Preparation method of isoxazole-oxadiazole compound

Abstract

The invention provides a preparation method of an isoxazole-oxadiazole compound, which comprises the following steps: reacting 4-chloro-2-fluoro-3-vinylbenzoic acid with tert-butyloxycarboryl hydrazine in the presence of a condensing agent and a catalyst, then removing a protecting group under an acidic condition to obtain an intermediate 4-chloro-2-fluoro-3-vinylbenzoyl hydrazine, and then reacting with N, N-dimethylformamide to obtain the isoxazole-oxadiazole compound. The method comprises the following steps: cyclizing N, N '-carbonyldiimidazole in the presence of alkali, carrying out an O-alkylation reaction with an alkylation reagent R1-X in the presence of alkali, and carrying out an olefin dihydroxylation-sodium periodate oxidation cleavage reaction in the presence of an oxidant and a catalyst; reacting with hydroxylamine in the presence of alkali, and finally carrying out 1, 3-dipolar cycloaddition reaction with an acrylate compound in the presence of alkali and an oxidizing agent. The method is carried out at room temperature, has the advantages of mild conditions, simplicity in operation and the like, is wider in application range compared with a traditional synthesis method, and has important synthesis application value.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an isoxazol-oxadiazole compound. BACKGROUND

[0002] Isoxazole and oxadiazole derivatives have a wide range of applications in the fields of medicinal chemistry and pesticide chemistry due to their unique biological and pharmacological activities. In recent years, isoxazole and oxadiazole derivatives have been a hot spot of research in organic chemistry.

[0003] Isoxazole and oxadiazole derivatives not only have a wide range of biological activities, such as fungicidal, insecticidal, anti-plant viral, herbicidal and other activities, but also have the characteristics of good selectivity, high activity and low toxicity, and are widely used in pesticide chemistry. At present, isoxazole and oxadiazole pesticides are gradually becoming an important part of the field of pesticides, and especially have a large number of applications in the field of herbicides. Herbicides with isoxazole and oxadiazole structures, such as pyroxasulfone, fenoxasulfone, topramezone, methiozolin, ethyl isoxazolate, oxadiazon and flusulfinam, are widely used in the field of herbicides and have a wide market application prospect.

[0004] Isoxazole and oxadiazole derivatives have a wide range of applications in the fields of medicinal chemistry and pesticide chemistry due to their unique biological and pharmacological activities. In recent years, isoxazole and oxadiazole derivatives have been a hot spot of research in organic chemistry. SUMMARY

[0005] In view of the above technical problems, the present application provides a preparation method of an isoxazole-oxadiazole compound, the molar yield of which is greater than or equal to 83%, the target compound is synthesized with high selectivity through the mode of 'amino protection-directional condensation-acid deprotection / cyclization', the operation process is simplified, and energy consumption and wastes are reduced. The method is carried out at room temperature, has the advantages of mild conditions and simple operation, and has a wider application range than traditional synthesis methods, and has important synthesis application value. In addition, the high-activity isoxazole and oxadiazole groups of the compound make it have potential applications in the field of pesticides, especially in the field of herbicides, the method of the present application provides a convenient route for further directional modification and synthesis of subsequent derivatives.

[0006] The technical scheme of the present application is as follows:

[0007] A preparation method of an isoxazole-oxadiazole compound, which synthesizes a 5-chloro-4-fluoro-2-[5-alkyl-5-carboxylate-3-(1,3-isoxazole-4-yl)] phenyl-1,3-oxazole-4-carboxylate compound represented by general formula (I),

