Cycloalkyl substituted triazolopicolinamide compound as well as preparation method and application thereof

Abstract

The invention provides a naphthenic base substituted triazolopicolinamide compound as well as a preparation method and application thereof, and belongs to the technical field of pesticides. According to the cycloalkyl substituted triazolo picolinamide compound provided by the invention, unsubstituted or substituted cyclohexyl and unsubstituted or substituted cyclopentyl are introduced to a triazole ring, so that the cycloalkyl substituted triazolo picolinamide compound has an excellent inhibition effect on phytophthora capsici in important oomycetes diseases, and the EC50 of the cycloalkyl substituted triazolo picolinamide compound to the phytophthora capsici is as low as 0.3 mu mol / L; the naphthenic base substituted triazolopicolinamide compound and the derivative thereof have a significant effect on rhizoctonia solani, rhizoctonia cerealis, sclerotinia sclerotiorum, fusarium graminearum, gaeumannomyces graminis, botrytis cinerea, phytophthora infestans, phytophthora capsici, alternaria solani, fusarium moniliforme, potato dry rot pathogen, phytophthora capsici and the like. Cucumber colletotrichum gloeosporioides and magnaporthe oryzae also have broad-spectrum antibacterial activity, and the compound has a good application prospect in preparation of drugs for resisting plant pathogenic fungi.

Description

Technical Field

[0001] The present invention relates to the technical field of pesticides, and in particular to a cycloalkyl-substituted triazolopyridineamide compound, a preparation method and application thereof, and a derivative of the cycloalkyl-substituted triazolopyridineamide compound and application thereof. Background Art

[0002] The active group of methoxyacrylate fungicides is methoxyacrylate (ester / amide), which mainly acts on the cytochrome bCl complex in the mitochondrial respiratory chain of fungi, preventing electron transfer and thus inhibiting fungal growth. It has the characteristics of protection, treatment, eradication, and penetration, and is non-carcinogenic and non-mutagenic. It can effectively prevent and treat diseases caused by fungi such as ascomycetes, basidiomycetes, deuteromycetes and oomycetes, and has a high degree of environmental safety. It is currently the most widely used fungicide for plant diseases. However, the resistance of methoxyacrylate fungicides has begun to restrict the development of this type of fungicide. Amide fungicides can effectively overcome the resistance problem of methoxyacrylate fungicides and are one of the fungicide varieties that have been actively studied in recent years. The main representative of amide fungicides is succinate dehydrogenase inhibitor SDHIs. With the extensive use of SDHIs, many pathogens in the field have developed resistance to this type of agent. Therefore, the discovery of chemical small molecule pesticides with new structures provides a new way to solve the above problems.

[0003] A triazolopyridineamide compound (structural formula shown below) is disclosed in the related art, which has a broad spectrum and good antibacterial effect on plant pathogenic fungi. However, the antibacterial effect of the triazolopyridineamide compound on pepper phytophthora, an important oomycete disease, is relatively poor.

[0004] Summary of the invention

[0005] In view of this, the object of the present invention is to provide a cycloalkyl-substituted triazolopyridineamide compound and a preparation method and application thereof, a derivative of a cycloalkyl-substituted triazolopyridineamide compound and an application thereof. The cycloalkyl-substituted triazolopyridineamide compound provided by the present invention has excellent inhibitory effect on pepper phytophthora.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a cycloalkyl-substituted triazolopyridine amide compound having a structure shown in Formula I:

[0008]

[0009] wherein X comprises oxygen or sulfur;

[0010] R1 and R 2 independently include hydrogen, C 1 ~C 6 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted heterocyclic group; when R 1 and R 2 When both are not hydrogen, * indicates a chiral center; R 1 and R 2 The stereo configuration of the carbon chiral center is independently R-type or S-type;

[0011] R 3 Including hydrogen, C 1 ~C 6 Alkyl, halogen, hydroxyl, amino, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkylamino or C 1 ~C 6 haloalkyl; said R 3 The number of is 1 to 3;

[0012] R 4 Including hydrogen, halogen, C 1 ~C 6 Alkyl, cyclohexyl, unsubstituted or substituted aryl, phenoxy, C 1 ~C 6 Haloalkyl, alkylcarbonyl or C 1 ~C 6 Alkoxy;

[0013] R 5 Included are unsubstituted or substituted cyclohexyl, and unsubstituted or substituted cyclopentyl.

[0014] Preferably, R 1 and R 2 middle,

[0015] The substituents in the substituted phenyl group include phenyl, halogen, hydroxyl, amino, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkylamino or C 1 ~C 6 Haloalkyl;

[0016] The substituents in the substituted heterocyclic group include heterocyclic groups, halogen, hydroxyl, amino, C 1 ~C 6 Alkoxy or C 1 ~C 6 Alkylamino;

[0017] The heterocyclic group in the unsubstituted or substituted heterocyclic group includes pyridyl, thienyl or furyl;

[0018] R 4 In the substituted aryl group, the substituents include halogen, trifluoromethyl, C 1 ~C 6 Hydroxyl, C 1 ~C 6 Hydrocarbon or C 1 ~C 6 Hydrocarbylamino;

[0019] R 5 wherein the substituents in the substituted cyclohexyl group and the substituents in the substituted cyclopentyl group independently include C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Alkylamino, C 1 ~C 3 Haloalkyl or halogen.

[0020] Preferably, the C 1 ~C 6 Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;

[0021] The C 1 ~C 6 Alkoxy groups include -OCH 3 、-OCH 2 CH 3 、-O(CH 2 ) 2 CH 3 、-OCH(CH 3 ) 2 、-O(CH 2 ) 3 CH 3 、-OCH 2 CH(CH 3 ) 2 、-OCHCH 3 CH 2 CH 3 、-O(CH 3 ) 3 、-O(CH 2 ) 4 CH 3 、-OCH(CH 3 )CH 2 CH 2 CH 3 、-OCH 2CH(CH 3 )CH 2 CH 3 、 -OCH 2 CH 2 CH(CH 3 ) 2 、 -OCH(CH 3 ) 2 CH 2 CH 3 或 -OCH 2 C(CH 3 ) 3 ;

[0022] The C 1 -C 6 alkylamine group includes -NHCH 3 、 -NHCH 2 CH 3 、 -NH(CH 2 ) 2 CH 3 、 -NHCH(CH 3 ) 2 、 -NH(CH 2 ) 3 CH 3 、 -NHCH 2 CH(CH 3 ) 2 、 -NHCH(CH 3 )CH 2 CH 3 、 -NH(CH 3 ) 3 、 -NH(CH 2 ) 4 CH 3 、 -NHCH(CH 3 )CH 2 CH 2 CH 3 、 -NHCH 2 CH(CH 3 )CH 2 CH 3 、 -NHCH 2 CH 2 CH(CH 3 ) 2 、 -NHC(CH 3 ) 2 CH 2 CH 3 或 -NHCH 2 C(CH 3 ) 3 ;

[0023] The C 1 ~C 6 Haloalkyl groups include -CF 2 H or -CF 3 .

[0024] Preferably, the cycloalkyl-substituted triazolopyridine amide compound has a structure shown in Formula I-1 or Formula I-2:

[0025]

[0026] The present invention provides a method for preparing the cycloalkyl-substituted triazolopyridine amide compound described in the above technical scheme, comprising the following steps:

[0027] Mixing compound II, compound III, a condensing agent, triethylamine and an organic solvent to carry out a condensation reaction to obtain the cycloalkyl-substituted triazolopyridine amide compound;

[0028]

[0029] Among them, R 1 ~R 5 The same as in Formula I.

