阅读说明：本技术 一种吲哚取代酰胺类化合物及其制备方法和用途 (Indole substituted amide compound and preparation method and application thereof ) 是由 吐松 邓斌 高玉兴 李欣 叶李艺 陈学云 尹应武 于 2021-06-24 设计创作，主要内容包括：本发明涉及一种吲哚取代酰胺类化合物及其制备方法和用途,其化学结构通式如式VI:或VII:本发明公开了上述化合物的结构通式、合成路线及制备方法与用作杀菌剂的用途,以及其与农业上可接受的助剂或增效剂以及商品杀菌剂组合使用在防治农业、林业、园艺病害中的用途。(The invention relates to an indole substituted amide compound, a preparation method and application thereof, wherein the chemical structure general formula is as shown in formula VI: or VII:)

1. An indole-substituted amide compound, which is characterized in that: has a general structural formula shown as formula VI or VII:

wherein:

R₁is hydrogen, chlorine, fluorine, methyl or methoxy;

R₂is hydrogen, chlorine, fluorine, methyl or methoxy;

R₃is hydrogen or methyl.

2. The indole-substituted amide compound according to claim 1, wherein the compound having the general structural formula shown in formula VI is at least one of the following compounds:

[3- [3, 4-Dimethoxyphenyl ] -6-chloro-indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -5-chloro-indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -6-fluoro-indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -5-fluoro-indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -6-methoxy-indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -5-methoxy-indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -5-methyl-indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -5-chloro-indol-2-yl ] - [ 3-methyl-morpholin-1-yl ] -methanone

[3- [3, 4-dimethoxyphenyl ] -5-fluoro-indol-2-yl ] - [ 3-methyl-morpholin-1-yl ] -methanone.

3. The indole-substituted amide compound according to claim 1, wherein the compound having the general structural formula shown in formula VII is at least one of the following compounds:

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -6-chloro-indol-2-yl ] -morpholin-1-yl-methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -5-chloro-indol-2-yl ] -morpholin-1-yl-methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -6-fluoro-indol-2-yl ] -morpholin-1-yl-methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -5-fluoro-indol-2-yl ] -morpholin-1-yl-methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -6-methoxy-indol-2-yl ] -morpholin-1-yl-methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -5-methoxy-indol-2-yl ] -morpholin-1-yl-methanone

[1, 5-dimethyl-3- [3, 4-dimethoxyphenyl ] -indol-2-yl ] -morpholin-1-yl-methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -indol-2-yl ] -morpholin-1-yl-methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -5-chloro-indol-2-yl ] - [ 3-methyl-morpholin-1-yl ] -methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -5-fluoro-indol-2-yl ] - [ 3-methyl-morpholin-1-yl ] -methanone.

4. A pesticidal composition comprising the indole-substituted amide compound according to any one of claims 1 to 3 as an active ingredient.

5. A pesticidal composition according to claim 4 comprising from 0.1% to 99.9% by weight of the active ingredient, from 99.9% to 0.1% by weight of the solid or liquid adjuvant, and optionally from 0 to 25% by weight of the surfactant.

6. The use of indole-substituted amides according to claims 1 to 3 for the preparation of fungicides.

7. The synthesis method of the indole-substituted amide compound as claimed in any one of claims 1 to 3, the synthesis route and the preparation method comprise the following steps:

A. preparation steps of intermediate III:

preparing an intermediate III by taking a compound I as a raw material: carrying out ammonolysis reaction on the compound I and the compound II to prepare an intermediate III; or preparing an intermediate III by taking the compound I' as a raw material: the compound I ' and thionyl chloride are subjected to chlorination reaction to prepare an intermediate I ', and the obtained intermediate I ' and the compound II are subjected to amidation reaction to prepare an intermediate III;

B. the preparation steps of the intermediate IV are as follows:

carrying out bromination reaction on the intermediate III and hydrogen bromide to obtain an intermediate IV;

C. the preparation method of the indole-substituted amide compound VI comprises the following steps:

carrying out Suzuki coupling reaction on the intermediate IV and the compound V to prepare an indole substituted amide compound VI;

D. the preparation method of the indole-substituted amide compound VII comprises the following steps:

and carrying out methylation reaction on the compound VI and methyl iodide to obtain an indole substituted amide compound VII.

