新型吡唑酰胺类化合物的合成及抑菌活性的研究
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摘要
20世纪80年代以来,农药的研发进入了一个新的时期,农药开始朝着高效、低毒、环境友好的方向发展。杀菌剂作为现代农药的重要组成部分,在植物保护、农作物增产等方面发挥着不可替代的作用。吡唑甲酰胺类化合物含有吡唑基和酰胺基两种高活性的结构,往往具有高效、广谱的生物活性,在医药和农药领域有着广泛的应用。其中尤以日本三井化学研制开发的Penthiopyra(d吡噻菌胺)、住友化学工业公司开发的Furametpyr(呋吡菌胺)和最近上市的由先正达公司开发的Isopyrazam、Sedaxane为代表。此外,吡唑环上的四个取代位点使其具有结构多样性,由此可以得到不同活性,这也是引起人们关注的重要原因。
为了寻找到新型高效的吡唑甲酰胺类杀菌剂,本文结合吡噻菌胺和呋吡菌胺的结构特点,根据亚结构拼接的原理,以1-甲基-3-二氟甲基吡唑-4-甲酸为原料,与杂环、氨基苯并杂环类、芳胺类化合物连接得到了32个吡唑-4-甲酰胺类化合物,其中31个化合物未见文献报道。化合物的结构均通过1~H-NMR、MS和IR表征。
对所合成的化合物进行了活性测试,初步生测结果表明,在100 mg/L浓度下,目标化合物对小麦赤霉病菌(Fusarium graminerum)、棉花枯萎病菌(Fusarium oxysporum vasinfectum)、水稻稻瘟病菌(Pyricularia grisea)、番茄灰霉病菌(Botrytis cinerea)、苹果炭疽病菌(Colletotrichum gloeosporioides)及番茄早疫病菌(Altermaria sonali)等6种植物病原菌均有不同程度的抑菌活性,其中,G系列化合物的活性最高,对部分菌的抑菌率高于阳性对照嘧菌酯原药。此外化合物La、Lc对番茄灰霉菌抑制率分别达到87.1%、73.5%;化合物Ha对番茄灰霉病菌、苹果炭疽病菌和小麦赤霉病菌的抑制率为79%,77%,88.2%;化合物Hb对番茄灰霉病菌和苹果炭疽病菌的抑制率为87.5%,73.5%。
Since the 1980s, pesticide research and development have entered a full new stage, and the efficient, low toxicity, environment friendly have become the new trend. As an important part of modern pesticides, fungicides are playing an irreplaceable role in plant protection and crop production. Pyrazolecarboxamides are widely used in the field of medicine and pesticides, which often showed high efficiency and broad-spectrum biological activity for its pyrazolyl and amide group. The pesticide Penthiopyrad launched by Mitsui, Furametpyr launched by Sumitomo, and the pesticide Isopyrazam, Sedaxane both recently launched by Syngenta are the commercialized representatives. In addition, the four different positions of the pyrazole ring make the carboxamides has structural diversity and a variety of bioactivities, which is also a cause for concern.
In order to create new and high-efficient pyrazolecarboxamide fungicides, this paper combining the structural characteristics of commercially pesticides Furamtpyr and Penthiopy- pyrad and according to substructure linking method, a series of pyrazole-4-carboxamide derivatives was synthesized by the reaction of 3-difluoromethyl-1-methyl-1H-pyrazole-4-car- boxylic acid with various amines, of which 31 derivatives are first studied. The structures of these compounds were confirmed by IR, 1H-NMR, and MS.
