N, N-disubstituted-4-(5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl) benzamide compound as well as preparation and application of N, N-disubstituted-4-(5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl) benzamide compound

Abstract

The invention relates to a novel compound as well as a preparation method and application thereof, in particular to an N, N-disubstituted-4-(5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl) benzamide compound as well as a preparation method and application of the N, N-disubstituted-4-(5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl) benzamide compound. The structural formula of the N, N-disubstituted-4-(5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl) benzamide compound is as shown in a formula I: # imgabs0 #, and the structural formula of the N, N-disubstituted-4-(5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl) benzamide compound is as shown in a formula II, in the formula I, R1 is selected from methoxyl or phenyl; r1 is selected from 4-methylphenyl, 4-methylbenzyl, 4-methoxyphenyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-bromobenzyl, 3-trifluoromethylphenyl or 4-trifluoromethylbenzyl, and R2 is selected from 4-methylphenyl, 4-methylbenzyl, 4-methoxyphenyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-bromobenzyl, 3-trifluoromethylphenyl or 4-trifluoromethylbenzyl. The compound disclosed by the invention especially shows relatively good antifungal activity on botryosphaeria dothidea and pythium aphanidermatum, and a part of the compound is equivalent to that of a drug fluxapyroxad on the market. The compound provided by the invention can provide more choices for research and development of antifungal drugs, and has a wide application prospect.

Description

Technical Field

[0001] The present invention relates to a new class of compounds and a preparation method and application thereof, and in particular to N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)benzamide compounds and a preparation method and application thereof. Background Art

[0002] Since the mid-20th century, the impact and scale of fungal diseases in crops have continued to increase, posing a serious threat to the production and safety of essential foods such as rice, corn, wheat and soybeans. It is estimated that crop losses caused by plant diseases and insect pests are as high as $22 billion worldwide each year. In order to reduce the losses caused by plant fungal diseases, pesticides are widely used to protect crops, and various chemical fungicides have been widely used. However, the widespread use of fungicides also causes problems such as resistance, toxicity and pesticide residues. Therefore, the development of new high-efficiency, low-toxic and environmentally friendly new compounds to replace fungicides with resistance problems is a long-standing major problem.

[0003] Amide compounds have been widely used in the field of anti-plant fungi for several decades. So far, more than 30 varieties have been commercialized. Among the fungicides currently on the market, succinate dehydrogenase inhibitor fungicides are all amide structures. In recent years, heterocyclic compounds have been widely used in the fields of pesticides and medicines due to their good selectivity, high activity, low dosage and environmental friendliness. Oxadiazole compounds, as an important class of five-membered N and O heterocyclic compounds, exhibit a variety of biological activities. For example, many literatures have reported that trifluoromethyl oxadiazole derivatives have the effect of preventing and controlling plant pathogenic microorganisms, especially fungi. Therefore, it is of great significance to develop new amide skeleton oxadiazole compounds. Summary of the invention

[0004] The purpose of the present invention is to provide a class of N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)benzamide compounds and a preparation method and application thereof.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions:

[0006] N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide compounds, the structural formula of which is shown in Formula I:

[0007]

[0008] Among them, R 1 is selected from methoxy or phenyl; R 2is selected from 4-methylphenyl, 4-methylbenzyl, 4-methoxyphenyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-bromobenzyl, 3-trifluoromethylphenyl or 4-trifluoromethylbenzyl.

[0009] Further, the N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide compound is selected from compound I-1, I-2, I-3, I-4, I-5 or I-6, and the structural formulas of I-1, I-2, I-3, I-4, I-5 and I-6 are as follows:

[0010]

[0011] The preparation method of the above-mentioned N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)benzamide compounds has the following reaction formula:

[0012]

[0013] Among them, R 1 is selected from methoxy or phenyl; R 2 Selected from 4-methylphenyl, 4-methylbenzyl, 4-methoxyphenyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-bromobenzyl, 3-trifluoromethylphenyl or 4-trifluoromethylbenzyl. The amount of each reaction raw material can refer to the reaction amount known to those skilled in the art.

