Diaryl ether compound as well as preparation method and application thereof

Abstract

The invention provides a diaryl ether compound as well as a preparation method and application thereof, and belongs to the technical field of agricultural chemicals. The preparation method comprises the following steps: mixing substituted thiophenol, anhydrous potassium carbonate and N, N-dimethylformamide, and carrying out primary reaction to obtain an intermediate product; and mixing the intermediate product with 2-nitro-5-chloromethyl benzoate, and carrying out a secondary reaction to obtain the diaryl ether compound. A biological activity determination result shows that the diaryl ether compound prepared by the invention has good insecticidal activity and can be popularized and applied as an insect trehalase inhibitor with a non-sugar structure.

Description

Technical Field

[0001] The present invention relates to the technical field of agricultural chemicals, and in particular to a diaryl ether compound and a preparation method and application thereof. Background Art

[0002] The Asian corn borer, O. furnacalis, belongs to the family Pyralidae in the order Lepidoptera and is one of the main insect pests of corn. Its rampant spread has also increased the occurrence of various corn ear rot diseases, causing greater pest and disease problems. Currently, the means of controlling corn borers include physical control (such as insect traps), chemical control (such as broad-spectrum insecticides), and biological control (such as the introduction of natural enemies of pests such as trichogrammatids). However, biological control and physical control are costly and slow in effect, while chemical control is facing the problems of increased insect resistance and residual toxicity of pesticides.

[0003] Trehalose is the blood sugar of insects. Trehalose metabolism is accompanied by the development of each stage of insects from eggs to larvae to pupae to adults, including synthesis and degradation. Its metabolic pathway is very important for insect life activities. Since the trehalose metabolic pathway only exists in insects and not in mammals, the key enzymes in the trehalose metabolic pathway can be used as potential targets for safe insecticides. Trehalase is the only key enzyme in insects that can hydrolyze trehalose. As a potential insecticide target, it has attracted widespread attention from researchers. Since the advent of the low-toxic fungicide Jinggangmycin targeting trehalase, many natural and synthetic 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 against a variety of insect and fungal trehalase, they are all sugar ring compounds with poor drugability and easy decomposition, so they have not been widely used. In addition, the existing trehalase inhibitors regulate insect growth activity by microinjection, and no trehalase inhibitors that directly affect insect growth activity by feeding have been reported.

[0005] Therefore, it is very important to provide a diaryl ether compound that can directly affect the growth activity of insects through feeding and has high drugability. Summary of the invention

[0006] The purpose of the present invention is to provide a diaryl ether compound and a preparation method and application thereof, so as to solve the technical problems in the prior art that the inhibitors have poor drugability, are easy to decompose and can only be administered by microinjection and cannot be directly fed.

[0007] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0008] The present invention provides a diaryl ether compound, the structural formula of the diaryl ether compound is:

[0009] Here, R is any one of a substituted or unsubstituted 1-20 C chain alkyl group, an aryl group, a 1-20 C chain alkoxy group, a nitro group, and a halogen group.

[0010] The present invention provides a method for preparing the diaryl ether compound, comprising the following steps:

[0011] 1) mixing substituted thiophenol, anhydrous potassium carbonate and N,N-dimethylformamide and reacting them once to obtain an intermediate product;

[0012] 2) The intermediate product and methyl 2-nitro-5-chlorobenzoate are mixed for secondary reaction to obtain a diaryl ether compound.

[0013] Furthermore, the usage ratio of the substituted thiophenol, anhydrous potassium carbonate and N,N-dimethylformamide is 3-7 mmol: 4-8 mmol: 20-30 mL.

[0014] Furthermore, the temperature of the primary reaction is 60-100° C., and the time of the primary reaction is 0.5-2 h.

[0015] Furthermore, the molar ratio of the substituted thiophenol to methyl 2-nitro-5-chlorobenzoate is 3-7:4-7.

[0016] Furthermore, the temperature of the secondary reaction is 110-130°C, and the secondary reaction is analyzed by TLC (V 石油醚 :V 乙酸乙酯 =8:1) monitoring to determine the progress of the reaction.

[0017] The present invention also provides an application of the diaryl ether compound as an agricultural insecticide, wherein the agricultural insecticide is used for preventing and controlling Asian corn borer.

