5-chloro-5-phenyl-4, 5-dihydroisoxazole-3-carboxylic acid compound as well as preparation method and application thereof

Abstract

The invention discloses 5-chloro-5-phenyl-4, 5-dihydroisoxazole-3-carboxylic acid and a derivative thereof (formula I): # imgabs0 #, and in the formula I, R is selected from H, C1-C6 alkyl and C3-C8 cycloalkyl, preferably H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. When the compound shown in the formula I is used for synthesizing related active compounds, the synthesis route can be greatly shortened, the yield is increased, and the application prospect is wide.

Description

Technical Field

[0001] The invention belongs to the field of pesticides, and specifically relates to a 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid compound and a synthesis method thereof and application of the compound in the synthesis of active compounds. Technical Background

[0002] Dihydroisoxazole compounds are a class of heterocyclic compounds with good biological activity and potential medicinal value. As important intermediates in the field of pesticides and medicines, they have long attracted extensive attention from researchers. For example, in the field of pesticides, there are herbicides such as benzathine, pyraclostrobin, flurellana and herbicide safener isoxadiazole.

[0003] At present, in the synthesis of dihydroisoxazole 5-disubstituted compounds, the commonly used method is to use disubstituted ethylene as a raw material for synthesis, such as using 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene to synthesize flurella (CN114394946), using diphenylethylene to synthesize ethyl bisoxadifen (CN108440435), the olefins used are complex in structure and are not cheap and easily available chemical raw materials, and the synthesis methods of some complex olefins are also relatively difficult, such as the raw materials for synthesizing 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene are (3,5-dichlorophenyl)boric acid and 2-bromo-3,3,3-trifluoro-1-propylene, the catalyst is dichlorobis(triphenylphosphine)palladium, etc., and the yield is 64%.

[0004] (CN115246825), high cost and low yield.

[0005]

[0006] Our laboratory has designed and developed a new dihydroisoxazole compound with a chiral center and an active reaction site. It can be used as a precursor compound to construct potentially active dihydroisoxazole derivatives, especially to more conveniently construct dihydroisoxazole 5-disubstituted compounds. For example, when constructing isoxadifen acid analogs, it overcomes the defect of using diphenylethylene as the starting material in the prior art, and uses cheaper and more readily available raw materials to first synthesize the key intermediate 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid and its derivatives, which can better reduce the difficulty of synthesizing the final product. Summary of the invention

[0007] The present invention aims at the defect of using relatively expensive raw material disubstituted ethylene in the prior art for synthesizing dihydroisoxazole 5-position disubstituted compounds, and provides a new key intermediate for synthesizing dihydroisoxazole structure potential active compounds.

[0008] Specifically, the present invention first provides a 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid and its derivatives as shown in Formula I:

[0009] Wherein, R is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, preferably H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0010] The present invention also provides a method for preparing 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid and its derivatives (Formula I), and the synthetic route thereof is as follows:

[0011]

[0012] The present invention also provides a method for preparing isoxadifen-ethyl, and the synthetic route thereof is as follows:

[0013]

[0014] Beneficial effects of the present invention

[0015] The 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid compounds developed by this laboratory provide a new synthesis idea for the construction of dihydroisoxazole derivatives with potential activity, and solve the problem that dihydroisoxazole 5-position disubstituted compounds are difficult to synthesize. The synthesis route is simpler, and the raw materials are cheaper and easier to obtain. For the synthesis of existing related active compounds, such as isoxadifen ethyl, the synthesis cost can be reduced, and the synthesis process is simpler and the conditions are milder. At the same time, the intermediates disclosed in the present invention can also be used as key intermediates for high-throughput compound synthesis screening. DETAILED DESCRIPTION

[0016] In order to make the purpose, 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 part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "including" will be understood to include the stated components or steps, without excluding other material components or steps.

[0017] In addition, in order to better illustrate the present invention, numerous specific details are given in the following detailed description.

[0018] Those skilled in the art will appreciate that the present invention can be implemented without certain specific details. In some embodiments, raw materials, methods, means, etc. that are well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

[0019] Where the compounds according to the invention are capable of existing in tautomeric forms, the compounds described above and hereinafter are to be understood, where applicable, as also comprising the corresponding tautomeric forms, even if these are not explicitly mentioned in each case.

[0020] If the compounds of the formula I according to the invention have functional groups which can be ionized, they can also be used in the form of their salts or mixtures thereof.

