CN116987100A - Isothiazole bithiazolopyrimidine amine derivatives, and preparation method and application thereof - Google Patents

Abstract

The invention provides isothiazole bithiazolopyrimidinamine derivatives, a preparation method and application thereof, and in particular relates to derivatives with a chemical structural general formula shown in formula I:

Description

Isothiazole bithiazolopyrimidine amine derivatives, and preparation method and application thereof

Technical Field

The technical scheme of the invention belongs to the field of pesticides, and particularly relates to an isothiazole-containing pyrimidamine derivative, a preparation method and application thereof.

Background

Rice is an important food crop in the world. As the population grows, so does the demand for rice. However, rice diseases affect not only rice production but also quality and commercial value of rice, in which rice sheath blight, rice blast and bacterial leaf blight are major three major rice diseases (Khush, g.s.et al plant Mol biol.2005, 59,1-6;Dean,R.A.et al.Nature.2015, 434, 980-986.). In the prevention and treatment of rice diseases, bactericides play an irreplaceable role. At present, the traditional pesticides for preventing and controlling rice diseases are fewer, and the development of new pesticides is to solve the rice diseases and ensure the key break of rice yield increase. The creation of new pesticides is an important guarantee for pesticide decrement and synergy in China. With the development of green ecological agriculture, the creation of green pesticides is a trend and challenge for the future development of pesticides (Shao Xusheng et al, world pesticides 2020, 42 (04): 16-24.).

The key problems to be solved in the field of new pesticide creation are the discovery problems of new targets and new leads, heterocyclic compounds are a wide source of new leads of pesticides, the new leads of the pesticides are often characterized by high efficiency, broad spectrum biological activity and low toxicity, the heterocyclic compounds in commercial pesticides account for a large part, among the heterocyclic rings, the skeleton of pyrimidine is commonly found in the medical field and contains antifungal, antiviral and anti-inflammatory (Zhou Yong, etc.), chemical researches and applications, 2018, 30 (2): 196-200), antineoplastic (Cong, etc.), organic chemistry, 2020, 40:1-16) and other biological active natural products and pesticide fields (Shang Ercai, etc., chemical progress, 1995 (5): 8) have wide sterilization, insecticidal (Xu Ying, etc.), pesticides, 2011, 50 (7): 474-478), acaricidal (Liu Chang command, pesticides, 2003, 40 (10): 3), and herbicidal active varieties, and the research of the compounds has wide development prospect. In 1968, the uk Bo Naka company successfully developed the first pyrimidine bactericide, bupirimate, and then several pesticide companies at home and abroad simulated their structures, developed tens of pyrimidine ring bactericides (Laws F a, et al annals of Applied Biology,1982, 100 (2): 253-262.): such as pyriminostrobin, haloxyfop, cyprodinil, azoxystrobin, methyl cyprodinil, kresoxim-methyl, and the like. Pyrimidine compounds, because of their unique mode of action and novel structure, are important components of pesticide and fungicide research (Wu Qin et al, organic chemistry 2009, 29 (03): 365-379.).

The invention combines two heterocycles of thiazole and pyrimidine to form a core skeleton of thiazolopyrimidinamine, and introduces the 3, 4-2-chloroisothiazole heterocycle with potential activity into the core skeleton, so as to expect to design and synthesize the bactericide with excellent activity. Therefore, based on the angles of reasonable design of pesticide molecules and creation of green pesticides, a series of isothiazole-containing thiazolopyrimidinamine derivatives are designed and synthesized by adopting a bioelectronic isostep replacement principle, and the bactericidal activity of the system is evaluated.

Disclosure of Invention

The technical problems to be solved by the invention are as follows: provides a novel synthesis method of isothiazole-thiazole pyrimidine amine derivatives, provides biological activities of the compounds for regulating agriculture, gardening and sanitation and forestry plant pests and plant pathogens and a determination method thereof, and simultaneously provides application of the compounds in the fields of agriculture, gardening, forestry and sanitation.

The technical scheme adopted by the invention for solving the technical problems is as follows: the chemical structural general formula of the isothiazole-containing thiazolopyrimidine amine derivative with insecticidal, acaricidal, bactericidal, anti-plant virus and induced plant disease resistance activity in the agricultural, horticultural and forestry fields is shown as I:

wherein R is ¹ Selected from: 4-fluorophenyl, cyclopropyl, 4-isopropylphenyl, 2-difluoroethyl, 4-methoxybenzyl, 4-methoxyphenyl, 3-ethylpyridine, 2-fluorophenylethyl, 2-fluorobenzyl, 2-chlorobenzyl, 2-methoxybenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3-chlorobenzyl, 2-methylbenzyl, ethyl, benzyl, cyclopentyl, 2-trifluoromethylbenzyl.

The synthetic route of the isothiazole bisthiazolopyrimidine amine derivative I and the intermediate thereof is as follows:

the synthetic method of the isothiazole bisthiazolopyrimidine amine derivative I comprises the following steps:

A. preparation of compound 2:

dropwise adding a catalytic amount of N, N-dimethylformamide into the compound 1 and thionyl chloride under stirring at room temperature, stirring overnight at room temperature, removing thionyl chloride under reduced pressure after the reaction is finished, washing with water, extracting with ethyl acetate for three times, washing an organic phase with saturated sodium chloride solution for three times, drying a combined organic layer with anhydrous sodium sulfate, concentrating a filtrate to remove a solvent, and performing column chromatography with pure dichloromethane as an eluent to obtain a purified compound 2;

B. preparation of Compound 4:

adding carbon disulfide into the compound 3 and absolute methanol under stirring at room temperature, heating and refluxing to react until the reaction is finished, standing, cooling, and carrying out suction filtration to obtain a solid, and recrystallizing a crude product with ethanol to obtain a purified compound 4;

preparation of compound 5: adding the compound 2 and water into a round-bottom flask, sequentially adding the compound 4, anhydrous potassium carbonate and potassium iodide under stirring at room temperature, heating and refluxing the reaction system to react until TLC monitoring reaction is finished, cooling to room temperature, filtering to obtain solid, and recrystallizing the crude product with ethanol to obtain a purified compound 5;