The preliminary biological activities of the target compounds were tested, and the result indicated that all compounds showed different inhibitory activites against Fusarium graminer- um, Fusarium oxysporum vasinfectum, Pyricularia grisea, Botrytis cinerea, Colletotrichum gloeosporioides and Altermaria sonali at the concentration of 100 mg/L. The compounds of G series exhibited excellent bactriostasis, some compounds has a higher rate of inhibition and better control effect than the positive control Azoxystrobin. Thebactriostasisof compound La and Lc against Botrytis cinerea was up to 87.1% and 73.5% separately; the inhibition rate of Ha against Botrytis cinerea, Colletotrichum gloeosporioides, and Fusarium graminrum was 79%, 77% and 88.2% separately; and Hb against Botrytis cinerea and Colletotrichum gloeosporioides was 87.5% and 73.5% separately.
为了寻找到新型高效的吡唑甲酰胺类杀菌剂,本文结合吡噻菌胺和呋吡菌胺的结构特点,根据亚结构拼接的原理,以1-甲基-3-二氟甲基吡唑-4-甲酸为原料,与杂环、氨基苯并杂环类、芳胺类化合物连接得到了32个吡唑-4-甲酰胺类化合物,其中31个化合物未见文献报道。化合物的结构均通过1~H-NMR、MS和IR表征。
对所合成的化合物进行了活性测试,初步生测结果表明,在100 mg/L浓度下,目标化合物对小麦赤霉病菌(Fusarium graminerum)、棉花枯萎病菌(Fusarium oxysporum vasinfectum)、水稻稻瘟病菌(Pyricularia grisea)、番茄灰霉病菌(Botrytis cinerea)、苹果炭疽病菌(Colletotrichum gloeosporioides)及番茄早疫病菌(Altermaria sonali)等6种植物病原菌均有不同程度的抑菌活性,其中,G系列化合物的活性最高,对部分菌的抑菌率高于阳性对照嘧菌酯原药。此外化合物La、Lc对番茄灰霉菌抑制率分别达到87.1%、73.5%;化合物Ha对番茄灰霉病菌、苹果炭疽病菌和小麦赤霉病菌的抑制率为79%,77%,88.2%;化合物Hb对番茄灰霉病菌和苹果炭疽病菌的抑制率为87.5%,73.5%。
Since the 1980s, pesticide research and development have entered a full new stage, and the efficient, low toxicity, environment friendly have become the new trend. As an important part of modern pesticides, fungicides are playing an irreplaceable role in plant protection and crop production. Pyrazolecarboxamides are widely used in the field of medicine and pesticides, which often showed high efficiency and broad-spectrum biological activity for its pyrazolyl and amide group. The pesticide Penthiopyrad launched by Mitsui, Furametpyr launched by Sumitomo, and the pesticide Isopyrazam, Sedaxane both recently launched by Syngenta are the commercialized representatives. In addition, the four different positions of the pyrazole ring make the carboxamides has structural diversity and a variety of bioactivities, which is also a cause for concern.
In order to create new and high-efficient pyrazolecarboxamide fungicides, this paper combining the structural characteristics of commercially pesticides Furamtpyr and Penthiopy- pyrad and according to substructure linking method, a series of pyrazole-4-carboxamide derivatives was synthesized by the reaction of 3-difluoromethyl-1-methyl-1H-pyrazole-4-car- boxylic acid with various amines, of which 31 derivatives are first studied. The structures of these compounds were confirmed by IR, 1H-NMR, and MS.
The preliminary biological activities of the target compounds were tested, and the result indicated that all compounds showed different inhibitory activites against Fusarium graminer- um, Fusarium oxysporum vasinfectum, Pyricularia grisea, Botrytis cinerea, Colletotrichum gloeosporioides and Altermaria sonali at the concentration of 100 mg/L. The compounds of G series exhibited excellent bactriostasis, some compounds has a higher rate of inhibition and better control effect than the positive control Azoxystrobin. Thebactriostasisof compound La and Lc against Botrytis cinerea was up to 87.1% and 73.5% separately; the inhibition rate of Ha against Botrytis cinerea, Colletotrichum gloeosporioides, and Fusarium graminrum was 79%, 77% and 88.2% separately; and Hb against Botrytis cinerea and Colletotrichum gloeosporioides was 87.5% and 73.5% separately.