[0008] wherein R1 is an alkyl group, and R2 is an alkyl group or hydrogen; The method comprises the following steps: S1: 4-chloro-2-fluoro-3-vinylbenzoic acid is reacted with tert-butyloxycarbonyl hydrazine in the presence of a condensing agent and a catalyst, and then a protective group is removed under acidic conditions to obtain an intermediate 4-chloro-2-fluoro-3-vinylbenzohydrazide; S2: the 4-chloro-2-fluoro-3-vinylbenzohydrazide obtained in step S1 is cyclized with N,N'-carbonyldiimidazole in the presence of a base to obtain an intermediate 5-chloro-2-vinyl-4-fluorophenyl-1,3-oxazol-5-one; S3: the 5-chloro-2-vinyl-4-fluorophenyl-1,3-oxazol-5-one obtained in step S2 is subjected to O-alkylation reaction with an alkylating agent R1-X in the presence of a base to obtain an intermediate 5-chloro-4-fluoro-2-vinylphenyl-4-alkyl-1,3-oxazol-5-one, wherein R1 is an alkyl group, and X is a halogen; S4: the 5-chloro-4-fluoro-2-vinylphenyl-4-alkyl-1,3-oxazol-5-one obtained in step S3 is subjected to olefin double hydroxylation-sodium periodate oxidative cleavage reaction in the presence of an oxidizing agent and a catalyst to obtain an intermediate 5-chloro-4-fluoro-2-formylphenyl-4-alkyl-1,3-oxazol-5-one; S5: 5-chloro-4-fluoro-2-formylphenyl-4-alkyl-1,3-oxazol-5-one obtained in step S4 is reacted with hydroxylamine in the presence of a base to obtain intermediate 5-chloro-4-fluoro-2-(nitrosomethyl)phenyl-4-alkyl-1,3-oxazol-5-one; S6: 5-chloro-4-fluoro-2-(nitrosomethyl)phenyl-4-alkyl-1,3-oxazol-5-one obtained in step S5 is subjected to 1,3-dipolar cycloaddition reaction with an acrylic ester compound in the presence of a base and an oxidant to obtain the compound of general formula (I) wherein R2 is alkyl or hydrogen.

[0009] Preferably, in the compound of general formula (I), R1 is methyl, R2 is methyl, and the compound is 5-chloro-4-fluoro-2-[5-methyl-5-methoxycarbonyl-3-(1,3-oxazol-4-yl)]phenyl-4-methyl-1,3-oxazole-5-carboxylic acid methyl ester.

[0010] Preferably, in step S1, the condensing agent is dicyclohexyl carbodiimide (DCC), the catalyst is 4-dimethylaminopyridine (DMAP), and the acidic condition is provided by hydrochloric acid solution of ethyl acetate.

[0011] Preferably, in step S1, 4-chloro-2-fluoro-3-vinylbenzoic acid and tert-butyloxycarbonyl hydrazine are dissolved in dichloromethane, dicyclohexyl carbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) are added at 0°C, and the reaction is carried out at room temperature; the reaction solution is washed with dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution and sodium chloride aqueous solution in sequence, dried and concentrated, and then stirred with ethyl acetate-HCl; the reaction solution is washed with sodium bicarbonate aqueous solution and concentrated to obtain 4-chloro-2-fluoro-3-vinylbenzohydrazide.

[0012] Further preferably, the molar ratio of 4-chloro-2-fluoro-3-vinylbenzoic acid, tert-butyloxycarbonyl hydrazine, dicyclohexyl carbodiimide and 4-dimethylaminopyridine is 1:1.2:1.4:0.2; the reaction temperature is room temperature, and the reaction time is 4 h; the concentration of HCl in ethyl acetate-HCl is 4.0 M, and the reaction time is 1 h.

[0013] Preferably, in step S2, the base is triethylamine.

[0014] Preferably, in step S2, 4-chloro-2-fluoro-3-vinylbenzohydrazide is dissolved in tetrahydrofuran, N,N'-carbonyldiimidazole (CDI) and triethylamine are added at 0°C, and the reaction is carried out at room temperature; the reaction solution is concentrated, redissolved with ethyl acetate, washed with dilute hydrochloric acid and saturated sodium bicarbonate aqueous solution in sequence, dried and concentrated to obtain 5-chloro-2-vinyl-4-fluorophenyl-1,3-oxazol-5-one. More preferably, the molar ratio of 4-chloro-2-fluoro-3-vinylbenzoylhydrazide, N,N'-carbonyldiimidazole and triethylamine is 1:1.25:1; the reaction temperature is room temperature and the reaction time is 2 hours.

