卤代苯醚类化合物的合成与抑菌活性研究
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摘要
氯代羟基二苯醚以广谱、高效的杀菌能力和低毒性广泛地应用于日化、医药、医疗器械、纺织、农业等领域，是一类重要的化合物。它的合成手段研究，衍生物的设计合成与性能测试一直都是国内外学者研究的热点，本文致力于该类化合物的研究并取得了一些重要的结果。
氯代羟基二苯醚常以三步法合成，首先以卤代苯酚与硝基氯苯为原料，采用醚缩合反应制备氯代硝基二苯醚，经还原制得氯代氨基二苯醚，最后氨基二苯醚通过重氮化水解制得目标物氯代羟基二苯醚化合物。我们在醚缩合反应步骤中采用了一种新的无溶剂熔融法，此法具有生产成本低，操作简便等优点。在氨基二苯醚重氮化水解制备羟基二苯醚过程中，对重氮盐的水解方法进行了条件优化实验，相对提高了此步反应的收率。采用改进后的方法合成了6个氯代羟基二苯醚类化合物，并详细的考察了各种因素的影响。
多溴代羟基二苯醚作为一种从海洋海绵体中提取出的天然物质，是国外学者近年来发现并详细研究的一类二苯醚化合物，经研究发现天然多溴代羟基二苯醚类化合物对革兰氏阳性、阴性菌有良好的抑菌能力。我们模拟天然溴代羟基二苯醚的结构，合成了含溴抑菌剂系列，通过氯代羟基二苯醚的溴代反应共制备了8个溴氯混合卤代羟基二苯醚。经抑菌测试研究证实，溴氯混合取代羟基二苯醚比只含有氯取代基的羟基二苯醚抑菌能力有所增强，且抑菌能力随着溴的数量增加而加强。同时证实了酚羟基位于醚键邻位比羟基位于醚键对位抑菌能力强。
以各种硝基氯苯和羟基二苯醚以无溶剂熔融法合成了6个硝基三苯醚类化合物。通过铁酸还原法对硝基三苯醚进行还原制备了6个氨基三苯醚类化合物。对硝基三苯醚和氨基三苯醚类化合物进行抑菌测试后发现，它们几乎不具有抑
菌生物活性.再经重氮化和水解制备了4个轻基三苯醚类化合物，经抑菌实验
发现其具有良好的生物活性，进一步证实了在苯醚类抑菌剂中轻基取代基的重
要性。
本文共合成了中间体12个，目标物卤代苯醚类化合物30个，其中23个为
未见文献报到的新化合物，所有化合物的结构经H.N侧眼、Ms、IR光谱和元素
分析所证实。
Halogenated hydroxy-diphenyl ethers are widely used as bactericide and germicide. They are applied in many fields, such as medicinal intermediates, agricultural pesticides, dyes, etc. It is valuable to study the new synthesis methods of halogenated hydroxy-diphenyl ethers and derivatives. In this dissertation a series of important results were obtained.
The hydroxy-diphenyl ethers were synthesized through three steps reaction. First substituted nitro-diphenyl ethers were synthesized by the reaction of chloro-phenol, dichloro-phenol with chloro-nitrobenzene. Then the substituted amino-diphenyl ethers were obtained by reduction of substituted nitro-diphenyl ethers using iron and hydrochloric acid. Last halogenated hydroxy-diphenyl ethers were synthesized by diazotization and h'ydrolyzing of amino-diphenyl ethers. In this dissertation we study a new solvent free method to synthesize substituted nitro-diphenyl ethers. We have ameliorated the process of hydrolyzing of diazonium salt by improving of acid degree of the reaction system.
For further studying the relationship of microorganism resistance and the chemical structure, we synthesized of a series of diphenyl ethers compounds which have different substituent and tested their bactericidal capability. Through this way we can find the relationship between the chemical structure and bactericidal capability. By simulation the structure of nature bacteriostat, we designed and synthesized of eight halogenated hydroxy-diphenyl ethers compounds based on the starting material hydroxy-diphenyl ethers and bromine. All of these halogenated hydroxyl-diphenyl ethers compounds have both chlorine and bromine as their
substituents. We test their bactericidal capability and find that these compounds have good antimicrobial on the grampositive-bacteria and gramnegative-bacteria.
