2-巯基氧化吡啶钠盐的合成及抑菌性能研究
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摘要
2-巯基氧化吡啶钠盐(2-mercapto-oxide-pyridine sodium salt, NaPT)是一种有良好应用前景的新型杀菌剂。本文对2-巯基氧化吡啶钠盐的制备及抑菌性能开展了研究。
以2-氨基吡啶为起始原料,经乙酰化、氧化、水解、重氮化、氯化、巯基化和成盐,合成出2-巯基氧化吡啶钠盐,并对关键步骤乙酰化、氧化、水解及巯基化的反应工艺进行了研究。乙酰化反应以冰乙酸为溶剂,不仅解决了乙酰化反应过热的问题,还减少了杂质的引入。氧化反应以顺丁烯二酸酐为催化剂,反应温度在75℃、反应时间3.5h时收率为82.5%;水解反应中温度在80℃、时间2h时收率为87%。巯基化反应中pH值控制在9,收率为85.2%。总反应收率约为61%。
使用2-巯基吡啶钠盐,在不同浓度条件下对室内常见细菌(大肠杆菌、白色葡萄球菌、枯草杆菌)和真菌(曲霉、毛霉、根霉)的抑菌性能进行了评价。实验结果表明,所有菌种在CNaPT≥10-3(mass%)时生长全部被抑制,无菌苔生长;杀菌剂在低浓度下对供试菌种即有很好的抑菌效果,在10-4、10-5(mass%)出现明显的抑菌环。采用紫外分光光度计测定杀菌剂的最低抑菌浓度MIC,杀菌剂对各菌种的MIC在5~15mg/L之间,大肠杆菌MIC为11mg/L;枯草杆菌MIC为9mg/L;白色葡萄球菌MIC为15mg/L。曲霉MIC为9mg/L;毛霉MIC为5mg/L;根霉MIC为7mg/L。
实验结果表明此种杀菌剂不仅对常见菌(如大肠杆菌)的抑菌性能优秀,而且对抗药性很强枯草杆菌亦有良好的抑制效果。其广谱、高效的杀菌能力决定了2-巯基氧化吡啶钠盐作为杀菌剂在医药卫生、农药抗害、涂料抗菌剂和室内消毒等方面具有广泛的应用。
2-mercapto-oxide-pyridine sodium salt is a new kind of bactericide which has very good prospect. In this study. 2-mercapto-sodium-oxide pyridine is researched for preparation and antibacterial properties , which provided a product for medicine, paint and indoor bactericide.
2-mercapto-oxide-pyridine sodium salt was synthesized by the processes of acetyl, oxidation, hydrolysis, diazotization, chlorination, sulphydryl and salification with the starting material 2-aminopyridine, and the synthetic craft was researched. The yield of oxidation was 82.5%, and the optimal temperature and reaction time of oxidation were 75℃and 3.5h respectively; the yield of hydrolysis was 87%, and the optimal temperature and reaction time of hydrolysis were 80℃and 2h respectively. When pH of solution in Sulfhydryl was 9, the yield is 85.2%. The total yield was 61% under above optimal conditions.
Six kinds of indoor common bacteria——bacterial (Escherichia coli, Bacillus subtilis, White staphylococcus) and fungi (Aspergillus, Mucor, Rhizopus) was used to do qualitative tests for the antibacterial effect on 2-mercapto-oxide-pyridine sodium salt. All bacteria was inhibited at CNaPT≥1×10-3(mass%); there were significant inhibition of centrals at 10-4、10-5(mass%), which showed good antibacterial effect at low concentration. Then UV spectrophoto-meter was used to measure the minimum inhibitory concentration (MIC), and the whole MIC of six kinds of indoor common bacteria were 11mg/L, 9mg/L, 15mg/L, 9mg/L, 5mg/L, 7mg/L respectively.
Experimental results showed that such compound had good antibacterial properties against common bacteria. And it has better inhibitory effect on fungi than bacteria generally. The performance broad-spectrum, highly antibacterial efficient of NaPT will lead to the extensive application in medicine and health care, anti-pesticide, paint antibacterial agent and indoor bactericide.
