Preparation method for uracil compound and use of uracil compound

Abstract

The present invention relates to the field of pesticides, and in particular to a preparation method for a compound of formula (III). The compound of formula (III) can be used for preparing a novel highly efficient uracil herbicide. The present invention further provides an intermediate compound used in the method, a method for producing the intermediate compound, and a sterilization use of the intermediate compound. The present invention has a simple synthetic route, and wide prospects of application.

Description

Preparation method and application of uracil compounds Technical Field

[0001] The present invention relates to the field of pesticides, and specifically to a method for preparing a compound of formula (III). The compound of formula (III) can be used to prepare a novel, highly effective uracil herbicide. The present invention further provides an intermediate compound used in the method, a method for producing the intermediate compound, and its fungicidal use. The synthetic route is simple and its application prospects are broad. Background Art

[0002] WO2022166938A1 specifically discloses a method for preparing uracil compounds containing carboxylate fragments using ethyl 2-chloro-4-fluoro-5-aminobenzoate as a raw material. This method requires multiple protection and deprotection of the carboxylic acid, which increases the reaction steps. As a result, nine reaction steps are required to prepare ethyl 2-chloro-4-fluoro-5-aminobenzoate from ethyl 2-chloro-4-fluoro-5-aminobenzoate to the final product. The overall reaction yield is low, and column chromatography purification is required, making it unsuitable for industrial production (see compound 207 in Example 32):

[0003] WO2001083459A2 specifically discloses a method for preparing the herbicide Saflufenacil using 2-chloro-4-fluoro-5-aminobenzoic acid as a raw material. This method requires the difficult-to-prepare raw material 2-(dimethylamino)-4-(trifluoromethyl)-6H-1,3-oxazin-6-one, as well as expensive and environmentally unfriendly BBr3. Furthermore, each reaction step cannot be performed continuously and requires additional post-processing operations, making it unsuitable for industrial production.

[0004] WO2022201155A1 specifically discloses a method for preparing the herbicide Saflufenacil using 2-chloro-4-fluoro-5-aminobenzoic acid ethyl ester as a raw material. This method requires the protection and deprotection of the carboxyl group, which increases the reaction steps and has poor atom economy. When 2-chloro-4-fluoro-5-aminobenzoic acid ethyl ester reacts with ethyl chloroformate, a large amount of base (such as N,N-diethylaniline) needs to be added as an acid binding agent, which increases the formation of by-products and increases the difficulty and cost of processing. Moreover, when 2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)-4-fluorobenzoic acid reacts with NH2SO2N(CH3)i-Pr, an expensive and difficult-to-remove condensing agent (such as 1,1'-carbonyldiimidazole (CDI)) needs to be added. The yield of this step is only 70%:

[0005] The existing method for preparing uracil compound herbicides requires first esterifying benzoic acid and then synthesizing the uracil ring or performing N-methylation of the uracil ring, followed by a one-step hydrolysis reaction of the benzoate, and finally splicing with the corresponding fragments to synthesize the final compound.

[0006] These routes all suffer from poor atom economy, long steps, high costs, low yields, environmental concerns, difficult post-processing, and the inability to conduct continuous reactions. Currently, the key step in the preparation of uracil herbicides lies in the synthesis of the uracil ring. However, the ring-forming methods reported for uracil herbicides are mostly relatively simple, hindering their industrial development. Summary of the Invention

[0007] The technical problem to be solved by the present invention is: in view of the deficiencies of the existing technology, a method for preparing uracil compounds is provided, as well as the use of the intermediates in preparing fungicides and uracil herbicides.

[0008] The technical solution of the present invention to solve the above technical problems is as follows:

[0009] The present invention provides a method for preparing a compound of formula (III), and the reaction formula is as follows:

[0010] The compound of formula (I) is reacted in an organic solvent A in the presence of a base A with a chlorinating agent at a temperature of 20° C. to 120° C. to prepare compound (II); wherein the organic solvent A is selected from at least one of dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, toluene or xylene; the base A is selected from at least one of N,N-dimethylformamide (DMF), 4-pyrrolidinylpyridine (4-PPY) or 4-dimethylaminopyridine (DMAP); the molar amount of the base A is equivalent to 0.001-0.2 equivalents of the compound of formula (I); and the chlorinating agent is selected from SOCl2, POCl3, PCl5, ClCOCOCl, COCl2, ClCOOCCl3 or Cl3COCOOCCl3;

[0011] Base A, as a catalyst in the reaction process for preparing the compound of formula (II), can reduce the reaction time, lower the reaction temperature, and improve the conversion rate when preparing the compound of formula (II). In addition, in a continuous reaction, base A can continue to be used as a catalyst during the reaction process for preparing the compound of formula (III), reducing the hydrolysis of the compound of formula (II) during the reaction process and increasing the conversion rate and yield of the reaction for preparing the compound of formula (III).

[0012] The compound of formula (II) is reacted with H-R2 in an organic solvent B in the presence of a base B at a temperature of 0°C-120°C to prepare compound (III); wherein the organic solvent B is selected from at least one of dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, toluene, xylene, tetrahydrofuran or 2-methyltetrahydrofuran; the base B is selected from at least one of 4-dimethylaminopyridine, trimethylamine, triethylamine, diisopropylethylamine, pyridine, 2-methylpyridine, 3-methylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 2,6-lutidine; and the molar amount of the base B is equivalent to 1-3.0 equivalents of the compound of formula (II);

[0013] R1 is selected from H or -CH3;

[0014] R2 is selected from -OC(CH3)2COOCH3, -OC(CH3)2COOCH2CH3, -OC(CH3)2COOCH2CH2OCH3, -OC(CH3)2COOCH2CH=CH2 or -NHSO2N(CH3)i-Pr.

[0015] Preferably,

[0016] When R1 is selected from H, R2 is selected from -OC(CH3)2COOCH3, -OC(CH3)2COOCH2CH3, -OC(CH3)2COOCH2CH2OCH3, -OC(CH3)2COOCH2CH=CH2 or -NHSO2N(CH3)i-Pr;

[0017] When R1 is selected from -CH3, R2 is selected from -OC(CH3)2COOCH3, -OC(CH3)2COOCH2CH3, -OC(CH3)2COOCH2CH2OCH3, -OC(CH3)2COOCH2CH=CH2 or -NHSO2N(CH3)i-Pr.

[0018] Some of the compounds (III) prepared by the present invention are shown in Table 1:

[0019] Table 1 Structures of some compounds of general formula (III)

[0020] In the compound of formula (III), when R1 is selected from H, it can be further reacted with a methylating agent CH3-X to prepare a compound of formula (III) wherein R1 is -CH3. The specific operation is carried out according to the method described in document WO2001083459A3, and the reaction formula is as follows:

[0021] In the above reaction, R2 in the compound of formula (III) is selected from -OC(CH3)2COOCH3, -OC(CH3)2COOCH2CH3, -OC(CH3)2COOCH2CH2OCH3, -OC(CH3)2COOCH2CH=CH2 or -NHSO2N(CH3)i-Pr, and X is selected from halogen, -OSO2OCH3, -OMs, -OTs or -OTf. Among them, -OMs is a methanesulfonate group; -OTs is a p-toluenesulfonate group with the chemical formula of p-CH3PhSO2O-; -OTf is a trifluoromethanesulfonate group with the chemical formula of CF3SO2O-.

[0022] Compared with the method described in WO2022166938A1, the above method avoids the protection of the carboxyl group, reduces the reaction steps, improves the atom utilization rate, increases the yield of the product and improves the purity of the product. Compared with the methods described in WO2001083459A2 and WO2022201155A1, the above method avoids the use of expensive and difficult-to-remove condensing agents or environmentally unfriendly reagents. At the same time, when R1 is selected from -CH3, the selectivity problem of uracil ring N-methylation and -NHSO2N(CH3)i-Pr side chain N-methylation in the methylation reaction for preparing the herbicide Saflufenacil can also be avoided, the content of side chain N-methylated impurities is reduced, the difficulty of purification is reduced, the quality of the product is improved, and it is suitable for industrial production.

[0023] The second aspect of the present invention provides a compound of formula (II):

[0024] wherein R1 is selected from H.

[0025] The present invention also provides a compound of formula (II) wherein R1 is selected from H and its use in preparing a compound of formula (III):

[0026] wherein R1 is selected from H, and R2 is selected from -OC(CH3)2COOCH3, -OC(CH3)2COOCH2CH3, -OC(CH3)2COOCH2CH2OCH3, -OC(CH3)2COOCH2CH=CH2 or -NHSO2N(CH3)i-Pr.

[0027] The third aspect of the present invention also provides a method for preparing the compound of formula (I), the reaction formula is as follows:

[0028] The compound of formula (IV) is reacted with 3-amino-4,4,4-trifluorocrotonate R4 in an organic solvent C in the presence of a base C at a temperature between -20°C and the boiling point of the solvent to obtain a compound of formula (V). The compound of formula (V) is treated with an inorganic acid to obtain a compound of formula (I), wherein the base C is selected from CH3OK, CH3CH2OK, (CH3)3COK, CH3ONa, CH3CH2ONa, (CH3)3CONa, K2CO3, Na2C At least one of O3, Cs2CO3, KOH, NaOH, LiOH, NaH or NaNH2, the organic solvent C is selected from at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, o-xylene, m-xylene, p-xylene, xylene, 4-methyl-2-pentanone, cyclohexanone, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide;

[0029] R1 is selected from H;

[0030] R3 is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkylC1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C1-C8 haloalkyl, C1-C6 alkoxyC1-C6 alkyl, C3-C6 epoxyalkyl, C3-C6 epoxyalkylC1-C6 alkyl, phenyl or benzyl;

[0031] R4 is selected from C1-C4 alkyl;

[0032] M is selected from K, Na, Li or Cs.

[0033] Preferably,

[0034] R3 is selected from C1-C7 alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, phenyl or benzyl; R4 is selected from methyl or ethyl; M is selected from K or Na;

[0035] The base C is selected from CH3OK, CH3CH2OK, (CH3)3COK, CH3ONa, CH3CH2ONa, (CH3)3CONa, K2CO3, Na2CO3, Cs2CO3, KOH, NaOH, LiOH, NaH or NaNH2;

[0036] The molar amount of base C is equivalent to 1.0-3.0 equivalents of the compound of formula (IV);

[0037] The inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid;

[0038] The organic solvent C is selected from at least one of methanol, ethanol, tert-butanol, acetonitrile, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide;

[0039] The reaction temperature is selected from 0°C to 120°C.

[0040] More preferably,

[0041] R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, cyclopentyl, allyl, phenyl or benzyl; R4 is selected from methyl or ethyl; M is selected from K or Na;

[0042] The base C is selected from CH3OK, CH3CH2OK, (CH3)3COK, CH3ONa, CH3CH2ONa or (CH3)3CONa;

[0043] The amount of base C is selected from 1.0-3.0 equivalents corresponding to the compound of formula (IV);

[0044] The inorganic acid is selected from hydrochloric acid;

[0045] The organic solvent C is selected from at least one of methanol, ethanol, acetonitrile, N-methylpyrrolidone, N,N-dimethylformamide or N,N-dimethylacetamide;

[0046] The reaction temperature is selected from 0°C to 100°C.

[0047] The present invention also provides a method for preparing the compound of formula (I), the reaction formula is as follows:

[0048] The compound of formula (IV) is reacted with 3-amino-4,4,4-trifluorocrotonic acid R4 ester in an organic solvent C in the presence of a base C at a temperature between -20°C and the boiling point of the solvent to obtain a compound of formula (V). The compound of formula (V) is reacted with R1-X in an organic solvent C at a temperature between -20°C and the boiling point of the solvent to obtain a compound of formula (VI). The compound of formula (VI) is reacted with an inorganic acid in an organic solvent D at a temperature between 0°C and the boiling point of the solvent to obtain a compound of formula (I), wherein the base C is selected from CH3OK, CH3CH2OK, (CH3)3COK, CH3ONa, CH 3CH2ONa, (CH3)3CONa, K2CO3, Na2CO3, Cs2CO3, KOH, NaOH, LiOH, NaH or NaNH2, the organic solvent C is selected from at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, o-xylene, m-xylene, p-xylene, xylene, 4-methyl-2-pentanone, cyclohexanone, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, and the organic solvent D is selected from formic acid or acetic acid;

[0049] wherein R1 is selected from -CH3;

[0050] R3 is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkylC1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C1-C8 haloalkyl, C1-C6 alkoxyC1-C6 alkyl, C3-C6 epoxyalkyl, C3-C6 epoxyalkylC1-C6 alkyl, phenyl or benzyl;

[0051] R4 is selected from C1-C4 alkyl;

[0052] M is selected from K, Na, Li or Cs;

[0053] X is selected from halogen, -OSO2OCH3, -OMs, -OTs or -OTf, wherein: -OMs is a methanesulfonate group; -OTs is a p-toluenesulfonate group, the chemical formula of which is p-CH3PhSO2O-; -OTf is a trifluoromethanesulfonate group, the chemical formula of which is CF3SO2O-.

