Process for preparation of 1-alkyl-1H-1, 2, 4-triazole-3-amine compounds

Abstract

The invention relates to a method for preparing a compound shown as a formula (I). The method comprises the following steps: reacting a compound shown as a formula (V) with a compound shown as a formula (VI) to generate a compound shown as a formula (IV); then hydrogenating the compound of formula (IV) to generate a compound of formula (III); and cyclizing the compound of formula (III) with a reactive compound of formula (II) to obtain a compound of formula (I) wherein R1, R2, R3 and LG are as described herein.

Description

Method for preparing 1-alkyl-1H-1,2,4-triazol-3-amine compounds Technical Field

[0001] This invention relates to a method for preparing compounds of formula (I), their N-oxides, or salts. More preferably, this invention relates to a method for preparing 1-alkyl-1H-1,2,4-triazol-3-amine compounds. The method, in which R 1 R 2 and R 3 As defined in this article. Background Technology

[0002] 1,2,4-Triazole systemic pesticides are widely used to control fungal diseases in agricultural products, protecting vegetables, fruits, and crops. The most commonly used triazole plant protection fungicides include: azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole, epoxyconazole, etaconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, and amideazole. The fungicidal activity of these triazole compounds stems from their direct inhibition of the lanosterol-14α-demethylase activity of the CYP51 enzyme in fungi, thereby inhibiting the biosynthesis of ergosterol, a fundamental component of fungal cell membranes. These triazole compounds include iminenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, simeconazole, prothioconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, and mefentrifluconazole.

[0003] 3-Amino-1,2,4-triazole (aminotriazole (Amitrole)) is a systemic, non-selective herbicide widely used to control a variety of perennial grass and broadleaf weeds.

[0004] EP0245058A3, EP0303114A2, WO1991010660A1, JP02174777, EP0364141, EP0336354, EP0393999, EP0385775, WO9506049, EP0555770, DE3826609, EP0313311, EP0342569, EP0342568, and WO2022123502A disclose a variety of sulfonylurea compounds containing a 1-alkyl-1H-1,2,4-triazole-3-amine moiety that can be used as plant growth regulators and herbicides.

[0005] In addition, 3-amino-1H-1,2,4-triazole and compounds containing 3-amino-1H-1,2,4-triazole are also used as drugs for the treatment or prevention of a variety of diseases and conditions, including cancer.

[0006] WO2010 / 052199 discloses a compound containing 3-amino-1H-1,2,4-triazole as a γ-secretase regulator for the production of drugs to treat Alzheimer's disease, cerebral amyloid angiopathy, and hereditary cerebral hemorrhage with amyloidosis.

[0007] WO2012 / 054366 describes the use of 3-amino-1H-1,2,4-triazole compounds as medicines for the treatment of diseases selected from psychotic disorders, paranoia and drug-induced psychosis; anxiety disorders, movement disorders, mood disorders and neurodegenerative diseases.

[0008] WO2017018119 describes a composition for treating epilepsy, comprising 3-amino-1H-1,2,4-triazole as the active ingredient.

[0009] WO2008058995 describes a compound containing a 3-amino-1H-1,2,4-triazole moiety for the treatment and / or prevention of diseases and pathological conditions associated with the regulation of insulin and / or insulin-like growth factor (IGF) signaling pathways.

[0010] US20050113283A1 discloses a 3-amino-1,2,4-triazole compound as a modulator to regulate Edg-4 receptor-mediated biological activity for cancer treatment.

[0011] Therefore, due to the enhanced herbicidal, fungicidal, or insecticidal activity and medicinal value associated with 1,2,4-triazole-3-amine compounds or compounds containing 1,2,4-triazole-3-amine, various methods for synthesizing 1,2,4-triazoles, especially 3-amino-1H-1,2,4-triazoles and their N1-alkylated derivatives, have been disclosed in the literature.

[0012] Satoshi Ueda (J. Am. Chem. Soc., 2009, 131, 15080–15081) described a method for synthesizing 1H-1,2,4-triazole from amidine and nitrile in the presence of CuBr, using Cs2CO3 as a base and molecular oxygen as an oxidant.

[0013]

[0014] Zhengkai Chen et al (Org. Lett.2016, 18, 1334 1337) discloses a metal-free synthesis of 1,3,5-trisubstituted-1,2,4-triazole from hydrazones and fatty amines under aerobic oxidation conditions, wherein the reaction proceeds via a cascade of C H-bond functionalization, double C The N-bond formation and oxidative aromatization sequence proceeds as shown below.

[0015]

[0016] However, the aforementioned prior art is limited to 3-phenyl-1H-1,2,4-triazole or 3-methyl-1H-1,2,4-triazole and does not include a method for synthesizing 3-amino-1H-1,2,4-triazole. Furthermore, the prior art uses additional reagents, such as bases, oxidants, or transition metal catalysts, in the process of cyclizing amidine or hydrazone to generate 1,2,4-triazole.

[0017] Kristinsson et al. (Helvetica Chimica Acta (1983), 1129-1133) disclosed a method for preparing 1,5-dimethyl-1H-1,2,4-triazol-3-amine by reacting methylhydrazine with N-cyanoethylimine thioethyl ester in chloroform, as shown below.

[0018]

[0019] Reiter et al. (Journal of Heterocyclic Chemistry (1986), 401-408) disclosed a method for preparing 1-methyl-1H-1,2,4-triazole-3,5-diamine by reacting methylhydrazine with N-cyano-S-methylisothiourea in 1-butanol, as shown below.

[0020]

[0021] Curtius et al. (Science of Synthesis (2004), 603-639) described a method for preparing 1,5-dimethyl-1H-1,2,4-triazole-3-amine from N-cyanoethyliminoethyl ester and methylhydrazine.

[0022]

[0023] However, the aforementioned prior art has disadvantages due to the use of methylhydrazine, which is highly corrosive, irritates the skin and eyes, affects the mucous membranes of the human respiratory system, and damages the kidney and liver functions. Therefore, it is unsafe for the commercial-scale preparation of 3-amino-1H-1,2,4-triazole.

[0024] Therefore, there is a need for an improved method for preparing structurally diverse 1-alkyl-1H-1,2,4-triazol-3-amines, which should be simple, safe, efficient and economical, and overcome at least one drawback of known methods.

[0025] This invention provides a novel, efficient, and economical method for preparing compounds of formula (I), their N-oxides, or salts, using safe and readily available starting materials and convenient operating steps. This method is efficient and suitable for commercial-scale production, and avoids the use of toxic starting materials and the additional reagents required in the cyclization process, such as oxidants, bases, or transition metal catalysts.