[0021] The term "alkyl" as used herein (and in other groups containing alkyl, such as the alkyl moiety of alkoxy, the alkyl moiety of haloalkyl, the alkyl moiety of arylalkyl) means in each case usually having 1 to 20 carbon atoms, often 1 to 6 carbon atoms. Examples of C1-C4 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl). Examples of C1-C6-alkyl radicals are, in addition to the radicals mentioned for C1-C4-alkyl radicals, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl.

[0022] In the present invention, "cycloalkyl" refers to a monocyclic monovalent hydrocarbon group of three to ten carbon atoms, which may be saturated or contain one double bond. The cycloalkyl group is preferably a C3-C8 cycloalkyl group, and examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., but are not limited thereto.

[0023] In the present invention, NCS is N-chlorosuccinimide

[0024] In the present invention, AIBN is azobisisobutyronitrile

[0025] In the present invention, AIBME is dimethyl azobisisobutyrate

[0026] In the present invention, AIBI is azodiisopropylimidazoline hydrochloride

[0027] In the present invention, BPO is dibenzoyl peroxide

[0028] In the present invention, TBHP is tert-butyl hydroperoxide.

[0029] In the present invention, DCP is dicumyl peroxide

[0030] In the present invention, DTBP is di-tert-butyl peroxide.

[0031] TBPB in the present invention is tert-butyl perbenzoate

[0032] In the present invention, TBPV is tert-butyl peroxypivalate

[0033] In the present invention, MEKP is methyl ethyl ketone peroxide

[0034] The present invention first provides a 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid and its derivatives (Formula I):

[0035]

[0036] Wherein, R is selected from H, C1-C6 alkyl or C3-C8 cycloalkyl, preferably one of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0037] The present invention also discloses a method for synthesizing 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid and its derivatives, which comprises the following steps:

[0038] Step 1), acrylic acid or its ester and benzyl trichloride react in the presence of DMF (N,N-dimethylformamide) or DMAC (N,N-dimethylacetamide) and magnesium to prepare 2-chloro-2-phenyl-cyclopropanecarboxylic acid or its ester;

[0039] Step 2), reacting 2-chloro-2-phenyl-cyclopropanecarboxylic acid or its ester with sodium nitrite in the presence of an acid to prepare 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester;

[0040] Its synthetic route is as follows:

[0041] Wherein, R is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, preferably H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0042] Preferably, in step 1) of the above synthesis method, the reaction is carried out in a solvent, the reaction temperature is -10 to 100° C., and the reaction time is 1 to 8 hours.

[0043] Preferably, there are four main ways of adding materials in step 1) of the above-mentioned synthesis method, namely, adding magnesium in batches, adding benzyl chloride to other reaction materials dropwise, adding DMF or DMAC to other reaction materials dropwise, and adding a mixture of benzyl chloride and acrylic acid or its ester to other reaction materials dropwise, wherein the molar ratio of magnesium, acrylic acid or its ester and benzyl chloride is 2 to 5:1:1 to 1.5, and the amount of DMF or DMAC added is 1 to 100 equivalents (based on acrylic acid or its ester), wherein the solvent is DMF, DMAC, ether, isopropyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, acetonitrile, DMSO, toluene, etc.; after the reaction is completed, pour into acid water for quenching, take the organic layer or extract with toluene and then take the organic layer to remove the solvent to obtain 2-chloro-2-phenyl-cyclopropanecarboxylic acid or its ester.

[0044] Preferably, in step 2) of the above-mentioned synthesis method, 2-chloro-2-phenyl-cyclopropanecarboxylic acid or its ester is reacted with sodium nitrite in the presence of an acid in a solvent, the reaction temperature is 0 to 100° C., preferably 0 to 50° C., and the reaction time is 1 to 3 hours, wherein the solvent is one or more of ethyl acetate, acetone, acetic acid, petroleum ether, acetonitrile, cyclohexane and tetrahydrofuran, and the acid is one or more of hydrochloric acid, sulfuric acid, formic acid, acetic acid, oxalic acid, methanesulfonic acid and trifluoroacetic acid.

[0045] The present invention also provides another method for preparing 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid and its derivatives, which comprises the following steps:

[0046] Step a), 2-chloro-2-(hydroxyimino)acetic acid or its ester, styrene and a base react in a solvent to prepare 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester;

[0047] Step b), reacting 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester with a chlorinating agent to prepare 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester;

[0048] The reaction route is as follows:

[0049]

[0050] Preferably, in step a), the reaction temperature of 2-chloro-2-(hydroxyimino)acetic acid or its ester, styrene and base in a solvent is 0-100° C. and the reaction time is 1-3 h, wherein the solvent is selected from one or more of dichloromethane, dichloroethane, toluene, ethyl acetate, ether, tetrahydrofuran, methanol and ethanol, and the base is selected from one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, sodium methoxide, potassium ethoxide and potassium tert-butoxide.