Technical Field

The invention belongs to the technical field of bacteriostat, relates to an indole morpholine compound, and particularly relates to an indole substituted amide compound, and a preparation method and application thereof.

Background

The cinnamamide bactericide is a high-efficiency bactericide which is derived from cinnamic acid and aims at preventing and treating oomycete diseases, and has excellent prevention and treatment effects on downy mildew and epidemic diseases. The cinnamamide bactericide has an activity of resisting the generation of spores, and can interfere the formation of cell walls to achieve a bacteriostatic effect by hindering the assembly of cell wall polymers (Huangyouth, et al. pesticide science and management 2000.21(5): 28-31). At present, the cinnamamides bactericide in the market mainly comprises three varieties of dimethomorph, flumorph, pyrimorph and the like, but all of the varieties have structural defects or the risk of drug resistance. In particular, the cis-isomer X (structure shown below) of dimethomorph has excellent bacteriostatic activity, while the trans-isomer Y (structure shown below) has extremely low bacteriostatic activity. Therefore, the method has extremely important significance for modification research and structure optimization of the cinnamamide bactericide.

Indole is a compound formed by connecting pyrrole and benzene in parallel, also called as benzopyrrole, and has a chemical formula of C₈H₇And N is added. There are two ways of combining pyrrole with benzene, known as indole and isoindole, respectively. Indoles and their homologues and derivatives are widely found in nature, mainly in natural flower oils, such as jasmine, bitter orange flower, narcissus, vanilla, and the like.

In order to develop a more efficient, broad-spectrum and environment-friendly cinnamamide bactericide and relieve the existing drug resistance risk of the cinnamamide bactericide, the invention introduces indole into the molecular structure of the cinnamamide compound so as to stabilize the cis-styrene group in the molecular structure of the cinnamamide compound. And then, a series of indole-substituted amide compounds designed and synthesized are tested for biological activity, so that the cinnamamide bactericide with more excellent biological activity and better practical application performance is obtained by screening.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides an indole substituted amide compound and a preparation method and application thereof.

One of the technical schemes adopted by the invention for solving the technical problems is as follows: an indole-substituted amide compound has a structural general formula shown as formula VI or VII:

wherein:

R₁is hydrogen, chlorine, fluorine, methyl or methoxy;

R₂is hydrogen, chlorine, fluorine, methyl or methoxy;

R₃is hydrogen or methyl.

Preferably, the indole-substituted amide compound having the general structural formula shown in formula VI is at least one of the following compounds:

[3- [3, 4-Dimethoxyphenyl ] -6-chloro-indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -5-chloro-indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -6-fluoro-indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -5-fluoro-indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -6-methoxy-indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -5-methoxy-indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -5-methyl-indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -indol-2-yl ] -morpholin-1-yl-methanone

[3- [3, 4-Dimethoxyphenyl ] -5-chloro-indol-2-yl ] - [ 3-methyl-morpholin-1-yl ] -methanone

[3- [3, 4-dimethoxyphenyl ] -5-fluoro-indol-2-yl ] - [ 3-methyl-morpholin-1-yl ] -methanone.

Preferably, the indole-substituted amide compound having the general structural formula shown in formula VII is at least one of the following compounds:

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -6-chloro-indol-2-yl ] -morpholin-1-yl-methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -5-chloro-indol-2-yl ] -morpholin-1-yl-methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -6-fluoro-indol-2-yl ] -morpholin-1-yl-methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -5-fluoro-indol-2-yl ] -morpholin-1-yl-methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -6-methoxy-indol-2-yl ] -morpholin-1-yl-methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -5-methoxy-indol-2-yl ] -morpholin-1-yl-methanone

[1, 5-dimethyl-3- [3, 4-dimethoxyphenyl ] -indol-2-yl ] -morpholin-1-yl-methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -indol-2-yl ] -morpholin-1-yl-methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -5-chloro-indol-2-yl ] - [ 3-methyl-morpholin-1-yl ] -methanone

[ 1-methyl-3- [3, 4-dimethoxyphenyl ] -5-fluoro-indol-2-yl ] - [ 3-methyl-morpholin-1-yl ] -methanone.