[0014] The present invention also provides the use of the above-mentioned N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)benzamide compounds in preventing and controlling plant pathogenic fungi.

[0015] Preferably, the plant pathogenic fungus is Botryosphaeria dothidea or Pythium aphanidermatum.

[0016] The present invention also provides a fungicide, which contains a fungicide-effective amount of at least one of the above-mentioned N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)benzamide compounds, and optionally contains auxiliary materials.

[0017] Preferably, the dosage form of the fungicide is selected from at least one of emulsifiable concentrate, suspension, wettable powder, dust, granule, aqueous solution, mother liquor or mother powder.

[0018] The beneficial effects of the present invention are:

[0019] (1) The present invention uses amide as a skeleton, 4-(5-(trifluoromethyl)-1,2,4-oxadiazole as the acid part of the amide, and a hydrophobic benzene ring as the amine part, and designs and synthesizes a class of N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)benzamide compounds. The N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)benzamide compounds have a novel molecular structure and distinct chemical structure characteristics. The structural formula contains an N,N-disubstituted amine group, wherein the N,N-disubstituted amine group is connected to 5-trifluoromethyloxadiazole benzoic acid through an amide bond, and shows a good effect on preventing and controlling Botryosphaeria dothidea and Pythium aphanidermatum.

[0020] (2) The preparation method of the compound of the present invention is simple, the raw materials are easily available, and the reaction conditions are easily controlled. For example, in the step of synthesizing N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide compounds, the product can be obtained by column chromatography.

[0021] (3) The compounds described in the present invention have good crop safety and can be developed into a new type of plant fungicide for controlling plant pathogenic fungi in the agricultural or forestry fields. DETAILED DESCRIPTION

[0022] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0023] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0024] The processes and methods not described in detail in the following examples are conventional methods known in the art, and the reagents used in the examples are all analytically pure or chemically pure, and can be purchased commercially or prepared by methods well known to those of ordinary skill in the art. The following examples all achieve the purpose of the present invention.

[0025] The reaction formula of the preparation method of N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)benzamide compounds in the embodiment of the present invention is as follows:

[0026]

[0027] Example 1

[0028] Preparation of N-phenyl-N-(4-methoxybenzyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide compounds:

[0029] (1) 4-Cyanobenzoic acid (0.034 mol) was dissolved in 50 mL of anhydrous ethanol and 20 mL of water, and the mixture was stirred evenly. Anhydrous sodium carbonate (0.0506 mol), hydroxylamine hydrochloride (0.0626 mol) and 8-hydroxyquinoline (0.0017 mol) were added under stirring, and the reaction solution was heated to reflux temperature for 5 h. TLC monitored the reaction of the raw materials to determine if the reaction was complete. The mixture was cooled to room temperature, ethanol was removed under reduced pressure, the precipitated solid was filtered out, the pH was adjusted to 5-6, and the mixture was stirred for 0.5 h. The solid was filtered out again, washed with distilled water, and dried under vacuum at 60° C. to obtain a white solid intermediate 1.

[0030] (2) Place intermediate 1 in a 250 mL single-mouth bottle, add 60 mL of dry tetrahydrofuran, cool to 0-5°C in an ice bath, take trifluoroacetic anhydride (0.0408 mol) and dissolve it in 60 mL of tetrahydrofuran, dilute and slowly add it dropwise to the reaction solution, remove the ice bath, stir for 5 h, monitor the reaction of the raw materials by TLC, concentrate under reduced pressure to obtain a solid, add distilled water and stir for 2 h, filter out the solid, and dry in vacuo at 60°C to obtain an off-white solid intermediate 2, i.e., 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid;

[0031] (3) Place intermediate 2 in a dry reaction bottle, add thionyl chloride, raise the temperature to reflux temperature, stir for 3 hours, cool to room temperature, and concentrate under reduced pressure to obtain a crude intermediate 3, i.e., 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoyl chloride. Intermediate 3 should be used as it is prepared;

