阅读说明：本技术 地克珠利衍生物及其应用和一种用于抗植物真菌病的杀菌剂 (Diclazuril derivative, application thereof and bactericide for resisting plant mycosis ) 是由 杨光富 陈涛 张璞 吴耀军 姜震 于 2021-03-23 设计创作，主要内容包括：本发明涉及农药杀菌剂领域,公开了地克珠利衍生物及其应用和一种用于抗植物真菌病的杀菌剂,该衍生物具有式(I)或式(II)所示的结构式。本发明提供的化合物在相对较低浓度下针对黄瓜霜霉病、大豆锈病和玉米锈病等真菌病具有明显比现有技术更好的效果。(The invention relates to the field of pesticide bactericides and discloses diclazuril derivatives and application thereof as well as a bactericide for resisting plant mycoses, wherein the derivatives have a structural formula shown in a formula (I) or a formula (II). The compound provided by the invention has obviously better effect on mycosis such as cucumber downy mildew, soybean rust, corn rust and the like at relatively low concentration than the prior art.)

1. A diclazuril derivative having the formula (I) or (II):

2. the use of diclazuril derivatives according to claim 1 as mitochondrial succinate dehydrogenase inhibitors in pesticides.

3. Use of the diclazuril derivative according to claim 1 for combating plant mycoses.

4. Use according to claim 3, wherein the plant mycosis is at least one of cucumber downy mildew, soybean rust and corn rust.

5. A fungicide for resisting plant mycoses, characterized in that the active ingredient of the fungicide is at least one of the diclazuril derivatives according to claim 1, and the content of the active ingredient is 0.1-100% by weight based on the total weight of the fungicide.

6. The bactericide as claimed in claim 5, wherein the content of said active ingredient is 1 to 98% by weight.

7. The bactericide as claimed in claim 5, wherein the content of said active ingredient is 5 to 90% by weight.

8. The bactericide according to any one of claims 5 to 7, wherein the bactericide is in a form selected from the group consisting of a hydrating agent, a powder, an emulsion, a suspension, an emulsifiable concentrate and a granule.

Technical Field

The invention relates to the field of pesticide bactericides, and particularly relates to a diclazuril derivative, application thereof and a bactericide for resisting plant mycosis.

Background

Diclazuril (Diclazuril) is an anticoccidial drug reported in 1986 by Yansen corporation in Belgium, structurally belongs to triazine phenylacetonitrile compounds, is used for preventing and treating coccidiosis of poultry, is mainly used for preventing and treating chicken coccidiosis, and has the advantages of high efficiency, broad spectrum, low toxicity, low drug resistance and small dosage.

Clinical tests show that diclazuril also has a very good control effect on resistant coccidia.

At present, the mechanism of action of diclazuril is not clear, and the mechanism of action is studied only on a cellular and subcellular level.

Taylor et al reported that diclazuril was effective in the first and second generation schizont and gametophyte stages of Eimeria infected lambs, and it also affected coccidian nucleic acid synthesis.

The general formula of diclazuril derivatives with diphenyl ether segments, which are used as fungicides, is disclosed in CN107459493A, and shows a good control effect on cucumber downy mildew at a concentration of 200 mg/L. Specifically, it is disclosed that the compounds shown below show 100% control effect against cucumber downy mildew at a concentration of 200mg/L, but the activity is significantly reduced or disappeared after the concentration is reduced.

Disclosure of Invention

The invention aims to provide a novel diclazuril derivative, which can realize obviously higher antifungal effect at low concentration.

In order to achieve the above object, a first aspect of the present invention provides a novel diclazuril derivative having a structural formula represented by formula (I) or formula (II):

the second aspect of the invention provides the use of the diclazuril derivative as a mitochondrial succinate dehydrogenase inhibitor in pesticides.

A third aspect of the invention provides the use of the aforementioned diclazuril derivative for combating plant mycoses.

The fourth aspect of the invention provides a bactericide for resisting plant mycoses, wherein the active ingredient of the bactericide is at least one of the diclazuril derivatives, and the content of the active ingredient is 0.1-100 wt% based on the total weight of the bactericide.

The compound provided by the invention has obviously better effect on cucumber downy mildew, soybean rust and corn rust at relatively low concentration than the prior art; has potential commercial value.

In particular, the compound provided by the invention has better control effect on cucumber downy mildew at low concentration than the known compound A15, the known compound A17 and the existing commercial medicaments of cyazofamid and amisulbrom.

Detailed Description

The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.