[0015] Preferably, in step S3, the alkylating agent is iodomethane (CH3I), and the base is potassium carbonate (K2CO3).

[0016] Preferably, step S3 specifically involves dissolving the 5-chloro-2-vinyl-4-fluorophenyl-1,3-oxazol-5-one obtained in step 2 and potassium carbonate in N,N-dimethylformamide, stirring, adding iodomethane, and reacting at room temperature; pouring the reaction solution into water, extracting with ethyl acetate, drying and concentrating to obtain 5-chloro-4-fluoro-2-vinylphenyl-4-methyl-1,3-oxazol-5-one.

[0017] More preferably, the molar ratio of 5-chloro-2-vinyl-4-fluorophenyl-1,3-oxazol-5-one, potassium carbonate, and iodomethane is 1:1.5:1.15; the stirring time is 30 minutes; the reaction temperature is room temperature; and the reaction time is 1 hour.

[0018] Preferably, in step S4, the oxidant is sodium periodate (NaIO4), and the catalyst is potassium osmium tetroxide dihydrate (K2OsO4·2H2O).

[0019] Preferably, step S4 specifically involves dissolving the 5-chloro-4-fluoro-2-vinylphenyl-4-methyl-1,3-oxazol-5-one obtained in step 3 in a mixed solution of tetrahydrofuran and water, adding sodium periodate and potassium osmium tetroxide dihydrate, and reacting at room temperature; pouring the reaction solution into water, extracting with ethyl acetate, drying and concentrating, and then purifying by column chromatography to obtain 5-chloro-4-fluoro-2-formylphenyl-4-methyl-1,3-oxazol-5-one.

[0020] More preferably, the molar ratio of 5-chloro-4-fluoro-2-vinylphenyl-4-methyl-1,3-oxazol-5-one, sodium periodate, and potassium osmium tetroxide dihydrate is 1:1.8:0.09; the volume ratio of tetrahydrofuran to water is 5:1; the reaction time is overnight; and the eluent used for column chromatography is petroleum ether:ethyl acetate = 3:1.

[0021] Preferably, in step S5, the hydroxylamine is added in the form of hydroxylamine hydrochloride (NH2OH·HCl) and sodium acetate (CH3COONa).

[0022] Preferably, step S5 specifically involves dissolving the 5-chloro-4-fluoro-2-formylphenyl-4-methyl-1,3-oxazol-5-one obtained in step 4 in ethanol with sodium acetate, adding an aqueous solution of hydroxylamine hydrochloride, and reacting at room temperature; pouring the reaction solution into water, extracting with ethyl acetate, drying and concentrating to obtain 5-chloro-4-fluoro-2-(nitrosomethyl)phenyl-4-methyl-1,3-oxazol-5-one.

[0023] More preferably, the molar ratio of 5-chloro-4-fluoro-2-vinylphenyl-4-methyl-1,3-oxazol-5-one, sodium acetate, and hydroxylamine hydrochloride is 1:1.2:2.0; the reaction temperature is room temperature, and the reaction time is 2 hours.

[0024] Preferably, in step S6, the acrylate compound is methyl methacrylate (CH2=C(CH3)COOCH3), the base is triethylamine, and the oxidizing agent is sodium hypochlorite (NaClO).

[0025] Preferably, step S6 specifically involves dissolving 5-chloro-4-fluoro-2-(nitrosomethyl)phenyl-4-methyl-1,3-oxazol-5-one obtained in step 5 in dichloromethane, adding triethylamine and sodium hypochlorite aqueous solution at 0°C, and reacting at room temperature; pouring the reaction solution into water, extracting with ethyl acetate, drying and concentrating, and purifying by column chromatography to obtain compound (I); More preferably, the molar ratio of 5-chloro-4-fluoro-2-(nitrosomethyl)phenyl-4-alkyl-1,3-oxazol-5-one, methyl methacrylate, triethylamine, and sodium hypochlorite is 1.2:1:0.6:5; the reaction temperature is room temperature, and the reaction time is overnight; the eluent used for column chromatography is petroleum ether:ethyl acetate = 3:1.