The indole substituted amide compound is applied to the pesticide composition for preventing and treating oomycete diseases.

The other technical scheme of the invention is a pesticide composition which comprises the indole-substituted amide compound VI or VII as an active ingredient, wherein the content of the active ingredient is 0.1 to 99.9 percent by weight, 99.9 to 0.1 percent by weight of solid or liquid auxiliary agent and optionally 0 to 25 percent by weight of surfactant.

The benzofuran substituted amide compound VII and the bactericide prepared by combining the bactericide are applied to preventing and treating diseases of agricultural, forestry and horticultural plants.

The third technical scheme adopted by the invention for solving the technical problems is as follows: a synthesis method of indole-substituted amide compounds comprises the following specific synthetic route and preparation steps:

A. preparation steps of intermediate III:

preparing an intermediate III by taking a compound I as a raw material:

adding 1.0 mmol of the compound I and 5 ml of tetrahydrofuran into a single-mouth bottle, adding 1.0 mmol of 1,5, 7-triazabicyclodecan-5-ene and 5.0 mmol of the compound II under stirring, and carrying out reflux reaction for 15 hours; after the reaction is finished, the solvent is removed under reduced pressure, and the residue is separated and purified by a 300-400-mesh silica gel column chromatography (the eluent is a mixed solution of ethyl acetate and petroleum ether, V)_{Petroleum ether}:V_{Ethyl acetate}3:1) to obtain intermediate III with a yield of 53-83%; the preparation amount of the intermediate III and the volume of the reaction vessel are enlarged or reduced according to corresponding proportion;

or preparing an intermediate III by taking the compound I' as a raw material:

adding 1.0 mmol of compound I' into a single-neck bottle, adding 6 ml of toluene and 2 drops of N, N-dimethylformamide under the protection of argon, finally adding 2.0 mmol of thionyl chloride, and reacting at 50 ℃ until the solid is dissolved; after the reaction is finished, removing the solvent and the unreacted thionyl chloride under reduced pressure to obtain a crude product of the intermediate I'; adding 6 ml of dichloromethane into the crude product of the intermediate I', then cooling the reaction liquid to 0 ℃, adding 1.5 mmol of the compound II into the reaction liquid, and reacting for 12 hours at 50 ℃; after the reaction, the reaction solution was washed with distilled water (10 ml), the aqueous phase was extracted with ethyl acetate (3X 10 ml), the organic phases were collected and combined, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was purified by 300-mesh 400-mesh silica gel column chromatography (the eluent was ethyl acetate-petroleum ether)Mixed solution of (2), V_{Petroleum ether}:V_{Ethyl acetate}3:1) to obtain intermediate III with a yield of 46-87%; the amount of intermediate III prepared and the volume of the reaction vessel are enlarged or reduced according to the corresponding proportion.

B. The preparation steps of the intermediate IV are as follows:

adding 1.0 mmol of the intermediate III and 1.2 mmol of dimethyl sulfoxide into a reaction bottle, then adding 4 ml of ethyl acetate, finally adding 1.2 mmol of 33 wt% aqueous hydrogen bromide, and reacting for 0.5 hour at 60 ℃; after the reaction is finished, washing the reaction solution by using distilled water, extracting the water phase by using ethyl acetate, collecting and combining the organic phases, drying by using anhydrous magnesium sulfate, removing the solvent by reducing pressure, and separating and purifying the residue by using a 300-mesh 400-mesh silica gel column chromatography (the eluent is a mixed solution of ethyl acetate and petroleum ether, V)_{Petroleum ether}:V_{Ethyl acetate}3:1) to obtain intermediate IV with a yield of 67-100%; the amount of intermediate IV prepared and the volume of the reaction vessel are enlarged or reduced according to the corresponding proportion.

