5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid compounds, and preparation method and application thereof

Abstract

The application discloses 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid and derivatives (formula I) thereof, wherein R is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, preferably H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The synthesis of related active compounds using the compound of formula I can greatly shorten the synthesis route, improve the yield, and has a wide application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pesticides, specifically relating to a 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid compound, its synthesis method, and its application 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. They have long been a focus of research as important intermediates in the pesticide and pharmaceutical fields. Examples include herbicides containing dihydroisoxazole structures such as benzoxazole, sulfopyrazol, insecticides such as flurranazine, and the herbicide safener ethyl bis(oxazolyl)ate.

[0003] Currently, in the synthesis of dihydroisoxazole compounds with disubstituted 5-position, the commonly used method is to use disubstituted ethylene as a raw material. For example, 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene is used to synthesize freranal (CN114394946), and stilbene is used to synthesize ethyl bis(benzazole) acid (CN108440435). The olefins used in these methods are complex in structure and are not inexpensive or readily available chemical raw materials. Furthermore, the synthesis of some complex olefins is quite difficult. For instance, 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-propene, with catalysts such as dichlorobis(triphenylphosphine)palladium, yielding a 64% yield.

[0004] (CN115246825) has high costs and low yields.

[0005]

[0006] This laboratory has designed and developed a novel dihydroisoxazole compound containing a chiral center and an active reaction site. This compound can be used as a precursor to construct potentially active dihydroisoxazole derivatives, especially facilitating the construction of dihydroisoxazole compounds with 5-position disubstituted derivatives. For example, in the construction of bisphenyloxazole acid analogs, this method overcomes the limitation of using stilbene as a starting material in existing technologies. Instead, it 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] This invention addresses the drawback of existing techniques for synthesizing dihydroisoxazole compounds with a 5-position disubstituted structure, which relies on the use of expensive disubstituted ethylene. It provides a novel key intermediate for synthesizing potentially active dihydroisoxazole 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] This invention also provides a method for preparing 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid and its derivatives (Formula I), the synthetic route of which is as follows:

[0011]

[0012] This invention also provides a method for preparing ethyl bis(benzyl)oxazolium, the synthetic route of which is as follows:

[0013]

[0014] Beneficial effects of the invention

[0015] The 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid compounds developed in this laboratory provide a new synthetic approach for constructing potentially active dihydroisoxazole derivatives. They also solve the problem of the difficulty in synthesizing dihydroisoxazole compounds with 5-position disubstituted forms, offering a simpler synthetic route and using cheaper and more readily available raw materials. For the synthesis of existing related active compounds, such as ethyl bis(benzoxazole)ate, this approach can reduce synthesis costs and simplify the process with milder conditions. Furthermore, the intermediates disclosed in this invention can also be used as key intermediates for high-throughput compound synthesis screening. Detailed Implementation

[0016] 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 other substances or steps.

[0017] Furthermore, to better illustrate the present invention, numerous specific details are provided in the following detailed embodiments.

[0018] 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.

[0019] 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.

[0020] If the compounds of Formula I described in this invention have functional groups that can be ionized, they can also be used in the form of their salts or mixtures thereof.

[0021] As used herein, the term "alkyl" (and in other groups containing alkyl, such as the alkyl moiety of alkoxy, the alkyl moiety of haloalkyl, and the alkyl moiety of arylalkyl) generally indicates a number of carbon atoms typically ranging from 1 to 20, often from 1 to 6. Examples of C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), and 1,1-dimethylethyl (tert-butyl). Examples of C1-C6 alkyl groups, in addition to those mentioned for C1-C4 alkyl groups, include 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 this invention, "cycloalkyl" refers to a monocyclic monovalent hydrocarbon group with three to ten carbon atoms, which may be saturated or contain a double bond. Cycloalkyl is preferably C3-C8 cycloalkyl, and examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0023] In this invention, NCS is N-chlorosuccinimide.

[0024] In this invention, AIBN is azobisisobutyronitrile.

[0025] In this invention, AIBME is dimethyl azobisisobutyrate.

[0026] In this invention, AIBI is azobisisopropylimidazoline hydrochloride.

[0027] In this invention, BPO is benzoyl peroxide.

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

[0029] In this invention, DCP is dicumyl peroxide.

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

[0031] In this invention, TBPB is tert-butyl peroxide.