[0030] Preferably, the condensation reaction temperature is 0 to 40°C and the time is 12 to 96 hours;

[0031] The compound II includes compound II-1 or compound II-2;

[0032]

[0033] The preparation method of the compound II-1 comprises the following steps:

[0034] Compound 1, compound 2, a catalyst and a benzene solvent are mixed to carry out a Witte seeliger cyclization reaction to obtain compound II-1;

[0035] The preparation method of the compound II-2 includes method 1 or method 2, wherein:

[0036] Method 1: Mix the compound II-1, phosphorus pentasulfide and a benzene solvent, and perform a replacement reaction to obtain compound II-2;

[0037] Method 2: Compound 7, compound 2 and a cyclic solvent are mixed and subjected to a decarboxylation amidation reaction to obtain compound 8;

[0038] The compound 8, phosphorus pentasulfide and a heterocyclic solvent are mixed to carry out a cyclization reaction to obtain compound II-2;

[0039]

[0040] Among them, R 1 ~R 3 The same as in Formula I.

[0041] Preferably, the preparation method of compound III comprises the following steps:

[0042] Compound 3, hydrazine hydrate and a heterocyclic solvent are mixed to carry out a substitution reaction to obtain compound 4;

[0043]

[0044] The compound 4, the compound 5, an oxidant and an organic solvent are mixed to carry out a condensation oxidation reaction to obtain a compound 6;

[0045]

[0046] The compound 6, lithium hydroxide and an organic solvent are mixed and subjected to a hydrolysis reaction to obtain a compound III;

[0047] Among them, R 4 and R 5 The same as in Formula I.

[0048] The present invention provides derivatives of the cycloalkyl-substituted triazolopyridine amide compounds described in the above technical solution, wherein the derivatives include pesticide chemically acceptable salts.

[0049] The present invention provides the use of the cycloalkyl substituted triazolopyridine amide compound described in the above technical solution or the derivative of the cycloalkyl substituted triazolopyridine amide compound described in the above technical solution in the preparation of an anti-plant pathogenic fungus drug.

[0050] Preferably, the plant pathogenic fungi include one or more of rice sheath blight, wheat sheath blight, rapeseed sclerotinia, wheat fusarium rust, wheat take-all, tomato gray mold, potato infestation, pepper phytophthora, tomato early blight, rice seedling bakanae, potato dry rot, cucumber anthracnose and rice blast.

[0051] The present invention provides a cycloalkyl-substituted triazolopyridine amide compound having a structure shown in Formula I; wherein X comprises oxygen or sulfur; R 1 and R 2 independently include hydrogen, C 1 ~C 6 Alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted heterocyclic group; R 1 and R 2 The stereo configuration of the carbon chiral center is independently R or S; when R1 and R 2 When both are not hydrogen, * indicates a chiral center; R 3 Including hydrogen, C 1 ~C 6 Alkyl, halogen, hydroxyl, amino, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkylamino or C 1 ~C 6 haloalkyl; said R 3 The number of R is 1 to 3; 4 Including hydrogen, halogen, C 1 ~C 6 Alkyl, cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted heterocyclic group, C 1 ~C 6 Haloalkyl, alkylcarbonyl or C 1 ~C 6 Alkoxy; R 5 Including unsubstituted or substituted cyclohexyl, unsubstituted or substituted cyclopentyl. The present invention provides cycloalkyl substituted triazolopyridine amide compounds, in which unsubstituted or substituted cyclohexyl, unsubstituted or substituted cyclopentyl are introduced on the triazole ring, and have excellent inhibitory effects on pepper phytophthora in important oomycete diseases, and the EC50 (inhibitory median concentration) for pepper phytophthora is as low as 0.3 μmol / L; moreover, the cycloalkyl substituted triazolopyridine amide compounds and their derivatives provided by the present invention have broad-spectrum antibacterial activity against rice sheath blight, wheat sheath blight, rapeseed sclerotinia, wheat fusarium head blight, wheat take-all, tomato gray mold, potato late blight, pepper phytophthora, tomato early blight, rice seedling blight, potato dry rot, cucumber anthracnose and rice blast, and have good application prospects in the preparation of anti-plant pathogenic fungi drugs.

[0052] The present invention provides a method for preparing the cycloalkyl-substituted triazolopyridine amide compound described in the above technical scheme. The preparation method provided by the present invention is simple to operate, has low raw material cost, is green and environmentally friendly, and is suitable for industrial production. DETAILED DESCRIPTION

[0053] The present invention provides a cycloalkyl-substituted triazolopyridine amide compound having a structure shown in Formula I:

[0054]

[0055] In the present invention, in the formula I, X includes oxygen or sulfur.

[0056] In the present invention, in the formula I, R 1 Including hydrogen, C1 ~C 6 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted heterocyclic group; when R 1 When not hydrogen, * indicates a chiral center; R 1 The stereo configuration of the carbon chiral center is R type or S type. In the present invention, the C 1 ~C 6 The alkyl group preferably includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

[0057] In the present invention, the substituents in the substituted phenyl group preferably include phenyl, halogen, hydroxyl, amino, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkylamino or C 1 ~C 6 In the present invention, the C 1 ~C 6 Alkoxy groups preferably include -OCH 3 、-OCH 2 CH 3 、-O(CH 2 ) 2 CH 3 、-OCH(CH 3 ) 2 、-O(CH 2 ) 3 CH 3 、-OCH 2 CH(CH 3 ) 2 、-OCHCH 3 CH 2 CH 3 、-O(CH 3 ) 3 、-O(CH 2 ) 4 CH 3 、-OCH(CH 3 )CH 2 CH 2 CH 3 、-OCH 2 CH(CH 3 )CH 2 CH 3 、-OCH 2 CH 2 CH(CH 3 ) 2 、-OCH(CH 3 ) 2 CH 2 CH3 or -OCH 2 C(CH 3 ) 3 ; said C 1 ~C 6 Alkylamino groups preferably include -NHCH 3 、-NHCH 2 CH 3 、-NH(CH 2 ) 2 CH 3 、-NHCH(CH 3 ) 2 、-NH(CH 2 ) 3 CH 3 、-NHCH 2 CH(CH 3 ) 2 、-NHCH(CH 3 )CH 2 CH 3 、-NH(CH 3 ) 3 、-NH(CH 2 ) 4 CH 3 、-NHCH(CH 3 )CH 2 CH 2 CH 3 、-NHCH 2 CH(CH 3 )CH 2 CH 3 、-NHCH 2 CH 2 CH(CH 3 ) 2 、-NHC(CH 3 ) 2 CH 2 CH 3 or -NHCH 2 C(CH 3 ) 3 ; said C 1 ~C 6 Preferred haloalkyl groups include -CF 2 H or -CF 3 ; The halogen preferably includes fluorine, chlorine, bromine or iodine.

[0058] In the present invention, the substituents in the substituted heterocyclic group preferably include heterocyclic substituents, halogen, hydroxyl, amino, C 1 ~C 6 Alkoxy or C 1 ~C6 In the present invention, the heterocyclic substituent preferably includes pyridyl, thienyl or furyl; the heterocyclic group in the unsubstituted or substituted heterocyclic group preferably includes pyridyl, thienyl or furyl. In the present invention, the halogen, C 1 ~C 6 Alkoxy and C 1 ~C 6 The optional substituents of the alkylamino group are preferably the same as the aforementioned halogen, C 1 ~C 6 Alkoxy and C 1 ~C 6 The optional substituents of the alkylamino group are of the same type and will not be described in detail here.

[0059] In the present invention, in the formula I, R 2 Including hydrogen, C 1 ~C 6 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted heterocyclic group; when R 2 When not hydrogen, * indicates a chiral center; R 2 The stereo configuration of the carbon chiral center is R or S.

[0060] In the present invention, the C 1 ~C 6 The optional substituents of the alkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heterocyclic group are preferably the same as those in the above C 1 ~C 6 The optional substituents of the alkyl group, the unsubstituted or substituted phenyl group, and the unsubstituted or substituted heterocyclic group are of the same types and will not be described in detail here.

[0061] In the present invention, in the formula I, R 3 Including hydrogen, C 1 ~C 6 Alkyl, halogen, hydroxyl, amino, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkylamino or C 1 ~C 6 haloalkyl; said R 3 The number of C is 1 to 3, specifically 1, 2 or 3. 1 ~C 6 Alkyl, halogen, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkylamino and C 1 ~C 6 The optional substituents of the haloalkyl group are preferably the same as those in the above C 1 ~C6 Alkyl, halogen, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkylamino and C 1 ~C 6 The optional substituents of the haloalkyl group are the same and will not be described in detail here.

