An isoxazoline pyridine compound and application thereof

Abstract

The application belongs to the technical field of agricultural pest control, and provides an isoxazoline pyridine compound and application thereof.The isoxazoline pyridine compound has the following structure: The compound provided by the application has excellent control effect on various pests, is high in safety to non-target organisms, has good rainwater washing resistance, and has commercial development value.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis and agricultural pest and disease control technology, and relates to an isoxazoline pyridine compound. Background Technology

[0002] Agricultural pests are characterized by their diversity, significant impact, and frequent outbreaks causing widespread damage. Among them, the rice stem borer and the beet armyworm are major pests in my country's agricultural production, often causing substantial losses. The rice stem borer larvae commonly damage rice, causing sheath blight, heart blight, and whiteheads. The beet armyworm, an omnivorous pest, can simultaneously damage multiple crops, including corn, soybeans, cotton, and tomatoes, leading to fruit drop and rotting. Long-term reliance on chemical control has resulted in high resistance levels among these pests; therefore, developing highly effective, broad-spectrum insecticides without cross-resistance has become a current research focus.

[0003] Isoxazoline compounds are a new class of highly effective insecticides that work by interfering with the γ-aminobutyric acid (GABA) channel, leading to over-excitation of the nervous system and death. As early as 2004, Nissan Chemical Industries, Ltd. successfully developed and synthesized a broad-spectrum isoxazoline insecticide—flurane. In 2014, flurane was marketed as a veterinary insecticide (trade name Bravecto), primarily for use in companion animals for internal and external insecticidal purposes. Subsequent research revealed that flurane also exhibits good activity against agricultural pests. Therefore, other isoxazoline compounds such as fluoxazolamide, isoxazolamide, afolane, lotelane, and salorane have been subsequently developed. These compounds possess high insecticidal activity against a wide range of pests, including Lepidoptera, Hemiptera, Thysanoptera, Coleoptera, Diptera, and Acari, and have high safety profiles for mammals, crops, and the environment. Their production and application costs are relatively low, making them a promising candidate for market development and application in crop protection. Summary of the Invention

[0004] This invention provides an isoxazoline pyridine compound that has good control efficacy against agricultural or sanitary pests such as Lepidoptera, Diptera, and Coleoptera.

[0005] To achieve the above objectives, the present invention adopts the following technical solution.

[0006] An isoxazoline pyridine compound having the structure of formula (I) or an agriculturally or veterinarily acceptable salt thereof: Formula (I); in, X can be arbitrarily chosen as -Cl or -CF3; R is a substitution at least at position 3, 4, 5, or 6, and R is independently chosen to be -Br, -Cl, -F, -OCH3, -CF3, or -CH3.

[0007] The salt is preferably a sodium salt, potassium salt, hydrochloride, benzoate, methanesulfonate, tartrate, or citrate.

[0008] The above-mentioned compounds may also exist in different corresponding isomers, and the present invention also includes all isomers and mixtures thereof in any proportion.

[0009] In this invention, the S-configuration compound: The bioactivity is superior to that of the R configuration: Yes. Stereoisomers can be obtained from mixtures through resolution or generated directly through stereoselective synthesis.

[0010] The preparation method of the above-mentioned isoxazoline pyridine compound includes the following steps: The substituted aminopyridine of formula (II) and BOC-glycine were subjected to a condensation reaction in the presence of an activator, and then the BOC protecting group was removed to obtain intermediate 1 of formula (III); The substituted phenyl trifluoromethyl ketone of formula (IV) and 4-acetyl-2-methylbenzoic acid were reacted in the presence of an acid-binding agent to obtain intermediate 2 of formula (V); intermediate 2 was reacted with hydroxylamine hydrochloride under a protective atmosphere to obtain intermediate 3 of formula (VI); intermediate 3 was reacted to obtain intermediate 4 of formula (VII). Intermediate 1 and intermediate 4 were subjected to amidation in the presence of an activator and an acid-binding agent to obtain the final product.

