中間體衍生化方法

 1、發展符合我國國情的綠色新農藥創制方法、加速我國新農藥創制，是確保糧食生產安全的重大科學問題。

新農藥創制是多學科交叉的復雜系統工程，具有難度大、周期長、投入大、風險高、成功率低（四萬至十四萬分之一）等特點（不僅要世界首創，還要經過多年的嚴格檢驗與驗證，這個過程通常需要8-10年時間，大浪淘沙，確認是個“好”產品，獲準登記 — 需要進行各種生物學性能測試研究以及安全評價研究，包括毒理學、環境安全與風險研究如致癌、致畸、致突變，土壤殘留、植物殘留、果實殘留，對蜂鳥魚蠶、地下水、以及代謝與蓄積毒性研究等的，類似醫藥的一期、二期、三期、四期臨床試驗。“大浪淘沙”過后，還要進行合成方法、工藝過程和工程化研究，才能產業化，最后還要進行推廣應用。即使方法得當，各方面配合好，還有運氣特別好，從開始研究，到獲準登記，再到產業化，為農業增產增收產生很好的社會效益 — 整個過程也需要20年時間）。

農藥對糧食生產安全作用極大（據統計、如果不使用農藥，作物將減產40%以上，甚至絕收。如霜霉病、晚疫病等毀滅性氣傳病害，若不使用農藥將導致作物絕收， 1845年因馬鈴薯晚疫病爆發，造成愛爾蘭大饑荒：當時愛爾蘭共800多萬人，因饑荒死亡100多萬，150多萬人背井離鄉逃亡美洲等），但我國創制的農藥品種數量極少(世界常用600多個農藥品種中，我國發明的僅10多種)。因此發展符合我國國情的綠色新農藥創制方法、加速我國新農藥創制，是確保糧食生產安全的重大科學問題。

2、解決問題的途徑與效果

經過二十多年的潛心研究，劉長令在世界上首次提出了新農藥創制技術“中間體衍生化方法”，得到了國際同行的認可。利用該創制技術，從3萬多個新化合物中篩選出10多個具有產業化開發前景的候選品種，均獲得國內外發明專利授權。其中唑菌酯、丁香菌酯和唑胺菌酯已產業化。

“中間體衍生化方法”從有機合成角度出發，選擇“中間體”、利用化學反應，把新藥創制的復雜過程簡單化，如利用關鍵中間體進行多樣化衍生、重要基團替換和活性化合物衍生等多種方式進行全新 或 二次先導化合物的研制，可有效避開已有專利的保護，大幅提高新藥創制的效率和成功率。該創制技術還有助于發明性能更優、全新作用機制或多作用靶標藥物，不僅解決抗性問題，而且還可以減少農藥用量，更好的保護環境。

3、“中間體衍生化方法”的具體應用

眾所周知任何一個農藥或者醫藥品種，不管其分子結構簡單與復雜，都是由簡單的原料或者中間體經過各種化學反應得到。當然，中間體的選擇在新農藥創制過程中是非常重要的。“中間體衍生化方法”中，中間體的選擇也是重要的一環，它們或選自天然產物中的片段，或選自農藥品種、醫藥品種中有活性的片段（包括其合成的原料），或選自上述片段經化學反應得到的新中間體，亦可選自簡單的化工原料經化學反應合成得到的全新中間體。“中間體衍生化方法”在實際應用中，根據原料或中間體的來源和特征，又分為如下三種：

1）用上述中間體，進行進一步化學反應包括衍生，經生物活性篩選，發現新的先導化合物—直接合成法（CIM）— 旨在發現全新結構、尤其是全新作用機制的化合物；

2）用上述中間體替換已知農藥品種的一部分，得到已有專利范圍外的新化合物，然后經生物活性篩選，發現新的先導化合物—替換法（TRM）—旨在發現性能更優的化合物；

3）利用已知具有生物活性的化合物作為中間體，進行衍生化，再經生物活性篩選，發現新的先導化合物—衍生法（ADM）—旨在發現新結構或者性能更優的化合物；

在發現新先導化合物的基礎上，再經設計、合成、篩選，并進行結構活性關系研究，發明性能更優、或結構新穎、或作用機理獨特的候選新農藥品種；然后進入10年開發階段，經各種性能測試、毒理學和安全評價獲準登記；最后再進行工藝與過程，工程化研究，實現工業化生產；接下來還要進行多年的推廣應用，只有如此，才能確保農業增產增收。

