中间体衍生化法与新农药创制
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摘要
针对新农药创制难度大、成功率低等特点,创建了"中间体衍生化法"。该方法的特点:在研究之初就考虑开发,选用便宜易得、安全环保的原料,采用易于产业化的反应,确保产品专利权稳定、性价比优势显著。大量实践证明该方法可大幅提高新农药创制的成功率。针对农业生产中重大病虫草害防治难题,采用"中间体衍生化法"设计新农药分子,发明了系列农药新品种,均获国内外发明专利授权,部分品种已实现产业化,并产生很好的经济、社会和环境效益,市场前景广阔。
Aiming at the characteristics of great difficulty and low success rate in the discovery and development of novel agrochemicals, 'the intermediate derivatization method' was established. This method has the following advantages: the future development is concomitantly considered at early research stage, selecting economically available and environmentally friendly raw materials, adopting easy-to-industrialized chemical reactions, to ensure the product with stability of patent rights and high cost-effectiveness advantages. A lot of practices have proved that the method can improve significantly the success rate of new agrochemical discovery. Faced with prevention and control of major diseases/pests/weeds in agriculture, the intermediate derivatization method was employed to design new agrochemical molecules, the patents of a series of new agrochemical candidates were all granted by domestic and foreign countries, some products were successfully launched to market with good economic, social and environmental benefits, and broad market prospects.
Aiming at the characteristics of great difficulty and low success rate in the discovery and development of novel agrochemicals, 'the intermediate derivatization method' was established. This method has the following advantages: the future development is concomitantly considered at early research stage, selecting economically available and environmentally friendly raw materials, adopting easy-to-industrialized chemical reactions, to ensure the product with stability of patent rights and high cost-effectiveness advantages. A lot of practices have proved that the method can improve significantly the success rate of new agrochemical discovery. Faced with prevention and control of major diseases/pests/weeds in agriculture, the intermediate derivatization method was employed to design new agrochemical molecules, the patents of a series of new agrochemical candidates were all granted by domestic and foreign countries, some products were successfully launched to market with good economic, social and environmental benefits, and broad market prospects.
引文
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[9]宋宝安,吴剑.我国农药产业创新发展的路径思考[J].农药市场信息,2015(21):28-31.
[10]黄文耀,李钟华.中国农药技术创新的进展[J].今日农药,2013(6):25-26.
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[17]LA Clair J J.Natural Product Mode of Action(MOA)Studies:ALink Between Natural and Synthetic Worlds[J].Nat Prod Rep,2010,27(7):965-969.
[18]见礼朝正(沈寅初摘译).新农药的开发方法[J].农药译丛,1986(6):2-7.
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[20]刘长令,钟滨,李正名.以天然产物为先导化合物开发的农药品种--杀虫杀螨剂[J].农药,2003,42(12):1-8.
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[26]GUAN Ai-ying,LIU Chang-ling,YANG Xiao-ping,et al.Application of the Intermediate Derivatization Approach in Agrochemical Discovery[J].Chem Rev,2014,114(14):7079-7107.
[27]LIU Chang-ling,GUAN Ai-ying,YANG Jin-dong J D,et al.Efficient Approach to Discover Novel Agrochemical Candidates:Intermediate Derivatization Method[J].J Agric Food Chem,2016,64:45-51.
[28]LI Hui-chao,GUAN Ai-ying,HUANG Guang,et al.Design,Synthesis and Structure Activity Relationship of Novel Diphenylamine Derivatives[J].Bioorgan Med Chem,2016,24:453-461.
[29]GUAN Ai-ying,LIU Chang-ling,Sun Xu-feng,et al.Discovery of Pyridine-based Agrochemicals by Using Intermediate Derivatization Methods[J].Bioorg Med Chem,2016,24:342-353.
[30]GUAN Ai-ying,LIU Chang-ling,HUANG Guang,et al.Design,Synthesis,and Structure Activity Relationship of Novel Aniline Derivatives of Chlorothalonil[J].J Agric Food Chem,2013,61:11929-11936.
[31]GUAN Ai-ying,LIU Chang-ling,HUANG Guang,et al.Synthesis and Fungicidal Activity of Fluorine-containing Chlorothalonil Derivatives[J].J Fluorine Chem,2014,160:82-87.
[32]张霁.科里教授和逆合成分析法[J].化学教育,1992(1):4-6.
[33]刘长令.国外农药开发现状与中间体需求(1)[J].农药,1996,35(10):32-35.
[34]刘长令.国外农药开发现状与中间体需求(2)[J].农药,1996,35(11):26-29.