引文
陈万义.2007.新农药的研发:方法·进展.北京,化学工业出版社:171-176
杜海棠,欧阳贵平,杜海军,史大斌,金林红.2006.N-(取代)对三氟甲基苯基-1,3,5-三取代吡唑-4-酰胺衍生物的合成与活性.有机化学,26(3):383-386
董新荣,李辉,杨建奎,李霞,李宇.胡椒环的合成.化工技术与开发,2006,35(1):7-9
范文政,顾保权,朱伟清,张一宾.2005.唑虫酰胺的合成.现代农药,4(2):9-11
贺洪武.农药活性分子的生物合理设计.2007.见:陈万义(主编).新农药的研发—方法·进展.北京:化学工业出版社:20-21
胡利明.2003.含1H-吡唑和噻(二)唑的新型双杂环化合物的合成极其生物活性.有机化学,23(10):1131-1134
马海军,郭丽琴,倪玉萍,王晓军,徐尚成.2007.1-芳基-3-吡唑酰胺类化合物的合成与生物活性研究.精细化工中间体,37(3):27-29
刘婷,田辉凯,童益利,杨春龙,倪玉萍.2009.吡唑甲酰胺类农药的研究进展.现代农药,8(6):5-11
刘长令.2006.世界农药大全.北京。化学工业出版社:103-107
刘长令.2009.2008年公开的新农药品种.农药,48(1):60-61
李鑫,赵世举,吴娟,苏惠,陈见.1,2-亚甲二氧基苯的合成工艺研究.科技导报,2007,25(15): 40-43
郎玉成,柏亚罗.2006.吡唑类农药品种的研究开发进展.现代农药,5(5):6-12
陶贤鉴,庞怀林,杨剑波,黄超群,熊莉莉.2007.吡螨胺的合成与应用.农药研究与应用,11(2):19-20
徐尚成,俞犹芬,王晓军,万琴.2008.新杀虫剂氯虫苯甲酰胺极其研究进展.现代农药,7(5):8-11
张一宾,张怿,伍贤英.2010.世界农药新进展(二).北京.化学工业出版社:168-172
张一宾.2003.新颖杀虫杀螨剂——唑虫酰胺.世界农药,25(6):45-53
朱丽华.2005.新型1-烷基-3-芳氧基吡唑-4-甲酰胺衍生物的合成方法和除草活性.世界农药,27(4):21-26
张袖丽,吕献海,江万全.2008.新型吡唑甲酰胺基含氟芳基硫脲的合成及其杀菌活性.应用化学,25(4):459-463
张一宾.2006.新农药创制方法概述.农药,45(6):364-367
Andree Bugant, Boulogne-Billancourt; Alex Junino, Livry-Gargan; Alain Genet, Limay. 1989. Dyeing compositions for keratinous fibres, especially for human hair, congaing oxidation dye precursors and heter- ocyclic couplers, US 4865617A
Dietz J, Stierl R, Strathmann S. 2010-02. Method for Controlling Rust in Leguningous Plants, WO 200717409
Dunkel R, Rieck H, Elbe H, Wachendorff-neumann U, Kuck K. 2003-08-28. Disubstituted Pyrazolyl Carboxamides, WO 03070705
Dunkel R, Elbe H, Greul J, Hartmann B, Wachendorff-neumann U, Dahmen P, Kuck K. 2005-05-12. N-substituted Pyrazolyl Carboxamides, WO 2005042480
D.G. Orphanos, A.Tarins. 1966. 3, 4-Methylenedioxy- and 3,4-dimethoxy-6-aminophenol. Canadian Jounral of Chemistry, 44:1872-1875
Elbe H, Bielefeldt D, Tiemann R, Stefan D, Kugler, M, Wachtler P. 2000-04-25. 1, 3-Dimethyl-5-fluo- ropyrazole-4-carboxamide Derivatives, Their Preparation and Their Use as Microbicides, US 6054473
Elbe H, Rieck H, Dunkel R, Wachendorff-neumann U, Mauler-machnik A, Kuck K, Kugler M, Jaetsch T. 2002-01-31. Pyrazoyl Biphenyl Carboxamides, WO 0208195A1
Enrenfreund J, Tobler H, Walter H. 2003-09-12. O-cyclopropyl-carboxamides and Their Use as Fungicides, WO 03074491
Elbe H, Rieck H, Dunkel R, Zhu-ohlbach Q, Mauler-machnik A, Wachendorff-neumann U, Kuck K.. 2003-02-06. Pyrazolycarboxamides as Fungicides, WO 03010149