[0026] Purpose of the invention

[0027] The object of this invention is to provide a novel and improved method for the commercial-scale preparation of compounds of formula (I), their N-oxides, or salts.

[0028] The present invention overcomes at least one disadvantage of the methods described in the prior art by providing a simple, safe and economically feasible method for preparing a compound of formula (I), its N-oxide or salt, comprising cyclizing an alkylated aminoguanidine of formula (III) with an acid or acid derivative of formula (II) to obtain a compound of formula (I), its N-oxide or salt.

[0029]

[0030] Among them, R 1 R 2 and R 3 As described in this article. Summary of the Invention

[0031] The object of this invention is to provide an efficient and commercially viable method for synthesizing compounds of formula (I), their N-oxides, or salts.

[0032] Among them, R 1 The compounds are selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, phenyl, and 4- to 6-membered heterocycles containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the alkyl and haloalkyl groups are optionally selected from halogen, cyano, C1-C6 alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C 3- One or more substituents of a C6 cycloalkyl or amino group are used; wherein the cycloalkyl, phenyl, and heterocyclic groups are optionally substituted with one or more substituents selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or amino groups; R 2 Selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; or R 1 and R 2 They can collectively form a 3-6 membered saturated carbocyclic or heterocyclic ring, which may optionally be substituted by one or more substituents selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or amino; and R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C6 cycloalkyl, phenyl, and 4- to 6-membered heterocycles containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the alkyl and haloalkyl groups are optionally selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, or C6 cycloalkyl groups. 3- One or more substituents of C6 cycloalkyl are substituted; wherein the cycloalkyl, phenyl and heterocyclic are optionally substituted by one or more substituents selected from halogens, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, the method comprising the steps of: a. reacting an aminoguanidine of formula (V) with a compound of formula (VI) in solvent A to give a compound of formula (IV), wherein, optionally, compound (IV) is isolated;

[0033] b. Hydrogenating compound (IV) in the presence of solvent B to produce compound (III), wherein, optionally, compound (III) is isolated; and

[0034] c. Cyclate compound (III) with compound (II) in solvent C to obtain compound (I) or its N-oxide or salt.

[0035] LG is selected from halogens, OH, C1-C6 alkoxy groups, and -OC(O)-R. 4 , where R 4 The molecule is selected from C1-C6 alkyl, C1-C6 haloalkyl, or phenyl groups, optionally substituted with one or more substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups, and X is an anion selected from halide ions, carbonate, bicarbonate, nitrate, perchlorate, carboxylate, sulfate, sulfonate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, acetate, trifluoroacetate, benzoate, tetrafluoroborate, or hexafluorophosphate.

[0036] This method also relates to a method for preparing a compound of formula (I) or its N-oxide or salt. The method includes the step of cyclizing a compound of formula (III) with a compound of formula (II) in solvent C to obtain a compound of formula (I) or its N-oxide or salt.

[0037] Among them, R 1 R 2 R 3 R 4 LG and X are as described above. Detailed Implementation

[0038] As used herein, the terms “comprising,” “containing,” “including,” or any variation thereof are intended to cover non-exclusive inclusion, but are subject to any expressly stated limitations. For example, a process or method that comprises a list of elements is not necessarily limited to those elements and may include other elements not expressly listed or inherent to the process or method.

[0039] Furthermore, the indefinite article "a (and an)" preceding an element or component of this invention is intended not to limit the number of times that element or component appears (i.e., the number of occurrences). Therefore, "a" should be understood to include one or at least one, and unless explicitly specified as singular, the singular form of an element or component also includes the plural form.

[0040] The compounds disclosed herein may exist in pure form or as mixtures of different possible isomers (e.g., stereoisomers or structural isomers). Various stereoisomers include enantiomers, diastereomers, chiral isomers, rotation-blocked isomers, conformational isomers, rotational isomers, tautomers, optical isomers, polymorphs, and geometric isomers. Any desired mixture of these isomers is within the scope of the claims of this disclosure. Those skilled in the art will understand that when a stereoisomer is enriched relative to or separated from other isomers, it may exhibit higher activity and / or beneficial effects. Furthermore, those skilled in the art understand processes, methods, or techniques for separating, enriching, and / or selectively preparing said isomers.

[0041] The compounds disclosed herein can exist in the form of N-oxides or salts. The compounds of this invention can be acid addition salts or base addition salts. The acid addition salts include inorganic or organic acids, preferably hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, or p-toluenesulfonic acid. The base addition salts include inorganic or organic bases, preferably alkali metal or alkaline earth metal salts.

[0042] The term "halogen" as used in this invention refers to fluorine, chlorine, bromine, or iodine.

[0043] The term "C1-C6 alkyl" as used in this invention refers to a straight-chain or branched alkyl group containing 1 to 6 carbon atoms. Examples of C1-C6 or C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl.

[0044] As used in this invention, the term "C1-C6 haloalkyl" refers to a straight-chain or branched alkyl group containing 1 to 6 carbon atoms, which is substituted with one or more halogens. Examples include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, difluoromethyl, trifluoroethyl, perfluoroethyl, etc.

[0045] The term "C1-C6 alkoxy" as used in this invention refers to a straight-chain or branched alkoxy group containing 1 to 6 carbon atoms. Examples include, but are not limited to, methoxy, ethoxy, isopropoxy, and n-butoxy.

[0046] The term "C1-C6 haloalkoxy" as used in this invention refers to a straight-chain or branched alkoxy group containing 1 to 6 carbon atoms substituted with one or more halogens. Examples include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, etc.

[0047] The term "C" used in this invention 3- "C6 cycloalkyl" refers to a 3-6 member saturated non-aromatic carbon ring. Examples include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0048] Unless otherwise specified, the term "heterocyclic group" as used in this invention refers to a 4- to 6-membered saturated or unsaturated non-aromatic ring comprising 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. The heterocyclic group may also be in an oxidized state.

[0049] As used in this invention, the term "heteroaryl" refers to a 5- or 6-membered monocyclic heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to, furanyl, thiopheneyl, pyrroleyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, and tetraazinyl.

[0050] In this invention, the term "optionally" is used to refer to any element, intermediate, reagent, or condition (including any method step, such as the isolation of an intermediate) when the element is isolated or not isolated from the reaction mixture and used directly in subsequent chemical reactions. Similarly, this definition also applies to the case of reagents or reaction conditions.

[0051] This specification and its various features and advantageous details are explained with reference to non-limiting embodiments in the specification. To avoid unnecessarily obscuring the embodiments described herein, descriptions of well-known components and processing techniques have been omitted. The embodiments used herein are intended only to aid in understanding the embodiments described herein and to further enable those skilled in the art to implement this specification. Therefore, these embodiments should not be construed as limiting the scope of this specification.