以2-氨基吡啶为起始原料,经乙酰化、氧化、水解、重氮化、氯化、巯基化和成盐,合成出2-巯基氧化吡啶钠盐,并对关键步骤乙酰化、氧化、水解及巯基化的反应工艺进行了研究。乙酰化反应以冰乙酸为溶剂,不仅解决了乙酰化反应过热的问题,还减少了杂质的引入。氧化反应以顺丁烯二酸酐为催化剂,反应温度在75℃、反应时间3.5h时收率为82.5%;水解反应中温度在80℃、时间2h时收率为87%。巯基化反应中pH值控制在9,收率为85.2%。总反应收率约为61%。
使用2-巯基吡啶钠盐,在不同浓度条件下对室内常见细菌(大肠杆菌、白色葡萄球菌、枯草杆菌)和真菌(曲霉、毛霉、根霉)的抑菌性能进行了评价。实验结果表明,所有菌种在CNaPT≥10-3(mass%)时生长全部被抑制,无菌苔生长;杀菌剂在低浓度下对供试菌种即有很好的抑菌效果,在10-4、10-5(mass%)出现明显的抑菌环。采用紫外分光光度计测定杀菌剂的最低抑菌浓度MIC,杀菌剂对各菌种的MIC在5~15mg/L之间,大肠杆菌MIC为11mg/L;枯草杆菌MIC为9mg/L;白色葡萄球菌MIC为15mg/L。曲霉MIC为9mg/L;毛霉MIC为5mg/L;根霉MIC为7mg/L。
实验结果表明此种杀菌剂不仅对常见菌(如大肠杆菌)的抑菌性能优秀,而且对抗药性很强枯草杆菌亦有良好的抑制效果。其广谱、高效的杀菌能力决定了2-巯基氧化吡啶钠盐作为杀菌剂在医药卫生、农药抗害、涂料抗菌剂和室内消毒等方面具有广泛的应用。
2-mercapto-oxide-pyridine sodium salt is a new kind of bactericide which has very good prospect. In this study. 2-mercapto-sodium-oxide pyridine is researched for preparation and antibacterial properties , which provided a product for medicine, paint and indoor bactericide.
2-mercapto-oxide-pyridine sodium salt was synthesized by the processes of acetyl, oxidation, hydrolysis, diazotization, chlorination, sulphydryl and salification with the starting material 2-aminopyridine, and the synthetic craft was researched. The yield of oxidation was 82.5%, and the optimal temperature and reaction time of oxidation were 75℃and 3.5h respectively; the yield of hydrolysis was 87%, and the optimal temperature and reaction time of hydrolysis were 80℃and 2h respectively. When pH of solution in Sulfhydryl was 9, the yield is 85.2%. The total yield was 61% under above optimal conditions.
Six kinds of indoor common bacteria——bacterial (Escherichia coli, Bacillus subtilis, White staphylococcus) and fungi (Aspergillus, Mucor, Rhizopus) was used to do qualitative tests for the antibacterial effect on 2-mercapto-oxide-pyridine sodium salt. All bacteria was inhibited at CNaPT≥1×10-3(mass%); there were significant inhibition of centrals at 10-4、10-5(mass%), which showed good antibacterial effect at low concentration. Then UV spectrophoto-meter was used to measure the minimum inhibitory concentration (MIC), and the whole MIC of six kinds of indoor common bacteria were 11mg/L, 9mg/L, 15mg/L, 9mg/L, 5mg/L, 7mg/L respectively.
Experimental results showed that such compound had good antibacterial properties against common bacteria. And it has better inhibitory effect on fungi than bacteria generally. The performance broad-spectrum, highly antibacterial efficient of NaPT will lead to the extensive application in medicine and health care, anti-pesticide, paint antibacterial agent and indoor bactericide.