[0032] (4) In a dry reaction bottle, add N-phenyl-1-(4-methoxyphenyl)ethylamine in an amount equivalent to that of intermediate 3 and 1.5 times the amount of triethylamine, dissolve them evenly with dichloromethane, dissolve intermediate 3 in dichloromethane, add dropwise to the reaction solution under stirring in an ice bath, and react for 3-8 hours. TLC monitors the complete reaction of the raw materials, wash the organic layer with water (10 mL×3), wash with saturated brine (10 mL×3), dry, filter, and concentrate under reduced pressure to remove dichloromethane to obtain a crude product, which is purified by column chromatography (eluent petroleum ether: ethyl acetate = 20:1) to obtain the target compound I-1. The yield is 67.5%.

[0033]

[0034] I-1: light yellow oil. 1 H NMR (600 MHz, CDCl 3 )δ1.52(d,J=7.2Hz,3H,CH3 ),3.82(s,3H,OCH 3 ),6.39(s,1H,CH),6.63(s,2H,C 6 H 4 OMe 3,5-H),6.85(d,J=8.6Hz,2H,C 6 H 4 OMe 2,6-H),7.11–7.04(m,3H,C 6 H 5 3,4,5-H),7.23(d,J=8.2Hz,2H,C 6 H 5 2,6-H),7.37(d,J=7.8Hz,2H,C 6 H 4 -oxadiazole 3,5-H),7.86(d,J=7.9Hz,2H,C 6 H 4 -oxadiazole 2,6-H).HRMS:HR-MS(ESI):m / z calcd for C 25 H 20 F 3 N 3 O 3 [M+H] + 468.1530, found 468.1512.

[0035] Example 2

[0036] Steps (1) to (4) are the same as those in Example 1, wherein in step (4), N-phenyl-1-(4-methoxybenzyl)ethylamine is used to replace N-phenyl-1-(4-methoxyphenyl)ethylamine in Example 1, to obtain the target compound I-2. The yield is 72.1%.

[0037]

[0038] I-2: light yellow oil. 1 H NMR (600 MHz, CDCl 3 )δ1.30(d,J=6.7Hz,3H,CH 3 ),2.72(dd,J=13.5,7.6Hz,1H,CH 2 ),3.24(dd,J=12.9,7.6Hz,1H,CH),3.81(s,3H,OCH 3 ),4.93(d,J=4.8Hz,1H,CH),6.82(s,2H,C 6 H 4OMe 3,5-H),6.87(d,J=8.4Hz,2H,C 6 H 4 OMe 2,6-H),7.14(d,J=6.7Hz,3H,C 6 H 5 3,4,5-H),7.21(d,J=7.2Hz,2H,C 6 H 5 2,6-H),7.29(d,J=7.8Hz,2H,C 6 H 4 -oxadiazole 3,5-H),7.85(d,J=7.5Hz,2H,C 6 H 4 -oxadiazole 2,6-H).HRMS:HR-MS(ESI):m / z calcd for C 26 H 22 F 3 N 3 O 3 [M+H] + 482.1686, found 482.1696.

[0039] Example 3

[0040] Steps (1) to (4) are the same as those in Example 1, wherein in step (4), N-phenyl-1-(4-bromobenzyl)ethylamine is used to replace N-phenyl-1-(4-methoxyphenyl)ethylamine in Example 1 to obtain the target compound I-3. The yield is 73.2%.

[0041]

[0042] I-3: light yellow oil, 1 H NMR (600 MHz, CDCl 3 )δ1.30(d,J=6.8Hz,3H,CH 3 ),2.72(dd,J=13.7,7.8Hz,1H,CH 2 ),3.26(dd,J=13.3,7.6Hz,1H,CH 2 ),4.95(d,J=5.8Hz,1H,CH),6.82(d,J=5.6Hz,2H,C 6 H 4 Br 2,6-H),7.21–7.12(m,5H,C 6 H 5 ),7.28(d,J=7.9Hz,2H,C 6 H 4Br3,5-H),7.45(d,J=8.1Hz,2H,C 6 H 4 -oxadiazole 3,5-H),7.86(d,J=7.8Hz,2H,C 6 H 4 oxadiazole 2,6-H).HRMS:HR-MS(ESI):m / z calcd for C 25 H 19 F 3 N 3 O 2 [M+H] + 530.0686, found 530.0692.