[0052] The description of specific embodiments will fully reveal the general nature of the embodiments herein, enabling others to easily modify and / or adapt these specific embodiments to various applications using existing knowledge without departing from the general concepts. Therefore, such modifications and adaptations should and are intended to be understood as being within the equivalent meaning and scope of the disclosed embodiments. It should be understood that the wording or terminology used herein is for descriptive purposes only and not for limiting purposes. Therefore, although embodiments have been described herein according to preferred embodiments, those skilled in the art will understand that these embodiments can be implemented with modifications within the spirit and scope of the embodiments described herein.

[0053] Any discussion of documents, actions, materials, devices, articles, etc., contained in this specification is merely to provide background for the disclosure. This invention does not acknowledge that any or all of the foregoing constitutes part of the prior art or is common general knowledge in the field related to the disclosure of this invention because it existed somewhere prior to the priority date of this application.

[0054] Therefore, the present invention provides a method for preparing a compound of formula (I) or its N-oxide or salt.

[0055] Among them, R 1 The compounds are selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, phenyl, and 4- to 6-membered heterocycles containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the alkyl and haloalkyl groups are optionally selected from halogen, cyano, C1-C6 alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C 3- One or more substituents of a C6 cycloalkyl or amino group are used; wherein the cycloalkyl, phenyl, and heterocyclic groups are optionally substituted with one or more substituents selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or amino groups; R 2 Selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; or R 1 and R 2 They can collectively form a 3-6 membered saturated carbocyclic or heterocyclic ring, which may optionally be substituted by one or more substituents selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or amino; and R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C6 cycloalkyl, phenyl, and 4- to 6-membered heterocycles containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the alkyl and haloalkyl groups are optionally selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, or C6 cycloalkyl groups. 3- One or more substituents of C6 cycloalkyl are substituted; wherein the cycloalkyl, phenyl and heterocyclic are optionally substituted by one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy, the method comprising the steps of: a. reacting an aminoguanidine of formula (V) with a compound of formula (VI) in solvent A to give a compound of formula (IV), wherein, optionally, compound (IV) is isolated;

[0056] b. Hydrogenating compound (IV) in the presence of solvent B to produce compound (III), wherein, optionally, compound (III) is isolated; and

[0057] c. Cyclate compound (III) with compound (II) in solvent C to obtain compound (I) or its N-oxide or salt.

[0058] LG is selected from halogens, OH, C1-C6 alkoxy groups, and -OC(O)-R. 4 R 4 The X is selected from C1-C6 alkyl, C1-C6 haloalkyl, or phenyl groups, optionally substituted with one or more substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups, and X is an anion selected from halide ions, carbonate, bicarbonate, nitrate, perchlorate, carboxylate, sulfate, sulfonate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, acetate, trifluoroacetate, benzoate, tetrafluoroborate, phosphate, or hexafluorophosphate.

[0059] In one embodiment, the intermediate compound of formula (IV) is directly subjected to a hydrogenation step without separation to obtain the compound of formula (III).

[0060] In another embodiment, the intermediate compound of formula (IV) is first separated and then hydrogenated to obtain the compound of formula (III).

[0061] In one embodiment, the amine compound of formula (III) is directly subjected to a cyclization step without separation to obtain the compound of formula (I).

[0062] In another embodiment, the amine compound of formula (III) is first separated and then subjected to a cyclization reaction to obtain the compound of formula (I).

[0063] In one embodiment, step b is carried out using a metal borohydride (e.g., lithium borohydride, sodium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride) in solvent B (selected from, but not limited to, water, alcohol, ether, or acid, such as methanol, ethanol, isopropanol, toluene, dichloromethane, tetrahydrofuran, dioxane, tert-butylmethyl ether, acetic acid, and trifluoroacetic acid, or mixtures thereof).

[0064] In another embodiment, the hydrogenation reaction in step b is carried out using hydrogen gas in the presence of a homogeneous or heterogeneous catalyst.

[0065] In another embodiment, the hydrogenation reaction in step b is carried out in the presence of a homogeneous or heterogeneous catalyst using a hydrogen source (e.g., hydrogen, formic acid, isopropanol, trichlorosilane (SiCl3H), phenyl dimethylsilane (SiPhMe2), pinacolborane, triethylamine, formic acid, and a mixture thereof).

[0066] In one embodiment, the cyclization reaction of compound (III) with compound (II) can be carried out under alkaline-free conditions.

[0067] In another embodiment, the cyclization reaction of compound (III) with compound (II) can be carried out in the presence of a base.

[0068] In one embodiment, the compound of formula (V) is selected from, but not limited to: aminoguanidine bicarbonate (2582-30-1); aminoguanidine chloride (1937-19-5); aminoguanidine nitrate (10308-82-4); aminoguanidine hydrochloride (16139-18-7); hydrazine sulfate (1068-42-4); aminoguanidine carbonate (2200-97-7); aminoguanidine hemisulfate (996-19-0); hydrazine sulfate (1:1) (2834-84-6); aminoguanidine phosphate (26071-57-8); hydrazine conjugated monoacid salt (58688-90-7); hydrazine nitrate (21150-30-1); a compound of carbonic acid and hydrazine (1:2) (13998-67-9); hydrazine dihydrochloride (55457-88). -0); hydrazine perchlorate (1:1) (41195-24-8); hydrazine acetate (1:1) (37598-37-1); compound of formic acid and hydrazine (1:1) (104188-36-5); hydrazine monohydrobromide (18807-65-3); hydrazine oxalate (1:1) (1070778-03-8); hydrazine phosphate (1: 1)(24413-21-6); hydrazine methanesulfonate (1:2) (676353-80-3); hydrazine methanesulfonate (1:1) (87533-58-2); hydrazine 2,2,2-trifluoroacetate (1:1) (1070777-96-6); hydrazine nitrate (1:2) (159024-39-2); hyponitric acid Compounds of 4-methylbenzoic acid and hydrazine (1:2) (90311-89-0); hydrazine oxalate (51601-65-1); hydrazine monohydroiodate (133082-93-6); hydrazine phosphate (2:1) (94345-42-3); hydrazine sulfate (1:2) (1111225-02-5); hydrazine oxalate (2:1) (195886-50-1); hydrazine conjugated disodium (188539-84-6); Compounds of 4-methylbenzoic acid and hydrazine (1:1) (2307749) -95-5); hydrazine ammonium salt (1:1) (1195372-39-4); a compound of 2-hydroxyacetic acid and hydrazine ammonium salt (1:1) (1070778-17-4); hydrazine ammonium acetate (146396-83-0); a compound of carbonic acid and hydrazine ammonium salt (2:1) (10587-01-6); a compound of hydrazine ammonium salt and 1-methyltrioxide (1:1) (2108288-73-7); in a preferred embodiment, the compound of formula (V) is selected from aminoguanidine bicarbonate, aminoguanidine chloride, aminoguanidine hydrochloride or aminoguanidine carbonate.

