Thiophosphonate compound and preparation method and application thereof

Abstract

The invention relates to the technical field of pesticides, and particularly discloses a thiophosphonate compound as well as a preparation method and application thereof, and the structure of the thiophosphonate compound is shown as a formula (I). The compound disclosed by the invention has stable chemical properties and higher insecticidal activity, also has excellent insecticidal activity under lower medicament concentration, particularly has higher insecticidal activity on plant root-knot nematode, is efficient, low in toxicity, safe to human, livestock, aquatic organisms and the like, is environment-friendly, can relieve the drug resistance of diseases and insect pests to the existing thiophosphonate insecticides, and has broad application prospects. The compound has a very high pesticide research value, and has a wide application prospect in agriculture. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of pesticides, and particularly relates to a thiophosphonate compound, a preparation method thereof, and an application thereof. Background Art

[0002] Plant nematodes refer to a type of nematodes that parasitize various tissues of plants, causing poor plant development, and spreading other plant pathogens while infecting the host, resulting in disease symptoms in plants. The plant parasitic nematodes discovered so far include root-knot nematodes, stem nematodes, pine wood nematodes, and soybean cyst nematodes, etc. Root-knot nematodes are the most widely distributed and most harmful type of plant parasitic nematodes in the world. After infecting the root tissue cells of the host, they form root knots, destroying the normal differentiation and physiological activities of the root tissue, affecting the plant's absorption of water and nutrients, leading to poor growth of the above-ground part of the plant, deformed fruits, and even death of the whole plant, causing serious reduction in crop yield and quality decline.

[0003] At present, chemical nematicides are still the main means for controlling nematode diseases. According to the application method, nematicides can be divided into fumigants and non-fumigants. Fumigants are applied through an irrigation system or soil injection equipment, directly volatilizing and diffusing in the soil, or volatilizing and diffusing after decomposition, thereby acting on nematodes. Such nematicides include halogenated hydrocarbons and isothiocyanates, and common ones are methyl bromide, chloropicrin, metam-sodium, and dazomet, etc. Non-fumigants act after being contacted, ingested, or inhaled by nematodes in the form of non-gaseous molecules, including organophosphorus and carbamates, and common ones are ethoprophos, fosthiazate, carbofuran, and aldicarb, etc. Compared with fumigants, non-fumigants have a wider application period, simple usage, low dosage, and higher safety for non-target organisms and crops. However, these nematicides are likely to cause nematodes to develop drug resistance, and there are also problems of pesticide residues, bringing certain pollution to the environment.

[0004] Organophosphorus nematicides have developed rapidly and have a rich variety. Among them, thiophosphonate nematicides have attracted much attention due to their broad nematode control spectrum. Its mechanism of action is to inhibit the synthesis of nematode acetylcholinesterase, and at the same time has contact and systemic effects, and can effectively act on nematodes. However, currently, the research on thiophosphonate nematicides is relatively less, and the commercialized products are only ethoprophos, fosthiazate, and cadusafos. With the increase in the use time and the number of applications, the resistance problem of nematodes to this type of nematicide is becoming increasingly serious. Even if the application concentration is continuously increased, the nematicidal effect is still difficult to achieve the expected level. Therefore, finding new, green, and highly efficient nematicides has become the key to current nematode disease control work. Summary of the Invention

[0005] In view of the above problems, the present invention provides a thiophosphonate compound, a preparation method thereof and an application thereof. The present invention uses thiophosphonate as the parent nucleus, and introduces alkyl or pharmacologically active heterocyclic groups at different sites, obtaining a series of new compounds with high activity against nematodes, providing more efficient candidate compounds for the pesticide field and having broad application prospects in the agricultural market.

[0006] To solve the above technical problems, the technical solution provided by the present invention is:

[0007] In the first aspect, the present invention provides a thiophosphonate compound, the structure of which is shown in formula (I):

[0008]

[0009] Wherein, R1 is isopropyl or tert-butyl; R2 is methyl or ethyl;

[0010] R3 is

[0011] By introducing a specific heterocyclic structure R3 group onto the thiophosphonate parent nucleus, the present invention can enhance the specific interaction of the compound with different biomolecules in nematodes, such as enzymes, receptors, etc., and enhance the nematicidal effect; by introducing specific R1 and R2 groups onto the thiophosphonate parent nucleus, the lipophilicity of the compound is improved, enabling it to more easily penetrate biomembrane structures such as the body wall and cell membrane of nematodes, quickly enter the nematodes to play a role, and improve the action efficiency; the combination of specific R1 (isopropyl, tert-butyl), R2 (methyl, ethyl) and R3 may enable the compound to act more precisely on nematodes with less impact on non-target organisms, thus ensuring the control effect on harmful nematodes and reducing the harm to beneficial organisms in the environment, meeting the development trend of green pesticides.