[0043] Example 4

[0044] Steps (1) to (4) are the same as those in Example 1, wherein in step (4), N-methoxy-1-(4-nitrobenzyl)ethylamine is used to replace N-phenyl-1-(4-methoxyphenyl)ethylamine in Example 1 to obtain the target compound I-4. The yield is 65.0%.

[0045]

[0046] I-4: light yellow oil, 1 H NMR (600 MHz, CDCl 3 )δ1.48(d,J=6.7Hz,3H,CH 3 ),2.98–2.82(m,1H,CH 2 ),3.27(dd,J=13.5,9.4Hz,1H,CH 2 ),3.63(s,3H,OCH 3 ),4.66(s,1H,CH),7.38(m,4H,C 6 H 4 NO 2 2,6-H,C 6 H 4 -oxadiazole 3,5-H),8.10–8.05(m,2H,C 6 H 4 -oxadiazole2,6-H,),8.14(dd,J=8.4,3.3Hz,2H,C 6 H 4 NO 2 3,5-H).HRMS:HR-MS(ESI):m / z calcd forC 20 H 17 F3 N 4 O 5 [M+H] + 451.1224, found 451.1234.

[0047] Example 5

[0048] Steps (1) to (4) are the same as those in Example 1, wherein in step (4), N-phenyl-1-(4-trifluoromethylphenyl)ethylamine is used to replace N-phenyl-1-(4-methoxyphenyl)ethylamine in Example 1 to obtain the target compound I-5. The yield is 66.7%.

[0049]

[0050] I-5: light yellow oil, 1 H NMR (600 MHz, CDCl 3 )δ1.58(d,J=7.2Hz,3H,CH 3 ),6.41(d,J=6.6Hz,1H,CH),6.67(s,2H,C 6 H 4 CF 3 2,6-H),7.12(dt,J=19.7,6.9Hz,3H,C 6 H 5 3,4,5-H),7.38(d,J=8.3Hz,2H,C 6 H 4 CF 3 3,5-H),7.48(d,J=8.0Hz,2H,C 6 H 5 2,6-H),7.60(d,J=8.2Hz,2H,C 6 H 4 -oxadiazole 3,5-H),7.88(d,J=8.3Hz,2H,C 6 H 4 -oxadiazole2,6-H).HRMS:HR-MS(ESI):m / z calcd for C 25 H 17 F 6 N 3 O 2 [M+H] + 506.1298, found 506.1308.

[0051] Example 6

[0052] Steps (1) to (4) are the same as those in Example 1, wherein in step (4), N-phenyl-1-(4-chlorobenzyl)ethylamine is used to replace N-phenyl-1-(4-methoxyphenyl)ethylamine in Example 1 to obtain the target compound I-6. Yield 73.1%

[0053]

[0054] I-6: light yellow oil. 1 H NMR (600 MHz, CDCl 3 )δ1.31(d,J=6.8Hz,3H,CH 3 ),2.74(dd,J=13.7,7.7Hz,1H,CH 2 ),3.28(dd,J=13.3,7.6Hz,1H,CH 2 ),4.95(d,J=5.8Hz,1H,CH),6.82(d,J=5.5Hz,2H,C 6 H 4 Cl 2,6-H),7.16(d,J=7.0Hz,3H,C 6 H 5 3,4,5-H),7.23(d,J=7.6Hz,2H,C 6 H 4 Cl 3,5-H),7.29(t,J=9.0Hz,4H,C 6 H 5 2,6-H,C 6 H 4 -oxadiazole 3,5-H),7.86(d,J=7.8Hz,2H,C 6 H 4 -oxadiazole 2,6-H).HRMS:HR-MS(ESI):m / z calcd forC 25 H 19 CIF 3 N 3 O 2 [M+H] + 486.1191, found 486.1201.