As previously mentioned, a first aspect of the present invention provides a diclazuril derivative having a formula represented by formula (I) or formula (II):

the method for preparing the diclazuril derivative is not particularly limited by the present invention, and can be obtained by combining the characteristics of the structural formula and the common general knowledge in the field of organic synthesis by the skilled person, and the method for preparing the diclazuril derivative is provided by the examples of the present invention, and the skilled person is not to be understood as the limitation of the present invention.

As mentioned above, the second aspect of the present invention provides the use of the aforementioned diclazuril derivative as a mitochondrial succinate dehydrogenase inhibitor in pesticides.

As mentioned above, a third aspect of the present invention provides the use of the aforementioned diclazuril derivative for combating plant mycoses.

Preferably, the plant fungal disease is at least one of cucumber downy mildew, soybean rust and corn rust.

As described above, the fourth aspect of the present invention provides a fungicide for controlling plant fungal diseases, which has an active ingredient of at least one of the aforementioned diclazuril derivatives in an amount of 0.1 to 100% by weight based on the total weight of the fungicide.

Preferably, the active ingredient is present in an amount of 1 to 98% by weight.

More preferably, the content of the active ingredient is 5 to 90% by weight.

Preferably, the formulation of the bactericide is selected from the group consisting of hydrating agents, powders, emulsions, suspensions, creamers and granules.

The present invention will be described in detail below by way of examples. In the following examples, various raw materials used are commercially available ones unless otherwise specified.

Unless otherwise specified, the room temperature described below indicates 25. + -. 1 ℃.

Without being particularly specified, the compounds a15, a17 below as control agents were each obtained by the method disclosed in CN107459493A, and the purity for the test was each higher than 98%.

Diclazuril: purchased from Bidi pharmaceutical science and technology Co., Ltd, purity 98%;

penthiopyrad: purchased from Shanghai Aladdin Biotechnology, Inc., with a purity of 99.8%;

cyazofamid: purchased from Taishiai (Shanghai) chemical industry development Limited, with a purity of 97%;

amisulbrom: purchased from Biderived pharmaceutical science and technology Co., Ltd, and having a purity of 97%.

In the following examples:

disease index ∑ (number of diseased leaves at each stage × number of relative stages) × 100/(total number of leaves × 9);

the preventing and treating effect (%) is (contrast disease index-treatment disease index) × 100/contrast disease index.

A: indicating that the control effect is 100%;

b: the control effect is more than or equal to 90 percent and less than 100 percent;

c: the control effect is more than or equal to 80 percent and less than 90 percent;

d: the control effect is more than or equal to 70 percent and less than 80 percent;

e: the control effect is more than or equal to 50 percent and less than 70 percent;

f: the control effect is more than or equal to 30 percent and less than 50 percent;

g: the control effect is more than or equal to 15 percent and less than 30 percent;

h: indicating a control effect of < 15%.

Preparation example

Synthetic route to the target compound:

step a-1: a100 mL round-bottom flask was charged with 10mmol of the compound represented by the formula (2-1), 11mmol of 3,4, 5-trifluorophenol and 13mmol of potassium carbonate, and then 20mL of DMF was added, followed by heating to 100 ℃. Stopping the reaction after TLC monitoring that the raw materials completely react, cooling to room temperature, pouring ice water while stirring, precipitating yellow solid, performing suction filtration, washing a filter cake with water, and drying to obtain a compound shown as a formula (2-21); the reaction mixture was fed to the next reaction without purification.

Step a-2: a100 mL round-bottom flask was charged with 10mmol of the compound represented by the formula (2-1), 11mmol of 2, 4-dimethylphenol and 13mmol of potassium carbonate, and then 20mL of DMF was added thereto, followed by heating to 100 ℃. Stopping the reaction after TLC monitoring that the raw materials completely react, cooling to room temperature, pouring ice water while stirring, precipitating yellow solid, performing suction filtration, washing a filter cake with water, and drying to obtain a compound shown as a formula (2-22); the reaction mixture was fed to the next reaction without purification.

