Imidazole derivative as well as preparation method and application thereof

Abstract

The invention discloses an imidazole derivative as shown in a formula (I), or a salt, a stereoisomer or a nitrogen oxide thereof, and R and R1 are defined in the description. The compound shown in the formula (I) can be used as a reagent for killing harmful microorganisms, and especially has a good effect on fungi causing damping-off.

Description

Technical Field

[0001] This invention belongs to the field of pesticide synthesis, specifically relating to an imidazole derivative, its preparation method, and its application as a fungicide. Technical Background

[0002] Investigations have revealed over 80,000 species of microorganisms harmful to crops globally, leading to severe crop diseases and causing enormous economic losses. Historically, numerous pandemics caused by plant diseases have resulted in famine and mass starvation.

[0003] In recent years, a large number of new agricultural fungicides with different skeleton structures have appeared on the market to prevent and treat various crop diseases. Data shows that the market size of fungicides in my country is approaching 6 billion yuan. Therefore, the discovery and preparation of new fungicides remains of great significance and has broad market prospects.

[0004] Imidazole structures are widely found in commercially available fungicides, such as imazalil, tebuconazole, cyprodinil, and oxadixyl. The strong fungicidal activity of these drugs sufficiently demonstrates the unique characteristics of the imazalil structure.

[0005] Therefore, the structural design and preparation of imidazole derivatives is a highly promising research direction for the discovery of novel fungicides. Based on this, the applicant has completed this invention. Summary of the Invention

[0006] The purpose of this invention is to provide an imidazole derivative with excellent bactericidal effect.

[0007] Specifically, the present invention first provides a compound of formula (I),

[0008]

[0009] Its salts, its stereoisomers, or nitrogen oxides,

[0010] Wherein, R is H, C1-C6 alkyl, or halo-C1-C6 alkyl;

[0011] R1 is R2 is H, C1-C6 alkyl, or halo-C1-C6 alkyl;

[0012] In this context, “” represents the connection end.

[0013] Preferably, the compound of formula (I) is the compound of formula A.

[0014]

[0015] R and R2 are defined as described above.

[0016] Preferably, the compound of formula (I) is a compound of formula B.

[0017]

[0018] R is defined as described above.

[0019] This invention also provides a method for preparing compound A, the synthetic route of which is as follows:

[0020]

[0021] Where R and R2 are defined as above, and X is a leaving group.

[0022] This invention also provides a method for preparing compound B, the synthetic route of which is as follows:

[0023]

[0024] Wherein, R is H, C1-C6 alkyl, or halogenated C1-C6 alkyl.

[0025] This invention also provides a method for preparing compound (4'), characterized by the following synthetic route:

[0026]

[0027] The present invention also provides a method for preparing compound (3), the synthetic route of which is as follows:

[0028]

[0029] The present invention also provides the following intermediate compounds:

[0030]

[0031] The present invention also provides a bactericidal composition comprising the compound of the present invention, its salt, its stereoisomer, or a nitrogen oxide compound. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprising of," etc., will be understood to include the stated components or steps, without excluding the presence of other substances or steps.

[0033] Furthermore, to better illustrate the present invention, numerous specific details are provided in the following detailed embodiments.

[0034] Those skilled in the art will understand that the present invention can be practiced even without certain specific details. In some embodiments, materials, methods, and means well known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.

[0035] To more clearly illustrate the purpose, technical solutions, and advantages of the embodiments of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprising of," etc., will be understood to include the stated components or steps, without excluding other substances or steps.

[0036] Furthermore, to better illustrate the present invention, numerous specific details are provided in the following detailed embodiments.

[0037] Those skilled in the art will understand that the present invention can be practiced even without certain specific details. In some embodiments, materials, methods, and means well known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.

[0038] When the compounds of the present invention can exist in tautomer form, the compounds described above and below should be understood, where applicable, to also include the corresponding tautomer forms, even if such tautomer forms are not explicitly mentioned in each case.

[0039] If the compound of Formula I described in this invention has one or more chiral centers and is therefore present as an enantiomer or diastereomer, then the pure enantiomer, the racemic version, or the diastereomer may be used in the compositions of this invention.

[0040] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in racemic or enantiomerically enriched forms, such as (R)-, (S)-, or (R,S)- configurations.

[0041] If the compounds of Formula I described in this invention have functional groups that can be ionized, they can also be used as agricultural salts or mixtures thereof. The salts described in this invention can be inorganic salts such as hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates, but are not limited thereto. They can also be organic acid salts such as formates, acetates, oxalates, fumarates, methanesulfonates, and benzenesulfonates, but are not limited thereto.

[0042] Unless otherwise stated, all technical and technical terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents and publications referenced in this disclosure are incorporated herein by reference in their entirety.