引文
1唐除痴.农药化学.南开大学出版社, 1998: 416~417
2刘长令.农用杀菌剂开发的新进展.农药科学与管理. 2000, 21(3): 20~26
3柏亚罗.世界杀菌剂市场的发展潜力.江苏农药. 2001, 24(3): 8~10
4 S. L. Malhotra, R. W. Wong. Conductive inks containing pyridine compo-unds. Journal of chemistry. 2005, 40(5): 6~8
5郭一平.世界杀菌剂研究进展.农药科学与管理. 1999, 12(5): 67~68
6小坂璋吾,焦书梅.杀菌剂的现状和问题.世界农药. 2006, 3: 33
7 G. D. Xi. Study on the Synthesis and Biological Activity of Novel Triazole Compounds and Synthesis of the New Nicotinci Insecticide Thiamethoxam. World Pesticide. 2004, 2(14): 68~70
8关爱莹.新型三唑硫酮类杀菌剂丙硫菌唑.农药. 2003, 42(9): 41~43
9张仲贞.含吡咯环农药的研究开发概述.上海化工. 2001, 1: 19~22
10孙晓红.嘧啶基硫代脲酸酯类化合物的合成及生物活性.化学通报. 2006, 11: 826~827
11司乃国.异丙菌胺杀菌剂的研究与开发.农药. 2003, 42(9): 6~8
12刘长令. 2003年BCPC国际植保会议公开的农药新品种.新农药. 2003, (5): 29~30
13 D. C. Feng. Progress in Antibacterial Agents and Antibacterial Fibers. Syntheyic Fiber Industry. 2005, 28(4): 40~42
14王长守,黄建良,张志杰等.聚季铵盐抗菌剂的研究.陕西化工. 1999, 23(28): 23~25
15 E. S. Lazer, J. Adams, C. K. Miao, etal. Condensed Oxazole and Thiazole Derivatives Asleukotrienes Biosynthesis Inhibitors. American Chemistry. Soc. 1995, 81: 24~26
16刘红英.含氮杂环化合物作为农用杀菌剂的开发应用.德州学院学报. 2006, 22(6): 93~96
17周立山,冯亚青.吡啶氮氧化物研究进展.化工时刊. 1999, 43(13): 11~13
18 J. David, G. Adrew. Process for the Preparation of Pyrimidine Compound. Pesticide. 2005, 7(21): 98~102
19 W. Y. Fan. A New Fungicide Picoxystrobin. Journal of Pesticides. 2005, 6(44):269~270
20 R. Maag. Effect of the Fungicide Pyrifenox on Sterol Biosynthesis in Ustilago Maydis. Agrobiological Research. 1987, 9(11): 373~375
21邓南.蒋忠良.王宇.吡啶硫酮锌合成方法的改进.精细与专用化学品. 6(13):20~21
22 I. Chistie, H. Rolfe, R. Legard. Cleaner production in industry. London: PSI Publishing. 1995, 19(3): 1~16
23 E. S. Lazer, J. Adams, C. K. Miao, etal. Condensed oxazole and thiazole deriva-tives as leukotrienes biosynthesis inhibitors. Chemical Industry. 1996, (29): 5621~5627
24 E. Ann. P. Richard. Ph-dependent Partitioning in Room Temperature Pesti-cide. Organic chemistry. 1999, 8: 1~7
25 A. Kanazawa. Novel Polycationic Biocides: Synthesis and Antibacterial Activity of Polymeric Phosphonium Salts. Polymer Chemistry. 1996, 67: 4110~4115.
26 A. H. Richard, R. F. Engert, J. M. Ostresh, et al. A Com-pletely Synthetic Toxoid Vaccine Containing Escherichia coli Heat-stable Toxin and Antige-nic Determinants of the Heat-labile toxin B Subunit. Infection Immunity. 1985, 26(2): 735~740
27 Z. L. Zhao, G. D. Ma. Rapid Identification of Coagulase-Negative Staphylo-cocci from Fermented Meat. Meat Research. 2007, 5: 33~35
28 Q. Tian. Detection of Spoilage Bacteria in Beer by Polymerase Chain. Micro-biology. 2006, 33(1): 59~61
29 B. A. Michell, M. H. Brown. QacA Multi-drug Efflux Pump from Staphylo-coccus Aureus: Comparative Analysis of Resistance to Diamidines, Biguanid-ines, and Guanylhydrazones. Antimicrob A-gents Chemother. 1998, 42(2): 475~477
30 S. Mayer, M. Boos, A. Beyer, et al. Distribution of the Antiseptic Resistance Genes QacA, QacB and QacC in Methicillin Resistant and Susceptible European Isolates of Staphylococcus Aureus. Antimicrob Agents Chemother. 2001, 47: 896~897
31 M. C. Cramp, J. Gilmour, E. W. Pamell. Herbicidal nicotinamide derivatives. Pesticide Research. 2002, 207: 34~51
32 L. Amia, W. Jiang. Purification and partial characterization of fructosyltrans-erase and invertase from Aspergillus. Journal of Biotechnology. 2000, 2(4): 143~146