[0069] As described above, the method of the present invention for preparing compounds of formula (I) and their salts or N-oxides uses readily available and safe starting materials and reagents, and employs simple operating procedures, making it suitable for commercial-scale applications and economical. Furthermore, the method of the present invention does not require the use of additional reagents such as oxidants, iodine and / or bases or transition metal catalysts, which are typically used in known methods / processes for obtaining 1,2,4-triazole compounds. Therefore, the total cost of the method and the amount of wastewater generated during the process can be minimized, making this method both environmentally friendly and economically efficient.

[0070] As described herein, the method for preparing compound (I), its salt or N-oxide of the present invention uses aminoguanidine, which is a very safe and non-toxic reactant that can be used in large quantities without causing any harmful effects on the human body and the environment.

[0071] Furthermore, even without the use of any additional base, this method can simultaneously generate 1,2,4-triazole and introduce the desired R at the 5-position of the 1,2,4-triazole ring. 3 Substituents are used to minimize waste generated during the process and ultimately reduce the overall cost of the process.

[0072] Furthermore, this method can also be used to prepare structurally diverse 1-alkyl-1H-1,2,4-triazol-3-amines with C5-substituted structures of formula (I), wherein the preparation is achieved by using an acid derivative R. 3 -C(O)-LG (formula (II)) cyclization of formula (III) compounds is achieved, where R 3 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C6 cycloalkyl, phenyl, or 4 to 6-membered heterocyclic rings.

[0073] In one implementation, R in equations (I), (III), (IV), and (VI) 1 The heteroaromatic ring is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, phenyl, and a 5- or 6-membered monocyclic heteroaromatic ring selected from furanyl, thiophene, pyrrole, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the phenyl and heteroaromatic ring are optionally substituted by one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy. Preferably, R 1 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, trifluoromethyl, phenyl, thienyl, thiazolyl, pyrazolyl, pyridyl, or pyrimidinyl. More preferably, R 1 It is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, trifluoromethyl, phenyl, 2-furanyl, 3-pyrroleyl and 4-pyridyl.

[0074] In a preferred embodiment, R in formulas (I), (III), (IV) and (VI) 2 Selected from hydrogen, C1-C2 alkyl, and C1-C2 haloalkyl. More preferably, R 2 It can be hydrogen, methyl, ethyl, or trifluoromethyl.

[0075] In a preferred embodiment, R in formulas (I) and (II) 3 The group is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, and phenyl, wherein the phenyl group is optionally substituted with one or more substituents selected from halogen, C1-C3 alkyl, and C1-C3 alkoxy. More preferably, R 3 It is selected from hydrogen, methyl, ethyl, CHF2, CF3, CH2-CF3, CF2-CF3 and phenyl.

[0076] In a preferred embodiment, LG in formula (II) is selected from halogens, OH, C1-C3 alkoxy groups, or -OC(O)-R. 4 , where R 4 It is selected from C1-C2 alkyl, C1-C2 haloalkyl, or phenyl. More preferably, LG is selected from chlorine, bromine, OH, -OCH3, -O-CH2CH3, -O-CO-CH3, -O-CO-CF3, and -O-CO-Ph.

[0077] In a preferred embodiment, formula (II) is selected from H-COOH, CH3-CO2H, CH3-CH2-COOH, CF3-CO2H, Ph-CO2H, CF3-CF2-CO2H, CF3-CH2-CO2H, CF3-CO-Cl, CF3-CO-OCH2CH3, CF3-CO-O-CO-CF3, CH3-CO-O-CO-CH3, and Ph-CO-O-CO-Ph.

[0078] In a preferred embodiment, the anion X is selected from halide ions, bicarbonate ions, carbonate ions, nitrate ions, acetate ions, trifluoroacetate ions, or trifluoromethanesulfonate ions. More preferably, the anion X is selected from chloride ions, bicarbonate ions, carbonate ions, and trifluoroacetate ions.

[0079] In a preferred embodiment, the present invention provides a method for preparing compounds of formula (I), their N-oxides, or salts as described herein, wherein: R 1 The phenyl ring is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, phenyl, and a 5- or 6-membered monocyclic heteroaromatic ring selected from furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, or pyrimidinyl, wherein the phenyl ring and the heteroaromatic ring are optionally substituted by one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; R 2Selected from hydrogen, C1-C2 alkyl and C1-C2 haloalkyl; and R 3 The group is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl and phenyl, wherein the phenyl is optionally substituted by one or more substituents selected from halogen, C1-C3 alkyl and C1-C3 alkoxy.

[0080] In one embodiment, preferably, LG is selected from halogens, OH, C1-C3 alkoxy groups, or -OC(O)-R. 4 ;R 4 It is selected from C1-C2 alkyl, C1-C2 haloalkyl or phenyl; and X is selected from halide ions, bicarbonate, carbonate, nitrate, acetate, trifluoroacetate or trifluoromethanesulfonate.

[0081] In a more preferred embodiment, the method for preparing compounds of formula (I), their N-oxides, or salts thereof according to the present invention is as described herein, wherein R 1 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, trifluoromethyl, phenyl, furanyl, thiophene, and pyridyl; R 2 Selected from hydrogen, methyl, ethyl, or trifluoromethyl; R 3 It is selected from hydrogen, methyl, ethyl, CF3, CH2-CF3, CF2-CF3 or phenyl.

[0082] In a preferred embodiment, LG is selected from chlorine, bromine, OH, -OCH3, -O-CH2CH3, -O-CO-CH3, -O-CO-CF3 or -O-CO-Ph; and X is selected from chloride ion, bicarbonate ion, carbonate ion or trifluoroacetate ion.

[0083] In one embodiment, the solvent A in step a of the method for preparing compound (I) according to the present invention is selected from, but not limited to, polar solvents, such as water, methanol, ethanol, isopropanol, acetonitrile, dimethylformamide, and dimethyl sulfoxide. Preferably, the solvent in step a is selected from water, methanol, and ethanol, and more preferably, water.