Fritz M, Rainer F, Christoph E, Angelika L, Andreas T. 2005-05-19. Substituted Pyrzolines for Use as Pesticides. US 2005107456
Funke C, Fischer Reiner, Fischer Rüdiger, Hungenberg H, Andersch W, Bergisch G, Thielert W, Kraus A.2005-07-07. Active Substance Combinations Having Insecticidal Properties. DE 10356550
FENG Bai-cheng, HAN De-zhang, WU Zu-wang, Wu Zuo-lin. 2006. Synthesis and crystal structure of 3,4-methylenedioxy-nitrobenzene. Journal of Dalian University of Technonlogy, 46(4):488-490
Gewehr M, Dietz J, Grote T, Blettner, C. 2006-08-24. Pyrazole Carboxylic Acid Anilides, Method for the Production Thereof and Agents Containing Them for Controlling Pathogenic Fungi, WO 2006087343
Gewehr M, Dietz J, Grote T, Grammenos S, Hünger U, Müller B, Schieweck F, Schw?gler, A, Lohmann J, Renner J, Sch?fer P.2006-11-16. Pyrazolycarboxamides as Fungicides, WO 2006120219 Graneto M J, Phillips W G. 1992-03-03. 3-Difluoromethyl-pyrazolecarboxamide Fungicides, Compositions and Use, US 509334
M Gewehr, J Dietz, T Grote, A Gypser, W Grammenos, B Müller. 2007-02-15. Fungicidal N-[2-(baloalkoxy)phenyl]-heteroarylcarboxamides, US 20100222217
Nakamura Y, Mitani S, Yoneda T. 2006-02-16.Fungicidal Composition Containing Acid Amide Derivative, WO 2006016708
Ramadas Sathunuru,Ed Biehl. 2004. Facile, high-yield, regioselectivesynthesis of ortho-nitroderivati- ves of hydroxyl heterocycles using cerium(Ⅳ) ammonium nitrate. ARKIVOC, (xiv)89-95
Rack Michael; Smidt, Sebastian Peer, Loehr, Sandra; Keil, Michael; Dietz, Jochen; Rheinheimer, Joachim; Grote, Thomas; Zierke, Thomas; Lohmann, Jan Klaas; Sukopp, Martin. 2008-05-08. PROESS FOR PREPARING DIFLUOROMETHYLPYRAZOLYL CARBO-XYLATES, WO 08053043
Ryuta OHNO, Atsuko WATANABE, Tomoko MATSUKAWA, Takuya UEDA, Hiroshi SAKURAL, Mashiro HORI and Kenji HIRAI. 2004. Synthesis and Herbicidal Acitvity of New Pyrazole-4- carboxamide Derivatives. Journal of Pesticide Science, 15(26):1526
Simonitsch, E.. Frei, H.. Schmid, H. 1957. The constitution of pachyrrhizin. Monat shefte fuer Chemie, 88:541-59
Suzuki H, Mita T, Takeyama T, Hanaue M, Nishikubo M. 1991-08-20. Amide derivatives and fungicide for agricultural and horticultural use, JP 3190862
Alex Junino, Alain Genet, Gerard Lang. 1989-9-12. Dyeing compositions for keratinous fibres, especially for human hair, containing oxidation dye precursors and heterocyclic couplers, US 4865617
