Pyridylpiperazine compounds and preparation methods and uses thereof

Abstract

The present invention discloses a pyridylpiperazine compound and a preparation method and use thereof. The structure of the pyridylpiperazine compound is shown in formula (I). The compound of general formula (I) or its salt can be used as a fungicide in the fields of agriculture, forestry or sanitation, and has a good control effect on agricultural diseases, especially a good control effect on plant rust and downy mildew.

Description

Technical Field

[0001] The invention belongs to the field of agricultural fungicides, and specifically relates to a pyridylpiperazine compound and a preparation method thereof, as well as the use of the pyridylpiperazine compound as a fungicide in agriculture or other fields. Background Art

[0002] Chinese patent CN1938292 discloses a cyclic amine compound with the general formula shown below as a miticide:

[0003]

[0004] R2 represents a halogen atom, a nitro group, a C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 a haloalkoxy group, a heterocyclic group which may be substituted by G4 (a 5- or 6-membered heterocyclic group having at least one heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom) or C 1-6 In the haloalkoxy group, k represents 0 or an integer of 1 to 4; and X represents an oxygen atom, a sulfur atom, a sulfinyl group or a sulfonyl group.

[0005] The structures of the compounds reported in the prior art are very different from those of the compounds of the present invention, and there are no reports on the use of compounds with structures as shown in the general formula (I) of the present invention as agricultural fungicides. Summary of the invention

[0006] The present invention aims to provide a pyridylpiperazine compound and a preparation method thereof. The pyridylpiperazine compound can be used as an agricultural fungicide to control diseases.

[0007] The technical solution of the present invention is as follows:

[0008] A pyridylpiperazine compound, the structure of which is shown in formula (I):

[0009]

[0010] In formula (I):

[0011] R 1 Selected from hydrogen, halogen, CN, NO 2 , alkyl, haloalkyl, alkoxy or haloalkoxy; m is selected from an integer from 0 to 5; when m is greater than 1, R 1 Can be the same or different;

[0012] R 2 is selected from hydrogen, alkoxycarbonyl, C(=O)R 4 , CO 2 H, CO 2 Na or CN; R 4 Selected from alkylamine, NH 2, cyclopropylamino or cyclopropylmethylamino;

[0013] R 3 Selected from hydrogen, halogen, CN, C(=S)NH 2 、NO 2 , alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl or R 1 Substituted phenyl; X is selected from N or C; when X is selected from N, n is selected from an integer from 0 to 4; when X is selected from C, n is selected from an integer from 0 to 5; when n is greater than 1, R 3 Can be the same or different.

[0014] Preferably, in formula (I):

[0015] R 1 Selected from hydrogen, F, Cl, Br, I, CN, NO 2 , C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy or halogenated C 1 -C 4 Alkoxy; m is an integer selected from 0 to 5; when m is greater than 1, R 1 Can be the same or different;

[0016] R 2 Selected from hydrogen, C 1 -C 4 Alkoxycarbonyl, C(=O)R 4 , CO 2 H, CO 2 Na or CN; R 4 Selected from C 1 -C 4 Alkylamine, NH 2 , cyclopropylamino or cyclopropylmethylamino;

[0017] R 3 Selected from hydrogen, F, Cl, Br, I, CN, C(=S)NH 2 、NO 2 , C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, halogenated C 1 -C 4 Alkoxy, C 1 -C 4 Alkoxycarbonyl or R 1Substituted phenyl; X is selected from N or C; when X is selected from N, n is selected from an integer from 0 to 4; when X is selected from C, n is selected from an integer from 0 to 5; when n is greater than 1, R 3 Can be the same or different.

[0018] Further preferably, in formula (I):

[0019] R 1 Select hydrogen, F, Cl, Br, I, CN, NO 2 , CH 3 、OCH 3 CF 3 、OCF 3 ; m is an integer selected from 0 to 5; when m is greater than 1, R 1 Can be the same or different;

[0020] R 2 Selected from H, CN, methoxycarbonyl, ethoxycarbonyl, CO 2 H, CO 2 Na or C(=O)R 4 ; R 4 Selected from methylamino, ethylamino, NH 2 , cyclopropylamino or cyclopropylmethylamino;

[0021] R 3 Selected from hydrogen, F, Cl, Br, I, CN, NO 2 , CH 3 、OCH 3 CF 3 、OCF 3 , methoxycarbonyl, ethoxycarbonyl or R 1 Substituted phenyl; X is selected from N or C; when X is selected from N, n is selected from an integer from 0 to 4; when X is selected from C, n is selected from an integer from 0 to 5; when n is greater than 1, R 3 Can be the same or different.