[0018] Beneficial effects of the present invention:

[0019] The diaryl ether compound prepared by the present invention is the first discovered trehalase inhibitor that can directly affect the normal physiological activities of insects through feeding. The substituted thiophenol and 2-nitro-5-chlorobenzoic acid methyl ester used are both hydrophobic compounds with high drugability and high prospects for pesticide development. The results of biological activity determination show that the diaryl ether compound prepared by the present invention has good insecticidal activity, can be promoted and applied as a non-sugar structure insect trehalase inhibitor, and has an inhibitory effect on the growth of Asian corn borer. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 A line graph showing the effect of feeding the diaryl ether compound prepared in Example 1 on the weight change of the Asian corn borer;

[0021] Figure 2 This is a bar graph showing the effect of feeding the diaryl ether compound prepared in Example 1 on the age change of the Asian corn borer. DETAILED DESCRIPTION

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

[0023] Here, R is any one of a substituted or unsubstituted 1-20 C chain alkyl group, an aryl group, a 1-20 C chain alkoxy group, a nitro group, and a halogen group.

[0024] The present invention provides a method for preparing the diaryl ether compound, comprising the following steps:

[0025] 1) mixing substituted thiophenol, anhydrous potassium carbonate and N,N-dimethylformamide and reacting them once to obtain an intermediate product;

[0026] 2) The intermediate product and methyl 2-nitro-5-chlorobenzoate are mixed for secondary reaction to obtain a diaryl ether compound.

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

[0028] In the present invention, the temperature of the primary reaction is 60-100° C., preferably 70-90° C., more preferably 80° C.; the time of the primary reaction is 0.5-2 h, preferably 0.8-1.5 h, more preferably 1 h.

[0029] In the present invention, the primary reaction is carried out under stirring, and the stirring speed is 400 to 600 rpm, preferably 450 to 550 rpm, and more preferably 500 rpm.

[0030] In the present invention, the molar ratio of the substituted thiophenol to methyl 2-nitro-5-chlorobenzoate is 3-7:4-7, preferably 4-6:5-6.5, and more preferably 5:5.5-6.

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

[0032] In the present invention, after the reaction is completed, the reaction solution is preferably cooled to room temperature and then filtered using a sand core funnel padded with diatomaceous earth, washed with ethyl acetate, and then water is added to the filtrate to quench and shake well, extracted with ethyl acetate (15 mL×3 times), the organic phase is collected, and then washed with saturated sodium chloride solution 3 times, dried with anhydrous sodium sulfate, filtered, spin-dried, and filtered with V 石油醚 :V 乙酸乙酯 =5:1, collect and spin-dry to obtain diaryl ether compounds.

[0033] In the present invention, the preparation process of diaryl ether compounds is as follows:

[0034]

[0035] The present invention also provides an application of the diaryl ether compound as an agricultural insecticide, wherein the agricultural insecticide is used for preventing and controlling Asian corn borer.

[0036] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0037] Example 1

[0038] 5 mmol of 2,4-dichlorobenzenethiol was dissolved in 25 mL of N,N-dimethylformamide, and then 6 mmol of anhydrous potassium carbonate was added to carry out a primary reaction at 80°C. The primary reaction was carried out under stirring at a speed of 500 rpm. After the primary reaction for 1 hour, 5.5 mmol of methyl 2-nitro-5-chlorobenzoate was added to carry out a secondary reaction at 120°C. The secondary reaction was analyzed by TLC (V 石油醚 :V 乙酸乙酯 =8:1) monitoring to determine the progress of the reaction. After the reaction is completed, the reaction solution is cooled to room temperature and filtered using a sand core funnel padded with diatomaceous earth, washed with ethyl acetate, and then water is added to the filtrate to quench and shake well, extracted with ethyl acetate (15 mL×3 times), the organic phase is collected, and then washed with saturated sodium chloride solution 3 times, dried with anhydrous sodium sulfate, filtered, spin-dried, and filtered with V 石油醚 :V 乙酸乙酯 =5:1, collect and spin-dry to obtain diaryl ether compounds.

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

[0040]

[0041] Example 2

[0042] Compared with Example 1, the only difference is that the substituted thiophenol in Example 2 is 4-fluorothiophenol.

[0043] Example 3

[0044] Compared with Example 1, the only difference is that the substituted thiophenol in Example 3 is 4-chlorothiophenol.

[0045] Example 4

[0046] Compared with Example 1, the only difference is that the substituted thiophenol in Example 4 is 4-bromothiophenol.