For studying the new derivatives of the hydroxy polyphenyl ethers, we design the triphenyl compounds. The halogenated triphenyl ethers are potential bactericide and insecticide. The third part of this article described the preparation of six halogenated nitro-triphenyl compounds with new structures by the reaction of hydroxy-diphenyl ethers with chloro-nitrobenzene. Six halogenated amido-triphenyl compounds were synthesized with new structures by reduction of substituted nitro triphenyl ethers using iron and hydrochloric acid We test their bactericidal capability and find that these two kinds of new derivatives have no bactericidal capability. In this part of our dissertation four halogenated hydroxyl triphenyl ethers were synthesized too and bactericidal capability testing show that this kind of new derivatives have good ability of microorganism resistance. From the study we can see the hydroxy is a important substituent in the structure of the polyphenyl ethers bacteria inhibitor.
Thirty compounds were reported in this dissertation, twenty-three of them are reported for the first time. The chemical structure of these compounds have been confirmed by means of H1 NMR, MS, IR spectrum and elemental analyses.
氯代羟基二苯醚常以三步法合成，首先以卤代苯酚与硝基氯苯为原料，采用醚缩合反应制备氯代硝基二苯醚，经还原制得氯代氨基二苯醚，最后氨基二苯醚通过重氮化水解制得目标物氯代羟基二苯醚化合物。我们在醚缩合反应步骤中采用了一种新的无溶剂熔融法，此法具有生产成本低，操作简便等优点。在氨基二苯醚重氮化水解制备羟基二苯醚过程中，对重氮盐的水解方法进行了条件优化实验，相对提高了此步反应的收率。采用改进后的方法合成了6个氯代羟基二苯醚类化合物，并详细的考察了各种因素的影响。
多溴代羟基二苯醚作为一种从海洋海绵体中提取出的天然物质，是国外学者近年来发现并详细研究的一类二苯醚化合物，经研究发现天然多溴代羟基二苯醚类化合物对革兰氏阳性、阴性菌有良好的抑菌能力。我们模拟天然溴代羟基二苯醚的结构，合成了含溴抑菌剂系列，通过氯代羟基二苯醚的溴代反应共制备了8个溴氯混合卤代羟基二苯醚。经抑菌测试研究证实，溴氯混合取代羟基二苯醚比只含有氯取代基的羟基二苯醚抑菌能力有所增强，且抑菌能力随着溴的数量增加而加强。同时证实了酚羟基位于醚键邻位比羟基位于醚键对位抑菌能力强。
以各种硝基氯苯和羟基二苯醚以无溶剂熔融法合成了6个硝基三苯醚类化合物。通过铁酸还原法对硝基三苯醚进行还原制备了6个氨基三苯醚类化合物。对硝基三苯醚和氨基三苯醚类化合物进行抑菌测试后发现，它们几乎不具有抑
菌生物活性.再经重氮化和水解制备了4个轻基三苯醚类化合物，经抑菌实验
发现其具有良好的生物活性，进一步证实了在苯醚类抑菌剂中轻基取代基的重
要性。
本文共合成了中间体12个，目标物卤代苯醚类化合物30个，其中23个为
未见文献报到的新化合物，所有化合物的结构经H.N侧眼、Ms、IR光谱和元素
分析所证实。
Halogenated hydroxy-diphenyl ethers are widely used as bactericide and germicide. They are applied in many fields, such as medicinal intermediates, agricultural pesticides, dyes, etc. It is valuable to study the new synthesis methods of halogenated hydroxy-diphenyl ethers and derivatives. In this dissertation a series of important results were obtained.
The hydroxy-diphenyl ethers were synthesized through three steps reaction. First substituted nitro-diphenyl ethers were synthesized by the reaction of chloro-phenol, dichloro-phenol with chloro-nitrobenzene. Then the substituted amino-diphenyl ethers were obtained by reduction of substituted nitro-diphenyl ethers using iron and hydrochloric acid. Last halogenated hydroxy-diphenyl ethers were synthesized by diazotization and h'ydrolyzing of amino-diphenyl ethers. In this dissertation we study a new solvent free method to synthesize substituted nitro-diphenyl ethers. We have ameliorated the process of hydrolyzing of diazonium salt by improving of acid degree of the reaction system.