[0022] Some of the compounds of the general formula (I) of the present invention can be illustrated by the specific compounds listed in the following table, but the present invention is not limited thereto.

[0023] When in the general formula (I), (R 1 ) m =H, R 2 =CO 2 C 2 H 5 , when X=N, the substituent (R 3 ) n See Table 1, representative compounds are numbered 1-99.

[0024] Table 1

[0025]

[0026]

[0027] When in the general formula (I), (R 3 ) n =3-CN, R 2 =CO 2 C 2 H 5 , when X=N, the substituent (R 1 ) m See Table 2, representative compound numbers are 100-139.

[0028] Table 2

[0029] Serial number <![CDATA[(R 1 ) m ]]> Serial number <![CDATA[(R 1 ) m ]]> Serial number <![CDATA[(R 1 ) m ]]> Serial number <![CDATA[(R 1 ) m ]]> 100 2-Cl 110 4-CN 120 <![CDATA[3-NO 2 ]]> 130 2-Cl-4-F 101 3-Cl 111 <![CDATA[2-CF 3 ]]> 121 <![CDATA[4-NO 2 ]]> 131 2-Cl-4-Br 102 4-Cl 112 <![CDATA[3-CF 3 ]]> 122 <![CDATA[2,4-F 2 ]]> 132 <![CDATA[2-Cl-4-CH 3 ]]> 103 2-F 113 <![CDATA[4-CF 3 ]]> 123 <![CDATA[2,4-Cl 2 ]]> 133 <![CDATA[2-Cl-4-NO 2 ]]> 104 3-F 114 <![CDATA[4-OCF 3 ]]> 124 <![CDATA[2,6-Cl 2 ]]> 134 2-Cl-4-CN 105 4-F 115 <![CDATA[2-CH 3 ]]> 125 <![CDATA[4-OCH 3 ]]> 135 2-F-4-Cl 106 2-Br 116 <![CDATA[3-CH 3 ]]> 126 <![CDATA[2,3,4-F 3 ]]> 136 2-Br-4-Cl 107 3-Br 117 <![CDATA[4-CH 3 ]]> 127 3-F-4-Cl 137 2-CN 108 4-Br 118 <![CDATA[2-NO 2 ]]> 128 3-Br-4-Cl 138 3-CN 109 <![CDATA[2,3-F 2 ]]> 119 <![CDATA[3,5-Cl 2 ]]> 129 <![CDATA[2,5-F 2 ]]> 139 <![CDATA[3,4,5-F 3 ]]>

[0030] When in the general formula (I), (R 1 ) m =H, R 2 =CO 2 C 2 H 5 , when X=C, the substituent (R 3 ) n See Table 3, representative compound numbers are 140-147.

[0031] Table 3

[0032] Serial number <![CDATA[(R 3 ) n ]]> Serial number <![CDATA[(R 3 ) n ]]> 140 2-CN 144 <![CDATA[2-NO 2 ]]> 141 <![CDATA[2,6-(Cl) 2 -4-NO 2 ]]> 145 <![CDATA[2,6-(NO 2 ) 2 -3-Cl-4-CF 3 ]]> 142 <![CDATA[2-CH 3 -3-Cl-4,6-(NO 2 ) 2 ]]> 146 <![CDATA[2,3,5-Cl 3 -4,6-(CN) 2 ]]> 143 2-F-4-CN 147 <![CDATA[2-CN-4-NO 2 ]]>

[0033] Table 4: When in the general formula (I), (R 1 ) m =H, R 2 =CO 2 CH 3 , when X=N, the substituent (R 3 ) n See 1-99 in Table 1, representing compound numbers 148-246.