[0051] Preferably, the chlorination agent in step b) is preferably NCS, dichlorohydantoin, sulfonyl chloride or chlorine, the reaction temperature is 0-100°C, the reaction time is 0.5-3h, wherein the solvent is selected from one or more of dichloromethane, dichloroethane, toluene, ethyl acetate, acetonitrile, ether and tetrahydrofuran; more preferably, an initiator is added to the reaction of 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester and the chlorination agent, and the initiator is selected from one or more of AIBN, AIBME, AIBI, BPO, TBHP, DCP, DTBP, TBPB, TBPV and MEKP. Adding an initiator in some reactions can speed up the reaction and improve the reaction yield.

[0052] The present invention also provides a synthesis of isoxadifen-ethyl, which comprises the following steps:

[0053] Ethyl 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylate (Formula Ia) and benzene are reacted in the presence of an acidic catalyst to synthesize ethyl isoxadifen.

[0054] The reaction route is as follows

[0055]

[0056] Preferably, ethyl 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylate and benzene are reacted in a solvent under acid catalysis, wherein the reaction temperature is 0 to 100° C., the reaction time is 0.5 to 3 h, the reaction solvent is selected from one or more of dichloromethane, nitromethane, benzene, nitrobenzene, and carbon disulfide, and the acidic catalyst is selected from one or more of aluminum chloride, tin tetrachloride, ferric chloride, zinc chloride, boron trifluoride, aluminum tribromide, boric acid, hydrochloric acid, hydrofluoric acid, sulfuric acid, perchloric acid, trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid. After the reaction is completed, the reaction is quenched, and the solvent is removed to obtain ethyl isoxadifen.

[0058] Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified. The raw materials, reagents, etc. used to prepare the compounds of the present invention are commercially available or can be prepared by conventional methods in the art.

[0059] Example 1 Synthesis of 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid methyl ester

[0060] Take 80 ml of tetrahydrofuran, add 4.3 g of methyl acrylate, 2.64 g of magnesium and 3.65 g of DMF, stir evenly, add a tetrahydrofuran solution of benzyl trichloride (including 10.75 g of benzyl trichloride) dropwise at 60°C, react for 2 hours, cool to room temperature after the reaction, pour into aqueous hydrochloric acid solution to quench, extract with toluene, take the organic layer, concentrate and remove the solvent to obtain 10.32 g of 2-chloro-2-phenyl-cyclopropanecarboxylic acid methyl ester.

[0061] Take 100 ml of ethyl acetate, add 10.32 g of 2-chloro-2-phenyl-cyclopropanecarboxylic acid methyl ester, 1.48 g of concentrated hydrochloric acid, and 3.45 g of sodium nitrite, and react at 45°C for 2 hours. After the reaction, add water, take the organic layer, concentrate and remove the solvent to obtain 11.51 g of 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid methyl ester, with a yield of 96%.

[0062] 1H NMR (300MHz, CDCl3) δ7.34-7.44 (m, 5H), δ3.86 (s, 2H), δ3.65 (s, 3H)

[0063] Example 2 Synthesis of 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid ethyl ester

[0064] Take 100 ml of DMF, add 5.0 g of ethyl acrylate, 11.73 g of benzyl chloride, add 4.32 g of magnesium in batches at 80°C, react for 2 hours, cool to room temperature after the reaction, pour into aqueous sulfuric acid solution to quench, extract with toluene, take the organic layer, concentrate and remove the solvent to obtain 11.01 g of 2-chloro-2-phenyl-cyclopropanecarboxylic acid ethyl ester.

[0065] Take 100 ml of tetrahydrofuran, add 11.01 g of ethyl 2-chloro-2-phenyl-cyclopropanecarboxylate, 1.0 g of concentrated sulfuric acid, and 3.45 g of sodium nitrite, and react at 5°C for 2 h. After the reaction, add water, extract with toluene, and concentrate the organic layer to remove the solvent to obtain 12.31 g of ethyl 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylate, with a yield of 97%.

