A diaryl ether compound, a preparation method and application thereof

Abstract

The application provides a diaryl ether compound and a preparation method and application thereof, and belongs to the technical field of agricultural chemicals. Substituted phenylthiol, anhydrous potassium carbonate and N,N-dimethylformamide are mixed to perform a first reaction to obtain an intermediate product; the intermediate product and methyl 2-nitro-5-chlorobenzoate are mixed to perform a second reaction to obtain the diaryl ether compound. The bioactivity determination result shows that the diaryl ether compound prepared by the application has good insecticidal activity and can be applied as a non-sugar structure insect trehalase inhibitor.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of agrochemical technology, in particular to a diaryl ether compound and a preparation method and application thereof. BACKGROUND

[0002] O.furnacalis belongs to Lepidoptera Pyralidae, and is one of the main pests of corn, and its rampant also increases the occurrence of various ear rot diseases of corn, causing greater pest problems. At present, the means for preventing and controlling O.furnacalis include physical prevention (such as insect luring lamp), chemical prevention (such as broad-spectrum insecticide) and biological prevention (such as introducing natural enemies of pests such as trichogramma). However, biological prevention and physical prevention have high cost and slow effect, and chemical prevention is facing the problems of increasing insecticide resistance and pesticide residue toxicity.

[0003] Trehalose is the blood sugar of insects, and its metabolism process, including synthesis and degradation, accompanies the development of each stage of insects, i.e. egg-larva-pupa-adult. The metabolic pathway is very important for the life activities of insects. Since the trehalose metabolic pathway only exists in insects and does not exist in mammals, the key enzymes of the trehalose metabolic pathway can be used as potential targets of safe insecticides. Trehalase is the only key enzyme in insects that can hydrolyze trehalose, and as a potential insecticidal target, it has attracted widespread attention from researchers. Since the low-toxicity fungicide Jinggangmycin, which targets trehalase, was introduced, many natural and artificially synthesized trehalose analogs with trehalase inhibitory activity have been reported, mainly including Jinggangmycin, natural products salbostatin and trehazolin and their synthetic analogs, deoxynojirimycin and its synthetic analogs.

[0004] Although these inhibitors show certain inhibitory activity on trehalase of various insects and fungi, since these compounds are all sugar ring compounds, they have poor drug properties and are prone to decomposition, and have not been widely used. And the existing trehalase inhibitors all regulate insect growth activity through microinjection, and no trehalase inhibitor that can directly affect insect growth activity by feeding has been reported.

[0005] Therefore, it is very important to provide a diaryl ether compound that can directly affect the growth activity of insects by feeding and has high drug properties. SUMMARY

[0006] The present application aims to provide a diaryl ether compound and a preparation method and application thereof, to solve the technical problems in the prior art that the inhibitors have poor drug properties, are prone to decomposition and can only be directly fed by microinjection.

[0007] In order to achieve the above-mentioned application purposes, the present application provides the following technical solutions:

[0008] The application provides a diaryl ether compound, and a structural formula of the diaryl ether compound is as follows:

[0009] wherein R is any one of substituted or unsubstituted alkyl of 1-20 C chains, aryl, alkoxy of 1-20 C chains, nitro, halogen.

[0010] The application further provides a preparation method of the diaryl ether compound.

[0011] 1) substituting phenyl mercaptan, anhydrous potassium carbonate and N, N-dimethylformamide are mixed to perform a first reaction to obtain an intermediate product;

[0012] 2) the intermediate product and methyl 2-nitro-5-chlorobenzoate are mixed to perform a second reaction to obtain the diaryl ether compound.

[0013] Further, the substituting phenyl mercaptan, the anhydrous potassium carbonate and the N, N-dimethylformamide are used in a ratio of 3-7 mmol: 4-8 mmol: 20-30 mL.

[0014] Further, the first reaction is performed at a temperature of 60-100 DEG C, and the first reaction is performed for 0.5-2 h.