Step b-1: adding 4mmol of the compound represented by the formula (2-21) and 4.8mmol of ammonium chloride into a 100mL round-bottom flask, adding 50mL of ethanol and 6mL of water, heating to reflux, adding reduced iron powder (12mmol), stopping the reaction after TLC monitoring the reaction of the raw materials, filtering with diatomite, concentrating the filtrate under reduced pressure, distilling under reduced pressure to remove most of the solvent, adding 50mL of ethyl acetate for extraction, washing the organic phase with saturated saline, adding anhydrous sodium sulfate for drying, removing the solvent, and carrying out column chromatography to obtain the compound represented by the formula (2-31). Pale yellow solid, yield 95%,¹H NMR(600MHz,DMSO)δ6.84–6.77(m,2H),6.68(s,2H),5.72(s,2H).

step b-2: adding 4mmol of compound represented by formula (2-22) and ammonium chloride (4.8mmol) into 100mL round bottom flask, adding 50mL ethanol and 6mL water, heating to reflux, adding reduced iron powder (12mmol), stopping reaction by TLC, filtering with diatomite, concentrating the filtrate under reduced pressure, distilling under reduced pressure to remove most solvent, adding 50mL ethyl acetate, extracting the organic phase with saturated saline, washing with anhydrous sodium sulfate, drying, removing solvent, and performing column chromatography to obtain the final productTo compounds represented by the formula (2-32). Pale yellow solid, yield 94%,¹H NMR(600MHz,DMSO)δ6.98(d,J＝8.4Hz,1H),6.65(s,2H),6.55(s,1H),6.39(d,J＝8.4Hz,1H),5.58(s,2H),2.11(s,3H),2.09(s,3H).

step c-1: adding 3.1mmol of the compound represented by formula (2-31), 10mL of acetic acid and 1mL of concentrated hydrochloric acid into a 100mL round-bottom flask, controlling the temperature at 0-5 ℃, dropwise adding an aqueous solution of sodium nitrite (3.4mmol,1mL of water), keeping the temperature and stirring for 30min after the dropwise adding is finished, adding NaOAc (7.75mmol) and CH₂(CONHCOOEt)₂(3.72mmol) and the reaction was then allowed to warm to room temperature. Reacting for 30min, adding NaOAc (2.5mmol), heating to reflux, monitoring by TLC (thin layer chromatography) that the raw materials are completely converted, adding 5mL of concentrated hydrochloric acid, continuing to react, monitoring by TLC that the reaction is stopped after hydrolysis is finished, removing most of solvent by decompression, adding 50mL of water, precipitating a large amount of solid, performing suction filtration and drying to obtain a compound shown as a formula (2-41), wherein the compound is yellow solid; the reaction was carried out without purification.

Step c-2: adding 3.1mmol of the compound represented by formula (2-32), 10mL of acetic acid and 1mL of concentrated hydrochloric acid into a 100mL round-bottom flask, controlling the temperature at 0-5 ℃, dropwise adding an aqueous solution of sodium nitrite (3.4mmol,1mL of water), keeping the temperature and stirring for 30min after the dropwise adding is finished, adding NaOAc (7.75mmol) and CH₂(CONHCOOEt)₂(3.72mmol) and the reaction was then allowed to warm to room temperature. Reacting for 30min, adding NaOAc (2.5mmol), heating to reflux, monitoring by TLC (thin layer chromatography) that the raw materials are completely converted, adding 5mL of concentrated hydrochloric acid, continuing to react, monitoring by TLC that the reaction is stopped after hydrolysis is finished, removing most of solvent by decompression, adding 50mL of water, precipitating a large amount of solid, performing suction filtration and drying to obtain a compound shown as a formula (2-42), wherein the compound is yellow solid; the reaction was carried out without purification.

Step d: preparation of Compounds of formula (I) and Compounds of formula (II)

Adding 3mmol of compound represented by formula (2-41) or 3mmol of compound represented by formula (2-42) into 50mL round bottom flask, adding 5mL mercaptoacetic acid, heating to 180 deg.C, TLC monitoring for complete conversion of raw material, stopping reaction, cooling, adding saturated NaHCO₃Neutralizing excessive thioglycollic acid with water solution, precipitating a large amount of solid, and filtering to obtain the targetDrying the crude product of the compound, and carrying out column chromatography to obtain the compound shown in the formula (I) and the compound shown in the formula (II).

A compound of formula (I):

pale yellow solid, yield 48%, melting point 157.6-158.9 ℃.¹H NMR(400MHz,DMSO)δ12.52(s,1H),7.86(s,2H),7.74(s,1H),7.08(dd,J＝8.8,6.0Hz,2H).¹³CNMR(100MHz,DMSO)δ158.21,151.44,146.47,141.08,140.99,139.17,138.61,138.52,138.38,137.15,136.97,136.69,136.57,130.75,126.48,126.41.HRMS(ESI)calcd for C₁₅H₆Cl₂F₃N₃O₃[M]⁺:402.9738,found:402.9700.