[0084] In one embodiment, the suitable reaction temperature for step a of the method for preparing compound (I) according to the present invention is 20-100°C. In a preferred embodiment, the temperature is 20-70°C, more preferably 20-50°C, and even more preferably 20-25°C.

[0085] In a preferred embodiment, according to the present invention, as described herein, wherein i. solvent A in step a is selected from water, methanol, ethanol, isopropanol, acetonitrile, dimethylformamide, and dimethyl sulfoxide; ii. step a can be carried out in a temperature range of 20-100°C.

[0086] The homogeneous or heterogeneous catalyst in step b of the method for preparing compound (I) as described herein according to the present invention may be selected from, but is not limited to, platinum oxide (PtO2), palladium supported on activated carbon, platinum supported on carbon, palladium supported on activated charcoal, palladium supported on carbon, Raney nickel, Lindela catalyst, or RhCl(PPh3)3. Preferably, it is selected from platinum oxide (PtO2), 10% palladium supported on carbon, or Raney nickel.

[0087] In step b of this method, the hydrogen pressure used to hydrogenate compound (IV) to compound (III) is 10-50 bar. In a preferred embodiment, the pressure is 15-25 bar.

[0088] The amount of homogeneous or heterogeneous catalyst used in step b of the method for preparing compound (I) is 1-15% (w / w).

[0089] Step b of the method for preparing compound (I) according to the present invention can be carried out in the presence of solvent B using a metal borohydride selected from lithium borohydride, sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.

[0090] The solvent B in step b of the method for preparing compound (I) as described herein according to the present invention is selected from, but not limited to, water, alcohol, ether or acid; for example, methanol, ethanol, isopropanol, toluene, dichloromethane, tetrahydrofuran, dioxane, tert-butyl methyl ether, formic acid, acetic acid and trifluoroacetic acid or mixtures thereof.

[0091] In a preferred embodiment, the solvent B used in step b of the method for preparing compound (I) according to the present invention is selected from water and alcohols, such as methanol, ethanol or isopropanol, more preferably water.

[0092] The suitable reaction temperature for step b of the method for preparing compound (I) as described herein is 0-90 °C.

[0093] In a preferred embodiment, the suitable reaction temperature for step b of the method for preparing compound (I) as described herein is 20-50°C, more preferably 40-45°C.

[0094] In a preferred embodiment, in step b of the method for preparing compound (I) according to the present invention, wherein i. the homogeneous or heterogeneous catalyst in step b is selected from platinum oxide (PtO2), carbon-supported platinum, activated carbon-supported palladium, activated charcoal-supported palladium, carbon-supported palladium, Raney nickel, Lindela catalyst, or RhCl(PPh3)3; ii. the solvent B in step b is selected from water, methanol, ethanol, isopropanol, toluene, dichloromethane, tetrahydrofuran, dioxane, tert-butyl methyl ether, formic acid, acetic acid, and trifluoroacetic acid or mixtures thereof; iii. the hydrogen pressure in step b is 10-50 bar; iv. the amount of homogeneous or heterogeneous catalyst used is 1-15% (w / w); and v. the suitable reaction temperature in step b is 0-90°C.

[0095] In a more preferred embodiment, the present invention provides a method for synthesizing a compound of formula (III), the method comprising the steps of: a. reacting an aminoguanidine of formula (V) with a compound of formula (VI) to obtain a compound of formula (IV), wherein the compound of formula (IV) is optionally isolated;

[0096] b. Hydrogenating the compound of formula (IV) to produce the compound of formula (III), wherein, optionally, the compound of formula (III) is isolated;

[0097] The solvents used in steps a and b are selected from water or alcohol solvents, more preferably water.

[0098] In one embodiment, the alcohol solvent is selected from methanol, ethanol, or isopropanol.

[0099] In one embodiment, the hydrogenation reaction is carried out using a Raney nickel catalyst.

[0100] In one embodiment, the present invention also provides a method for preparing a compound of formula (I) or its N-oxide or salt.

[0101] Among them, R 1 The compounds are selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, phenyl, and 4- to 6-membered heterocycles containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the alkyl and haloalkyl groups are optionally selected from halogen, cyano, C1-C6 alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C 3-One or more substituents of a C6 cycloalkyl or amino group are used; wherein the cycloalkyl, phenyl, and heterocyclic groups are optionally substituted with one or more substituents selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or amino groups; R 2 Selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; or R 1 and R 2 They can collectively form a 3-6 membered saturated carbocyclic or heterocyclic ring, which may optionally be substituted by one or more substituents selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or amino; and R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C6 cycloalkyl, phenyl, and 4- to 6-membered heterocycles containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the alkyl and haloalkyl groups are optionally selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, or C6 cycloalkyl groups. 3- One or more substituents of the C6 cycloalkyl group are substituted; wherein the cycloalkyl, phenyl, and heterocyclic groups are optionally substituted with one or more substituents selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, and C1-C6 haloalkoxy groups; the method comprises the following steps: c. cyclizing the compound of formula (III) with the compound of formula (II) in solvent C to obtain the compound of formula (I) or its N-oxide or salt.

[0102] LG is selected from halogens, OH, C1-C6 alkoxy groups, and -OC(O)-R. 4 , where R 4 It is selected from C1-C6 alkyl, C1-C6 haloalkyl or phenyl, and optionally substituted by one or more substituents selected from halogen, C1-C6 alkyl and C1-C6 alkoxy, and X is an anion selected from halide, bicarbonate, carbonate, nitrate, perchlorate, carboxylate, sulfonate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, acetate, trifluoroacetate, benzoate, tetrafluoroborate or hexafluorophosphate.

[0103] In one embodiment, step c is performed in the presence of a base.

[0104] In another embodiment, step c is carried out under alkali-free conditions.

[0105] According to the present invention, in step c of the method for preparing compound (I) as described herein, the cyclization solvent C is a polar or nonpolar solvent selected from, but not limited to, dimethylformamide, acetonitrile, tetrahydrofuran, dimethoxyethane, dioxane, tert-butyl methyl ether, and toluene. Preferably, the cyclization solvent C in step c is selected from acetonitrile, toluene, and dimethylformamide, more preferably acetonitrile and toluene.

[0106] According to the present invention, the base (if used) in step c of the method for preparing compound (I) described herein can be an organic or inorganic base, selected from, but not limited to, triethylamine, isopropylamine, diisopropylethylamine, pyridine, methylpyridine, alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal bicarbonates, alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal hydrides, alkali metal or alkaline earth metal alkoxides, acetates, or benzoates. In a preferred embodiment, the base is selected from triethylamine, potassium carbonate, cesium carbonate, or sodium carbonate.