[0015] Further, the substituting phenyl mercaptan and the methyl 2-nitro-5-chlorobenzoate are used in a molar ratio of 3-7: 4-7.

[0016] Further, the second reaction is performed at a temperature of 110-130 DEG C, and the second reaction is monitored by TLC (V 石油醚 :V 乙酸乙酯 = 8:1) to determine the reaction progress.

[0017] The application further provides application of the diaryl ether compound in an agricultural insecticide for preventing and treating Ostrinia furnacalis.

[0018] The application has the following beneficial effects:

[0019] The diaryl ether compound prepared by the application is a trehalase inhibitor that can directly affect normal physiological activities of insects by feeding for the first time, and the substituting phenyl mercaptan and the methyl 2-nitro-5-chlorobenzoate are both hydrophobic compounds, have high drug properties and have high prospects for pesticide development. The biological activity determination result shows that the diaryl ether compound prepared by the application has good insecticidal activity, can be used as an insect trehalase inhibitor of non-sugar structure and has an inhibiting effect on the growth of Ostrinia furnacalis. BRIEF DESCRIPTION OF DRAWINGS

[0020] Fig. 1 Modulated line graph of the influence of feeding the diaryl ether compound prepared in Example 1 on the body weight change of the Asian corn borer;

[0021] Fig. 2 Modulated column chart of the influence of feeding the diaryl ether compound prepared in Example 1 on the age change of the Asian corn borer. DETAILED DESCRIPTION

[0022] The present application provides a diaryl ether compound, the structural formula of which is:

[0023] Wherein, R is any one of substituted or unsubstituted 1-20 C chain alkyl, aryl, 1-20 C chain alkoxy, nitro, halogen.

[0024] The present application provides a preparation method of the diaryl ether compound, comprising the following steps:

[0025] 1) mixing substituted phenylthiol, anhydrous potassium carbonate and N,N-dimethylformamide and then performing a first reaction to obtain an intermediate product;

[0026] 2) mixing the intermediate product and 2-nitro-5-chlorobenzoic acid methyl ester and then performing a second reaction to obtain the diaryl ether compound.

[0027] In the present application, the amount ratio of the substituted phenylthiol, the anhydrous potassium carbonate and the N,N-dimethylformamide is 3-7 mmol: 4-8 mmol: 20-30 mL, preferably 4-6 mmol: 5-7 mmol: 22-28 mL, and further preferably 5 mmol: 6 mmol: 25 mL.

[0028] In the present application, the temperature of the first reaction is 60-100℃, preferably 70-90℃, and further preferably 80℃; and the time of the first reaction is 0.5-2 h, preferably 0.8-1.5 h, and further preferably 1 h.

[0029] In the present application, the first reaction is performed under stirring, and the stirring speed is 400-600 rpm, preferably 450-550 rpm, and further preferably 500 rpm.

[0030] In the present application, the molar ratio of the substituted phenylthiol and the 2-nitro-5-chlorobenzoic acid methyl ester is 3-7: 4-7, preferably 4-6: 5-6.5, and further preferably 5: 5.5-6.

[0031] In the present application, the temperature of the secondary reaction is 110-130°C, preferably 115-125°C, and further preferably 120°C; the secondary reaction is monitored by TLC (V 石油醚 :V 乙酸乙酯 =8:1) to determine the reaction progress.

[0032] In the present application, after the reaction is completed, the reaction solution is preferably cooled to room temperature, then filtered by using a sand core funnel padded with diatomite, washed with ethyl acetate, then water is added to the filtrate to quench, shaken well, extracted with ethyl acetate (15mL x 3 times), the organic phase is collected, washed with saturated sodium chloride solution for 3 times, dried with anhydrous sodium sulfate, filtered, rotary evaporated, column chromatographed, eluted with V 石油醚 :V 乙酸乙酯 =5:1, collected, rotary evaporated, to obtain the diaryl ether compound.