[0062] In the present invention, in the formula I, R 4 Including hydrogen, halogen, C 1 ~C 6 Alkyl, cyclohexyl, unsubstituted or substituted aryl, phenoxy, C 1 ~C 6 Haloalkyl, alkylcarbonyl or C 1 ~C 6 In the present invention, the alkylcarbonyl group preferably includes methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl or benzylcarbonyl; the substituent in the substituted aryl group preferably includes halogen, trifluoromethyl, C 1 ~C 6 Hydroxyl, C 1 ~C 6 Hydrocarbon or C 1 ~C 6 Alkylamino, more preferably halogen, trifluoromethyl, methyl, methoxy, ethoxy, methylamino or ethylamino; said C 1 ~C 6 The alkoxy group preferably includes methoxy, ethoxy, isopropoxy or cyclopropyloxy; the aryl group in the unsubstituted or substituted aryl group preferably includes phenyl. 1 ~C 6 Alkyl and C 1 ~C 6 The optional substituents of the haloalkyl group are preferably the same as the aforementioned halogen, C 1 ~C 6 Alkyl and C 1 ~C 6 The optional substituents of the haloalkyl group are the same and will not be described in detail here.

[0063] In the present invention, in the formula I, R 5 Including unsubstituted or substituted cyclohexyl, unsubstituted or substituted cyclopentyl. In the present invention, the substituents in the substituted cyclohexyl and the substituents in the substituted cyclopentyl independently preferably include C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Alkylamino, C1 ~C 3 In the present invention, the C 1 ~C 3 Alkyl preferably includes methyl or ethyl; C 1 ~C 3 Alkoxy preferably includes methoxy, ethoxy, isopropoxy or cyclopropyloxy; C 1 ~C 3 The alkylamino group preferably includes methylamino, ethylamino, isopropylamino or cyclopropylamino; C 1 ~C 3 The haloalkyl group preferably includes chloromethyl, dichloromethyl, difluoromethyl or trifluoromethyl; the halogen group preferably includes fluorine, chlorine, bromine or iodine.

[0064] In the present invention, the cycloalkyl-substituted triazolopyridine amide compound preferably has a structure shown in Formula I-1 or Formula I-2:

[0065]

[0066] The present invention provides a method for preparing the cycloalkyl-substituted triazolopyridine amide compound described in the above technical scheme, comprising the following steps:

[0067] Mixing compound II, compound III, a condensing agent, triethylamine and an organic solvent to carry out a condensation reaction to obtain the cycloalkyl-substituted triazolopyridine amide compound;

[0068]

[0069] Among them, R 1 ~R 5 The same as in Formula I.

[0070] In the present invention, unless otherwise specified, the raw material components used are commercially available products well known to those skilled in the art.

[0071] In the present invention, the compound II preferably includes compound II-1 or compound II-2;

[0072]

[0073] In the present invention, the preparation route of compound II is shown in route 1:

[0074]

[0075] Among them, R 1 ~R 3 The same as in Formula I.

[0076] In the present invention, the preparation method of the compound II-1 preferably comprises the following steps: mixing compound 1, compound 2, a catalyst and a benzene solvent, and performing a Witte seeliger cyclization reaction to obtain compound II-1;

[0077]

[0078] Among them, R 1 ~R 3 The same as in Formula I.

[0079] In the present invention, the molar ratio of compound 1 (o-aminobenzonitrile) to compound 2 (chiral amino alcohol) is preferably 1:1-1.5, more preferably 1:1.1-1.4, and most preferably 1:1.2-1.3. In the present invention, the catalyst preferably includes a zinc salt, and the zinc salt preferably includes one or more of zinc chloride, zinc fluoride, zinc bromide and zinc acetate; more preferably anhydrous zinc chloride. In the present invention, the molar ratio of compound 1 to the catalyst is preferably 1:0.5-3, more preferably 1:1-2.5, and most preferably 1:1.5-2. In the present invention, the benzene solvent preferably includes one or more of chlorobenzene, toluene, xylene, fluorobenzene and bromobenzene; the benzene solvent is preferably an anhydrous benzene solvent. The present invention has no special limitation on the amount of the benzene solvent, as long as the Witte seeliger cyclization reaction can proceed smoothly. The present invention has no special limitation on the mixing method, as long as the raw materials can be mixed evenly, such as stirring and mixing. In the present invention, the temperature of the Witteseeliger cyclization reaction is preferably 100-150°C, more preferably 110-140°C, and most preferably 120-130°C; the time of the Witteseeliger cyclization reaction is preferably 12-96h, more preferably 20-80h, and most preferably 30-50h.

[0080] After completing the Witte seeliger cyclization reaction, the present invention preferably further comprises concentrating the cyclization liquid obtained by the Witte seeliger cyclization reaction, adding a quencher to quench the reaction, extracting with an extractant, and drying and purifying the organic phase obtained by the extraction to obtain compound II-1. The present invention has no special limitation on the concentration, and a concentration method familiar to those skilled in the art can be used, such as vacuum distillation. The present invention has no special limitation on the vacuum distillation, and the solvent can be removed. In the present invention, the quencher preferably includes an aqueous hydroxide solution; the hydroxide in the aqueous hydroxide solution preferably includes sodium hydroxide and / or ammonium hydroxide; the mass concentration of the hydroxide in the aqueous hydroxide solution is preferably 0 to 35%, more preferably 10 to 20%, and most preferably 15 to 18%; the ratio of the amount of the compound 1 to the volume of the quencher is preferably 1 mmol: 0.2 to 1 mL, more preferably 1 mmol: 0.5 to 0.8 mL, and most preferably 1 mmol: 0.6 to 0.7 mL. In the present invention, the extractant preferably includes ethyl acetate or dichloromethane; the ratio of the amount of the compound 1 to the volume of the extractant is preferably 1 mmol: 5-15 mL, more preferably 1 mmol: 8-12 mL, and most preferably 1 mmol: 9-10 mL.

[0081] In the present invention, the desiccant used for the drying preferably includes anhydrous sodium sulfate. The present invention has no special limitation on the amount of the desiccant, and the amount can be sufficient to completely dry the water in the organic phase. In the present invention, the purification preferably includes column chromatography separation; the column filler used for the column chromatography separation preferably includes silica column chromatography silica gel (i.e., silica filler); the eluent used for the column chromatography separation preferably includes ethyl acetate-petroleum ether mixed solvent; the elution method is preferably gradient elution; the volume ratio of petroleum ether and ethyl acetate in the ethyl acetate-petroleum ether mixed solvent during the gradient elution is preferably 1:1-1.5, more preferably 1:1.1-1.4, and further preferably 1:1.2-1.3. In a specific embodiment of the present invention, the volume ratio of petroleum ether and ethyl acetate in the ethyl acetate-petroleum ether mixed solvent is 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 and 1:1.5, respectively.

[0082] In the present invention, the preparation method of the compound II-2 preferably includes method 1 or method 2, wherein:

[0083] Method 1: Mix the compound II-1, phosphorus pentasulfide and a benzene solvent, and perform a replacement reaction to obtain compound II-2;

[0084] Method 2: Compound 7, compound 2 and a cyclic solvent are mixed and subjected to a decarboxylation amidation reaction to obtain compound 8;

[0085] The compound 8, phosphorus pentasulfide and a heterocyclic solvent are mixed to carry out a cyclization reaction to obtain compound II-2;

[0086]

[0087] Method 1: In the present invention, the compound II-1, phosphorus pentasulfide and a benzene solvent are mixed to carry out a replacement reaction to obtain compound II-2.