C. preparation of compound 7:

dissolving the compound 5 in N, N-dimethylformamide, adding the N-dimethylformamide into a round-bottom flask, stirring at room temperature, sequentially adding triethyl orthoformate and p-toluenesulfonic acid, heating for reaction until TLC monitoring is finished, cooling to room temperature, removing most of N, N-dimethylformamide in the system under reduced pressure, washing with water to remove the N, N-dimethylformamide, extracting an organic phase with dichloromethane, washing with saturated sodium chloride solution, merging the organic phases, drying with anhydrous sodium sulfate, removing anhydrous sodium sulfate by suction filtration, concentrating the filtrate to remove the solvent, and carrying out column chromatography with dichloromethane/anhydrous methanol eluent to obtain a purified compound 7;

D. preparation of Compound 8:

dissolving the compound 7 in phosphorus oxychloride, adding the phosphorus oxychloride into a round-bottom flask, reacting, stirring, heating, reacting until TLC monitoring reaction is finished, cooling, slowly dripping the reaction liquid into ice water, precipitating a large amount of solid, filtering out the solid under pressure, and performing column chromatography by using pure dichloromethane as an eluent to obtain a purified compound 8;

E. preparation of Compound I:

adding a compound 8 and absolute ethyl alcohol into a round-bottom flask, stirring at room temperature, sequentially adding triethylamine and substituted amine, heating and refluxing the system to react until TLC monitoring reaction is finished, removing most absolute ethyl alcohol under reduced pressure, adding water, extracting with dichloromethane, combining organic layers, washing the organic layers with water, washing with saturated saline, adding anhydrous sodium sulfate for drying, filtering out anhydrous sodium sulfate solid, removing solvent in filtrate under reduced pressure, and performing column chromatography by using dichloromethane/absolute methanol as eluent to obtain the purified compound I.

F. Use of isothiazole-containing bisthiazolopyrimidine amine derivatives I:

the invention provides application of the isothiazole bithiazolopyrimidinamine derivative I in preparing fungicides.

The invention provides application of the isothiazole bithiazolopyrimidine amine derivative I in preparing a tobacco mosaic virus resisting agent.

The invention provides application of an isothiazole bithiazolopyrimidine amine derivative I in preparing a plant activator for inducing tobacco to resist tobacco mosaic virus.

The invention provides application of the isothiazole-benzothiazole pyrimidine amine derivative I in preventing and controlling insect pests of agricultural and forestry and gardening plants.

The biological activity of the isothiazole bisthiazolopyrimidinamine derivative I is measured as follows:

the bactericidal activity of the isothiazole bisthiazolopyrimidine amine derivative I is measured:

the sterilization or bacteriostasis activity of the isothiazole-combined pyrimidine amine derivative I adopts a thallus growth rate measuring method, and comprises the following specific steps: 1.8 mg of sample is dissolved in 2 drops of dimethyl sulfoxide, the aqueous solution containing a certain amount of Tween 20 emulsifier is used for diluting the sample to 500 micrograms/ml of reagent, 1 ml of reagent to be tested is respectively sucked into a culture dish under the aseptic condition, 9 ml of PDA culture medium is respectively added, 50 micrograms/ml of reagent-containing flat plate is prepared after shaking, 1 ml of sterilized water is added to serve as a blank control, a bacterial dish is cut along the outer edge of hypha by a puncher with the diameter of 4 millimeters, the bacterial dish is moved onto the reagent-containing flat plate to be placed in an equilateral triangle, each treatment is repeated for 3 times, the culture dish is placed into a constant temperature incubator with the temperature of 24+/-1 ℃ for culture, the expansion diameter of each bacterial dish is investigated after the diameter of a control colony is expanded to 2-3 cm, the average value is calculated, the relative antibacterial rate is compared with the blank control, and the bacterial is the species of most typical plant pathogenic bacteria actually generated in the field in agricultural production of China, and the product has the code and name as follows: a.s: the Latin name of the early blight bacteria of tomato is: alternaria solani, b.c: the Latin name of the Botrytis cinerea is: botrytis cinerea, C.a: peanut brown spot germ, its latin name is: cercospora arachidicola, G.z: the gibberella wheat germ has the Latin name: gibberella zeae, P.p: apple ring rot germ, its latin name is: physalospora piricola, R.s: rhizoctonia solani, its Latin name is: rhizoctonia solani, S.s: sclerotinia sclerotiorum, the Latin name of which is: sclerotinia sclerotiorum.

The beneficial effects of the invention are as follows: leading optimization is carried out on the isothiazole bithiazolopyrimidine amine derivative I, and antibacterial activity screening is carried out on the isothiazole bithiazolopyrimidine amine derivative I.

The synthesis and biological activity and application of the isothiazole bisthiazolopyrimidine amine derivatives I are more specifically illustrated by specific preparation and biological activity assay examples which are only used for specifically illustrating the invention and not limiting the invention, particularly the biological activity is only used for illustrating the patent and is not limited by the patent, and the specific embodiments are as follows:

example 1: preparation of Compound I-5:

(1) To a 250 ml round bottom flask was added compound 1 (3.5 g, 19.02 mmol) and thionyl chloride (3.4 g, 28.53 mmol), a catalytic amount of N, N-dimethylformamide (139 mg, 1.9 mmol) was added dropwise with stirring at room temperature, the reaction system was stirred overnight at room temperature after the addition was completed, after the reaction was completed, the thionyl chloride was removed under reduced pressure, after the removal of the N, N-dimethylformamide by washing with water, the organic phase was extracted three times with ethyl acetate (50 ml×3) and washed three times with saturated sodium chloride solution (75 ml×3), the organic layers were combined, dried with anhydrous sodium sulfate, the filtrate was concentrated to remove the solvent, and purified by column chromatography with pure dichloromethane as eluent to give compound 2,3.1 g, yield 81%;