C. Preparation procedure of compound VI:

1.0 mmol of intermediate VI, 6 ml of toluene, 6 ml of ethanol and 2.5 ml of aqueous sodium carbonate solution (1M) are added to a 50 ml single-neck flask, 1.5 mmol of compound V is added with stirring, 5 mol% of tetrakis (triphenylphosphine) palladium is added, finally 3.0 mmol of lithium chloride is added, and reaction is carried out at 110 ℃ for 4 hours; after the reaction, extracting the reaction solution with ethyl acetate (3 × 20 ml), collecting and combining organic phases, drying with anhydrous magnesium sulfate, removing the solvent under reduced pressure, and separating and purifying the residue by 300-mesh 400-mesh silica gel column chromatography (the eluent is ethyl acetate-petroleum ether mixed solution, V)_{Petroleum ether}:V_{Ethyl acetate}1:1) obtaining the indole substituted amide compound VI with the yield of 44-78%; the preparation amount of the indole substituted amide compound VI and the volume of the reaction vessel are enlarged or reduced according to the corresponding proportion.

D. Preparation procedure of compound VII:

adding 1.0 mmol of compound VI into a reaction bottle, and adding 4 ml of N, N-dimethylformamide under the argon atmosphere; cooling the reaction solution to 0 ℃, adding 1.2 millimole of sodium hydride, and reacting at room temperature for 0.5 hour; then the reaction is carried out againCooling the solution to 0 ℃, adding 1.2 millimole of methyl iodide, and reacting for 2 hours at 40 ℃; after the reaction, the reaction solution was washed with distilled water (6 ml), the aqueous phase was extracted with ethyl acetate (3 × 10 ml), the organic phases were collected and combined, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was purified by 300-mesh 400-mesh silica gel column chromatography (eluent was ethyl acetate-petroleum ether mixed solution, V)_{Petroleum ether}:V_{Ethyl acetate}1:1) obtaining the indole substituted amide compound VII with the yield of 88.7-96.2%; the preparation amount of the indole substituted amide compound VII and the volume of the reaction vessel are enlarged or reduced according to the corresponding proportion.

Wherein:

R₁hydrogen, chlorine, fluorine, methyl and methoxy;

R₂hydrogen, chlorine, fluorine, methyl and methoxy;

R₃hydrogen and methyl.

Compared with the background technology, the technical scheme of the invention has the following advantages:

1. lead optimization is carried out on the indole-substituted cinnamamide compound, and an indole group is used for stabilizing a cis-styrene group in a molecular structure of the cinnamamide bactericide dimethomorph Y, so that the optimization can improve the practical application performance of the cinnamamide bactericide dimethomorph Y;

2. the indole group is used for stabilizing the cis-styrene group in the molecular structure of the cinnamide bactericide dimethomorph Y, or chlorine and fluorine substituents are introduced into the molecular structure of the compound and methylation of nitrogen atoms in indole rings is promoted to the bacteriostatic activity and bacteriostatic broad spectrum of the compound.

Detailed Description

The present invention will be described in further detail with reference to examples, but the present invention is not limited to these examples.

The synthesis, biological activity and application of indole-substituted amide compounds VI and VII are more specifically illustrated by specific preparation and antibacterial activity determination examples, and the following examples and biological activity determination results are only used for further detailed description of the present invention, but are not intended to limit the present invention to these examples.

The specific method for measuring the biological activity of the indole-substituted amide compound comprises the following steps:

(1) in-vitro antibacterial activity determination of the indole-substituted amide compounds:

the method comprises the following specific steps: dissolving the sample with appropriate amount of dimethyl sulfoxide, diluting with 0.05% Tween 80 water solution to desired concentration, adding the medicinal liquid into sterilized culture solution under aseptic condition, shaking to obtain medicinal culture medium with desired concentration, using culture medium without medicinal agent as blank control, and inoculating the cultured pathogenic bacteria onto the culture medium with sterilized perforator. After inoculation, culturing in a constant-temperature incubator at 25 +/-1 ℃, calculating the diameter of a bacteria disc by using a cross method after three days, comparing with a blank control to calculate the relative bacteriostasis rate, "0" represents the most serious disease degree (usually taking the value as a basic survey standard), "100" represents the aseptic colony growth, and the tested bacteria are most typical plant pathogenic bacteria species actually occurring in the field in agricultural production in China, and the code number and the name are as follows: PS is rice sheath blight bacteria, whose latin names are Pellicularia sasakii, GZ are wheat scab bacteria, whose latin names are Gibberella zeae, AS are tomato early blight bacteria, whose latin names are Alternaria solani, PP are apple ring rot bacteria, whose latin names are Physalospora piricola, PA are fruit Pythium, whose latin names are Pythium aphanidermatum, PI are tomato late blight bacteria, whose latin names are Phytophtora infestans, melon Phytophthora melonis, whose latin names are Phytophtora dreschsleri.