[0011] Specifically, the above preparation method includes the following steps: (1) Substituted aminopyridine (II) and BOC-glycine undergo a condensation reaction in an organic solvent in the presence of N,N'-carbonyldiimidazole (CDI), and then the BOC group is removed in the presence of TFA to obtain aminopyridine acetyl (III) with different substituents. (2) Substituted phenyl trifluoromethyl ketone (IV) and 4-acetyl-2-methylbenzoic acid undergo an aldol condensation reaction in the presence of potassium carbonate. After the reaction is completed, the mixture is acidified and filtered to obtain intermediate 2 (V). (3) Intermediate 2 (V) undergoes a dehydration reaction with acetic anhydride, DMAP, and triethylamine. After terminating the reaction, intermediate 3 (VI) is obtained by separation and purification. (4) Under nitrogen protection, intermediate 2 (VI) and hydroxylamine hydrochloride were subjected to a cyclization reaction at low temperature in the presence of inorganic base and TBAB. After the reaction was complete, intermediate 4 (VII) was obtained by separation and purification. (5) After intermediate 4 is mixed with HATU and DIPEA, intermediate 1 is added to react and the target product is obtained by separation and purification.

[0012] In step (1), the amount of substituted aminopyridine added is 1 to 1.2 times the molar amount of Boc-glycine. The amount of CDI added is 1 to 1.2 times the molar amount of Boc-glycine. The organic solvent is one or more of dichloromethane, acetonitrile, and DMF. The reaction temperature is 25 to 30°C. The amount of TFA added is 5 to 10 times the molar amount of the product, the solvent for the BOC group removal reaction is dichloromethane, and the BOC group removal temperature is 0 to 25°C.

[0013] In step (2), the amount of substituted phenyltrifluoromethyl ketone added is 1 to 1.5 times the molar amount of 4-acetyl-2-methylbenzoic acid. The amount of potassium carbonate added is 1.5 to 2.0 times the molar amount of substituted phenyltrifluoromethyl ketone. The solvent is water; the volume of the solvent is 5 to 10 times the mass of the substituted phenyltrifluoromethyl ketone. The reaction temperature is 60 to 65°C.

[0014] In step (3), the amount of triethylamine added is 2 to 3 times the molar amount of intermediate 2; the amount of DMAP added is 0.1 to 0.3 times the molar amount of the intermediate obtained in (2); and the amount of acetic anhydride added is 1.5 to 2 times the molar amount of the intermediate obtained in (2). The solvent for the reaction is selected from one or more of tetrahydrofuran, toluene, and xylene. The volume of the solvent is 5 to 10 times the mass of intermediate 1; and the stirring temperature is 40 to 80°C.

[0015] In step (4), the amount of hydroxylamine hydrochloride added is 1.5 to 2 times the amount of intermediate 3 moles. The amount of inorganic base added is 2 to 10 times the amount of intermediate 3 moles; the inorganic base is selected from NaOH, Ca(OH)2, KOH, CsOH, or LiOH. The solvent for the reaction is selected from tetrahydrofuran, methyltetrahydrofuran, toluene, xylene, dichloromethane, chloroform, or more; the mass ratio of the solvent to intermediate 3 is 5 to 10 times; the reaction temperature is -20 to 0℃.

[0016] In step (5), the amount of HATU added is 1.2 to 1.5 times the amount of intermediate 4 moles; the amount of DIPEA added is 2 to 4 times the amount of intermediate 4 moles; and the amount of intermediate 1 added is 1.2 to 1.5 times the amount of intermediate 4 moles. The solvent for the reaction is selected from one or more of tetrahydrofuran, N,N-dimethylformamide, methyltetrahydrofuran, and acetonitrile; the mass ratio of the solvent to intermediate 4 is 5 to 10 times.

[0017] To obtain salts of the above compounds, they can be reacted with the corresponding acids or bases to form salts.

