Thiazole methylpyridine amine compounds and preparation methods and applications thereof

Abstract

The present invention discloses a thiazole methylpyridine amine compound represented by formula (I) and a preparation method and application thereof. 1 , R 2 , R 3 and R 4 The compounds of formula (I) of the present invention have bactericidal and insecticidal biological activities, especially high activity against Botrytis cinerea.

Description

Technical Field

[0001] The present invention belongs to the field of bactericides and insecticides, and specifically relates to thiazolylmethylpyridinamine compounds having bactericidal and insecticidal biological activities and a preparation method thereof, a bactericidal and insecticide composition containing the compounds, and uses and methods of using the compounds to control harmful pathogens and pests. Background Art

[0002] The prevention and control of harmful pathogens and pests is very important in the process of achieving efficient agriculture, and is also important in forestry, animal husbandry, sideline production, fishery and public health. Although there are many harmful pathogens and pest control agents on the market, due to the continuous expansion of the market, foreign harmful pathogens and pests, harmful pathogens and pests resistance, drug life and drug economy, and people's increasing attention to the environment and beneficial organisms, scientists need to continue research and develop new safe, efficient, economical and new fungicides and insecticides with new mechanisms of action.

[0003] CN201110443914.1 and CN030797924.9, as the closest prior art, respectively disclose thiazolidinylpyridinamine compounds, and found that some compounds have high fungicidal activity, such as compound 05 (D1) in CN201110443914.1 and compound 07 (D2) in CN030797924.9, which have higher fungicidal activity against targets such as gray mold fungi than commercial control fungicides such as methyl thiophanate and procymidone. In order to further improve the biological activity of thiazolidinylpyridinamine compounds, the applicant has been committed to the research of pyridinamine compounds, especially thiazolidinylpyridinamine compounds. Through research, the applicant found that a class of novel structural thiazolylmethylpyridinamine compounds have high biological activity. Compared with the prior art, the compounds of the present invention not only have significantly different structural characteristics, but also these structural differences make the compounds of the present invention have a more convenient preparation method, a broader spectrum and more excellent biological activity. For example, the compound 02 of the present invention shows higher insecticidal and fungicidal activity than D1 and D2.

[0004] Summary of the invention

[0005] The present invention provides a biologically active thiazole methylpyridine amine compound represented by formula (I):

[0006]

[0007] in:

[0008] IR represents halogen, methoxy, dimethylamino, allyloxy or propargyloxy;

[0009] II.R1 represents methyl, ethyl or cyclopropylmethyl;

[0010] III.R 2 , R 3 and R 4 are the same or different and represent hydrogen, halogen, methyl, ethyl, propyl, butyl, R 3 and R 4 It can also be linked to form cyclopropyl, cyclobutyl or cyclopentyl;

[0011] In the above definition of compound (I), the terms used, whether used alone or in compound words, represent the following substituents:

[0012] Halogen: refers to fluorine, chlorine, bromine or iodine;

[0013] Alkyl: refers to a straight chain or branched chain alkyl group.

[0014] The compound represented by formula (I) of the present invention can form geometric isomers (different configurations are represented by Z and E, respectively) due to the carbon-carbon double bond and carbon-nitrogen double bond connecting different substituents. The present invention includes Z-isomers and E-isomers and mixtures thereof in any proportion.

[0015] The compounds represented by formula (I) of the present invention may form stereoisomers (different configurations are represented by R and S, respectively) due to different substituents attached to the carbon or nitrogen atoms. The present invention includes R-isomers and S-isomers and mixtures thereof in any proportion.

[0016] The compounds represented by formula (I) of the present invention not only involve geometric isomers (Z / E formula) and stereoisomers (R / S formula), but also involve mixtures of geometric isomers (Z and / or E) and stereoisomers (R and / or S) in any proportion.

[0017] The preferred compounds of the present invention are: wherein:

[0018] IR represents methoxy, dimethylamino, allyloxy or propargyloxy;

[0019] II.R 1 represents a methyl or ethyl group;

[0020] III.R 2 , R 3 and R 4 are the same or different and represent hydrogen, methyl or ethyl.

[0021] The further preferred compounds of the present invention are: wherein:

[0022] IR represents methoxy or propargyloxy;

[0023] II.R1 represents a methyl or ethyl group;

[0024] III.R 2 , R 3 and R 4 are the same or different and represent hydrogen, methyl or ethyl.

[0025] A further preferred compound of the present invention is: wherein:

[0026] IR represents methoxy or propargyloxy;

[0027] II.R 1 represents ethyl;

[0028] III.R 2 , R 3 and R 4 are the same or different and represent hydrogen or methyl.