[0107] In step c of the method for preparing compound (I) described herein, the suitable reaction temperature can vary in the range of -30 to 120 °C.

[0108] In one embodiment, step c of the present invention is preferably carried out under alkali-free conditions.

[0109] In a preferred embodiment, the method described herein, wherein: i. the base (if used) in step c is selected from triethylamine, isopropylamine, diisopropylethylamine, pyridine, methylpyridine, alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal bicarbonates, alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal hydrides, alkali metal or alkaline earth metal alkoxides, acetates or benzoates, preferably selected from triethylamine, potassium carbonate, cesium carbonate or sodium carbonate; ii. the solvent C in step c is selected from dimethylformamide, acetonitrile, tetrahydrofuran, dimethoxyethane, dioxane, tert-butyl methyl ether and toluene; iii. the suitable reaction temperature in step c can vary in the range of -30 to 120°C.

[0110] The method for preparing compound (I) disclosed herein (where LG in formula (II) is a halogen, C1-C6 is an alkoxy group, and -OC(O)-R) 4 In step c, the suitable reaction temperature is -30 to 120°C. In a preferred embodiment, the temperature range is -10 to 40°C, and more preferably -5 to 10°C.

[0111] In the method for preparing compound (I) disclosed herein (where LG in formula (II) is -OH), the suitable reaction temperature for step c is -20 to 120 °C.

[0112] In a preferred embodiment, the acid is added at a temperature ranging from 10 to 40°C, followed by heating to 110°C.

[0113] In one embodiment, after the reactions in steps a to c are completed, the pH of the mixture is adjusted to 5 to 8 depending on the substitution situation.

[0114] Reaction time is not a critical factor; it depends on batch size, temperature, type of reaction, and reagents used, and typically ranges from a few minutes to a few hours.

[0115] The present invention provides a method for preparing a compound of formula (I) as described herein, wherein the steps can be carried out in a batch, semi-continuous or continuous reaction mode, particularly under semi-continuous or continuous flow reaction conditions.

[0116] Those skilled in the art understand the optimal post-treatment methods for the reaction mixtures after each reaction. Post-treatment typically includes separating the products and, selectively, washing with a solvent, and, if useful or necessary, selectively drying the products.

[0117] The reaction products can be separated by a number of techniques, including but not limited to decantation, filtration, centrifugation, evaporation, liquid-liquid extraction, distillation, recrystallization, chromatography, or combinations thereof.

[0118] The reaction steps according to the invention are typically carried out at atmospheric pressure. Alternatively, the method steps can be carried out under reduced or increased pressure.

[0119] The following embodiments further illustrate the present invention. These embodiments are intended to illustrate the invention by way of example and do not limit the scope of the invention. Although the invention has been described according to its specific embodiments, it will be apparent to those skilled in the art that certain modifications and equivalents can be made thereto, and these modifications and equivalents should also be included within the scope of the invention.

[0120] Although the subject matter has been described in considerable detail with reference to certain embodiments and their implementations, other implementations exist.

[0121] Experimental Examples:

[0122] Scheme 1: Preparation of Compound (I) All solvents and reagents used in this invention were purchased commercially. Reactants such as aminoguanidine hydrochloride (Formula V), ketone compounds (Formula VI), and compounds (Formula II) were purchased from commercial suppliers.

[0123] Example 1: Step a: Synthesis of imine compound of formula (IV) Method I:

[0124] Add 110 g (1 mol) of aminoguanidine hydrochloride to a solvent (ethanol, methanol, or water, 330 mL) and stir at 22–24 °C. Add 1 mol of formula (VI) aldehyde / ketone to the reaction mixture over 15–90 minutes at 22–24 °C. Continue stirring the reaction mixture at 22–70 °C for 2–12 hours. After the reaction is complete, adjust the pH with an aqueous sodium hydroxide solution and use the crude reaction mixture directly for the next reaction step.

[0125] Method II:

[0126] Add 136 g (1 mol) of aminoguanidine bicarbonate to a solvent (ethanol, methanol, or water, 400 mL), then add concentrated hydrochloric acid (1 mol) and stir at 22–24 °C. Add the aldehyde / ketone of formula (VI) (1 mol) to the reaction mixture over 15–90 minutes at 22–24 °C. Continue stirring at 22–70 °C for 2–12 hours. After the reaction is complete, adjust the pH with an aqueous sodium hydroxide solution and use the crude reaction mixture directly for the next reaction step.

[0127] Step b: Synthesis of amine compounds of formula (III)

[0128] Method I: The crude reaction mixture obtained in step (a) and PtO2 (1.1 g, 1% w / w) were added to an autoclave using PtO2 (1% w / w). A flow rate of 50 kg / cm³ was introduced into the autoclave. 2 The reaction mixture was pressurized with hydrogen gas (approximately 50 bar) and heated at 25–30 °C for 24 hours. After the reaction was complete, the catalyst was removed by filtration, and the pH of the filtrate was adjusted to acidic using a 15% hydrochloric acid aqueous solution. The reaction mixture was concentrated under reduced pressure. The resulting residue was suspended in isopropanol (330 mL) and heated with stirring at 55–60 °C for 60 minutes, followed by gradual cooling to 5–10 °C over 60 minutes. The resulting solid was filtered and washed with cold isopropanol (100 mL). The resulting wet filter cake was dried under reduced pressure to give the corresponding pure amine hydrochloride.

[0129] Method II: The crude reactant obtained in step a and Pd / C (11.0 g, 10% w / w) were added to an autoclave using Pd / C (10% w / w). The autoclave was then purged with 50 kg / cm³ of gas. 2 The mixture was pressurized with hydrogen gas (approximately 50 bar) and heated at 25–30°C for 24 hours. After the reaction was complete, the catalyst was removed by filtration, and the pH of the filtrate was adjusted to 2–3 with a 15% hydrochloric acid aqueous solution. The reaction mixture was concentrated under reduced pressure to obtain crude amine hydrochloride, which could be used for the next reaction without purification.

[0130] Method III: The crude reactant obtained in step a and Raney nickel (16.5 g, 15% w / w) were added to an autoclave using Raney nickel (15% w / w). The autoclave was then purged with 25 kg / cm³ of gas. 2 The reaction mixture was pressurized with hydrogen (approximately 25 bar) and heated at 35–40 °C for 4 h. After the reaction was complete, the catalyst was removed by filtration, and the pH of the filtrate was adjusted to acidic using a 15% hydrochloric acid aqueous solution. The reaction mixture was concentrated under reduced pressure. The resulting residue was suspended in isopropanol (330 mL) and heated with stirring at 55–60 °C for 60 min, followed by gradual cooling to 5–10 °C over 60 min. The solid was filtered and washed with cold isopropanol (110 mL). The resulting wet filter cake was dried under reduced pressure to give the corresponding pure amine hydrochloride.