(2) Compound 3 (5.0 g, 50.46 mmol) and absolute methanol (40 ml) are added into a 250 ml round bottom flask, carbon disulfide (11.5 g, 151.38 mmol) is added under stirring at room temperature, the temperature is heated to 40 ℃ until reflux reaction is carried out for 4-5 h, after the reaction is finished, the mixture is stood and cooled to room temperature, the solid obtained by suction filtration is filtered, the crude product is washed by ethyl acetate, and 4,8.8 g of compound is obtained by recrystallization by ethanol, and the yield is 99%;

(3) Compound 2 (3.7 g, 18.27 mmol) and water (100 ml) were added to a 250 ml round bottom flask, compound 4 (3.5 g, 20.10 mmol), anhydrous potassium carbonate (3.3 g, 23.76 mmol) and potassium iodide (0.3 g, 1.83 mmol) were added sequentially with stirring at room temperature, the reaction system was heated to 100 ℃ to reflux for 3-4 hours, after TLC monitoring the reaction, cooled to room temperature, the solid obtained by suction filtration was filtered, and the crude product was recrystallized from ethanol to give compound 5,5.1 g, yield 81%;

(4) Compound 5 (5.0 g, 14.65 mmol) was dissolved in N, N-dimethylformamide (100 ml) and added to a 500 ml round bottom flask, triethyl orthoformate (6.5 g, 43.95 mmol) and p-toluenesulfonic acid (252 mg, 1.47 mmol) were added sequentially with stirring at room temperature and heated to 110 ℃ for 4 to 5 hours, after the reaction was completed by TLC, cooled to room temperature and most of the N, N-dimethylformamide in the system was removed under reduced pressure by an oil pump. After removal of N, N-dimethylformamide by washing with water, the organic phase was extracted with dichloromethane (75 ml. Times.3) and washed with saturated sodium chloride solution (100 ml. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered off with suction to remove anhydrous sodium sulfate, the filtrate was concentrated to remove the solvent, and purified by column chromatography with an eluent of dichloromethane/anhydrous methanol (80:1 to 20:1, v/v) to give 7,4.2 g of the compound in 82% yield;

(5) Compound 7 (4.0 g, 11.39 mmol) was dissolved in phosphorus oxychloride (25 ml) and added to a 250 ml round bottom flask, the reaction was stirred and heated to 110 degrees celsius for 1-2 hours, after TLC monitoring the reaction was completed, cooled to 0 degrees celsius. Slowly dripping the reaction solution into ice water, precipitating a large amount of solids, filtering out the solids under pressure, and purifying the obtained solids by column chromatography with pure dichloromethane as an eluent to obtain 8,2.3 g of a compound, wherein the yield is 55%;

(6) To a 50 ml round bottom flask was added compound 8 (200 mg, 0.54 mmol) and absolute ethanol (10 ml), triethylamine (109 mg, 1.08 mmol) and 4-methoxybenzylamine (89 mg, 0.60 mmol) were added sequentially with stirring at room temperature, and then the system was heated to reflux to 78 ℃ and stirred for 4-8 hours. TLC was monitored, the reaction was cooled to room temperature, most of the absolute ethanol was removed under reduced pressure, water (25 ml) was added, extracted with dichloromethane (20 ml×3), the combined organic layers were washed with water (20 ml×2), then brine (25 ml) was used, dried over anhydrous sodium sulfate was added, the anhydrous sodium sulfate solid was filtered off with suction after drying was completed, the solvent was removed from the filtrate under reduced pressure, and the residue was purified by column chromatography using dichloromethane/absolute methanol (200:1, v/v) eluent to give compound I-5, 230 mg, 91% yield.

Example 2: the antibacterial activity measurement result of the isothiazole bisthiazolopyrimidine amine derivative I provided by the invention is as follows:

the codes and names of the common plant pathogenic fungi tested by the invention are as follows: AS: the Latin name of the early blight bacteria of tomato is: alternaria solani, BC: the Latin name of the Botrytis cinerea is: botrytis cinerea, CA: peanut brown spot germ, its latin name is: cercospora arachidicola, GZ: the gibberella wheat germ has the Latin name: gibberella zeae, PP: apple ring rot germ, its latin name is: physalospora piricola, RS: rhizoctonia solani, its Latin name is: rhizoctonia solani, SS: sclerotinia sclerotiorum, the Latin name of which is: sclerotinia sclerotior. These species are well representative and can represent the species of most pathogenic bacteria occurring in the field in agricultural production.

The results of the cell growth rate method are shown in Table 2, and Table 2 shows that all the compounds synthesized by the invention have bactericidal activity with different degrees at 50 micrograms/milliliter; commercial fluoxastrobin is the most closely related commercial germicide to the chemical structure of the present patent. The invention uses fluoxastrobin as positive control to carry out the determination of the biological activity of the novel compound; the results show that the series of compounds have better biological activity on rhizoctonia solani (R.solani), and the inhibition rate of the compounds I-4, I-13, I-14, I-15, I-17, I-18 and I-19 is higher than 70%, wherein under the concentration of 50 micrograms/milliliter, the inhibition rates of the compounds I-17 and I-19 on rhizoctonia solani are respectively 78.4 percent and 79.1 percent, which are superior to positive control fluoxastrobin; has no obvious inhibiting effect on wheat gibberella, cucumber gray mold and peanut brown spot; the inhibition rate of the compound I-4 on the tomato early blight is 68.2 percent, which is better than 55.3 percent of fluoxastrobin; for sclerotinia rot of colza, I-19 is higher than 50%, I-6 exceeds 80%, and the compound is superior to fluoxastrobin; for apple ring rot, the inhibition rate of the compounds I-4 and I-17 is superior to that of positive control fluoxastrobin.