[0054] Preferably,

[0055] R3 is selected from C1-C7 alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, phenyl or benzyl; R4 is selected from methyl or ethyl; M is selected from K or Na; X is selected from Cl, Br, I, -OSO2OCH3 or -OMs;

[0056] The base C is selected from CH3OK, CH3CH2OK, (CH3)3COK, CH3ONa, CH3CH2ONa, (CH3)3CONa, K2CO3, Na2CO3, Cs2CO3, KOH, NaOH, LiOH, NaH or NaNH2;

[0057] The molar amount of base C is equivalent to 1.0-3.0 equivalents of the compound of formula (IV);

[0058] The inorganic acid is selected from hydrochloric acid, sulfuric acid or nitric acid;

[0059] The organic solvent C is selected from at least one of methanol, ethanol, tert-butanol, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide;

[0060] The organic solvent D is selected from acetic acid;

[0061] The reaction temperature is selected from 0-120°C.

[0062] More preferably,

[0063] R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, cyclopentyl, allyl, phenyl or benzyl; R4 is selected from methyl or ethyl; M is selected from K or Na; X is selected from I or -OSO2OCH3;

[0064] The base C is selected from CH3OK, CH3CH2OK, (CH3)3COK, CH3ONa, CH3CH2ONa or (CH3)3CONa;

[0065] The amount of base C is selected from 1.0-3.0 equivalents corresponding to the compound of formula (IV);

[0066] The inorganic acid is selected from hydrochloric acid or sulfuric acid;

[0067] The organic solvent C is selected from methanol, ethanol, N-methylpyrrolidone, N,N-dimethylformamide or N,N-dimethylacetamide;

[0068] The organic solvent D is selected from acetic acid;

[0069] The reaction temperature is selected from 0-110°C.

[0070] Compared with the methods described in WO2022166938A1, WO2001083459A2 and WO2022201155A1, each step of the reaction in the above method can be carried out continuously, reducing post-processing operations, avoiding the use of expensive raw materials and environmentally unfriendly reagents, reducing the number of reaction steps, improving atom utilization, and increasing reaction yield.

[0071] The fourth aspect of the present invention further provides a method for preparing a compound of formula (IV), the reaction formula of which is as follows:

[0072] The compound of formula (VII) is reacted with R3 chloroformate in an organic solvent E at a temperature between -20°C and the boiling point of the solvent to obtain compound (IV), wherein the organic solvent E is selected from at least one of dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, chlorobenzene, dichlorobenzene, N-methylpyrrolidone, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol diethyl ether, 1,4-dioxane, tetrahydrofuran or 2-methyltetrahydrofuran;

[0073] R3 is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkylC1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C1-C8 haloalkyl, C1-C6 alkoxyC1-C6 alkyl, C3-C6 epoxyalkyl, C3-C6 epoxyalkylC1-C6 alkyl, phenyl or benzyl.

[0074] Preferably,

[0075] R3 is selected from C1-C7 alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, phenyl or benzyl;

[0076] The organic solvent E is selected from toluene, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran or N-methylpyrrolidone;

[0077] The reaction temperature is selected from 60-110°C.

[0078] More preferably,

[0079] wherein R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, cyclopentyl, allyl, phenyl or benzyl;

[0080] The organic solvent E is selected from ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran or 2-methyltetrahydrofuran.

[0081] Compared to the methods described in WO2022166938A1 and WO2022201155A1, the above method does not require the use of esterified 2-chloro-4-fluoro-5-aminobenzoic acid (such as ethyl 2-chloro-4-fluoro-5-aminobenzoate) as a raw material, but can selectively react between -NH2 and -COOH of 2-chloro-4-fluoro-5-aminobenzoic acid, avoiding the use of an acid binding agent, and there is no need to esterify benzoic acid, thereby reducing the reaction steps, improving atom utilization, increasing the yield of the product and improving the purity of the product, which is suitable for industrial production. Compared to the method described in WO2001083459A2, the use of expensive and difficult-to-prepare raw materials 2-(dimethylamino)-4-(trifluoromethyl)-6H-1,3-oxazine-6-one is avoided, reducing costs.

[0082] In a fifth aspect of the present invention, the present invention further provides a compound of formula (IV):

[0083] wherein R3 is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkylC1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C1-C8 haloalkyl, C1-C6 alkoxyC1-C6 alkyl, C3-C6 epoxyalkyl, C3-C6 epoxyalkylC1-C6 alkyl, phenyl or benzyl.

[0084] Preferably,

[0085] R3 is selected from C1-C7 alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, phenyl or benzyl.

[0086] More preferably,

[0087] R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, cyclopentyl, allyl, phenyl or benzyl.

[0088] The present invention also provides a compound of formula (IV) and its use in preparing a compound of formula (I).

[0089] In the definition of the compounds of the general formula given above, the terms used are generally defined as follows:

[0090] Halogen: refers to fluorine, chlorine, bromine or iodine. Alkyl: straight-chain or branched alkyl groups, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or sec-butyl and isomers. Alkenyl: straight-chain or branched alkenes, such as vinyl, 1-propenyl, 2-propenyl and different butenyl, pentenyl and hexenyl isomers. Alkenyl also includes polyenes, such as 1,2-propadienyl and 2,4-hexadienyl. Alkynyl: straight-chain or branched alkynes, such as ethynyl, propynyl and different butynyl, pentynyl and hexynyl isomers. Alkynyl also includes polyenes, such as 2,4-hexadiynyl. Cycloalkenyl: cyclic alkenyl, such as 3-cyclopentenyl. Cycloalkyl: substituted or unsubstituted cyclic alkyl groups, such as cyclobutyl and cyclopentyl. Substituents include methyl, halogen, cyano, etc. Cycloalkylalkyl: A substituted or unsubstituted alkyl group with a cyclic alkyl group, such as cyclopropylmethyl and cyclobutylmethyl, and substituents such as methyl, halogen, and cyano. Haloalkyl: A straight-chain or branched alkyl group, in which the hydrogen atoms may be partially or completely replaced by halogen atoms, such as chloropropyl and bromopropyl. Alkoxy-alkyl: An alkyl-O-alkyl- group, such as CH3OCH2-. Epoxyalkyl: A cycloalkyl group containing one or more oxygen atoms, such as tetrahydrofuran-2-yl. Epoxyalkyl-alkyl: An alkyl group with an epoxyalkyl group, such as oxiran-2-ylmethyl.

[0091] The aforementioned method of the present invention may further include necessary pretreatment of the aforementioned raw materials and necessary post-treatment of the reaction products. The pre-treatment and post-treatment operations include, but are not limited to, drying, washing, beating, filtration, centrifugation, column chromatography, recrystallization, etc. The examples of the present invention provide several specific treatment methods, which should not be construed by those skilled in the art as limiting the present invention.

[0092] Some of the compounds of the general formula (IV) of the present invention can be illustrated by the specific compounds listed in Table 2, but the present invention is not limited to these compounds.

[0093] Table 2 Structures of some compounds of general formula (IV) 1 H-NMR

[0094] The sixth aspect of the present invention further provides the use of the compound of formula (IV) in preventing and controlling plant diseases.

[0095] As used herein, control or controlling includes protective, curative and eradicative treatment of phytopathogenic fungi.

[0096] Application to plants is understood to mean application to all parts and organs of the plant above and below the ground, such as buds, leaves, needles, stems, trunks, flowers, fruit bodies, fruits, seeds, roots, tubers and rhizomes. This also includes application to harvested material and vegetative and generative propagation material, such as cuttings, tubers, rhizomes, divisions and seeds.

[0097] Plant diseases that can be controlled according to the present invention include:

[0098] Rice diseases: rice blast (Magnaporthe grisea), brown spot (Cochliobolus miyabeanus), sheath blight (Rhizoctonia solani), bakanae (Gibberella fujikuroi), and false smut (Ustilaginoidea virens (Cke,) Tak.);

[0099] Wheat diseases: powdery mildew (Erysiphe graminis), head blight (Fusarium gaminearum, F. avenaceum, F. culmorum, Microdochium nivale, Fusarium asiaticum), rust (Puccinia striiformis, P. graminis, P. recondita), snow mold (Micronectriella nivale), snow rot (Typhula sp.), loose smut (Ustilago tritici), bunt (Tilletia caries), eye stripe (Pseudocercosporella herpotrichoides), leaf blight (Mycosphaerella graminicola), glumen blight (Stagonospora nodorum), and brown spot (Pyrenophora tritici-repentis);

[0100] Barley diseases: powdery mildew (Erysiphe graminis), wilt (Fusarium gaminearum, F. avenaceum, F. culmorum, Microdochium nivale), rust (Puccinia striiformis, P. graminis, P. hordei), loose smut (Ustilago nuda), cloud blotch (Rhynchosporium secalis), net blotch (Pyrenophora teres), spot (Cochliobolus sativus), leaf stigma (Pyrenophora graminea) and seedling blight caused by Rhizoctonia solani (Rhizoctonia solani);

[0101] Corn diseases: Corn leaf spot (Helminthosporium maydis), smut (Ustilago maydis), southern leaf blight (Cochliobolus heterostrophus), leopard spot (Gloeocercospora sorghi), southern rust (Puccinia polysora), gray leaf spot (Cercospora zeae-maydis), and seedling blight caused by Rhizoctonia solani.

[0102] Citrus diseases: black spot (Diaporthe citri), scab (Elsinoe fawcetti), fruit rot (Penicillium digitatum, P. italicum), blight (Phytophthora parasitica and Phytophthora citrophthora);

[0103] Apple diseases: apple anthracnose (Colletotrichum gloeosporioides), blossom blight (Monilinia mali), rot (Valsa ceratosperma), powdery mildew (Podosphaera leucotricha), leaf spot (Alternaria alternat aapplepathotype), scab (Venturia inaequalis), bitter rot (Colletotrichum acutatum), and crown rot (Phytophtora cactorum).

[0104] Pear diseases: scab (Venturia nashicola, V. pirina), black spot (Alternaria alternate Japanese pear pathotype), rust (Gymnosporangium haraeanum), and phytophthora fruit rot (Phytophtora cactorum);

[0105] Peach diseases: brown rot (Monilinia fructicola), scab (Cladosporium carpophilum), and phomopsis (Phomopsis sp.);

[0106] Grape diseases: anthracnose (Elsinoe ampelina), late rot (Glomerella cingulata), powdery mildew (Uncinula necator), rust (Phakopsora ampelopsidis), black rot (Guignardia bidwellii), and downy mildew (Plasmopara viticola);

[0107] Persimmon diseases: Anthracnose (Gloeosporium kaki), and leaf spot (Cercospora kaki, Mycosphaerella nawae);

[0108] Cucurbitaceae diseases: anthracnose (Colletotrichum lagenarium), powdery mildew (Sphaerotheca fuliginea), stem blight (Mycosphaerella melonis), fusarium wilt (Fusarium oxysporum), downy mildew (Pseudoperonospora cubensis), blight (Phytophthora sp.), and damping-off (Pythium sp.);

[0109] Tomato diseases: gray mold (Botrytis cinerea), early blight (Alternaria solani), leaf mold (Cladosporium fulvum), and late blight (Phytophthora infestans);

[0110] Eggplant diseases: brown spot (Phomopsis vexans) and powdery mildew (Erysiphe cichoracearum);

[0111] Crucifer diseases: Alternaria leaf spot (Alternaria japonica), white spot (Cercosporella brassicae), clubroot (Plasmodiophora brassicae), and downy mildew (Peronospora parasitica);

[0112] Onion diseases: rust (Puccinia allii) and downy mildew (Peronospora destructor);

[0113] Soybean diseases: purple spot (Cercospora kikuchii), scab (Elsinoe glycines), black spot (Diaporthe phaseolorum var. sojae), septoria brown spot (Septoria glycines), gray leaf spot (Cercospora sojina), rust (Phakopsora pachyrhizi), root rot (Phytophthora sojae), aboveground blight caused by Rhizoctonia (Rhizoctonia solani), brown ring rot (Corynespora cassiicola), and sclerotinia (Sclerotinia sclerotiorum).

[0114] Bean diseases: Anthracnose (Colletotrichum lindemthianum);

[0115] Peanut diseases: black spot (Cercospora personata), brown spot (Cercospora arachidicola), and white rot (Sclerotium rolfsii);

[0116] Pea diseases: powdery mildew (Erysiphe pisi);

[0117] Potato diseases: early blight (Alternaria solani), late blight (Phytophthora infestans), red rot (Phytophthora Erythroseptica), and powdery scab (Spongospora subterraneanf.sp.subterranea);

[0118] Strawberry diseases: powdery mildew (Sphaerotheca humuli) and anthracnose (Glomerella cingulata);

[0119] Tea tree diseases: web cake disease (Exobasidium reticulatum), white spot disease (Elsinoe leucospila), ring spot disease (Pestalotiopsis sp.), and anthracnose (Colletotrichum theae-sinensis);

[0120] Tobacco diseases: brown spot (Alternaria longipes), powdery mildew (Erysiphe cichoracearum), anthracnose (Colletotrichum tabacum), downy mildew (Peronospora tabacina), and blackleg (Phytophthora nicotlanae);

[0121] Oilseed rape diseases: Sclerotinia sclerotiorum and Rhizoctonia solani;

[0122] Cotton diseases: seedling blight caused by Rhizoctonia solani (Rhizoctonia solani);

[0123] Sugar beet diseases: Cercospora leaf spot (Cercospora beticola), leaf blight (Thanatephorus cucumeris), root rot (Thanatephorus cucumeris), and aphanomyces root rot (Aphanomyces cochlioides);

[0124] Rose diseases: black spot (Diplocarpon rosae), powdery mildew (Sphaerotheca pannosa), and downy mildew (Peronospora sparsa);

[0125] Chrysanthemum diseases: downy mildew (Bremia lactucae), leaf blight (Septoria chrysanthemi-indici), white rust (Puccinia horiana), leaf blight (Septoria chrysanthemi-indici), and white rust (Puccinia horiana);

[0126] Pepper diseases: pepper blight (Phytophthora capsici) and pepper cotton rot (Pythium deliense Meurs);

[0127] Various crop diseases: diseases caused by Pythium spp. (Pythium aphanidermatum, Pythium debarianum, Pythium irregulare, and Pythium ultimum), gray mold (Botrytis cinerea), and sclerotinia (Sclerotinia sclerotiorum);

[0128] Radish diseases: Alternaria leaf spot (Alternaria brassicicola);

[0129] Turfgrass diseases: Dollar spot (Sclerotinia homeocarpa), brown spot, and giant spot (Rhizoctonia solani);

[0130] Banana diseases: Black leaf spot (Mycosphaerella fijiensis, Mycosphaerella musicola);

[0131] Seed diseases or diseases in the early stages of growth of various plants caused by Aspergillus spp., Penicillium spp., Fusarium spp., Gibberella spp., Tricoderma spp., Thielaviopsis spp., Rhizopus spp., Mucor spp., Corticium spp., Phoma spp., Rhizoctonia spp. or Diplodia spp.; and viral diseases of various plants transmitted by Polymixa or Olpidium.