[0043] As used in this disclosure, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. When the number of carbon atoms is not used when describing "alkyl," it means that the alkyl group has any number of carbon atoms. When the number of carbon atoms is used when describing "alkyl," it means that the alkyl group has the stated number of carbon atoms. For example, an alkyl group can be C1-C1. 20 Alkyl group refers to a saturated, straight-chain or branched monovalent hydrocarbon group containing 1-20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in this disclosure. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms, such as "C1-C2". 12 "alkyl"; in some embodiments, the alkyl group is an alkyl group containing 1-6 (1, 2, 3, 4, 5 or 6) carbon atoms, i.e. "C1-C6 alkyl"; in still other embodiments, the alkyl group is an alkyl group containing 1-4 (1, 2, 3 or 4) carbon atoms, i.e. "C1-C4 alkyl"; in still other embodiments, the alkyl group contains 1-3 carbon atoms, i.e. "C1-C3 alkyl".

[0044] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), and tert-butyl (t-B). u、-C(CH3)3), n-pentyl(-CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH(CH3)2), 3-methyl-1-butyl(-CH2CH2CH(CH3)2), 2-methyl-1 -Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3) ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0045] The term "halogenated alkyl" refers to a straight-chain or branched alkoxyalkyl group, for example, substituted with one or more halogen atoms that may be the same or different from each other. For example, "halogenated C1-C6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, substituted with one or more halogen atoms that may be the same or different from each other. Examples include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoroisopropyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 1,3-difluoro-2-propyl, 1,3-dichloro-2-propyl, and 1-chloro-3-fluoro -2-propyl, 1,1,1-trifluoro-2-propyl, 2,3,3,3-tetrafluoropropyl, 1,1,1,3,3,3-hexafluoro-2-propyl, 1,1,1,3,3,3-hexafluoro-2-chloro-2-propyl, 1,1,1,3,3,3-hexafluoro-2-bromo-2-propyl, 1,1,2,3,3,3-hexafluoro-2-chloropropyl, 1,1,2,3,3,3-hexafluoro-2-bromopropyl, 1,1,2,3,3,3-hexafluoro-1-bromo-2-propyl, 2,2,3,3,3-pentafluoropropyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl, nonafluorobutyl, nonafluoroisobutyl, nonafluorosec-butyl, or nonafluorotert-butyl, etc., but not limited to these.

[0046] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0047] The term "salt" in this disclosure includes salts formed by acid addition and salts formed by base addition, with suitable bases being hydroxides, carbonates, bicarbonates of alkali metals and alkaline earth metals, particularly sodium, potassium, magnesium, and calcium salts, as well as ammonium. Salts can be salts formed by addition to an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or salts formed by addition to an organic acid, such as formic acid, carbonic acid, and alkyl acids such as acetic acid, trifluoroacetic acid, trichloroacetic acid, and propionic acid, as well as glycolic acid, thiocyanate, lactic acid, succinic acid, citric acid, benzoic acid, cinnamic acid, oxalic acid, toluenesulfonic acid, salicylic acid, para-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, etc.

[0048] The leaving group of this invention is usually a halogen (such as fluorine, chlorine, bromine or iodine), p-toluenesulfonyl, methanesulfonyl or other easily leaving groups, but is not limited to these.

[0049] Those skilled in the art understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires the lone pair of electrons to be oxidized into oxides. They also know which nitrogen-containing heterocycles can form N-oxides. Tertiary amines can also form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and diethylene oxides such as dimethyldiethylene oxide. These methods for preparing N-oxides have been extensively described and reviewed in the literature.

[0050] The present invention first provides a compound of formula (I),

[0051]

[0052] Its salts, its stereoisomers, or nitrogen oxides,

[0053] Wherein, R is H, C1-C6 alkyl, or halo-C1-C6 alkyl;

[0054] R1 is R2 is H, C1-C6 alkyl, or halo-C1-C6 alkyl;

[0055] in, Indicates the connection end.

[0056] Preferably, R and R2 are independently selected from H, methyl, ethyl, propyl or trifluoromethyl.

[0057] Preferably, the compound of formula (I) is the compound of formula A.

[0058]

[0059] Wherein, R is H, C1-C6 alkyl or halo-C1-C6 alkyl, preferably H, methyl, ethyl, propyl or trifluoromethyl; R2 is H, C1-C6 alkyl or halo-C1-C6 alkyl, preferably H, methyl, ethyl, propyl or trifluoromethyl;

[0060] Preferably, the compound of formula (I) is a compound of formula B.

[0061]

[0062] Wherein, R is H, C1-C6 alkyl or halogenated C1-C6 alkyl, preferably H, methyl, ethyl, propyl or trifluoromethyl.