(2) And (3) determining the in-vivo antibacterial activity of the indole-substituted amide compound:

the specific method comprises the following steps: dissolving a sample by using a proper amount of dimethyl sulfoxide, diluting the sample to a required concentration by using 0.05 percent of Tween 80 aqueous solution, then uniformly spraying liquid medicine on leaves, setting the leaves which are not treated by the pesticide as blank control, carrying out disease inoculation after 24 hours, putting the plants in a constant-temperature and constant-humidity incubator after inoculation, keeping illumination/darkness for 12 hours alternately, carrying out evaluation and investigation after the control is fully developed, comparing the blank control to calculate the disease inhibition percentage, "0" represents the most serious disease degree (usually using the value as a basic investigation standard), "100" represents no disease spot, and the tested strain is most of typical plant pathogenic bacteria species which actually occur in the field in agricultural production of China, wherein the code number and the name are as follows: PS refers to Rhizoctonia solani, Latin names of the Rhizoctonia solani and the Pc refer to Pseudoperonospora cubensis, PI refers to tomato late blight, and Latin names of the Phytophthora infestans.

Example 1

Preparing an intermediate III by taking a compound I as a raw material:

adding 1.0 mmol of the compound I and 5 ml of tetrahydrofuran into a single-mouth bottle, adding 1.0 mmol of 1,5, 7-triazabicyclodecan-5-ene and 5.0 mmol of the compound II under stirring, and carrying out reflux reaction for 15 hours; after the reaction is finished, the solvent is removed under reduced pressure, and the residue is separated and purified by a 300-400-mesh silica gel column chromatography (the eluent is a mixed solution of ethyl acetate and petroleum ether, V)_{Petroleum ether}:V_{Ethyl acetate}3:1) to give intermediate III in 53-83% yield. The following intermediate III was prepared by the above method:

example 2

Preparing an intermediate III by taking a compound I' as a raw material:

adding 1.0 mmol of compound I' into a single-neck bottle, adding 6 ml of toluene and 2 drops of N, N-dimethylformamide under the protection of argon, finally adding 2.0 mmol of thionyl chloride, and reacting at 50 ℃ until the solid is dissolved; after the reaction is finished, removing the solvent and the unreacted thionyl chloride under reduced pressure to obtain a crude product of the intermediate I'; adding 6 ml of dichloromethane into the crude product of the intermediate I', then cooling the reaction liquid to 0 ℃, adding 1.5 mmol of the compound II into the reaction liquid, and reacting for 12 hours at 50 ℃; after the reaction was completed, the reaction solution was washed with distilled water (10 ml), and the aqueous phase was extracted with ethyl acetate three times with 10ml of ethyl acetate each time; the organic phases are collected and combined, dried over anhydrous magnesium sulphate, the solvent is removed under reduced pressure and the residue is taken up 3Separating and purifying with 00-400 mesh silica gel column chromatography (the eluent is mixed solution of ethyl acetate-petroleum ether, V)_{Petroleum ether}:V_{Ethyl acetate}3:1) to give intermediate III in a yield of 46-87%.

The following intermediate III was prepared by the above method:

example 3

Preparation of intermediate IV:

adding 1.0 mmol of the intermediate III and 1.2 mmol of dimethyl sulfoxide into a reaction bottle, then adding 4 ml of ethyl acetate, finally adding 1.2 mmol of 33 wt% aqueous hydrogen bromide, and reacting for 0.5 hour at 60 ℃; after the reaction is finished, washing the reaction solution by using distilled water, extracting the water phase by using ethyl acetate, collecting and combining the organic phases, drying by using anhydrous magnesium sulfate, removing the solvent by reducing pressure, and separating and purifying the residue by using a 300-mesh 400-mesh silica gel column chromatography (the eluent is a mixed solution of ethyl acetate and petroleum ether, V)_{Petroleum ether}:V_{Ethyl acetate}3:1) to give intermediate IV in 67-100% yield.