[0018] The above-mentioned compounds can be used to control various agricultural and sanitary pests and ticks. For example, the liquid containing the compound or the solid mixture with other inert carriers can be applied to the affected crops, host animals, or suitable environment, so that the pests and ticks come into contact with or ingest the compound. Specifically, the above-mentioned compounds are effective against the following: Lepidoptera, such as rice stem borer, rice leaf roller, rice leaf roller, beet armyworm, cabbage caterpillar, pine caterpillar, fall webworm, etc.; Coleoptera, such as grubs, wireworms, longhorn beetles, red flour beetles, etc.; Blattodea, such as cockroaches, termites, etc.; Hymenoptera, such as ants, red imported fire ants, etc.; Hemiptera, such as stink bugs, cicadas, leafhoppers, planthoppers, whiteflies, aphids, scale insects, bedbugs, etc.; Lobelia, Orthoptera, such as locusts, mole crickets; Diptera, such as mosquitoes, flies, horseflies, etc.; Parasitic mites, such as hard ticks, small ticks, Persian ticks, etc.; Ephemeroptera, such as carmine spider mite, two-spotted spider mite, hawthorn spider mite, citrus spider mite, etc.

[0019] An agricultural composition comprising an effective dose of the aforementioned isoxazoline pyridine compound and an agronomically acceptable inert component.

[0020] The above-mentioned agricultural compositions may also contain other active ingredients in effective doses, such as profenofos, trichlorfon, abamectin, emamectin benzoate, chlorpyrifos, indoxacarb, chlorantraniliprole, and bromocyanamide.

[0021] The inert components in the above composition are used to stabilize the active ingredients, make them easier to apply to crops or to adhere to targets, such as fillers, wetting agents, dispersants, defoamers, antifreeze agents, solvents, emulsifiers, preservatives, disintegrants, etc.

[0022] The above-mentioned compositions can be processed using methods commonly used in the prior art. Preferred dosage forms include suspensions, oil suspensions, granules, large granules, microcapsule suspensions, wettable powders, water-dispersible granules, emulsifiable concentrates, water-in-oil emulsions, microemulsions, seed coating agents, seed treatment suspensions, seed treatment microcapsule suspensions, seed treatment dispersible powders, and seed treatment liquids.

[0023] The compositions of the present invention contain at least one surfactant to facilitate the dispersion of the active component in water upon application. The surfactant content is 1%-35% of the total weight of the formulation, with the remainder being a solid or liquid diluent. The surfactants used in the compositions of the present invention are known to those skilled in the art, and may be selected from one or more of dispersants, wetting agents, emulsifiers, or defoamers.

[0024] A veterinary drug comprising an effective dose of the aforementioned isoxazoline pyridine compound and a veterinarily acceptable inert ingredient.

[0025] The veterinary drug is preferably a topical preparation, such as a liniment, drops, lotion, ointment, gel, spray, or aerosol. The above-mentioned veterinary drug preparations are applied to the surface of animals through contact with harmful insects or ticks / mites.

[0026] The present invention has the following advantages: The compound provided by this invention has excellent control efficacy against a variety of pests, high safety against non-target organisms, and good resistance to rain washout, making it commercially valuable. Detailed Implementation

[0027] The present invention will be further described below with reference to the embodiments, but the present invention is not limited to the following embodiments.

[0028] Example 1 Synthesis of isoxazoline pyridine compounds Synthesize target compounds with different substituents according to the following route: The specific steps are as follows: 1. Synthesis of Boc-protected glycine aminopyridines with different substituents Boc-glycine (10 mmol), CDI (12 mmol), and dichloromethane (40 mL) were added to a 100 mL three-necked flask. After reacting at room temperature for 30 min, a dichloromethane solution containing aminopyridines with different substituents (12 mmol) was added dropwise. The reaction progress was monitored by TLC during the reaction. After the reaction was complete, water was added to quench the reaction. The aqueous phase was extracted with dichloromethane, washed three times with saturated sodium chloride solution, and recrystallized by column chromatography (petroleum ether / ethyl acetate, 3:1 v / v) or by solvents such as ethanol, methanol, acetonitrile, diethyl ether, and ethyl acetate to obtain Boc-protected glycine aminopyridines with different substituents. 10 mmol of tert-butylpyridine carbamates with different substituents were dissolved in 40 mL of dichloromethane. 50 mmol of TFA was added dropwise at 0 °C. After the addition was complete, the reaction was carried out at room temperature for 2 h. After the reaction was completed, the pH was adjusted to 8-9 with Na2CO3 solution. The aqueous phase was extracted with ethyl acetate and concentrated under reduced pressure to obtain glycine aminopyridines with different substituents.