[0063] Preferably, the compound of formula (I) is selected from the following compounds:

[0064]

[0065] This invention also provides a method for preparing compound A, characterized by the following synthetic route:

[0066]

[0067] Wherein, R is H, C1-C6 alkyl or halo-C1-C6 alkyl, preferably H, methyl, ethyl, propyl or trifluoromethyl; R2 is H, C1-C6 alkyl or halo-C1-C6 alkyl, preferably H, methyl, ethyl, propyl or trifluoromethyl;

[0068] X is a leaving group, preferably a halogen.

[0069] Preferably, in the preparation method of the above compound A, compound (5) reacts with thionyl chloride to form acyl chloride compound (5'), compound (5') then reacts with 2-fluoroaniline compounds in organic solvent A, with the addition of an acid-binding agent, and finally undergoes an alkylation reaction to obtain compound A; wherein the organic solvent A is one or a mixture of acetonitrile, 1,2-dichloroethane, dichloromethane and N,N-dimethylformamide; and the acid-binding agent is one of sodium carbonate, potassium carbonate, triethylamine and diisopropylethylamine.

[0070] This invention also provides a method for preparing compound B, the synthetic route of which is as follows:

[0071]

[0072] Wherein, R is H, C1-C6 alkyl or halogenated C1-C6 alkyl, preferably H, methyl, ethyl, propyl or trifluoromethyl.

[0073] In the above preparation method, preferably, compound (5) reacts with hydroxylamine hydrochloride to form an oxime, and then reacts with methyl 2-chloropropionate in an organic solvent B, and an inorganic base is added to obtain compound B; wherein the organic solvent B is one or a mixture of acetonitrile, tetrahydrofuran, acetone and N,N-dimethylformamide; and the inorganic base is one of sodium carbonate and potassium carbonate.

[0074] This invention also provides a method for preparing compound (4'), the synthetic route of which is as follows:

[0075]

[0076] Preferably, the method for preparing compound (4') described above includes the following steps:

[0077] Step (1) Compound (3) is reacted with a chlorination reagent to synthesize compound (4);

[0078] In step (2), compound (4) was synthesized by reacting it with oxide in the presence of phase transfer catalyst A, accelerating catalyst B and oxidation catalyst C;

[0079] The chlorination reagent mentioned in step (1) is selected from one or more of hypochlorite, sodium chlorate, calcium hypochlorite, N-chlorosuccinimide, dichlorohydantoin, trichloroisocyanuric acid and sulfonyl chloride; the molar ratio of the amount of the chlorination reagent to compound (3) is 1-2:1.

[0080] In step (2), the phase transfer catalyst A is selected from one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltriethylammonium chloride, and tetramethylammonium chloride; the accelerating catalyst B is selected from one or more of potassium bromide and sodium bromide; and the oxidation catalyst C is selected from one or more of 2,2,6,6-tetramethylpiperidine oxide and 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide. The molar ratio of the phase transfer catalyst A to compound (4) is 0.01-0.2:1; the molar ratio of the accelerating catalyst B to compound (4) is 0.01-0.25:1; and the molar ratio of the oxidation catalyst C to compound (4) is 0.01-0.2:1. The oxide is selected from one or more of sodium hypochlorite, hypochlorous acid, sodium hypochlorite, N-chlorosuccinimide, and sulfonyl chloride; and the molar ratio of the oxide to compound (4) is 0.8-1.5:1.

[0081] The present invention also provides a method for preparing compound (3), the synthetic route of which is as follows:

[0082]

[0083] The preparation method of the above compound (3) includes the following steps:

[0084] In step (a), compound (1) reacts with a metal salt of glycolic acid under the action of a phase transfer catalyst to obtain compound (2); the metal salt of glycolic acid is selected from sodium, potassium or calcium salts of glycolic acid; the molar ratio of the metal salt of glycolic acid to α-halo-p-methylacetophenone is 1-1.5:1; the phase transfer catalyst is selected from one or more of tetrabutylammonium bromide, tetrabutylammonium chloride and benzyltriethylammonium chloride; the mass ratio of the phase transfer catalyst to compound (1) is 0.05-0.2:1.

[0085] In step (b), compound (2) undergoes a rearrangement and cyclization reaction with an ammonia source under the action of an organic acid to obtain compound (3); the organic acid is selected from one or more of formic acid, acetic acid and propionic acid; the molar ratio of the amount of organic acid to compound (2) is 1-10:1; the ammonia source is one or more of ammonia water, ammonium formate, ammonium acetate, ammonium isobutyrate and hexamethyldisilazane; the molar ratio of the amount of ammonia source to compound (2) is 3-10:1.

[0086] This invention also provides intermediate compounds for preparing compounds of formula (I):

[0087]

[0088] Wherein, R is H, C1-C6 alkyl or halogenated C1-C6 alkyl, preferably H, methyl, ethyl, propyl or trifluoromethyl.

