中间体衍生化方法
1、发展符合我国国情的绿色新农药创制方法、加速我国新农药创制，是确保粮食生产安全的重大科学问题。
新农药创制是多学科交叉的复杂系统工程，具有难度大、周期长、投入大、风险高、成功率低（四万至十四万分之一）等特点（不仅要世界首创，还要经过多年的严格检验与验证，这个过程通常需要8-10年时间，大浪淘沙，确认是个“好”产品，获准登记 — 需要进行各种生物学性能测试研究以及安全评价研究，包括毒理学、环境安全与风险研究如致癌、致畸、致突变，土壤残留、植物残留、果实残留，对蜂鸟鱼蚕、地下水、以及代谢与蓄积毒性研究等的，类似医药的一期、二期、三期、四期临床试验。“大浪淘沙”过后，还要进行合成方法、工艺过程和工程化研究，才能产业化，最后还要进行推广应用。即使方法得当，各方面配合好，还有运气特别好，从开始研究，到获准登记，再到产业化，为农业增产增收产生很好的社会效益 — 整个过程也需要20年时间）。
农药对粮食生产安全作用极大（据统计、如果不使用农药，作物将减产40%以上，甚至绝收。如霜霉病、晚疫病等毁灭性气传病害，若不使用农药将导致作物绝收， 1845年因马铃薯晚疫病爆发，造成爱尔兰大饥荒：当时爱尔兰共800多万人，因饥荒死亡100多万，150多万人背井离乡逃亡美洲等），但我国创制的农药品种数量极少(世界常用600多个农药品种中，我国发明的仅10多种)。因此发展符合我国国情的绿色新农药创制方法、加速我国新农药创制，是确保粮食生产安全的重大科学问题。
2、解决问题的途径与效果
经过二十多年的潜心研究，刘长令在世界上首次提出了新农药创制技术“中间体衍生化方法”，得到了国际同行的认可。利用该创制技术，从3万多个新化合物中筛选出10多个具有产业化开发前景的候选品种，均获得国内外发明专利授权。其中唑菌酯、丁香菌酯和唑胺菌酯已产业化。
“中间体衍生化方法”从有机合成角度出发，选择“中间体”、利用化学反应，把新药创制的复杂过程简单化，如利用关键中间体进行多样化衍生、重要基团替换和活性化合物衍生等多种方式进行全新 或 二次先导化合物的研制，可有效避开已有专利的保护，大幅提高新药创制的效率和成功率。该创制技术还有助于发明性能更优、全新作用机制或多作用靶标药物，不仅解决抗性问题，而且还可以减少农药用量，更好的保护环境。
3、“中间体衍生化方法”的具体应用
众所周知任何一个农药或者医药品种，不管其分子结构简单与复杂，都是由简单的原料或者中间体经过各种化学反应得到。当然，中间体的选择在新农药创制过程中是非常重要的。“中间体衍生化方法”中，中间体的选择也是重要的一环，它们或选自天然产物中的片段，或选自农药品种、医药品种中有活性的片段（包括其合成的原料），或选自上述片段经化学反应得到的新中间体，亦可选自简单的化工原料经化学反应合成得到的全新中间体。“中间体衍生化方法”在实际应用中，根据原料或中间体的来源和特征，又分为如下三种：
1）用上述中间体，进行进一步化学反应包括衍生，经生物活性筛选，发现新的先导化合物—直接合成法（CIM）— 旨在发现全新结构、尤其是全新作用机制的化合物；
2）用上述中间体替换已知农药品种的一部分，得到已有专利范围外的新化合物，然后经生物活性筛选，发现新的先导化合物—替换法（TRM）—旨在发现性能更优的化合物；
3）利用已知具有生物活性的化合物作为中间体，进行衍生化，再经生物活性筛选，发现新的先导化合物—衍生法（ADM）—旨在发现新结构或者性能更优的化合物；
在发现新先导化合物的基础上，再经设计、合成、筛选，并进行结构活性关系研究，发明性能更优、或结构新颖、或作用机理独特的候选新农药品种；然后进入10年开发阶段，经各种性能测试、毒理学和安全评价获准登记；最后再进行工艺与过程，工程化研究，实现工业化生产；接下来还要进行多年的推广应用，只有如此，才能确保农业增产增收。
“中间体衍生化方法”具体三种创新途径图解
4、新农药创制技术“中间体衍生化方法”逐步得到了国际同行的认可
自2003年至今，刘长令相继受邀在国内相关大学、科研单位，以及农药会议上作关于“中间体衍生化方法”及其应用报告，于2010年2月和2011年4月分别在美国陶氏益农、富美实公司作关于“中间体衍生化方法” 及其应用的报告，均得到好评。2014年8月受邀在美国旧金山召开的世界最重要的IUPAC国际农药会议上作大会主题报告。同时刘长令团队在农药化学领域影响因子最高的两个国际期刊《Journal of Agricultural and Food Chemistry》（JAFC）和《Pest Management Science》（PMS）发表与“中间体衍生化方法”及其应用有关的论文10余篇。并于2014年受邀为Chemical Reviews撰写关于“中间体衍生化方法”及其应用的综述性论文。
“IUPAC国际农药会议”是世界上最重要的农药会议，每4年召开一次。2010年7月受邀在澳大利亚墨尔本召开的第12届IUPAC国际农药会议分会上作报告，首次在国际上介绍了中间体衍生化方法及其在新型杀螨剂发明中的应用。
受邀撰写新农药创制技术论文“Application of the Intermediate Derivatization Approach in Agrochemical Discovery”于2014年5月发表在国际权威杂志《Chemical Reviews》，详见：http://pubs.acs.org/doi/abs/10.1021/cr4005605。
2014年8月受邀在美国旧金山召开的第13届IUPAC国际农药会议作大会主题报告《Efficient Approach To Discover Novel Agrochemical Candidates: Intermediate Derivatization Method（创制新农药品种的有效途径：中间体衍生化方法）》，该报告整理后发表于农药化学领域影响因子最高的国际期刊JAFC，详见：http://pubs.acs.org/doi/abs/10.1021/jf5054707。
“世界农用化学品会议”是世界上另一个重要的农药会议。英国Agranova公司总裁Rob Bryant博士在2012年11月世界农用化学品会议上作报告，正面评价了该方法及其应用。详见：http://www.agranova.co.uk/pdf/RJB20121127.pdf。
5、有关“中间体衍生化方法”及其应用的论文
部分论文如下：
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.
部分会议论文如下：
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. |