[0132] The seventh aspect of the present invention further provides a composition, wherein the fungicidal composition comprises an active substance and an agriculturally acceptable carrier, wherein the active substance is a compound of formula (IV), and the weight percentage of the active substance in the composition is 1-99%.

[0133] Typically, the compound of formula (IV) is used in the form of a composition (eg, a formulation) containing a carrier. The compounds of formula (IV) and their compositions can be used in different forms, such as aerosol sprayers, capsule suspensions, cold atomization concentrates, dustable powders, emulsifiable concentrates, oil-in-water emulsions, water-in-oil emulsions, encapsulated granules, fine granules, flowable concentrates for seed treatment, gases (under pressure), gas-producing products, granules, hot atomization concentrates, macrogranules, microgranules, oil-dispersible powders, oil-miscible flowable concentrates, oil-miscible liquids, pastes, plant sticks, powders for dry seed treatment, seeds coated with pesticides, soluble concentrates, soluble powders, solutions for seed treatment, suspension concentrates (flowable concentrates), ultra-low volume (ulv) liquids, ultra-low volume (ulv) suspensions, water-dispersible granules or tablets, water-dispersible powders for slurry treatment, water-soluble granules or tablets, water-soluble powders for seed treatment and wettable powders.

[0134] The formulation typically comprises a liquid or solid carrier and optionally one or more conventional formulation adjuvants, which may be solid or liquid adjuvants, for example, non-epoxidized or epoxidized vegetable oils (e.g., epoxidized coconut oil, rapeseed oil or soybean oil), defoamers (e.g., silicone oils), preservatives, clays, inorganic compounds, viscosity modifiers, surfactants, binders and / or tackifiers. The composition may further comprise a fertilizer, a micronutrient donor or other preparation that influences plant growth, and includes combinations containing a compound of the invention and one or more other biologically active agents, such as bactericides, fungicides, nematicides, plant activators, acaricides and insecticides.

[0135] The compositions are prepared in a manner known per se, in the absence of auxiliaries, for example by grinding, screening and / or compressing the solid compound according to the invention, and in the presence of at least one auxiliary agent, for example by intimately mixing and / or grinding the compound according to the invention together with one or more auxiliary agents. In the case of the solid compound according to the invention, the grinding / milling of the compound is to ensure a specific particle size.

[0136] Examples of compositions for use in agriculture are emulsifiable concentrates, suspension concentrates, microemulsions, oil dispersibles, directly sprayable or dilutable solutions, spreadable pastes, dilute emulsions, soluble powders, dispersible powders, wettable powders, dusts, granules or capsules in a polymeric mass, said compositions comprising a compound of formula (IV) and the type of composition being chosen to be appropriate for the intended purpose and the prevailing circumstances.

[0137] Typically, the composition comprises 0.1% to 99% (especially 0.1% to 95%) of a compound of formula (IV) and 1% to 99.9% (especially 5% to 99.9%) of at least one solid or liquid carrier, and in principle it is possible that 0 to 25% (especially 0.1% to 20%) of the composition is a surfactant (% in each case means percentage by weight). While for commercial products, concentrated compositions tend to be preferred, end users generally use diluted compositions with substantially lower concentrations of active ingredients.

[0138] Examples of the types of leaf formulations used in premix compositions are:

[0139] GR: Granules

[0140] WP: Wettable Powder

[0141] WG: Water dispersible granules (powders)

[0142] SG: Water-soluble granules

[0143] SL: Soluble Concentrate

[0144] EC: Emulsifiable Concentrate

[0145] EW: Oil-in-water emulsion

[0146] ME: Microemulsion

[0147] SC: Aqueous Suspension Concentrate

[0148] CS: Aqueous Capsule Suspension

[0149] OD: Oil-based suspension concentrates, and

[0150] SE: aqueous suspension emulsion.

[0151] Examples of the types of seed treatment formulations used in premix compositions are:

[0152] WS: Wettable powder for seed treatment slurry

[0153] LS: Solution for seed treatment

[0154] ES: Emulsion for seed treatment

[0155] FS: Suspension concentrate for seed treatment

[0156] WG: water dispersible granules, and

[0157] CS: aqueous capsule suspension.

[0158] Examples of suitable formulation types for tank-mix compositions are solutions, dilute emulsions, suspensions or mixtures thereof, and dusts.

[0159] Regarding the properties of the formulation, the method of application (such as foliar application, spray application, atomization application, atomization application, dusting application, broadcasting application, coating application or pouring application) can be selected according to the intended purpose and the prevailing environment. Tank mix compositions are generally prepared by diluting one or more premix compositions containing different pesticides and, optionally, additional adjuvants, with a solvent (e.g., water).

[0160] Suitable carriers and adjuvants can be solid or liquid and are the substances customary in formulation technology, such as natural or regenerated mineral substances, solvents, dispersants, wetting agents, tackifiers, thickeners, binders or fertilizers.

[0161] Generally, tank mix formulations for foliar or soil application contain 0.1% to 20%, especially 0.1% to 15%, of the desired ingredients and 99.9% to 80%, especially 99.9% to 85%, of solid or liquid adjuvants (including, for example, solvents such as water), wherein the adjuvant may be a surfactant, in an amount of 0 to 20%, especially 0.1% to 15%, based on the tank mix formulation.

[0162] Typically, premix formulations for foliar application contain from 0.1% to 99.9%, especially from 1% to 95%, of the desired

[0163] The invention relates to a premix formulation comprising the desired ingredients and 99.9% to 0.1%, in particular 99% to 5%, of solid or liquid adjuvants (including, for example, solvents such as water), wherein the adjuvant may be a surfactant, in an amount of 0 to 50%, in particular 0.5% to 40%, based on the premix formulation.

[0164] Typically, tank mix formulations for seed treatment applications contain 0.25% to 80%, especially 1% to 75%, of the desired ingredients and 99.75% to 20%, especially 99% to 25%, of solid or liquid adjuvants (including, for example, solvents such as water), wherein the adjuvant may be a surfactant, in an amount of 0 to 40%, especially 0.5% to 30%, based on the tank mix formulation.

[0165] Typically, premix formulations for seed treatment applications contain 0.5% to 99.9%, especially 1% to 95% of the desired ingredients and 99.5% to 0.1%, especially 99% to 5%, of solid or liquid adjuvants (including, for example, solvents such as water), wherein the adjuvant may be a surfactant, in an amount of 0 to 50%, especially 0.5% to 40%, based on the premix formulation.

[0166] While commercial products will preferably be formulated as concentrates (eg, premix compositions (formulations)), the end user will typically employ a diluted formulation (eg, a tank-mix composition).

[0167] Preferred seed treatment premix formulations are aqueous suspension concentrates. Conventional processing techniques and machines, such as fluidized bed technology, drum milling method, static rotation (rotostatic) seed processor and drum coater, can be used to apply the formulation to the seed. Other methods (such as spouted bed) can also be useful. The seeds can be pre-sized before coating. After coating, the seeds are typically dried and then transferred to a sizing machine to be sized. Such procedures are known in the art. The compound of the present invention is particularly suitable for use in soil and seed treatment applications.

[0168] The composition has a broad spectrum of efficacy as a crop fungicide. The exact amount of the composition to be applied depends not only on the relative amounts of the components, but also on the specific effect desired, the type of phytopathogenic microorganism to be controlled and its growth stage, and the plant part or other product with which the composition will come into contact. Thus, formulations containing the composition may not be equally effective at similar concentrations or may not be effective against the same type of phytopathogenic microorganism.

[0169] In an eighth aspect, the present invention also provides a method for preventing or controlling plant diseases using a fungicidal composition, characterized in that a composition comprising a compound of formula (IV) as an active ingredient is applied to a plant, thereby treating the plant to resist infection by plant pathogenic microorganisms.

[0170] The compositions of the present invention can be applied to the phytopathogenic microorganisms or their locus by using conventional ground sprayers, and granule applicators, and by other conventional methods known to those skilled in the art.

[0171] Furthermore, the present invention also provides a method for preventing or controlling plant diseases using the fungicidal composition described above, characterized in that an effective amount of the composition is applied to the plant, thereby treating the plant to resist infection by plant pathogenic microorganisms, wherein the composition is described above.

[0172] Plant pathogens include fungi that are resistant to other fungicides. A fungus that is "resistant" to a particular fungicide is, for example, a strain that is less sensitive to that fungicide than would be expected for the same species. Expected sensitivity can be measured using, for example, a strain that has not been previously exposed to the fungicide.

[0173] The above-mentioned method or purposes are preferably applied to plant crops, their place or their propagation material.Preferably applied to the place of plant or the propagation material of plant, more preferably applied to the propagation material.Application can be carried out according to any common mode of application (such as leaf application, spray application, soil application, furrow irrigation application, seed treatment application etc.).

[0174] The compounds of formula (IV) are preferably used for disease control at 1 to 500 g / ha, preferably 50-200 g / ha.

[0175] The compounds of formula (IV) are suitable for use on any vegetables, fruits, or food plants, including those useful plants that have been genetically modified to be resistant to active ingredients (such as herbicides), or those useful plants that have been genetically modified to produce biologically active compounds that control infection by phytopathogenic microorganisms.

[0176] Plants and plant cultivars treated with compounds of formula (IV) include plants and plant cultivars that are hybrid plants that already express the characteristic of heterosis or hybrid vigour, which generally results in greater yield, vigour, health and resistance to biotic and abiotic stresses.

[0177] The present invention includes within its scope a method for preventing or controlling or preventing plant pathogenic microorganisms from invading. The method includes applying a composition of a bactericidal effective amount to the locus of the plant pathogenic microorganism or to the locus where infection is to be prevented (e.g., applied to wheat or barley plants). The composition is suitable for treating various plants at an antimicrobial level while exhibiting low phytotoxicity. The composition is used in the form of a protectant or eradicant. The composition is applied by any of a variety of known techniques, or as a composition or as a formulation comprising the composition. For example, the composition can be applied to the roots, seeds, or leaves of a plant for preventing and controlling various plant pathogenic microorganisms without compromising the commercial value of the plant. The application form of the composition can be any of the commonly used formulation types, for example, as a solution, pulvis, wettable powder, flowable concentrate, or emulsifiable concentrate. These substances can be conveniently applied in various known ways.

[0178] The control method of the present invention can also control plant diseases by applying the composition of the present invention to plants or soil for cultivating plants.

[0179] There are no particular limitations on the method for applying the composition of the present invention, as long as the application form is a form by which the compound of the present invention can be substantially applied, and includes, for example, application to plants such as foliar application; application to areas for cultivating plants such as immersion application; and application to seeds such as seed disinfection.

[0180] The application dosage of the composition of the present invention varies depending on weather conditions, administration form, application timing, application method, area to be applied, target disease, target crop, etc., and is generally 1 to 500 g, and preferably 2 to 200 g / 1,000 m 2 The amount of the composition of the present invention is generally within the range of the area to be applied. Emulsifiable concentrates, wettable powders, suspensions, etc. are usually applied by diluting them with water. In this case, the concentration of the composition of the present invention after dilution is generally in the range of 0.0005 to 2% by weight, and preferably 0.005 to 1% by weight, and powders or granules are usually applied as is without dilution. When applied to seeds, the amount of the composition of the present invention is generally in the range of 0.001 to 100g, and preferably 0.01 to 50g per 1kg of seeds.

[0181] Examples of places where plant diseases grow include paddy fields, fields, tea gardens, orchards, non-agricultural lands, houses, nursery trays, nursery boxes, nursery soils and seedbeds.

[0182] The composition of the present invention can be used as an agent for controlling plant diseases in agricultural land such as fields, rice fields, lawns and orchards. The composition of the present invention can control diseases occurring in agricultural land or other land used for cultivating the following "plants" etc.