[0012] The present invention has designed and synthesized a thiophosphonate compound with a novel structure, which has stable chemical properties and higher insecticidal activity, and also has excellent insecticidal activity at a lower pesticide concentration. In particular, it has high insecticidal activity against plant root-knot nematodes, is highly efficient, low-toxic, safe for humans, livestock, aquatic organisms, etc., environmentally friendly, can alleviate the resistance of pests and diseases to existing thiophosphonate insecticides, has high pesticide research value, and has broad application prospects in agriculture.

[0013] Furthermore, the structural formula of the thiophosphonate compound is shown in formula (I-10) or (I-12):

[0014]

[0015] The preferred thiophosphonate compound can obtain higher insecticidal activity against root-knot nematodes at a lower application concentration.

[0016] In a second aspect, the present invention also provides a method for preparing a thiophosphonate compound, comprising the following steps:

[0017] Step a, in an organic solvent, an organic sulfur compound R1-S-R4 reacts with phosphorus trichloride, glacial acetic acid, and sulfonyl chloride in an acylation reaction to obtain a compound represented by formula (II); wherein, R1 is isopropyl or tert-butyl; R4 is H or -S-R1;

[0018]

[0019] Step b, in an organic solvent, the compound represented by formula (II) reacts with an anhydrous fatty alcohol R2-OH under the action of an acid-binding agent in an esterification reaction to obtain a compound represented by formula (III); wherein, R2 is methyl or ethyl;

[0020]

[0021] Step c, in an organic solvent, the compound represented by formula (III) reacts with a heterocyclic compound R3-H under the action of a base in a condensation reaction to obtain the thiophosphonate compound represented by formula (I);

[0022] wherein, R3 is

[0023] The method for preparing the thiophosphonate compound provided by the present invention has a simple reaction route, high atom economy, and the yield and purity of the target product can both reach over 90%, which is suitable for industrial-scale production and has high practical value.

[0024] Specifically, the organic sulfur compound is an alkyl mercaptan R1-SH or a dialkyl disulfide R1-S-S-R1.

[0025] The specific reaction route is as follows:

[0026]

[0027] Further, in step a, the organic solvent includes at least one of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, or chlorobenzene.

[0028] Preferably, in step a, the organic solvent is dichloromethane, toluene, or a mixed solvent of 1,2-dichloroethane and toluene. Specifically, the volume ratio of 1,2-dichloroethane to toluene is 1:1 to 1:5.

[0029] Further, in step a, the temperature of the acylation reaction is -5°C to 35°C, and the reaction time is 2 h to 8 h.

[0030] Further, in step a, when R4 is H, the molar ratio of the organic sulfur compound, phosphorus trichloride, glacial acetic acid, and sulfonyl chloride is 1:(1.1 - 1.5):(1.1 - 1.5):(0.6 - 1); when R4 is -S-R1, the molar ratio of the organic compound, phosphorus trichloride, glacial acetic acid, and sulfonyl chloride is 1:(2.2 - 3):(2.2 - 3):(1.2 - 2).

[0031] Further, in step a, the mass-volume ratio of the organic sulfur compound to the organic solvent is 1 g:(3 - 10) mL.

[0032] It should be noted that in step a, phosphorus trichloride, glacial acetic acid, and sulfonyl chloride are all added dropwise, and the temperature is controlled at -5°C to 20°C during the dropping process. After the acylation reaction is completed, the solvent is removed under reduced pressure to obtain the compound shown in formula (II). Specifically, the temperature for solvent removal under reduced pressure is 35°C to 80°C.

[0033] Further, in step b, the organic solvent includes at least one of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, or chlorobenzene.

[0034] Preferably, in step b, the organic solvent is dichloromethane, toluene, or a mixed solvent of 1,2-dichloroethane and toluene. Specifically, the volume ratio of 1,2-dichloroethane to toluene is 1:1 to 1:5.

[0035] Further, in step b, the acid-binding agent includes at least one of triethylamine, triethylenediamine, tetramethylethylenediamine, N,N-dimethylaniline, N,N-diisopropylethylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, anhydrous sodium acetate, anhydrous potassium acetate, anhydrous disodium hydrogen phosphate, or anhydrous dipotassium hydrogen phosphate.

[0036] Preferably, in step b, the acid-binding agent is pyridine, sodium bicarbonate, or anhydrous potassium acetate.

[0037] Further, in step b, the temperature of the esterification reaction is -25°C to 0°C, and the reaction time is 2 h to 6 h.

[0038] Further, in step b, the molar ratio of the compound shown in formula (II), anhydrous fatty alcohol R2-OH, and the acid-binding agent is 1:(1 - 1.2):(0.7 - 1.8).