[0032] In this invention, TBPV is tert-butyl peroxypentanoate.

[0033] In this invention, MEKP is methyl ethyl ketone peroxide.

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

[0035]

[0036] 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] This invention also discloses a method for synthesizing 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid and its derivatives, comprising the following steps:

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

[0039] Step 2) 2-Chloro-2-phenyl-cyclopropane carboxylic acid or its ester is reacted with sodium nitrite in the presence of 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 one 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 one of the above synthesis method: first, adding magnesium in batches; second, adding benzyl trichloride dropwise to other reactants; third, adding DMF or DMAC dropwise to other reactants; and fourth, adding a mixture of benzyl trichloride and acrylic acid or its ester dropwise to other reactants. The molar ratio of magnesium, acrylic acid or its ester and benzyl trichloride is 2-5:1:1-1.5, and the amount of DMF or DMAC added is 1-100 equivalents (based on acrylic acid or its ester). The solvents are DMF, DMAC, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, acetonitrile, DMSO, toluene, etc. After the reaction is completed, the mixture is poured into acid water for quenching, and the organic layer is taken or extracted with toluene and the organic layer is taken to remove the solvent to obtain 2-chloro-2-phenyl-cyclopropane carboxylic acid or its ester.

[0044] Preferably, in step two of the above synthesis method, 2-chloro-2-phenyl-cyclopropane carboxylic acid or its ester reacts with sodium nitrite in a solvent in the presence of an acid, the reaction temperature is 0-100°C, preferably 0-50°C, and the reaction time is 1-3 hours. 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 includes the following steps;

[0046] Step a) 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester is prepared by reacting 2-chloro-2-(hydroxyimino)acetic acid or its ester, styrene and a base in a solvent.

[0047] Step b) 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester is prepared by reacting 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester with a chlorinating agent.

[0048] The reaction pathway 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 the solvent is 0-100°C, and the reaction time is 1-3 h. The solvent is selected from one or more of dichloromethane, dichloroethane, toluene, ethyl acetate, diethyl 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 chlorinating agent in step b) is NCS, dichlorohydantoin, sulfonyl chloride, or chlorine gas; the reaction temperature is 0–100°C; the reaction time is 0.5–3 h; and the solvent is selected from one or more of dichloromethane, dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, and tetrahydrofuran. More preferably, an initiator is added to the reaction of 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester with the chlorinating agent. The initiator is selected from one or more of AIBN, AIBME, AIBI, BPO, TBHP, DCP, DTBP, TPB, TBPV, and MEKP. Adding an initiator to some reactions can accelerate the reaction rate and increase the reaction yield.

[0052] This invention also provides a synthesis of ethyl bis(benzyl)oxazolium, comprising the following steps:

[0053] Ethyl 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid (Formula Ia) and benzene react under acidic catalyst to synthesize ethyl bisbenzoxazole acid.

[0054] Its 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 0-100°C and the reaction time is 0.5-3 h. The reaction solvent is selected from one or more of dichloromethane, nitromethane, benzene, nitrobenzene, and carbon disulfide. The acid catalyst is selected from one or more of aluminum trichloride, tin tetrachloride, ferric trichloride, 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 bis(phenyloxazole)ate.

[0057] Generally, the compounds of the present invention can be prepared by the methods described herein, 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.

[0058] Example 1: Synthesis of methyl 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylate

[0059] Take 80 ml of tetrahydrofuran, add 4.3 g of methyl acrylate, 2.64 g of magnesium and 3.65 g of DMF, stir well, and then add a tetrahydrofuran solution of benzyl trichloride (10.75 g of benzyl trichloride) dropwise at 60 °C. After the reaction is completed, cool to room temperature and quench in hydrochloric acid aqueous solution. After extraction with toluene, take the organic layer and concentrate to remove the solvent to obtain 10.32 g of methyl 2-chloro-2-phenyl-cyclopropanecarboxylate.

[0060] 100 ml of ethyl acetate was added to 10.32 g of methyl 2-chloro-2-phenyl-cyclopropanecarboxylate, 1.48 g of concentrated hydrochloric acid, and 3.45 g of sodium nitrite. The mixture was reacted at 45 °C for 2 h. After the reaction was completed, water was added, and the organic layer was concentrated to remove the solvent, yielding 11.51 g of methyl 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylate, with a yield of 96%.