[0029] Particularly preferred compounds of formula (I) according to the present invention are:

[0030] N-methyl-N-((2-methylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine (01);

[0031] N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine (02);

[0032] N-Cyclopropylmethyl-N-((2-methylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine (03);

[0033] N-methyl-N-((2-ethylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine (04);

[0034] N-ethyl-N-((2-ethylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine (05);

[0035] N-methyl-N-((2-propylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine (06);

[0036] N-ethyl-N-((2-propylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine (07);

[0037] N-methyl-N-((2-isopropylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine (08);

[0038] N-ethyl-N-((2-isopropylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine (09);

[0039] N-methyl-N-((2-cyclopropylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine (10);

[0040] N-ethyl-N-((2-cyclopropylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine (11);

[0041] N-methyl-N-((2-trifluoromethylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine (12);

[0042] N-ethyl-N-((2-trifluoromethylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine (13);

[0043] N-methyl-N-((2-methylthiazol-5-yl)methyl)-6-allyloxy-3-nitropyridin-2-amine (14);

[0044] N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-allyloxy-3-nitropyridin-2-amine (15);

[0045] N-methyl-N-((2-methylthiazol-5-yl)methyl)-6-propargyloxy-3-nitropyridin-2-amine (16);

[0046] N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-propargyloxy-3-nitropyridin-2-amine (17);

[0047] N-methyl-N-((2-methylthiazol-5-yl)methyl)-6-dimethylamino-3-nitropyridin-2-amine (18);

[0048] N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-dimethylamino-3-nitropyridin-2-amine (19);

[0049] N-Ethyl-N-((2-methylthiazol-5-yl)methyl)-6-chloro-3-nitropyridin-2-amine (20).

[0050] Although the compounds of formula (I) of the present invention and some compounds disclosed in the prior art both belong to the class of thiazolidinylpyridineamine compounds, they have significantly different structural features compared with the prior art. And the differences in these structural features make the compounds of formula (I) of the present invention have a more convenient preparation method, a wider spectrum and more excellent biological activity.

[0051] The compound of formula (I) of the present invention shows excellent activity against a variety of pathogens in agriculture or other fields, and also shows high activity against pests. Therefore, the technical scheme of the present invention also includes the use of the compound of formula (I) in agriculture or other fields as a fungicide or insecticide.

[0052] The present invention also relates to a composition for controlling harmful pathogens and pests, comprising a biologically effective amount of a compound of formula (I) and at least one additional agent selected from a surfactant, a solid diluent and a liquid diluent.

[0053] The present invention also relates to a composition for controlling harmful pathogens and pests, comprising a biologically effective amount of a compound of formula (I) and an effective amount of at least one other biologically active compound or preparation.

[0054] The present invention also relates to a method for controlling harmful pathogens and pests, comprising contacting the harmful pathogens, pests or their environment with a biologically effective amount of a compound of formula (I). It also relates to a method for controlling harmful pathogens and pests, wherein the harmful pathogens, pests or their environment are contacted with a biologically effective amount of a compound of formula (I) or a mixture containing the compound of formula (I) and a biologically effective amount of at least one other compound or formulation to control the harmful pathogens and pests.

[0055] The compounds of formula (I) of the present invention have broad-spectrum activity at a dosage of 15-5000 g of active ingredient / hectare: some compounds can be used to control harmful pathogens and pests; and some compounds have high biological activity against certain targets, so that good effects can be obtained at very low dosages.

[0056] The preferred compositions of the present invention are compositions containing the preferred compounds described above. The preferred methods are methods using the preferred compounds described above.

[0057] The compounds of formula (I) of the present invention have biological activity and some of the compounds have good biological activity. In particular, they show activity in the prevention and treatment of agricultural, horticultural, flower and sanitary pathogens. The harmful organisms described herein include, but are not limited to, and do not limit the present invention in any way.

[0058] The compounds of formula (I) of the present invention can be used to prevent and control the following diseases:

[0059] Oomycete diseases, such as downy mildew, white rust, damping-off, cotton rot, blight, late blight, etc.;

[0060] Deuteromycin diseases, such as wilt, root rot, damping-off, anthracnose, verticillium wilt, black spot, gray mold, brown spot, black spot, leaf spot, early blight, ring rot, leaf blight, stem base rot, etc.

[0061] Basidiomycete diseases, such as rust and smut;

[0062] Ascomycete diseases, such as powdery mildew, sclerotinia (flax sclerotinia, rape sclerotinia, soybean sclerotinia, peanut sclerotinia, tobacco sclerotinia, pepper sclerotinia, eggplant sclerotinia, bean sclerotinia, pea sclerotinia, cucumber sclerotinia, bitter melon sclerotinia, wax gourd sclerotinia, watermelon sclerotinia, celery sclerotinia), black spot, etc.;

[0063] The compounds of formula (I) of the present invention can be used to control the following pests: aphids, pea aphids, cotton aphids, apple aphids and the like.

[0064] In particular, the compounds of the present invention have good activity against Sclerotinia sclerotiorum, Botrytis cinerea and the like at relatively low dosages.

[0065] Due to their positive properties, the above compounds can be advantageously used for protecting agriculturally and horticulturally important crops, livestock and breeding stock, as well as the environment frequented by humans from pathogens and pests.

[0066] The amount of compound used to obtain the desired effect will vary depending on factors such as the compound used, the pre-protectant, the type of pest, the degree of infestation, climatic conditions, the method of application, and the formulation applied.

[0067] The present invention also includes a fungicide and insecticide composition with the compound of formula (I) as an active component. The weight percentage of the active component in the fungicide and insecticide composition is between 0.5-99%. The fungicide and insecticide composition also includes a carrier acceptable for agriculture, forestry and hygiene.

[0068] The composition of the present invention can be applied in the form of a preparation. The compound of formula (I) of the present invention is dissolved or dispersed in a carrier as an active ingredient or formulated into a preparation so that it is easier to disperse when used as a fungicide or insecticide. In these compositions, at least one liquid or solid carrier is added, and a suitable surfactant can be added when necessary.