33 X. Qian, X. Y. Xu. Synthesis, structures and bioactivities offluorine-containing phenylimino-thia(oxa)zolidine derivatives as agricultural bioreg-laors. Organic Chemistry. 2006, 207: 34~51
34 A. Douglas, J. R. Farmor. Process for Producing Sodium and Zinc Pyrithione. 2004, US: 4396766
35沈萍,范蓉秀,李广斌.微生物学实验教程.高等教育出版社, 1999: 30~31
36唐丽杰.微生物学试验.哈尔滨工业大学出版社, 2005: 45~47
37赵斌,何绍江.微生物学实验.科学出版社, 2006: 67~69
38唐丽杰.微生物学试验.哈尔滨工业大学出版社, 2005: 26~27
39沈评.微生物学.高等教育出版社, 2002: 74~76
40 A. Douglas, J. R. Farmor. Process for Producing Sodium and Zinc Pyrithione. 2004, US: 4396766
41 E. Laerence, O. Katz, H. Riohard. Process for Oxidizing Halopyridines to Haloyridine-N-oxides. 2003, US: 4504667
42王元祥.洗发膏添加剂PDX的研制.日用化学工业. 1990, (3): 5~7
43郑占淼,张建民,田军.双-(2-巯基吡啶-1-氧化物)锌盐螯合物的合成.化学世界. 1993, 34(9): 437~440
44王元祥.合成与应用.江苏化工. 1991, 21(2):31~33
45 E. Shaw, J. Bernstein. Analogs of Aspergillic Acid IV. American Chemistry. Soc. 1950, 72: 4362~4364
46 A. O. Ralph, T. Colerain, Hamilton. Process for Preparing Pyridine N-oxide Carbanion Salts and Derivatives. 1993, US: 3773779
47樊能廷.有机合成事典.北京理工大学出版社, 1995:6661
48张昌军,宋卫红,孙霞等.新型季磷盐的合成及其杀菌性能研究.山东科技大学学报. 2006, 3(25): 71~73
49王瑞芯,郭剑峰,高保娇.高分子吡啶季铵盐的抗菌性能及机理的探讨.应用化学. 2006, 2(23):184~187
50刘学. HXY高效氧化型杀菌剂杀菌性能的测试.锦州医学院学报. 2005, 27(2): 57
2刘长令.农用杀菌剂开发的新进展.农药科学与管理. 2000, 21(3): 20~26
3柏亚罗.世界杀菌剂市场的发展潜力.江苏农药. 2001, 24(3): 8~10
4 S. L. Malhotra, R. W. Wong. Conductive inks containing pyridine compo-unds. Journal of chemistry. 2005, 40(5): 6~8
5郭一平.世界杀菌剂研究进展.农药科学与管理. 1999, 12(5): 67~68
6小坂璋吾,焦书梅.杀菌剂的现状和问题.世界农药. 2006, 3: 33
7 G. D. Xi. Study on the Synthesis and Biological Activity of Novel Triazole Compounds and Synthesis of the New Nicotinci Insecticide Thiamethoxam. World Pesticide. 2004, 2(14): 68~70
8关爱莹.新型三唑硫酮类杀菌剂丙硫菌唑.农药. 2003, 42(9): 41~43
9张仲贞.含吡咯环农药的研究开发概述.上海化工. 2001, 1: 19~22
10孙晓红.嘧啶基硫代脲酸酯类化合物的合成及生物活性.化学通报. 2006, 11: 826~827
11司乃国.异丙菌胺杀菌剂的研究与开发.农药. 2003, 42(9): 6~8
12刘长令. 2003年BCPC国际植保会议公开的农药新品种.新农药. 2003, (5): 29~30
13 D. C. Feng. Progress in Antibacterial Agents and Antibacterial Fibers. Syntheyic Fiber Industry. 2005, 28(4): 40~42
14王长守,黄建良,张志杰等.聚季铵盐抗菌剂的研究.陕西化工. 1999, 23(28): 23~25
15 E. S. Lazer, J. Adams, C. K. Miao, etal. Condensed Oxazole and Thiazole Derivatives Asleukotrienes Biosynthesis Inhibitors. American Chemistry. Soc. 1995, 81: 24~26
16刘红英.含氮杂环化合物作为农用杀菌剂的开发应用.德州学院学报. 2006, 22(6): 93~96
17周立山,冯亚青.吡啶氮氧化物研究进展.化工时刊. 1999, 43(13): 11~13
18 J. David, G. Adrew. Process for the Preparation of Pyrimidine Compound. Pesticide. 2005, 7(21): 98~102
19 W. Y. Fan. A New Fungicide Picoxystrobin. Journal of Pesticides. 2005, 6(44):269~270
20 R. Maag. Effect of the Fungicide Pyrifenox on Sterol Biosynthesis in Ustilago Maydis. Agrobiological Research. 1987, 9(11): 373~375
21邓南.蒋忠良.王宇.吡啶硫酮锌合成方法的改进.精细与专用化学品. 6(13):20~21
22 I. Chistie, H. Rolfe, R. Legard. Cleaner production in industry. London: PSI Publishing. 1995, 19(3): 1~16
23 E. S. Lazer, J. Adams, C. K. Miao, etal. Condensed oxazole and thiazole deriva-tives as leukotrienes biosynthesis inhibitors. Chemical Industry. 1996, (29): 5621~5627
24 E. Ann. P. Richard. Ph-dependent Partitioning in Room Temperature Pesti-cide. Organic chemistry. 1999, 8: 1~7
25 A. Kanazawa. Novel Polycationic Biocides: Synthesis and Antibacterial Activity of Polymeric Phosphonium Salts. Polymer Chemistry. 1996, 67: 4110~4115.