[0039] Further, in step b, the mass-volume ratio of the compound shown in formula (II) to the organic solvent is 1 g:(3 - 10) mL.

[0040] It should be noted that in step b, the anhydrous fatty alcohol R2-OH is added dropwise, and the acid-binding agent is added dropwise or in batches. During the feeding process, the temperature is controlled at -15°C to 0°C.

[0041] It should be noted that in step b, after the esterification reaction is completed, the salt formed by the reaction of hydrogen chloride and the acid-binding agent is removed by filtration, and then concentrated under reduced pressure to dryness to obtain the compound shown in formula (III).

[0042] Furthermore, in step c, the organic solvent includes at least one of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.

[0043] Preferably, in step c, the organic solvent is dichloromethane, toluene or tetrahydrofuran.

[0044] Furthermore, in step c, the base includes at least one of triethylamine, tetramethylethylenediamine, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), N,N-dimethylaniline, N,N-diisopropylethylamine, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydride, sodium hydroxide or potassium hydroxide.

[0045] Preferably, in step c, the base is triethylamine, sodium methoxide, sodium bicarbonate or sodium hydroxide.

[0046] Furthermore, in step c, the temperature of the condensation reaction is -10°C to 30°C, and the reaction time is 2 h to 6 h.

[0047] Furthermore, in step c, the molar ratio of the compound shown in formula (III) to the heterocyclic compound R3-H and the base is 1:(1.2 - 1.5):(1.2 - 2).

[0048] Furthermore, in step c, the mass-volume ratio of the compound shown in formula (III) to the organic solvent is 1 g:(5 - 15) mL.

[0049] It should be noted that in step c, after the condensation reaction is completed, it further includes a purification step: adding water to the reaction solution, separating the layers, adding activated carbon to the obtained organic phase for decolorization, drying with anhydrous magnesium sulfate, and concentrating under reduced pressure to dryness to obtain the thiophosphonate compound shown in formula (I).

[0050] The present invention also provides the application of the above-mentioned thiophosphonate compounds in controlling plant root-knot nematodes.

[0051] Furthermore, the thiophosphonate compounds shown in formula (I) have a high control effect on plant root-knot nematodes.

[0052] The present invention also provides a pharmaceutical composition for preventing and treating plant root-knot nematodes, comprising the thiophosphonate compound represented by formula (I).

[0053] The present invention also provides an insecticide for preventing and treating root-knot nematodes, comprising the above-mentioned pharmaceutical composition for preventing and treating plant root-knot nematodes.

[0054] When used as a drug active ingredient for preventing and treating plant root-knot nematodes, there can be various usage methods or techniques. For example, the thiophosphonate compound represented by formula (I) is made into various dosage forms with conventional auxiliaries in the pesticide field, such as emulsifiable concentrates, granules or powders, etc. Conventional pesticide application methods are adopted, such as root irrigation or furrow application, hole application, etc. The agent concentration of 0.5 mg / L to 1.0 mg / L has a high control effect on root-knot nematodes. Specific Embodiments

[0055] In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0056] The HPLC detection conditions of the thiophosphonate compound in the following examples are as follows:

[0057] Chromatographic column: 250 mm × 4.6 mm stainless steel column, filled with Novapak C 18 , 10 μm packing material;

[0058] Detection wavelength: 220 nm;

[0059] Mobile phase: methanol: water = 70:30;

[0060] Flow rate: 1 mL / min.

[0061] Example 1

[0062] This example provides a preparation method of the thiophosphonate compound represented by formula (I-4):

[0063] S1, Add 45.1 g (0.50 mol) of tert-butyl mercaptan to a four-necked flask, add 270 mL of toluene, stir and mix evenly, cool down to 15 - 20 °C, and sequentially dropwise add 82.4 g (0.60 mol) of phosphorus trichloride, 36 g (0.60 mol) of glacial acetic acid, and 47.2 g (0.35 mol) of sulfonyl chloride. After dropping, keep the reaction at 20 °C for 1 h, heat up to 30 °C and stir for 1 h. Concentrate the reaction solution under reduced pressure to dryness to obtain 97.6 g of a light yellow oily substance, which is the compound represented by formula (II), and the yield is 94.27%;

[0064]

[0065] S2, Add 83 g (0.40 mol) of the compound shown in formula (II) and 19.3 g (0.42 mol) of absolute ethanol to 700 mL of toluene, stir and mix evenly, cool down to 0 - 5 °C, add 52.3 g (0.30 mol) of dipotassium hydrogen phosphate anhydrous in batches, keep the temperature during the process not exceeding 5 °C. After dropping, keep the temperature at 5 °C and react for 1.5 h, then raise the temperature to 20 - 25 °C, filter to remove potassium chloride and unreacted dipotassium hydrogen phosphate, concentrate the filtrate under reduced pressure to dryness, and obtain 83 g of a pale yellow oily substance, which is the compound shown in formula (III), with a yield of 95.77%;