[35]刘长令.浅谈农药中间体的共用性-目前国外新农药创制的新特点之一[J].化工科技动态,1997(6):20-21.
[36]刘长令.含氟农药的创制途径[J].农药,1998,37(8):1-5
[37]刘长令.生物电子等排及其在新农药创制中的应用[J].农药,1998,37(2):1-7.
[38]潘光民,唐剑峰,吴建挺,等.新型杀线虫剂三氟杀线酯的合成及其应用[J].农药,2018,57(5):329-330.
[39]唐剑峰,刘杰.氟醚菌酰胺的创制与开发,Http://cn.agropages.com/News/NewsDetail——16106.htm.
[40]BRYANT R.Agrochemical Pest Control:New Active Ingredients are Still Needed.Http://www.agranova.co.uk/pdf/RJB20121127.pdf.
[41]HAN S Y.New Agrochemicals Invented in China in Recent Years[J].Agrow,2013,660:VI-VII.
[42]JEANMART S.Recent Development in Agrochemistry[J].Bioorg Med Chem,2016,24(3):315-316.
[43]Mc Connell L L.13th IUPAC International Congress of Pesticide Chemistry:Crop,Environment,and Public Health Protection,Technologies for a Changing World[J].J Agric Food Chem,2016,64:4-5.
[44]刘武成,刘长令.新型高效杀菌剂氟吗啉[J].农药,2002,41(1):8-11.
[45]刘武成,李志念,张越,等.氟吗啉药效应用研究(Ⅰ)-室内生物活性测定[J].农药,1999,38(4):10-13.
[46]GUAN Ai-ying,LIU Chang-ling,LI Miao,et al.Design,Synthesis and Structure Activity Relationship of Novel Coumarin Derivatives[J].Pest Manag Sci,2011,67(6):647-655.
[47]关爱莹,刘长令,李志念,等.杀菌剂丁香菌酯的创制经纬[J].农药,2011,50(2):90-92.
[48]陈亮,刘君丽,司乃国,等.丁香菌酯对苹果树腐烂病的防治[J].农药,2009,48(6):402-404.
[49]宋益民,刁亚梅,顾春燕,等.10种杀菌剂防治水稻纹枯病的田间药效比较[J].现代农药,2012,11(2):55-56.
[50]LI Miao,LIU Chang-ling,LI Lin,et al.Design,Synthesis and Biological Activities of New Strobilurin Derivatives Containing Substituted Pyrazoles[J].Pest Manag Sci,2010,66:107-112.
[51]李淼,刘长令,李志念,等.杀菌剂唑菌酯的创制经纬[J].农药,2011,50(2):20-22.
[52]汪建沃.坚持技术创新实现零的突破沈阳化工研究院两项农药产品标准通过FAO评审[J].今日农药,2016(8):22.
[53]杨吉春,吴峤,关爱莹,等.灭生性除草剂SY-1604的创制[C].中国化工学会农药专业委员会第十八届年会论文集,2018:113-118.
[54]GUAN Ai-ying,LIU Chang-ling,CHEN Wei,et al.Design,Synthesis,and Structure Activity Relationship of New Pyrimidinamine Derivatives Containing an Aryloxy Pyridine Moiety[J].J Agric Food Chem,2017,65:1272-1280.
[55]GUAN Ai-ying,WANG Ming-an,YANG Jin-long,et al.Discovery of a New Fungicide Candidate Through Lead Optimization of Pyrimidinamine Derivatives and Its Activity Against Cucumber Downy Mildew[J].J Agric Food Chem,2017,65:10829-10835.
[56]GUAN Ai-ying,WANG Ming-an,CHEN Wei,et al.Design,Synthesis and Antifungal Activity of New Substituted Difluoromethylpyrimidinamine Derivatives:A Structure Activity Relationship Study[J].J Fluorine Chem,2017,201:49-54.
[57]刘长令,李淼,王军锋,等.具有含氮五元杂环的醚类化合物及其应用:CN,101747276[P].2010-06-23.
[58]LI Miao,LIU Chang-ling,ZHANG Jing,et al.Design,Synthesis and Structure Activity Relationship of Novel Insecticidal Dichloro-allyloxy-phenol Derivatives Containing Substituted Pyrazol-3-ols[J].Pest Manage Sci,2013,69(5):635-641.
[2]LAMBERTH C.Current Challenges and Trends in the Discovery of Agrochemicals[J].Science,2013,341:742-746.
[3]李正名.农药化学现状与发展动向[J].应用化学,1993,10:14-21.