[0069] For certain applications, such as in agriculture, one or more other pesticides, fungicides, herbicides, plant growth regulators or fertilizers may be added to the fungicidal and insecticidal composition of the present invention, thereby producing additional advantages and effects.

[0070] The agricultural preparations with the compound of formula (I) of the present invention as the active ingredient can be made into any desired dosage form such as dry compressed granules, easy-flowing mixtures, granules, wettable powders, water-dispersible granules, emulsifiable concentrates, dusts, powdery concentrates, microemulsions, suspensions, emulsifiable oils, aqueous emulsions, soluble liquids, aqueous solutions, dispersible liquids, suitable adjuvants include carriers (diluents) and other adjuvants such as spreaders, emulsifiers, wetting agents, dispersants, adhesives and decomposers. These preparations contain the compound of formula (I) of the present invention mixed with an inert, pharmacologically acceptable solid or liquid diluent.

[0071] The composition examples of the present invention can also be made into any desired dosage form such as dry compressed granules, easy flowable mixtures, granules, wettable powders, water-dispersible granules, emulsifiable concentrates, dusts, powder concentrates, microemulsions, suspensions, emulsifiable concentrates, aqueous emulsions, soluble liquids, aqueous solutions, dispersible liquids, suitable adjuvants include carriers (diluents) and other adjuvants such as spreaders, emulsifiers, wetting agents, dispersants, adhesives and decomposers. These preparations contain a compound of formula (I) of the present invention mixed with an inert, pharmacologically acceptable solid or liquid diluent.

[0072] It should be understood that various changes and modifications can be made within the scope of the present invention as defined by the claims.

[0073] The present invention is further described below using some of the compounds of formula (I) listed in Table 1 and Table 2, but the present invention is not limited thereto. The melting points given in the present invention are all uncorrected. When the compounds of formula (I) synthesized by the present invention are viscous solids, some of the viscous solids will solidify into non-viscous solids after being left standing. When the compounds of formula (I) synthesized by the present invention are viscous liquids, some of the viscous liquids will solidify after being left standing. The molecular ion peaks of the compounds in Table 1 can be observed in LC-Mass (Agilent 1260 / 6120) and / or GC-Mass (7890-5975C). The compounds in Table 1 1 H NMR (Varian INOVA-300 spectrometer or Varian INOVA-400 spectrometer) uses tetramethylsilane (TMS) as the internal standard and deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO) as the solvent.

[0074] Table 1

[0075]

[0076] Table 2

[0077]

[0078]

[0079]

[0080] The compound of formula (I) of the present invention can be prepared by the reaction formula 1 shown below, II in the reaction formula 1 can be prepared by the reaction formula 2 shown below, III in the reaction formula 1 can be prepared by the reaction formula 3 shown below, or can be purchased, IV in the reaction formula 1, RH and R in the reaction formula 1NH2HL can be purchased or prepared by referring to relevant literature. The substituents in the reaction formula are as defined above unless otherwise specified. L represents a leaving group such as a halogen or a sulfonate.

[0081] Reaction formula 1-1:

[0082]

[0083] Reaction 1-2:

[0084]

[0085] Reaction 2:

[0086]

[0087] Reaction 3:

[0088]

[0089] The compound of formula (I) can be prepared as follows (reaction formula 1-1): in a solvent such as dichloromethane, dichloroethane, acetonitrile, toluene, xylene, ethyl acetate, acetone, N,N-dimethylformamide, tetrahydrofuran or dioxane, in the presence of a base such as sodium hydride, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium hydroxide, potassium carbonate, triethylamine, pyridine or diisopropylethylamine, at 5°C to the reflux temperature of the system, the compound represented by formula (II) and the compound represented by formula (III) are reacted to obtain the compound of formula (I).

[0090] The compound of formula (I) can also be prepared as follows (reaction formula 1-2): in a solvent such as dichloromethane, dichloroethane, acetonitrile, toluene, xylene, ethyl acetate, acetone, N,N-dimethylformamide, tetrahydrofuran or dioxane, in the presence of a base such as sodium hydride, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, pyridine or diisopropylethylamine, at 5°C to the reflux temperature of the system , react the compound of formula (II) with the compound of formula (IV) to obtain the compound of formula (V); in a solvent such as methanol, ethanol, water, tetrahydrofuran or dioxane, in the absence of a base or in the presence of a suitable base, at a temperature between 5°C and the reflux temperature of the system, react the compound of formula (V) with RH to obtain the compound of formula (I); the suitable base is selected from sodium hydride, sodium hydroxide, NaR, KR, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, pyridine or diisopropylethylamine.

[0091] The compound of formula (II) can be prepared as follows (reaction formula 2): in a solvent selected from the group consisting of dichloromethane, chloroform, water, methanol, ethanol, dichloroethane, acetonitrile, toluene, xylene, ethyl acetate, acetone, N,N-dimethylformamide, tetrahydrofuran or dioxane or a mixture of any two thereof, in the presence of a base such as sodium hydride, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, pyridine or diisopropylethylamine, at a temperature between 5°C and the reflux temperature of the system, reacting the compound of formula (VI) with R 1 After NH2HL is reacted for 0.5-5.0 h, the reaction mixture is reacted with a suitable reducing agent such as sodium borohydride, potassium borohydride, borane or hydrogen at 0°C to the reflux temperature of the system to obtain the compound of formula (II).