[0033] In the present application, the preparation process flow of the diaryl ether compound is as follows:

[0034]

[0035] The present application also provides the use of the diaryl ether compound in an agricultural insecticide for controlling the Asian corn borer.

[0036] The technical solutions provided by the present application are described in detail below in combination with examples, but they should not be understood as limiting the scope of protection of the present application.

[0037] Example 1

[0038] 5mmol of 2,4-dichlorobenzenethiol is dissolved in 25mL of N,N-dimethylformamide, then 6mmol of anhydrous potassium carbonate is added, and a primary reaction is carried out at 80°C; the primary reaction is carried out under stirring, and the stirring speed is 500rpm; 5.5mmol of 2-nitro-5-chlorobenzoic acid methyl ester is added after 1h of the primary reaction, and a secondary reaction is carried out at 120°C; the reaction progress is monitored by TLC (V 石油醚 :V 乙酸乙酯 =8:1); after the reaction is completed, the reaction solution is cooled to room temperature, then filtered by using a sand core funnel padded with diatomite, washed with ethyl acetate, then water is added to the filtrate to quench, shaken well, extracted with ethyl acetate (15mL x 3 times), the organic phase is collected, washed with saturated sodium chloride solution for 3 times, dried with anhydrous sodium sulfate, filtered, rotary evaporated, column chromatographed, eluted with V 石油醚 :V 乙酸乙酯 =5:1, collected, rotary evaporated, to obtain the diaryl ether compound.

[0039] The preparation process flow of the diaryl ether compound of Example 1 is as follows:

[0040]

[0041] Example 2

[0042] The only difference compared to Example 1 is that in Example 2 the substituted benzenethiol is 4-fluorobenzenethiol.

[0043] Example 3

[0044] The only difference compared to Example 1 is that in Example 3 the substituted benzenethiol is 4-chlorobenzenethiol.

[0045] Example 4

[0046] The only difference compared to Example 1 is that in Example 4 the substituted benzenethiol is 4-bromobenzenethiol.

[0047] Example 5

[0048] The only difference compared to Example 1 is that in Example 5 the substituted benzenethiol is 4-nitrobenzenethiol.

[0049] Example 6

[0050] The only difference compared to Example 1 is that in Example 6 the substituted benzenethiol is 4-trifluoromethylbenzenethiol.

[0051] Example 7

[0052] The only difference compared to Example 1 is that in Example 7 the substituted benzenethiol is 4-methylbenzenethiol.

[0053] Example 8

[0054] The only difference compared to Example 1 is that in Example 8 the substituted benzenethiol is 4-methoxybenzenethiol.

[0055] Example 9

[0056] The only difference compared to Example 1 is that in Example 9 the substituted benzenethiol is 3-fluorobenzenethiol.

[0057] Example 10

[0058] The only difference compared to Example 1 is that in Example 10 the substituted benzenethiol is 3-chlorobenzenethiol.

[0059] Example 11

[0060] The only difference compared to Example 1 is that in Example 11 the substituted benzenethiol is 3-bromobenzenethiol.

[0061] Example 12

[0062] The only difference compared to Example 1 is that in Example 12 the substituted benzenethiol is 3-nitrobenzenethiol.

[0063] Example 13

[0064] The only difference compared to Example 1 is that in Example 13 the substituted benzenethiol is 3-trifluoromethylbenzenethiol.

[0065] Example 14

[0066] The only difference compared to Example 1 is that in Example 14 the substituted benzenethiol is 3-methylbenzenethiol.

[0067] Example 15

[0068] The only difference compared to Example 1 is that in Example 15 the substituted benzenethiol is 3-methoxybenzenethiol.

[0069] Example 16

[0070] The only difference compared to Example 1 is that in Example 16 the substituted benzenethiol is 2-fluorobenzenethiol.

[0071] Example 17

[0072] The only difference compared to Example 1 is that in Example 17 the substituted benzenethiol is 2-chlorobenzenethiol.