[0088] In the present invention, the molar ratio of the compound II-1 to phosphorus pentasulfide is preferably 1:1.5-3, more preferably 1:2-2.5, and most preferably 1:2.2-2.4. In the present invention, the benzene solvent preferably includes one or more of toluene and xylene; the benzene solvent is preferably an anhydrous benzene solvent; the present invention has no special limitation on the amount of the benzene solvent, as long as the replacement reaction can proceed smoothly. The present invention has no special limitation on the mixing, as long as the raw materials can be mixed evenly, such as stirring and mixing. In the present invention, the temperature of the replacement reaction is preferably 90-110°C, more preferably 95-105°C, and most preferably 100°C; the time of the replacement reaction is preferably 6-72h, more preferably 20-60h, and most preferably 30-50h.

[0089] After completing the replacement reaction, the present invention preferably further comprises cooling the replacement reaction liquid obtained by the replacement reaction to room temperature, adding a quencher to quench the reaction, separating the solid and liquid, separating the obtained liquid components, drying the obtained organic phase with a desiccant, concentrating and purifying to obtain compound II-2. The present invention has no special limitation on the cooling, and a cooling method well known to those skilled in the art can be used, such as natural cooling. In the present invention, the quencher preferably includes an alkaline aqueous solution, more preferably an aqueous NaOH solution, NaHCO 3 Aqueous solution and Na 2 CO 3One or more of the aqueous solution, the mass concentration of the alkaline aqueous solution is preferably 10-50%, more preferably 15-40%, and most preferably 20-30%; the amount of the compound II-1 and the volume ratio of the quencher are preferably 1mmol: 0.4-1mL, more preferably 1mmol: 0.5-0.8mL, and most preferably 1mmol: 0.6-0.7mL. The present invention has no special restrictions on the solid-liquid separation, and the solid-liquid separation method well known to those skilled in the art can be used, such as centrifugal separation, filtration or suction filtration. In the present invention, the phase separation preferably includes phase separation using a separatory funnel. In the present invention, the desiccant preferably includes anhydrous sodium sulfate. The present invention has no special restrictions on the amount of the desiccant, and the water in the organic phase can be completely dried. The present invention has no special restrictions on the concentration, and the concentration method well known to those skilled in the art can be used, such as reduced pressure distillation. The present invention has no special restrictions on the conditions of the reduced pressure distillation, and the solvent can be removed. In the present invention, the purification preferably includes column chromatography separation; the column filler used in the column chromatography separation preferably includes silica column chromatography silica gel; the eluent used in the column chromatography separation preferably includes ethyl acetate-petroleum ether mixed solvent; the elution method is preferably gradient elution; during the gradient elution process, the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate-petroleum ether mixed solvent is preferably 1:1-15, more preferably 1:5-12, and most preferably 1:8-10.

[0090] Method 2: In the present invention, compound 7 (isatoic anhydride), compound 2 and a cyclic solvent are mixed and subjected to a decarboxylation amidation reaction to obtain compound 8.

[0091] In the present invention, the molar ratio of compound 7 to compound 2 is preferably 1:1-1.5, more preferably 1:1.1-1.4, and most preferably 1:1.2-1.3. In the present invention, the cyclic solvent preferably includes 1,4-dioxane; the present invention has no special limitation on the amount of the cyclic solvent, as long as the decarboxylation amidation reaction can proceed smoothly. The present invention has no special limitation on the mixing, as long as the raw materials can be mixed evenly, such as stirring and mixing. In the present invention, the temperature of the decarboxylation amidation reaction is preferably 40-150°C, more preferably 50-100°C, and most preferably 60-80°C; the time of the decarboxylation amidation reaction is preferably 12-18h, more preferably 14-17h, and most preferably 15-16h; the decarboxylation amidation reaction is preferably carried out under reflux conditions.

[0092] After the decarboxylation amidation reaction is completed, the present invention preferably further comprises concentrating the amidation reaction solution obtained by the decarboxylation amidation reaction, adding a quencher to quench the reaction, extracting with an extractant, and drying and purifying the organic phase obtained by the extraction to obtain compound 8. The present invention has no special limitation on the concentration, and a concentration method well known to those skilled in the art can be used, such as vacuum distillation. The present invention has no special limitation on the vacuum distillation, and the solvent can be removed. In the present invention, the quencher preferably comprises an aqueous hydroxide solution; the hydroxide in the aqueous hydroxide solution preferably comprises sodium hydroxide and / or ammonium hydroxide; the mass concentration of the hydroxide in the aqueous hydroxide solution is preferably 0 to 35%, more preferably 10 to 20%, and most preferably 15 to 18%; the ratio of the amount of the compound 7 to the volume of the quencher is preferably 1 mmol: 5 to 10 mL, more preferably 1 mmol: 6 to 9 mL, and most preferably 1 mmol: 7 to 8 mL. In the present invention, the extractant preferably comprises ethyl acetate or dichloromethane. In the present invention, the drying agent used in the drying preferably comprises anhydrous sodium sulfate. The present invention has no special limitation on the amount of the desiccant, as long as the amount of the desiccant can completely dry the water in the organic phase. In the present invention, the purification preferably includes column chromatography separation; the column filler used in the column chromatography separation preferably includes silica column chromatography silica gel; the eluent used in the column chromatography separation preferably includes a dichloromethane-methanol mixed solvent; the elution method is preferably gradient elution; the volume ratio of dichloromethane and methanol in the dichloromethane-methanol mixed solvent during the gradient elution is preferably 20:0.5-5, more preferably 20:0.8-3, and most preferably 20:1-2.

[0093] After obtaining compound 8, the present invention mixes compound 8, phosphorus pentasulfide and a heterocyclic solvent to perform a cyclization reaction to obtain compound II-2.

[0094] In the present invention, the molar ratio of the compound 8 to phosphorus pentasulfide is preferably 1:1.5-3, more preferably 1:2-2.5, and most preferably 1:2.2-2.4. In the present invention, the heterocyclic solvent preferably includes pyridine; the heterocyclic solvent is preferably an anhydrous heterocyclic solvent; the present invention has no special limitation on the amount of the heterocyclic solvent, as long as the cyclization reaction can proceed smoothly. The present invention has no special limitation on the mixing, as long as the raw materials can be mixed evenly, such as stirring and mixing. In the present invention, the temperature of the cyclization reaction is preferably 90-110°C, more preferably 95-105°C, and most preferably 100°C; the time of the cyclization reaction is preferably 4-24h, more preferably 8-20h, and most preferably 12-16h.

[0095] After completing the cyclization reaction, the present invention preferably further comprises cooling the cyclization reaction liquid obtained by the cyclization reaction to room temperature, adding a quencher to quench the reaction, separating the solid and liquid, separating the obtained liquid components, drying the obtained organic phase with a desiccant, concentrating and purifying to obtain compound II-2. The present invention has no special limitation on the cooling, and a cooling method well known to those skilled in the art can be adopted, such as natural cooling. In the present invention, the quencher preferably includes an acidic aqueous solution, more preferably one or more of hydrochloric acid aqueous solutions, and the mass concentration of the acidic aqueous solution is preferably 5-25%, more preferably 10-22%, and most preferably 15-20%; the ratio of the amount of the compound 8 to the volume of the quencher is preferably 1mmol:5-10mL, more preferably 1mmol:6-9mL, and most preferably 1mmol:7-8mL. The present invention has no special limitation on the solid-liquid separation, and a solid-liquid separation method well known to those skilled in the art can be adopted, such as centrifugal separation, filtration or suction filtration. In the present invention, the phase separation preferably includes phase separation using a separatory funnel. In the present invention, the desiccant preferably includes anhydrous sodium sulfate. The present invention has no special limitation on the amount of the desiccant, as long as the water in the organic phase can be completely dried. The present invention has no special limitation on the concentration, and a concentration method well known to those skilled in the art can be used, such as vacuum distillation. The present invention has no special limitation on the conditions of the vacuum distillation, as long as the solvent can be removed. In the present invention, the purification preferably includes column chromatography separation; the column filler used in the column chromatography separation preferably includes silica column chromatography silica gel; the eluent used in the column chromatography separation preferably includes ethyl acetate-petroleum ether mixed solvent; the elution method is preferably gradient elution; the volume ratio of ethyl acetate and petroleum ether in the ethyl acetate-petroleum ether mixed solvent during the gradient elution is preferably 1:1-15, more preferably 1:5-12, and most preferably 1:8-10.