[0026] The compound prepared by the method has the following structural formula: Ethyl 5-chloro-4-fluoro-2-[5-methyl-5-carboxy-3-(1,3-oxazol-4-yl)]phenyl-1,3-oxazol-4-carboxylate; or Methyl 5-chloro-4-fluoro-2-[5-methyl-5-carboxy-3-(1,3-oxazol-4-yl)]phenyl-1,3-oxazol-4-carboxylic acid.

[0027] The beneficial effects of this invention are as follows: This invention provides a method for the orderly construction of oxadiazole and isoxazole rings under mild conditions using readily available raw materials. This method offers advantages such as simple operation and low experimental cost. The reaction conditions are mild, the operation is simple, and high-temperature, high-pressure equipment is not required. Furthermore, it maintains the stability of the other heterocycle while constructing a single heterocycle, filling a gap in the field of medicinal chemistry, especially pesticide chemistry, for the direct construction of isoxazole and oxadiazole bicyclic heterocycles. The readily available raw materials and simple operation make it suitable for large-scale production. Attached Figure Description

[0028] Figure 1 Example 1: Product 1 Characterization Diagram; Figure 2 Example 2: Product 2 Characterization Diagram; Figure 3 Example 2 Product 3 characterization diagram. Detailed Implementation

[0029] The technical solution of the present invention will be further explained and described below with reference to specific embodiments. It is worth noting that the following embodiments are only preferred embodiments of the present invention and should not be construed as limiting the present invention. The scope of protection of the present invention should be determined by the contents of the claims. Modifications and substitutions made by those skilled in the art to the technical solution of the present invention without creative effort all fall within the scope of protection of the present invention.

[0030] Example 1 methyl 5-chloro-4-fluoro-2-[5-methyl-5-carboxy-3-(1,3-oxazol-4-yl)]phenyl-1,3-oxazol-4-carboxylate, with R1= -CH3 and R2= -CH 3， The structural formula is The synthesis method is as follows: Step 1: 4-Chloro-2-fluoro-3-vinylbenzoic acid (5.014 g, 25.0 mmol), tert-butyloxycarbonylhydrazine (3.964 g, 30 mmol), and 90 mL of dichloromethane were added to a 250 mL reaction flask. Dicyclohexylcarbodiimide (DCC, 7.221 g, 35 mmol) and 4-dimethylaminopyridine (DMAP, 0.610 g, 5.0 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 4 h. The reaction solution was washed successively with 100 mL of 0.5 M dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution. After drying and concentrating the organic phase, ethyl acetate-HCl (4.0 M, 7.5 mL) was added, and the mixture was stirred for 1 h. The reaction solution was washed with a saturated sodium bicarbonate aqueous solution and then concentrated to obtain 4.529 g of pale yellow liquid 4-chloro-2-fluoro-3-vinylbenzoylhydrazide (4.529 g, 84%), which was used directly in the next step.

[0031] Step 2: 4-Chloro-2-fluoro-3-vinylbenzoylhydrazine (4.529 g, 21.1 mmol) and 80 mL of tetrahydrofuran were added to a 250 mL reaction flask. N,N'-carbonyldiimidazole (CDI, 4.280 g, 26.4 mmol) and triethylamine (2.131 g, 21.1 mmol) were added at 0 °C, and the reaction was carried out at room temperature for 2 h. The reaction solution was concentrated, redissolved in 80 mL of ethyl acetate, and washed successively with 80 mL of 1 M dilute hydrochloric acid and saturated sodium bicarbonate aqueous solution. After drying and concentrating the organic phase, 5-chloro-2-vinyl-4-fluorophenyl-1,3-oxazol-5-one was obtained. The pale yellow liquid (4.296 g, 85%) was used directly in the next step.