[4]李宗成.国外农药研究动向[J].农药,1998,37(1):1-12.
[5]BASF Innovation:the Secret of Our Success,Research&Development Process.Http://www.agro.basf.com/agr/AP-Internet/en/content/competences/r_and_d_strategy/index.
[6]刘长令,柴宝山.新农药创制与合成[C].北京:化学工业出版社,2013.
[7]刘长令.新农药研究开发文集[C].北京:化学工业出版社,2002.
[8]QIAN Xu-hong,LEE P W,CAO Song.Forward to the Green Pesticides via a Basic Research Program[J].J Agric Food Chem,2010,58(5):2613-2623.
[9]宋宝安,吴剑.我国农药产业创新发展的路径思考[J].农药市场信息,2015(21):28-31.
[10]黄文耀,李钟华.中国农药技术创新的进展[J].今日农药,2013(6):25-26.
[11]李钟华.农药产业崛起中国力量[J].农药市场信息,2018(29):1.
[12]中国青年报.中国科协发布60个重大科技难题:代表我国科技领域真正的“硬骨头”.Http://www.cast.org.cn/art/2018/5/28/art_90_77659.html.
[13]WALTER M W.Structure-based Design of Agrochemicasl[J].Nat Prod Rep,2002,19(3):278-291.
[14]NESHICH I A,NISHIMURA L,DE MORAES F R,et al.Computational Biology Tools for Identifying Specific Ligand Binding Residues for Novel Agrochemical and Drug Design[J].Curr Protein Pept Sci,2015,16(8):701-717.
[15]刘长令.以市场为导向,破解农药创新难题.Http://www.agroinfo.com.cn/other_detail_5370.html.
[16]STETTER J.Pesticide Innovation:Trends in Research and Development.Http://dialnet.unirioja.es/descarga/articulo/1039285.pdf.
[17]LA Clair J J.Natural Product Mode of Action(MOA)Studies:ALink Between Natural and Synthetic Worlds[J].Nat Prod Rep,2010,27(7):965-969.
[18]见礼朝正(沈寅初摘译).新农药的开发方法[J].农药译丛,1986(6):2-7.
[19]刘长令,李正名.以天然产物为先导化合物开发的农药品种——杀菌剂[J].农药,2003,42(11):1-4.
[20]刘长令,钟滨,李正名.以天然产物为先导化合物开发的农药品种--杀虫杀螨剂[J].农药,2003,42(12):1-8.
[21]刘长令,韩亮,李正名.以天然产物为先导化合物开发的农药品种--除草剂[J].农药,2004,43(1):1-4.
[22]杨华铮.农药分子设计[C].北京:科学出版社,2003.
[23]张一宾.新农药创制方法概述[J].农药,2006,45(6):364-367.
[24]刘长令.创新研究方法及候选农药品种[J].高科技与产业化,2008,9:79-81.
[25]刘长令.新农药创新方法与应用-中间体衍生化法[J].农药,2011,50(1):20-23.
[26]GUAN Ai-ying,LIU Chang-ling,YANG Xiao-ping,et al.Application of the Intermediate Derivatization Approach in Agrochemical Discovery[J].Chem Rev,2014,114(14):7079-7107.
[27]LIU Chang-ling,GUAN Ai-ying,YANG Jin-dong J D,et al.Efficient Approach to Discover Novel Agrochemical Candidates:Intermediate Derivatization Method[J].J Agric Food Chem,2016,64:45-51.
[28]LI Hui-chao,GUAN Ai-ying,HUANG Guang,et al.Design,Synthesis and Structure Activity Relationship of Novel Diphenylamine Derivatives[J].Bioorgan Med Chem,2016,24:453-461.
[29]GUAN Ai-ying,LIU Chang-ling,Sun Xu-feng,et al.Discovery of Pyridine-based Agrochemicals by Using Intermediate Derivatization Methods[J].Bioorg Med Chem,2016,24:342-353.
[30]GUAN Ai-ying,LIU Chang-ling,HUANG Guang,et al.Design,Synthesis,and Structure Activity Relationship of Novel Aniline Derivatives of Chlorothalonil[J].J Agric Food Chem,2013,61:11929-11936.
[31]GUAN Ai-ying,LIU Chang-ling,HUANG Guang,et al.Synthesis and Fungicidal Activity of Fluorine-containing Chlorothalonil Derivatives[J].J Fluorine Chem,2014,160:82-87.
[32]张霁.科里教授和逆合成分析法[J].化学教育,1992(1):4-6.