[0066] 1H NMR (300MHz, CDCl3) δ7.32-7.43 (m, 5H), δ4.33-4.41 (q, 2H), δ3.90 (s, 2H), δ1.36-1.41 (t, 3H)

[0067] Example 3 Synthesis of 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid isopropyl ester

[0068] Take 80 ml of methyl tert-butyl ether, add 5.7 g of isopropyl acrylate, 3.6 g of magnesium and 4.35 g of DMAC, stir evenly, add methyl tert-butyl ether solution of benzyl trichloride (including 11.73 g of benzyl trichloride) dropwise at 20°C, react for 3 hours, cool to room temperature after the reaction, pour into aqueous hydrochloric acid solution to quench, take the organic layer, concentrate and remove the solvent to obtain 11.46 g of 2-chloro-2-phenyl-cyclopropanecarboxylic acid isopropyl ester.

[0069] Take 100 ml of acetonitrile, add 11.46 g of 2-chloro-2-phenyl-cyclopropanecarboxylic acid isopropyl ester, 1.2 g of acetic acid, and 3.45 g of sodium nitrite, react at 80°C for 1 hour, add water after the reaction, extract with toluene, and concentrate the organic layer to remove the solvent to obtain 12.46 g of 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid isopropyl ester, with a yield of 93%.

[0070] 1H NMR (300MHz, CDCl3) δ7.32-7.43(m,5H), δ4.31-4.44(m,1H), δ3.88(s,2H), δ1.35-1.37(d,6H)

[0071] Example 4 Synthesis of 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid

[0072] Take 100 ml of dichloroethane, add 6.17 g of 2-chloro-2-(hydroxyimino)acetic acid, 5.21 g of styrene and 5.06 g of triethylamine, react at 80°C for 2 hours, extract with water after the reaction, take the organic layer, concentrate and remove the solvent to obtain 9.46 g of 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid.

[0073] Take 100 ml of dichloroethane, add 9.46 g of 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid and 6.67 g of NCS, raise the temperature to 50°C, add 0.08 g of AIBN, maintain the reaction at 50°C for 2 hours, add water for extraction after the reaction, take the organic layer and concentrate to remove the solvent to obtain 10.83 g of 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid, with a yield of 96%.

[0074] 1H NMR (300MHz, CDCl3) δ7.35-7.44 (m, 5H), δ3.91 (s, 2H)

[0075] Example 5 Synthesis of 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid propyl ester

[0076] Take 150 ml of ethanol, add 8.28 g of 2-chloro-2-(hydroxyimino)acetic acid propyl ester, 5.21 g of styrene and 6.9 g of potassium carbonate, react at 40°C for 3 hours, add water after the reaction, extract with toluene, take the organic layer and concentrate to remove the solvent to obtain 11.2 g of 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid propyl ester.

[0077] Take 100 ml of acetonitrile, add 11.2 g of 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid propyl ester and 6.75 g of sulfonyl chloride, react at 80°C for 1 hour, add water after the reaction, extract with toluene, take the organic layer and concentrate to remove the solvent to obtain 12.59 g of 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid propyl ester, with a yield of 94%.

[0078] 1H NMR (300MHz, CDCl3) δ7.32-7.44 (m, 5H), δ4.19-4.21 (t, 2H), δ3.87 (s, 2H),

[0079] δ1.62-1.67(m,2H), δ0.98-1.12(t,3H)

[0080] Example 6 Synthesis of ethyl isoxadifen

[0081] 100 ml of benzene was added with 5.07 g of ethyl 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylate and 4.0 g of aluminum chloride, and the mixture was reacted at 70° C. for 1 h. After the reaction was completed, hydrochloric acid was added to quench the mixture. The organic layer was concentrated to remove the solvent to obtain 5.79 g of ethyl isoxadifen, with a yield of 98%.

[0082] 1H NMR (300MHz, DMSO) δ7.26-7.44 (m, 10H), δ4.19-4.26 (q, 2H), δ3.90 (s, 2H),

[0083] δ1.21-1.26(t,3H)

[0084] Comparison of Synthesis of Isoxadiazole

[0085] Comparison column 1

[0086] The prior art (refer to Example 1 of patent CN108440435) has the following synthetic route: the synthesis of ethyl isoxadiazole requires five steps, of which three steps are required to prepare diphenylethylene. The route is long, the yield is low (the yield of the last step is 34%), and the cost is high.

[0087]

[0088] Comparative Example 2

[0089] The prior art (patent CN107652245 Example 1) has the following synthesis route: the synthesis of ethyl isoxadifen requires three steps, but the raw material benzophenone used has a high cost, and the yield is 67.5%.

[0090]

[0091] Compared with the prior art, the synthesis of isoxadiazole ethyl in the present invention (illustrated using Examples 2 and 6 as examples) requires only three steps, with a total yield of 95%. The raw materials used, including benzyl trichloride, ethyl acrylate, sodium nitrite, aluminum trichloride, etc., are all cheap and readily available chemical raw materials, with lower costs and higher yields.