[0066]

[0067] S3, Add 35.3 g (0.43 mol) of 4 - methylpyrazole to 400 mL of toluene, stir evenly, cool down to 0 - 5 °C, dropwise add 50.6 g (0.50 mol) of triethylamine. After dropping, stir for 0.5 h. At this temperature, dropwise add a mixed solution composed of 78 g (0.36 mol) of the compound shown in formula (III) and 70 mL of toluene. Keep the temperature during the dropping process not exceeding 5 °C. After dropping, keep the temperature at 5 °C and react for 1 h, then raise the temperature to 20 - 25 °C, wash the reaction solution with 2 × 200 mL of water, separate the layers, add 1.5 g of activated carbon to the organic phase for decolorization and anhydrous magnesium sulfate for drying, concentrate under reduced pressure to dryness, and obtain 86.6 g of a pale yellow oily substance, which is the compound shown in formula (I), denoted as compound (I - 4), with a yield of 91.71% and an HPLC purity of 98.26%.

[0068]

[0069] 1 H NMR (400 MHz, CDCl3) δ ppm: 7.32 (s, 1H), 7.24 (s, 1H), 4.19 (m, 2H), 2.11 (s, 3H), 1.50 (s, 9H), 1.22 (t, J = 6.7 Hz, 3H).

[0070] 13 C NMR (CDCl3) δ ppm: 136.1, 132.0, 115.1, 66.1, 35.9, 33.4, 33.2, 33.1, 16.3, 9.2.

[0071] LC - MS, [M + H] + : 263.28.

[0072] Using other reaction conditions and reaction solvents etc. defined in the specification of the present invention to prepare the compound shown in formula (I - 4) can also achieve substantially equivalent technical effects to the above.

[0073] Example 2

[0074] This example provides a method for preparing a thiophosphonate compound represented by formula (Ⅰ-6):

[0075] S1. Add 45.1 g (0.30 mol) of diisopropyl disulfide to a four-necked flask, add 360 mL of dichloromethane, stir and mix evenly, cool down to 15 - 20 °C, and successively dropwise add 94.8 g (0.69 mol) of phosphorus trichloride, 41.4 g (0.69 mol) of glacial acetic acid, and 60.7 g (0.45 mol) of sulfonyl chloride. After the addition, keep the reaction at 20 °C for 1 h, then raise the temperature to 30 °C and stir for 1 h. Concentrate the reaction solution under reduced pressure to dryness to obtain 108.7 g of a light yellow oily substance, which is the compound represented by formula (Ⅱ), with a yield of 93.86%;

[0076]

[0077] S2. Add 96.5 g (0.50 mol) of the compound represented by formula (Ⅱ) to 600 mL of dichloromethane, stir and mix evenly, cool down to -5 - 0 °C, and slowly dropwise add a mixed solution composed of 25.3 g (0.55 mol) of absolute ethanol, 44.9 g (0.4 mol) of triethylenediamine, and 150 mL of dichloromethane. The temperature during the addition process does not exceed 0 °C. After the addition, keep the reaction at 0 °C for 1 h, then raise the temperature to 20 - 25 °C, filter to remove triethylenediamine hydrochloride, and concentrate the filtrate under reduced pressure to dryness to obtain 96.6 g of a light yellow oily substance, which is the compound represented by formula (Ⅲ), with a yield of 95.34%;

[0078]

[0079] S3. Add 48.1 g (0.48 mol) of 1-methyl-2-imidazolidinone to 800 mL of tetrahydrofuran, stir evenly, cool down to -5 - 0 °C, add 25.9 g (0.48 mol) of sodium methoxide, and stir for 0.5 h. At this temperature, dropwise add 81.1 g (0.40 mol) of the compound represented by formula (Ⅲ). The temperature during the addition process does not exceed 0 °C. After the addition, keep the reaction at 0 °C for 1 h. Dropwise add 10% hydrochloric acid to the reaction solution to adjust the pH to 6.5 - 7, remove the solvent under reduced pressure, cool down to 20 - 25 °C, add 400 mL of dichloromethane to the substrate, stir evenly, wash the material liquid with 2×200 mL of water, separate the layers, add 2.5 g of activated carbon to the organic phase for decolorization and anhydrous magnesium sulfate for drying, and concentrate under reduced pressure to dryness to obtain 96.3 g of a light yellow oily substance, which is the compound represented by formula (Ⅰ), denoted as compound (Ⅰ-6), with a yield of 90.41% and an HPLC purity of 98.89%.