[0089] This invention provides the following intermediate compounds:

[0090]

[0091] Wherein, R is H, C1-C6 alkyl or halogenated C1-C6 alkyl, preferably H, methyl, ethyl, propyl or trifluoromethyl.

[0092] The last bactericidal composition contains the compounds of the present invention, their salts, their stereoisomers, or nitrogen oxides.

[0093] The technical solution of the present invention will be clearly and completely described below through specific embodiments. Obviously, the listed embodiments are only a part of the implementation cases of the present invention and not all of them. Therefore, the described examples should not limit the full scope of protection of the present invention.

[0094] Example 1 Synthesis of compound (2):

[0095]

[0096] In a 250 ml four-necked flask, 15 g (88.96 mmol) of α-chloro-p-methylacetophenone was added, followed by 60 ml of N,N-dimethylformamide. Then, 8.72 g (88.96 mmol) of sodium glycolate was added with stirring at room temperature. The reaction mixture was then heated to an internal temperature of 100 °C and stirred for 3 hours. Liquid chromatography monitoring showed that the reaction proceeded completely. After removing the solvent under reduced pressure, the mixture was cooled to room temperature, and 90 ml of water was added to the four-necked flask. The mixture was stirred, filtered, and dried to obtain 18.49 g of the crude product. Crystallization from the crude product in toluene yielded 16.83 g of the target compound, with a purity of 98.5% and a yield of 89.51%.

[0097] 1HNMR(500MHz,DMSO-d6)δ2.40(s,3H),4.18(d,J=6.6Hz,2H),5.50(m,2H),7.37(d,J=8.0Hz,2H),7.87(d,J=8.2Hz,2H).MS(ESI + )m / z:209[M+H] +

[0098] Example 2 Synthesis of compound (2):

[0099] In a 250 ml four-necked flask, 15 g (88.96 mmol) of α-chloro-p-methylacetophenone was added, followed by 150 ml of 1,2-dichloroethane. Then, 8.72 g (88.96 mmol) of sodium glycolate was added with stirring. The reaction mixture was then heated to reflux (internal temperature 83 °C) and stirred for 9 hours. Liquid chromatography revealed that less than 5% of the reactants remained. After removing the solvent under reduced pressure, the mixture was cooled to room temperature, and 90 ml of water was added with stirring. The mixture was filtered and dried to obtain 18.74 g of the product. The crude product was crystallized from toluene to obtain 16.69 g of the product, with a purity of 95.6% and a yield of 86.15%.

[0100] Example 2 Synthesis of compound (2):

[0101] In a 250 ml four-necked flask, 20 g (118.61 mmol) of α-chloro-p-methylacetophenone was added, along with 150 ml of 1,2-dichloroethane and 15 ml of N,N-dimethylformamide. While stirring, 13.95 g (142.34 mmol) of sodium glycolate and 2 g of benzyltriethylammonium chloride were added. The reaction mixture was then heated to reflux (internal temperature 83 °C) and stirred for 7 hours. Liquid chromatography monitoring confirmed complete reaction of the reactants. After removing the reaction solvent under reduced pressure, the mixture was cooled to room temperature, and 90 ml of water was added. The mixture was stirred, filtered, and dried to obtain 22.26 g of the crude product. Crystallization from toluene yielded 22.15 g of the crude product, with a purity of 92% and a yield of 82.51%.

[0102] Example 4 Synthesis of compound (3):

[0103]

[0104] In a 500ml four-necked flask, 15g (66.28mmol, purity 92%) of compound (3) and 150ml of n-butanol were added, followed by 19.9g (331.39mmol) of acetic acid and 22.22g (288.32mmol) of ammonium acetate. The reaction solution was then heated to an internal temperature of 90℃ and stirred for 5 hours. Liquid phase monitoring showed that the reactants reacted completely. After concentrating the solvent under reduced pressure, the reaction solution was cooled to room temperature, and the pH was adjusted to 8-9 with sodium hydroxide aqueous solution. The mixture was stirred at room temperature for 1 hour, filtered, and dried to obtain the crude product. After purification by ethyl acetate slurry, 7.93g (purity 91.3%) of the target compound was obtained, with a yield of 58.08%.

[0105] 1 HNMR(500MHz,DMSO-d6)δ2.29(s,3H),4.49(s,2H),5.47(s,1H),7.14(d,J=7.9Hz,2H),7.40(s,1H),7.63(d,J=7.9Hz,2H),12.05(s,1H).MS(ESI + )m / z:189[M+H] +

[0106] Example 5 Synthesis of compound (3):

[0107] In a 500ml four-necked flask, 15g (67.44mmol, purity 93.61%) of compound (3) and 150ml of ethylene glycol monomethyl ether were added. Then, 26g (432.96mmol) of acetic acid and 30.67g (397.90mmol) of ammonium acetate were added sequentially. The reaction solution was then heated to an internal temperature of 90℃ and stirred for 4 hours. Liquid phase monitoring showed that the reaction was complete. After concentrating the solvent under reduced pressure, the reaction solution was cooled, and the pH was adjusted to 8-9 with sodium hydroxide aqueous solution. The mixture was stirred at room temperature for 1 hour, filtered, and dried to obtain the crude product. Purification with ethyl acetate yielded 9.32g (purity 92.8%) of the target compound, with a yield of 68.13%.