[0096] In the present invention, the preparation method of the compound III preferably comprises the following steps: mixing compound 3, hydrazine hydrate and a heterocyclic solvent, and performing a substitution reaction to obtain compound 4;

[0097]

[0098] The compound 4, the compound 5, an oxidant and an organic solvent are mixed to carry out a condensation oxidation reaction to obtain a compound 6;

[0099]

[0100] The compound 6, lithium hydroxide and an organic solvent are mixed and hydrolyzed to obtain compound III; wherein R 4 and R 5 The same as in Formula I.

[0101] In the present invention, the preparation route of compound III is shown in Route 2.

[0102]

[0103] Route 2

[0104] The present invention mixes compound 3 (nicotinate ethyl ester), hydrazine hydrate and a heterocyclic solvent, and performs a substitution reaction to obtain compound 4.

[0105] In the present invention, the mass concentration of the hydrazine hydrate is preferably 40-81%, more preferably 50-81%, and most preferably 70-81%; the molar ratio of the compound 3 to the hydrazine hydrate is preferably 1:1-5, more preferably 1:2-4, and most preferably 1:3-4. In the present invention, the heterocyclic solvent preferably includes dioxane and / or tetrahydrofuran; the present invention has no special restrictions on the amount of the heterocyclic solvent, as long as the substitution reaction can proceed smoothly. The present invention has no special restrictions on the mixing, as long as the raw materials can be mixed evenly, such as stirring and mixing. In the present invention, the temperature of the substitution reaction is preferably 20-100°C, more preferably 30-80°C, and most preferably 50-60°C; the time of the substitution reaction is preferably 2-40h, more preferably 5-30h, and most preferably 10-20h.

[0106] After completing the substitution reaction, the present invention preferably further cools the substitution reaction solution obtained by the substitution reaction to room temperature, concentrates and purifies to obtain compound 4. The present invention has no special limitation on the cooling, and a cooling method well known to those skilled in the art can be used, such as natural cooling. The present invention has no special limitation on the concentration, and a concentration method well known to those skilled in the art can be used, such as vacuum distillation. The present invention has no special limitation on the vacuum distillation, and the solvent can be removed. In the present invention, the purification preferably includes column chromatography separation; the column filler used in the column chromatography separation preferably includes silica column chromatography silica gel; the eluent used in the column chromatography separation preferably includes ethyl acetate-petroleum ether mixed solvent; the elution method is preferably gradient elution; the volume ratio of ethyl acetate and petroleum ether in the ethyl acetate-petroleum ether mixed solvent during the gradient elution is preferably 1:0.5-5, more preferably 1:1.5-4, and most preferably 1:2.5-3.

[0107] After obtaining compound 4, the present invention mixes compound 4, compound 5, an oxidant and an organic solvent to carry out a condensation oxidation reaction to obtain compound 6.

[0108] In the present invention, the molar ratio of compound 4 to compound 5 is preferably 1:1-1.2, more preferably 1:1.05-1.15, and most preferably 1:1.1-1.12. In the present invention, the oxidant preferably includes iodophenyl diacetic acid (PIDA), iodophenyl ditrifluoroacetic acid, manganese dioxide or potassium permanganate; the organic solvent preferably includes one or more of alcohol solvents, heterocyclic solvents and benzene solvents, more preferably includes one or more of ethanol, methanol, tetrahydrofuran and dioxane; the organic solvent is preferably an anhydrous organic solvent; the present invention has no special limitation on the amount of the organic solvent, as long as the condensation oxidation reaction can proceed smoothly.

[0109] In the present invention, mixing the compound 4, compound 5, an oxidant and an organic solvent for a condensation oxidation reaction preferably includes: mixing the compound 4, compound 5 and an organic solvent for a condensation reaction to obtain a condensation product; mixing the condensation product, a dichloroalkane solvent and an oxidant for an oxidation reaction to obtain a compound 6.

[0110] In the present invention, the dichloroalkane solvent preferably includes dichloromethane and / or dichloroethane; the temperature of the condensation reaction is preferably 60-70°C, more preferably 62-68°C, and most preferably 64-65°C; the time of the condensation reaction is preferably 1-6h, more preferably 2-5h, and most preferably 3-4h.

[0111] After the condensation reaction is completed, the present invention preferably further comprises concentrating the condensation reaction solution obtained by the condensation reaction to obtain a condensation product. The present invention has no particular limitation on the concentration, and a concentration method well known to those skilled in the art can be used, such as vacuum distillation. The present invention has no particular limitation on the vacuum distillation, and the solvent can be removed.

[0112] After obtaining the condensation product, the present invention mixes the condensation product, dichloromethane and iodophenyldiacetic acid oxidant to carry out an oxidation reaction to obtain compound 6.

[0113] During the oxidation reaction, the present invention preferably further comprises thin layer chromatography (TLC) until the condensation product reacts completely. In the present invention, the eluent used in the thin layer chromatography preferably comprises an ethyl acetate-petroleum ether mixed solvent, and the volume ratio of ethyl acetate and petroleum ether in the ethyl acetate-petroleum ether mixed solvent during the elution process is preferably 1:0.1-10, more preferably 1:1-8, and most preferably 1:2-5. In the present invention, the temperature of the oxidation reaction is preferably room temperature, more preferably 15-40°C, and most preferably 25-30°C. The present invention does not specifically limit the time of the oxidation reaction, as long as the condensation product reacts completely. In the present invention, compound 4, compound 5 and an organic solvent are first mixed, dehydration condensation cyclization is carried out, and then mixed with an oxidant, dehydrogenation oxidation is carried out to obtain compound 6.

[0114] After completing the oxidation reaction, the present invention preferably further comprises adding a saturated sodium bicarbonate solution to the oxidation reaction liquid obtained by the oxidation reaction to quench the reaction, extracting with an organic solvent and then separating the phases, drying the obtained organic phase with a desiccant, concentrating and purifying to obtain compound 6. In the present invention, the organic solvent for extraction preferably comprises dichloromethane. In the present invention, the phase separation preferably comprises phase separation using a separatory funnel. In the present invention, the desiccant preferably comprises anhydrous sodium sulfate. In the present invention, the column chromatography separation preferably utilizes a silica column chromatography silica gel column for gradient elution; the eluent used in the column chromatography separation preferably comprises an ethyl acetate-petroleum ether mixed solvent, and the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate-petroleum ether mixed solvent is preferably 1:1-2, more preferably 1:1.2-1.8, and most preferably 1:1.4-1.6.

[0115] After obtaining compound 6, the present invention mixes the compound 6, lithium hydroxide and an organic solvent to carry out a hydrolysis reaction to obtain compound III.

[0116] In the present invention, the molar ratio of the compound 6 to lithium hydroxide is preferably 1:1-10, more preferably 1:2-8, and most preferably 1:3-5. In the present invention, the organic solvent is preferably methanol and / or tetrahydrofuran; the present invention has no special limitation on the amount of the organic solvent, as long as the hydrolysis reaction can proceed smoothly. The present invention has no special limitation on the mixing, as long as the raw materials can be mixed evenly, such as stirring and mixing. In the present invention, the temperature of the hydrolysis reaction is preferably 0-80°C, more preferably 10-60°C, and most preferably 20-40°C; the time of the hydrolysis reaction is preferably 6-72h, more preferably 10-60h, and most preferably 30-50h.