[0080]

[0081] 11H NMR (400 MHz, CDCl3) δ ppm: 4.39 (m, 2H), 3.41 (s, 4H), 2.77 (m, 4H), 1.64 (d, J = 5.1 Hz, 6H), 1.20 (t, J = 9.1 Hz, 3H).

[0082] 13 13C NMR (CDCl3) δ ppm: 171.4, 62.8, 54.0, 35.3, 31.7, 25.3, 25.2, 22.1, 13.3.

[0083] LC-MS, [M+H] + : 267.33.

[0084] Using other reaction conditions and reaction solvents defined in the specification of the present invention to prepare the compound shown in formula (I-6) can also achieve substantially the same technical effects as above.

[0085] Example 3

[0086] This example provides a method for preparing a thiophosphonate compound shown in formula (I-10):

[0087] S1, Add 45.7 g (0.60 mol) of isopropyl mercaptan to a four-necked flask, add 320 mL of chlorobenzene, stir and mix evenly, cool down to 10 - 15 °C, and sequentially add 98.9 g (0.72 mol) of phosphorus trichloride, 43.7 g (0.72 mol) of glacial acetic acid, and 56.7 g (0.42 mol) of sulfonyl chloride dropwise. After dropping, keep the reaction at 20 °C for 1 h, then raise the temperature to 30 °C and stir for 1 h. Concentrate the reaction solution under reduced pressure to dryness to obtain 108.4 g of a light yellow oily substance, which is the compound shown in formula (II), with a yield of 93.59%;

[0088]

[0089] S2, Add 96.5 g (0.50 mol) of the compound shown in formula (II) and 24.4 g (0.53 mol) of absolute ethanol to 580 mL of chlorobenzene, stir and mix evenly, cool down to -15 - -10 °C, and slowly add 60.76 g (0.6 mol) of triethylamine dropwise. During the dropping process, the temperature does not exceed -10 °C. After dropping, keep the reaction at -10 °C for 1 h, then slowly raise the temperature to 20 - 25 °C, filter to remove triethylamine hydrochloride, and concentrate the filtrate under reduced pressure to dryness to obtain 95.8 g of a light yellow oily substance, which is the compound shown in formula (III), with a yield of 94.56%;

[0090]

[0091] S3. Add 60.4 g (0.52 mol) of 5-methyl-1,3,4-thiadiazol-2(3H)-one to 880 mL of chloroform, stir evenly, cool down to 0 - 5 °C, add 82.9 g (0.60 mol) of anhydrous potassium carbonate, stir for 0.5 h. At this temperature, dropwise add a mixed solution composed of 81.1 g (0.40 mol) of the compound shown in formula (Ⅲ) and 100 mL of chloroform. During the dropping process, the temperature does not exceed 5 °C. After dropping, keep the reaction at 5 °C for 1 h, then raise the temperature to 20 - 25 °C, wash the reaction solution with 2 × 400 mL of water, separate the layers, add 2.5 g of activated carbon to the organic phase for decolorization, dry with anhydrous magnesium sulfate, concentrate under reduced pressure to dryness, and obtain 102.8 g of a brownish-yellow oily substance, which is the compound shown in formula (Ⅰ), denoted as compound (Ⅰ-10), with a yield of 91.03% and an HPLC purity of 98.46%.

[0092]

[0093] 1 H NMR (400 MHz, CDCl3) δ ppm: 4.41 (m, 2H), 2.63 (m, 1H), 1.51 (m, 6H), 1.23 (t, J = 6.2 Hz, 3H), 0.82 (s, 3H).

[0094] 13 C NMR (CDCl3) δ ppm: 170.0, 154.7, 61.8, 25.4, 25.3, 20.0, 18.5, 13.3.

[0095] LC-MS, [M + H] + : 283.31.

[0096] Using other reaction conditions and reaction solvents defined in the specification of the present invention to prepare the compound shown in formula (Ⅰ-10) can also achieve substantially the same technical effects as above.

[0097] Example 4

[0098] This example provides a preparation method of a thiophosphonate compound shown in formula (Ⅰ-12):

[0099] S1. Add 45.1 g (0.50 mol) of tert-butyl mercaptan to a four-necked flask, add 270 mL of dichloromethane, stir and mix evenly, cool down to 15 - 20 °C, dropwise add 82.4 g (0.60 mol) of phosphorus trichloride, 36 g (0.60 mol) of glacial acetic acid, and 47.2 g (0.35 mol) of sulfonyl chloride in sequence. After dropping, keep the reaction at 20 °C for 1 h, then raise the temperature to 30 °C and stir for 1 h while keeping warm. Concentrate the reaction solution under reduced pressure to dryness, and obtain 97.5 g of a light yellow oily substance, which is the compound shown in formula (Ⅱ), with a yield of 94.17%;