[0029] 2. Synthesis of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid 4-Acetyl-2-methylbenzoic acid (20 mmol), 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one (24 mmol), potassium carbonate (40 mmol), and water (40 mL) were added to a 100 mL three-necked flask. The mixture was reacted at 60 °C for 12 hours to produce a white precipitate. The precipitate was filtered, and the filter cake was washed with 2 M hydrochloric acid to obtain 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid.

[0030] 3. Synthesis of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)-2-methylbenzoic acid 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid (10 mmol), DMAP (1 mmol), and toluene (40 mL) were added to a 100 mL three-necked flask. The temperature was raised to 65 °C, and acetic anhydride (20 mmol) was added dropwise. After the addition was complete, triethylamine (20 mmol) was added dropwise. The reaction progress was monitored by TLC. After the reaction was complete, the pH was adjusted to 2 with 2 M hydrochloric acid, the aqueous phase was extracted with toluene, washed three times with sodium bicarbonate solution, and washed three times with water. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobutyryl)-2-methylbenzoic acid. 4. Synthesis of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)-2-methylbenzoic acid (10 mmol), TABA (15 mmol), and THF (45 mL) were added to a 100 mL three-necked flask. The mixture was cooled to -20 °C. A mixture of 50% potassium hydroxide solution (100 mmol) and 50% hydroxylamine hydrochloride solution (25 mmol) was added dropwise to the above solution, and the reaction was allowed to proceed for four hours. After the reaction was completed, the pH was adjusted to 2 with 2 M hydrochloric acid, the aqueous phase was extracted with ethyl acetate, concentrated under reduced pressure, and recrystallized from methanol to obtain 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid.

[0031] 5. Synthesis of isoxazoline pyridine compounds DMF (20 mL), 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (5 mmol), DIPEA (15 mmol), and HATU (6 mmol) were added to a 50 mL three-necked flask. After reacting at room temperature for 30 min, a solution of dichloromethane (5 mL) containing glycine aminopyridine with different substituents (6 mmol) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. Column chromatography yielded a series of isoxazoline pyridine compounds, all of which appeared as white solids.

[0032] The NMR and mass spectrometry data of each compound are shown in Table 1.

[0033] Table 1 .

[0034] Example 2 Synthesis of isoxazoline pyridine compounds Synthesize target compounds with different substituents according to the following route: Following the method of Example 1, the raw material in step 2 was replaced with 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one instead of 1-(3-chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethane-1-one to finally synthesize the intermediate 4-(5-(3-chloro-5-trifluoromethylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid; then it was reacted with the intermediate obtained in step 1 to finally obtain a series of isoxazoline pyridine compounds, all of which were white solids.

[0035] The obtained NMR and mass spectrometry data of each compound are shown in Table 2.

[0036] Table 2 .

[0037] Example 3: Activity of isoxazoline pyridine compounds against thrips, two-spotted spider mite, rice stem borer, and beet armyworm. The insecticidal activity of all target compounds against the sensitive strain of Spodoptera litura was tested in the laboratory at a concentration of 5 mg / L using the artificial feed-mixed stomach poisoning method. The insecticidal activity of all target compounds against chlorantraniliprole rice stem borer at a concentration of 10 mg / L was tested using the immersion method. Fluoxazolamide was selected as a pesticide control to evaluate the insecticidal activity of the target compounds.

