氘标记稻瘟酯的合成及其杀菌活性

范鑫鑫; 韩敏晖; 丁宇轩; 张学博; 李恒朝; 安杰

doi:10.16801/j.issn.1008-7303.2020.0011

氘标记稻瘟酯的合成及其杀菌活性

doi: 10.16801/j.issn.1008-7303.2020.0011

范鑫鑫^1,,
韩敏晖²,
丁宇轩²,
张学博²,
李恒朝^2, ,,
安杰^2, ,

1.
国家知识产权局专利局专利审查协作北京中心，北京 100160
2.
中国农业大学理学院，北京 100193

基金项目: 国家自然科学基金青年项目 (21602248)；国家重点研发计划 (2017YFD0200504)

详细信息

作者简介:
范鑫鑫，男，助理研究员，从事有机化学领域发明专利审查工作，E-mail：fanxinxin@cnipa.gov.cn

通讯作者:
李恒朝，共同通信作者 (Co-author for correspondence)，男，农药学专业在读博士，E-mail：lihengzhao@cau.edu.cn

安杰，通信作者 (Author for correspondence)，女，教授，主要从事氘化学研究，E-mail：jie_an@cau.edu.cn

中图分类号: TQ450.1; TQ455
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出版历程
- 收稿日期: 2019-07-26
- 录用日期: 2019-09-06
- 刊出日期: 2020-02-01

Synthesis and fungicidal activity of deuterated pefurazoate

Xinxin FAN^1
,,
Minhui HAN²,
Yuxuan DING²,
Xuebo ZHANG²,
Hengzhao LI^{2
, ,},
Jie AN^{2
, ,}

1.
Patent Examination Cooperation (Beijing) Center of the Patent Office, CNIPA, Beijing 100160, China
2.
College of Science, China Agricultural University, Beijing 100193, China

摘要

摘要: 氘标记农药作为探针或者内标在农药代谢、毒理研究或者农药残留分析中发挥着重要作用。由于动力学同位素效应，C−D键比C−H键更为稳定，因此氘标记农药可能具有更长的半衰期，以及对非靶标生物更小的毒性。稻瘟酯是一种对水稻恶苗病和稻瘟病有良好防治效果的农用杀菌剂。本项研究利用单电子转移还原氘化反应和氘标记中间体，成功合成了4个不同位点被选择性氘代的稻瘟酯，其中3个化合物未见文献报道，并对其进行了杀菌活性测试。离体杀菌活性测试结果显示，上述4种氘代稻瘟酯对水稻稻瘟病菌和水稻恶苗病菌均具有良好的生物活性，与未被标记的稻瘟酯无显著差异。氘标记稻瘟酯未来可作为代谢、毒理研究的探针及农药残留分析中的内标。
- 氘标记农药 /
- 氘代稻瘟酯 /
- 还原氘化反应 /
- 杀菌活性
Abstract: Deuterium labeled agrochemicals have been widely used as probes in the metabolism and toxicology study or internal standards in the agrochemical residue analysis. Because of the primary deuterium kinetic isotope effect, the cleavage of C−D bonds requires higher activation energy than that of C−H bonds. Deuterium labelled agrochemicals may have longer half-lives and reduced toxicity to non-target organism. Pefurazoate has good control effect on rice bakanae disease and rice blast. In this study, four types of deuterated pefurazoate was synthesized using novel sodium dispersions mediated single electron transfer reductive deuterations developed by Jie An’s lab, and three of them were first reported in this work. Their fungicidal activities against Pyricularia oryzae and Gibberella fujikuroi were evaluated, which were comparable to that of the unlabeled pefurazoate. The deuterated pefurazoate can be used as the probe in the metabolism study, the toxicity study or as the MS internal standard in the residue analysis.
- deuterium labeled agrochemicals /
- deuterated pefurazoate /
- reductive deuteration reaction /
- fungicidal activity

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1 氘代丁苯那嗪和氘代甲萘威的结构式

1. Structual formular of deutetrabenazine and carbaryl-(methyl-d₃)

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2 氘代化合物的合成策略

2. Strategies for the synthesis of deuterium labeled compounds

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3 新型单电子转移还原氘化反应

3. Novel single electron transfer reactions of reductive deuteration

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4 氘代稻瘟酯及其合成路线

4. The structural formula and synthesis route of deuterated pefurazoate

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5 氘代稻瘟酯合成方法的逆合成分析

5. Retro sythesis analysis of deuterated pefurazoate

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表 1 目标化合物1a~1d和稻瘟酯的 ¹H NMR 和 ¹³C NMR