[0034] When the substituents in the general formula (I) are as shown in Table 5, the representative compound numbers are 247-272.

[0035] Table 5

[0036]

[0037]

[0038] The preparation method of the pyridylpiperazine compound represented by formula (I) of the present invention is as follows:

[0039] (1) Compound (II), a condensation reagent and a solvent are mixed, reacted at 30 to 150° C. for 0.5 to 15 h, and then post-treated to obtain compound (III);

[0040] The molar ratio of the compound (II) to the condensation reagent is 1:1 to 4;

[0041] The condensation reagent is selected from one of N,N-dimethylformamide dimethyl acetal, trimethyl orthoformate, triethyl orthoformate, or a mixture of two or more in any proportion;

[0042] The solvent is selected from one of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylformamide dimethyl acetal, dimethyl sulfoxide, ethanol, toluene, acetone, acetonitrile, acetic anhydride, or a mixed solvent of two or more in any proportion; the volume amount of the solvent is 1 to 20 mL / g based on the mass of compound (II);

[0043] (2) Compound (III), a cyclization reagent, a solvent, and an alkaline substance are mixed, reacted at 20 to 100° C. for 0.5 to 25 h, and then post-treated to obtain compound (IV);

[0044] The molar ratio of the compound (III), the cyclization reagent and the alkaline substance is 1:1-4:0.1-3;

[0045] The cyclization reagent is selected from cyanoacetamide or malononitrile;

[0046] The alkaline substance is selected from sodium methoxide, sodium ethoxide, triethylamine or sodium hydride;

[0047] The solvent is selected from one of methanol, ethanol, acetic acid, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide, or a mixed solvent of two or more in any proportion; the volume amount of the solvent is 1 to 10 mL / g based on the mass of compound (III);

[0048] (3) Compound (IV), a halogenating agent, a solvent, and a catalyst are mixed, reacted at 20 to 130° C. for 0.5 to 25 h, and then post-treated to obtain compound (V);

[0049] The molar ratio of the compound (IV), the halogenating agent and the catalyst is 1:1-8:0.001-3;

[0050] The halogenating agent is selected from one of thionyl chloride, phosphorus oxybromide, phosphorus tribromide, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, N-bromosuccinimide, and N-chlorosuccinimide, or a mixture of two or more thereof in any proportion;

[0051] The catalyst is selected from N,N-dimethylformamide, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, thiourea or dimethylthiourea;

[0052] The solvent is selected from toluene, acetonitrile, xylene, chlorobenzene, dichloromethane, dichloroethane, or a mixed solvent of two or more in any proportion; the volume amount of the solvent is 0 to 10 mL / g based on the mass of compound (III);

[0053] (4) Compound (V), piperazine, a solvent, and an acid-binding agent are mixed, reacted at 20 to 130° C. for 0.5 to 20 h, and then post-treated to obtain compound (VI);

[0054] The molar ratio of the compound (V), piperazine and acid-binding agent is 1:1-1.5:0.5-3;

[0055] The acid binding agent is selected from sodium hydride, potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or sodium carbonate;

[0056] The solvent is selected from toluene, xylene, trimethylbenzene, chlorobenzene, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, dimethyl sulfone, N-methylpyrrolidone, N,N-dimethylacetamide, cyclopentane or hexamethylphosphoramide; the volume amount of the solvent is 1 to 10 mL / g based on the mass of compound (V);

[0057] (5) Compound (VI), compound (VII), a solvent and an acid binding agent are mixed, reacted at 20 to 130° C. for 0.5 to 20 h, and then post-treated to obtain compound (I);

[0058] The molar ratio of the compound (VI), the compound (VII) and the acid-binding agent is 1:0.8-1.2:0.5-3;

[0059] The acid binding agent is selected from sodium hydride, potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, potassium bicarbonate or sodium carbonate;

[0060] The solvent is selected from toluene, xylene, trimethylbenzene, chlorobenzene, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, dimethyl sulfone, N-methylpyrrolidone, N,N-dimethylacetamide, cyclopentane or hexamethylphosphoramide; the volume amount of the solvent is 1 to 10 mL / g based on the mass of compound (VI);

[0061] The reaction process is as follows:

[0062]

[0063] In formula (II), (III), (IV), (V) or (VI), R 1 , R 2 , m are defined as in formula (I);

[0064] In formula (III), Y 1 Selected from N,N-dimethylamino, methoxy or ethoxy;

[0065] In formula (V), Y 2 is selected from chlorine or bromine;

[0066] In formula (VII), R 3 , X, and n are defined the same as in formula (I), and G is a halogen (eg, Cl).