26 A. H. Richard, R. F. Engert, J. M. Ostresh, et al. A Com-pletely Synthetic Toxoid Vaccine Containing Escherichia coli Heat-stable Toxin and Antige-nic Determinants of the Heat-labile toxin B Subunit. Infection Immunity. 1985, 26(2): 735~740
27 Z. L. Zhao, G. D. Ma. Rapid Identification of Coagulase-Negative Staphylo-cocci from Fermented Meat. Meat Research. 2007, 5: 33~35
28 Q. Tian. Detection of Spoilage Bacteria in Beer by Polymerase Chain. Micro-biology. 2006, 33(1): 59~61
29 B. A. Michell, M. H. Brown. QacA Multi-drug Efflux Pump from Staphylo-coccus Aureus: Comparative Analysis of Resistance to Diamidines, Biguanid-ines, and Guanylhydrazones. Antimicrob A-gents Chemother. 1998, 42(2): 475~477
30 S. Mayer, M. Boos, A. Beyer, et al. Distribution of the Antiseptic Resistance Genes QacA, QacB and QacC in Methicillin Resistant and Susceptible European Isolates of Staphylococcus Aureus. Antimicrob Agents Chemother. 2001, 47: 896~897
31 M. C. Cramp, J. Gilmour, E. W. Pamell. Herbicidal nicotinamide derivatives. Pesticide Research. 2002, 207: 34~51
32 L. Amia, W. Jiang. Purification and partial characterization of fructosyltrans-erase and invertase from Aspergillus. Journal of Biotechnology. 2000, 2(4): 143~146
33 X. Qian, X. Y. Xu. Synthesis, structures and bioactivities offluorine-containing phenylimino-thia(oxa)zolidine derivatives as agricultural bioreg-laors. Organic Chemistry. 2006, 207: 34~51
34 A. Douglas, J. R. Farmor. Process for Producing Sodium and Zinc Pyrithione. 2004, US: 4396766
35沈萍,范蓉秀,李广斌.微生物学实验教程.高等教育出版社, 1999: 30~31
36唐丽杰.微生物学试验.哈尔滨工业大学出版社, 2005: 45~47
37赵斌,何绍江.微生物学实验.科学出版社, 2006: 67~69
38唐丽杰.微生物学试验.哈尔滨工业大学出版社, 2005: 26~27
39沈评.微生物学.高等教育出版社, 2002: 74~76
40 A. Douglas, J. R. Farmor. Process for Producing Sodium and Zinc Pyrithione. 2004, US: 4396766
41 E. Laerence, O. Katz, H. Riohard. Process for Oxidizing Halopyridines to Haloyridine-N-oxides. 2003, US: 4504667
42王元祥.洗发膏添加剂PDX的研制.日用化学工业. 1990, (3): 5~7
43郑占淼,张建民,田军.双-(2-巯基吡啶-1-氧化物)锌盐螯合物的合成.化学世界. 1993, 34(9): 437~440
44王元祥.合成与应用.江苏化工. 1991, 21(2):31~33
45 E. Shaw, J. Bernstein. Analogs of Aspergillic Acid IV. American Chemistry. Soc. 1950, 72: 4362~4364
46 A. O. Ralph, T. Colerain, Hamilton. Process for Preparing Pyridine N-oxide Carbanion Salts and Derivatives. 1993, US: 3773779
47樊能廷.有机合成事典.北京理工大学出版社, 1995:6661
48张昌军,宋卫红,孙霞等.新型季磷盐的合成及其杀菌性能研究.山东科技大学学报. 2006, 3(25): 71~73
49王瑞芯,郭剑峰,高保娇.高分子吡啶季铵盐的抗菌性能及机理的探讨.应用化学. 2006, 2(23):184~187
50刘学. HXY高效氧化型杀菌剂杀菌性能的测试.锦州医学院学报. 2005, 27(2): 57