[0092] The compound of formula (III) can be prepared as follows (reaction formula 3): in a mixed solvent of one or any two of methanol, ethanol, RH, water, tetrahydrofuran or dioxane, at 5°C to the reflux temperature of the system, in the absence of a base or a suitable base, a compound of formula (IV) is reacted with RH to obtain a compound of formula (III), wherein the suitable base is selected from sodium hydride, sodium hydroxide, NaR, KR, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, pyridine or diisopropylethylamine.

[0093] The specific synthesis method is described in more detail in the following examples.

[0094] The present invention is further described below in conjunction with the examples, but the present invention is not limited thereto, and the yields in the examples are not optimized. DETAILED DESCRIPTION

[0095] Synthesis Example

[0096] Example 1 This example illustrates the preparation of compound 01 in Table 1 (Method A)

[0097]

[0098] A mixture of N-((2-methylthiazol-5-yl)methyl)methylamine hydrochloride (0.10 mol), potassium carbonate (0.05 mol) and ethanol (35 mL) was stirred at room temperature for 0.5-1.5 h, and then 2-methylthiazole-5-carboxaldehyde (0.08 mol) was added dropwise, and the stirring was continued for 1-2 h after the addition was completed. Sodium borohydride (0.10 mol) was added to the reaction mixture in batches under ice-water cooling and stirring conditions, and the stirring was continued until the reaction was complete after the addition. The reaction mixture was poured into an appropriate amount of ice brine, extracted with ethyl acetate, and the organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 9.86 g of the title compound, which was directly used in the next step reaction.

[0099] N-methyl-N-((2-methylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridine-2-amine 2-chloro-6-methoxy-3-nitropyridine (0.01 mol), N-((2-methylthiazol-5-yl)methyl)methylamine (0.01 mol), potassium carbonate (0.01 mol) and N,N-dimethylformamide (15 mL) were stirred at 25-50°C to react until completion. The reaction mixture was poured into an appropriate amount of ice brine, extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound, which was separated and purified by vacuum column chromatography with ethyl acetate and petroleum ether to obtain 1.82 g of the title compound as a yellow solid, with a melting point of 114.2-114.8°C.

[0100] Example 2 This example illustrates the preparation of compound 01 in Table 1 (Method B)

[0101]

[0102] N-methyl-N-((2-methylthiazol-5-yl)methyl)-6-chloro-3-nitropyridine-2-amine 2,6-dichloro-3-nitropyridine (0.05 mol), N-(2-methylthiazol-5-ylmethyl)methylamine (0.05 mol), potassium carbonate (0.05 mol) and N,N-dimethylformamide (75 mL) were stirred at room temperature until the reaction was complete. The reaction mixture was poured into an appropriate amount of ice brine, extracted with ethyl acetate, and the organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 13.12 g of the title compound, which was directly used in the next step.

[0103] N-methyl-N-((2-methylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridine-2-amine was dried at room temperature and stirred. A solution of N-methyl-N-((2-methylthiazol-5-yl)methyl)-6-chloro-3-nitropyridine-2-amine in methanol (5mL) was added dropwise to a solution of sodium methoxide (0.01mol) in methanol (10mL). After the addition was complete, the mixture was stirred at 25-50°C until the reaction was complete. The reaction mixture was poured into an appropriate amount of ice brine and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound. The crude product was separated and purified by vacuum column chromatography with ethyl acetate and petroleum ether to obtain 1.21g of the title compound as a yellow solid.

[0104] Example 3 This example illustrates the preparation of compound 02 in Table 1

[0105]

[0106] A mixture of N-((2-methylthiazol-5-yl)methyl)ethylamineethylamine hydrochloride (0.10mol), potassium carbonate (0.05mol) and ethanol (35mL) was stirred at room temperature for 0.5-1.5h, and then 2-methylthiazole-5-carboxaldehyde (0.08mol) was added dropwise, and stirring was continued for 1-2h after the addition was completed. Sodium borohydride (0.10mol) was added to the reaction mixture in batches under ice-water cooling and stirring conditions, and stirring was continued until the reaction was complete after the addition was completed. The reaction mixture was poured into an appropriate amount of ice brine, extracted with ethyl acetate, and the organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 10.62g of the title compound, which was directly used in the next step reaction.

[0107] N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridine-2-amine 2-chloro-6-methoxy-3-nitropyridine (0.01 mol), N-((2-methylthiazol-5-yl)methyl)ethylamine (0.01 mol), potassium carbonate (0.01 mol) and N,N-dimethylformamide (15 mL) were stirred at 25-50°C until the reaction was complete. The reaction mixture was poured into an appropriate amount of ice brine and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound. The crude product was separated and purified by vacuum column chromatography with ethyl acetate and petroleum ether to obtain 1.72 g of the title compound as a yellow viscous liquid.

[0108] Example 4 This example illustrates the preparation of compound 05 in Table 1

[0109]

[0110] N-((2-ethylthiazol-5-yl)methyl)ethylamine The title compound was synthesized by using 2-ethylthiazole-5-carboxaldehyde instead of 2-methylthiazole-5-carboxaldehyde according to the method of the above example.