[0183] The plants include but are not limited to:

[0184] Vegetables or vegetable plants: including but not limited to okra, spinach, lettuce, asparagus, cabbage, carrots, onions, peppers, hot peppers, bell peppers, cucumbers, corn, lettuce, asparagus, bok choy, tomatoes, squash, eggplant, and beets;

[0185] Fruits or fruit plants: including but not limited to grapes, apples, pears, peaches, hawthorns, persimmons, dates, tangerines, cherries, strawberries, blueberries, oranges, lemons, grapefruits, plums, apricots, bananas, sugar cane, and lychees;

[0186] Grains or grain plants: including but not limited to wheat, barley, rye, rice, oats, sorghum, soybeans, and potatoes;

[0187] Oil crops: rapeseed, mustard, poppy, olive, sunflower, coconut, castor oil plant, cocoa and peanuts;

[0188] Other plants: turf, tobacco, nuts, coffee, tea, pepper, grapevines, hops, and latex plants;

[0189] Ornamental plants: flowers, shrubs, deciduous trees and conifers.

[0190] Plants and plant cultivars treated with the compositions of the present invention include plants and plant cultivars that are hybrid plants that already express the characteristic of heterosis or hybrid vigor, which generally results in greater yield, vigor, health and resistance to biotic and abiotic stresses.

[0191] The compositions of the present invention can be used to protect plants from plant diseases.

[0192] Formula (IV) compound can be advantageously used for processing transgenic plants, plant cultivars or plant parts that have received genetic material, and these genetic materials give these plants, plant cultivars or plant parts advantageous and / or useful characteristics (properties).Therefore, it is contemplated that the present invention will be combined with one or more recombinant traits or transgenic events or their combination.For the purposes of this application, transgenic events are produced by inserting specific recombinant DNA molecules into the specific location (site) of the plant genome chromosome. The insertion creates a new DNA sequence that is referred to as "event", characterized in that the recombinant DNA molecules inserted and a certain amount of genomic DNA are adjacent to / flanking the two ends of the inserted DNA. This proterties or transgenic events include but are not limited to resistance to pests and diseases, water use efficiency, yield performance, drought tolerance, seed quality, improved nutritional quality, hybrid seed production and herbicide tolerance, wherein the proterties are measured relative to the plant lacking this proterties or transgenic events. Specific examples of such advantageous and / or useful properties (traits) are better plant growth, vigor, stress tolerance, stand growth ability, lodging resistance, nutrient uptake, plant nutrition and / or yield, in particular improved growth, increased tolerance to high or low temperatures, increased tolerance to drought or to water or soil salinity levels, enhanced flowering performance, easier harvesting, accelerated ripening, higher yield, higher quality and / or higher nutritional value of the harvested product, better storage life and / or processability of the harvested product, and increased resistance to animal and microbial pests (e.g. insects, arachnids, nematodes, mites, slugs and snails).

[0193] Among the DNA sequences encoding proteins that confer tolerance properties on these animal and microbial pests (particularly insects), mention may be made in particular of the genetic material encoding the Bt protein from Bacillus thuringiensis, which is widely described in the literature and is well known to those skilled in the art. Mention may also be made of proteins extracted from bacteria such as Photorhabdus (WO 97 / 17432 and WO 98 / 08932). In particular, mention will be made of BtCry or VIP proteins including Cry1A, Cry1Ab, Cry1Ac, Cry1IA, CryIIIA, CryIIIB2, Cry9c, Cry2Ab, Cry3Bb and CryIF proteins or toxic fragments thereof, as well as hybrids or combinations thereof, in particular Cry1F protein or hybrids derived from Cry1F protein (such as hybrid Cry1A-Cry1F protein or toxic fragments thereof), Cry1A-type proteins or toxic fragments thereof, preferably Cry1Ac protein or hybrids derived from Cry1Ac protein (such as hybrid Cry1Ab-Cry1Ac protein) or Cry1Ab or Bt2 protein or toxic fragments thereof, Cry2Ae, Cry2Af or Cry2Ag protein or toxic fragments thereof, Cry1A.105 protein or toxic fragments thereof, VIP3Aa19 protein, VIP3Aa20 protein, VIP3A protein produced in COT202 or COT203 cotton events, as described in Estruch et al. (1996), Proc Natl Acad Sci. Sci US A. 28; 93 (11): 5389-94 or a toxic fragment thereof, a Cry protein described in WO 2001 / 47952, an insecticidal protein from a strain of Xenorhabdus (such as described in WO 98 / 50427), Serratia (especially from S. entomophila) or Photorhabdus species, for example, the Tc protein from Photorhabdus described in WO 98 / 08932. In addition, the present invention also includes any variant or mutant of any of the above-mentioned proteins that differs from any of the above-mentioned sequences (especially the sequences of their toxic fragments) in some amino acids (1-10, preferably 1-5), or any variant or mutant of the above-mentioned proteins fused with a transit peptide (such as a plastid transit peptide) or another protein or peptide. DETAILED DESCRIPTION

[0194] The present invention is described below with reference to examples, but is not limited thereto. Simple replacements or improvements made by those skilled in the art to the present invention fall within the technical solutions protected by the present invention.

[0195] Several methods for preparing the compounds of the present invention are described in detail in the following schemes and examples. The starting materials can be purchased commercially or can be prepared by methods known in the literature or as described in detail. It will be understood by those skilled in the art that other synthetic routes can also be used to synthesize the compounds of the present invention. Although the specific starting materials and conditions in the synthetic routes have been described below, they can be easily replaced with other similar starting materials and conditions, and these modifications or variations of the preparation methods of the present invention that result in various isomerizations of the compounds are included within the scope of the present invention. In addition, the preparation methods described below can be further modified according to the present disclosure using conventional chemical methods well known to those skilled in the art. For example, appropriate groups can be protected during the reaction, etc.

[0196] The following process examples are provided to facilitate a further understanding of the preparation methods of the present invention. The specific substances, types, and conditions used are intended to further illustrate the present invention and are not intended to limit its reasonable scope. The raw materials and reagents used in the synthetic compounds described below are either commercially available or can be readily prepared by one of ordinary skill in the art.

[0197] The abbreviations used in the examples have the following meanings:

[0198] THF: Tetrahydrofuran

[0199] DMF: N,N-dimethylformamide

[0200] DMAC: N,N-dimethylacetamide

[0201] NMP: N-methylpyrrolidone

[0202] DMAP: 4-dimethylaminopyridine

[0203] 1,2-DCE: 1,2-dichloroethane

[0204] The analytical instruments described in the examples are as follows:

[0205] 1. High Performance Liquid Chromatography (HPLC):

[0206] Method A:

[0207] Agilent Technologies, 1260 Infinity II instrument

[0208] Column: Agilent Eclipse Plus C18 3.5 μm, 4.6*100 mm

[0209] Mobile phase: A: water + 0.1% phosphoric acid; B: acetonitrile, temperature: 30°C

[0210] Gradient: 5% B to 95% B in 15 min; 95% B 3 min

[0211] Flow rate: 1 mL / min

[0212] Method B:

[0213] Agilent Technologies, 1260 Infinity II instrument

[0214] Column: Agilent Eclipse Plus C 18 3.5μm,4.6*100mm

[0215] Mobile phase: A: water + 0.1% phosphoric acid; B: methanol, temperature: 30°C

[0216] Gradient: 30% B to 95% B in 20 min; 95% B 3 min

[0217] Flow rate: 1 mL / min

[0218] 2. Ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS): Waters ACQUITY H-Class UPLC-SQ Detector 2

[0219] Column: ACQUITY UPLC BEH C18 1.7μm,2.1*50mm Column

[0220] Mobile phase: A: water + 0.2% formic acid; B: acetonitrile, temperature: 30°C

[0221] Gradient: 10% B to 95% B in 5 min; 95% B 1 min

[0222] Flow rate: 0.5 mL / min

[0223] MS method: ESI positive, negative, mass range (m / z): 100-800

[0224] 3. Gas Chromatograph (GC): Agilent Technologies, 7890B GC equipment

[0225] Detector: FID

[0226] Chromatographic column: HP-1 30m*530μm*10.5μm

[0227] Inlet temperature: 250°C

[0228] Split ratio: 40:1

[0229] Flow rate: 20mL / min

[0230] H2: 30mL / min

[0231] Air: 300mL / min

[0232] He: 25 mL / min

[0233] Detector temperature: 280°C

[0234] Method: maintain at 40℃ for 2 minutes, increase the temperature at 20℃ / min to 260℃, maintain at 260℃ for 5 minutes, total time 18 minutes

[0235] 4. Gas Chromatography-Tandem Mass Spectrometry (GC-MS): Agilent Technologies, 7890B GC System-5977A MSD equipment

[0236] Column: Agilent Technologies, HP-5MS UI 0.25μm, 30m*0.250mm

[0237] Injector temperature: 250°C

[0238] Column flow rate: Helium 1mL / min

[0239] Method: maintain at 40℃ for 2 minutes, increase the temperature at 20℃ / min to 280℃, maintain at 280℃ for 5 minutes, total time 19 minutes

[0240] MSD transfer line temperature: 280°C

[0241] EI ion source temperature: 230°C, MS quadrupole temperature: 150°C, scan range: 30.00-400.00

[0242] In addition, the proton nuclear magnetic resonance spectrum (hereinafter referred to as 1 The chemical shift values ​​of H-NMR were measured at 400 MHz (Bruker, AVANCE III HD 400M) in deuterated chloroform using Me4Si (tetramethylsilane) as a reference substance. When measured in deuterated dimethyl sulfoxide solvent, the chemical shift value data are displayed as "(DMSO-d6)". It should be noted that 1 The symbols in the chemical shift values ​​of H-NMR have the following meanings.

[0243] s: singlet, d: doublet, dd: doublet of doublets, dt: doublet of triplets, td: triplet of doublets, ddd: doublet of doublets, t: triplet, q: quartet, sep: septet, m: multiplet, brs: broad singlet. In the case of two or more stereoisomers, the chemical shift values ​​for resolvable signals are indicated with "and".

[0244] Examples of representative reaction operations are as follows. Other reaction operations or syntheses of compounds can be successfully carried out in a similar manner and will not be described in detail here.

[0245] Example 1: Preparation of Compound IV-1

[0246] In a 2L four-necked flask, 189.57g (1.00mol) of 2-chloro-4-fluoro-5-aminobenzoic acid and 800g of THF were added, stirred, and dissolved. The system was heated to reflux (69°C), and 113.40g (1.20mol) of methyl chloroformate was slowly added dropwise over 2h. After the addition was complete, the reflux reaction was continued for 4h. The reaction was completed when the raw material content was less than 0.5% by liquid chromatography. The solvent was evaporated under reduced pressure to obtain 243.15g of compound IV-1 as a white solid with a liquid chromatography area normalized purity of 98.8% (Method B) and a yield of 98.2%. 1 H NMR (400MHz, DMSO-d6) δ13.49(s,1H),9.68(s,1H),8.22(d,J=8.5Hz,1H),7.58(d,J=10.6Hz,1H),3.69(s,3H).

[0247] Example 2: Preparation of Compound IV-2

[0248] In a 2L four-necked flask, 189.57g (1.00mol) of 2-chloro-4-fluoro-5-aminobenzoic acid and 800g of THF were added, stirred, and dissolved. The system was heated to reflux (69°C), and 130.22g (1.20mol) of ethyl chloroformate was slowly added dropwise over 2h. After the addition was complete, the reflux reaction was continued for 4h. The reaction was completed when the raw material content was less than 0.5% by liquid chromatography. The solvent was evaporated under reduced pressure to obtain 254.04g of compound IV-2 as a white solid with a liquid chromatography area normalized purity of 98.2% (Method B) and a yield of 97.1%.

[0249] Example 3: Preparation of Compound IV-2

[0250] In a 2L four-necked flask, 189.57g (1.00mol) of 2-chloro-4-fluoro-5-aminobenzoic acid and 800g of 2-methyltetrahydrofuran were added, stirred, and dissolved. The system was heated to reflux temperature (81°C), and 130.23g (1.20mol) of ethyl chloroformate was slowly added dropwise over 2h. After the addition was complete, the reflux reaction was continued for 4h. The reaction was completed when the raw material content was less than 0.5% by liquid chromatography. The solvent was evaporated under reduced pressure to obtain 253.78g of compound IV-2 as a white solid with a liquid chromatography area normalized purity of 98.3% (Method B) and a yield of 97.0%.

[0251] Referring to the methods of Examples 1-3, compounds IV-3 to IV-73 can be prepared similarly. Some examples are shown in Table 3:

[0252] Table 3

[0253] Example 4: Preparation of Compound I-1

[0254] 800 g of DMAC and 247.61 g (1.00 mol) of compound IV-1 were added to a 2L four-necked flask and stirred evenly. 180.07 g (1.00 mol) of a methanol solution of sodium methoxide (30%) was added dropwise at room temperature. After the addition was complete, 219.75 g (1.20 mol) of ethyl 3-amino-4,4,4-trifluorocrotonate was added. The system was then heated to 90-100 ° C. and 198.14 g (1.10 mol) of a methanol solution of sodium methoxide (30%) was slowly added dropwise over 4 h. While the mixture was being added, distillation was continued and the distilled methanol and ethanol were received. After the addition was complete, the reaction was maintained at 90-100 ° C until no more methanol and ethanol were distilled off. The reaction time was about 4 h. The reaction was terminated when the raw material was less than 0.5% by liquid phase detection. Most of the solvent was evaporated under reduced pressure, 1000 g of water was added with stirring, and concentrated hydrochloric acid (36%) was added dropwise to adjust the pH to 1-2. During the addition, a large amount of white solid precipitated, which was obtained by filtration. The filter cake was washed with water and dried to obtain 329.71 g of the title compound I-1, with a yield of 93.5% and a liquid chromatography area-normalized purity of 98.1% (Method B).