Example 3: the application of the isothiazole bisthiazolopyrimidine amine derivative I in preparing pesticide compositions is as follows:

the isothiazole-di-thiazole pyrimidine amine derivative I is used for preparing a pesticide composition, the composition contains the isothiazole-di-thiazole pyrimidine amine derivative I and an intermediate thereof as active ingredients, the mass percentage of the active ingredients is 0.1-99.9%, the mass percentage of solid or liquid auxiliary agents is 99.9-0.1%, and the composition further contains optional surfactant 0-50%.

Example 4: the application of the isothiazole bisthiazolopyrimidine amine derivative I in preparing the pesticide compound composition comprises the following steps:

the isothiazolopyrimidine amine derivative I and the intermediate thereof can be compounded with other commercial pesticides, namely, insecticides, acaricides, bactericides, antiviral agents or plant activators to prepare pesticide compound compositions, the compound compositions comprise the isothiazolopyrimidine amine derivative I and the intermediate thereof and commercial pesticides, namely, insecticides, acaricides, bactericides, antiviral agents or plant activators as active ingredients, and the weight percentage of the isothiazolopyrimidine amine derivative I and the intermediate thereof and other commercial pesticides, namely, insecticides, acaricides, bactericides, antiviral agents or plant activators is 1% -99% -1%, the weight percentage of the active ingredients is 0.1% -99.9%, the weight percentage of the active ingredients is 99.9% -0.1% of solid or liquid auxiliaries, and the weight percentage of the optional surfactant is 0% -50%.

Example 5: the application of the isothiazole-thiazolopyrimidine amine derivative I and the pesticide combination in the control of agricultural and forestry plant insect pests:

the isothiazole-benzothiazole pyrimidine amine derivative I is combined with any one or two of commercial pesticides to form an insecticidal composition for preventing and controlling insect pests of agriculture, forestry and horticultural plants, wherein the commercial pesticides are selected from the group consisting of: permethrin, ethofenprox, flumethrin, cyhalothrin, imidacloprid, nitenpyram imidaclothiz, thiacloprid, thiamethoxam, clothianidin, dinotefuran, collidine permethrin, ethofenprox, flumethrin, cyhalothrin, imidacloprid, nitenpyram, imidaclothiz, thiacloprid, thiamethoxam, clothianidin, dinotefuran, collidine, tolfenpyrad daphne, chlorfluazuron, polyfluorourea, flufenuron, bisfenuron fluazuron, oxazine, bistrifluron, furtebufenozide, tebufenozide, chlorfenozide, methomyl, chromafenozide, dichlorvos, quetiapine, pyridaphethione, leafhopper powder, carbaryl, pirimicarb, carbofuran, isoprocarb, cartap, fenobucarb, she Feisan, carbaryl, cartap, fenitrothion, hexythiazox, fenpyroximate, pyridaben, clofentezine, propargite, diafenthiuron, pymetrozine, spirodiclofen, spirotetramat, azocyclotin, buprofezin, monosultap, dimefon, chlorfenapyr, tetrachlorethamide, flufenamid, cyantraniliprole, chlorfenapyr, tolfenpyrad, pyrazinone, etoxazole, tebufenpyrad, flufenamid, pyridaben; the mass percentage of the isothiazole-thiazolopyrimidine amine derivative I in the insecticidal composition is 1% -90%, and the mass percentage of the isothiazole-thiazolopyrimidine amine derivative I to the commercial insecticide is 1% -99% -1%; the formulation of the insecticidal composition is selected from the group consisting of: seed treatment emulsions, aqueous emulsions, microemulsions, suspoemulsions, capsule suspensions, water-soluble granules, fine granules, soluble concentrates, cereals, blocky baits, granular baits, sheeted baits, concentrated baits, slow release blocks, electrostatic sprays, oil-in-water emulsions, aerosol cans, aerosol candles, aerosol cans, aerosol sticks, aerosol flakes, aerosol pellets, aerosols, ointments, hot aerosols, cold aerosols, solid/liquid mixed packages, liquid/liquid mixed packages, solid/solid mixed packages, paint, microgranules, tracing powders, oil suspensions, oil dispersible powders, concentrated gels, sprinkles, seed coatings, spreads, film forming oils, ultra low volume liquids, vapor release agents; the plant insect pest for which the insecticidal composition is suitable is selected from the group consisting of: spodoptera frugiperda, red spider, migratory locust, fomes officinalis, chinese rice locust, japanese Huang Jihuang, mole cricket, thrips oryzae, thrips tabaci, thrips pratensis, thrips oryzae, thrips katzenii, thrips mairei Jian Guan, white fly, bemisia tabaci, black tail leafhopper, dyer woad leaf hopper, cotton leafhopper, cerclage, brown planthopper, white-back planthopper, white planthopper, sugarcane horn planthopper, cotton aphid, wheat binary aphid, wheat long tube aphid, peach aphid sorghum aphid, radish aphid, meadow bug, sang Dun meadow bug, cerclage, meadow wax bug, red meadow bug, korean meadow bug, pear net bug, banana net bug, tendril bug, tiny flower bug, needle bug, red meadow bug, and red meadow bug the plant bug comprises Oryza sativa Linne, apolygus lucorum, hyriopsis schlegeli, hyriopsis sinensis, plutella xylostella, apolylis armyworm, phlebia xylostella, philippica armyworm, apolylis, apolytis sinensis, oryza sativa Linne, orthosiphon, and Orthosiphon moths, pink bollworms, sweet potato moths, plutella xylostellas, peach fruit borers, soybean fruit borers, apple leaf roller, brown leaf roller, yellow leaf roller, chilo suppressalis, pod borers, and corn borer, rice borer, cabbage borer, rice leaf roller, striped borer, cotton roll She Yeming, peach borer, armyworm, prodenia litura, rice borer fly, cotton budworm, beet armyworm, borer, cotton bollworm, ding point diamond-back, cotton bollworm, cotton boll moth, cotton bollworm, cotton boll moth, cotton tiger, cutworm, yellow cutworm, pirate, gypsy, sweet potato astromoth, bean astromoth, straight line rice butterfly, hidden line valley butterfly, citrus phoenix butterfly, yu bel phoenix butterfly, cabbage butterfly, ramie red vanity butterfly, ramie yellow vanity butterfly, bean genkwa, jin Xingbu nail, cuckoo-bark beetle, ear beetle, ditch needle worm, fine chest needle worm, valley bark beetle, black bark beetle, citrus gill worm, jin Yuanji butcher, yellow meal worm, black meal worm, red-yellow larch, hybrid larch, copper green ali tortoise, dark black tortoise, giant black gill tortoise, mulberry longhorn, star longhorn, orange-brown longhorn, peach-red longhorn beetle, great ape leaf worm, small ape leaf worm, yellow-head melon, yellow-curved striped flea beetle, green bean image, pea image, broad bean image, corn image, rice image, wheat leaf bee, pear fruit bee, yellow-banded cornflower, armyworm white star-shaped hornet, bollworm cantilever, cotton bollworm tooth-lip hornet, borer black spot wart, mosquito, fly, tabanus, wheat red-absorbing plasmach, wheat Huang Xi thick beetle, rice gall midge, citrus fruit fly, melon fruit fly, wheat She Hui, american leaf fly, bean stalk black fly, wheat straw fly, seed fly, onion fly, radish fly, umbrella-skirt, corn borer, myza fly, and insect; plants to which the insecticidal composition is applicable are selected from: rice, wheat, barley, oat, corn, sorghum, sweet potato, tapioca, soybean, netherlands, broad bean, pea, mung bean, cotton, mulberry, peanut, canola, sesame, sunflower, sugar beet, sugarcane, coffee, cocoa, ginseng, fritillaria, rubber, coconut, oil palm, sisal, tobacco, tomato, chilli, radish, cucumber, cabbage, celery, mustard, beet, rape, onion, garlic, watermelon, melon, cantaloupe, papaya, apple, citrus and peach, tea, wild herbs, bamboo shoots, hops, peppers, banana, papaya, orchid, bonsai.