[0038] The mortality rate is calculated using the following formula: Mortality rate (%) = ×100% If the mortality rate of the blank control group is in the range of 5-20%, the corrected mortality rate is calculated according to Abbott's formula.

[0039] Corrected mortality rate (%) = ×100%.

[0040] Table 3. Indoor activity of different compounds against thrips, rice stem borer, two-spotted spider mite, and beet armyworm. The structural formula of the reference compound is: .

[0041] The activity data in the table shows that: Most compounds showed good insecticidal activity against thrips, rice stem borer, beet armyworm, and two-spotted spider mite. Nine compounds, including 4a, 6b, 1c, 2d, 2e, and 6f, had insecticidal activity exceeding 90% against thrips; compounds 1e, 2e, 3e, 4e, 1f, 2f, 6f, and 7f had insecticidal activity exceeding 70% against rice stem borer; 15 compounds, including 1a, 1c, 5d, 1e, and 6f, had insecticidal activity exceeding 90% against two-spotted spider mite; and 18 compounds, including 1a, 6b, 1c, 1d, 1e, and 6f, had insecticidal activity exceeding 90% against beet armyworm. Among them, compound 2e showed 100% activity against thrips. 1a, 4a, 5a, 1c, 5e, 1e, 2e, 5e, and 6f showed 100% activity against the two-spotted spider mite; 6b, 5d, 1e, 2e, 3e, 4e, 6f, and 7f showed 100% activity against the beet armyworm.

[0042] Example 4: Indoor activity of isoxazoline pyridine compounds against beet armyworm For the insecticidal activity test, second-instar beet armyworms with uniform growth and strong vitality were selected as test insects. The artificial feed mixing method was used to evaluate their indoor insecticidal activity. (1) Preparation of the drug solution: Weigh 20 mg of the compound, dissolve it in a small amount of DMSO, and prepare a solution containing 0.1% Tween 80 to make a 1.0 × 10⁻⁶ solution. 4 mg / L stock solution for later use.

[0043] (2) Insect treatment: Mix an appropriate amount of diluted drug solution evenly into the prepared artificial feed (the content of DMSO in the feed shall not exceed 0.2%), and after solidification, cut it into small pieces and transfer it into a 24-well plate for later use. Inoculate 2nd instar insects that have been starved for 4 h, one insect per well, and 20 insects per plate. The blank control is the treatment with 0.2% DMSO, and the positive control is the treatment with flenazo and indoxacarb. Each treatment is repeated 3 times. The treated insects are kept in a light incubator with a relative humidity of 35 ± 5%, a temperature of 26 ± 1℃, and a photoperiod of L / D = 14 h / 10 h.

[0044] (3) Results observation: The number of dead insects was counted 24 h and 48 h after drug administration. The mortality standard was that the test insects were muscle relaxed and unable to feed. If the larvae could not be turned over within one minute when gently touched with a brush and showed no reaction or uncoordinated movement, they were considered dead. The mortality rate and corrected mortality rate were calculated according to the formula in Example 3.

[0045] The following compounds were prepared as controls using a method similar to that in Example 2: .

[0046] 1 H NMR (500 MHz, DMSO) δ 10.79 (s, 1H), 7.97 (d, J = 14.6 Hz, 2H), 7.69(s, 1H), 7.63 (s, 4H), 7.50 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 7.0 Hz, 1H), 4.34(dd, J = 43.1, 18.3 Hz, 2H), 2.42 (s, 3H) 13 C NMR (126 MHz, DMSO) δ 169.22, 157.84, 150.53, 144.41, 139.16,136.79, 135.06, 129.96, 129.64, 128.53, 128.17, 126.13, 124.68, 110.76,40.00, 19.68 HRMS, (ESI, m / z): [M+H] + Calcd for C 23 H 16 Cl2F4N3O2: 512.0550; found:512.0563.