[0047] Example 5

[0048] Compared with Example 1, the only difference is that the substituted thiophenol in Example 5 is 4-nitrothiophenol.

[0049] Example 6

[0050] Compared with Example 1, the only difference is that the substituted thiophenol in Example 6 is 4-trifluoromethylthiophenol.

[0051] Example 7

[0052] Compared with Example 1, the only difference is that the substituted thiophenol in Example 7 is 4-methylthiophenol.

[0053] Example 8

[0054] Compared with Example 1, the only difference is that the substituted thiophenol in Example 8 is 4-methoxythiophenol.

[0055] Example 9

[0056] Compared with Example 1, the only difference is that the substituted thiophenol in Example 9 is 3-fluorothiophenol.

[0057] Example 10

[0058] Compared with Example 1, the only difference is that the substituted thiophenol in Example 10 is 3-chlorothiophenol.

[0059] Embodiment 11

[0060] Compared with Example 1, the only difference is that the substituted thiophenol in Example 11 is 3-bromothiophenol.

[0061] Example 12

[0062] Compared with Example 1, the only difference is that the substituted thiophenol in Example 12 is 3-nitrothiophenol.

[0063] Embodiment 13

[0064] Compared with Example 1, the only difference is that the substituted thiophenol in Example 13 is 3-trifluoromethylthiophenol.

[0065] Embodiment 14

[0066] Compared with Example 1, the only difference is that the substituted thiophenol in Example 14 is 3-methylthiophenol.

[0067] Embodiment 15

[0068] Compared with Example 1, the only difference is that the substituted thiophenol in Example 15 is 3-methoxythiophenol.

[0069] Example 16

[0070] Compared with Example 1, the only difference is that the substituted thiophenol in Example 16 is 2-fluorothiophenol.

[0071] Embodiment 17

[0072] Compared with Example 1, the only difference is that the substituted thiophenol in Example 17 is 2-chlorothiophenol.

[0073] Embodiment 18

[0074] Compared with Example 1, the only difference is that the substituted thiophenol in Example 18 is 2-bromothiophenol.

[0075] Embodiment 19

[0076] Compared with Example 1, the only difference is that the substituted thiophenol in Example 19 is 2-nitrothiophenol.

[0077] Embodiment 20

[0078] Compared with Example 1, the only difference is that the substituted thiophenol in Example 20 is 2-trifluoromethylthiophenol.

[0079] Embodiment 21

[0080] Compared with Example 1, the only difference is that the substituted thiophenol in Example 21 is 2-methylthiophenol.

[0081] Embodiment 22

[0082] Compared with Example 1, the only difference is that the substituted thiophenol in Example 22 is 2-methoxythiophenol.

[0083] Embodiment 23

[0084] Compared with Example 1, the only difference is that the substituted thiophenol in Example 23 is 3,5-difluorothiophenol.

[0085] Embodiment 24

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

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

[0088] Table 1 Physicochemical data of diaryl ether compounds

[0089]

[0090] Table 2 Diaryl ether compounds 1 HNMR, 13 CNMR and MS data

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098] Determination of the inhibitory activity of the diaryl ether compounds prepared in Examples 1 to 24 on insect trehalase:

[0099] The inhibitory activity of the compound on insect trehalase was determined by enzymatic activity assay, and the specific method is as follows:

[0100] Reaction system: 4 μL of diaryl ether compound dissolved in DMSO (the concentration of diaryl ether compound is 100 μM) was added to 186 μL of enzyme diluted in 20 mM desalting buffer, and then 10 μL of 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 conditions: incubate at 30°C for 30 min.

[0102] Reaction termination buffer: The preparation method of potassium ferrocyanide solution is as follows: Weigh 53 g of sodium carbonate solid and 2 g of potassium ferrocyanide solid, add 800 mL of deionized water to fully dissolve and then dilute to 1 L, filter with a 0.22 μm filter membrane and put into a brown bottle for later use.

[0103] Determination method: End point determination. After the reaction is completed, add 200 μL potassium ferrocyanide solution to terminate the reaction, and use an enzyme reader to detect the absorbance of the sample at a wavelength of 420 nm.

[0104] After calculation, the inhibitory activities of the diaryl ether compounds prepared in Examples 1 to 24 on insect trehalase are shown in Table 3.