Example 6: the application of the isothiazole-benzothiazole pyrimidine amine derivative I and the bactericide combination in preventing and controlling agricultural and forestry and gardening plant diseases:

the isothiazole-benzothiazole pyrimidine amine derivative I is combined with any one or two of commercial bactericides to form a bactericidal composition for preventing and controlling plant diseases of agriculture, forestry and gardening, wherein the commercial bactericides are selected from the group consisting of: benzothiadiazole, tiadinil, mefenamide, DL-beta-aminobutyric acid, isotiadinil, ribavirin, antofine, ningnanmycin or salicylic acid, cymoxanil, thiram, ziram, mancozeb, fosetyl-aluminum, thiophanate-methyl, chlorothalonil, cortisone, procymidone, fenpropidin, thiophanate-methyl, metalaxyl-M, flumorph, dimethomorph, high-efficiency metalaxyl, high-efficiency benalaxyl, dicyclopentadienyl-amine Sulfosamine, methanesulfonamide, thiaflufenamid, phyllostatin, cyclopropylamide, cycloflufenamid, cycloxaprid, cyromazine, silthiopham, carboxin, mefloxamide, mefenamid, flufenamid, furazamide, thifluzamide, boscalid, pyrimethanil, boscalid, isopyrazam, bixafen, fluopyram, epoxiconazole, fluxapyroxad, fluxad penflufen, ipratropium, fluoxastrobin amide, fluocinolone acetonide, mandipropamid, zoxamide, ethirimol, iprodione, azoxystrobin, dimoxystrobin, fluoxastrobin, trifloxystrobin, and other drugs kresoxim-methyl, phenoxymycylamine, trifloxystrobin, picoxystrobin, pyraclostrobin, trifloxystrobin, enestroburin, epoxiconazole, furfuryl, cyproconazole, difenoconazole, diniconazole, cyproconazole, trifloxystrobin, and trifloxystrobin kresoxim-methyl, phenoxymycylamine, orysastrobin, picoxystrobin, pyraclostrobin, trifloxystrobin, enoxystrobin, trifloxystrobin, pyraclostrobin, trifloxystrobin, the composition comprises the components of the alkene oxime amine, the epoxiconazole, the furfuryl myclobutanil, the cyproconazole, the difenoconazole, the diniconazole, famoxadone, boscalid, hymexazol, oxadixyl, ethaboxam, hymexazol, xin Sai ketone, thiocyanogen, dodecorph, fenpropimorph, tridemorph, fenpiclonil, fludioxonil, fluazinam pyripyroxime, cyprodinil, fluopicolide, boscalid, cyprodinil, fluoxastrobin, azohydrazone, cyprodinil, pyrimethanil, flubenyrimidine, fenamic acid, dithianon ethoxyquin, hydroxyquinoline, propoxyquinoline, phenoxyquinoline, diethofencarb, iprovalicarb, benthiavalicarb, propamocarb, thiodicarb, diphenfos, iprobenfos, piroxicam, tolclofos-methyl, blasticidin, kasugamycin, polyoxin, validamycin, streptomycin, metalaxyl, furalaxyl, benalaxyl, furalamide, carbendazim, benomyl, thiophanate-methyl, triadimefon bupirimate, dimethirimol, ethirimol, captan, folpet, captan, benomyl, fluocinolone acetochlor, dimethachlon, chlorothalonil, isoprothiolane, metrafenib, quintozene, propineb, aluminum triethyl phosphonate, sulfur, bordeaux, copper sulfate, copper oxychloride, cuprous oxide, copper hydroxide, metrafenone, pencycuron, pyridalyl, cloquintocet, spiroxamine, tricyclazole, zindolac, biguanide octopamine, chlorethamine, benomyl, tosulfamet, indoxyl, diussodium, fluquintoxyl, probenazole, bronopol, methyl iodide, valicarb, diuron, isopropyl ether, fosthiazate, fenphos, carbosulfan, fenphos, thiofide, thiofluoride, dichloropropene, ipratropium, probenazole; the total mass percentage of the isothiazole-di-thiazolopyrimidine amine derivative I in the sterilization composition is 1% -90%, and the weight percentage of the isothiazole-di-thiazolopyrimidine amine derivative I and the commercial sterilization agent is 1% -99% -1%; the dosage form of the bactericidal composition is selected from the group consisting of: seed treatment emulsions, aqueous emulsions, microemulsions, suspoemulsions, capsule suspensions, water-soluble granules, fine granules, soluble concentrates, cereals, blocky baits, granular baits, sheeted baits, concentrated baits, slow release blocks, electrostatic sprays, oil-in-water emulsions, aerosol cans, aerosol candles, aerosol cans, aerosol sticks, aerosol flakes, aerosol pellets, aerosols, ointments, hot aerosols, cold aerosols, solid/liquid mixed packages, liquid/liquid mixed packages, solid/solid mixed packages, paint, microgranules, tracing powders, oil suspensions, oil dispersible powders, concentrated gels, sprinkles, seed coatings, spreads, film forming oils, ultra low volume liquids, vapor release agents; plant diseases for which the fungicidal composition is suitable are selected from: seedling blight, tomato root rot, potato late blight, tobacco black shank, millet powdery mildew, grape downy mildew, lettuce downy mildew, cucumber anthracnose; plants for which the fungicidal composition is suitable are selected from: rice, wheat, barley, oat, corn, sorghum, sweet potato, tapioca, soybean, netherlands, broad bean, pea, mung bean, cotton, mulberry, peanut, canola, sesame, sunflower, sugar beet, sugarcane, coffee, cocoa, ginseng, fritillaria, rubber, coconut, oil palm, sisal, tobacco, tomato, chilli, radish, cucumber, cabbage, celery, mustard, beet, rape, onion, garlic, watermelon, melon, cantaloupe, papaya, apple, citrus and peach, tea, wild herbs, bamboo shoots, hops, peppers, banana, papaya, orchid, bonsai.