[0117] After completing the hydrolysis reaction, the present invention preferably further comprises concentrating the hydrolysis reaction liquid obtained after the hydrolysis reaction, adding water, adjusting the pH value to 5-8, and performing solid-liquid separation to obtain compound III. The present invention has no special limitation on the concentration, and a concentration method well known to those skilled in the art can be used, such as vacuum distillation. The present invention has no special limitation on the vacuum distillation, and the solvent can be removed. In the present invention, the pH adjusting agent used to adjust the pH value preferably includes sulfuric acid, hydrochloric acid, acetic acid or malic acid. The present invention has no special limitation on the solid-liquid separation, and a solid-liquid separation method well known to those skilled in the art can be used, such as centrifugal separation, filtration or suction filtration.

[0118] After obtaining compound II and compound III, the present invention mixes compound II, compound III, a neutralizing agent, a condensing agent and an organic solvent to carry out a condensation reaction to obtain the cycloalkyl substituted triazolopyridine amide compound.

[0119] In the present invention, the condensing agent preferably includes one or more of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU). In the present invention, the molar ratio of compound III to compound II is preferably 1:0.8-2, more preferably 1:0.8-1.2, and most preferably 1:0.9-1. In the present invention, the molar ratio of compound III to the condensing agent is preferably 1:1.1-3, more preferably 1:1.5-2.5, and most preferably 1:1.8-2.

[0120] In the present invention, the neutralizing agent preferably includes triethylamine; the molar ratio of the compound III to the neutralizing agent is preferably 1:1.3-2, more preferably 1:1.4-1.8, and most preferably 1:1.5-1.6. In the present invention, the organic solvent preferably includes a heterocyclic solvent and / or a substituted benzene solvent, more preferably one or more of dichloromethane, tetrahydrofuran, dioxane, toluene and chlorobenzene; the organic solvent is preferably an anhydrous solvent; the present invention does not specifically limit the amount of the organic solvent, as long as the condensation reaction can proceed smoothly. In a specific embodiment of the present invention, the mixing is preferably to dissolve the compound III in an organic solvent, add the condensing agent under ice bath (0°C) conditions and mix for 12-96h (more preferably 20-80h, most preferably 30-60h), and then add the neutralizing agent and compound II to mix. In the present invention, the temperature of the condensation reaction is preferably 0-40°C, more preferably 10-30°C, more preferably 20-25°C; the time of the condensation reaction is preferably 12-96h, more preferably 20-80h, most preferably 30-60h.

[0121] After the condensation reaction is completed, the present invention preferably further comprises adding a quencher to the condensation reaction solution obtained by the condensation reaction to quench the reaction, washing with water, concentrating and purifying to obtain the cycloalkyl substituted triazolopyridine amide compound. In the present invention, the quencher preferably comprises an alkaline aqueous solution, more preferably comprises NH 4 Cl aqueous solution, NaHCO 3 Aqueous solution and Na 2 CO 3 One or more of the aqueous solution, the mass concentration of the alkaline aqueous solution is preferably 10-50%, more preferably 20-40%; the ratio of the amount of the compound III to the volume of the quencher is preferably 1mmol:2-10mL, more preferably 1mmol:5-8mL. The present invention has no special limitation on the water washing, and water washing until neutrality is sufficient. The present invention has no special limitation on the concentration, and a concentration method well known to those skilled in the art can be adopted, such as vacuum distillation; the present invention has no special limitation on the vacuum distillation, and the solvent can be removed. In the present invention, the purification preferably includes column chromatography separation; the column filler used in the column chromatography separation preferably includes silica column chromatography silica gel; the eluent used in the column chromatography separation preferably includes ethyl acetate-petroleum ether mixed solvent; the elution method is preferably gradient elution; the volume ratio of ethyl acetate and petroleum ether in the ethyl acetate-petroleum ether mixed solvent during the gradient elution is preferably 1:1-15, more preferably 1:5-12, and most preferably 1:8-10

[0122] The present invention provides a derivative of the cycloalkyl-substituted triazolopyridine amide compound described in the above technical solution, wherein the derivative comprises a pesticide chemically acceptable salt. In the present invention, the pesticide chemically acceptable salt preferably comprises one or more of sodium salt, potassium salt, phosphate, hydrochloride, sulfate, oxalate, citrate, succinate, malate, maleate, salicylate and sulfonate.

[0123] The present invention provides the use of the cycloalkyl substituted triazolopyridine amide compound described in the above technical solution or the derivative of the cycloalkyl substituted triazolopyridine amide compound described in the above technical solution in the preparation of an anti-plant pathogenic fungus drug. In the present invention, the plant pathogenic fungi preferably include one or more of rice sheath blight fungus (Rhizoctonia solani), wheat sheath blight fungus (Rhizoctonia cerealis), rapeseed sclerotinia sclerotiorum (Sclerotiniascleotiorum), wheat fusarium graminearum (Fusarium graminearum), wheat take-all fungus (Gaeumanomycegraminis), tomato gray mold fungus (Botrytis cinerea), potato late blight fungus (Phytophthora infestans), pepper phytophthora capsici, tomato early blight fungus (Alternaria solani), rice seedling blight fungus (Fusarium fujikuroi), potato dry rot fungus (Fusarium sulphureum), cucumber anthracnose fungus (Colletotrichum lagenarium) and rice blast fungus (Pyricularia oryzac). The invention provides a cycloalkyl-substituted triazolopyridineamide compound, in which an unsubstituted or substituted cyclohexyl group or an unsubstituted or substituted cyclopentyl group is introduced into a triazole ring, and the compound has an excellent inhibitory effect on pepper phytophthora, an important oomycete disease, and the EC50 (inhibitory median concentration) for pepper phytophthora is as low as 0.3 μmol / L; moreover, the cycloalkyl-substituted triazolopyridineamide compound and its derivatives provided by the invention have a broad-spectrum antibacterial activity against rice sheath blight, wheat sheath blight, rapeseed sclerotinia, wheat fusarium head blight, wheat take-all, tomato gray mold, potato late blight, pepper phytophthora, tomato early blight, rice seedling blight, potato dry rot, cucumber anthracnose and rice blast, and have a good application prospect in the preparation of anti-plant pathogenic fungi drugs.

[0124] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0125] Example 1

[0126] Synthesis of Cycloalkyl-Substituted Triazolopyridine Amide Compound Z46

[0127]

[0128] (R)-2-amino-1-butanol (10 mmol) was added to a stirred solution of isatoic anhydride (10 mmol) and 1,4-dioxane, and the mixture was refluxed for 16 h until the raw material was completely consumed as monitored by TLC. The mixture was cooled to room temperature, diluted with 30 mL of ice water, and extracted with ethyl acetate for 3 times (the volume for a single extraction was 15 mL, recorded as 15 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated in vacuo, and separated by silica gel column chromatography (200-300 mesh, petroleum ether:ethyl acetate volume ratio = 20:1) to obtain intermediate B1 as a white solid, 1265 mg, with a yield of 61%.

[0129]

[0130] Hydrazine hydrate (60 mmol) was added to a stirred solution of ethyl 2-chloronicotinate (50 mmol) and 1,4-dioxane. The mixture was refluxed for 18 h until the raw material was completely consumed as monitored by TLC, cooled to room temperature, concentrated in vacuo, and separated by silica gel column chromatography (200-300 mesh, petroleum ether: ethyl acetate volume ratio = 1:2) to obtain ethyl 2-hydrazinonicotinate 4-A as a yellow filamentous solid, 7241 mg, with a yield of 41%.

[0131] Add 2-hydrazinonicotinic acid ethyl ester 4-A (10mmol), cyclohexylcarboxaldehyde (11mmol) in sequence to a clean and dry round-bottom flask, and add 50mL methanol to dissolve. Stir the reaction at 65°C for 2 hours until the raw material is completely consumed as monitored by TLC. Cool to room temperature and concentrate in vacuo. Add 20mL of anhydrous dichloromethane to the residue and dissolve it, and slowly add iodophenyldiacetic acid (PIDA, 13mmol). Stir the reaction at room temperature until the raw material reaction is complete as detected by TLC. The mixture is quenched with 20mL of saturated sodium bicarbonate solution, and the aqueous phase is extracted 3 times with anhydrous dichloromethane (the volume for a single extraction is 10mL, recorded as 10mL×3). After the organic phases are combined, they are dried over anhydrous sodium sulfate, concentrated in vacuo, and separated by silica gel column chromatography (200-300 mesh, petroleum ether: ethyl acetate volume ratio = 1:1) to obtain the intermediate triazolopyridinecarboxylate 6-A as a yellow solid, 1146mg, with a yield of 42%.