[0131] Method IV (using NaBH4): The crude reaction mixture obtained in step a is cooled to 8 to 10 °C. Solid NaBH4 or an aqueous solution of NaBH4 (1 to 3 mol) is added over 30 to 90 minutes. The reaction mixture is then heated to 22 to 24 °C and stirred for 20 hours. After the reaction is complete, the reaction mixture is cooled to 0 to 5 °C, and the pH is adjusted to acidic with a 15% aqueous hydrochloric acid solution. The reaction mixture is concentrated under reduced pressure to give the corresponding crude amine hydrochloride.

[0132] Step c: Synthesis of the triazole compound of formula (I)

[0133] Method I (using anhydride reactants): The amine hydrochloride (1 mol) obtained in step b was added to acetonitrile (400 mL) with stirring. The reaction mixture was cooled to -10 °C. At -10 to -5 °C, a solution of the corresponding anhydride (1 mol) in acetonitrile (250 mL) was added over 5 to 120 minutes. The reaction mixture was stirred at -5 to 0 °C for 1 to 5 hours. After the reaction was complete, the pH of the reaction mixture was adjusted with a 20% sodium hydroxide aqueous solution. Acetonitrile was removed by distillation, and the pH was adjusted to approximately 10 with a 20% sodium hydroxide aqueous solution. The crude reaction mixture was stirred at 0 to 5 °C for 60 minutes, the solid was filtered, washed with cold water (150 mL), and dried under reduced pressure to give the corresponding substituted triazole compound in an overall three-step yield of 60-70%.

[0134] Method II (using acid reactants): The amine hydrochloride (1 mol) obtained in step b was added to toluene (500 mL) with stirring. HCOOH or CF3COOH (1.2-2.5 mol) was added over 5-15 minutes at 110 °C, and the reaction was allowed to proceed for 1-12 hours. During this time, the water and excess acid produced were collected using a Dean-Stark apparatus. After the reaction was complete, the reaction mixture was cooled to 22-24 °C, and the pH was adjusted to neutral to alkaline with a 20% sodium hydroxide aqueous solution. The organic layer was separated, the aqueous layer was extracted with toluene, filtered, and dried under reduced pressure to give the corresponding substituted triazole compound, with an overall yield of 60-70% for the three steps.

[0135] Method III (using acyl chloride reactants): Under stirring, triethylamine (1 mol) and the amine hydrochloride obtained in step b (1 mol) were added to acetonitrile (900 mL). The reaction mixture was cooled to -30 °C, and then trifluoroacetyl chloride (1 mmol) was added over 5–120 minutes. After the addition was complete, the reaction mixture was heated to 22–24 °C and stirred for another 30–60 minutes. After the reaction was complete, the pH of the reaction mixture was adjusted to neutral to alkaline with a 10% sodium hydroxide aqueous solution. Acetonitrile was removed by distillation, and the pH was adjusted to approximately 10 with a 10% sodium hydroxide aqueous solution. The residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the corresponding substituted triazole compound.

[0136] Method IV (using esters as reactants): Acetonitrile (900 mL), followed by ethyl trifluoroacetate (1 mol) and 1-methylaminoguanidine (1 mol) obtained in step b were added to an autoclave and heated at 100 °C for 10 hours. After the reaction was complete, the pH of the reaction mixture was adjusted with a 10% sodium hydroxide aqueous solution. Acetonitrile was removed by distillation, and the pH was adjusted to approximately 10 with a 10% sodium hydroxide aqueous solution. The residue was extracted with ethyl acetate (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the substituted triazole compound.

[0137] The following compounds were synthesized according to this method using the general steps described in Example 1.

[0138] Table 1: Compounds of Formula (I) synthesized using this method

[0139] After the invention has been described with reference to certain preferred embodiments, those skilled in the art will be able to understand other embodiments by reading the specification.

Claims

1. A method for preparing a compound of formula (I) or its N-oxide or salt, in, R 1 The compounds are selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, phenyl, and 4- to 6-membered heterocycles containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the alkyl and haloalkyl groups are optionally selected from halogen, cyano, C1-C6 alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C 3- One or more substituents of a C6 cycloalkyl or amino group are used; wherein the cycloalkyl, phenyl, and heterocyclic groups are optionally substituted with one or more substituents selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or amino groups; R 2 Selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; or R 1 and R 2 They can collectively form a 3-6 membered saturated carbocyclic or heterocyclic ring, which may optionally be substituted by one or more substituents selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or amino; and R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C6 cycloalkyl, phenyl, and 4- to 6-membered heterocycles containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the alkyl and haloalkyl groups are optionally selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, or C6 cycloalkyl groups. 3- One or more substituents of C6 cycloalkyl are substituted; wherein the cycloalkyl, phenyl and heterocyclic are optionally substituted by one or more substituents selected from halogens, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, the method comprising the steps of: a. reacting an aminoguanidine of formula (V) with a compound of formula (VI) in solvent A to give a compound of formula (IV), wherein, optionally, compound (IV) is isolated; b. Hydrogenating compound (IV) in the presence of solvent B to produce compound (III), wherein, optionally, compound (III) is isolated; and c. Cyclate compound (III) with compound (II) in solvent C to obtain compound (I) or its N-oxide or salt. LG is selected from halogens, OH, C1-C6 alkoxy groups, and -OC(O)-R. 4 , where R 4 The X is selected from C1-C6 alkyl, C1-C6 haloalkyl, or phenyl groups, optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy groups, and X is an anion selected from halide, bicarbonate, nitrate, perchlorate, carboxylate, sulfonate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, acetate, trifluoroacetate, benzoate, tetrafluoroborate, or hexafluorophosphate.