[0255] Example 5: Preparation of Compound I-1

[0256] 800 g of DMF and 247.61 g (1.00 mol) of compound IV-1 were added to a 2L four-necked flask and stirred evenly. 180.07 g (1.00 mol) of sodium methoxide methanol solution (30%) was added dropwise at room temperature. After the addition was complete, 219.75 g (1.20 mol) of 3-amino-4,4,4-trifluorocrotonic acid ethyl ester was added. The system was then heated to 90-100 ° C. and 198.14 g (1.10 mol) of sodium methoxide methanol solution (30%) was slowly added dropwise over 4 h. While the mixture was being added, distillation was continued and the distilled methanol and ethanol were collected. After the addition was complete, the reaction was maintained at 90-100 ° C until no more methanol and ethanol were distilled. The reaction time was about 4 h. The reaction was terminated when the raw material was less than 0.5% by liquid phase detection. Most of the solvent was evaporated under reduced pressure, 1000 g of water was added with stirring, and concentrated hydrochloric acid (36%) was added dropwise to adjust the pH to 1-2. During the addition, a large amount of white solid precipitated, which was obtained by filtration. The filter cake was washed with water and dried to obtain 331.12 g of the title compound I-1, with a yield of 93.9% and a liquid chromatography area-normalized purity of 98.4% (Method B).

[0257] Example 6: Preparation of Compound I-1

[0258] 800 g of NMP and 247.61 g (1.00 mol) of compound IV-1 were added to a 2L four-necked flask and stirred evenly. 180.07 g (1.00 mol) of sodium methoxide methanol solution (30%) was added dropwise at room temperature. After the addition was complete, 219.75 g (1.20 mol) of ethyl 3-amino-4,4,4-trifluorocrotonate was added. The system was then heated to 90-100 ° C. and 198.14 g (1.10 mol) of sodium methoxide methanol solution (30%) was slowly added dropwise over 4 h. While the mixture was being added, distillation was continued and the distilled methanol and ethanol were received. After the addition was complete, the reaction was maintained at 90-100 ° C until no more methanol and ethanol were distilled. The reaction time was about 4 h. The reaction was terminated when the raw material was less than 0.5% by liquid phase detection. Most of the solvent was evaporated under reduced pressure, 1000 g of water was added with stirring, and concentrated hydrochloric acid (36%) was added dropwise to adjust the pH to 1-2. During the addition, a large amount of white solid precipitated, which was obtained by filtration. The filter cake was washed with water and dried to obtain 321.95 g of the title compound I-1, with a yield of 91.3% and a liquid chromatography area-normalized purity of 97.5% (Method B).

[0259] Example 7: Preparation of Compound I-2

[0260] 800 g of DMF and 247.61 g (1.00 mol) of compound IV-1 were added to a 2L four-necked flask and stirred evenly. 180.07 g (1.0 mol) of a methanol solution of sodium methoxide (30%) was added dropwise at room temperature. After the addition was complete, 219.75 g (1.20 mol) of ethyl 3-amino-4,4,4-trifluorocrotonate was added. The system was then heated to 90-100 ° C. and 198.14 g (1.10 mol) of a methanol solution of sodium methoxide (30%) was slowly added dropwise over 4 h. While the addition was being continued, the distilled methanol and ethanol were continuously distilled and received. After the addition was complete, the reaction was kept warm until no more methanol and ethanol were distilled off. The reaction time was about 4 h. The reaction was terminated when the raw material was less than 0.5% by liquid phase detection. The reaction solution was cooled to 0-5°C and 378.39g (3.00mol) of dimethyl sulfate was added dropwise over 2h. The reaction system temperature was controlled at 0-5°C. After the addition was complete, the reaction was continued at this temperature for 2h. The temperature was then slowly raised to room temperature. A large amount of solid precipitated. The reaction was continued at this temperature for 3h. The conversion of intermediate V-1 was essentially complete, with a liquid chromatography content of 90.9%. 800g of water was added and stirred for 30min. The white solid was filtered and washed with water to obtain 445.20g of the title compound VI-1 as a wet product. The liquid chromatography area normalized purity was 97.7%. The wet product was used directly in the subsequent step without additional treatment. In a 3L four-necked reaction flask, the above 445.20g of the wet product of compound VI-1 and 1200g of acetic acid were added dropwise. The temperature was raised to 100°C and 1000g of concentrated hydrochloric acid (36%) was slowly added dropwise over 2h. The reaction was continued for 8h after the addition was complete. The reaction was considered complete when the content of raw material VI-1 was less than 1.0% after sampling and testing. After the reaction, the mixed solution of acetic acid and hydrochloric acid (about 1800 g) was distilled off under reduced pressure and cooled to room temperature. The residue was filtered to obtain a white solid. The filter cake was washed with water and dried to obtain 303.59 g of the title compound I-2, with a three-step yield of 82.8% and a liquid chromatography area-normalized purity of 98.2% (Method B). 1 H NMR (400MHz, DMSO-d6) δ13.72(s,1H),8.05(d,J=7.9Hz,1H),7.83(d,J=9.6Hz,1H),6.60(s,1H),3.42(s,3H).

[0261] Example 8: Preparation of Compound I-1

[0262] 800 g of DMAC and 261.63 g (1.00 mol) of compound IV-2 (prepared according to the method in Example 1) were added to a 2L four-necked flask and stirred evenly. 180.07 g (1.00 mol) of a methanol solution of sodium methoxide (30%) was added dropwise at room temperature. After the addition was complete, 219.75 g (1.20 mol) of ethyl 3-amino-4,4,4-trifluorocrotonate was added. The system was then heated to 90-100 ° C. and 198.14 g (1.10 mol) of a methanol solution of sodium methoxide (30%) was slowly added dropwise over 4 h. The mixture was continuously distilled while being added, and the distilled methanol and ethanol were received. After the addition was complete, the reaction was maintained at 90-100 ° C until no more methanol and ethanol were distilled off. The reaction time was about 4 h, and the reaction was terminated when the raw material was less than 0.5% by liquid phase detection. Most of the solvent was evaporated under reduced pressure, 1000 g of water was added with stirring, and concentrated hydrochloric acid (36%) was added dropwise to adjust the pH to 1-2. During the addition, a large amount of white solid precipitated, which was obtained by filtration. The filter cake was washed with water and dried to obtain 326.54 g of the title compound I-1, with a yield of 92.6% and a liquid chromatography area-normalized purity of 98.1% (Method B). 1 H NMR (400MHz, DMSO-d6) δ13.68(s,1H),12.83(s,1H),8.09(d,J=7.9Hz,1H),7.82(d,J=9.6Hz,1H),6.45(s,1H).

[0263] Example 9: Preparation of Compound I-1

[0264] 800 g of DMF and 261.63 g (1.00 mol) of compound IV-2 were added to a 2L four-necked flask and stirred evenly. 180.07 g (1.0 mol) of sodium methoxide methanol solution (30%) was added dropwise at room temperature. After the addition was complete, 219.75 g (1.20 mol) of 3-amino-4,4,4-trifluorocrotonic acid ethyl ester was added. The system was then heated to 90-100 ° C. and 198.14 g (1.10 mol) of sodium methoxide methanol solution (30%) was slowly added dropwise over 4 h. While adding dropwise, the distilled methanol and ethanol were continuously distilled and received. After the addition was complete, the reaction was maintained at 90-100 ° C until no more methanol and ethanol were evaporated. The reaction time was about 4 h. The reaction was terminated when the raw material was less than 0.5% by liquid phase detection. Most of the solvent was evaporated under reduced pressure, 1000 g of water was added with stirring, and concentrated hydrochloric acid (36%) was added dropwise to adjust the pH to 1-2. During the addition, a large amount of white solid precipitated, which was obtained by filtration. The filter cake was washed with water and dried to obtain 329.36 g of the title compound I-1, with a yield of 93.4% and a liquid chromatography area-normalized purity of 98.6% (Method B).

[0265] Example 10: Preparation of Compound I-1

[0266] 800 g of NMP and 261.63 g (1.00 mol) of compound IV-2 were added to a 2L four-necked flask and stirred evenly. 180.07 g (1.00 mol) of sodium methoxide methanol solution (30%) was added dropwise at room temperature. After the addition was complete, 219.75 g (1.20 mol) of ethyl 3-amino-4,4,4-trifluorocrotonate was added. The system was then heated to 90-100 ° C. and 198.14 g (1.10 mol) of sodium methoxide methanol solution (30%) was slowly added dropwise over 4 h. While the mixture was being added, distillation was continued and the distilled methanol and ethanol were received. After the addition was complete, the reaction was maintained at 90-100 ° C until no more methanol and ethanol were distilled. The reaction time was about 4 h. The reaction was terminated when the raw material was less than 0.5% by liquid phase detection. Most of the solvent was evaporated under reduced pressure, 1000 g of water was added with stirring, and concentrated hydrochloric acid (36%) was added dropwise to adjust the pH to 1-2. During the addition, a large amount of white solid precipitated, which was obtained by filtration. The filter cake was washed with water and dried to obtain 322.30 g of the title compound I-1, with a yield of 91.4% and a liquid chromatography area-normalized purity of 97.3% (Method B).

[0267] Example 11: Preparation of Compound V-1

[0268] 60 g of DMAC and 20 g (76.4 mmol) of compound IV-2 were added to a 250 mL four-necked flask and stirred evenly. 7.34 g (76.4 mmol) of sodium tert-butoxide was added at room temperature. After the addition was complete, 15.38 g (84.0 mmol) of ethyl 3-amino-4,4,4-trifluorocrotonate was added. The system was then heated to 90-100 ° C., and 11.07 g (115.2 mmol) of sodium tert-butoxide was added. After the addition was complete, the reaction was maintained at 90-100 ° C. The reaction time was about 2 h. The raw material was no longer reduced by liquid phase detection. The liquid phase qualitative yield of compound V-1 was 86.62% (Method B).

[0269] Example 12: Preparation of Compound V-1

[0270] 60 g of DMAC and 20 g (76.4 mmol) of compound IV-2 were added to a 250 mL four-necked flask and stirred evenly. 7.88 g (197.0 mol) of sodium hydride (60%) was added at room temperature. After the addition was completed, 15.38 g (84.0 mmol) of ethyl 3-amino-4,4,4-trifluorocrotonate was added. After the addition was completed, the reaction was maintained at 90-100 ° C. The reaction time was about 1 h. The raw material was no longer reduced by liquid phase detection. The liquid phase qualitative yield of compound V-1 was 88.43% (Method B).

[0271] Example 13: Preparation of Compound I-2

[0272] 800 g of DMF and 261.63 g (1.00 mol) of compound IV-2 were added to a 2L four-necked flask and stirred evenly. 180.07 g (1.0 mol) of a methanol solution of sodium methoxide (30%) was added dropwise at room temperature. After the addition was complete, 219.75 g (1.20 mol) of ethyl 3-amino-4,4,4-trifluorocrotonate was added. The system was then heated to 90-100 ° C. and 198.14 g (1.10 mol) of a methanol solution of sodium methoxide (30%) was slowly added dropwise over 4 h. While the addition was being continued, the distilled methanol and ethanol were continuously distilled and received. After the addition was complete, the reaction was kept warm until no more methanol and ethanol were distilled out. The reaction time was about 4 h. The reaction was terminated when the raw material was less than 0.5% by liquid phase detection. The reaction mixture was cooled to 0-5°C and 378.39 g (3.00 mol) of dimethyl sulfate was added dropwise over 2 hours. The reaction system temperature was maintained at 0-5°C. After the addition was complete, the reaction was maintained at this temperature for 2 hours. The temperature was then slowly raised to room temperature, whereupon a large amount of solid precipitated. The reaction was maintained at this temperature for 3 hours. The conversion of intermediate V-1 was essentially complete, with a liquid chromatography assay showing a content of 90.3%. 800 g of water was added, stirred for 30 minutes, and filtered to obtain a white solid. The filter cake was washed with water to obtain 437.07 g of the title compound VI-1 as a wet product, with a liquid chromatography area-normalized purity of 97.7% (Method B). The wet product was used directly in subsequent reactions without additional treatment.

[0273] In a 3L four-necked reaction flask, 437.07g of the wet product of compound VI-1 and 1200g of acetic acid were added. The temperature was raised to 100°C, and 1000g of concentrated hydrochloric acid (36%) was slowly added dropwise over 2 hours. The reaction was continued for 8 hours after the addition was complete. The reaction was considered complete when the content of the raw material VI-1 was less than 1.0%. After the reaction was completed, the mixed solution of acetic acid and hydrochloric acid (about 1800g) was distilled off under reduced pressure, cooled to room temperature, and the residue was filtered to obtain a white solid. The filter cake was washed with water and dried to obtain 301.02g of the title compound I-2, with a three-step yield of 82.1% and a liquid chromatography area-normalized purity of 98.0% (Method B).