[0100]

[0101] S2. Add 83 g (0.40 mol) of the compound shown in formula (II) and 19.3 g (0.42 mol) of absolute ethanol to 665 mL of dichloromethane, stir and mix evenly, cool down to -5 to 0 °C, slowly add dropwise 47.5 g (0.60 mol) of pyridine, and keep the temperature not exceeding 0 °C during the dropping process. After the dropping is completed, keep the reaction at 0 °C for 1 h, then raise the temperature to 20 to 25 °C, filter to remove pyridine hydrochloride, and concentrate the filtrate under reduced pressure to dryness to obtain 82.2 g of a pale yellow oily substance, which is the compound shown in formula (III), and the yield is 94.86%;

[0102]

[0103] S3. Add 60.4 g (0.52 mol) of 5-methyl-1,3,4-thiadiazol-2(3H)-one to 800 mL of dichloromethane, stir evenly, cool down to 0 to 5 °C, add 77.6 g (0.60 mol) of N,N-diisopropylethylamine, stir for 0.5 h. At this temperature, add dropwise a mixed solution composed of 86.7 g (0.40 mol) of the compound shown in formula (III) and 100 mL of dichloromethane, and keep the temperature not exceeding 5 °C during the dropping process. After the dropping is completed, keep the reaction at 5 °C for 1 h, then raise the temperature to 20 to 25 °C, wash the reaction solution with 2×400 mL of water, separate the layers, add 2.5 g of activated carbon to the organic phase for decolorization and anhydrous magnesium sulfate for drying, and concentrate under reduced pressure to dryness to obtain 107.7 g of a brownish-yellow oily substance, which is the compound shown in formula (I), denoted as compound (I-12), with a yield of 90.83% and an HPLC purity of 98.25%.

[0104]

[0105] 1 H NMR (400 MHz, CDCl3) δ ppm: 4.31 (m, 2H), 1.64 (m, 9H), 1.10 (m, 3H), 0.94 (s, 3H).

[0106] 13 C NMR (CDCl3) δ ppm: 169.4, 156.6, 66.9, 40.5, 37.7, 37.4, 37.3, 25.2, 17.3.

[0107] LC-MS, [M+H] + : 297.33.

[0108] Using other reaction conditions and reaction solvents defined in the specification of the present invention to prepare the compound shown in formula (I-12) can also achieve substantially the same technical effects as above.

[0109] Example 5

[0110] This example provides a method for preparing a thiophosphonate compound represented by formula (Ⅰ-16):

[0111] S1. Add 45.1 g (0.50 mol) of tert-butyl mercaptan to a four-necked flask, add a mixed solvent composed of 135 mL of 1,2-dichloroethane and 135 mL of toluene, stir and mix evenly, cool down to 15-20 °C, and successively dropwise add 82.4 g (0.60 mol) of phosphorus trichloride, 36 g (0.60 mol) of glacial acetic acid, and 47.2 g (0.35 mol) of sulfonyl chloride. After dropping, keep the reaction at 20 °C for 1 h, then raise the temperature to 30 °C and stir for 1 h. Concentrate the reaction solution under reduced pressure to dryness to obtain 97.1 g of a light yellow oily substance, which is the compound represented by formula (Ⅱ), and the yield is 93.79%;

[0112]

[0113] S2. Add 83 g (0.40 mol) of the compound represented by formula (Ⅱ) and 20.3 g (0.44 mol) of absolute ethanol to a mixed solvent composed of 375 mL of 1,2-dichloroethane and 375 mL of toluene, stir and mix evenly, cool down to -5-0 °C, and add 58.9 g (0.60 mol) of anhydrous potassium acetate in batches. After adding, keep the reaction at 0 °C for 1 h, then raise the temperature to 20-25 °C, filter to remove potassium chloride and unreacted anhydrous potassium acetate, and concentrate the filtrate under reduced pressure to dryness to obtain 82.3 g of a light yellow oily substance, which is the compound represented by formula (Ⅲ), and the yield is 94.96%;

[0114]

[0115] S3. Add 42.60 g (0.43 mol) of 2-amino-5-methyl-1,3,4-oxadiazole to 660 mL of 1,2-dichloroethane, stir evenly, cool down to -5-0 °C, add 44.5 g (0.53 mol) of anhydrous sodium bicarbonate, stir for 0.5 h. At this temperature, dropwise add a mixed solution composed of 75.8 g (0.35 mol) of the compound represented by formula (Ⅲ) and 100 mL of 1,2-dichloroethane. The temperature during the dropping process does not exceed 0 °C. After dropping, keep the reaction at 0 °C for 1 h, then raise the temperature to 20-25 °C, wash the reaction solution with 2×300 mL of water, separate the layers, add 1.5 g of activated carbon to the organic phase for decolorization and anhydrous magnesium sulfate for drying, and concentrate under reduced pressure to dryness to obtain 90.3 g of a yellow oily substance, which is the compound represented by formula (Ⅰ), denoted as compound (Ⅰ-16), with a yield of 92.37% and an HPLC purity of 98.32%.