[0073] Example 18

[0074] The only difference compared to Example 1 is that in Example 18 the substituted benzenethiol is 2-bromobenzenethiol.

[0075] Example 19

[0076] The only difference compared to Example 1 is that in Example 19 the substituted benzenethiol is 2-nitrobenzenethiol.

[0077] Example 20

[0078] The only difference compared to Example 1 is that in Example 20 the substituted benzenethiol is 2-trifluoromethylbenzenethiol.

[0079] Example 21

[0080] The only difference compared to Example 1 is that in Example 21 the substituted benzenethiol is 2-methylbenzenethiol.

[0081] Example 22

[0082] The only difference compared to Example 1 is that in Example 22 the substituted benzenethiol is 2-methoxybenzenethiol.

[0083] Example 23

[0084] The only difference compared to Example 1 is that in Example 23 the substituted benzenethiol is 3,5-difluorobenzenethiol.

[0085] Example 24

[0086] The only difference between Example 1 and Example 24 is that the substituted thiophenol in Example 24 is 3,4-dichlorothiophenol.

[0087] The diaryl ether compounds prepared in Examples 1-24 were tested, and the physicochemical data of the diaryl ether compounds are shown in Table 1, 1 HNMR, 13 CNMR and MS data are shown in Table 2.

[0088] Table 1 Physicochemical data of the diaryl ether compounds

[0089]

[0090] Table 2 HNMR, CNMR and MS data of the diaryl ether compounds 1 HNMR, 13 CNMR and MS data

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098] Inhibition activity of the diaryl ether compounds prepared in Examples 1-24 on insect trehalase was determined:

[0099] The inhibition activity of the compounds on insect trehalase was determined by enzymatic activity determination method, and the specific method is as follows:

[0100] Reaction system: 4 μL of the diaryl ether compound (the concentration of the diaryl ether compound was 100 μM) dissolved in DMSO was added to 186 μL of the enzyme diluted in 20 mM desalted buffer, and then 10 μL of the substrate trehalose with a final concentration of 1 mM was added to form a reaction system with a total volume of 200 μL.

[0101] Reaction condition: incubation at 30°C for 30 min.

[0102] Reaction termination buffer: The potassium ferricyanide solution was prepared as follows. 53 g of sodium carbonate solid and 2 g of potassium ferricyanide solid were weighed, added to 800 mL of deionized water, dissolved thoroughly, and then diluted to 1 L. The solution was filtered through a 0.22 μm filter and stored in a brown bottle.

[0103] Measurement method: End-point measurement. After the reaction was completed, 200 μL of potassium ferricyanide solution was added to terminate the reaction. The absorbance of the sample was measured at 420 nm using a microplate reader.

[0104] The calculated inhibitory activity of the diaryl ether compounds prepared in Examples 1 to 24 against insect trehalase is shown in Table 3.

[0105] Table 3 Inhibitory activity of the diaryl ether compounds prepared in Examples 1 to 24 against insect trehalase

[0106]

[0107]

[0108] As shown in Table 3, most of the compounds had an inhibitory effect on insect trehalase, and the diaryl ether compound prepared in Example 1 had the highest inhibition rate of 73.5%.

[0109] The insecticidal effect of the diaryl ether compound prepared in Example 1 was tested by observing the growth state of the Asian corn borer using a feeding method. The test method was as follows.

[0110] The feeding experiment was performed on the Asian corn borer larvae at 30°C in an environment with a relative humidity of 40 to 50% under conditions of 16 h of light and 8 h of darkness per day. The growth and development of the larvae were recorded every day during the experiment, including the growth stage, mortality rate, and average body weight of the larvae, to evaluate the effect of the compound on the growth activity regulation of the insects. The compound was dissolved in acetone and uniformly mixed with the feed of the Asian corn borer. The content of the compound in the feed was controlled to be 0.05 mmol, and the feed was left at room temperature for a period of time to ensure that the acetone was completely volatilized. The control group was fed only with the feed treated with acetone. The artificial feed obtained was used for the feeding experiment on the Asian corn borer. Fifteen larvae were fed in each of the experimental and control groups, and larvae of the first day of the second instar stage were selected for feeding. The growth state, body weight change, and mortality rate of the larvae were recorded every day to determine whether the compound was effective. The feeding experiment was continued until most of the larvae in the control group reached the fourth instar stage. The test results are shown in Table 4. Figs. 1-2

