1.超高效、低毒、广谱性除草剂双草醚的合成研究 2.带有多个羟基的非环状化合物及其金属配合物的合成研究
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摘要
在查阅国内外有关除草剂文献的基础上，对世界三大类农药尤其是除草剂工业的历史、现状和发展趋势，我国除草剂的研发、应用情况和今后发展方向等进行了概述；阐述了除草剂的分类，介绍了从大用量、低效到抑制乙酰乳酸合成酶的低用量、高效、安全性除草剂的研创过程，并详细介绍了嘧啶水杨酸类除草剂的合成路线和方法、作用机制及毒性等情况以及超高效水稻田新型除草剂----双草醚的理化性质、毒性、制剂、作用机制和应用活性。
在市场需求和文献调研的基础上，着重对双草醚(Bispyribac-sodium，又称农美利Nominee)的合成进行了研究。采用以硫脲、丙二酸二乙酯和甲醇钠为主要起始原料，经缩合环化(包括酯的胺解、芳构化、成盐)、甲基化、氯化、甲氧基化、氧化、缩合等八步反应，最终合成超高效水稻田除草剂----双草醚原药和配制10％悬浮剂。研究采用的合成工艺先进、可行，研究了以水代替48％氢氧化钠为反应介质，合成甲硫嘧啶，节省了大量酸碱，降低了成本，减少了三废；用溶剂萃取二氯嘧啶，解决了二氯嘧啶熔点低、易吸潮、不易干燥的难题：选用的双溶剂法分离甲氧嘧啶和无机盐，提高了反应收率；研究的氯化、甲氧基化和氧化连续进行的新工艺，不仅解决上述的关键问题，而且收率提高了10％；以氢氧化钠和甲苯代替氢化钠和四氢呋喃，既提高收率和降低成本，又能安全生产。经过上述重要创新，使双草醚投入了规模化生产。
合成的最终产物双草醚通过紫外光谱、红外光谱、核磁共振和质谱等分析，证实了与目标产品的分子结构完全相符。
本项目已通过省级鉴定，专家一致认为该项成果达到了国际先进水平。
Based on extensive study of domestic and foreign journals in the field of herbicide, the history, current status, and development of three kinds of pesticides have been given in the first part of the dissertation. The industrial situation about herbicide in China has been introduced as well as the research and development of the herbicides aiming at high effect and classification of the inhibitors to ALS (Acetolactate Synthase). Moreover, the synthetic routes and methods, acting mechanism, and toxicity about pyrimidinylether herbicides have been described, especially, the physical and chemical properties, toxicity, reaction mechanism, and application about the world novel herbicide-Bispyribac-sodium( or Nominee) on rice have been summarized in detail.
This dissertation is particularly focused on studying, innovating, and optimizing of the synthesis of Bispyribac-sodium, a kind of herbicide with high effect on rice and wheat against barnyard grass, green foxtail, and other weeds. The technical material (TC) and its 10% aqueous suspension concentrate (SC) of Bispyribac-sodium were prepared via eight steps, including cycloamination (consisting ammonolysis of ester, aromatization, and salify), methylation, chlorination, methoxylation, oxidation and condensation, and so on, using thiourea, diethyl malonate and sodium methanol as main starting materials. 4,6-dihydroxyl-2-methythio pyrimidine was successfully synthesized by using water instead of 48% sodium hydroxide (NaOH) as reaction solvent. This innovation leds to a great cutting down on amounts of acid and NaOH, more economic, and decrease of pollution. Due to its low melt point and high sensitivity to moisture, 4,6-dichloro-2-methylthio pyrimidine is commonly regarded as a difficult point for dry. In our research, this problem was economically solved, through extracting the product from reaction aqueous with organic solvent. The separation of 4,6-dimethoxy-2-methylthio pyrimidine from inorganic salt and improvement of yield benefited from selecting two kinds of solvents in this methoxylation . Contributed to continuous process of chlorination, methoxylation, and oxidation, not only problems depicted above have been solved, but also the overall
yield has been increased by 10% in the three steps. Additionally, the safely synthetic manner of Bispyribac-sodium as well as improvement of yield and reduction of cost by utilizing sodium hydroxide (NaOH) and toluene^HsCHa) replace of sodium hydride (NaH) and tetrahydrofuran (THF) have been obtained. As a result of these innovations, TC and 10% SC of Bispyribac-sodium are being produced in a relatively large scale at some pesticide companies.