“中間體衍生化方法”具體三種創新途徑圖解

4、新農藥創制技術“中間體衍生化方法”逐步得到了國際同行的認可

自2003年至今，劉長令相繼受邀在國內相關大學、科研單位，以及農藥會議上作關于“中間體衍生化方法”及其應用報告，于2010年2月和2011年4月分別在美國陶氏益農、富美實公司作關于“中間體衍生化方法” 及其應用的報告，均得到好評。2014年8月受邀在美國舊金山召開的世界最重要的IUPAC國際農藥會議上作大會主題報告。同時劉長令團隊在農藥化學領域影響因子最高的兩個國際期刊《Journal of Agricultural and Food Chemistry》（JAFC）和《Pest Management Science》（PMS）發表與“中間體衍生化方法”及其應用有關的論文10余篇。并于2014年受邀為Chemical Reviews撰寫關于“中間體衍生化方法”及其應用的綜述性論文。

“IUPAC國際農藥會議”是世界上最重要的農藥會議，每4年召開一次。2010年7月受邀在澳大利亞墨爾本召開的第12屆IUPAC國際農藥會議分會上作報告，首次在國際上介紹了中間體衍生化方法及其在新型殺螨劑發明中的應用。

受邀撰寫新農藥創制技術論文“Application of the Intermediate Derivatization Approach in Agrochemical Discovery”于2014年5月發表在國際權威雜志《Chemical Reviews》，詳見：http://pubs.acs.org/doi/abs/10.1021/cr4005605。

2014年8月受邀在美國舊金山召開的第13屆IUPAC國際農藥會議作大會主題報告《Efficient Approach To Discover Novel Agrochemical Candidates: Intermediate Derivatization Method（創制新農藥品種的有效途徑：中間體衍生化方法）》，該報告整理后發表于農藥化學領域影響因子最高的國際期刊JAFC，詳見：http://pubs.acs.org/doi/abs/10.1021/jf5054707。

“世界農用化學品會議”是世界上另一個重要的農藥會議。英國Agranova公司總裁Rob Bryant博士在2012年11月世界農用化學品會議上作報告，正面評價了該方法及其應用。詳見：http://www.agranova.co.uk/pdf/RJB20121127.pdf。

5、有關“中間體衍生化方法”及其應用的論文

部分論文如下：

1、Application of the Intermediate Derivatization Approach in Agrochemical Discovery

•By Guan, Aiying; Liu, Changling; Yang, Xiaoping; Dekeyser, Mark

•From Chemical Reviews (Washington, DC, United States) (2014), 114(14), 7079-7107

2、Efficient Approach To Discover Novel Agrochemical Candidates: Intermediate Derivatization Method

•By Liu, Changling; Guan, Aiying; Yang, Jindong; Chai, Baoshan; Li, Miao; Li, Huichao; Yang, Jichun; Xie, Yong

•From Journal of Agricultural and Food Chemistry (2014), Ahead of Print.

3、N-Phenyl heteroarylamine analogues of fluazinam using the intermediate derivatization methods approach

•By Guan, Aiying; Li, Huichao; Li, Zhinian; Yang, Fan; Xie, Yong; Yang, Xiaoping; Liu, Changling

•From Journal of Chemical Sciences (Bangalore, India) (2014), 126(4), 1107-1114.

4、Synthesis and fungicidal activity of fluorine-containing chlorothalonil derivatives

•By Guan, Aiying; Liu, Changling; Huang, Guang; Li, Huichao; Hao, Shulin; Xu, Ying; Xie, Yong; Li, Zhinian

•From Journal of Fluorine Chemistry (2014), 160, 82-87.

5、Synthesis of novel strobilurin-pyrimidine derivatives and their antiproliferative activity against human cancer cell lines

•By Chai, Baoshan; Wang, Shuyang; Yu, Wenquan; Li, Huichao; Song, Chuanjun; Xu, Ying; Liu, Changling; Chang, Junbiao

•From Bioorganic & Medicinal Chemistry Letters (2013), 23(12), 3505-3510.

6、Design, Synthesis, and Herbicidal Activity of Novel Substituted 3-(Pyridin-2-yl)benzenesulfonamide Derivatives

•By Xie, Yong; Chi, Hui-Wei; Guan, Ai-Ying; Liu, Chang-Ling; Ma, Hong-Juan; Cui, Dong-Liang

•From Journal of Agricultural and Food Chemistry (2014), 62(52), 12491-12496.

7、Design, synthesis and structure-activity relationship of novel oxime ether strobilurin derivatives containing substituted benzofurans

•By Xie, Ya-Qiang; Huang, Yi-Bing; Liu, Jian-She; Ye, Li-Yi; Che, Li-Ming; Tu, Song; Liu, Chang-Ling

•From Pest Management Science (2015), 71(3), 404-414.