杜海棠,欧阳贵平,杜海军,史大斌,金林红.2006.N-(取代)对三氟甲基苯基-1,3,5-三取代吡唑-4-酰胺衍生物的合成与活性.有机化学,26(3):383-386
董新荣,李辉,杨建奎,李霞,李宇.胡椒环的合成.化工技术与开发,2006,35(1):7-9
范文政,顾保权,朱伟清,张一宾.2005.唑虫酰胺的合成.现代农药,4(2):9-11
贺洪武.农药活性分子的生物合理设计.2007.见:陈万义(主编).新农药的研发—方法·进展.北京:化学工业出版社:20-21
胡利明.2003.含1H-吡唑和噻(二)唑的新型双杂环化合物的合成极其生物活性.有机化学,23(10):1131-1134
马海军,郭丽琴,倪玉萍,王晓军,徐尚成.2007.1-芳基-3-吡唑酰胺类化合物的合成与生物活性研究.精细化工中间体,37(3):27-29
刘婷,田辉凯,童益利,杨春龙,倪玉萍.2009.吡唑甲酰胺类农药的研究进展.现代农药,8(6):5-11
刘长令.2006.世界农药大全.北京。化学工业出版社:103-107
刘长令.2009.2008年公开的新农药品种.农药,48(1):60-61
李鑫,赵世举,吴娟,苏惠,陈见.1,2-亚甲二氧基苯的合成工艺研究.科技导报,2007,25(15): 40-43
郎玉成,柏亚罗.2006.吡唑类农药品种的研究开发进展.现代农药,5(5):6-12
陶贤鉴,庞怀林,杨剑波,黄超群,熊莉莉.2007.吡螨胺的合成与应用.农药研究与应用,11(2):19-20
徐尚成,俞犹芬,王晓军,万琴.2008.新杀虫剂氯虫苯甲酰胺极其研究进展.现代农药,7(5):8-11
张一宾,张怿,伍贤英.2010.世界农药新进展(二).北京.化学工业出版社:168-172
张一宾.2003.新颖杀虫杀螨剂——唑虫酰胺.世界农药,25(6):45-53
朱丽华.2005.新型1-烷基-3-芳氧基吡唑-4-甲酰胺衍生物的合成方法和除草活性.世界农药,27(4):21-26
张袖丽,吕献海,江万全.2008.新型吡唑甲酰胺基含氟芳基硫脲的合成及其杀菌活性.应用化学,25(4):459-463
张一宾.2006.新农药创制方法概述.农药,45(6):364-367
Andree Bugant, Boulogne-Billancourt; Alex Junino, Livry-Gargan; Alain Genet, Limay. 1989. Dyeing compositions for keratinous fibres, especially for human hair, congaing oxidation dye precursors and heter- ocyclic couplers, US 4865617A
Dietz J, Stierl R, Strathmann S. 2010-02. Method for Controlling Rust in Leguningous Plants, WO 200717409
Dunkel R, Rieck H, Elbe H, Wachendorff-neumann U, Kuck K. 2003-08-28. Disubstituted Pyrazolyl Carboxamides, WO 03070705
Dunkel R, Elbe H, Greul J, Hartmann B, Wachendorff-neumann U, Dahmen P, Kuck K. 2005-05-12. N-substituted Pyrazolyl Carboxamides, WO 2005042480
D.G. Orphanos, A.Tarins. 1966. 3, 4-Methylenedioxy- and 3,4-dimethoxy-6-aminophenol. Canadian Jounral of Chemistry, 44:1872-1875
Elbe H, Bielefeldt D, Tiemann R, Stefan D, Kugler, M, Wachtler P. 2000-04-25. 1, 3-Dimethyl-5-fluo- ropyrazole-4-carboxamide Derivatives, Their Preparation and Their Use as Microbicides, US 6054473
Elbe H, Rieck H, Dunkel R, Wachendorff-neumann U, Mauler-machnik A, Kuck K, Kugler M, Jaetsch T. 2002-01-31. Pyrazoyl Biphenyl Carboxamides, WO 0208195A1
Enrenfreund J, Tobler H, Walter H. 2003-09-12. O-cyclopropyl-carboxamides and Their Use as Fungicides, WO 03074491
Elbe H, Rieck H, Dunkel R, Zhu-ohlbach Q, Mauler-machnik A, Wachendorff-neumann U, Kuck K.. 2003-02-06. Pyrazolycarboxamides as Fungicides, WO 03010149