[0032] Step 3: 5-Chloro-2-vinyl-4-fluorophenyl-1,3-oxazol-5-one (4.296 g, 17.9 mmol), potassium carbonate (3.544 g, 26.8 mmol), and 80 mL of N,N-dimethylformamide were added to a 250 mL reaction flask. After stirring for 30 min, iodomethane (R1=-CH3, 2.794 g, 19.6 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction solution was poured into 300 mL of water and extracted three times with 90 mL of ethyl acetate. The organic phase was collected, dried, and concentrated to obtain 5-chloro-4-fluoro-2-vinylphenyl-4-methyl-1,3-oxazol-5-one, a pale yellow solid (3.987 g, 88%), which was used directly in the next step.

[0033] Step 4: 5-Chloro-4-fluoro-2-vinylphenyl-4-methyl-1,3-oxazol-5-one (3.987 g, 15.7 mmol), 60 mL of tetrahydrofuran, and 12 mL of water were added to a 250 mL reaction flask. Sodium periodate (6.717 g, 31.4 mmol) and potassium osmium tetroxide dihydrate (0.552 g, 1.5 mmol) were then added, and the mixture was reacted overnight at room temperature. The reaction solution was poured into 100 mL of water and extracted three times with 60 mL of ethyl acetate. The organic phase was collected, dried, concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 5-chloro-4-fluoro-2-formylphenyl-4-methyl-1,3-oxazol-5-one, a pale yellow liquid (3.233 g, 80%).

[0034] Step 5: 5-Chloro-4-fluoro-2-formylphenyl-4-methyl-1,3-oxazol-5-one (3.233 g, 12.6 mmol), sodium acetate (1.270 g, 15.1 mmol), and 40 mL of ethanol were added to a 250 mL reaction flask, followed by 10 mL of an aqueous solution of hydroxylamine hydrochloride (1.778 g, 25.2 mmol). The reaction mixture was reacted at room temperature for 2 h. The reaction solution was poured into 100 mL of water, extracted with ethyl acetate, dried, and concentrated to obtain 5-chloro-4-fluoro-2-(nitrosomethyl)phenyl-4-methyl-1,3-oxazol-5-one, a white solid (3.122 g, 91%), which was used directly in the next step.

[0035] Step 6: Add 5-chloro-4-fluoro-2-(nitrosomethyl)phenyl-4-methyl-1,3-oxazol-5-one (0.271 g, 1.2 mmol), methyl methacrylate (R2=-CH3, 0.100 g, 1.0 mmol), and 5 mL of dichloromethane to a 50 mL reaction flask. Add triethylamine (0.06 g, 0.05 mmol) and a 10% sodium hypochlorite (0.372 g, 5 mmol) aqueous solution at 0°C and react overnight at room temperature. The reaction solution was poured into 20 mL of water, extracted three times with 10 mL of ethyl acetate, and the organic phase was collected. After drying and concentration, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 1: methyl 5-chloro-4-fluoro-2-[5-methyl-5-carboxy-3-(1,3-oxazol-4-yl)]phenyl-1,3-oxazol-4-carboxylate, a white solid (0.281 g, 76%).

[0036] like Figure 1 Product characterization: 1 H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.4 Hz, 1H), 7.37(d, J = 9.9 Hz, 1H), 4.01 (d, J = 17.4 Hz, 1H), 3.86 (s, 3H), 3.56 (s, 3H), 3.42(d, J = 17.4 Hz, 1H), 1.77 (s, 3H). Example 2 Product 2: Ethyl 5-chloro-4-fluoro-2-[5-methyl-5-carboxy-3-(1,3-oxazol-4-yl)]phenyl-1,3-oxazol-4-carboxylate, with R1= -CH3, R2= -C2H3, and the structural formula is as follows. The synthesis method is similar to that in Example 1, and it is a white solid.