8、Design, Synthesis, and Structure-Activity Relationship of Novel Aniline Derivatives of Chlorothalonil

•By Guan, Ai-Ying; Liu, Chang-Ling; Huang, Guang; Li, Hui-Chao; Hao, Shu-Lin; Xu, Ying; Li, Zhi-Nian

•From Journal of Agricultural and Food Chemistry (2013), 61(49), 11929-11936.

9、Synthesis and acaricidal activity of strobilurin-pyrimidine derivatives

•By Chai, Bao-Shan; Liu, Chang-Ling; Li, Hui-Chao; Liu, Shao-Wu; Xu, Ying; Song, Yu-Quan; Chang, Jun-Biao

•From Chinese Chemical Letters (2014), 25(1), 137-140. |

10、Design, synthesis and structure-activity relationship of novel insecticidal dichloro-allyloxy-phenol derivatives containing substituted pyrazol-3-ols

•By Li, Miao; Liu, Chang-Ling; Zhang, Jing; Wu, Qiao; Hao, Shu-Lin; Song, Yu-quan

•From Pest Management Science (2013), 69(5), 635-641.

11、Synthesis and bioactivity of novel coumarin derivatives

•By Guan, Ai-Ying; Liu, Chang-Ling; Li, Miao; Li, Zhi-Nian; Zhang, Ming-Xing; Zhang, Hong

•From Natural Product Communications (2011), 6(12), 1917-1920.

12、The discovery of SYP-10913 and SYP-11277: novel strobilurin acaricides

•By Chai, Bao-Shan; Liu, Chang-Ling; Li, Hui-Chao; Zhang, Hong; Liu, Shao-Wu; Huang, Guang; Chang, Jun-Biao

•From Pest Management Science (2011), 67(9), 1141-1146.

13、Design, synthesis and structure-activity relationship of novel coumarin derivatives

•By Guan, Ai-Ying; Liu, Chang-Ling; Li, Miao; Zhang, Hong; Li, Zhi-Nian; Li, Zheng-Ming

•From Pest Management Science (2011), 67(6), 647-655.

14、Synthesis and bioactivity of novel coumarin derivatives containing (E)-methyl 2-(methoxyimino)-2-phenylacetates

•By Guan, Ai Ying; Liu, Chang Ling; Li, Zhi Nian; Zhang, Ming Xing

•From Chinese Chemical Letters (2011), 22(6), 663-666.

15、Design, synthesis and acaricidal activity of novel strobilurin derivatives containing pyrimidine moieties

•By Chai, Bao-Shan; Liu, Chang-Ling; Li, Hui-Chao; He, Xiao-Min; Luo, Yan-Mei; Huang, Guang; Zhang, Hong; Chang, Jun-Biao

•From Pest Management Science (2010), 66(11), 1208-1214.

16、Synthesis and fungicidal activity of novel strobilurin analogues containing substituted N-phenylpyrimidin-2-amines

•By Li, Hui Chao; Chai, Bao Shan; Li, Zhi Nian; Yang, Ji Chun; Liu, Chang Ling

•From Chinese Chemical Letters (2009), 20(11), 1287-1290.

17、Design, synthesis and biological activities of new strobilurin derivatives containing substituted pyrazoles

•By Li, Miao; Liu, Chang-Ling; Li, Lin; Yang, Hao; Li, Zhi-Nian; Zhang, Hong; Li, Zheng-Ming

•From Pest Management Science (2010), 66(1), 107-112.

18、Synthesis and Biological Activity of New (E)-α-(Methoxyimino)benzeneacetate Derivatives Containing a Substituted Pyrazole Ring

•By Li, Miao; Liu, Chang-Ling; Yang, Ji-Chun; Zhang, Jin-Bo; Li, Zhi-Nian; Zhang, Hong; Li, Zheng-Ming

•From Journal of Agricultural and Food Chemistry (2010), 58(5), 2664-2667.

19、Design, synthesis and biological activity of new strobilurin derivatives with a 1H-pyrazol-5-oxy side chain

•By Li, Miao; Liu, Chang-Ling; Yang, Ji-Chun; Li, Lin; Li, Zhi-Nian; Zhang, Hong; Li, Zheng-Ming

•From Natural Product Communications (2009), 4(9), 1215-1220.

20、Design, synthesis and fungicidal activity of novel strobilurin analogues containing substituted N-phenylpyrimidin-2-amines

•By Li, Hui-Chao; Liu, Chang-Ling; Chai, Bao-Shan; Li, Miao; Li, Zhi-Nian; Yang, Ji-Chun

•From Natural Product Communications (2009), 4(9), 1209-1214.