[0108] Example 6 Synthesis of compound (3):

[0109] In a 500 ml four-necked flask, 15 g (67.63 mmol, purity 93.88%) of compound (3) and 150 ml of isopropanol were added. Then, 32.49 g (541.07 mmol) of acetic acid and 20.85 g (270.52 mmol) of ammonium acetate were added sequentially. The reaction solution was then heated to reflux at 85 °C and stirred for 7 h. Liquid phase monitoring showed that the reaction was complete. After concentrating the solvent under reduced pressure, the reaction solution was cooled, and the pH was adjusted to 8-9 with sodium hydroxide aqueous solution. The mixture was stirred at room temperature for 1 h, filtered, and dried to obtain the crude product. The crude product was purified by slurrying with ethyl acetate to obtain 9.59 g (purity 93.4%) of the target compound, with a yield of 70.34%.

[0110] Synthesis of compound (4) in Example 7:

[0111]

[0112] In a 250 ml four-necked flask, 15 g (79.69 mmol) of compound (3) and 130 ml of N,N-dimethylformamide were added. 10.64 g (79.69 mmol) of N-chlorosuccinimide was added in portions at room temperature. The reaction was allowed to proceed for 2 h. The reaction was monitored at room temperature until the starting material was fully reacted. 300 ml of water was added to the reaction solution, and the mixture was stirred for 30 min. The mixture was then filtered and dried to obtain 17.23 g of the target compound (purity 95.18%), with a yield of 92.42%. 1 HNMR(500MHz,DMSO-d6)δ2.32(s,3H),4.49(s,2H),5.49(s,1H),7.27(d,J=7.9Hz,2H),7.64(d,J=7.9Hz,2H),12.69(s,1H).MS(ESI+)m / z:223[M+H] +

[0113] Synthesis of compound (4) in Example 8:

[0114] In a 250 ml four-necked flask, 10 g (53.12 mmol) of compound (3) and 50 ml of anhydrous methanol were added. The reaction solution was cooled to 10 °C, and 4.00 g of 90% trichloroisocyanuric acid was slowly added in portions. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 1 h. The liquid phase was monitored, and the remaining raw material was below 5%. The solvent was removed by vacuum evaporation at 60 °C. Then, 25 ml of 10% sodium hydroxide solvent was added, and the mixture was stirred at room temperature for 1 h. The mixture was then filtered and dried to obtain 9.89 g of the target compound with a purity of 83.17% and a yield of 84.62%.

[0115] Example 9 Synthesis of compound (4):

[0116] In a 250 ml four-necked flask, 5 g (26.03 mmol) of compound (3) and 30 ml of anhydrous methanol were added. The reaction solution was cooled to 0 °C, and 3.33 g of dichlorodimethylhydantoin (16.92 mmol) was added in portions. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 4 h. The liquid phase was monitored, and the remaining raw material was below 5%. The solvent was removed by vacuum evaporation at 40 °C. Then, 25 ml of 10% sodium carbonate aqueous solvent was added, and the mixture was stirred at 40 °C for 1 h. The mixture was filtered and dried to obtain 5.21 g of the target compound with a purity of 93.98% and a yield of 84.47%.

[0117] Example 102: Synthesis of 2-formyl-4-(p-tolyl)-5-chloro-1H imidazole:

[0118]

[0119] In a 250 ml four-necked flask, 13.7 g (61.53 mmol) of compound (4), 140 ml of ethyl acetate, 11 ml of water, and 20.55 g of acetic acid were added. The reaction solution was then cooled to 10 °C, and tetrabutylammonium bromide (1.37 g), TEMPO (0.96 g), and potassium bromide (0.74 g) were added sequentially. Calcium hypochlorite (7.87 g) was then added in portions. After the addition was complete, the ice bath was removed, and the mixture was stirred vigorously at room temperature. The reaction was carried out for 4 h, and the reaction was monitored by liquid chromatography. The reaction was complete. The pH was adjusted to 9 with sodium hydroxide aqueous solution, filtered, and separated. 30 ml of saturated sodium bisulfite solution was added to the organic phase, and the mixture was stirred for 10 min. The solid obtained by vacuum filtration was stirred with sodium hydroxide aqueous solution and ethyl acetate, separated, and the organic solvent was evaporated to dryness to obtain 13.4 g of the target compound 2-formyl-4-(p-tolyl)-5-chloro-1H imidazole, with a purity of 94.2% and a yield of 92.96%. 1 HNMR(500MHz,DMSO-d6)δ2.35(s,3H),7.33(d,J=8.0Hz,2H),7.73(d,J=8.2Hz,2H),9.57(s,1H),9.67(s,1H).MS(ESI+)m / z:221[M+H] +