[0037] like Figure 2 Product characterization: 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.5 Hz, 1H), 7.36(d, J = 9.9 Hz, 1H), 4.30 (qd, J = 7.1, 1.0 Hz, 2H), 4.00 (d, J = 17.3 Hz, 1H), 3.55 (s, 3H), 3.39 (d, J = 17.4 Hz, 1H), 1.76 (q, 3H), 1.36 (t, J = 7.2 Hz, 3H). Product 3: 5-chloro-4-fluoro-2-[5-methyl-5-carboxy-3-(1,3-oxazol-4-yl)]phenyl-1,3-oxazol-4-carboxylic acid, with R1= -C2H3, R2= -CH3, and the structural formula is as follows. The synthesis method is similar to that in Example 1, and it is a white solid.

[0038] like Figure 3 Product characterization: 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.4 Hz, 1H), 7.34 (d, J = 9.9 Hz, 1H), 3.99 (d, J = 17.5 Hz, 1H), 3.54 (s, 3H), 3.49 – 3.35 (m,1H), 1.78 (s, 3H). Comparative Example 1 Some traditional synthetic methods cannot achieve this technical effect. For example, in the synthesis of compound methyl 5-chloro-4-fluoro-2-[5-methyl-5-carboxy-3-(1,3-oxazol-4-yl)]phenyl-1,3-oxazol-4-carboxylate in Example 1, some synthetic steps cannot successfully construct the bi-heterocyclic structure if other conventional chemical synthesis methods are used. For instance, step 6, when using the commonly used synthetic strategy of N-chlorosuccinimide chlorination and olefin cycloaddition, cannot yield the isoxazole ring, as detailed below: 5-Chloro-4-fluoro-2-(nitrosomethyl)phenyl-4-methyl-1,3-oxazol-5-one (0.271 g, 1.5 mmol) was dissolved in 5 mL of dimethylformamide, followed by the addition of N-chlorosuccinimide (0.240 g, 1.8 mmol), and the reaction was carried out at 35 °C with stirring for 2 h. The reaction solution was poured into 25 mL of water, and extracted three times with 5 mL of dichloromethane. The organic phase was collected, dried, concentrated, and added to a 50 mL reaction flask. Methyl methacrylate (R2=-CH3, 0.150 g, 1.5 mmol), triethylamine (0.181 g, 1.8 mmol), and 5 mL of dichloromethane were added at 0 °C, and the reaction was carried out at room temperature for 2 h. Thin-layer chromatography (PE:EA=1:1) of the reaction solution did not reveal any new spots, and the mass-charge ratio (m / z) of the undetectable product by gas chromatography-mass spectrometry was 355.04. Therefore, compound 1: methyl 5-chloro-4-fluoro-2-[5-methyl-5-carboxy-3-(1,3-oxazol-4-yl)]phenyl-1,3-oxazol-4-carboxylate could not be synthesized using this strategy.

[0039] Furthermore, the synthetic strategy of this patent has a certain order. If the construction order of isoxazole and dioxazole rings is reversed: Taking the synthesis of compound methyl 5-chloro-4-fluoro-2-[5-methyl-5-carboxy-3-(1,3-oxazol-4-yl)]phenyl-1,3-oxazol-4-carboxylate in Example 1 as an example, if isoxazole is constructed first using steps 4, 5, and 6, and then dioxazole is constructed using steps 1, 2, and 3, it will lead to the ring-opening destruction of isoxazole, as shown in the NMR data of the compound, the isoxazole alkyl characteristic peak - [4.01 (d, J = 17.4 Hz, 1H), 3.42 (d, J The missing value is 17.4 Hz, 1H.

[0040] Based on the preferred embodiments of the present invention described above, those skilled in the art can make various changes and modifications without departing from the inventive concept. The technical scope of this invention is not limited to the contents of the specification, but must be determined according to the scope of the claims.