[0067] The pyridylpiperazine compounds represented by formula (I) of the present invention or their salts can be used as fungicides in the fields of agriculture, forestry or health to prevent and control plant rust and downy mildew, including leguminous plant rust, wheat rust, corn rust, fruit and vegetable plant rust, flower rust, melon and fruit plant downy mildew, sugarcane downy mildew, leguminous plant downy mildew, vegetable plant downy mildew and the like.

[0068] For practical application in agriculture, the compound of general formula (I) can be used alone to control agricultural diseases, or it can be compounded with commonly used fungicides in existing agriculture to delay resistance, while broadening the spectrum of disease control and improving efficacy.

[0069] The present invention also relates to a fungicide composition, which contains the compound of general formula (I) or its salt as an active component and an agriculturally acceptable carrier, wherein the weight percentage of the active component in the composition is 0.5-99%.

[0070] The composition can be prepared into a dosage form permitted by pesticides, such as wettable powder, emulsifiable concentrate, microemulsion, granule, solution, suspension, oil suspension, etc. The selection of the composition type depends on the specific application.

[0071] The beneficial effects of the present invention are:

[0072] The present invention uses acetophenone compounds as raw materials, and obtains pyridylpiperazine compounds shown in formula (I) through condensation, cyclization, chlorination and condensation reactions. The compounds of general formula (I) have good control effects on agricultural diseases, especially good control effects on plant rust and downy mildew. DETAILED DESCRIPTION

[0073] The present invention is further described below by means of specific embodiments, but the protection scope of the present invention is not limited thereto.

[0074] Synthesis Example

[0075] Example 1: Select (R1 ) m When it is H, the preparation process of pyridylpiperazine compounds is described, and other compounds can be synthesized by similar methods.

[0076]

[0077] 1) Preparation of intermediate III-1

[0078] 19.2g (0.1mol) of ethyl benzoyl acetate was placed in a 500mL single-mouth bottle, 20mL of DMFDMA and 20mL of DMF were added thereto, the temperature was raised to 110°C, after the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, DMFDMA and DMF were removed under reduced pressure at 100°C, and a large amount of solid was precipitated when the mixture was cooled to 0°C. The mixture was filtered, the filter cake was washed with petroleum ether for 2-3 times, and 17.50g of solid was obtained after drying, with a yield of 70.5%. The crude intermediate III-1 was directly used in the next step without purification.

[0079] 2) Preparation of Intermediate IV-1

[0080] 8.5 g (0.125 mol) of sodium ethoxide was poured into a 500 mL four-necked bottle, 100 mL of ethanol was added thereto, and then 6.3 g (0.075 mol) of cyanoacetamide was added thereto. After reacting at 25°C for 1 hour, 12.35 g (0.05 mol) of an ethanol solution of the intermediate III-1 was added dropwise. After the addition was completed, the reaction was continued. After the reaction was completed as monitored by TLC, the reaction solution was poured into water, the pH was adjusted to about 5 with 30% hydrochloric acid, and the solution was filtered and dried to obtain 6.7 g of a yellow solid with a yield of 50%. The solid was used directly in the next step without purification.

[0081] 3) Preparation of intermediate V-1

[0082] 13.4 g (0.05 mol) of intermediate IV-1 was placed in a 250 mL single-mouth bottle, 50 mL of phosphorus oxychloride and 1 drop of DMF were added thereto, the temperature was raised to 110 ° C and refluxed for reaction, after the reaction was completed under TLC monitoring, the phosphorus oxychloride was recovered under reduced pressure at 100 ° C until no liquid flowed out, cooled to room temperature, the residue was poured into ice water, the solid was precipitated, filtered, and dried to obtain 8.6 g of brown solid, yield: 60%, which can be directly used in the next step reaction without purification.