The following intermediate IV was prepared by the above method:

example 4

Preparation of Compound VI:

1.0 mmol of intermediate IV, 6 ml of toluene, 6 ml of ethanol and 2.5 ml of aqueous sodium carbonate solution (1M) were added to a 50 ml single-neck flask, and stirredAdding 1.5 mmol of the compound V under stirring, then adding 5 mol% of tetratriphenylphosphine palladium, finally adding 3.0 mmol of lithium chloride, and reacting for 4 hours at 110 ℃; after the reaction is finished, extracting the reaction solution by using ethyl acetate for three times, wherein 20ml of ethyl acetate is used each time; collecting and combining organic phases, drying by anhydrous magnesium sulfate, removing the solvent under reduced pressure, and separating and purifying the residue by 300-mesh 400-mesh silica gel column chromatography (the eluent is a mixed solution of ethyl acetate and petroleum ether, V)_{Petroleum ether}:V_{Ethyl acetate}1:1) to obtain the indole substituted amide compound VI with the yield of 44-78 percent.

The following compound VI was prepared in the above manner:

example 5

Preparation of compound VII:

adding 1.0 mmol of compound VI into a reaction bottle, and adding 4 ml of N, N-dimethylformamide under the argon atmosphere; cooling the reaction solution to 0 ℃, adding 1.2 millimole of sodium hydride, and reacting at room temperature for 0.5 hour; then, cooling the reaction solution to 0 ℃, adding 1.2 millimole of methyl iodide, and reacting for 2 hours at 40 ℃; after the reaction was completed, the reaction solution was washed with distilled water (6 ml), and the mixture was washed withExtracting the water phase with ethyl acetate for three times, wherein 10ml of ethyl acetate is used each time; collecting and combining organic phases, drying by anhydrous magnesium sulfate, removing the solvent under reduced pressure, and separating and purifying the residue by 300-mesh 400-mesh silica gel column chromatography (the eluent is a mixed solution of ethyl acetate and petroleum ether, V)_{Petroleum ether}:V_{Ethyl acetate}1:1) to obtain the indole substituted amide compound VII with the yield of 88.7-96.2%.

The following compound VII was prepared by the above method:

example 6

The in vitro antibacterial activity determination results of the indole substituted amide compounds VI and VII are as follows:

the in vitro bacteriostatic activity of indole-substituted amide compounds VI and VII is shown in table 1, and the results in table 1 show that most of the compounds VI and VII of the invention have better or equal inhibition rate on the growth of tested thalli under in vitro conditions than or equal to dimethomorph and flumorph with the closest chemical structure to the chemical structure of the invention; most indole-substituted cinnamoyl compounds have 1-12 times of inhibition rate of flumorph on tomato early blight, and dimethomorph has no inhibition effect on tomato early blight. The inhibition rate of most indole substituted cinnamoyl compounds on the pythium aphanidermatum is 1-5 times of that of dimethomorph and 1-10 times of that of flumorph. The bacteriostasis rate of the synthesized indole substituted cinnamoyl compounds to tomato late blight reaches 100 percent. Obviously, the cis-styrene group in the indole ring stabilized cinnamamide compound has certain promotion effect on the bacteriostatic activity and bacteriostatic broad spectrum of the compound.

TABLE 1 in vitro bacteriostatic activity of indole-substituted amide compounds VI and VII

Example 7

The in vivo antibacterial activity determination results of the indole-substituted amide compounds VI and VII are as follows:

the living body bacteriostatic activity of indole-substituted amide compounds VI and VII is shown in table 1, and the table 1 shows that the synthesized part of indole-substituted cinnamoyl compounds has certain inhibition effect on rice sheath blight disease, wherein the inhibition rate of the compound VI-8 with all substituents being hydrogen atoms on rice sheath blight disease can reach 80%, and dimethomorph and flumorph have no inhibition effect on the disease. The steric hindrance of the compound is presumed to be one of important factors influencing the bacteriostatic effect of the compound on rice sheath blight disease, and the smaller the steric hindrance of the compound is, the more beneficial the compound to inhibit the disease is. The synthesized partial indole substituted cinnamoyl compounds show better inhibition effect on cucumber downy mildew, wherein the inhibition rates of the compounds VI-10, VII-1, VII-5, VII-9 and VII-10 are all different from 80% to 100%, and the contrast reagent has no inhibition effect on the cucumber downy mildew. The indole benzene ring in the chemical structure of the compound is substituted by chlorine atom or methylation of nitrogen atom in the indole ring, which is beneficial to inhibiting cucumber downy mildew. In addition, the methyl substituent is innovatively introduced into a morpholine ring in the chemical structure of the compound, so that the compound is also beneficial to inhibiting cucumber downy mildew. Most of the synthesized indole-substituted cinnamoyl compounds have excellent inhibition effect on tomato late blight, the inhibition rate of the synthesized indole-substituted cinnamoyl compounds on the tomato late blight is close to or equal to 100%, and the inhibition effect of the synthesized indole-substituted cinnamoyl compounds on the tomato late blight is equivalent to that of dimethomorph and flumorph on the tomato late blight.