For further studying the relationship of microorganism resistance and the chemical structure, we synthesized of a series of diphenyl ethers compounds which have different substituent and tested their bactericidal capability. Through this way we can find the relationship between the chemical structure and bactericidal capability. By simulation the structure of nature bacteriostat, we designed and synthesized of eight halogenated hydroxy-diphenyl ethers compounds based on the starting material hydroxy-diphenyl ethers and bromine. All of these halogenated hydroxyl-diphenyl ethers compounds have both chlorine and bromine as their
substituents. We test their bactericidal capability and find that these compounds have good antimicrobial on the grampositive-bacteria and gramnegative-bacteria.
For studying the new derivatives of the hydroxy polyphenyl ethers, we design the triphenyl compounds. The halogenated triphenyl ethers are potential bactericide and insecticide. The third part of this article described the preparation of six halogenated nitro-triphenyl compounds with new structures by the reaction of hydroxy-diphenyl ethers with chloro-nitrobenzene. Six halogenated amido-triphenyl compounds were synthesized with new structures by reduction of substituted nitro triphenyl ethers using iron and hydrochloric acid We test their bactericidal capability and find that these two kinds of new derivatives have no bactericidal capability. In this part of our dissertation four halogenated hydroxyl triphenyl ethers were synthesized too and bactericidal capability testing show that this kind of new derivatives have good ability of microorganism resistance. From the study we can see the hydroxy is a important substituent in the structure of the polyphenyl ethers bacteria inhibitor.
Thirty compounds were reported in this dissertation, twenty-three of them are reported for the first time. The chemical structure of these compounds have been confirmed by means of H1 NMR, MS, IR spectrum and elemental analyses.
引文
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2．邱立军；李景琴；王惠芬．中国消毒学杂志．1998，15(2)，70～73
3．傅剑云；许天新等．中国公共卫生．1998，14(10)，627～628
4．王国庆；刘衡川；张朝武．中国消毒学杂志 2000，17(7)，207～211
5．魏兰芬；许激；申屠金胜等．中国消毒学杂志．2001，18(1)，41～43
6．王莉：张章为．中国公共卫生．2001，17(9)，781
7．孟庆增；于钦问：李爱萍等．中国消毒学杂志．2001，18(3)，154～158
8．胡德渝；张锦才；万呼春等．华西口腔医学杂志．1997，24(12)，873
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15. Barry L. US594508. 1999
16. Wei H; Karen K L. Text. Chem. Color. 1999, 31(3), 11～16
17. Grealo; Peter J; John S. WO 9714447. 1999
18．朱泉，李世琪；何瑾馨等，中国纺织大学学报．1991，17(3)，48～55
19. Ernst M. B; Jakob B. R. US3629477. 1971
20. Teodoro D. WO00/20366 1998
21. Mao J; Schnyder M. EPO908553. 1998
22. Kurt A. D; Thomas A. F. US3816071. 1974
23. Heward A. V. US3736291. 1973
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25. Geigy J. R. BE659636. 1965
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29．李少华；匡滨海；汪玢．江西医学院学报．1999，39(6)，13～14
30．眭伟民；徐国平．纺织高校基础科学学报．1996，9(2)，140～144
31. Cook A N.J. Am. Chem. Soc. 1903, 25(1), 60
32. Scarborough H.A.J. chem. Soc. 1929, 2361
33. Attilio F. US1292253. 1971
34. Robert J. T. US1377677. 1972
35. Robert J. T; Westifild N. J. US3776961. 1973
36．陈继畴；陈绍瑗；王兰芳等．高等学校化学学报．1984，5(4)，591～592
37. Fiaud; Mckillop A; Hug J. C. Etc. Tetrahedron. 1974, 30(11), 1379
38．陈继畴；戴瑜嘉．高等学校化学学报．1987，8(3)，240～242
39．邵玉昌；杨锦宗．化学试剂．1994，16(5)，305～306
40．吴立城；谭平；张秋萍．化学世界．1992，4，157～159
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