[0116]

[0117] 11H NMR (400 MHz, CDCl3) δ ppm: 6.2 (s, 1H), 4.23 (m, 2H), 2.64 (s, 3H), 1.54 (s, 9H), 1.28 (t, J = 12.1 Hz, 3H).

[0118] 13 13C NMR (CDCl3) δ ppm: 169.4, 164.6, 62.5, 38.2, 35.5, 35.4, 35.3, 21.2, 13.3.

[0119] LC-MS, [M+H] + : 280.28.

[0120] Using other reaction conditions and reaction solvents defined in the specification of the present invention to prepare the compound shown in formula (I-16) can also achieve substantially the same technical effects as above.

[0121] Example 6-16

[0122] Referring to the above method for the synthesis of thiophosphonate compounds, the specific process parameters can be obtained by conventional adjustment according to Example 1.

[0123]

[0124]

[0125]

[0126] Pharmacodynamic test

[0127] The thiophosphonate compounds prepared in Examples 1 to 17 of the present invention, as well as fosthiazate, abamectin, and fluxapyroxad, were assayed for toxicity against Meloidogyne incognita indoors to evaluate their insecticidal activities comparatively.

[0128] The test was carried out with reference to the immersion method for the test of inhibiting plant pathogenic nematodes in Part 1 of NY / T 1833.1-2009 "Guidelines for Pesticide Bioassay in the Laboratory - Nematicides".

[0129] 1 Preparation of test materials

[0130] The Meloidogyne incognita for the test was cultured on tomatoes and reserved for the egg stage.

[0131] 2 Test agents and initial screening concentrations

[0132] Test agents: (I-1) to (I-16) prepared in the examples.

[0133] Control agents: fosthiazate, abamectin, fluxapyroxad.

[0134] Refer to the concentration of 0.5 mg / L and 1.0 mg / L of fosthiazate, abamectin, and fluopyram for Meloidogyne incognita.

[0135] 3 Preparation of nematode suspension

[0136] Wash the fresh plant roots infected with root-knot nematodes, cut them into 1-cm-long segments, put them into a tissue grinder, add 3 times the amount of water, and grind for 30 s. Transfer them to a combined standard sieve of 200 mesh (aperture 75 μm) and 500 mesh (aperture 26 μm). Rinse the plant tissues in the sieve with tap water, collect the nematode eggs in the 500-mesh standard sieve, surface-sterilize them with 0.5% NaClO solution for 3 min, rinse them 5 times with sterile water, then put them into a Baermann funnel, and culture them in the dark in an incubator at 25 °C. Collect Meloidogyne incognita J2 once every 24 h for standby.

[0137] 4 Chemical treatment

[0138] According to the experimental design, dilute the above experimental chemicals with 0.1% Tween-80 aqueous solution in gradients, use 0.1% Tween-80 aqueous solution as the control. Prepare the J2 of root-knot nematodes hatched within 24 h into a suspension (200 nematodes / mL) with clear water. Use a pipette to transfer 0.5 mL of the chemical solution and 0.5 mL of the J2 suspension into a 24-well plate, repeat 3 times. After mixing well with a fine glass rod, place them in the dark in an incubator at 25 °C. Check the total number of J2 and the number of dead nematodes at 24 h, 48 h, and 72 h, and calculate the mortality rate and corrected mortality rate.

[0139] 5 Result inspection

[0140] Under a stereomicroscope, use the acupuncture method to determine whether the nematodes are dead, count the number of dead nematodes, and calculate the nematode mortality rate and corrected mortality rate. The calculation formulas are as follows:

[0141] Mortality rate (%) = Number of dead nematodes / Number of treated nematodes × 100%

[0142] Corrected mortality rate (%) = (Treatment mortality rate - Control mortality rate) / (1 - Control mortality rate) × 100%

[0143] If the control mortality rate is less than 5%, no correction is required; if the control mortality rate is between 5% and 15%, the corrected mortality rate should be calculated according to the formula; if the control mortality rate is greater than 15%, the experiment needs to be redone. The results are shown in Table 2.