[0083] 4) Preparation of intermediate VI-1

[0084] 14.3 g (0.05 mol) of intermediate V-1 was placed in a 250 mL single-mouth bottle, 100 mL of DMF was added thereto, and then 6.9 g (0.05 mol) of potassium carbonate and 4.3 g (0.05 mol) of piperazine were added thereto, and the temperature was raised to 90°C for reaction. After the reaction was completed as monitored by TLC, the reaction was cooled to room temperature, and the reaction solution was poured into water. After extraction with ethyl acetate, hydrogen chloride gas was introduced, and solid precipitated. 7.5 g of light yellow solid was obtained by suction filtration. The yield was 40.2%, and the solid could be directly used in the next step without purification.

[0085] 5) Preparation of Compound 1

[0086] 1 g (2.7 mmol) of intermediate VI-1 was placed in a 50 mL single-mouth bottle, 20 mL of DMF was added thereto, and then 0.37 g (2.7 mmol) of potassium carbonate and 0.4 g (2.7 mmol) of 2,3-dichloropyridine were added thereto. The temperature was raised to 90°C for reaction. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered under reduced pressure to remove the solid residue. The solvent was removed from the filtrate, and then separated and purified by silica gel column chromatography (eluent: ethyl acetate / 60-90°C petroleum ether) to obtain 0.40 g of solid, with a yield of 32.8%.

[0087] 6) Preparation of Compound 40

[0088] 1 g (2.7 mmol) of intermediate VI-1 was placed in a 50 mL single-mouth bottle, 20 mL of DMF was added thereto, and then 0.37 g (2.7 mmol) of potassium carbonate and 0.37 g (2.7 mmol) of 2-chloronicotinonitrile were added thereto, and the temperature was raised to 90°C for reaction. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, and then washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered under reduced pressure to remove the solid residue. The solvent was removed from the filtrate, and then separated and purified by silica gel column chromatography (eluent: ethyl acetate / 60-90°C petroleum ether) to obtain 0.31 g of solid, with a yield of 26.2%.

[0089] Embodiment 2:

[0090] 1) Preparation of Compound 90

[0091] 1 g (2.7 mmol) of intermediate VI-1 was placed in a 50 mL single-mouth bottle, 20 mL of DMF was added thereto, and then 0.37 g (2.7 mmol) of potassium carbonate and 0.77 g (2.7 mmol) of V-1 were added thereto. The temperature was raised to 90°C for reaction. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered off under reduced pressure to remove the solid residue. The solvent was removed from the filtrate, and then separated and purified by silica gel column chromatography (eluent: ethyl acetate / 60-90°C petroleum ether) to obtain 0.67 g of solid, with a yield of 42.5%.

[0092] 2) Preparation of Compound 253

[0093]

[0094] 1 g (2.3 mmol) of compound 40 was placed in a 50 mL single-mouth bottle, 20 mL of ethanol was added thereto, and then 0.27 g (6.9 mmol) of an aqueous solution of sodium hydroxide was dropped thereinto. The temperature was raised to 40°C for reaction. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature, a large amount of solvent was removed under reduced pressure, 10 mL of water was added thereto, and the pH was adjusted to 1 with hydrochloric acid. The precipitated solid was filtered off and recrystallized from ethanol to obtain 0.47 g of a solid with a yield of 50.2%.

[0095] 3) Preparation of Compound 187

[0096]

[0097] 1 g (2.3 mmol) of compound 253 was placed in a 50 mL single-mouth bottle, 20 mL of methanol was added thereto, and 0.82 g (6.9 mmol) of thionyl chloride was dropped thereinto. The temperature was raised to 50°C for reaction. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature, a large amount of solvent was removed under reduced pressure, 10 mL of water was added thereto, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered off under reduced pressure to remove solid residues. The solvent was removed from the filtrate, and the mixture was separated and purified by silica gel column chromatography (eluent: ethyl acetate / 60-90°C petroleum ether) to obtain 0.57 g of solid. The yield was 61.5%.