[0274] Example 14: Preparation of Compound I-2

[0275] 800 g of DMF and 261.63 g (1.00 mol) of compound IV-2 were added to a 2L four-necked flask and stirred evenly. 180.07 g (1.0 mol) of a methanol solution of sodium methoxide (30%) was added dropwise at room temperature. After the addition was complete, 219.75 g (1.20 mol) of ethyl 3-amino-4,4,4-trifluorocrotonate was added. The system was then heated to 90-100 ° C. and 198.14 g (1.10 mol) of a methanol solution of sodium methoxide (30%) was slowly added dropwise over 4 h. While the addition was being continued, the distilled methanol and ethanol were continuously distilled and received. After the addition was complete, the reaction was kept warm until no more methanol and ethanol were distilled out. The reaction time was about 4 h. The reaction was terminated when the raw material was less than 0.5% by liquid phase detection. The reaction mixture was cooled to 0-5°C and 378.39 g (3.00 mol) of dimethyl sulfate was added dropwise over 2 hours. The reaction system temperature was maintained at 0-5°C. After the addition was complete, the reaction was maintained at this temperature for 2 hours. The temperature was then slowly raised to room temperature, whereupon a large amount of solid precipitated. The reaction was maintained at this temperature for 3 hours. The conversion of intermediate V-1 was essentially complete, with an HPLC assay showing a content of 90.3%. 800 g of water was added, stirred for 30 minutes, and filtered to obtain a white solid. The filter cake was washed with water to yield 437.07 g of the title compound VI-1 as a wet product, with a liquid chromatography area-normalized purity of 97.7% (Method B). The wet product was used directly in subsequent reactions without additional treatment.

[0276] In a 3L four-necked reaction flask, 437.07g of the wet product of compound VI-1 and 1200g of acetic acid were added. The temperature was raised to 100°C, and 490g of concentrated sulfuric acid (98%) was slowly added dropwise over 2 hours. The reaction was continued for 8 hours after the addition was complete. The reaction was considered complete when the content of the raw material VI-1 was less than 1.0% by HPLC. After the reaction was completed, the temperature was lowered to 20-25°C, and 500g of water was slowly added dropwise in an ice bath. After the addition was complete, the mixture was stirred at 10-15°C for 1 hour, filtered, and the filter cake was washed with water. The filter cake was dried to obtain 303.95g of the title compound I-2, with a three-step yield of 82.9% and a liquid chromatography area-normalized purity of 98.3% (Method B).

[0277] Example 15: Preparation of Compound I-2

[0278] 60 g of DMAC and 20 g (76.4 mmol) of compound IV-2 were added to a 250 mL four-necked flask and stirred evenly. 13.76 g (76.4 mmol) of a methanol solution of sodium methoxide (30%) was added dropwise at room temperature. After the addition was complete, 15.38 g (84.0 mmol) of ethyl 3-amino-4,4,4-trifluorocrotonate was added. The system was then heated to 90-100 ° C. and 15.12 g (84.0 mmol) of a methanol solution of sodium methoxide (30%) was slowly added dropwise over 1 h. While the methanol and ethanol were being distilled and received, the reaction was continued until no more methanol and ethanol were distilled off. The reaction time was about 3 h. The reaction was terminated when the raw material was less than 0.5% by HPLC. The reaction mixture was cooled to 0-10°C and 42.68 g (229.2 mol) of methyl p-toluenesulfonate was added dropwise over 1 hour. The reaction temperature was maintained at 0-10°C. After the addition was complete, the reaction was maintained at this temperature for 5 hours. The temperature was then slowly raised to room temperature and allowed to stand overnight. A large amount of solid precipitated, indicating that the conversion of intermediate V-1 was essentially complete, with an HPLC qualitative assay of 87.24% (Method B). After adding 60 g of water and stirring for 30 minutes, the mixture was filtered to obtain a white solid. The filter cake was washed with water to obtain 31.72 g of a wet product of compound VI-1, which was used directly in subsequent reactions without further treatment.

[0279] In a 500mL four-necked reaction flask, 31.72g of the wet product of compound VI-1 and 150g of acetic acid were added, the temperature was raised to 100°C, and 30g of concentrated sulfuric acid (98%) was slowly added dropwise for 30min. After the addition was completed, the reaction was continued for 3h. Sampling HPLC showed that the remaining raw material VI-1 was 1.6% (Method B), and the raw material VI-1 decreased slowly as the reaction continued. After the reaction was completed, the temperature was lowered to 20-25°C, and 50g of water was slowly added dropwise under an ice bath. After the addition was complete, the mixture was stirred at 10-15°C for 1h, filtered, and the filter cake was washed with water. The filter cake was dried to obtain 21.99g of the title compound I-2, with a three-step yield of 78.52% and a liquid chromatography area-normalized purity of 98.3% (Method B).

[0280] Example 16: Preparation of Compound I-2

[0281] 60 g of DMAC and 20 g (76.4 mmol) of compound IV-2 were added to a 250 mL four-necked flask and stirred evenly. 13.76 g (76.4 mmol) of a methanol solution of sodium methoxide (30%) was added dropwise at room temperature. After the addition was complete, 15.38 g (84.0 mmol) of ethyl 3-amino-4,4,4-trifluorocrotonate was added. The system was then heated to 90-100 ° C. and 15.12 g (84.0 mmol) of a methanol solution of sodium methoxide (30%) was slowly added dropwise over 1 h. While the methanol and ethanol were being distilled and received, the reaction was kept warm until no more methanol and ethanol were distilled off. The reaction time was about 3 h. The reaction was terminated when the raw material was less than 0.5% by liquid phase detection. The reaction mixture was cooled to 0-10°C and 32.53 g (229.2 mol) of iodomethane was added dropwise over 1 hour. The reaction temperature was maintained at 0-10°C. After the addition was complete, the reaction was maintained at this temperature for 5 hours. The temperature was then slowly raised to room temperature and allowed to stand overnight. A large amount of solid precipitated, indicating that the conversion of intermediate V-1 was essentially complete, with a HPLC qualitative content of 89.01% (Method B). After adding 60 g of water and stirring for 30 minutes, the mixture was filtered to obtain a white solid. The filter cake was washed with water to obtain 32.36 g of a wet product of compound VI-1, which was used directly in subsequent reactions without further treatment.

[0282] In a 500mL four-necked reaction flask, 32.36g of the wet product of compound VI-1 was added, 150.0g of formic acid was heated to 100°C, and 30.0g of concentrated sulfuric acid (98%) was slowly added dropwise for 30min. After the addition was completed, the reaction was continued for 3h. Sampling HPLC showed that 3.6% of the raw material VI-1 remained (Method B), and the raw material VI-1 decreased slowly as the reaction continued. After the reaction was completed, the temperature was lowered to 20-25°C, and 50g of water was slowly added dropwise under an ice bath. After the addition was complete, the mixture was stirred at 10-15°C for 1h, filtered, and the filter cake was washed with water. The filter cake was dried to obtain 22.94g of the title compound I-2, with a three-step yield of 81.89% and a liquid chromatography area-normalized purity of 97.1% (Method B).

[0283] Example 17: Preparation of Compound I-2

[0284] 60 g of DMAC and 20 g (76.4 mmol) of compound IV-2 were added to a 250 mL four-necked flask and stirred evenly. 13.76 g (76.4 mmol) of a methanol solution of sodium methoxide (30%) was added dropwise at room temperature. After the addition was complete, 15.38 g (84.0 mmol) of ethyl 3-amino-4,4,4-trifluorocrotonate was added. The system was then heated to 90-100 ° C. and 15.12 g (84.0 mmol) of a methanol solution of sodium methoxide (30%) was slowly added dropwise over 1 h. While the methanol and ethanol were being distilled and received, the reaction was kept warm until no more methanol and ethanol were distilled off. The reaction time was about 3 h. The reaction was terminated when the raw material was less than 0.5% by liquid phase detection. The reaction mixture was cooled to 0-10°C and 37.61 g (0.2292 mol) of methyl trifluoromethanesulfonate was added dropwise over approximately 1 hour. A large amount of solid precipitated after the addition, indicating that the conversion of intermediate V-1 was essentially complete, with a qualitative HPLC content of 88.12% (Method B). After adding 60 g of water and stirring for 30 minutes, the mixture was filtered to obtain a white solid. The filter cake was washed with water to obtain 32.06 g of a wet product of compound VI-1, which was used directly in subsequent reactions without further treatment.

[0285] In a 500mL four-necked reaction flask, 32.06g of the wet product of compound VI-1 and 150g of formic acid were added, the temperature was raised to 100°C, and 60g of concentrated hydrochloric acid (36%) was slowly added dropwise for 1h. After the addition was completed, the reaction was continued for 8h. Sampling HPLC showed that 2.12% of the raw material VI-1 remained (Method B), and the raw material VI-1 decreased slowly as the reaction continued. After the reaction was completed, the temperature was lowered to 20-25°C, and 100g of water was slowly added dropwise under an ice bath. After the addition was complete, the mixture was stirred at 10-15°C for 1h, filtered, and the filter cake was washed with water. The filter cake was dried to obtain 22.22g of the title compound I-2, with a three-step yield of 79.31% and a liquid chromatography area-normalized purity of 97.7% (Method B).

[0286] Referring to the method of the above embodiment, similarly, other compounds of formula (IV) can be used with ethyl 3-amino-4,4,4-trifluorocrotonate to prepare compound I-1 or I-2. Some examples are shown in Table 4:

[0287] Table 4

[0288] Example 18: Preparation of Compound III-5

[0289] To a 1L four-necked flask, add 500g of 1,2-DCE, 105.79g (0.30mol) of I-1, and 1.83g (0.015mol) of DMAP. The system was heated to 80°C and 42.84g (0.36mol) of thionyl chloride was slowly added dropwise over 2 hours. After the addition was complete, the mixture was incubated for 3 hours. This prepared a solution of compound II-1. The solution was heated to approximately 83°C and maintained at reflux. A 20-30g fraction was distilled under atmospheric pressure. This fraction consisted of a mixture of the remaining thionyl chloride and 1,2-DCE. The residue was cooled to room temperature and set aside for use. HPLC analysis revealed a content of 97.5% (methanol-derived). 1 H NMR (400MHz, CD3CN) δ9.90 (s, 1H), 8.30 (d, J = 7.5Hz, 1H), 7.59 (d, J = 9.3Hz, 1H), 6.26 (s, 1H).

[0290] To a 1L four-necked flask, add 54.80g (0.36mol) of N-methyl-N-isopropylaminosulfonamide, 91.08g (0.90mol) of triethylamine, 80g of 1,2-DCE, and 7.33g (0.06mol) of DMAP, stirring, and heat to 60°C. Add the 1,2-DCE solution of Compound II-1 above dropwise to the flask over 2 hours. Incubate for 1 hour after the addition is complete. Liquid chromatography indicates that the starting material content is less than 0.2%, indicating the reaction is complete. Add 400g of water and stir for 10 minutes. Then, slowly add 60.83g (0.6mol) of 36% hydrochloric acid. A large amount of white solid precipitates. Filter to obtain 192.64g of the wet product of Compound III-5, with a liquid chromatography area-normalized purity of 98.22% (Method B). 1 H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 12.27 (s, 1H), 7.81 (dd, J = 19.1, 8.3 Hz, 2H), 6.46 (s, 1H), 4.32–3.92 (m, 1H), 2.83 (s, 3H), 1.14 (d, J = 6.2 Hz, 6H). mp 242.9–244.7°C (decomposition).

[0291] A mixture of toluene, tetrahydrofuran, and water was added to a 1L glass four-necked flask and stirred until uniform. Then, the wet product of compound III-5 (192.64 g, 0.28 mol), tetrabutylammonium bromide (9.35 g, 0.029 mol), and dimethyl sulfate (64.50 g, 0.51 mol) were added sequentially to the mixed solvent at 25°C. The mixture was heated to 40-45°C. The pH of the reaction mixture was controlled between 4-5 by dropwise addition of 10% aqueous NaOH at 40-45°C. The reaction was continued until the starting material concentration was less than 1.5% (HPLC, Method B). The reaction was then complete. The organic phase was washed with water and the solvent was removed under reduced pressure. The residue was recrystallized, filtered, and the filter cake was washed with a small amount of toluene. The wet product was dried to yield 106.22 g of a white solid, with a three-step yield of 70.69% and a liquid chromatography area-normalized purity of 97.5% (Method B). This was compound III-10. 1 H NMR (400MHz, DMSO) δ12.28(s,1H),7.85(d,J=9.6Hz,1H),7.72(d,J=7.6Hz,1H),6 .61(s,1H),4.17–4.04(m,1H),3.42(s,3H),2.82(s,3H),1.14(d,J=6.7Hz,6H).mp 186.8-190.3℃.

[0292] WO2005054208A1 specifically discloses compound III-5 and compound III-10 (Saflufenacil):

[0293] 2-Chloro-5-[3,6-dihydro-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluoro-N-[[methyl(1-methylethyl)amino]sulfonyl]benzamide:

[0294] mp 233-236℃(decomposition). 1 H-NMR(400MHz,DMSO-d6)δ(ppm):12,8(br,NH),12,25(s,NH),7,82(d,1H),7,76(d,1H),6,4(s,1H),4,1(m,1H),2,8(s,3H),1,12(d,3H),1,12(d,6H).

[0295] 2-Chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluoro-N-[[methyl(1-methylethyl)amino]sulfonyl]benzamide (Saflufenacil):

[0296] 1H-NMR (400MHz, CDCl3) δ (ppm): 9.5 (br, NH), 7.63 (d, 1H), 7.37 (d, 1H), 6.37 (s, 1H), 4.29 (m, 1H), 3.58 (s, 3H), 2.92 (s, 3H), 1.18 (d, 6H).