Example 7: the application of the isothiazole-thiazolopyrimidine amine derivative I and the anti-plant virus agent combination in preventing and controlling the virus diseases of agriculture and forestry and gardening plants:

the isothiazole-benzothiazole pyrimidine amine derivative I is combined with any one or two of commercial antiviral agents to form an antiviral composition for preventing and treating viral diseases of agriculture, forestry and horticultural plants, wherein the commercial antiviral agents are selected from the group consisting of: benzothiadiazole, tiadinil, isothiabendazole DL-beta-aminobutyric acid, N-cyanomethyl-2-chloroisonicotinamide, allylisothiazole, ribavirin, antofine, ningnanmycin, methimazole or salicylic acid, pyrimidomycin, dichloroisonicotinic acid, allylisothiazole, validamycin, moroxydine hydrochloride; the total mass percentage of the isothiazole-thiazolopyrimidine amine derivative I in the antiviral composition is 1% -90%, and the mass percentage of the isothiazole-thiazolopyrimidine amine derivative I to the commercial plant virus resisting agent is 1% -99% -1%; the antiviral composition is formulated in a dosage form selected from the group consisting of: seed treatment emulsions, aqueous emulsions, microemulsions, suspoemulsions, capsule suspensions, water-soluble granules, fine granules, soluble concentrates, cereals, blocky baits, granular baits, sheeted baits, concentrated baits, slow release blocks, electrostatic sprays, oil-in-water emulsions, aerosol cans, aerosol candles, aerosol cans, aerosol sticks, aerosol flakes, aerosol pellets, aerosols, ointments, hot aerosols, cold aerosols, solid/liquid mixed packages, liquid/liquid mixed packages, solid/solid mixed packages, paint, microgranules, tracing powders, oil suspensions, oil dispersible powders, concentrated gels, sprinkles, seed coatings, spreads, film forming oils, ultra low volume liquids, vapor release agents; the virus diseases prevented and treated by the antiviral composition are selected from the following: rice dwarf, yellow dwarf, stripe disease, tomato fern leaf virus, pepper mosaic virus, tobacco vein necrosis virus, maize dwarf mosaic, cauliflower mosaic virus, citrus virus, cymbidium mosaic virus, cymbidium ringspot virus; the plants for which the antiviral composition is used for control are selected from: rice, wheat, barley, oat, corn, sorghum, sweet potato, tapioca, soybean, netherlands, broad bean, pea, mung bean, cotton, mulberry, peanut, canola, sesame, sunflower, sugar beet, sugarcane, coffee, cocoa, ginseng, fritillaria, rubber, coconut, oil palm, sisal, tobacco, tomato, chilli, radish, cucumber, cabbage, celery, mustard, beet, rape, onion, garlic, watermelon, melon, cantaloupe, papaya, apple, citrus and peach, tea, wild herbs, bamboo shoots, hops, peppers, banana, papaya, orchid, bonsai.