[0132] Lithium hydroxide (2.0 mmol) was added to a tetrahydrofuran solution of triazolopyridinecarboxylate 6-A (1.0 mmol). The mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, and dissolved in water. The mixture was adjusted to pH = 2 with hydrochloric acid to obtain intermediate pZ46 as a yellow solid, 214 mg, with a yield of 87%.

[0133] Triazolopyridinecarboxylic acid pZ46 (0.5 mmol) and intermediate B1 (0.5 mmol) were added to a clean and dry round-bottom flask in sequence, and 10.0 mL of anhydrous dichloromethane was added to dissolve. HATU (1.3 mmol) and triethylamine (0.8 mmol) were added under ice bath conditions, and the system was naturally restored to room temperature. The mixture was stirred at room temperature until the raw material was completely consumed as monitored by TLC. The mixture was washed twice with sodium bicarbonate solution (the volume for a single wash was 10 mL, recorded as 10.0 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Silica gel column chromatography (200-300 mesh, petroleum ether:ethyl acetate volume ratio = 2:1) was used to obtain the target compound 3-cyclohexyl-N-(2-(4-ethyl-4,5-dihydrothiazol-2-yl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide, denoted as Z46, as a white solid with a yield of 55%.

[0134] The hydrogen and carbon spectra of cycloalkyl substituted triazolopyridine amide compound Z46 are as follows:

[0135] 1 H NMR(400MHz,Chloroform-d)δ13.04(s,1H),8.76-8.68(m,1H),8.09(dd,J=15.1,6.8Hz,2H), 7.65(dd,J=7.8,1.5Hz,1H),7.47(dd,J=8.6,7.4,1.6Hz,1H),7.20-7.12(m,1H),6.97(t,J=6 .9Hz,1H),4.75(m,J=8.5,6.7Hz,1H),3.47(dd,J=10.7,8.4Hz,1H),3.13-2.96(m,2H),2.15- 1.78(m,8H),1.77-1.67(m,1H),1.63-1.55(m,1H),1.53-1.39(m,3H),0.71(t,J=7.4Hz,3H);

[0136] 13C NMR(101MHz,Chloroform-d)δ166.1,161.4,150.9,147.1,137.4,131.2,131.0,129.9,124 .5,123.8,123.3,122.3,113.2,79.8,37.1,34.7,30.6,30.5,28.0,25.9,25.8,24.9,10.7.

[0137] Example 2

[0138] Synthesis of Cycloalkyl-Substituted Triazolopyridine Amide Compound Z47

[0139]

[0140] Hydrazine hydrate (60 mmol) was added to a stirred solution of ethyl 2-chloronicotinate (50 mmol) and 1,4-dioxane. The mixture was refluxed for 18 h until the raw material was completely consumed as monitored by TLC, cooled to room temperature, concentrated in vacuo, and separated by silica gel column chromatography (200-300 mesh, petroleum ether: ethyl acetate volume ratio = 1:2) to obtain ethyl 2-hydrazinonicotinate 4-A as a yellow filamentous solid, 7241 mg, with a yield of 41%.

[0141] Add 2-hydrazinonicotinic acid ethyl ester 4-A (10mmol), cyclopentylcarboxaldehyde (11mmol) in sequence to a clean and dry round-bottom flask, and add 50mL methanol to dissolve. Stir the reaction at 65°C for 2 hours until the raw material is completely consumed as monitored by TLC. Cool to room temperature and concentrate in vacuo. Add 20mL of anhydrous dichloromethane to the residue to dissolve, and then slowly add iodophenyldiacetic acid (PIDA, 13mmol). Stir the reaction at room temperature until the raw material reacts completely as detected by TLC. The mixture is quenched with 20mL of saturated sodium bicarbonate solution, and the aqueous phase is extracted 3 times with anhydrous dichloromethane (the volume for a single extraction is 10mL, recorded as 10mL×3). After the organic phases are combined, they are dried over anhydrous sodium sulfate, concentrated in vacuo, and separated by silica gel column chromatography (200-300 mesh, petroleum ether: ethyl acetate volume ratio = 1:1) to obtain the intermediate triazolopyridinecarboxylate 6-B as a yellow solid, 1632mg, with a yield of 63%.

[0142] Lithium hydroxide (2.0 mmol) was added to a tetrahydrofuran solution of triazolopyridinecarboxylate 6-B (1.0 mmol). The mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, and dissolved in water. The mixture was adjusted to pH = 2 with hydrochloric acid to obtain intermediate pZ47 as a yellow solid, 183 mg, with a yield of 79%.

[0143] Triazolopyridinecarboxylic acid pZ47 (0.5 mmol) and intermediate B1 (0.5 mmol) were added to a clean and dry round-bottom flask in sequence, and 10.0 mL of anhydrous dichloromethane was added to dissolve. HATU (1.3 mmol) and triethylamine (0.8 mmol) were added under ice bath conditions, and the system was naturally restored to room temperature. The mixture was stirred at room temperature until the raw material was completely consumed as monitored by TLC. The mixture was washed twice with sodium bicarbonate solution (the volume for a single wash was 10 mL, recorded as 10.0 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Silica gel column chromatography (200-300 mesh, petroleum ether:ethyl acetate volume ratio = 2:1) was used to obtain the target compound 3-cyclopentyl-N-(2-(4-ethyl-4,5-dihydrothiazol-2-yl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide, denoted as Z47, as a yellow solid with a yield of 42%.

[0144] The hydrogen spectrum results of cycloalkyl substituted triazolopyridine amide compound Z47 are as follows:

[0145] 1 HNMR(500MHz,Chloroform-d)δ9.86(s,1H),8.56(dd,J=9.3,1.3Hz,1H),8.11(dd,J=8.2,1.3 Hz,1H),7.96(dd,J=8.0,1.4Hz,1H),7.59(dd,J=7.1,1.7Hz,1H),7.55(m,J=7.9,1.7Hz,1H), 7.41(dd,J=9.4,8.3Hz,1H),7.24(m,J=8.2,7.1,1.4Hz,1H),4.26-4.17(m,1H),3.29-3.18(m ,2H),2.87(p,J=4.5Hz,1H),2.07-1.96(m,2H),1.87-1.63(m,6H),1.02(t,J=7.2,1.5Hz,3H).

[0146] Comparative Example 1

[0147] The triazolopyridineamide compound boscalid has the following structural formula.

[0148]

[0149] Test Case

[0150] Determination of antibacterial activity of cycloalkyl-substituted triazolopyridine amides

[0151] The in vitro antibacterial activity was evaluated by the method of inhibiting mycelium growth rate, and the test strains were selected for activation on PDA plates, including rice sheath blight, rapeseed sclerotinia, tomato gray mold and pepper phytophthora. The cycloalkyl-substituted triazolopyridine amide compounds were respectively configured into a series of gradient concentrations (the concentrations were 30 μmol / L, 10 μmol / L, 3.3 μmol / L, 1.1 μmol / L, 0.37 μmol / L, 0.12 μmol / L and 0.04 μmol / L) of PDA drug-containing plates, and the test strains were made into 5 mm diameter bacterial cakes and placed in the center of the drug-containing culture dish, and cultured at a constant temperature of 25°C until the test strains of the blank control dish grew close to the edge of the culture dish, and the colony diameters of each drug-containing plate were measured by the cross method, and the inhibition rate of the compound on mycelium growth was calculated. The inhibition rate on the disease was calculated according to Formula I:

[0152] Disease inhibition rate (%) = (colony diameter of the control group - colony diameter of the drug group) / colony diameter of the control group × 100% Formula I.