[0111] N-ethyl-N-((2-ethylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridine-2-amine 2-chloro-6-methoxy-3-nitropyridine (0.01 mol), N-((2-ethylthiazol-5-yl)methyl)ethylamine (0.01 mol), potassium carbonate (0.01 mol) and tetrahydrofuran (15 mL) were stirred at 25-50°C until the reaction was complete. The reaction mixture was poured into an appropriate amount of ice brine and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound. The crude product was separated and purified by vacuum column chromatography with ethyl acetate and petroleum ether to obtain 1.62 g of the title compound as a yellow viscous liquid.

[0112] Example 5 This example illustrates the preparation of compounds 15 and 20 in Table 1

[0113]

[0114] N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-chloro-3-nitropyridine-2-amine (Compound 20 in Table 1) 2,6-dichloro-3-nitropyridine (0.01 mol), N-((2-methylthiazol-5-yl)methyl)ethylamine (0.01 mol), potassium carbonate (0.01 mol) and N,N-dimethylformamide (15 mL) were stirred at 25-50°C to react until complete. The reaction mixture was poured into an appropriate amount of ice brine, extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound, which was separated and purified by vacuum column chromatography with ethyl acetate and petroleum ether to obtain 1.76 g of the title compound as a yellow viscous liquid.

[0115] N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-allyloxy-3-nitropyridine-2-amine (Compound 15 in Table 1) A mixture of sodium allyl alcohol (0.01 mol) and tetrahydrofuran (15 mL) was added dropwise to a solution of N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-chloro-3-nitropyridine-2-amine (0.01 mol) in tetrahydrofuran (10 mL) at 5-10°C under dry and stirring conditions. After the addition was complete, the temperature was raised to 25-50°C and stirred to react until complete. The reaction mixture was poured into an appropriate amount of ice brine and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound. The crude product was separated and purified by vacuum column chromatography with ethyl acetate and petroleum ether to obtain 1.16 g of the title compound as a yellow viscous liquid.

[0116] Example 6 This example illustrates the preparation of compound 17 in Table 1

[0117]

[0118] N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-propargyloxy-3-nitropyridine-2-amine was dried at 5-10°C and stirred. To a solution of N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-chloro-3-nitropyridine-2-amine (0.01 mol) in tetrahydrofuran (10 mL) was added dropwise a mixture of sodium propargyl alcohol (0.01 mol) and tetrahydrofuran (15 mL). After the addition was complete, the mixture was heated to 25-50°C and stirred to react completely. The reaction mixture was poured into an appropriate amount of ice brine and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound. The crude product was separated and purified by vacuum column chromatography with ethyl acetate and petroleum ether to obtain 1.02 g of the title compound as a yellow solid with a melting point of 65.4-66.8°C.

[0119] Example 7 This example illustrates the preparation of compound 19 in Table 1

[0120]

[0121] N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-dimethylamino-3-nitropyridine-2-amine was dried at 5-10°C and stirred. Sodium hydride (0.01 mol) was added in batches to a solution of N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-chloro-3-nitropyridine-2-amine (0.01 mol), a dimethylamine aqueous solution (33%, 0.01 mol) and tetrahydrofuran (15 mL). After the addition was completed, the temperature was raised to 25-50°C and stirred to react completely. The reaction mixture was poured into an appropriate amount of ice brine, extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound. The crude product was separated and purified by vacuum column chromatography with ethyl acetate and petroleum ether to obtain 1.36 g of the title compound as a yellow solid, with a melting point of 59.8-61.3°C.

[0122] Other compounds of the present invention can be synthesized by referring to the above examples and corresponding literature.

[0123] Biological Activity Assay Example The compounds of the present invention were tested for insecticidal and fungicidal activity. The results showed that the compounds of the present invention exhibited good fungicidal and insecticidal activity. Some of the experimental results are as follows:

[0124] Example 8 Evaluation of acaricidal activity against Tetranychus urticae

[0125] Method: The test compound is dissolved in a suitable solvent such as N,N-dimethylformamide, and diluted to the required concentration with water containing 0.1% Tween 80 emulsifier. A blank without the test compound is set as a blank control, and each treatment is repeated 3 times; select bean seedlings with good growth to inoculate red spider mites, and there are 100-200 mites on the bean seedlings. After the red spider mites are colonized, the bean seedlings with mites are cut and immersed in the prepared liquid of the compound of formula (I) of the present invention for 5 seconds, taken out and the excess liquid is absorbed with filter paper, and then inserted into a beaker filled with water and cultured in an observation room. After 48 hours, the number of surviving and dead mites is checked and recorded, and the results are averaged. The results show that the compounds of the present invention are active against cotton red spider mites. At a dosage of 500 mg / L, compounds 01 and 05 have more than 60% acaricidal activity against cotton red spider mites, while D1 and D2 do not show acaricidal activity under the same conditions.

[0126] Example 9 Insecticidal activity against aphids (Aphis fabae)

[0127] In order to evaluate the activity of the compounds of the present invention against pests, aphids were selected as the subjects and the activity of the compounds of the present invention against aphids was determined by the immersion method.