A compound represented by the formula (II):

yellow solid, yield 53%, melting point 89.5-90.4 ℃.¹H NMR(400MHz,DMSO)δ12.51(s,1H),7.82(s,2H),7.72(s,1H),7.11(s,1H),6.88(d,J＝8.0Hz,1H),6.21(d,J＝8.4Hz,1H),2.35(s,3H),2.22(s,3H).¹³C NMR(100MHz,DMSO)δ156.97,152.31,147.67,146.17,137.76,136.82,132.06,131.68,128.33,127.37,126.54,125.56,111.91,20.12,15.86.HRMS(ESI)calcd for C₁₇H₁₃Cl₂N₃O₃[M]⁺:377.0334,found:377.0300.

Test example 1: bactericidal activity screening results

The test method comprises the following steps: the target compound obtained in the preparation example and a control agent were each formulated into 5 wt% emulsifiable concentrates, wherein the effective concentrations of the respective compounds are shown in table 1.

The test adopts living potted plants, and the specific test process is as follows:

downy mildew of cucumber

Selecting potted cucumber seedlings with consistent growth vigor at the 2-leaf stage, inoculating a cucumber downy mildew spore suspension, placing the inoculated seedlings in an artificial climate chamber (the temperature is 20 ℃, and the relative humidity is more than 85%) for moisturizing culture, carrying out leaf surface spraying treatment according to the designed concentration (shown in table 1) after 24 hours, additionally arranging a blank control for spraying clear water, and repeating the steps for 3 times. And (5) placing the mixture in a greenhouse (room temperature) for normal management. After 5 days, the control effect is investigated when the disease is fully developed according to blank control.

Rust of soybean

Selecting potted soybean seedlings with regular and consistent growth in the 2-leaf stage, carrying out leaf surface spraying treatment according to the designed concentration (shown in table 1), additionally setting a blank control for spraying clear water, and repeating for 3 times. Inoculating the soybean rust spore suspension the next day after treatment, placing the suspension in an artificial climate chamber (temperature: 20 ℃, relative humidity: 95%) for moisture-keeping culture, and placing the suspension in a greenhouse (room temperature) for normal management after 16 hours. After 7 days, the control effect is investigated when the disease is fully developed according to blank control.

Rust disease of corn

Selecting 2-3 leaf-stage corn potted seedlings with regular and consistent growth, carrying out leaf surface spraying treatment according to the designed concentration (shown in table 1), additionally arranging a blank control for spraying clear water, and repeating for 3 times. Inoculating the corn rust spore suspension on the next day after treatment, placing the inoculated corn rust spore suspension in a climatic chamber (the temperature is 25 ℃ in the day, 20 ℃ in the night, and the relative humidity is more than 95%) for moisture preservation and culture, and placing the corn rust spore suspension in a greenhouse (room temperature) for normal management after 24 hours. After 7 days, the control effect is investigated when the disease is fully developed according to blank control.

The investigation method comprises the following steps: the grading standard adopts 'pesticide field efficacy test criteria' and the prevention and treatment effect is calculated by disease index.

The test results are shown in table 1.

TABLE 1

Test example 2: bactericidal activity screening results for cucumber downy mildew

The test method comprises the following steps: the target compound obtained in the preparation example and a control agent were each formulated into 5 wt% emulsifiable concentrates, wherein the effective concentrations of the respective compounds are shown in table 2.

Selecting potted cucumber seedlings with consistent growth vigor at the 2-leaf stage, inoculating a cucumber downy mildew spore suspension, placing the inoculated seedlings in an artificial climate chamber (the temperature is 20 ℃, and the relative humidity is more than 85%) for moisturizing culture, carrying out leaf surface spraying treatment according to the designed concentration (shown in table 2) after 24 hours, additionally arranging a blank control for spraying clear water, and repeating the steps for 3 times. And (5) placing the mixture in a greenhouse (room temperature) for normal management. After 5 days, the control effect is investigated when the disease is fully developed according to blank control.

The investigation method comprises the following steps: the grading standard adopts 'pesticide field efficacy test criteria' and the prevention and treatment effect is calculated by disease index.

The test results are shown in table 2.

TABLE 2

As can be seen from table 1, at the same concentration, compound I, II provided by the present invention has better or equivalent control effect against cucumber downy mildew and corn rust than control compounds a15 and a 17. At the same concentration, compound II had better control of soybean rust than control compounds a15 and a 17. Under the same concentration, the control effect of the compound I on the corn rust is equivalent to that of the control compound A17 and better than that of the control compound A15, and the control effect of the compound II on the corn rust is better than that of the control compounds A15 and A17.

Further, as shown in table 2, at a low concentration, compound I, II provided by the present invention has better control effect on cucumber downy mildew than control compound a15 and control compound a17, and compound II has better control effect than existing commercial agents cyazofamid and amisulbrom.

The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.