[0120] Example 1. Synthesis of 112-formyl-4-(p-tolyl)-5-chloro-1H imidazole

[0121] In a 500 ml four-necked flask, 24.4 g (109.58 mmol) of compound (4), 240 ml of 1,2-dichloroethane, 10 ml of water, and 32.91 g of acetic acid were added. The reaction solution was then cooled to 10 °C, and tetrabutylammonium bromide (2.4 g), 2,2,6,6-tetramethylpiperidine oxide (1.72 g), and potassium bromide (1.31 g) were added sequentially. Then, calcium hypochlorite (15.73 g) was added in portions. After the addition was complete, the ice bath was removed, and the mixture was stirred vigorously at room temperature. The reaction was allowed to proceed for 6 h, and the reaction was monitored by liquid chromatography, indicating that the starting materials had reacted completely. The pH was adjusted to 9 with sodium hydroxide aqueous solution, filtered, and separated. 40 ml of saturated sodium bisulfite solution was added to the organic phase, and the mixture was stirred for 20 min. The solid obtained by vacuum filtration was stirred with sodium hydroxide aqueous solution and ethyl acetate, separated, and the organic solvent was evaporated to dryness to obtain 18.2 g of the target compound 2-formyl-4-(p-tolyl)-5-chloro-1H imidazole, with a purity of 92.8% and a yield of 69.84%.

[0122] Example 12: Synthesis of 2-formyl-4-(p-tolyl)-5-chloro-1H imidazole

[0123] In a 250 ml four-necked flask, 12 g (54.79 mmol) of compound (4), 120 ml of 1,2-dichloroethane, 10 ml of water, and 16.5 g of acetic acid were added. The reaction solution was then cooled to 10 °C, and tetrabutylammonium bromide (1.2 g), 4-hydroxy-2,2,4,4,4,tetramethylpiperidine oxide (0.88 g), and potassium bromide (0.66 g) were added sequentially. Then, calcium hypochlorite (7.88 g) was added in portions. After the addition was complete, the ice bath was removed, and the mixture was stirred vigorously at room temperature. The reaction was allowed to proceed for 6 h, and the reaction was monitored by liquid chromatography. The reaction was complete. The pH was adjusted to 9 with sodium hydroxide aqueous solution, filtered, separated, and the organic phase was concentrated to obtain 9.43 g of the target compound 2-formyl-4-(p-tolyl)-5-chloro-1H imidazole, with a purity of 93.1% and a yield of 72.60%.

[0124] Example 134: Synthesis of 4-chloro-5-(p-tolyl)-1H-imidazol-2-carboxaldehyde oxime:

[0125]

[0126] In a 100ml four-necked flask, 6.0g of compound 2-formyl-4-(p-tolyl)-5-chloro-1H imidazole and 1.9g of hydroxylamine hydrochloride were added, followed by 50ml of anhydrous methanol. The reaction solution was heated to 60℃ and stirred for 4h. The reaction was monitored by liquid chromatography until the reactants were completely reacted. The solvent was removed by concentration under reduced pressure. Then, 20ml of saturated sodium bicarbonate was added, and the mixture was stirred at room temperature for 1h. After filtration and drying, 6.32g of the target compound 4-chloro-5-(p-tolyl)-1H-imidazole-2-carboxaldehyde oxime was obtained, with a purity of 95.2% and a yield of 93.63%. 1 HNMR(500MHz,DMSO-d6)δ2.40(s,3H),7.33(d,J=8.0Hz,2H),7.72(d,J=8.1Hz,2H),7.98(s,1H),11.65(s,1H),13.25(s,1H).MS(ESI+)m / z:236[M+H] +

[0127] Example 14 Synthesis of compound 4-chloro-5-(4-methylphenyl)-1H-imidazol-2-formyl chloride:

[0128]

[0129] In a 250 ml four-necked flask, 10 g of compound 2-formyl-4-(p-tolyl)-5-chloro-1H imidazole was added, followed by 100 ml of thionyl chloride. The reaction was carried out under reflux with stirring, and the reaction proceeded to completion after 6 hours. After evaporating the thionyl chloride under reduced pressure, the mixture was directly added to the next step.