TABLE 2 in vivo bacteriostatic activity of indole-substituted amide compounds VI and VII

Example 8

The application of indole-substituted amide compounds VI and VII in the pesticide composition is as follows:

both the indole-substituted amide compound VI and the indole-substituted amide compound VII can be used for preparing a pesticide mixture, and the pesticide mixture contains the indole-substituted amide compound VI or the indole-substituted amide compound VII as an active ingredient; the pesticidal mixtures contain 0.1 to 99.9% by weight of active ingredient, 99.9 to 0.1% by weight of solid or liquid adjuvant, and optionally 0 to 25% by weight of surfactant.

Example 9

The application of the combination of the indole-substituted amide compound VI or VII and the bactericide in preventing and treating agricultural, forestry and horticultural plant diseases:

the indole substituted amide compounds VI or VII and any one or two or more than two of the commercial bactericides are combined to form the bactericidal composition for preventing and treating agricultural, forestry and gardening plant diseases, and the commercial bactericides are selected from: benzothiadiazole, tiadinil, abbreviated as TDL, thiamide, methiazide, 4-methyl-1, 2, 3-thiadiazole-5-carboxylic acid, 4-methyl-1, 2, 3-thiadiazole-5-sodium formate, 4-methyl-1, 2, 3-thiadiazole-5-ethyl formate, DL-beta-aminobutyric acid, isotianil, the english generic name of which is: isotianil, 3, 4-dichloroisothiazole-5-carboxylic acid, 3, 4-dichloroisothiazole-5-sodium formate, 3, 4-dichloroisothiazole-5-ethyl formate, ribavirin, antofine, ningnanmycin or salicylic acid, cymoxanil, thiram, ziram, mancozeb, fosetyl-aluminium, thiophanate-methyl, chlorothalonil, dichlorvos, procymidone, fenpropidin, thiophanate-methyl, metalaxyl-M, flumorph, dimethomorph, metalaxyl-M, benalaxyl-M, diclocyanide, sulfflusulfamide, flutolanilide, bismeryl, cyprodinil, cyhalodiamide, silthiopham, furamex, furametpyr, fenpyrad, fenpropam, metoclopramide, isoxarin, iprodione, pyrimethanil, trifloxystrobin, mepirimate, metosulam, metominostrobilum, mepirimate, metominostrobilum, metoclopramide, metosulam, metoclopramide, metosulam, and, Dimoxystrobin, fluoxastrobin, kresoxim-methyl, metominostrobin, orysastrobin, picoxystrobin, pyraclostrobin, trifloxystrobin, enestrobin, epoxiconazole, bromuconazole, cyproconazole, difenoconazole, diniconazole, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, prothioconazole, simeconazole, tebuconazole, tetraconazole, triadimenol, triticonazole, bitertanol, thiabendazole, fuberidazole, imazalil, prochloraz, triflumizole, cyazofamid, fenamidone, oxpoconazole, fenpyrad, famoxadone, pyridaben, oxadixyl, thiabendazole, trifloxystrobin, octopirox, fenbuconazole, tridemorph, fenpropimorph, fenpropiconazole, fenpyroxapyroxapyrone, fludioxonil, fenpropiconazole, fenpyroxapyroxapyroxapyroxapyroxad-ethyl, flufen, fludioxonil, flunil, fludioxonil, and a, Fluazinam, pyribenzoxim, cyprodinil, boscalid, fluopicolide, pyrimethanil, cyprodinil, fluoxamid, mepizone, mepanipyrim, pyrimethanil, fenarimol, fluoropyrimidinol, fenaminosulf, dithianon, oxyquinoline, hydroxyquinoline, propoxymine, phenoxyquinoline, diethofencarb, iprovalicarb, benthiavalicarb, propamocarb, edifenphos, iprobenfos, pyrazofos, tolclofos-methyl, blasticidin, kasugamycin, polyoxin, validamycin, streptomycin, metalaxyl, furalaxyl, benalaxyl, furalamide, fenbutamide, carbendazim, benomyl, thiophanate-methyl, triadimefon, bupirimate, dimeticonol, ethirimol, fenarimol, captan, fenflurazole, vinclozolirtide, flufenapyr, dimethachlon, chlorothalonil, fenozide, isoprothiolane, pyriminostrobilyn, pyriminostrobilurin, pyrimethanil, pyriprox, pyricularia