[0092] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A compound of formula I and its stereoisomers, characterized in that: Wherein, R is selected from H, C1-C6 alkyl or C3-C8 cycloalkyl, preferably one of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

2. A method for preparing the compound of formula I according to claim 1, characterized in that: The following steps are included: Step 1), acrylic acid or its ester and benzyl trichloride react in the presence of DMF (N,N-dimethylformamide) or DMAC (N,N-dimethylacetamide) and magnesium to prepare 2-chloro-2-phenyl-cyclopropanecarboxylic acid or its ester; Step 2), reacting 2-chloro-2-phenyl-cyclopropanecarboxylic acid or its ester with sodium nitrite in the presence of an acid to prepare a compound of formula I; Its synthetic route is as follows: Wherein, R is selected from H, C1-C6 alkyl or C3-C8 cycloalkyl, preferably one of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

3. The preparation method according to claim 2, characterized in that: The reaction in step 1) is carried out in a solvent, wherein the solvent is one of DMF, DMAC, ether, isopropyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, acetonitrile, DMSO and toluene. Preferably, the reaction temperature is -10 to 100° C., and the reaction time is 1 to 8 hours.

4. The preparation method according to claim 2 or 3, characterized in that: In step 1), the molar ratio of magnesium, acrylic acid or its ester and benzyl trichloride is 2-5:1:1-1.5; preferably, the amount of DMF or DMAC added is 1-100 equivalents of acrylic acid or its ester.

5. The preparation method according to claim 2, characterized in that: In step 2), 2-chloro-2-phenyl-cyclopropanecarboxylic acid or its ester is reacted with sodium nitrite in a solvent in the presence of an acid.

6. The preparation method according to claim 5, characterized in that: The solvent in step 2) is one or more of ethyl acetate, acetone, acetic acid, petroleum ether, acetonitrile, cyclohexane and tetrahydrofuran, and the acid is one or more of hydrochloric acid, sulfuric acid, formic acid, acetic acid, oxalic acid, methanesulfonic acid and trifluoroacetic acid; preferably, the reaction temperature is 0 to 100° C. and the reaction time is 1 to 3 h.

7. A method for preparing the compound of formula I according to claim 1, characterized in that: The steps include: Step a), 2-chloro-2-(hydroxyimino)acetic acid or its ester, styrene and a base react in a solvent to prepare 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester; Step b), reacting 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester with a chlorinating agent in a solvent to prepare 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester; The reaction route is as follows: Wherein, R is selected from H, C1-C6 alkyl or C3-C8 cycloalkyl, preferably one of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

8. The preparation method according to claim 7, characterized in that: In step a), the solvent is selected from one or more of dichloromethane, dichloroethane, toluene, ethyl acetate, ether, tetrahydrofuran, methanol and ethanol; the base is selected from one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, sodium methoxide, potassium ethoxide and potassium tert-butoxide; preferably, the reaction temperature is 0 to 100° C. and the reaction time is 1 to 3 hours.

9. The preparation method according to claim 7, characterized in that: In step b), an initiator may be added when 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester and a chlorinating agent react in a solvent, and the initiator is selected from one or more of AIBN, AIBME, AIBI, BPO, TBHP, DCP, DTBP, TBPB, TBPV and MEKP.

10. The preparation method according to claim 7 or 9, characterized in that: The chlorination reagent described in step b) is preferably NCS, dichlorohydantoin, sulfonyl chloride and chlorine, and the solvent is selected from one or more of dichloromethane, dichloroethane, toluene, ethyl acetate, acetonitrile, ether and tetrahydrofuran; preferably, the reaction temperature is 0-100° C. and the reaction time is 0.5-3h.

11. A method for synthesizing isoxadiazole, characterized in that: The method comprises the following steps: reacting a compound of formula Ia with benzene under the catalysis of an acidic catalyst to synthesize isoxadifen-ethyl; The reaction route is as follows:

12. The synthesis method according to claim 11, characterized in that The reaction is carried out in a solvent, the solvent is selected from one or more of dichloromethane, nitromethane, benzene, nitrobenzene, and carbon disulfide, the acidic catalyst is selected from one or more of aluminum trichloride, tin tetrachloride, ferric chloride, zinc chloride, boron trifluoride, aluminum tribromide, boric acid, hydrochloric acid, hydrofluoric acid, sulfuric acid, perchloric acid, trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid, the reaction temperature is 0 to 100° C., and the reaction time is 0.5 to 3 hours.

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