Table 1. ¹H NMR and ¹³C NMR spectra of compounds 1a-1d and pefurazoate

化合物 Compound	¹H NMR (300 MHz, CDCl₃)	¹³C NMR (75 MHz, CDCl₃)
1a	8.13 (s, 1H), 7.49 (m, 1H), 7.45 (m, 1H), 7.11 (m, 1H), 6.38 – 6.33 (m, 2H), 5.78 (m, 1H), 5.08 – 4.92 (m, 2H), 4.72 (d, J = 16.3 Hz, 1H), 4.47 (d, J = 16.3 Hz, 1H), 3.99 (dd, J = 9.4, 5.7 Hz, 1H), 2.19 – 1.89 (m, 4H), 1.72 (t, J = 7.4 Hz, 2H), 0.74 (t, J = 7.5 Hz, 3H).	170.1, 151.4, 148.4, 143.4, 137.2 × 2, 129.3, 118.4, 115.7, 110.7 × 2, 65.1 (m), 62.5, 46.6, 30.0, 27.5, 21.6, 10.8.
1b	8.16 (s, 1H), 7.51 (m, 1H), 7.47 (m, 1H), 7.13 (m, 1H), 6.40 – 6.36 (m, 2H), 4.74 (d, J = 16.2 Hz, 1H), 4.49 (d, J = 16.2 Hz, 1H), 4.01 (dd, J = 9.5, 5.7 Hz, 1H), 2.15 – 1.98 (m, 4H), 1.74 (t, J = 7.4 Hz, 2H), 0.77 (t, J = 7.5 Hz, 3H).	170.2, 151.8, 148.7, 143.3, 137.3, 137.0 (m), 130.2, 118.2, 115.2 (m), 110.7, 110.6, 64.8 (m), 62.4, 46.4, 29.8, 27.6, 21.7, 10.8.
1c	7.47 (m, 1H), 6.40 – 6.35 (m, 2H), 5.80 (m, 1H), 5.08 – 4.97 (m, 2H), 4.74 (d, J = 16.3 Hz, 1H), 4.49 (d, J = 16.3 Hz, 1H), 4.16 (t, J = 6.6 Hz, 2H), 4.01 (dd, J = 9.4, 5.7 Hz, 1H), 2.18 – 1.97 (m, 4H), 1.75 (m, 2H), 0.77 (t, J = 7.5 Hz, 3H).	170.1, 151.7, 148.6, 143.2, 137.1, 137.0 (m), 129.6 (m), 117.8 (m), 115.6, 110.6, 110.5, 65.0, 62.4, 46.3, 29.9, 27.7, 21.6, 10.7.
1d	7.47 (m, 1H), 6.40 – 6.35 (m, 2H), 5.80 (m, 1H), 5.09 – 4.97 (m, 2H), 4.74 (d, J = 16.3 Hz, 1H), 4.49 (d, J = 16.3 Hz, 1H), 4.01 (dd, J = 9.4, 5.7 Hz, 1H), 2.19 – 1.99 (m, 4H), 1.74 (t, J = 7.4 Hz, 2H), 0.77 (t, J = 7.4 Hz, 3H).	170.0, 151.7, 148.6, 143.2, 137.1, 136.8 (m), 129.4 (m), 117.6 (m), 115.5, 110.6, 110.5, 64.6 (m), 62.3, 46.3, 29.9, 27.5, 21.6, 10.7.
稻瘟酯 pefurazoate	8.15 (s, 1H), 7.52 (m, 1H), 7.47 (m, 1H), 7.12 (m, 1H), 6.40 – 6.35 (m, 2H), 5.81 (m, 1H), 5.15 – 4.89 (m, 2H), 4.74 (d, J = 16.2 Hz, 1H), 4.49 (d, J = 16.2 Hz, 1H), 4.16 (t, J = 6.5 Hz, 2H), 4.01 (dd, J = 9.4, 5.7 Hz, 1H), 2.25 – 1.99 (m, 4H), 1.81 – 1.70 (m, 2H), 0.76 (t, J = 7.5 Hz, 3H).	169.8, 151.5, 148.4, 143.1, 137.0 × 2, 129.9, 117.9, 115.4, 110.5, 110.4, 64.8, 62.2, 46.2, 29.8, 27.50, 21.4, 10.5.

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表 2 氘代稻瘟酯对水稻稻瘟病菌和水稻恶苗病菌的离体活性

Table 2. In vitro antibacterial activity of the deuterated pefurazoate against Pyricularia oryzae and Gibberella fujikuroi

化合物 Compound	水稻稻瘟病菌 Pyricularia oryzae			水稻恶苗病菌 Gibberella fujikuroi
化合物 Compound	回归方程 Regression equation	相关系数 r	EC₅₀/(mg/L)	回归方程 Regression equation	相关系数 r	EC₅₀/(mg/L)
稻瘟酯 pefurazoate	y = 0.801 2x + 4.819 1	0.986 4	1.68	y = 0.849 4x + 5.580 7	0.984 9	0.20
1a	y = 0.723 2x + 4.870 6	0.998 0	1.51	y = 1.116 4x + 5.581 8	0.949 2	0.19
1b	y = 0.658 8x + 4.848 3	0.995 0	1.70	y = 0.961 8x + 5.718 0	0.963 0	0.18
1c	y = 0.813 4x + 4.782 0	0.974 7	1.85	y = 1.073 6x + 5.791 4	0.965 2	0.18
1d	y = 0.752 4x + 4.808 0	0.984 9	1.80	y = 1.102 4x + 5.800 0	0.964 4	0.19

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