21、Design, synthesis and fungicidal activity of novel (E)-methyl 2-{2-[(coumarin-7-yloxy)methyl]phenyl}-3-methoxyacrylates

•By Liu, Chang-Ling; Li, Miao; Guan, Ai-Ying; Zhang, Hong; Li, Zheng-Ming

•From Natural Product Communications (2007), 2(8), 845-848.

22、Synthesis and biological activity of novel 2-(3-trifluoromethylphenoxy)-4-trifluoromethylthiazole-5-carboxamide derivatives

•By Liu, Chang-Ling; Li, Miao; Chi, Hui-Wei; Hou, Chun-Qing; Li, Zheng-Ming

•From Journal of Fluorine Chemistry (2006), 127(6), 796-799.

23、Design, synthesis, and biological activity of novel 4-(3,4-dimethoxyphenyl)-2-methylthiazole-5-carboxylic acid derivatives

•By Liu, Chang-Ling; Li, Lin; Li, Zheng-Ming

•From Bioorganic & Medicinal Chemistry (2004), 12(11), 2825-2830.

部分會議論文如下：

1、Natural coumarin and methoxyacrylate hybrids: Anticancer activity, SAR, and mode of action studies

•By Guan, Aiying; Liu, Changling; Zhang, Mingxing; Yang, Fan; Xie, Yong

•From Abstracts of Papers, 248th ACS National Meeting & Exposition, San Francisco, CA, United States, August 10-14, 2014 (2014), MEDI-138. |

2、Substituted diarylamine compounds with antineoplastic activity

•By Li, Huichao; Guan, Aiying; Liu, Changling

•From Abstracts of Papers, 248th ACS National Meeting & Exposition, San Francisco, CA, United States, August 10-14, 2014 (2014), MEDI-137. |

3、Novel substituted anilinopyrimidine compounds: Design, synthesis, and fungicidal activity

•By Chai, Baoshan; Sun, Xufeng; Liu, Changling

•From Abstracts of Papers, 248th ACS National Meeting & Exposition, San Francisco, CA, United States, August 10-14, 2014 (2014), AGRO-725. |

4、N-Phenyl benzothiazolamine compounds using the intermediate derivatization methods approach

•By Guan, Aiying; Liu, Changling; Li, Huichao; Chen, Wei; Xie, Yong; Yang, Fan; Li, Zhinian

•From Abstracts of Papers, 248th ACS National Meeting & Exposition, San Francisco, CA, United States, August 10-14, 2014 (2014), AGRO-724. |

5、Novel fluorinated strobilurin-pyrimidine acaricide: Design, synthesis, and acaricidal activity

•By Chai, Baoshan; Liu, Changling; Chang, Junbiao

•From Abstracts of Papers, 246th ACS National Meeting & Exposition, Indianapolis, IN, United States, September 8-12, 2013 (2013), AGRO-213. |

6、Design, synthesis, and acaricidal activity of strobilurin-pyrimidine conjugates

•By Chai, Baoshan; Liu, Changling; Li, Huichao

•From Abstracts of Papers, 246th ACS National Meeting & Exposition, Indianapolis, IN, United States, September 8-12, 2013 (2013), AGFD-193. |

7、Novel pyrazolone fungicide: Applications of byproducts in agrochemicals

•By Chai, Baoshan; Liu, Changling

•From Abstracts of Papers, 244th ACS National Meeting & Exposition, Philadelphia, PA, United States, August 19-23, 2012 (2012), AGRO-105. |

8、Novel substituted diphenylamine fungicide

•By Li, Huichao; Liu, Changling; Huang, Guang; Li, Zhinian; Zhu, Minna

•From Abstracts of Papers, 241st ACS National Meeting & Exposition, Anaheim, CA, United States, March 27-31, 2011 (2011), AGFD-99. |

9、Design, synthesis and structure-activity relationship of novel dichloro-allyloxy-phenol derivaties containing substituted pyrazoles

•By Li, Miao; Liu, Changling; Zhang, Jing; Wu, Qiao; Song, Yuquan

•From Abstracts of Papers, 241st ACS National Meeting & Exposition, Anaheim, CA, United States, March 27-31, 2011 (2011), AGFD-96. |

10、SYP-11277: A novel strobilurin containing phenylaminopyrimidine acaricide

•By Chai, Baoshan; Liu, Changling; Li, Huichao; Liu, Shaowu; Song, Yuquan; Chang, Junbiao

•From Abstracts of Papers, 241st ACS National Meeting & Exposition, Anaheim, CA, United States, March 27-31, 2011 (2011), AGFD-94. |