Example 8: the application of the isothiazole-benzothiazole pyrimidine amine derivative I and acaricide combination in preventing and controlling agricultural and forestry and gardening plant mites is that:

the isothiazole-benzothiazole pyrimidine amine derivative I is combined with any one or two of commercial acaricides to form an acaricide composition which is used for preventing and controlling agricultural, forestry and horticultural plant acarid, wherein the commercial acaricide is selected from the group consisting of: dichlorvos, heptylphosphines, fast-acting phoxims, dibromophoxims, pyrimidophos, chlormethiphos, ethion, chlorfenphos, valphos, methyl pyrimidothioate, quetiaphos, triazamate, chlorpyrifos, fenphos, flumethrin, bifenthrin, cyhalothrin, lambda-cyhalothrin, fenpropathrin, flumethrin, cyfluthrin, bromfluthrin, bifenazate, benfuracarb, butanone, carbofuran, mefenoxam, benomyl, chlormefos, ding Liusu carbofuran acarb, benzyl benzoate, bromopropylate, cyflumetofen, chloranil, flumetofen, flufenoxuron, liuyangmycin, chongmycin, thuringiensis, acaricide, liuyangmycin, avermectin, doramectin, eprinomectin, ivermectin, siramectin, moxidectin, pyrethrin, nicotine, matrine, azadirachtin, rotenone, tebufenpyrad, pyridaben, fenpyroximate, clofentezine, propargite, hexythiazox, spirodiclofen, azoxystrobin, acaricide, clofentezine; the total mass percentage of the isothiazole-di-thiazolopyrimidine amine derivative I in the acaricidal composition is 1% -90%, and the mass percentage of the isothiazole-di-thiazolopyrimidine amine derivative I to the commercial acaricide is 1% -99% -1%; the formulation of the acaricidal composition is selected from the group consisting of: seed treatment emulsions, aqueous emulsions, microemulsions, suspoemulsions, capsule suspensions, water-soluble granules, fine granules, soluble concentrates, cereals, blocky baits, granular baits, sheeted baits, concentrated baits, slow release blocks, electrostatic sprays, oil-in-water emulsions, aerosol cans, aerosol candles, aerosol cans, aerosol sticks, aerosol flakes, aerosol pellets, aerosols, ointments, hot aerosols, cold aerosols, solid/liquid mixed packages, liquid/liquid mixed packages, solid/solid mixed packages, paint, microgranules, tracing powders, oil suspensions, oil dispersible powders, concentrated gels, sprinkles, seed coatings, spreads, film forming oils, ultra low volume liquids, vapor release agents; the mite injury prevented and controlled by the mite-killing composition is selected from the following components: the mites are selected from the group consisting of Tetranychidae, phyllophaceae, fusarium, goiter, tetranychus, and goiter, and are world agricultural, forestry, horticultural, and hygiene mites; the plants for which the acaricidal composition is used for control are selected from the group consisting of: rice, wheat, barley, oat, corn, sorghum, sweet potato, tapioca, soybean, netherlands, broad bean, pea, mung bean, cotton, mulberry, peanut, canola, sesame, sunflower, sugar beet, sugarcane, coffee, cocoa, ginseng, fritillaria, rubber, coconut, oil palm, sisal, tobacco, tomato, chilli, radish, cucumber, cabbage, celery, mustard, beet, rape, onion, garlic, watermelon, melon, cantaloupe, papaya, apple, citrus and peach, tea, wild herbs, bamboo shoots, hops, peppers, banana, papaya, orchid, bonsai.

Industrial applicability

The invention provides isothiazole bithiazolopyrimidine amine derivatives. The derivative can regulate and control the biological activity of plant pests and plant pathogens in agriculture, gardening and sanitation and forestry, can be used for killing insects, mites, bacteria and plant viruses in the agricultural field, the gardening field and the forestry field, induces plants to generate disease resistance, and has good economic value and application prospect.

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TABLE 2 bacteriostatic Activity of the thiadiazolopyrimidinone derivatives I of the invention (inhibition rate 50. Mu.g/ml/%)

Sequence number	Numbering of compounds	R.s	G.z	B.c	A.s	S.s	P.p	C.a
									1	I-1	5.4	21.1	44.9	17.8	11.2	16.3	22.2
2	I-2	6.9	23.5	36.9	19.1	9.2	17.7	15.7
									3	I-3	2.1	20.4	36.8	15.8	7.1	15.2	5.5
4	I-4	66.77	56.6	53.1	68.2	35.7	48.4	65.4
									5	I-5	58.6	31.5	27.1	10.7	17.8	26.6	46.2
6	I-6	29.1	27.5	45.2	21.0	13.9	21.7	25.4
									7	I-7	34.7	22.4	28.7	17.7	14.4	18.4	23.2
8	I-8	50.2	29.3	41.2	14.0	6.9	9.2	12.7
									9	I-9	46.4	24.2	48.4	22.9	10.8	11.4	21.9
10	I-10	12.1	11.7	33.1	7.7	2.4	12.2	22.8
									11	I-11	5.7	8.2	25.4	10.3	6.3	10.1	12.1
12	I-12	21.1	7.7	37.1	7.1	20.4	9.0	7.4
									13	I-13	66.2	24.6	41.7	30.8	27	21.9	44.2
14	I-14	67.1	16.5	47.3	25.6	11.3	13.6	40.4
									15	I-15	70.0	11.5	40.4	25.6	12.1	9.5	20.8
16	I-16	52.8	33.4	51.9	33.5	20.8	8.2	40.6
									17	I-17	78.4	53.6	46.8	52.2	52.2	48.2	50.1
18	I-18	69.3	26.5	51.6	33.0	8.4	10.5	34.4
									19	I-19	79.1	43.4	50.1	38.7	34.6	41.1	48.8
20	I-20	61.2	47.7	49.9	35.1	39.7	31.4	46.4
									21	I-21	33.4	18.6	18.9	14.3	26.1	19.7	37.4
22	I-22	18.5	3.7	85.2	26.6	5.9	5.3	12.2
									23	I-23	43.4	22.9	50.1	24.6	12.4	11.6	31.1
24	I-24	21.2	19.1	34.3	29.8	3.6	3.2	37.7
									20	Fluoxamide	74.0	48.2	44.0	55.3	44.7	39.1	66.8

A.s: the Latin name of the early blight bacteria of tomato is: alternaria solani, b.c: the Latin name of the Botrytis cinerea is: botrytis cinerea, C.a: peanut brown spot germ, its latin name is: cercospora arachidicola, G.z: the gibberella wheat germ has the Latin name: gibberella zeae, P.p: apple ring rot germ, its latin name is: physalospora piricola, P.s: rhizoctonia solani, its Latin name is: pellicularia sasakii, S.s: sclerotinia sclerotiorum, the Latin name of which is: sclerotinia sclerotiorumalis.

