联苯吡菌胺的合成
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摘要
[目的]合成新型杀菌剂联苯吡菌胺及对相关杂质进行分离、鉴定。[方法]以3,4-二氯苯胺为起始原料,经重氮化反应、Gomberg-Bachmann反应制得中间体3′,4′-二氯-5-氟-2-联苯胺,再与1-甲基-3-二氟甲基-1H-吡唑-4-甲酰氯发生酰化反应制得目标化合物联苯吡菌胺。[结果]目标化合物的结构经~1H NMR确证,收率为62.87%(以3,4-二氯苯胺为基准)。反应过程中分离得到2个相关杂质,结构经~1H NMR及HRMS进行确证。[结论]重氮化反应的最佳反应条件:反应时间30 min,NaOH质量浓度8 mol/L;Gomberg-Bachmann反应的最佳反应条件:反应时间45 min,4-氟苯胺预热及反应温度90℃,4-氟苯胺用量为重氮盐的10 eq;相关杂质分别为1,3-二(3,4-二氯苯基)-1-三氮烯和3-(二氟甲基)-N-(4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺。
[Aims]The study aims to synthesis of a new fungicide bixafen and separation of related impurities was conducted. [Methods]The intermediate of 3′,4′-dichloro-5-fluoro-2-diphenylamine was synthesized from 3,4-dichloroaniline via diazotization and Gomberg-Bachmann reaction. Then the intermediate underwent acylation reaction with3-difluoromethyl-1H-pyrazole-4-carbonyl chloride to obtain the bixafen. [Results]Target compound was confirmed by ~1H NMR. The yield of bixafen was 62.87%(based on 3,4-dichloroaniline). Two important impurities were separated and their structure were confirmed by ~1H NMR and H RMS. [Conclusions]Optimal condition for diazo-reaction was determined as the reaction time of 30 min and concentration of NaOH with 8 mol/L. Optimal condition for Gomberg-Bachmann reaction was determined as preheating 4-fluoro aniline to 90 ℃ and reacting for 45 min at 90 ℃with 10 eq of 4-fluoroaniline to the dosage of diazonium salt. The characterized two relevant impurities in the manufacture process were 1,3-bis(3,4-dichlorophenyl)-1-triazene and 3-(difluoromethyl)-N-(4-fluorophenyl)-1-methyl-1 H-pyrazole-4-carboxamide.
[Aims]The study aims to synthesis of a new fungicide bixafen and separation of related impurities was conducted. [Methods]The intermediate of 3′,4′-dichloro-5-fluoro-2-diphenylamine was synthesized from 3,4-dichloroaniline via diazotization and Gomberg-Bachmann reaction. Then the intermediate underwent acylation reaction with3-difluoromethyl-1H-pyrazole-4-carbonyl chloride to obtain the bixafen. [Results]Target compound was confirmed by ~1H NMR. The yield of bixafen was 62.87%(based on 3,4-dichloroaniline). Two important impurities were separated and their structure were confirmed by ~1H NMR and H RMS. [Conclusions]Optimal condition for diazo-reaction was determined as the reaction time of 30 min and concentration of NaOH with 8 mol/L. Optimal condition for Gomberg-Bachmann reaction was determined as preheating 4-fluoro aniline to 90 ℃ and reacting for 45 min at 90 ℃with 10 eq of 4-fluoroaniline to the dosage of diazonium salt. The characterized two relevant impurities in the manufacture process were 1,3-bis(3,4-dichlorophenyl)-1-triazene and 3-(difluoromethyl)-N-(4-fluorophenyl)-1-methyl-1 H-pyrazole-4-carboxamide.
引文
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[8]刘安昌,余彩虹,张树康,等.新型杀菌剂氟唑菌酰胺和联苯吡菌胺的合成研究[J].现代农药,2016(1):16-18,53.
[9]DOCKNER M,RIECK H.Process for Preparing Substituted Biphenylamilides:WO,2009106234[P].2009-12-02.
[10]DDUNKEL R,RIECK H,ELBE H L,et al.Disubstituted Pyrazolyl Carboxamides:US,20060116414[P].2006-06-01.
[11]STRAUB A,HIMMER T.Verfahren zum Hertellen von Biphenylaminen uber Vinylaniline:DE,102006016462[P].2006-07-04.
[12]GERALP P,TINA W,MARKUS R H.The Gomberg-Bachmann Reaction for the Arylation of Anilines with Aryl Diazotates[J].Chemistry-A European Journal,2012,18(37):11555-11559.
[13]DAVID J C,PETER J,JOHN D,et al.Key Green Chemistry Research Areas-A Perspective from Pharmaceutical Manufacturerss[J].Green Chem,2007(9):411-420.
[2]霍妍丽.线粒体呼吸链膜蛋白复合体II的三维结构解析[J].中国基础科学,2005,7(4):16.
[3]RUSSELL P E.Fungicide Resistance Action Commitee(FRAC):A Resistance Activity Update[J].Outlooks on Pest Management.2009,20(3):122-125.
[4]李良孔,袁善奎,潘洪玉,等.琥珀酸脱氢酶抑制剂类(SDHIs)杀菌剂及其抗性研究进展[J].农药,2011,50(3):165-169.
[5]MICHAEL D.Process for Preparing Substituted Biphenylanilides:US,2011092736[P].2011-04-21.
[6]ZIERKE T,RHEINHEIMER J,RACK M,et al.Method for the Production of N-Substituited(3-dihalomethyl-1-methyl-pyrazole-4-yl)Carboxamides:EP,WO2008145740[P].2008-12-04.
[7]REICHERT W,KORADIN C,SMIDT S P,et al.Method for Manufacturing Aryl Carboxamides:US,2001054183[P].2011-03-03.
[8]刘安昌,余彩虹,张树康,等.新型杀菌剂氟唑菌酰胺和联苯吡菌胺的合成研究[J].现代农药,2016(1):16-18,53.
[9]DOCKNER M,RIECK H.Process for Preparing Substituted Biphenylamilides:WO,2009106234[P].2009-12-02.
[10]DDUNKEL R,RIECK H,ELBE H L,et al.Disubstituted Pyrazolyl Carboxamides:US,20060116414[P].2006-06-01.
[11]STRAUB A,HIMMER T.Verfahren zum Hertellen von Biphenylaminen uber Vinylaniline:DE,102006016462[P].2006-07-04.
[12]GERALP P,TINA W,MARKUS R H.The Gomberg-Bachmann Reaction for the Arylation of Anilines with Aryl Diazotates[J].Chemistry-A European Journal,2012,18(37):11555-11559.
[13]DAVID J C,PETER J,JOHN D,et al.Key Green Chemistry Research Areas-A Perspective from Pharmaceutical Manufacturerss[J].Green Chem,2007(9):411-420.