[0297] Example 19: Preparation of Compound III-7

[0298] To a 1L four-necked flask, add 500g of 1,2-DCE, 105.79g (0.30mol) of I-1, and 1.83g (0.015mol) of DMAP. Heat the system to 80°C and slowly add 45.69g (0.36mol) of oxalyl chloride dropwise over 2 hours. After the addition is complete, incubate for 3 hours. This yields a solution of II-1. This solution is then heated to approximately 83°C and maintained at reflux. A 20-30g fraction is then distilled under atmospheric pressure. This fraction consists of a mixture of the remaining oxalyl chloride and 1,2-DCE. The residue is cooled to room temperature and set aside for further use. HPLC analysis indicates a 97.2% content (Method B, methanol derivatization).

[0299] To a 1L four-necked flask, add 47.58g (0.36mol) of ethyl 2-hydroxy-2-methylpropionate, 91.08g (0.90mol) of triethylamine, 80g of 1,2-DCE, and 7.33g (0.06mol) of DMAP, stirring, and heat to 60°C. Add a 1,2-DCE solution containing 0.30mol of compound II-1 dropwise to the flask over 2 hours. After the addition is complete, incubate for 1 hour. Liquid chromatography indicates that the starting material content is less than 0.2%, indicating completion. Add 400g of water, stir for 10 minutes, and allow the mixture to stand for stratification. Separate the organic phase and remove the solvent under reduced pressure to yield 132.22g of compound III-2, a 94.42% yield with a liquid chromatography area-normalized purity of 93.8% (Method B). This is a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ10.52 (s, 1H), 7.87 (d, J = 7.7Hz, 1H), 7.40 (s, 1H), 6.25 (s,1H),4.23(q,J=7.1Hz,2H),1.68(d,J=2.5Hz,6H),1.26(t,J=7.1Hz,3H).

[0300] 93.55 g (0.2 mol) of compound III-2, 55.28 g (0.4 mol) of potassium carbonate, and 400 g of N,N-dimethylformamide were added to a reaction flask and stirred at room temperature for 0.5 h. 30.27 g (0.24 mol) of dimethyl sulfate was slowly added dropwise. The reaction was continued until the starting material disappeared. The reaction solution was filtered, and the mother liquor was partially decompressed to remove DMF. The mother liquor was then poured into 500 g of water and extracted with 1000 g of ethyl acetate. The organic phase was washed twice with saturated brine and dried to obtain 83.39 g of the title compound III-7, with a yield of 86.72% and a liquid chromatography area-normalized purity of 92.1% (Method B). 85 g of an 80% aqueous isopropanol solution was added for recrystallization, and the solution was filtered at low temperature to obtain a powdery white solid, which after drying yielded 78.11 g, a yield of 81.23%, and a liquid chromatography area-normalized purity of 97.7%. 1 H NMR (400MHz, DMSO) δ8.07(d,J=7.8Hz,1H),7.91(d,J=9.6Hz,1H),6.62(s,1H),4.16(q,J=7.1Hz,2H),3.43(s,3H),1.62(s,6H),1.19(t,J=7.1Hz,3H).

[0301] Example 20: Preparation of Compound III-8

[0302] To a 1L four-necked flask, add 500g of 1,2-DCE, 105.79g (0.30mol) of I-1, and 1.83g (0.015mol) of DMAP. The system was heated to 80°C and 42.84g (0.36mol) of thionyl chloride was slowly added dropwise over 2 hours. After the addition was complete, the mixture was incubated for 3 hours. This prepared a solution of compound II-1. The solution was heated to approximately 83°C and maintained at reflux. A 20-30g fraction was distilled under atmospheric pressure. This fraction consisted of a mixture of the remaining thionyl chloride and 1,2-DCE. The residue was cooled to room temperature and set aside for use. HPLC analysis revealed a content of 97.5% (methanol-derived).

[0303] To a 250 mL four-necked flask, add 17.30 g (0.12 mol) of allyl 2-hydroxy-2-methylpropionate (prepared according to the method described in WO2009046665), 30.36 g (0.30 mol) of triethylamine, 20 g of 1,2-DCE, and 2.44 g (0.02 mol) of DMAP. Stir and heat to 60°C. Add a 1,2-DCE solution containing 0.10 mol of compound II-1 dropwise to the flask over 1 hour. After the addition is complete, incubate for 1 hour. Liquid chromatography indicates that the starting material content is less than 0.2%, indicating completion. Add 100 g of water, stir for 10 minutes, and allow the mixture to stand for stratification. The organic phase is separated and desolvated under reduced pressure to yield 42.75 g of compound III-3, with a yield of 89.29% and a liquid chromatography area-normalized purity of 92.3% (Method B). This is a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ10.49(s,1H),7.79(d,J=7.7Hz,1H),7.30(d,J=9.1Hz,1H),6.17(s,1H),5.82(ddt,J =16.2,10.7,5.7Hz,1H),5.19(ddd,J=13.8,11.5,1.2Hz,2H),4.58(d,J=5.7Hz,2H),1.62(d,J=2.3Hz,6H).

[0304] 23.94 g (0.05 mol) of compound III-3, 13.82 g (0.1 mol) of potassium carbonate, and 90 g of N,N-dimethylformamide were added to a reaction flask and stirred at room temperature for 0.5 h. 7.57 g (0.06 mol) of dimethyl sulfate was slowly added dropwise. After the addition was completed, the reaction was continued until the raw material disappeared. The reaction liquid was filtered, and the mother liquor was decompressed to remove part of the DMF and poured into 100 g of water. It was extracted with 200 g of ethyl acetate, and the organic phase was washed twice with saturated brine and dried to obtain 20.63 g of the title compound III-8 as an oil, with a yield of 83.71% and a liquid chromatography area normalized purity of 91.7%. 1 H NMR (400MHz, DMSO) δ8.09(d,J=7.8Hz,1H),7.91(d,J=9.6Hz,1H),6.62(s,1H),5.90(ddt,J=17.2,10.7,5.4Hz,1 H),5.37–5.29(m,1H),5.22(ddd,J=10.5,2.7,1.3Hz,1H),4.64(dt,J=5.4,1.4Hz,2H),3.43(s,3H),1.65(s,6H).

[0305] Example 21: Preparation of Compound III-9

[0306] To a 1L four-necked flask, add 550g of 1,2-DCE, 110.00g (0.30mol) of compound I-2, and 1.83g (0.015mol) of DMAP. The system was heated to 80°C and 42.84g (0.36mol) of thionyl chloride was slowly added dropwise over 2 hours. After the addition was complete, the mixture was incubated for 3 hours. This prepared a solution of compound II-2. The solution was heated to approximately 83°C and maintained at reflux. A 20-30g fraction was distilled under atmospheric pressure. This fraction consisted of a mixture of the remaining thionyl chloride and 1,2-DCE. The residue was cooled to room temperature and set aside. HPLC analysis indicated a content of 97.4% (methanol-derived). 1 H NMR (400MHz, CD3CN) δ8.27 (d, J = 7.5Hz, 1H), 7.59 (d, J = 9.3Hz, 1H), 6.38 (s, 1H), 3.44 (d, J = 1.2Hz, 3H).

[0307] To a 1L four-necked flask, add 58.38g (0.36mol) of 2-methoxyethyl 2-hydroxy-2-methylpropionate (prepared according to a literature method), 45.54g (0.45mol) of triethylamine, 80g of 1,2-DCE, and 1.83g (0.015mol) of DMAP. Stir and heat to 60°C. Add a 1,2-DCE solution containing 0.30mol of compound II-2 dropwise to the flask over 2 hours. After the addition is complete, incubate for 1 hour. Liquid chromatography indicates that the starting material content is less than 0.2%, indicating completion. Add 400g of water, stir for 10 minutes, allow to stand, and separate the organic phase. The organic phase is then desolvated under reduced pressure to yield 145.40g of compound III-9, a 95.1% yield with a liquid chromatography area-normalized purity of 96.8% (Method B), as a pale yellow oil. 120 g of isopropanol was added for recrystallization, and a powdery white solid was obtained by filtration. After drying, the solid weighed 129.95 g, with a yield of 84.8% and a liquid chromatography area-normalized purity of 99.2% (Method B). 1 H NMR(400MHz,DMSO-d6)δ8.07(d,J=7.8Hz,1H),7.92(d,J=9.6Hz,1H),6.63(s,1H),4.25–4 .17(m,2H),3.52–3.49(m,2H),3.42(d,J=1.3Hz,3H),2.51(d,J=1.8Hz,3H),1.63(s,6H).

[0308] The preparation method of 2-methoxyethyl 2-hydroxy-2-methylpropionate is described in the following reference: Preparation of allyl and methallyl methacrylates by the thermal decomposition of allyl and methallyl α-acetoxyisobutyrates, by Rehberg, Chessie E. et al., Journal of the American Chemical Society (1943), 65, 1003-6.

[0309] Example 22: Preparation of Compound II-2

[0310] To a 1L four-necked flask, 500g of toluene, 110.00g (0.30mol) of compound I-2, and 1.83g (0.015mol) of DMAP were added. The system was heated to 60°C, and a toluene solution containing 44.51g (0.15mol) of triphosgene was slowly added dropwise over 2 hours. After the addition was complete, the mixture was incubated for 3 hours. This yielded a solution of compound II-2. The solution was heated to approximately 110°C and stirred at reflux for 2 hours. Exhaust gas was collected and absorbed with aqueous sodium hydroxide solution. The reaction solution was cooled to room temperature and set aside. HPLC analysis revealed a content of 97.8% (methanol-derived).

[0311] Example 23: Preparation of Compound II-2

[0312] To a 1L four-necked flask, add 550g of 1,2-DCE, 110.00g (0.30mol) of compound I-2, and 1.83g (0.015mol) of DMAP. The system was heated to 80°C and 45.69g (0.36mol) of oxalyl chloride was slowly added dropwise over 2 hours. After the addition was complete, the mixture was incubated for 3 hours. This prepared a solution of compound II-2. The solution was heated to approximately 83°C and maintained at reflux. A 20-30g fraction was distilled under atmospheric pressure. This fraction consisted of a mixture of the remaining oxalyl chloride and 1,2-DCE. The residue was cooled to room temperature and set aside for use. HPLC analysis indicated a content of 97.5% (methanol-derived).

[0313] Example 24: Preparation of Compound II-2

[0314] To a 100 mL four-necked flask, 55 g of chlorobenzene, 11.00 g (0.03 mol) of compound I-2, and 0.130 g (0.0015 mol) of DMF were added. The system was heated to 80°C, and a chlorobenzene solution containing 3.56 g (0.012 mol) of triphosgene was slowly added dropwise over 2 hours. After the addition was complete, the mixture was incubated for 2 hours. This yielded a solution of compound II-2. The solution was heated to approximately 110°C and stirred at reflux for 2 hours. The reaction solution was cooled to room temperature and set aside. HPLC analysis revealed a content of 98.27% (methanol-derived).

[0315] Example 25: Preparation of Compound II-2

[0316] To a 100 mL four-necked flask, 55 g of xylene, 11.00 g (0.03 mol) of compound I-2, and 0.130 g (0.0015 mol) of DMF were added. The system was heated to 80°C, and a xylene solution containing 3.56 g (0.012 mol) of triphosgene was slowly added dropwise over 2 hours. After the addition was complete, the mixture was incubated for 2 hours. This yielded a solution of compound II-2. The solution was heated to approximately 110°C and stirred at reflux for 2 hours. The reaction solution was cooled to room temperature and set aside. HPLC analysis revealed a content of 96.52% (methanol-derived).

[0317] Biological Example 1

[0318] Antibacterial activity assay

[0319] Complete Medium (CM): 50 mL of 20× Nitrate Salts, 1 mL of Trace Elements, 1 mL of Vitamin Solution, 10 g of D-Glucose, 2 g of Peptone, 1 g of Yeast Extract, and 1 g of Casamino Acids. Add dd H2O (double distilled water) to a volume of 1 L. To prepare solid culture medium, aliquot and add 1.5% agar powder. Autoclave at 121°C for 20 min and store at room temperature. 20× Nitrate Salts: Sodium nitrate (NaNO3) 120 g, potassium chloride (KCl) 10.4 g, magnesium sulfate heptahydrate (MgSO4·7H2O) 10.4 g, potassium dihydrogen phosphate (KH2PO4) 30.4 g, add dd H2O (double distilled water) to 1 L, autoclave at 121°C for 20 min, and store at 4°C.

[0320] Trace elements: zinc sulfate heptahydrate (ZnSO4·7H2O) 2.2 g, boric acid (H3BO3) 1.1 g, manganese chloride tetrahydrate (MnCl2·4H2O) 0.5 g, ferrous sulfate heptahydrate (FeSO4·7H2O) 0.5 g, cobalt chloride hexahydrate (CoCl2·6H2O) 0.17 g, copper sulfate pentahydrate (CuSO4·5H2O) 0.16 g, sodium molybdate dihydrate (Na2MoO4·2H2O) 0.15 g. Add dd H2O (double distilled water) to 100 mL and store at 4°C.

[0321] Vitamin Solution: Biotin 0.1g, Thiamine 0.1g, Riboflavin 0.1g, Pyridoxin 0.1g, Nicotinic Acid 0.1g, Para Aminobenzoic Acid 0.1g. Add double distilled water to 100mL and store at 4°C in the dark.