[0128] Method: The test compound is dissolved in a suitable solvent such as N,N-dimethylformamide, and diluted to the required concentration with water containing 0.1% Tween 80 emulsifier. The blank without the test compound is set as the blank control, and each treatment is repeated 3 times. The broad bean aphids are inoculated on the newly unearthed bean seedlings, and there are more than 100 broad bean aphids on the bean seedlings. Then the bean seedlings and the test insects are immersed in the liquid of the compound of formula (I) of the present invention, taken out after 5 seconds, and after absorbing the excess liquid, inserted into a water-absorbing sponge, covered with a glass tube, and checked and recorded after 24 hours. The number of surviving and dead insects is averaged. The activity (mortality) is calculated as a percentage relative to the blank control, and is divided into four levels: A, B, C, and D. 100% ≥ mortality ≥ 90% is grade A, 90%> mortality ≥ 70% is grade B, 70%> mortality ≥ 50% is grade C, and 50%> mortality ≥ 0 is grade D. The results show that the compounds of the present invention are active against aphids, and some compounds are still highly active at lower concentrations. Some of the results are listed below:

[0129] At a concentration of 500 mg / L, compounds 01, 02, 04, 05, 06, 08, 12, 13 and 16 of the present invention have grade A activity against aphids, and compounds 07, 09, 10, 11 and 14 have grade B activity against aphids. Under the same conditions, D1 has grade A activity against aphids, and D2 has grade D activity against aphids.

[0130] At a concentration of 200 mg / L, compounds 01, 02, 05, 06, 08, 12, 13 and 16 of the present invention had grade A activity against aphids, and compounds 07 and 09 had grade B activity against aphids. Under the same conditions, D1 had grade A activity against aphids.

[0131] At a concentration of 50 mg / L, compounds 01 and 02 of the present invention had grade A activity against aphids, and compounds 12, 13 and 16 had grade B activity against aphids. Under the same conditions, D1 had grade B activity against aphids.

[0132] At a concentration of 12.5 mg / L, compounds 01 and the like of the present invention had a B-level activity against aphids, and compounds 02 and the like had a C-level activity against aphids. Under the same conditions, D1 had a D-level activity against aphids.

[0133] Example 10 Fungicidal activity against cucumber gray mold (Botrytis cinerea)

[0134] Method: The test compound was dissolved in a suitable solvent such as N,N-dimethylformamide, and then diluted to the required concentration with sterile water containing 0.1% Tween 80 emulsifier. The blank without the test compound was set as the blank control, and each treatment was repeated 4 times; 3mL of the drug solution was taken with a pipette and added to 27mL of potato agar medium (PDA) cooled to 45℃ and shaken thoroughly before pouring into a culture dish; after cooling, a 6mm diameter mycelium block was taken from the edge of the pathogen colony cultured for 7 days with an inoculation needle and moved to the center of the culture dish with the mycelium facing down; after the treatment, the culture dish was placed in a constant temperature biochemical incubator at 28℃ for culture, and the mycelium growth diameter was measured after 4 days, and the mycelium growth inhibition rate (%) was calculated using EXCEL statistical software. The activity (inhibition rate) is expressed as a percentage relative to the blank control and is divided into four levels: A, B, C, and D. 100%≧inhibition rate≧90% is level A, 90%>inhibition rate≧70% is level B, 70%>inhibition rate≧50% is level C, and 50%>inhibition rate≧0% is level D. The results show that the compounds of the present invention are active against cucumber gray mold, and some compounds still have excellent activity at very low doses. Some of the results are as follows:

[0135] At a concentration of 25 mg / L, compounds 01, 02, 16 and 19 of the present invention have grade A activity against cucumber gray mold, and compounds 03, 04, 05, 07, 08, 09, 14 and 18 have grade B activity against cucumber gray mold. Under the same conditions, D1 and D2 have grade A activity against cucumber gray mold.

[0136] At a concentration of 10 mg / L, compounds 01, 02 and 16 of the present invention have grade A activity against cucumber gray mold, and compounds 19 have grade B activity against cucumber gray mold. Under the same conditions, D1 and D2 have grade A activity.

[0137] At a concentration of 5 mg / L, the compounds 02 and the like of the present invention have A-level activity against cucumber gray mold, 01 and 16 and the like have B-level activity against cucumber gray mold, and under the same conditions, D1 and D2 have B-level activity;

[0138] At a concentration of 2.5 mg / L, compounds 02 and the like of the present invention have grade A activity against cucumber gray mold, and compounds 16 and the like have grade B activity against cucumber gray mold. Under the same conditions, D1 and D2 have grade C activity.

[0139] The evaluation results of cucumber gray mold in CN201110443914.1 show that D1 has grade A activity against cucumber gray mold at a concentration of 2.5-5.0 mg / L. The reason for this is probably that the test target used in the present invention and CN201110443914.1 - cucumber gray mold - is not exactly the same.

[0140] In order to further study the activity of the compounds of the present invention against cucumber gray mold, the compound 02 of the present invention was selected as the object, and D1 was used as the control, and their activities against cucumber gray mold were repeatedly compared in parallel using the above method. The results showed that the compound 02 of the present invention had a good activity against cucumber gray mold, and was much better than the activity of D1 against cucumber gray mold under the same conditions. Some of the results are listed below (Table 3).