[0098] Example 3: Select (R 1 ) m When it is m-trifluoromethyl, the preparation process of pyridylpiperazine compounds is described, and other compounds can be synthesized by similar methods.

[0099]

[0100] 1) Preparation of intermediate III-2

[0101] 47 g (0.25 mol) of m-trifluoromethylacetophenone was placed in a 1000 mL single-mouth bottle, 200 mL of DMFDMA and 100 mL of DMF were added thereto, the temperature was raised to 110°C and refluxed, after the reaction was completed under TLC monitoring, the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure at 100°C, and a large amount of solid was precipitated when it was cooled to 0°C. The solid was filtered, the filter cake was washed with petroleum ether 2-3 times, and 36 g of solid was obtained after drying. The yield was 60%.

[0102] 2) Preparation of Intermediate IV-2

[0103] 36 g (0.148 mol) of intermediate III-2 was placed in a 1000 mL single-mouth bottle, 300 mL of DMF was added thereto, and then 20 g of sodium methoxide and 15 g of cyanoacetamide were added thereto. The temperature was raised to 100 ° C for reaction. After the reaction was completed as monitored by TLC, it was cooled to room temperature, the reaction solution was poured into water, the pH was adjusted to about 5 with 30% hydrochloric acid, and the solution was filtered and dried to obtain 19.6 g of a yellow solid with a yield of 50%, which can be directly used in the next step without purification.

[0104] 3) Preparation of intermediate V-2

[0105] 13.2 g (0.05 mol) of intermediate IV-2 was placed in a 250 mL single-mouth bottle, 100 mL of phosphorus oxychloride and 1 drop of DMF were added thereto, the temperature was raised to 110°C for reflux reaction, after the reaction was completed as monitored by TLC, the phosphorus oxychloride was recovered under reduced pressure at 100°C until no liquid flowed out, cooled to room temperature, poured into ice water, the solid precipitated, filtered, recrystallized with ethyl acetate solvent, and dried to obtain 5.6 g of brown solid, yield: 40%.

[0106] 4) Preparation of intermediate VI-2

[0107] 2.8 g (0.01 mol) of intermediate V-2 was placed in a 250 mL single-mouth bottle, 50 mL of DMF was added thereto, and then 1.38 g (0.01 mol) of potassium carbonate and 0.86 g (0.01 mmol) of piperazine were added thereto, and the temperature was raised to 90°C for reaction. After the reaction was completed as monitored by TLC, the reaction was cooled to room temperature, and the reaction solution was poured into water. After extraction with ethyl acetate, hydrogen chloride gas was introduced, and solid precipitated. 1.55 g of light yellow solid was obtained by suction filtration. The yield was 42%, and the solid was directly used in the next step without purification.

[0108] Embodiment 4:

[0109] Preparation of Compound 266

[0110] 1 g (2.71 mmol) of intermediate VI-2 was placed in a 50 mL three-necked flask, 10 mL of DMF was added thereto, and then 0.37 g (2.71 mmol) of 2-chloronicotinonitrile and 0.75 g (5.42 mmol) of potassium carbonate were added thereto, and the temperature was raised to 85°C for reaction. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate solvent, washed with water, washed with saturated sodium chloride solution, dried, and subjected to column chromatography (eluent: ethyl acetate / 60-90°C petroleum ether) to obtain 0.53 g of a white solid, with a yield of 45%.

[0111] Embodiment 5:

[0112] Preparation of Compound 268

[0113]

[0114] 1 g (3.07 mmol) of 2-phenyl-6-(piperazine-1-yl)-3,5-dicyanopyridine hydrochloride was placed in a 50 mL three-necked flask, 10 mL of DMF was added thereto, and then 0.43 g (3.07 mmol) of 2-chloronicotinonitrile and 0.85 g (6.14 mmol) of potassium carbonate were added thereto, and the temperature was raised to 85°C for reaction. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, and the reaction solution was poured into water, extracted with ethyl acetate solvent, washed with water, washed with saturated sodium chloride solution, dried, and subjected to column chromatography (eluent: ethyl acetate / 60-90°C petroleum ether) to obtain 0.42 g of a yellow solid with a yield of 35%.