[0322] PSA medium: Wash and peel potatoes, cut 200 g into small pieces, add 1 L of double-distilled water (ddH2O), and boil for 30 minutes. Filter through two layers of gauze and discard the residue. Add 20 g of sucrose and stir thoroughly. After slight cooling, add double-distilled water (ddH2O) to make up to 1 L. Aliquot and add 1.5% agar powder. Autoclave at 121°C for 20 minutes and store at room temperature.

[0323] PDA medium (potato agar-dextrose medium): Wash and peel 200 g of potatoes, cut into small pieces, and boil in boiling water (boil for 30 minutes). Filter through four layers of gauze and remove the filter residue. Add 20 g of glucose and 20 g of agar. Add dd H2O (double distilled water) to 1000 mL. Stir to fully dissolve the solution. Dispense into 250 mL Erlenmeyer flasks, sterilize at 121°C for 20 minutes, and cool for later use.

[0324] Rye culture medium: Weigh two 30g portions of rye and place them into 1L conical flasks respectively, add 500mL of ultrapure water to each, sterilize at 121℃ for 20 minutes, take the softened rye, crush it into a homogenous slurry with a juicer, filter the rye juice, and adjust the volume to 1L. Weigh 2.7g of agar and 4g of sucrose into 250mL conical flasks, add 200mL of rye juice to each flask, sterilize at 121℃ for 20 minutes, and set aside after cooling.

[0325] Target species: Fusarium graminearum, Fusarium asiaticum, Magnaporthe oryzae, Ustilaginoidea virens, and Phytophthora infestans.

[0326] Assay Method: Dissolve the compound of formula (IV) in DMSO and add it to the appropriate culture medium at a concentration of 1500 μg / mL to prepare drug-containing plates. A blank control should be established and repeated three times. The plate method was used. Under sterile conditions, a 5 mm diameter sterile punch was used to cut a bacterial cake from the edge of the colony. This cake was inoculated with an inoculator onto the center of the drug-containing plate, mycelium side facing up. The plate was then covered with a lid. Once the control group had fully grown colonies, the colony diameter was measured, and the percentage of mycelial growth inhibition achieved by each agent was calculated. Among them, Fusarium graminearum (F.graminearum) and Fusarium asiaticum (F.asiaticum) were cultured in PDA medium in an incubator at 25°C in the dark; Rice blast fungus (M.oryzae) was cultured in CM medium in an incubator at 28°C in the dark; U.virens was cultured in PSA medium in an incubator at 25°C in the dark; and Phytophthora infestans (P.infestans) was cultured in rye medium in an incubator at 18°C ​​in the dark.

[0327] Mycelial growth inhibition rate (%) = (blank control colony diameter - drug-treated colony diameter) / (blank control colony diameter - 5) * 100.

[0328] The test results showed that the following compounds exhibited 100% inhibition against rice blast fungus at a concentration of 1500 μg / mL: IV-5, IV-9, IV-14, IV-69, and IV-71;

[0329] The following compounds showed 100% inhibition against U. oryzae var. oryzae at a concentration of 1500 μg / mL: IV-9, IV-14, and IV-21;

[0330] The following compounds showed 100% inhibition rate against Phytophthora infestans at a concentration of 1500 μg / mL: IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-9, IV-14, IV-21, IV-33, IV-38, IV-69, IV-70, IV-71.

[0331] The above description is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this field, several changes and improvements can be made without departing from the creative concept of the present invention, which all fall within the scope of protection of the present invention.

Claims

1. A method for preparing a compound of formula (III), the reaction formula is as follows: The compound of formula (I) is reacted with a chlorinating agent in an organic solvent A in the presence of a base A at a temperature of 20°C-120°C to obtain a compound (II); wherein, The organic solvent A is selected from at least one of dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, toluene or xylene; the base A is selected from at least one of N,N-dimethylformamide, 4-pyrrolidinopyridine or 4-dimethylaminopyridine; The amount of base A is equivalent to 0.001-0.2 equivalents of the compound of formula (I); The chlorinating agent is selected from SOCl2, POCl3, PCl5, ClCOCOCl, COCl2, ClCOOCCl3 or Cl3COCOOCCl3; The compound of formula (II) is reacted with H-R2 in an organic solvent B in the presence of a base B at a temperature of 0°C-120°C to obtain a compound (III); wherein the organic solvent B is selected from at least one of dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, toluene, xylene, tetrahydrofuran or 2-methyltetrahydrofuran; the base B is selected from at least one of 4-dimethylaminopyridine, trimethylamine, triethylamine, diisopropylethylamine, pyridine, 2-methylpyridine, 3-methylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 2,6-lutidine; The amount of base B is equivalent to 1.0-3.0 equivalents of the compound of formula (II); R1 is selected from H or -CH3; R2 is selected from -OC(CH3)2COOCH3, -OC(CH3)2COOCH2CH3, -OC(CH3)2COOCH2CH2OCH3, -OC(CH3)2COOCH2CH=CH2 or -NHSO2N(CH3)i-Pr.

2. The method according to claim 1, characterized in that: wherein R1 is selected from H; R2 is selected from -OC(CH3)2COOCH3, -OC(CH3)2COOCH2CH3, -OC(CH3)2COOCH2CH2OCH3, -OC(CH3)2COOCH2CH=CH2 or -NHSO2N(CH3)i-Pr.

3. The method according to claim 1, characterized in that: wherein R1 is selected from -CH3; R2 is selected from -OC(CH3)2COOCH3, -OC(CH3)2COOCH2CH3, -OC(CH3)2COOCH2CH2OCH3, -OC(CH3)2COOCH2CH=CH2 or -NHSO2N(CH3)i-Pr.

4. A compound of formula (II): Wherein R1 is selected from H.

5. Use of a compound of formula (II) as claimed in claim 4 in the preparation of a compound of formula (III) as claimed in claim 2.

6. A method for preparing a compound of formula (I), wherein the reaction formula is as follows: The compound of formula (IV) is reacted with 3-amino-4,4,4-trifluorocrotonic acid R4 ester in an organic solvent C in the presence of a base C at a temperature between -20°C and the boiling point of the solvent to obtain a compound of formula (V), and the compound of formula (V) is treated with an inorganic acid to obtain a compound of formula (I), wherein the base C is selected from CH3OK, CH3CH2OK, (CH3)3COK, CH3ONa, CH3CH2ONa, (CH3)3CONa, K2CO3, Na2C At least one of O3, Cs2CO3, KOH, NaOH, LiOH, NaH or NaNH2, the organic solvent C is selected from at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, o-xylene, m-xylene, p-xylene, xylene, 4-methyl-2-pentanone, cyclohexanone, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; R1 is selected from H; R3 is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkylC1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C1-C8 haloalkyl, C1-C6 alkoxyC1-C6 alkyl, C3-C6 epoxyalkyl, C3-C6 epoxyalkylC1-C6 alkyl, phenyl or benzyl; R4 is selected from C1-C4 alkyl; M is selected from K, Na, Li or Cs.

7. The method according to claim 6, characterized in that: R3 is selected from C1-C7 alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, phenyl or benzyl; R4 is selected from methyl or ethyl; M is selected from K or Na; The base C is selected from CH3OK, CH3CH2OK, (CH3)3COK, CH3ONa, CH3CH2ONa, (CH3)3CONa, K2CO3, Na2CO3, Cs2CO3, KOH, NaOH, LiOH, NaH or NaNH2; The amount of base C is equivalent to 1.0-3.0 equivalents of the compound of formula (IV); The inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid; The organic solvent C is selected from at least one of methanol, ethanol, tert-butanol, acetonitrile, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; The reaction temperature is selected from 0°C to 120°C.

8. The method according to claim 7, characterized in that: R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, cyclopentyl, allyl, phenyl or benzyl; R4 is selected from methyl or ethyl; M is selected from K or Na; The base C is selected from CH3OK, CH3CH2OK, (CH3)3COK, CH3ONa, CH3CH2ONa or (CH3)3CONa; The amount of base C is equivalent to 1.0-3.0 equivalents of the compound of formula (IV); The inorganic acid is selected from hydrochloric acid; The organic solvent C is selected from at least one of methanol, ethanol, acetonitrile, N-methylpyrrolidone, N,N-dimethylformamide or N,N-dimethylacetamide; The reaction temperature is selected from 0°C to 100°C.

9. A method for preparing a compound of formula (I), wherein the reaction formula is as follows: The compound of formula (IV) is reacted with 3-amino-4,4,4-trifluorocrotonic acid R4 ester in an organic solvent C in the presence of a base C at a temperature between -20°C and the boiling point of the solvent to obtain a compound of formula (V). The compound of formula (V) is reacted with R1-X in an organic solvent C at a temperature between -20°C and the boiling point of the solvent to obtain a compound of formula (VI). The compound of formula (VI) is reacted with an inorganic acid in an organic solvent D at a temperature between 0°C and the boiling point of the solvent to obtain a compound of formula (I), wherein the base C is selected from CH3OK, CH3CH2OK, (CH3)3COK, CH3ONa, CH 3CH2ONa, (CH3)3CONa, K2CO3, Na2CO3, Cs2CO3, KOH, NaOH, LiOH, NaH or NaNH2, the organic solvent C is selected from at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, o-xylene, m-xylene, p-xylene, xylene, 4-methyl-2-pentanone, cyclohexanone, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, and the organic solvent D is selected from formic acid or acetic acid; wherein R1 is selected from -CH3; R3 is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkylC1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C1-C8 haloalkyl, C1-C6 alkoxyC1-C6 alkyl, C3-C6 epoxyalkyl, C3-C6 epoxyalkylC1-C6 alkyl, phenyl or benzyl; R4 is selected from C1-C4 alkyl; M is selected from K, Na, Li or Cs; X is selected from halogen, -OSO2OCH3, -OMs, -OTs or -OTf.

10. The method according to claim 9, characterized in that: R3 is selected from C1-C7 alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, phenyl or benzyl; R4 is selected from methyl or ethyl; M is selected from K or Na; X is selected from Cl, Br, I, -OSO2OCH3 or -OMs; The base C is selected from CH3OK, CH3CH2OK, (CH3)3COK, CH3ONa, CH3CH2ONa, (CH3)3CONa, K2CO3, Na2CO3, Cs2CO3, KOH, NaOH, LiOH, NaH or NaNH2; The amount of the base C is equivalent to 1.0-3.0 equivalents of the compound of formula (IV); The inorganic acid is selected from hydrochloric acid, sulfuric acid or nitric acid; The organic solvent C is selected from at least one of methanol, ethanol, tert-butanol, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; The organic solvent D is selected from acetic acid; The reaction temperature is selected from 0-120°C.

11. The method according to claim 10, characterized in that: R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, cyclopentyl, allyl, phenyl or benzyl; R4 is selected from methyl or ethyl; M is selected from K or Na; X is selected from I or -OSO2OCH3; The base C is selected from CH3OK, CH3CH2OK, (CH3)3COK, CH3ONa, CH3CH2ONa or (CH3)3CONa; The amount of base C is equivalent to 1.0-3.0 equivalents of the compound of formula (IV); The inorganic acid is selected from hydrochloric acid or sulfuric acid; The organic solvent C is selected from methanol, ethanol, N-methylpyrrolidone, N,N-dimethylformamide or N,N-dimethylacetamide; The organic solvent D is selected from acetic acid; The reaction temperature is selected from 0-110°C.

12. A method for preparing a compound of formula (IV), wherein the reaction formula is as follows: The compound of formula (VII) is reacted with chloroformic acid R3 ester in an organic solvent E at a temperature between -20°C and the boiling point of the solvent to obtain compound (IV), wherein the organic solvent E is selected from at least one of dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, chlorobenzene, dichlorobenzene, N-methylpyrrolidone, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol diethyl ether, 1,4-dioxane, tetrahydrofuran or 2-methyltetrahydrofuran; R3 is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkylC1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C1-C8 haloalkyl, C1-C6 alkoxyC1-C6 alkyl, C3-C6 epoxyalkyl, C3-C6 epoxyalkylC1-C6 alkyl, phenyl or benzyl.

13. The method according to claim 12, characterized in that: R3 is selected from C1-C7 alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, phenyl or benzyl; The organic solvent E is selected from toluene, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran or N-methylpyrrolidone; The reaction temperature is selected from 60-110°C.

14. The method according to claim 13, characterized in that: wherein R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, cyclopentyl, allyl, phenyl or benzyl; The organic solvent E is selected from ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran or N-methylpyrrolidone.

15. A compound of formula (IV): Wherein R3 is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkylC1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C1-C8 haloalkyl, C1-C6 alkoxyC1-C6 alkyl, C3-C6 epoxyalkyl, C3-C6 epoxyalkylC1-C6 alkyl, phenyl or benzyl.

16. The compound of formula (IV) according to claim 15, characterized in that: R3 is selected from C1-C7 alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, phenyl or benzyl.

17. The compound of formula (IV) according to claim 16, characterized in that: R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, cyclopentyl, allyl, phenyl or benzyl.

18. Use of a compound of formula (IV) as claimed in any one of claims 15 to 17 in preventing and controlling plant diseases.

19. A composition, wherein the fungicidal composition is an active substance and an agriculturally acceptable carrier, wherein the active substance is a compound of formula (IV) according to any one of claims 15 to 17 or an agriculturally acceptable salt thereof, and the weight percentage of the active substance in the composition is 1 to 99%.

20. Use of a compound of formula (IV) according to any one of claims 15 to 17 in the preparation of a compound of formula (I) according to claim 1, 6 or 9.