[0061] 1H NMR (300MHz, CDCl3) δ7.34-7.44 (m, 5H), δ3.86 (s, 2H), δ3.65 (s, 3H)

[0062] Example 2: Synthesis of ethyl 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylate

[0063] Take 100 ml of DMF, add 5.0 g of ethyl acrylate and 11.73 g of benzyl trichloride, add 4.32 g of magnesium in portions at 80 °C, react for 2 h, after the reaction is completed, cool to room temperature and quench in sulfuric acid aqueous solution, extract with toluene, take the organic layer and concentrate to remove solvent to obtain 11.01 g of ethyl 2-chloro-2-phenyl-cyclopropanecarboxylate.

[0064] 100 ml of tetrahydrofuran was mixed with 11.01 g of ethyl 2-chloro-2-phenyl-cyclopropane carboxylate, 1.0 g of concentrated sulfuric acid, and 3.45 g of sodium nitrite. The mixture was reacted at 5 °C for 2 h. After the reaction was completed, water was added, and the mixture was extracted with toluene. The organic layer was then concentrated to remove the solvent, yielding 12.31 g of ethyl 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylate, with a yield of 97%.

[0065] 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)

[0066] Example 3: Synthesis of isopropyl 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid

[0067] 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 well, and then add a solution of benzyl trichloride in methyl tert-butyl ether (11.73 g of benzyl trichloride) dropwise at 20 °C. After the reaction is completed, cool to room temperature and quench in hydrochloric acid aqueous solution. Take the organic layer and concentrate to remove the solvent to obtain 11.46 g of 2-chloro-2-phenyl-cyclopropanecarboxylic acid isopropyl ester.

[0068] 100 ml of acetonitrile was mixed with 11.46 g of 2-chloro-2-phenyl-cyclopropane isopropyl carboxylate, 1.2 g of acetic acid, and 3.45 g of sodium nitrite. The mixture was reacted at 80 °C for 1 h. After the reaction was completed, water was added, and the mixture was extracted with toluene. The organic layer was then concentrated to remove the solvent, yielding 12.46 g of 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylate isopropyl carboxylate, with a yield of 93%.

[0069] 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)

[0070] Example 4: Synthesis of 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid

[0071] 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 h, after the reaction is complete, extract with water, take the organic layer, concentrate and remove the solvent to obtain 9.46 g of 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid.

[0072] Take 100 ml of dichloroethane, add 9.46 g of 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid and 6.67 g of NCS, heat to 50 °C, add 0.08 g of AIBN, maintain the reaction at 50 °C for 2 h, after the reaction is complete, extract with water, take the organic layer, concentrate to remove solvent to obtain 10.83 g of 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid, yield 96%.

[0073] 1H NMR (300MHz, CDCl3) δ7.35-7.44 (m, 5H), δ3.91 (s, 2H)

[0074] Example 5: Synthesis of 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid propyl ester

[0075] 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 h, add water after the reaction is complete, 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.

[0076] 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 h, after the reaction is complete, add water, extract with toluene, and concentrate the organic layer to remove the solvent to obtain 12.59 g of 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid propyl ester, yield 94%.

[0077] 1H NMR (300MHz, CDCl3) δ7.32-7.44 (m, 5H), δ4.19-4.21 (t, 2H), δ3.87 (s, 2H),

[0078] δ1.62-1.67(m,2H), δ0.98-1.12(t,3H)

[0079] Example 6: Synthesis of ethyl bis(benzoxazole) acid

[0080] Take 100 ml of benzene, add 5.07 g of ethyl 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylate and 4.0 g of aluminum trichloride, react at 70 °C for 1 h, after the reaction is completed, add hydrochloric acid to quench, take the organic layer and concentrate to remove the solvent to obtain 5.79 g of ethyl bis(phenyloxazole) acid, yield 98%.

[0081] 1H NMR (300MHz, DMSO) δ7.26-7.44 (m, 10H), δ4.19-4.26 (q, 2H), δ3.90 (s, 2H),

[0082] δ1.21-1.26(t,3H)

[0083] Comparison of the synthesis of ethyl bis(benzoxazol) acid

[0084] Comparison Column 1

[0085] The existing technology (refer to Example 1 of patent CN108440435) has the following synthetic route, which requires five steps to synthesize ethyl bis(benzyl)oxazolate, of which three steps are required to prepare stilbene. The route is long, the yield is low (the yield of the last step is 34%), and the cost is high.