Claims

1. A method for preparing an isoxazole-oxadiazole compound, characterized in that: Synthesize 5-chloro-4-fluoro-2-[5-alkyl-5-carboxylate-3-(1,3-oxazol-4-yl)]phenyl-1,3-oxazol-4-carboxylate esters as shown in general formula (I). General formula (I), wherein R1 and R2 are alkyl groups, and R2 is either an alkyl group or hydrogen; The method includes the following steps: S1: 4-Chloro-2-fluoro-3-vinylbenzoic acid reacts with tert-butyloxycarbonylhydrazine in the presence of a condensing agent and a catalyst, and then the protecting group is removed under acidic conditions to give the intermediate 4-chloro-2-fluoro-3-vinylbenzoylhydrazine. S2: The 4-chloro-2-fluoro-3-vinylbenzoylhydrazide obtained in step S1 is cyclized with N,N'-carbonyldiimidazole in the presence of a base to give the intermediate 5-chloro-2-vinyl-4-fluorophenyl-1,3-oxazol-5-one. S3: The 5-chloro-2-vinyl-4-fluorophenyl-1,3-oxazol-5-one obtained in step S2 undergoes an O-alkylation reaction with alkylating agent R1-X in the presence of a base to give the intermediate 5-chloro-4-fluoro-2-vinylphenyl-4-alkyl-1,3-oxazol-5-one, wherein R1 is an alkyl group and X is a halogen. S4: The 5-chloro-4-fluoro-2-vinylphenyl-4-alkyl-1,3-oxazol-5-one obtained in step S3 is subjected to olefin dihydroxylation-sodium periodate oxidative cleavage reaction in the presence of oxidant and catalyst to give intermediate 5-chloro-4-fluoro-2-formylphenyl-4-alkyl-1,3-oxazol-5-one. S5: The 5-chloro-4-fluoro-2-formylphenyl-4-alkyl-1,3-oxazol-5-one obtained in step S4 reacts with hydroxylamine in the presence of a base to give the intermediate 5-chloro-4-fluoro-2-(nitrosomethyl)phenyl-4-alkyl-1,3-oxazol-5-one. S6: The 5-chloro-4-fluoro-2-(nitrosomethyl)phenyl-4-alkyl-1,3-oxazol-5-one obtained in step S5 undergoes a 1,3-dipolar cycloaddition reaction with an acrylate compound in the presence of a base and an oxidizing agent to obtain the compound of general formula (I), wherein R2 is an alkyl group or hydrogen.

2. The method according to claim 1, characterized in that, In the compound of general formula (I), R1 is methyl, R2 is methyl, and the compound is methyl 5-chloro-4-fluoro-2-[5-methyl-5-methoxycarbonyl-3-(1,3-oxazol-4-yl)]phenyl-4-methyl-1,3-oxazol-5-carboxylic acid.

3. The method according to claim 1, characterized in that, In step S1, the condensing agent is dicyclohexylcarbodiimide, the catalyst is 4-dimethylaminopyridine, and the acidic conditions are provided by a hydrochloric acid solution of ethyl acetate. Preferably, step S1 specifically involves dissolving 4-chloro-2-fluoro-3-vinylbenzoic acid and tert-butyloxycarbonylhydrazine in dichloromethane, adding dicyclohexylcarbodiimide and 4-dimethylaminopyridine at 0°C, and reacting at room temperature; the reaction solution is washed successively with dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution, and sodium chloride aqueous solution, dried and concentrated, and then ethyl acetate-HCl is added and the reaction is stirred; the reaction solution is washed with sodium bicarbonate aqueous solution and concentrated to obtain 4-chloro-2-fluoro-3-vinylbenzoylhydrazine. More preferably, the molar ratio of 4-chloro-2-fluoro-3-vinylbenzoic acid, tert-butyloxycarbonylhydrazine, dicyclohexylcarbodiimide, and 4-dimethylaminopyridine is 1:1.2:1.4:0.2; the reaction temperature is room temperature, and the reaction time is 4 h; the concentration of HCl in ethyl acetate-HCl is 4.0 M, and the reaction time is 1 h.