[0153] The statistical software SPSS 20.0 was used to calculate the concentration of cycloalkyl-substituted triazolopyridine amide compounds when the inhibition rate was 50%, that is, EC 50 The results were repeated 3 times and the average value was taken. Boscalid was used as the positive control in the experiment. The test results are shown in Table 1.

[0154] Table 1 Inhibitory concentrations of the compounds obtained in Examples 1 to 2 and Comparative Examples 1 to 4 on four kinds of agricultural fungi

[0155]

[0156] As shown in Table 1, cycloalkyl-substituted triazolopyridineamide compounds have good inhibitory effects on common agricultural fungi, and the substituents on the triazole ring and the amine fragments of the amide have a significant effect on the antibacterial activity. When cyclohexyl and other cycloalkyl groups are introduced into the triazole ring of pyridine-triazole compounds, the antibacterial activity is significantly higher than that of the positive control boscalid, and the antibacterial spectrum is significantly different from that of the original aromatic-substituted triazolopyridinecarboxylic acid amide. Cycloalkyl-substituted triazolopyridineamide compounds can effectively inhibit the pepper phytophthora, an important oomycete disease, and the EC of the pyridine-triazole compounds against the pepper phytophthora is 1.34. 50 As low as 0.3 μmol / L, while boscalid is basically ineffective against oomycetes. The cycloalkyl substituted triazolopyridine amide compounds provided by the present invention are expected to be used as a new type of fungicide candidate compound or directly used as a fungicide, which is of great significance for the creation of new pesticides.

[0157] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A cycloalkyl-substituted triazolopyridine amide compound, It is characterized in that It has the structure shown in Formula I: wherein X comprises oxygen or sulfur; R 1 and R 2 independently include hydrogen, C 1 ~C 6 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted heterocyclic group; when R 1 and R 2 When both are not hydrogen, * indicates a chiral center; R 1 and R 2 The stereo configuration of the carbon chiral center is independently R-type or S-type; R 3 Including hydrogen, C 1 ~C 6 Alkyl, halogen, hydroxyl, amino, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkylamino or C 1 ~C 6 haloalkyl; said R 3 The number of is 1 to 3; R 4 Including hydrogen, halogen, C 1 ~C 6 Alkyl, cyclohexyl, unsubstituted or substituted aryl, phenoxy, C 1 ~C 6 Haloalkyl, alkylcarbonyl or C 1 ~C 6 Alkoxy; R 5 Included are unsubstituted or substituted cyclohexyl, and unsubstituted or substituted cyclopentyl.

2. The cycloalkyl-substituted triazolopyridine amide compound according to claim 1, It is characterized in that R 1 and R 2 middle, The substituents in the substituted phenyl group include phenyl, halogen, hydroxyl, amino, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkylamino or C 1 ~C 6 Haloalkyl; The substituents in the substituted heterocyclic group include heterocyclic groups, halogen, hydroxyl, amino, C 1 ~C 6 Alkoxy or C 1 ~C 6 Alkylamino; The heterocyclic group in the unsubstituted or substituted heterocyclic group includes pyridyl, thienyl or furyl; R 4 In the case where the substituents in the substituted aryl group include halogen, trifluoromethyl, C 1 ~C 6 Hydroxyl, C 1 ~C 6 Hydrocarbon or C 1 ~C 6 Hydrocarbylamino; R 5 wherein the substituents in the substituted cyclohexyl group and the substituents in the substituted cyclopentyl group independently include C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Alkylamino, C 1 ~C 3 Haloalkyl or halogen.

3. The cycloalkyl-substituted triazolopyridine amide compound according to claim 2, It is characterized in that The C 1 ~C 6 Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl; The C 1 to C 6 alkoxy group includes -OCH 3 、-OCH 2 CH 3 、-O(CH 2 ) 2 CH 3 、-OCH(CH 3 ) 2 、-O(CH 2 ) 3 CH 3 、-OCH 2 CH(CH 3 ) 2 、-OCHCH 3 CH 2 CH 3 、-O(CH 3 ) 3 、-O(CH 2 ) 4 CH 3 、-OCH(CH 3 )CH 2 CH 2 CH 3 、-OCH 2 CH(CH 3 )CH 2 CH 3 、-OCH 2 CH 2 CH(CH 3 ) 2 、-OCH(CH 3 ) 2 CH 2 CH 3 or -OCH 2 C(CH 3 ) 3 ; Said C 1 ~C 6 alkylamine groups include -NHCH 3 、-NHCH 2 CH 3 、-NH(CH 2 ) 2 CH 3 、-NHCH(CH 3 ) 2 、-NH(CH 2 ) 3 CH 3 、-NHCH 2 CH(CH 3 ) 2 、-NHCH(CH 3 )CH 2 CH 3 、-NH(CH 3 ) 3 、-NH(CH 2 ) 4 CH 3 、-NHCH(CH 3 )CH 2 CH 2 CH 3 、-NHCH 2 CH(CH 3 )CH 2 CH 3 、-NHCH 2 CH 2 CH(CH 3 ) 2 、-NHC(CH 3 ) 2 CH 2 CH 3 or -NHCH 2 C(CH 3 ) 3 ; The C 1 ~C 6 Haloalkyl groups include -CF 2 H or -CF 3 .

4. The cycloalkyl-substituted triazolopyridine amide compound according to any one of claims 1 to 3, It is characterized in that The cycloalkyl-substituted triazolopyridine amide compound has a structure shown in Formula I-1 or Formula I-2:

5. A method for preparing the cycloalkyl-substituted triazolopyridine amide compound according to any one of claims 1 to 4, It is characterized in that The following steps are involved: Mixing compound II, compound III, a condensing agent, triethylamine and an organic solvent to carry out a condensation reaction to obtain the cycloalkyl-substituted triazolopyridine amide compound; Among them, R 1 ~R 5 The same as in Formula I.

6. The preparation method according to claim 5, It is characterized in that The condensation reaction temperature is 0 to 40°C and the time is 12 to 96 hours; The compound II includes compound II-1 or compound II-2; The preparation method of the compound II-1 comprises the following steps: Compound 1, compound 2, a catalyst and a benzene solvent are mixed to carry out a Witte seeliger cyclization reaction to obtain compound II-1; The preparation method of the compound II-2 includes method 1 or method 2, wherein: Method 1: Mix the compound II-1, phosphorus pentasulfide and a benzene solvent, and perform a replacement reaction to obtain compound II-2; Method 2: Compound 7, compound 2 and a cyclic solvent are mixed and subjected to a decarboxylation amidation reaction to obtain compound 8; The compound 8, phosphorus pentasulfide and a heterocyclic solvent are mixed to carry out a cyclization reaction to obtain compound II-2; Among them, R 1 ~R 3 The same as in Formula I.

7. The preparation method according to claim 5, It is characterized in that The preparation method of the compound III comprises the following steps: Compound 3, hydrazine hydrate and a heterocyclic solvent are mixed to carry out a substitution reaction to obtain compound 4; The compound 4, the compound 5, an oxidant and an organic solvent are mixed to carry out a condensation-oxidation reaction to obtain a compound 6; The compound 6, lithium hydroxide and an organic solvent are mixed and subjected to a hydrolysis reaction to obtain a compound III; Among them, R 4 and R 5 The same as in Formula I.

8. A derivative of the cycloalkyl-substituted triazolopyridine amide compound according to any one of claims 1 to 4, wherein the derivative comprises a pesticide chemically acceptable salt.

9. Use of the cycloalkyl-substituted triazolopyridineamide compound according to any one of claims 1 to 4 or the derivative of the cycloalkyl-substituted triazolopyridineamide compound according to claim 8 in the preparation of an anti-plant pathogenic fungus drug.

10. The use according to claim 9, It is characterized in that The plant pathogenic fungi include one or more of rice sheath blight, wheat sheath blight, rapeseed sclerotinia, wheat fusarium rust, wheat take-all, tomato gray mold, potato late blight, pepper phytophthora, tomato early blight, rice seedling bakanae, potato dry rot, cucumber anthracnose and rice blast.

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