[33]刘长令.国外农药开发现状与中间体需求(1)[J].农药,1996,35(10):32-35.
[34]刘长令.国外农药开发现状与中间体需求(2)[J].农药,1996,35(11):26-29.
[35]刘长令.浅谈农药中间体的共用性-目前国外新农药创制的新特点之一[J].化工科技动态,1997(6):20-21.
[36]刘长令.含氟农药的创制途径[J].农药,1998,37(8):1-5
[37]刘长令.生物电子等排及其在新农药创制中的应用[J].农药,1998,37(2):1-7.
[38]潘光民,唐剑峰,吴建挺,等.新型杀线虫剂三氟杀线酯的合成及其应用[J].农药,2018,57(5):329-330.
[39]唐剑峰,刘杰.氟醚菌酰胺的创制与开发,Http://cn.agropages.com/News/NewsDetail——16106.htm.
[40]BRYANT R.Agrochemical Pest Control:New Active Ingredients are Still Needed.Http://www.agranova.co.uk/pdf/RJB20121127.pdf.
[41]HAN S Y.New Agrochemicals Invented in China in Recent Years[J].Agrow,2013,660:VI-VII.
[42]JEANMART S.Recent Development in Agrochemistry[J].Bioorg Med Chem,2016,24(3):315-316.
[43]Mc Connell L L.13th IUPAC International Congress of Pesticide Chemistry:Crop,Environment,and Public Health Protection,Technologies for a Changing World[J].J Agric Food Chem,2016,64:4-5.
[44]刘武成,刘长令.新型高效杀菌剂氟吗啉[J].农药,2002,41(1):8-11.
[45]刘武成,李志念,张越,等.氟吗啉药效应用研究(Ⅰ)-室内生物活性测定[J].农药,1999,38(4):10-13.
[46]GUAN Ai-ying,LIU Chang-ling,LI Miao,et al.Design,Synthesis and Structure Activity Relationship of Novel Coumarin Derivatives[J].Pest Manag Sci,2011,67(6):647-655.
[47]关爱莹,刘长令,李志念,等.杀菌剂丁香菌酯的创制经纬[J].农药,2011,50(2):90-92.
[48]陈亮,刘君丽,司乃国,等.丁香菌酯对苹果树腐烂病的防治[J].农药,2009,48(6):402-404.
[49]宋益民,刁亚梅,顾春燕,等.10种杀菌剂防治水稻纹枯病的田间药效比较[J].现代农药,2012,11(2):55-56.
[50]LI Miao,LIU Chang-ling,LI Lin,et al.Design,Synthesis and Biological Activities of New Strobilurin Derivatives Containing Substituted Pyrazoles[J].Pest Manag Sci,2010,66:107-112.
[51]李淼,刘长令,李志念,等.杀菌剂唑菌酯的创制经纬[J].农药,2011,50(2):20-22.
[52]汪建沃.坚持技术创新实现零的突破沈阳化工研究院两项农药产品标准通过FAO评审[J].今日农药,2016(8):22.
[53]杨吉春,吴峤,关爱莹,等.灭生性除草剂SY-1604的创制[C].中国化工学会农药专业委员会第十八届年会论文集,2018:113-118.
[54]GUAN Ai-ying,LIU Chang-ling,CHEN Wei,et al.Design,Synthesis,and Structure Activity Relationship of New Pyrimidinamine Derivatives Containing an Aryloxy Pyridine Moiety[J].J Agric Food Chem,2017,65:1272-1280.
[55]GUAN Ai-ying,WANG Ming-an,YANG Jin-long,et al.Discovery of a New Fungicide Candidate Through Lead Optimization of Pyrimidinamine Derivatives and Its Activity Against Cucumber Downy Mildew[J].J Agric Food Chem,2017,65:10829-10835.
[56]GUAN Ai-ying,WANG Ming-an,CHEN Wei,et al.Design,Synthesis and Antifungal Activity of New Substituted Difluoromethylpyrimidinamine Derivatives:A Structure Activity Relationship Study[J].J Fluorine Chem,2017,201:49-54.
[57]刘长令,李淼,王军锋,等.具有含氮五元杂环的醚类化合物及其应用:CN,101747276[P].2010-06-23.
[58]LI Miao,LIU Chang-ling,ZHANG Jing,et al.Design,Synthesis and Structure Activity Relationship of Novel Insecticidal Dichloro-allyloxy-phenol Derivatives Containing Substituted Pyrazol-3-ols[J].Pest Manage Sci,2013,69(5):635-641.