[0130] Example 15 Synthesis of Compound I:

[0131]

[0132] In a 250ml four-necked flask, 15.0g of 4-chloro-5-(p-tolyl)-1H-imidazol-2-carboxaldehyde oxime was added, followed by 80ml of DMF and 13.2g of anhydrous potassium carbonate. The reaction mixture was heated to 80℃ and stirred for 8 hours. Liquid phase monitoring showed that the reactants were basically completely reacted. The reaction mixture was cooled, and then 100ml of water and 50ml of ethyl acetate were added. The mixture was separated, and the aqueous phase was extracted once again with 30ml of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was concentrated to dryness to obtain 19.30g of the target compound. After column purification, 13.5g of the target compound was obtained.

[0133] 1 HNMR(500MHz,DMSO-d6)δ1.47(d,J=8.1Hz,2H),2.34(s,3H),3.69(s,3H),4.88(q,J=8.0Hz,2H), 7.30(d,J=8.1Hz,2H),7.64(d,J=8.1Hz,2H),8.09(s,1H),13.33(s,1H).MS(ESI+)m / z:322[M+H] +

[0134] Example 16 Synthesis of Compound II

[0135]

[0136] In a 250 ml four-necked flask, 4.16 g of o-fluoroaniline, 5.68 g of triethylamine, and 20 ml of dichloromethane were added. A mixed solution of 4-chloro-5-(4-methylphenyl)-1H-imidazol-2-carboxyl chloride and 30 ml of dichloromethane, prepared in the previous step, was slowly added dropwise at room temperature. After the addition was complete, the mixture was stirred overnight at room temperature. 50 ml of water was added to the reaction solution, and the mixture was separated. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude compound. Column purification yielded 7.83 g of the target compound II.

[0137] 1 HNMR(500MHz,DMSO-d6)δ2.35(s,3H),7.21(m,5H),7.71(m,3H),10.09(s,1H).MS(ESI+)m / z:330[M+H] +

[0138] Example 17 Synthesis of Compound III

[0139]

[0140] In a 100 ml four-necked flask, 5 g of compound II and 20 ml of DMF were added, followed by 2.10 g of anhydrous potassium carbonate and 2.15 g of potassium iodide. The mixture was stirred at room temperature for 2 hours until the reaction was complete. 50 ml of water was added to the reaction solution, and the mixture was stirred for 1 hour. The mixture was then filtered and dried to obtain crude compound III. After crystallization with ethyl acetate, 3.12 g of the target compound III was obtained.

[0141] 1 HNMR(500MHz,DMSO-d6)δ2.34(s,3H),3.99(s,3H),7.22(m,5H),7.83(m,3H),10.04(s,1H).MS(ESI+)m / z:344[M+H] +

[0142] Experimental Example 1: Indoor toxicity assay of a compound against damping-off bacteria

[0143] 1. Test Methods

[0144] Five concentration gradients of the new compound were established: 100 ppm, 50 ppm, 25 ppm, 12.5 ppm, and 6.25 ppm. Under aseptic conditions, bacterial blocks were collected along the edge of the colonies using a 6 mm diameter punch and placed on culture media containing the pre-concentrated fungicide. A control culture medium without the fungicide was used. One bacterial block (6 mm in diameter) was inoculated per dish, with three replicates. After 7 days of incubation, the colony diameter was vertically measured using the cross-sectional method, and the mean of the three replicates was calculated.

[0145] 2. Calculation method

[0146] Based on the survey results, the mycelial growth inhibition rate of each concentration on the tested target bacteria was calculated according to formulas (1) and (2), in percentage (%), and the control efficacy results were rounded to two decimal places.

[0147] D = D1 - D2…………(1)

[0148]

[0149] Where: D—colon growth diameter; D1—colon diameter; D2—mushroom cake diameter; I—mycelial growth inhibition rate; D0—blank control colony growth diameter; D t —The diameter of colony growth after chemical treatment.

[0150] 3. Test Results

[0151] Table 1. Results of laboratory toxicity assays of the compounds of the present invention and control compounds against sudden-catch bacteria.

[0152]

[0153]

[0154] As shown in Table 1, compounds I, II, and III of this invention have high indoor toxicity against damping-off disease, with a control efficacy of over 90%, verifying the excellent bactericidal effect of imidazole derivatives.

[0155] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A compound of formula (I), Its salts, its stereoisomers, or nitrogen oxides, in, R is H, C1-C6 alkyl, or halo-C1-C6 alkyl; R1 is R2 is H, C1-C6 alkyl, or halo-C1-C6 alkyl; in, Indicates the connection end.

2. The compound, its salt, its stereoisomer, or nitrogen oxide compound according to claim 1, characterized in that, R and R2 are each independently selected from H, methyl, ethyl, propyl, or trifluoromethyl.

3. The compound, its salt, its stereoisomer, or nitrogen oxide compound according to claim 1 or 2, characterized in that, Compound (I) is compound A. R and R2 are defined as defined in claim 1 or 2.