Claims (7)

1. An isothiazole bithiazolopyrimidine amine derivative is characterized by having the following structural formula:

wherein R is ¹ Selected from: 4-fluorobenzenePhenyl, cyclopropyl, 4-isopropylphenyl, 2-difluoroethyl, 4-methoxybenzyl, 4-methoxyphenyl, 3-ethylpyridine, 2-fluorophenylethyl, 2-fluorobenzyl, 2-chlorobenzyl, 2-methoxybenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3-chlorobenzyl, 2-methylbenzyl, ethyl, benzyl, cyclopentyl, 2-trifluoromethylbenzyl.

2. The specific synthetic route and method of isothiazole bisthiazolopyrimidinamine derivative I according to claim 1 is as follows:

the definition of the substituent is as in claim 1, and the specific synthesis method comprises the following steps:

A. preparation of compound 2:

dropwise adding a catalytic amount of N, N-dimethylformamide into the compound 1 and thionyl chloride under stirring at room temperature, stirring overnight at room temperature, removing thionyl chloride under reduced pressure after the reaction is finished, washing with water, extracting with ethyl acetate for three times, washing an organic phase with saturated sodium chloride solution for three times, drying a combined organic layer with anhydrous sodium sulfate, concentrating a filtrate to remove a solvent, and performing column chromatography with pure dichloromethane as an eluent to obtain a purified compound 2;

B. preparation of Compound 4:

adding carbon disulfide into the compound 3 and absolute methanol under stirring at room temperature, heating and refluxing to react until the reaction is finished, standing, cooling, and carrying out suction filtration to obtain a solid, and recrystallizing a crude product with ethanol to obtain a purified compound 4;

C. preparation of compound 5:

adding the compound 2 and water into a round-bottom flask, sequentially adding the compound 4, anhydrous potassium carbonate and potassium iodide under stirring at room temperature, heating and refluxing the reaction system to react until TLC monitoring reaction is finished, cooling to room temperature, filtering to obtain solid, and recrystallizing the crude product with ethanol to obtain a purified compound 5;

D. preparation of compound 7:

dissolving the compound 5 in N, N-dimethylformamide, adding the N-dimethylformamide into a round-bottom flask, stirring at room temperature, sequentially adding triethyl orthoformate and p-toluenesulfonic acid, heating for reaction until TLC monitoring is finished, cooling to room temperature, removing most of N, N-dimethylformamide in the system under reduced pressure, washing with water to remove the N, N-dimethylformamide, extracting an organic phase with dichloromethane, washing with saturated sodium chloride solution, merging the organic phases, drying with anhydrous sodium sulfate, removing anhydrous sodium sulfate by suction filtration, concentrating the filtrate to remove the solvent, and carrying out column chromatography with dichloromethane/anhydrous methanol eluent to obtain a purified compound 7;

E. preparation of Compound 8:

dissolving the compound 7 in phosphorus oxychloride, adding the phosphorus oxychloride into a round-bottom flask, reacting, stirring, heating, reacting until TLC monitoring reaction is finished, cooling, slowly dripping the reaction liquid into ice water, precipitating a large amount of solid, filtering out the solid under pressure, and performing column chromatography by using pure dichloromethane as an eluent to obtain a purified compound 8;

F. preparation of Compound I:

adding a compound 8 and absolute ethyl alcohol into a round-bottom flask, stirring at room temperature, sequentially adding triethylamine and substituted amine, heating and refluxing the system to react until TLC monitoring reaction is finished, removing most absolute ethyl alcohol under reduced pressure, adding water, extracting with dichloromethane, combining organic layers, washing the organic layers with water, washing with saturated saline, adding anhydrous sodium sulfate for drying, filtering out anhydrous sodium sulfate solid, removing solvent in filtrate under reduced pressure, and performing column chromatography by using dichloromethane/absolute methanol as eluent to obtain the purified compound I.

3. Use of isothiazole bisthiazolopyrimidinamine derivatives I as defined in claim 1 for the preparation of agricultural fungicides.

4. An agricultural fungicidal composition comprising the isothiazolo-pyrimidamine derivative I of claim 1 and an intermediate for preparing an agricultural fungicidal composition comprising the isothiazolo-pyrimidamine derivative I of claim 1 as an active ingredient in an amount of 0.1 to 99.9% by weight, 99.9 to 0.1% by weight of a solid or liquid adjuvant, and optionally 0 to 25% by weight of a surfactant.

5. An agricultural sterilization compound composition comprises the isothiazole-combined pyrimidine amine derivative I and other commercial bactericides as active ingredients, wherein the weight percentage of the isothiazole-combined pyrimidine amine derivative I to the other commercial bactericides is 1 to 99 percent, the weight percentage of the active ingredients is 1 to 99 percent, and the weight percentage of the active ingredients is 99 to 1 percent of solid or liquid auxiliary agents.

6. An agricultural insecticidal and acaricidal compound composition comprises the isothiazole-pyrimidamine derivative I as an active ingredient and other commercial insecticidal and acaricidal compounds, wherein the proportion of the isothiazole-pyrimidamine derivative I to the other commercial insecticidal and acaricidal compounds is 1% -99% -1% by mass, and the content of the active ingredient is 1% -99% by weight and 99% -1% by weight of solid or liquid auxiliary.

7. An anti-plant virus agent compound composition, which comprises the isothiazole-thiazole pyrimidine amine derivative I and other commercial anti-plant virus agents as active ingredients, wherein the proportion of the isothiazole-thiazole pyrimidine amine derivative I and the other commercial anti-plant virus agents is 1 to 99 percent by mass, the content of the active ingredients is 1 to 99 percent by weight, and the content of the active ingredients is 99 to 1 percent by weight of solid or liquid auxiliary agent.