:Evidence for Rate-determining Reductive Elimination[J]. J Am Chem Soc,2009,131(45):16573-16579.
[14]	Amatore C,Jutand A. Rates and Mechanism of Biphenyl Synthesis Catalyzed by Electrogenerated Coordinatively Unsaturated Nickel Complexes[J]. Organometallics,1988,7(10):2203-2214.
[15]	LI Zhe. Mechanisms of Palladium and Nickel Catalyzed Cross Coupling Reactions[D]. Hefei:University of Science and Technology of China,2009(in Chinese). 李哲. 钯和镍催化的偶联反应的机理研究[D]. 合肥: 中国科学技术大学,2009.