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

[0106]

[0107]

[0108] It can be seen from Table 3 that most of the compounds have an inhibitory effect on insect trehalase, among which the diaryl ether compound prepared in Example 1 has 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 the feeding method. The test method is as follows:

[0110] In an environment of 30°C and relative humidity of 40-50%, a feeding experiment was conducted on the larvae of the Asian corn borer under the conditions of 16 hours of light and 8 hours of darkness per day. During the period, the growth and development of the larvae were recorded every day, including the larval growth age, mortality rate and average weight of the larvae, in order to evaluate the effect of the compound on the regulation of insect growth activity. After the compound was dissolved in acetone, it was evenly mixed into the feed of the Asian corn borer. The compound content in the feed was controlled to be 0.05mmol. It was left at room temperature for a period of time to ensure that the acetone was completely volatilized. The control group was only fed with the feed treated with acetone. The artificial feed obtained was used for feeding experiments on the Asian corn borer. Both the experimental group and the control group were fed with 15 larvae. The larvae on the first day of the 2nd instar were selected for feeding. The growth status of the larvae, the weight changes and mortality of the larvae were recorded every day to determine whether the compound was effective. The feeding experiment continued until most of the larvae in the control group reached the 4th instar. The test results are as follows Figures 1-2 shown.

[0111] Figure 1 A line graph showing the effect of feeding the diaryl ether compound prepared in Example 1 on the weight change of the Asian corn borer; Figure 2The bar graph is a graph showing the effect of feeding the diaryl ether compound prepared in Example 1 on the age change of the Asian corn borer, wherein 2L refers to the 2nd age, 3L refers to the 3rd age, and 4L refers to the 4th age. Figure 1 and Figure 2 It can be seen that the weight and age changes of the larvae in the experimental group were significantly different from those in the control group, and then as the feeding time increased, the weight of the experimental group was always smaller than that of the control group. The control group had fourth-instar larvae on the 5th day of feeding, while the experimental group had fourth-instar larvae on the 6th day, indicating that the compound can cause the larvae to molt and delay the time. The experimental group showed a lethal phenotype on the first day of feeding. After the 6th day of feeding, the mortality rate of the larvae fed with the diaryl ether compound prepared in Example 1 reached 57.7%, indicating that feeding compound I-1 has an inhibitory effect on the growth of corn borer.

[0112] As can be seen from the above examples, the present invention provides a diaryl ether compound and a preparation method and application thereof, wherein substituted thiophenol, anhydrous potassium carbonate and N,N-dimethylformamide are mixed and reacted once to obtain an intermediate product; the intermediate product and 2-nitro-5-chlorobenzoic acid methyl ester are mixed and reacted twice to obtain a diaryl ether compound. The results of biological activity assays show that the diaryl ether compound prepared by the present invention has good insecticidal activity and can be promoted and applied as a non-sugar structure insect trehalase inhibitor.

[0113] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A diaryl ether compound, characterized in that: The structural formula of the diaryl ether compound is: Here, R is any one of a substituted or unsubstituted 1-20 C chain alkyl group, an aryl group, a 1-20 C chain alkoxy group, a nitro group, and a halogen group.

2. A method for preparing a diaryl ether compound according to claim 1, characterized in that: The following steps are involved: 1) mixing substituted thiophenol, anhydrous potassium carbonate and N,N-dimethylformamide and reacting them once to obtain an intermediate product; 2) The intermediate product and methyl 2-nitro-5-chlorobenzoate are mixed for secondary reaction to obtain a diaryl ether compound.

3. The method for preparing a diaryl ether compound according to claim 2, characterized in that: The usage 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 a diaryl ether compound according to claim 2 or 3, characterized in that: The temperature of the primary reaction is 60-100° C., and the time of the primary reaction is 0.5-2 h.

5. The method for preparing a diaryl ether compound according to claim 4, characterized in that: The molar ratio of the substituted thiophenol to 2-nitro-5-chlorobenzoic acid methyl ester is 3-7:4-7.

6. The method for preparing a diaryl ether compound according to claim 2 or 5, characterized in that: The temperature of the secondary reaction is 110-130°C. The secondary reaction is analyzed by TLC (V 石油醚 :V 乙酸乙酯 =8:1) monitoring to determine the progress of the reaction.

7. Use of the diaryl ether compound according to claim 1 as an agricultural insecticide, characterized in that: The agricultural pesticide is used for controlling the Asian corn borer.

Images