The final product was characterized by NMR, 1R, UV, and MS spectrum and was proved to be consistent with the structure of the target product.
It is worthy to notice that this project has passed the authentication in Zhejiang province, and experts commended accordantly that this achievement reached international advanced level.
在市场需求和文献调研的基础上，着重对双草醚(Bispyribac-sodium，又称农美利Nominee)的合成进行了研究。采用以硫脲、丙二酸二乙酯和甲醇钠为主要起始原料，经缩合环化(包括酯的胺解、芳构化、成盐)、甲基化、氯化、甲氧基化、氧化、缩合等八步反应，最终合成超高效水稻田除草剂----双草醚原药和配制10％悬浮剂。研究采用的合成工艺先进、可行，研究了以水代替48％氢氧化钠为反应介质，合成甲硫嘧啶，节省了大量酸碱，降低了成本，减少了三废；用溶剂萃取二氯嘧啶，解决了二氯嘧啶熔点低、易吸潮、不易干燥的难题：选用的双溶剂法分离甲氧嘧啶和无机盐，提高了反应收率；研究的氯化、甲氧基化和氧化连续进行的新工艺，不仅解决上述的关键问题，而且收率提高了10％；以氢氧化钠和甲苯代替氢化钠和四氢呋喃，既提高收率和降低成本，又能安全生产。经过上述重要创新，使双草醚投入了规模化生产。
合成的最终产物双草醚通过紫外光谱、红外光谱、核磁共振和质谱等分析，证实了与目标产品的分子结构完全相符。
本项目已通过省级鉴定，专家一致认为该项成果达到了国际先进水平。
Based on extensive study of domestic and foreign journals in the field of herbicide, the history, current status, and development of three kinds of pesticides have been given in the first part of the dissertation. The industrial situation about herbicide in China has been introduced as well as the research and development of the herbicides aiming at high effect and classification of the inhibitors to ALS (Acetolactate Synthase). Moreover, the synthetic routes and methods, acting mechanism, and toxicity about pyrimidinylether herbicides have been described, especially, the physical and chemical properties, toxicity, reaction mechanism, and application about the world novel herbicide-Bispyribac-sodium( or Nominee) on rice have been summarized in detail.
This dissertation is particularly focused on studying, innovating, and optimizing of the synthesis of Bispyribac-sodium, a kind of herbicide with high effect on rice and wheat against barnyard grass, green foxtail, and other weeds. The technical material (TC) and its 10% aqueous suspension concentrate (SC) of Bispyribac-sodium were prepared via eight steps, including cycloamination (consisting ammonolysis of ester, aromatization, and salify), methylation, chlorination, methoxylation, oxidation and condensation, and so on, using thiourea, diethyl malonate and sodium methanol as main starting materials. 4,6-dihydroxyl-2-methythio pyrimidine was successfully synthesized by using water instead of 48% sodium hydroxide (NaOH) as reaction solvent. This innovation leds to a great cutting down on amounts of acid and NaOH, more economic, and decrease of pollution. Due to its low melt point and high sensitivity to moisture, 4,6-dichloro-2-methylthio pyrimidine is commonly regarded as a difficult point for dry. In our research, this problem was economically solved, through extracting the product from reaction aqueous with organic solvent. The separation of 4,6-dimethoxy-2-methylthio pyrimidine from inorganic salt and improvement of yield benefited from selecting two kinds of solvents in this methoxylation . Contributed to continuous process of chlorination, methoxylation, and oxidation, not only problems depicted above have been solved, but also the overall
yield has been increased by 10% in the three steps. Additionally, the safely synthetic manner of Bispyribac-sodium as well as improvement of yield and reduction of cost by utilizing sodium hydroxide (NaOH) and toluene^HsCHa) replace of sodium hydride (NaH) and tetrahydrofuran (THF) have been obtained. As a result of these innovations, TC and 10% SC of Bispyribac-sodium are being produced in a relatively large scale at some pesticide companies.
The final product was characterized by NMR, 1R, UV, and MS spectrum and was proved to be consistent with the structure of the target product.
It is worthy to notice that this project has passed the authentication in Zhejiang province, and experts commended accordantly that this achievement reached international advanced level.