[0047] Table 4. Indoor toxicity determination of the test agents against beet armyworm According to the data in Table 5, compounds 1e, 2e, 4e and 5e have high toxicity to beet armyworm, which is significantly better than the control agent and fluoxazolamide, and have good development prospects.

Claims

1. An isoxazoline pyridine compound, a compound having the structure of formula (I) or an agriculturally or veterinarily acceptable salt thereof: Formula (I); in, X can be arbitrarily chosen as -Cl or -CF3; R is a substitution at least at position 3, 4, 5, or 6, and R is independently chosen to be -Br, -Cl, -F, -OCH3, -CF3, or -CH3.

2. The isoxazoline pyridine compound according to claim 1, characterized in that, The salt is selected from sodium salts, potassium salts, hydrochlorides, benzoates, methanesulfonates, tartrates, or citrates.

3. The isoxazoline pyridine compound according to claim 1, characterized in that, The compound also includes all isomers and mixtures thereof in any proportion.

4. A method for preparing an isoxazoline pyridine compound as described in any one of claims 1-3, characterized in that, Includes the following steps: The substituted aminopyridine and BOC-glycine undergo a condensation reaction in the presence of an activator, followed by removal of the BOC protecting group to obtain intermediate 1: ; Intermediate 2 was obtained by reacting substituted phenyltrifluoromethyl ketone and 4-acetyl-2-methylbenzoic acid in the presence of an acid-binding agent. Intermediate 2 and hydroxylamine hydrochloride were reacted under a protective atmosphere to obtain intermediate 3: Intermediate 3 reacts to obtain intermediate 4: ; Intermediate 1 and intermediate 4 were subjected to amidation in the presence of an activator and an acid-binding agent to obtain isoxazoline pyridine compounds.

5. The use of isoxazoline pyridine compounds as described in any one of claims 1-3 in the control of harmful insects and ticks in agriculture and sanitation.

6. The application according to claim 4, characterized in that, The target pests for control include Lepidoptera, Coleoptera, Blattodea, Hymenoptera, Hemiptera, Pseudocoptera, Orthoptera, Diptera, Parasitica, and Ephemeroptera; such as rice stem borer, rice leaf roller, rice leaf roller, beet armyworm, cabbage caterpillar, pine caterpillar, fall webworm, white moth, grubs, wireworms, longhorn beetles, red flour beetle, cockroaches, termites, ants, red imported fire ants, stink bugs, cicadas, leafhoppers, planthoppers, whiteflies, aphids, scale insects, bedbugs, locusts, mole crickets, mosquitoes, flies, horseflies, hard ticks, small ticks, Persian ticks, carmine spider mite, two-spotted spider mite, hawthorn spider mite, and citrus spider mite.

7. An agricultural composition, characterized in that, It contains an effective dose of the isoxazoline pyridine compound as described in any one of claims 1-3 and an agronomically acceptable inert component.

8. The agricultural composition according to claim 7, characterized in that, It also contains other active ingredients in effective doses; such as profenofos, trichlorfon, abamectin, emamectin benzoate, chlorpyrifos, indoxacarb, chlorantraniliprole, and bromocyanamide; The inert component is selected from fillers, wetting agents, dispersants, defoamers, antifreeze agents, solvents, emulsifiers, preservatives, and disintegrants.

9. The agricultural composition according to claim 7, characterized in that, The formulation of the agricultural composition is selected from suspension concentrates, oil suspension concentrates, granules, large granules, microcapsule suspension concentrates, wettable powders, water-dispersible granules, emulsifiable concentrates, water-in-oil emulsions, microemulsions, seed coating agents, seed treatment suspension concentrates, seed treatment microcapsule suspension concentrates, seed treatment dispersible powders, and seed treatment liquids.

10. A veterinary drug, characterized in that, Contains an effective dose of the isoxazoline pyridine compound as described in any one of claims 1-3 and a veterinary-acceptable inert component; The veterinary drug is preferably a topical preparation, such as a liniment, drops, lotion, ointment, gel, spray, or aerosol.

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