[0055] Example 7

[0056] Bactericidal activity (in vitro) experiment

[0057] The plant fungi used in this example are Botryosphaeria dothidea and Pythium aphanidermatum stored at 4°C in the laboratory.

[0058] The medium used is potato agar glucose medium (PDA for short). PDA medium formula: 200g potato (peeled), 20g glucose, 15g agar, 1000mL distilled water; PDA medium preparation method: wash and peel the potato, weigh 200g and cut into small pieces, add water and cook until soft (boil for 20-30min, until it can be pierced by a glass rod), filter into a beaker with eight layers of gauze, add 20g agar and 20g glucose in turn according to experimental needs, stir evenly, cool slightly after fully dissolved, add water to 1000mL, sterilize at 121℃ for 30min after packaging, and set aside after cooling.

[0059] Experimental method: The mycelium growth rate method was used, which included the following steps:

[0060] (1) First, culture the above-mentioned plant fungi on a PDA plate at 25°C for about 3-6 days for use;

[0061] (2) Heat the PDA medium to melt, cool to 45-50°C, add 10 μL of 20 mg / mL concentration of the test compound according to the proportion to make a medium containing 100 μg / mL drug solution, and pour into the culture dishes to cool;

[0062] (3) Using aseptic operation procedures, use a cork puncher to punch a round bacterial cake (0.5 cm in diameter) at the edge of the hyphae of each strain after 6 days of culture (the growth conditions should be as consistent as possible), then use an inoculation needle to pick it to the center of the drug-containing plate, and then place the culture dish upside down in the incubator for culture;

[0063] (4) Observe and measure the growth of mycelium at different times after treatment, measure the diameter using the cross method, process the data, and calculate the inhibition rate;

[0064]

[0065] Each treatment was repeated 3 times.

[0066] The test results are shown in Table 1.

[0067] Table 1 Inhibition rate of compounds I-1 to I-6 against different fungi at a concentration of 100 mg / mL (%)

[0068]

[0069]

[0070] Considering that some target compounds have general inhibitory activity against Botryosphaeria dothidea and Pythium aphanidermatum, it can be seen from Table 1 that compound I-3 has the best inhibitory activity against Botryosphaeria dothidea and Pythium aphanidermatum.

[0071] The N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)benzamide compounds of the present invention have obvious structural differences and distinct chemical structure characteristics, and show good effects on preventing and treating Botryosphaeria dothidea and Pythium aphanidermatum. They can be used to prevent and treat fungal diseases of agricultural or forestry plants. The preparation method of the compounds is simple, the yield is high, and the product properties are stable. They have potential application value for the research and development of drugs against plant pathogens.

Claims

1. N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide compounds, whose structural formula is shown in Formula I: in, R1 is selected from methoxy or phenyl; R2 is selected from 4-methylphenyl, 4-methylbenzyl, 4-methoxyphenyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-bromobenzyl, 3-trifluoromethylphenyl or 4-trifluoromethylbenzyl.

2. The N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide compound according to claim 1, characterized in that: The N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide compound is selected from compound I-1, I-2, I-3, I-4, I-5 or I-6, and the structural formulas of I-1, I-2, I-3, I-4, I-5 and I-6 are as follows:

3. The method for preparing the N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide compound according to claim 1, characterized in that: The reaction formula is as follows: In the formula, R1 and R2 are as defined in claim 1.

4. Use of the N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide compound according to claim 1 or 2 in controlling plant pathogenic fungi.

5. The use according to claim 4, characterized in that: The plant pathogenic fungus is Botryosphaeria dothidea.

6. The use according to claim 4, characterized in that: The plant pathogenic fungus is Pythium aphanidermatum.

7. A bactericide, characterized in that: The bactericide contains a bactericidal effective amount of at least one of the N,N-disubstituted-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)benzamide compounds according to claim 1 or 2, and optionally contains auxiliary materials.

8. The fungicide according to claim 7, characterized in that The dosage form of the fungicide is selected from at least one of emulsifiable concentrate, suspension, wettable powder, dust, granule, aqueous solution, mother solution or mother powder.

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