[0144] Table 2

[0145]

[0146]

[0147] As can be seen from the results, the thiophosphonate compounds prepared in the embodiments of the present invention all showed certain pesticidal activities against root-knot nematodes. Among them, compounds I-10 and I-12 showed relatively good control effects. Especially at the dosage concentration of 0.5 mg / L, their control effects were better than those of the control agents fosthiazate, abamectin, and fluopyram. This not only greatly reduced the dosage of the agents, lowered the agricultural production cost, but also effectively reduced the residues of chemical agents in agricultural products and the environment, which was more in line with the concept of green and environmental-friendly agricultural development. At the same time, it provided more drug options for solving the problem of agricultural pests and diseases resistance to drugs, and had broad market application prospects in the agricultural market.

[0148] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, or improvements made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims

1. A thiophosphonate compound, characterized in that, Its structure is as shown in formula (I): Among them, R1 is isopropyl or tert-butyl; R2 is methyl or ethyl; R3 is 2. The thiophosphonate compound according to claim 1, wherein R2 is ethyl and R3 is 3. The preparation method of the thiophosphonate compound according to claim 1 or 2, characterized in that, It includes the following steps: Step a, in an organic solvent, an organic sulfur compound R1-S-R4 undergoes an acylation reaction with phosphorus trichloride, glacial acetic acid, and sulfonyl chloride to obtain a compound shown in formula (II); among them, R1 is isopropyl or tert-butyl; R4 is H or -S-R1; Step b, in an organic solvent, the compound shown in formula (II) undergoes an esterification reaction with an anhydrous fatty alcohol R2-OH under the action of an acid-binding agent to obtain a compound shown in formula (III); among them, R2 is methyl or ethyl; Step c, in an organic solvent, the compound shown in formula (III) undergoes a condensation reaction with a heterocyclic compound R3-H under the action of a base to obtain a thiophosphonate compound shown in formula (I); Among them, R3 is 4. The method for preparing the thiophosphonate compound according to claim 3, characterized in that, In steps a and b, the organic solvent includes at least one of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, or chlorobenzene.

5. The preparation method of the thiophosphonate compound according to claim 3, characterized in that, In step a, the temperature of the acylation reaction is -5°C to 35°C, and the reaction time is 2h to 8h; and / or In step a, when R4 is H, the molar ratio of the organic sulfur compound to phosphorus trichloride, glacial acetic acid, and sulfonyl chloride is 1:(1.1 - 1.5):(1.1 - 1.5):(0.6 - 1); when R4 is -S-R1, the molar ratio of the organic compound to phosphorus trichloride, glacial acetic acid, and sulfonyl chloride is 1:(2.2 - 3):(2.2 - 3):(1.2 - 2); and / or In step a, the mass-volume ratio of the organic sulfur compound to the organic solvent is 1g:(3 - 10)mL.

6. The method for preparing the thiophosphonate compound according to claim 3, characterized in that, In step b, the acid-binding agent includes at least one of triethylamine, triethylenediamine, tetramethylethylenediamine, N,N-dimethylaniline, N,N-diisopropylethylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, anhydrous sodium acetate, anhydrous potassium acetate, anhydrous disodium hydrogen phosphate, or anhydrous dipotassium hydrogen phosphate; and / or In step b, the temperature of the esterification reaction is -25°C to 0°C, and the reaction time is 2h to 6h; and / or In step b, the molar ratio of the compound shown in formula (II) to the anhydrous fatty alcohol R2-OH and the acid-binding agent is 1:(1 - 1.2):(0.7 - 1.8); and / or In step b, the mass-volume ratio of the compound shown in formula (II) to the organic solvent is 1g:(3 - 10)mL.

7. The preparation method of the thiophosphonate compound according to claim 3, wherein In step c, the organic solvent includes at least one of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide; and / or In step c, the base includes at least one of triethylamine, tetramethylethylenediamine, 1,8-diazabicyclo[5,4,0]-7-undecene, N,N-dimethylaniline, N,N-diisopropylethylamine, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydride, sodium hydroxide, or potassium hydroxide; and / or In step c, the temperature of the condensation reaction is -10°C to 30°C, and the reaction time is 2 h to 6 h; and / or In step c, the molar ratio of the compound shown in formula (III) to the heterocyclic compound R3-H and the base is 1:(1.2 to 1.5):(1.2 to 2); and / or In step c, the mass-volume ratio of the compound shown in formula (III) to the organic solvent is 1 g:(5 to 15) mL.

8. Use of the thiophosphonate compound according to claim 1 or 2 in controlling plant root-knot nematodes.

9. A pharmaceutical composition for preventing and treating plant root-knot nematodes, characterized in that, Comprising the thiophosphonate compound according to claim 1 or 2.

10. An insecticide for preventing and controlling root-knot nematodes, characterized in that, Comprising the pharmaceutical composition for controlling plant root-knot nematodes according to claim 9.

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