4. The compound, its salt, its stereoisomer, or nitrogen oxide compound according to claim 1 or 2, characterized in that, Compound (I) is compound B. Wherein, R is defined as in claim 1 or 2.

5. The compound, its salt, its stereoisomer, or its oxynitrite according to claim 1, characterized in that, Selected from the following compounds, 6. A method for preparing compound A according to claim 3, characterized in that, The synthesis route is as follows: Wherein, R and R2 are defined as defined in claim 3, and X is a leaving group, preferably a halogen; Preferably, the preparation method includes the following steps: compound (5) reacts with thionyl chloride to form acyl chloride compound (5'), and compound (5') then reacts with a 2-fluoroaniline compound in an organic solvent A, with the addition of an acid-binding agent to obtain compound A; wherein the organic solvent A is one or a mixture of acetonitrile, 1,2-dichloroethane, dichloromethane and N,N-dimethylformamide; and the acid-binding agent is one of sodium carbonate, potassium carbonate, triethylamine and diisopropylethylamine.

7. A method for preparing compound B according to claim 4, characterized in that, The synthesis route is as follows: Wherein, R is H, C1-C6 alkyl, or halo-C1-C6 alkyl; Preferably, the above preparation method includes the following steps: first, compound (4') reacts with compound RL to generate compound (5), wherein L is a leaving group, preferably a halogen; compound (5) reacts with hydroxylamine hydrochloride to form an oxime; then, it reacts with methyl 2-chloropropionate in an organic solvent B, and an inorganic base is added to obtain compound B; wherein the organic solvent B is one or a mixture of acetonitrile, tetrahydrofuran, acetone and N,N-dimethylformamide; and the inorganic base is one of sodium carbonate and potassium carbonate.

8. A method for preparing a compound (4'), characterized in that, The synthesis route is as follows: Preferably, the preparation method includes the following steps: Step (1) Compound (3) reacts with a chlorination reagent to synthesize compound (4); preferably, the chlorination reagent in step (1) is selected from one or more of hypochlorite, sodium chlorate, calcium hypochlorite, N-chlorosuccinimide, dichlorohydantoin, trichloroisocyanuric acid and sulfonyl chloride; the molar ratio of the amount of the chlorination reagent to compound (3) is 1-2:1; In step (2), compound (4) is synthesized by reacting it with an oxide in the presence of phase transfer catalyst A, accelerating catalyst B, and oxidizing catalyst C; preferably, the phase transfer catalyst A in step (2) is selected from one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltriethylammonium chloride, and tetramethylammonium chloride; the accelerating catalyst B is selected from one or more of potassium bromide and sodium bromide; and the oxidizing catalyst C is selected from one or more of 2,2,6,6-tetramethylpiperidine oxide and 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide. One or more; the oxide is selected from one or more of sodium hypochlorite, hypochlorous acid, sodium hypochlorite, N-chlorosuccinimide and sulfonyl chloride; more preferably, the molar ratio of the phase transfer catalyst A to compound (4) is 0.01-0.2:1; the molar ratio of the accelerating catalyst B to compound (4) is 0.01-0.25:1; the molar ratio of the oxidation catalyst C to compound (4) is 0.01-0.2:1; the molar ratio of the oxide to compound (4) is 0.8-1.5:

1.

9. A method for preparing compound (3), characterized in that, The synthesis route is as follows: Preferably, the preparation method includes the following steps: Step (a): Compound (1) reacts with a metal salt of glycolic acid under the action of a phase transfer catalyst to obtain compound (2); preferably, the metal salt of glycolic acid is selected from sodium, potassium or calcium salts of glycolic acid; the molar ratio of the metal salt of glycolic acid to α-halo-p-methylacetophenone is 1-1.5:1; the phase transfer catalyst is selected from one or more of tetrabutylammonium bromide, tetrabutylammonium chloride and benzyltriethylammonium chloride; the mass ratio of the phase transfer catalyst to compound (1) is 0.05-0.2:1; In step (b), compound (2) undergoes a rearrangement and cyclization reaction with an ammonia source under the action of an organic acid to obtain compound (3); preferably, the organic acid is selected from one or more of formic acid, acetic acid and propionic acid; the molar ratio of the amount of organic acid to compound (2) is 1-10:1; the ammonia source is one or more of ammonia water, ammonium formate, ammonium acetate, ammonium isobutyrate and hexamethyldisilazane; the molar ratio of the amount of ammonia source to compound (2) is 3-10:

1.

10. Compounds in, R is H, C1-C6 alkyl, or halogenated C1-C6 alkyl, preferably H or methyl.

11. Compounds in, R is H, C1-C6 alkyl, or halogenated C1-C6 alkyl, preferably H or methyl.

12. A bactericidal composition, characterized in that, It contains any one of the compounds of claims 1-5, its salts, its stereoisomers, or nitrogen oxides.

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