ferrea, pyricularia, Bismerthiazol, quintozene, propineb, fosetyl-aluminum, sulfur, bordeaux mixture, copper sulfate, copper oxychloride, cuprous oxide, copper hydroxide, metrafenone, pencycuron, pyridaben, tetrachlorophthalide, pyroquilon, spiroxamine, tricyclazole, azinam, dodine, iminoctadine, chloronitramine, bentiamine, tolfenpyrad, indolylate, sodium diuron, quinconazole, probenazole, bronopol, iodomethane, metam, fenaminoesters, dazomet, dichloroisopropyl ether, fosthiazate, fosfon, ethoprophos, dichlofenthion, buthion, oxamyl, sulfuryl fluoride, dichloropropylene, dichloroisonicotinic acid, probenazole; the total mass percentage of the indole-substituted amide compound VI or VII in the bactericidal composition is 1% -90%, 99% to 10% by weight of solid or liquid auxiliary agent and optionally 0 to 25% by weight of surfactant, and the mass percentage of the indole-substituted amide compound VI or VII in the bactericidal composition is 1% to 99% to 1% to the mass percentage of the commercial bactericide; the formulation of the bactericidal composition in the invention is selected from: any one of a seed treatment emulsion, an aqueous emulsion, a macrogranule, a microemulsion, a water-soluble granule, a soluble concentrate, a water-dispersible granule, a poison valley, an aerosol, a block poison bait, a sustained-release block, a concentrated poison bait, a capsule granule, a microcapsule suspension, a dry-mixed seed powder, a missible oil, an electrostatic spray, an aqueous-in-oil emulsion, an oil-in-water emulsion, a smoke canister, a fine granule, a smoke candle, a smoke canister, a smoke stick, a seed treatment suspension, a smoke tablet, a smoke pellet, a granular poison bait, a hot fogging concentrate, a medicinal paint, a fine granule, an oil suspension, an oil-dispersible powder, a flaky poison bait, a concentrated colloid, a pouring agent, a seed coating agent, a smearing agent, a suspending emulsion, a film-forming oil agent, a soluble powder, a seed treatment water-soluble powder, an ultra-low-volume suspension, a chasing powder, an ultra-low-volume liquid, and a wet-mixed seed water-dispersible powder; the plant diseases controlled by the bactericidal composition are selected from the following groups: rhizoctonia solani, fusarium graminearum, early blight of tomato, ring rot of apple, pythium aphanidermatum, late blight of potato, and phytophthora melonis; the plants to which the fungicidal composition of the present invention is applied are selected from: rice, wheat, barley, oats, corn, sorghum, sweet potato, cassava, soybean, sweet broad bean, pea, mung bean, small bean, cotton, silkworm, peanut, rape, sesame, sunflower, sugar beet, sugarcane, coffee, cocoa, ginseng, fritillaria, rubber, coconut, oil palm, sisal, tobacco, tomato, chili, radish, cucumber, cabbage, celery, mustard tuber, shallot, garlic, watermelon, melon, cantaloupe, papaya, apple, citrus and peach, tea, wild vegetables, bamboo shoots, hop, pepper, banana, papaya, orchid, bonsai.

The foregoing is for illustrative purposes only, and therefore the scope of the invention should not be limited by this description, and all modifications made within the scope of the invention and the contents of the description should be considered within the scope of the invention.