[0111] Fig. 1 The regulation of the effect of the diaryl ether compound prepared in Example 1 on the body weight change of the Asian corn borer is shown in the line graph. Fig. 2 ​The regulation column chart of the influence of feeding the diaryl ether compound prepared in Example 1 on the instar change of Ostrinia furnacalis is shown in the figure, wherein 2L refers to 2 instar, 3L refers to 3 instar, and 4L refers to 4 instar. Fig. 1 and Fig. 2 It can be seen that the larval weight and instar change of the experimental group are obviously different compared with the control group, and then with the increase of feeding time, the weight of the experimental group is always less than that of the control group, the control group appears four instar larvae on the fifth day of feeding, while the experimental group appears four instar larvae on the sixth day, which shows that the compound can cause the delay of larval molting time, and the experimental group appears lethal phenotype on the first day of feeding, and after the sixth day of feeding, the mortality rate of the larvae fed with the diaryl ether compound prepared in Example 1 reaches 57.7%, which shows that feeding the compound I-1 has an inhibitory effect on the growth of Ostrinia furnacalis.

[0112] It can be seen from the above examples that the present application provides a diaryl ether compound, a preparation method and application thereof, the substituted phenyl mercaptan, anhydrous potassium carbonate and N,N-dimethylformamide are mixed to carry out a first reaction to obtain an intermediate product; the intermediate product and 2-nitro-5-chlorobenzoic acid methyl ester are mixed to carry out a second reaction to obtain the diaryl ether compound. The biological activity determination result shows that the diaryl ether compound prepared in the present application has good insecticidal activity, and can be applied as a non-sugar structure insect trehalase inhibitor.

[0113] The above only describes the preferred embodiments of the present application, and it should be noted that for those skilled in the art, some improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A diaryl ether compound, characterized in that, The structural formula of the diaryl ether compound is: Wherein, R is 2,4-Cl2, 3-F, 3-Cl, 3-Br, 3-CF3, 2-Br, 3,5-F2 or 3,4-Cl2.

2. A method for preparing the diaryl ether compound according to claim 1, characterized in that, Includes the following steps: 1) A mixture of substituted thiophenol, anhydrous potassium carbonate, and N,N-dimethylformamide was reacted once to obtain an intermediate product; 2) The intermediate product and methyl 2-nitro-5-chlorobenzoate were mixed and subjected to a secondary reaction to obtain diaryl ether compounds.

3. The method for preparing diaryl ether compounds according to claim 2, characterized in that, The ratio of the substituted thiophenol, anhydrous potassium carbonate, and N,N-dimethylformamide is 3-7 mmol: 4-8 mmol: 20-30 mL.

4. The method for preparing diaryl ether compounds according to claim 2 or 3, characterized in that, The temperature of the first reaction is 60~100℃, and the reaction time is 0.5~2h.

5. The method for preparing diaryl ether compounds according to claim 4, characterized in that, The molar ratio of the substituted thiophenol and methyl 2-nitro-5-chlorobenzoate is 3~7:4~7.

6. The method for preparing diaryl ether compounds according to claim 2 or 5, characterized in that, The secondary reaction is carried out at a temperature of 110~130℃, and the secondary reaction is monitored by TLC (Voltage-Retrieval System). 石油醚 V 乙酸乙酯 =8:1) Monitoring to determine the reaction progress.

7. The application of a diaryl ether compound as described in claim 1 as an agricultural insecticide, characterized in that, The agricultural pesticide is used to control the Asian corn borer.

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