[0086]

[0087] Comparative Example 2

[0088] The existing technology (Patent CN107652245 Example 1) has the following synthetic route, which requires three steps to synthesize ethyl bisbenzoxazole, but the raw material benzophenone used is expensive and its yield is 67.5%.

[0089]

[0090] Compared with existing technologies, the synthesis of ethyl bis(benzoxazolyl) ester in this patent (described by taking Examples 2 and 6 as examples) requires only 3 steps, with a total yield of 95%. Moreover, the raw materials used, including benzyl trichloride, ethyl acrylate, sodium nitrite, and aluminum trichloride, are all inexpensive and readily available chemical raw materials, resulting in lower costs and higher yields.

[0091] 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 and its stereoisomers, characterized in that, ， R is selected from H, C1-C6 alkyl or C3-C8 cycloalkyl.

2. The compound of formula I and its stereoisomers according to claim 1, characterized in that... R is selected from one of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

3. A method for preparing the compound of formula I according to claim 1 or 2, characterized in that, Includes the following steps, Step 1) reacts acrylic acid or its esters with benzyl trichloride in the presence of DMF (N,N-dimethylformamide) or DMAC (N,N-dimethylacetamide) and magnesium to prepare 2-chloro-2-phenyl-cyclopropane carboxylic acid or its esters; Step 2) 2-Chloro-2-phenyl-cyclopropane carboxylic acid or its ester is reacted with sodium nitrite in the presence of an acid to prepare compound I; Its synthetic route is as follows: , R is selected from H, C1-C6 alkyl or C3-C8 cycloalkyl.

4. The preparation method according to claim 3, characterized in that, R is selected from one of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

5. The preparation method according to claim 3 or 4, characterized in that, The reaction in step one) is carried out in a solvent, wherein the solvent is one of DMF, DMAC, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, acetonitrile, DMSO and toluene, and the reaction temperature is -10~100℃, and the reaction time is 1~8h.

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

7. The preparation method according to claim 3 or 4, characterized in that, In step two, 2-chloro-2-phenyl-cyclopropane carboxylic acid or its ester reacts with sodium nitrite in a solvent in the presence of an acid.

8. The preparation method according to claim 7, characterized in that, The solvent mentioned 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; the reaction temperature is 0~100℃ and the reaction time is 1~3h.

9. A method for preparing the compound of formula I according to claim 1, characterized in that, Includes the following steps: Step a) 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester is prepared by reacting 2-chloro-2-(hydroxyimino)acetic acid or its ester, styrene and a base in a solvent. Step b) 5-chloro-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester is prepared by reacting 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester with a chlorinating agent in a solvent. The reaction pathway is as follows: ， R is selected from H, C1-C6 alkyl or C3-C8 cycloalkyl.

10. The preparation method according to claim 9, characterized in that, R is selected from one of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

11. The preparation method according to claim 9 or 10, characterized in that, The solvent in step a) is selected from one or more of dichloromethane, dichloroethane, toluene, ethyl acetate, diethyl 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; the reaction temperature is 0~100℃, and the reaction time is 1~3h.

12. The preparation method according to claim 9 or 10, characterized in that, In step b), when 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid or its ester reacts with the chlorinating agent in a solvent, an initiator may be added. The initiator is selected from one or more of AIBN, AIBME, AIBI, BPO, TBHP, DCP, DTBP, TBPB, TBPV, and MEKP.

13. The preparation method according to claim 9 or 10, characterized in that, The chlorination reagent mentioned in step b) is one of NCS, dichlorohydantoin, sulfonyl chloride and chlorine gas, and the solvent is selected from one or more of dichloromethane, dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether and tetrahydrofuran; the reaction temperature is 0~100℃ and the reaction time is 0.5~3h.

14. A method for synthesizing ethyl bis(benzoxazolyl) acid, characterized in that, The process includes the following steps: reacting compound Ia and benzene under an acidic catalyst to synthesize ethyl bis(benzoxazole) acid. The reaction pathway is as follows: 。 15. The synthesis method according to claim 14, characterized in that, The reaction is carried out in a solvent 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 trichloride, 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 0~100℃ and the reaction time is 0.5~3h.

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