[0141] Table 3 Activity of compounds 02 and D1 of the present invention against cucumber gray mold (%)

[0142] Concentration (mg / L) Compound 02 of the present invention D1 10 100 98.11 5.0 92.45 86.79 2.5 90.57 66.04

[0143] Example 11 Bactericidal activity against tobacco brown spot pathogen (Alternaria alternata)

[0144] Method: The test compound was dissolved in a suitable solvent such as N,N-dimethylformamide, and then diluted to the required concentration with sterile water containing 0.1% Tween 80 emulsifier. The blank without the test compound was set as the blank control, and each treatment was repeated 4 times; 3mL of the drug solution was taken with a pipette and added to 27mL of potato agar medium (PDA) cooled to 45℃ and shaken thoroughly before pouring into a culture dish; after cooling, a 6mm diameter mycelium block was taken from the edge of the pathogen colony cultured for 7 days with an inoculation needle and moved to the center of the culture dish with the mycelium facing down; after the treatment, the culture dish was placed in a constant temperature biochemical incubator at 28℃ for culture, and the mycelium growth diameter was measured after 4 days, and the mycelium growth inhibition rate (%) was calculated using EXCEL statistical software. The activity (inhibition rate) is expressed as a percentage relative to the blank control and is divided into four levels: A, B, C, and D. 100%≧inhibition rate≧90% is level A, 90%>inhibition rate≧70% is level B, 70%>inhibition rate≧50% is level C, and 50%>inhibition rate≧0% is level D. The results show that the compounds of the present invention are active against tobacco brown spot pathogens, and some compounds still have excellent activity at very low doses. Some of the results are as follows:

[0145] At a concentration of 25 mg / L, compounds 01, 02 and 14 of the present invention have grade A activity against tobacco brown spot pathogen, and compounds 03, 04, 05, 09, 11, 15, 16, 17, 18 and 19 have grade B activity against tobacco brown spot pathogen. Under the same conditions, D1 has grade A activity and D2 has grade B activity.

[0146] At a concentration of 10 mg / L, compounds 01 and 02 of the present invention have A-level activity against tobacco brown spot pathogen, and compounds 05, 14, 16 and 17 have B-level activity against tobacco brown spot pathogen. Under the same conditions, D1 and D2 have B-level activity.

[0147] At a concentration of 5 mg / L, compounds 01 and 02 of the present invention have grade A activity against tobacco brown spot pathogen, and compounds 14, 16 and 17 have grade B activity against tobacco brown spot pathogen.

[0148] Example 12 Control Effect on Corn Rust (Puccinia Polysora) (Pot Planting Method)

[0149] Method: The test compound was dissolved in a suitable solvent such as N,N-dimethylformamide, and then diluted to the required concentration with sterile water containing 0.1% Tween 80 emulsifier. A blank without the test compound was set as a blank control, and each treatment was repeated 4 times. The diseased corn leaves were cut off, and the spores were washed with 0.05% Tween 80 or other suitable surfactant aqueous solution, and filtered with 2-4 layers of gauze to make a concentration of 1×10 5 spores / mL suspension; spray the test compound solution when the corn grows to 2 leaves and 1 core, spray the spore suspension one day later, move to a moisturizing cabinet (relative humidity above 95%, temperature 20-22°C) after inoculation, and culture for 15-24h under weak light conditions (light intensity 5000-10000Lux); when the diseased leaf rate of the blank control reaches more than 50%, investigate the incidence of each treatment and calculate the efficacy of the drug. The results show that the compound of the present invention has a control effect on corn rust, and the control effect of the compound of the present invention on corn rust is better than that of D1 and D2 under the same conditions. Some results are as follows:

[0150] At a dosage of 500 mg / L, compounds 06, 16 and 18 of the present invention have more than 80% control activity against corn rust, and compounds 03, 08, 11, 19 and 20 have 70-80% control activity against corn rust; under the same conditions, the control activity of D1 and D2 against corn rust does not exceed 60%.

[0151] Example 13 Control activity against wheat powdery mildew (Erisiphe griminis) (pot culture method)

[0152] Method: The test compound is dissolved in a suitable solvent such as N,N-dimethylformamide, and then diluted to the required concentration with sterile water containing 0.1% Tween 80 emulsifier; take a pot with a straight stem of about 15 cm, sow 20 full and strong wheat seeds in each pot, and wait for two leaves and one core to grow for the test; take the prepared wheat seedlings and spray them with a certain concentration of the agent, and inoculate the pathogen one day later. Each treatment is repeated 3 times, and the blank without the test compound is set as the blank control; keep moist and keep the temperature until the blank control becomes ill, check the lesion area, and calculate the control effect of the agent. The activity is calculated as a percentage relative to the blank control, and is divided into four levels: A, B, C, and D. 100%≧control≧90% is level A, 90%>control≧70% is level B, 70%>50% is level C, and 50%>0% is level D. The results show that the compound of the present invention has a control effect on wheat powdery mildew, and is better than D1 and D2 under the same conditions. Some of the results are listed below:

[0153] At a dosage of 500 mg / L, compounds 07, 08 and 11 of the present invention have grade A control activity against wheat powdery mildew; compounds 05, 06, 09 and 10 have grade B control activity against wheat powdery mildew; under the same conditions, compounds D1 and D2 have grade D control activity against wheat powdery mildew.

[0154] Under the condition of 100 mg / L, compounds 07, 08 and 09 of the present invention have Class B control activity against wheat powdery mildew.

Claims

1. Thiazole methylpyridine amine compound, characterized in that Thiazole methylpyridine amine compounds represented by formula (I) yes: N-methyl-N-((2-methylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine; N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine.