Fritz M, Rainer F, Christoph E, Angelika L, Andreas T. 2005-05-19. Substituted Pyrzolines for Use as Pesticides. US 2005107456
Funke C, Fischer Reiner, Fischer Rüdiger, Hungenberg H, Andersch W, Bergisch G, Thielert W, Kraus A.2005-07-07. Active Substance Combinations Having Insecticidal Properties. DE 10356550
FENG Bai-cheng, HAN De-zhang, WU Zu-wang, Wu Zuo-lin. 2006. Synthesis and crystal structure of 3,4-methylenedioxy-nitrobenzene. Journal of Dalian University of Technonlogy, 46(4):488-490
Gewehr M, Dietz J, Grote T, Blettner, C. 2006-08-24. Pyrazole Carboxylic Acid Anilides, Method for the Production Thereof and Agents Containing Them for Controlling Pathogenic Fungi, WO 2006087343
Gewehr M, Dietz J, Grote T, Grammenos S, Hünger U, Müller B, Schieweck F, Schw?gler, A, Lohmann J, Renner J, Sch?fer P.2006-11-16. Pyrazolycarboxamides as Fungicides, WO 2006120219 Graneto M J, Phillips W G. 1992-03-03. 3-Difluoromethyl-pyrazolecarboxamide Fungicides, Compositions and Use, US 509334
M Gewehr, J Dietz, T Grote, A Gypser, W Grammenos, B Müller. 2007-02-15. Fungicidal N-[2-(baloalkoxy)phenyl]-heteroarylcarboxamides, US 20100222217
Nakamura Y, Mitani S, Yoneda T. 2006-02-16.Fungicidal Composition Containing Acid Amide Derivative, WO 2006016708
Ramadas Sathunuru,Ed Biehl. 2004. Facile, high-yield, regioselectivesynthesis of ortho-nitroderivati- ves of hydroxyl heterocycles using cerium(Ⅳ) ammonium nitrate. ARKIVOC, (xiv)89-95
Rack Michael; Smidt, Sebastian Peer, Loehr, Sandra; Keil, Michael; Dietz, Jochen; Rheinheimer, Joachim; Grote, Thomas; Zierke, Thomas; Lohmann, Jan Klaas; Sukopp, Martin. 2008-05-08. PROESS FOR PREPARING DIFLUOROMETHYLPYRAZOLYL CARBO-XYLATES, WO 08053043
Ryuta OHNO, Atsuko WATANABE, Tomoko MATSUKAWA, Takuya UEDA, Hiroshi SAKURAL, Mashiro HORI and Kenji HIRAI. 2004. Synthesis and Herbicidal Acitvity of New Pyrazole-4- carboxamide Derivatives. Journal of Pesticide Science, 15(26):1526
Simonitsch, E.. Frei, H.. Schmid, H. 1957. The constitution of pachyrrhizin. Monat shefte fuer Chemie, 88:541-59
Suzuki H, Mita T, Takeyama T, Hanaue M, Nishikubo M. 1991-08-20. Amide derivatives and fungicide for agricultural and horticultural use, JP 3190862
Alex Junino, Alain Genet, Gerard Lang. 1989-9-12. Dyeing compositions for keratinous fibres, especially for human hair, containing oxidation dye precursors and heterocyclic couplers, US 4865617