2. A method for preparing a compound of formula (I) or its N-oxide or salt, in, R 1 The compounds are selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, phenyl, and 4- to 6-membered heterocycles containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the alkyl and haloalkyl groups are optionally selected from halogen, cyano, C1-C6 alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C 3- One or more substituents of a C6 cycloalkyl or amino group are used; wherein the cycloalkyl, phenyl, and heterocyclic groups are optionally substituted with one or more substituents selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or amino groups; R 2 Selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; or R 1 and R 2 They can collectively form a 3-6 membered saturated carbocyclic or heterocyclic ring, which may optionally be substituted by one or more substituents selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or amino; and R 3 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C6 cycloalkyl, phenyl, and 4- to 6-membered heterocycles containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the alkyl and haloalkyl groups are optionally selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, or C6 cycloalkyl groups. 3- One or more substituents of the C6 cycloalkyl group are substituted; wherein the cycloalkyl, phenyl, and heterocyclic groups are optionally substituted with one or more substituents selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, and C1-C6 haloalkoxy groups; the method comprises the following steps: c. cyclizing the compound of formula (III) with the compound of formula (II) in solvent C to obtain the compound of formula (I) or its N-oxide or salt. LG is selected from halogens, OH, C1-C6 alkoxy groups, and -OC(O)-R. 4 , where R 4 It is selected from C1-C6 alkyl, C1-C6 haloalkyl or phenyl, and optionally substituted by one or more substituents selected from halogen, C1-C6 alkyl and C1-C6 alkoxy, and X is an anion selected from halide, bicarbonate, carbonate, nitrate, perchlorate, carboxylate, sulfonate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, acetate, trifluoroacetate, benzoate, tetrafluoroborate or hexafluorophosphate.

3. A method for synthesizing a compound of formula (III), the method comprising the following steps: a. Reacting the aminoguanidine of formula (V) with the compound of formula (VI) to give the compound of formula (IV), wherein the compound of formula (IV) is optionally isolated; b. In the presence of solvent B, the compound of formula (IV) is hydrogenated to produce the compound of formula (III), wherein the compound of formula (III) is optionally isolated; Among them, R 1 The compounds are selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, phenyl, and 4- to 6-membered heterocycles containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the alkyl and haloalkyl groups are optionally selected from halogen, cyano, C1-C6 alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C 3- One or more substituents of a C6 cycloalkyl or amino group are used; wherein the cycloalkyl, phenyl, and heterocyclic groups are optionally substituted with one or more substituents selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or amino groups; R 2 Selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; or R 1 and R 2 They can collectively form a 3-6 membered saturated carbocyclic or heterocyclic ring, which is optionally substituted by one or more substituents selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or amino; and X is an anion selected from halide, bicarbonate, carbonate, nitrate, perchlorate, carboxylate, sulfonate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, acetate, trifluoroacetate, benzoate, tetrafluoroborate, or hexafluorophosphate.

4. The method according to claim 1, 2 or 3, wherein, R 1 The phenyl ring is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, phenyl, and a 5- or 6-membered monocyclic heteroaromatic ring selected from furanyl, pyrroleyl, pyrazolyl, or pyridinyl, wherein the phenyl ring and the heteroaromatic ring are optionally substituted by one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; R 2 Selected from hydrogen, C1-C2 alkyl, and C1-C2 haloalkyl; R 3 Selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, and phenyl, wherein the phenyl is optionally substituted with one or more substituents selected from halogen, C1-C3 alkyl, and C1-C3 alkoxy; LG is selected from halogen, OH, C1-C3 alkoxy, or -OC(O)-R. 4 ;R 4 It is selected from C1-C2 alkyl, C1-C2 haloalkyl or phenyl; and X is selected from halide ions, bicarbonate, carbonate, nitrate, acetate, trifluoroacetate or trifluoromethanesulfonate.

5. The method according to claim 1, 2 or 3, wherein, R 1 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, trifluoromethyl, phenyl, furanyl, pyrrolyl, and pyridyl; R 2 Selected from hydrogen, methyl, ethyl, or trifluoromethyl; R 3 Selected from hydrogen, methyl, ethyl, CF3, CH2-CF3, CF2-CF3 and phenyl; LG selected from chlorine, bromine, OH, -OCH3, -O-CH2CH3, -O-CO-CH3, -O-CO-CF3 and -O-CO-Ph; and X selected from chloride ion, bicarbonate ion, carbonate ion or trifluoroacetate ion.

6. The method according to claim 1 or 3, wherein, Step b is carried out using hydrogen in the presence of a homogeneous or heterogeneous catalyst and solvent B.

7. The method according to claim 3 or 6, wherein, The hydrogenation reaction is carried out using a Raney nickel catalyst.

8. The method according to claim 1 or 3, wherein, Step b is performed in the presence of solvent B using a metal borohydride selected from lithium borohydride, sodium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride.

9. The method according to claim 1 or 3, wherein, Solvent B is selected from water, methanol, ethanol, isopropanol, toluene, dichloromethane, tetrahydrofuran, dioxane, tert-butyl methyl ether, acetic acid, and trifluoroacetic acid or mixtures thereof.

10. The method according to claim 1 or 2, wherein, Step c is carried out in the absence of alkali.

11. The method according to claim 1 or 3, wherein, i. Solvent A in step a is selected from water, methanol, ethanol, isopropanol, acetonitrile, dimethylformamide, and dimethyl sulfoxide; ii. Step a is carried out in the temperature range of 20-100°C.

12. The method according to claim 1 or 3, wherein, i. The homogeneous or heterogeneous catalyst in step b is selected from platinum oxide (PtO2), carbon-supported platinum, activated carbon-supported palladium, activated charcoal-supported palladium, carbon-supported palladium, Raney nickel, Lindela catalyst, or RhCl(PPh3)3; ii. Solvent B in step b is selected from water, methanol, ethanol, isopropanol, toluene, dichloromethane, tetrahydrofuran, dioxane, tert-butyl methyl ether, acetic acid, and trifluoroacetic acid, or mixtures thereof; iii. The hydrogen pressure in step b is 10-50 bar; iv. The amount of the homogeneous or heterogeneous catalyst used is 1-15% w / w; and v. The suitable reaction temperature in step b is 0-90°C.

13. The method according to claim 1 or 3, wherein, Solvent A and solvent B are selected from water, alcohol solvents, or mixtures thereof.

14. The method according to claim 1 or 2, wherein, i. The base in step c, if used, is selected from triethylamine, isopropylamine, diisopropylethylamine, pyridine, methylpyridine, alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal bicarbonates, alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal hydrides, alkali metal or alkaline earth metal alkoxides, acetates or benzoates, preferably triethylamine, potassium carbonate, cesium carbonate or sodium carbonate; ii. The solvent C in step c is selected from dimethylformamide, acetonitrile, tetrahydrofuran, dimethoxyethane, dioxane, tert-butyl methyl ether and toluene; iii. The suitable reaction temperature in step c can vary in the range of -30 to 120°C.

15. The method according to claim 2, wherein, i. Solvent C in step c is selected from dimethylformamide, acetonitrile, tetrahydrofuran, dimethoxyethane, dioxane, tert-butyl methyl ether, and toluene; and ii. The suitable reaction temperature in step c can vary in the range of -30 to 120°C.

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