引文
1．李斌，农药，1998，37(10)：1～7
2．唐除痴等编著，农药化学，南开大学出版社；1998：486
3．张一宾，农药，2000，39(9)：3～6
4．苏少泉，农药，1998，37(11)：1～7
5．曹坳程，赵国锋，张朝贤，农药译丛，1998，20(2)：11～20
6. Ian M.Heap, Pestic. Scie., 1997, 51：235～243;
7．刘长令，农药，2002，43(9)：44-45；
8．苏少泉，农药译丛，1997，19(3)：14～18．
9. Masatoshi Tamaru, Takayoshi Takehi, Naoshi Masuyama, 1996, Pesticide Science, 47. 325～335.
10. Masatoshi Tamaru, Yoshihiro Saito, Pesticide Science, 1996, 47: 125～130.
11. Peter Babczinski, Thomas Zelinski, 1991, Pesticide Science, 31. 305～323.
12. Toshio Akagi, Pesticide Science, 1996, 47:309～318
13. Tsutomu Shimizu et al., 1994, J. Pesticide Science, 19:257～266
14. Tsutomu Shimizu et al., 1994, J. Pesticide Science, 19: 59～67
15. Yukio Nezu et al., 1996, Pesticide Science, 47:103～113
16. Yukio Nezu et al., 1996, Pesticide Science, 47:115～124
17. Yukio Nezu et al., 1996, J. Pesticide Science, 21. 293～303
18．杨光富，刘华银，陆荣健，杨华铮，高等学校化学学报，1998，19(2)：222～227；
19．朱文达译，农药译丛，1997，19(5)：24～35；
20．许泳峰主编，农田杂草化学防除原理与方法，辽宁科学技术出版社，1992；
21．揭玉斌，化工科技动态，1996，7：1～3；
22．J.Weed Sci. Tech., 1997, 42:326～332;
23．J.WeedSci.Tech., 1997,42:400～414;
24．化学工业部信息中心，世界化学工业年鉴，1984-1993；
25．化工科技动态，1996，12：7～9；
26．李斌，农药译丛，1997，增刊：25～27；
27．强胜，杂草科学，1997，4：11～14：
28．化学工业部农药工业科技情报中心站，国内农药工业概况，内部资料；
29．农药工业编辑部编，国外农药新品种，1990；
30．农业部农药检定所，农药登记公告，1993～1997；
31．化学工业部信息中心，中国化学工业年鉴，1993～1997；
32．李宗成，农药，1998，37(1)：1～12；
33．化工部计划司，中国主要化工产品统计年鉴(1996)，化学工业出版社；
34．李正名等，CN1106393A
35．李斌等，CN1148043A
36．苏少泉，生物进展，1993，14：30-34；
37. F.James Retzinger, Jrand Carol Mallory-smith, Weed Tech., 1997, 11:384～396
38. Gcorge Marshall, Pestic. Sci., 1998, 52: 394～402;
39. Isn M.Heap., Pestic. Sci.1997,52: 235243;
40. 1998 North Dakota Weed Control Guide, Complied by R.k.Zollinger, NDSU ExtensionScrvice, Jap. 1998