[0115] The melting points and NMR data of some compounds are as follows:

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126] Biological Activity Assay Example

[0127] Embodiment 6:

[0128] The compounds of the present invention were tested against soybean rust. The test method is as follows:

[0129] Select 2-leaf soybean seedlings in pots that grow in a uniform pattern. Use an Airbrush to spray the leaves with the agent at the designed concentration, and set up a blank control of spraying water, and repeat 3 times. The next day after treatment, inoculate with a soybean rust spore suspension, place in an artificial climate chamber (temperature: 20℃-25℃, relative humidity: >95%) for moisturizing culture, and place in a greenhouse (25℃±1℃) for normal management after 8-16 hours. Investigate the control effect 10 days after inoculation. The results were investigated with reference to the "A Manual of Assessment Keys for Plant Diseases" compiled by the American Society of Plant Pathology. According to the degree of disease in the control, the fungicidal activity of the test samples was investigated by visual inspection.

[0130] The in vivo protective activity against soybean rust is as follows:

[0131] When the concentration of the solution was 400 mg / L, the protective effect of compounds 1, 40, 125, and 265 against soybean rust was not less than 90%;

[0132] When the concentration of the solution was 400 mg / L, the protective effects of compounds 60, 104, 110, 187, 247, 253, 261, and 266 against soybean rust were 70% to 85%;

[0133] When the concentration of the drug solution was 12.5 mg / L, the protective effect of compound 40 against soybean rust was 95%, which was equivalent to the control drugs benzovinflumizone and azoxystrobin at the same dosage.

[0134] Embodiment 7:

[0135] Determination of in vivo protective activity against cucumber downy mildew: Select 2-leaf cucumber seedlings in pots that grow neatly and uniformly. Use Airbrush to spray the leaves with the agent according to the designed concentration, and set up a blank control of spraying water, and repeat 3 times. The next day after treatment, inoculate with a suspension of cucumber downy mildew spores, place in an artificial climate chamber (temperature: 20℃-25℃, relative humidity: >95%) for moisturizing culture, and place in a greenhouse (25℃±1℃) for normal management after 8-16 hours. Investigate the control effect 10 days after inoculation. The results were investigated with reference to "A Manual of Assessment Keys for Plant Diseases" compiled by the American Society of Plant Pathology. According to the degree of disease in the control, the fungicidal activity of the test samples was investigated by visual inspection.

[0136] When the concentration of the drug solution was 400 mg / L, the protective effect of compounds 1, 125, 266, and 267 against cucumber downy mildew was not less than 90%;

[0137] When the concentration of the drug solution is 400 mg / L, the protective efficacy of compounds 16, 54, 100, 264, and 265 against cucumber downy mildew is 70% to 80%.

Claims

1. A pyridylpiperazine compound, the structure of which is shown in formula (I): In formula (I): R1 is selected from halogen, CN, NO2, C1-C4 alkyl, halogenated C1-C4 alkyl or halogenated C1-C4 alkoxy; m is selected from an integer from 1 to 5; when m is greater than 1, R1 may be the same or different; R2 is selected from hydrogen, C1-C4 alkoxycarbonyl, CO2H, CO2Na or CN; R3 is selected from hydrogen, halogen, CN, NO2, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy or halogenated C1-C4 alkoxy; X is selected from N or C; when X is selected from N, n is selected from an integer from 0 to 4; when X is selected from C, n is selected from an integer from 0 to 5; when n is greater than 1, R3 may be the same or different.

2. The pyridylpiperazine compound according to claim 1, characterized in that: R1 is selected from F, Cl, Br, I, CN, NO2, CH3, CF3, OCF3; m is selected from an integer from 1 to 5; when m is greater than 1, R1 may be the same or different; R2 is selected from H, CN, methoxycarbonyl, ethoxycarbonyl, CO2H or CO2Na; R3 is selected from hydrogen, F, Cl, Br, I, CN, NO2, CH3, OCH3, CF3 or OCF3; X is selected from N or C; when X is selected from N, n is selected from an integer from 0 to 4; when X is selected from C, n is selected from an integer from 0 to 5; when n is greater than 1, R3 may be the same or different.