2. Thiazole methylpyridine amine compounds, characterized in that Thiazole methylpyridine amine compounds represented by formula (I) yes: N-cyclopropylmethyl-N-((2-methylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine; N-ethyl-N-((2-ethylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine; N-methyl-N-((2-propylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine; N-ethyl-N-((2-propylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine; N-methyl-N-((2-isopropylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine; N-ethyl-N-((2-isopropylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine; N-methyl-N-((2-cyclopropylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine; N-ethyl-N-((2-cyclopropylthiazol-5-yl)methyl)-6-methoxy-3-nitropyridin-2-amine; N-methyl-N-((2-methylthiazol-5-yl)methyl)-6-propargyloxy-3-nitropyridin-2-amine; N-methyl-N-((2-methylthiazol-5-yl)methyl)-6-dimethylamino-3-nitropyridin-2-amine; N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-dimethylamino-3-nitropyridin-2-amine; N-ethyl-N-((2-methylthiazol-5-yl)methyl)-6-chloro-3-nitropyridin-2-amine.

3. The method for preparing the thiazole methylpyridine amine compound according to claim 1 or 2, characterized in that The compound of formula (I) is prepared by the reaction shown below: Reaction formula 1-1: Reaction 1-2: Reaction 2: Reaction 3: In a solvent of dichloromethane, dichloroethane, acetonitrile, toluene, xylene, ethyl acetate, acetone, N,N-dimethylformamide, tetrahydrofuran or dioxane, in the presence of sodium hydride, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium hydroxide, potassium carbonate, triethylamine, pyridine or diisopropylethylamine, at a temperature between 5°C and the reflux temperature of the system, reacting the compound represented by formula (II) with the compound represented by formula (III) to obtain the compound represented by formula (I); or In a solvent of dichloromethane, dichloroethane, acetonitrile, toluene, xylene, ethyl acetate, acetone, N,N-dimethylformamide, tetrahydrofuran or dioxane, in the presence of sodium hydride, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, pyridine or diisopropylethylamine, at a temperature between 5°C and the reflux temperature of the system, the compound of formula (II) is reacted with the compound of formula (IV) to obtain the compound of formula (V); in a solvent of methanol, ethanol, water, tetrahydrofuran or dioxane, in the absence of a base or in the presence of a suitable base, at a temperature between 5°C and the reflux temperature of the system, the compound of formula (V) is reacted with RH to obtain the compound of formula (I), wherein the suitable base is selected from sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, pyridine or diisopropylethylamine; In one or two solvents, in the presence of sodium hydride, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, pyridine or diisopropylethylamine, at 5°C to the reflux temperature of the system, a compound of formula (VI) and R 1 After NH2HL is reacted for 0.5-5.0h, the reaction mixture is reacted with a reducing agent, sodium borohydride, potassium borohydride, borane or hydrogen at 0°C to the reflux temperature of the system to obtain a compound of formula (II), wherein the solvent is selected from dichloromethane, chloroform, water, methanol, ethanol, dichloroethane, acetonitrile, toluene, xylene, ethyl acetate, acetone, N,N-dimethylformamide, tetrahydrofuran or dioxane; In one or two solvents, at 5°C to the reflux temperature of the system, in the absence of a base or a suitable base, reacting a compound of formula (IV) with RH to obtain a compound of formula (III), wherein the solvent is selected from methanol, ethanol, water, tetrahydrofuran or dioxane, and the suitable base is selected from sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, pyridine or diisopropylethylamine; Where R, R 1 , R 2 , R 3 and R 4 As defined in claim 1 or 2, L is a leaving group halogen.

4. The use of the thiazole methylpyridine amine compound according to claim 1, characterized in that Use for controlling aphids in plants at a dosage of 15-5000 g of active ingredient / hectare.

5. The use of the thiazole methylpyridine amine compound according to claim 1 or 2, characterized in that The invention is used for controlling harmful pathogens in plants at a dosage of 15-5000 g of active ingredient / hectare, wherein the harmful pathogens are cucumber gray mold, tobacco brown spot pathogen, corn rust pathogen or wheat powdery mildew pathogen.

6. Use of the thiazolylmethylpyridinamine compound according to claim 1 for preparing a medicament having aphid-killing activity in plants.

7. Use of the thiazolylmethylpyridinamine compound according to claim 1 or 2 for preparing a drug having activity of killing harmful pathogens in plants, wherein the harmful pathogens are cucumber gray mold, tobacco brown spot pathogen, corn rust pathogen or wheat powdery mildew pathogen.

8. The use of the thiazole methylpyridine amine compound according to claim 1, characterized in that A method for controlling aphids in plants comprises contacting the aphids in the plants with a biologically effective amount of an active ingredient.

9. The use of the thiazolylmethylpyridinamine compound according to claim 1 or 2, characterized in that The method for preventing and controlling harmful pathogens in plants is to contact the harmful pathogens in plants with a biologically effective amount of active ingredients, wherein the harmful pathogens are cucumber gray mold, tobacco brown spot pathogen, corn rust pathogen or wheat powdery mildew pathogen.

10. A bactericidal composition, characterized in that: The composition contains the thiazolylmethylpyridinamine compound as claimed in claim 1 or 2 as an active component, wherein the weight percentage of the active component in the composition is 0.5-99%.

11. An insecticidal composition, characterized in that: The composition contains the thiazolylmethylpyridinamine compound as claimed in claim 1 as an active component, wherein the weight percentage of the active component in the composition is 0.5-99%.

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