41. Timothy T. Obrigavvitch, Gilbert Cook, Jeff Wetherington, Pestic. Sci., 1998, 52: 199～217;
42. Yukio N., Nobuhide W., Yoshihiro S. et al., J. Pestic. Sci., 1996,21: 293;
43. EP315899 (1989)
44. EP347811 (1989)
45. US 5401711 (1995)
46. US 4932999 (1990)
47. JP01-301668 (1989)
48. Yang Guangfu, Yang Huazheng, Lu Rongjian et al., Chem.J. Chinese Univ., 1997,18(12): 1982
49．周卫平；编译 世界农药，2001，23(1)：7～11；
50．吴霞、张一宾；世界农药，2001，23(5)：1～7，16；
51．任太康、杨华铮；河南化工，1997，6：3～6；
52．刘常林；湖南化工，1996，26(4)：21-24，44；；
53．尚尔才；关于发展我国化学除草剂的建议，1979，内部资料；
54．张一宾；农药，1998，37(5)：1～2；
55．涂鹤龄；农药，2001，40(3)：1～3：
56．吴士雄；农药，2000，39(1)：7～10：
57．化工部计划司；中国主要化工产品统计年鉴(1996)；
58．陈良等；农药，2001，40(1)：6～7；
59．王强等；浙江省农科院植保所农美利试验报告；
60．于改莲，农药，2001，40(12)：43～45；
2．唐除痴等编著，农药化学，南开大学出版社；1998：486
3．张一宾，农药，2000，39(9)：3～6
4．苏少泉，农药，1998，37(11)：1～7
5．曹坳程，赵国锋，张朝贤，农药译丛，1998，20(2)：11～20
6. Ian M.Heap, Pestic. Scie., 1997, 51：235～243;
7．刘长令，农药，2002，43(9)：44-45；
8．苏少泉，农药译丛，1997，19(3)：14～18．
9. Masatoshi Tamaru, Takayoshi Takehi, Naoshi Masuyama, 1996, Pesticide Science, 47. 325～335.
10. Masatoshi Tamaru, Yoshihiro Saito, Pesticide Science, 1996, 47: 125～130.
11. Peter Babczinski, Thomas Zelinski, 1991, Pesticide Science, 31. 305～323.
12. Toshio Akagi, Pesticide Science, 1996, 47:309～318
13. Tsutomu Shimizu et al., 1994, J. Pesticide Science, 19:257～266
14. Tsutomu Shimizu et al., 1994, J. Pesticide Science, 19: 59～67
15. Yukio Nezu et al., 1996, Pesticide Science, 47:103～113
16. Yukio Nezu et al., 1996, Pesticide Science, 47:115～124
17. Yukio Nezu et al., 1996, J. Pesticide Science, 21. 293～303
18．杨光富，刘华银，陆荣健，杨华铮，高等学校化学学报，1998，19(2)：222～227；
19．朱文达译，农药译丛，1997，19(5)：24～35；
20．许泳峰主编，农田杂草化学防除原理与方法，辽宁科学技术出版社，1992；
21．揭玉斌，化工科技动态，1996，7：1～3；
22．J.Weed Sci. Tech., 1997, 42:326～332;
23．J.WeedSci.Tech., 1997,42:400～414;
24．化学工业部信息中心，世界化学工业年鉴，1984-1993；
25．化工科技动态，1996，12：7～9；
26．李斌，农药译丛，1997，增刊：25～27；
27．强胜，杂草科学，1997，4：11～14：
28．化学工业部农药工业科技情报中心站，国内农药工业概况，内部资料；
29．农药工业编辑部编，国外农药新品种，1990；
30．农业部农药检定所，农药登记公告，1993～1997；
31．化学工业部信息中心，中国化学工业年鉴，1993～1997；
32．李宗成，农药，1998，37(1)：1～12；
33．化工部计划司，中国主要化工产品统计年鉴(1996)，化学工业出版社；
34．李正名等，CN1106393A
35．李斌等，CN1148043A
36．苏少泉，生物进展，1993，14：30-34；
37. F.James Retzinger, Jrand Carol Mallory-smith, Weed Tech., 1997, 11:384～396
38. Gcorge Marshall, Pestic. Sci., 1998, 52: 394～402;
39. Isn M.Heap., Pestic. Sci.1997,52: 235243;
40. 1998 North Dakota Weed Control Guide, Complied by R.k.Zollinger, NDSU ExtensionScrvice, Jap. 1998
41. Timothy T. Obrigavvitch, Gilbert Cook, Jeff Wetherington, Pestic. Sci., 1998, 52: 199～217;
42. Yukio N., Nobuhide W., Yoshihiro S. et al., J. Pestic. Sci., 1996,21: 293;
43. EP315899 (1989)
44. EP347811 (1989)
45. US 5401711 (1995)
46. US 4932999 (1990)
47. JP01-301668 (1989)
48. Yang Guangfu, Yang Huazheng, Lu Rongjian et al., Chem.J. Chinese Univ., 1997,18(12): 1982
49．周卫平；编译 世界农药，2001，23(1)：7～11；
50．吴霞、张一宾；世界农药，2001，23(5)：1～7，16；
51．任太康、杨华铮；河南化工，1997，6：3～6；
52．刘常林；湖南化工，1996，26(4)：21-24，44；；
53．尚尔才；关于发展我国化学除草剂的建议，1979，内部资料；
54．张一宾；农药，1998，37(5)：1～2；
55．涂鹤龄；农药，2001，40(3)：1～3：
56．吴士雄；农药，2000，39(1)：7～10：
57．化工部计划司；中国主要化工产品统计年鉴(1996)；
58．陈良等；农药，2001，40(1)：6～7；
59．王强等；浙江省农科院植保所农美利试验报告；
60．于改莲，农药，2001，40(12)：43～45；