3. The method for preparing a pyridylpiperazine compound according to claim 1, wherein: The preparation method is: (1) Compound (II), a condensation reagent and a solvent are mixed, reacted at 30 to 150° C. for 0.5 to 15 h, and then post-treated to obtain compound (III); The molar ratio of the compound (II) to the condensation reagent is 1:1 to 4; The condensation reagent is selected from one of N,N-dimethylformamide dimethyl acetal, trimethyl orthoformate, triethyl orthoformate, or a mixture of two or more in any proportion; The solvent is selected from one of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylformamide dimethyl acetal, dimethyl sulfoxide, ethanol, toluene, acetone, acetonitrile, acetic anhydride, or a mixed solvent of two or more in any proportion; (2) Compound (III), a cyclization reagent, a solvent, and an alkaline substance are mixed, reacted at 20 to 100° C. for 0.5 to 25 h, and then post-treated to obtain compound (IV); The molar ratio of the compound (III), the cyclization reagent and the alkaline substance is 1:1-4:0.1-3; The cyclization reagent is selected from cyanoacetamide or malononitrile; The alkaline substance is selected from sodium methoxide, sodium ethoxide, triethylamine or sodium hydride; The solvent is selected from one of methanol, ethanol, acetic acid, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or a mixed solvent of two or more in any proportion; (3) Compound (IV), a halogenating agent, a solvent, and a catalyst are mixed, reacted at 20 to 130° C. for 0.5 to 25 h, and then post-treated to obtain compound (V); The molar ratio of the compound (IV), the halogenating agent and the catalyst is 1:1-8:0.001-3; The halogenating agent is selected from one of thionyl chloride, phosphorus oxybromide, phosphorus tribromide, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, N-bromosuccinimide, and N-chlorosuccinimide, or a mixture of two or more thereof in any proportion; The catalyst is selected from N,N-dimethylformamide, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, thiourea or dimethylthiourea; The solvent is selected from one of toluene, acetonitrile, xylene, chlorobenzene, dichloromethane, and dichloroethane, or a mixed solvent of two or more in any proportion; (4) Compound (V), piperazine, a solvent, and an acid-binding agent are mixed, reacted at 20 to 130° C. for 0.5 to 20 h, and then post-treated to obtain compound (VI); The molar ratio of the compound (V), piperazine and acid-binding agent is 1:1-1.5:0.5-3; The acid binding agent is selected from sodium hydride, potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or sodium carbonate; The solvent is selected from toluene, xylene, trimethylbenzene, chlorobenzene, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, dimethyl sulfone, N-methylpyrrolidone, N,N-dimethylacetamide, sulfolane or hexamethylphosphoramide; (5) Compound (VI), compound (VII), a solvent and an acid binding agent are mixed, reacted at 20 to 130° C. for 0.5 to 20 h, and then post-treated to obtain compound (I); The molar ratio of the compound (VI), the compound (VII) and the acid-binding agent is 1:0.8-1.2:0.5-3; The acid binding agent is selected from sodium hydride, potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, potassium bicarbonate or sodium carbonate; The solvent is selected from toluene, xylene, trimethylbenzene, chlorobenzene, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, dimethyl sulfone, N-methylpyrrolidone, N,N-dimethylacetamide, sulfolane or hexamethylphosphoramide; The reaction process is as follows: In formula (II), (III), (IV), (V) or (VI), R1, R2, and m are the same as those in formula (I); In formula (III), Y1 is selected from N,N-dimethylamino, methoxy or ethoxy; In formula (V), Y2 is selected from chlorine or bromine; In formula (VII), R3, X, and n are the same as those in formula (I), and G is halogen.

4. Use of the pyridylpiperazine compound or its salt as claimed in claim 1 as a fungicide in the fields of agriculture, forestry or sanitation; the fungicide has fungicidal activity against soybean rust and cucumber downy mildew.

5. A fungicidal composition comprising as an active ingredient the pyridylpiperazine compound or its salt as claimed in claim 1 and an agriculturally acceptable carrier, wherein the weight percentage of the active ingredient in the composition is 0.5 to 99%.

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