4. The method according to claim 1, characterized in that, In step S2, the base is triethylamine; Preferably, step S2 specifically involves dissolving 4-chloro-2-fluoro-3-vinylbenzoylhydrazide in tetrahydrofuran, adding N,N'-carbonyldiimidazole and triethylamine at 0°C, and reacting at room temperature; concentrating the reaction solution, resolving it in ethyl acetate, washing it successively with dilute hydrochloric acid and saturated sodium bicarbonate aqueous solution, drying and concentrating it to obtain 5-chloro-2-vinyl-4-fluorophenyl-1,3-oxazol-5-one; More preferably, the molar ratio of 4-chloro-2-fluoro-3-vinylbenzoylhydrazide, N,N'-carbonyldiimidazole and triethylamine is 1:1.25:1; the reaction temperature is room temperature and the reaction time is 2 hours.

5. The method according to claim 1, characterized in that, In step S3, the alkylating agent is iodomethane, and the base is potassium carbonate; Preferably, step S3 specifically involves dissolving the 5-chloro-2-vinyl-4-fluorophenyl-1,3-oxazol-5-one obtained in step 2 with potassium carbonate in N,N-dimethylformamide, stirring, adding iodomethane, and reacting at room temperature; pouring the reaction solution into water, extracting with ethyl acetate, drying and concentrating to obtain 5-chloro-4-fluoro-2-vinylphenyl-4-methyl-1,3-oxazol-5-one; More preferably, the molar ratio of 5-chloro-2-vinyl-4-fluorophenyl-1,3-oxazol-5-one, potassium carbonate, and iodomethane is 1:1.5:1.15; the stirring time is 30 minutes; the reaction temperature is room temperature; and the reaction time is 1 hour.

6. The method according to claim 1, characterized in that, In step S4, the oxidant is sodium periodate and the catalyst is potassium osmium tetroxide dihydrate; Preferably, step S4 specifically involves dissolving the 5-chloro-4-fluoro-2-vinylphenyl-4-methyl-1,3-oxazol-5-one obtained in step 3 in a mixed solution of tetrahydrofuran and water, adding sodium periodate and potassium osmium tetroxide dihydrate, and reacting at room temperature; pouring the reaction solution into water, extracting with ethyl acetate, drying and concentrating, and then purifying by column chromatography to obtain 5-chloro-4-fluoro-2-formylphenyl-4-methyl-1,3-oxazol-5-one; More preferably, the molar ratio of 5-chloro-4-fluoro-2-vinylphenyl-4-methyl-1,3-oxazol-5-one, sodium periodate, and potassium osmium tetroxide dihydrate is 1:1.8:0.09; the volume ratio of tetrahydrofuran to water is 5:1; the reaction time is overnight; and the eluent used for column chromatography is petroleum ether:ethyl acetate = 3:

1.

7. The method according to claim 1, characterized in that, In step S5, the hydroxylamine is added in the form of hydroxylamine hydrochloride and sodium acetate; Preferably, step S5 specifically involves dissolving the 5-chloro-4-fluoro-2-formylphenyl-4-methyl-1,3-oxazol-5-one obtained in step 4 in ethanol with sodium acetate, adding an aqueous solution of hydroxylamine hydrochloride, and reacting at room temperature; pouring the reaction solution into water, extracting with ethyl acetate, drying and concentrating to obtain 5-chloro-4-fluoro-2-(nitrosomethyl)phenyl-4-methyl-1,3-oxazol-5-one; More preferably, the molar ratio of 5-chloro-4-fluoro-2-vinylphenyl-4-methyl-1,3-oxazol-5-one, sodium acetate, and hydroxylamine hydrochloride is 1:1.2:2; the reaction temperature is room temperature, and the reaction time is 2 hours.

8. The method according to claim 1, characterized in that, In step S6, the acrylate compound is methyl methacrylate, the base is triethylamine, and the oxidizing agent is sodium hypochlorite; Preferably, step S6 specifically involves dissolving 5-chloro-4-fluoro-2-(nitrosomethyl)phenyl-4-methyl-1,3-oxazol-5-one obtained in step 5 in dichloromethane, adding triethylamine and sodium hypochlorite aqueous solution at 0°C, and reacting at room temperature; pouring the reaction solution into water, extracting with ethyl acetate, drying and concentrating, and purifying by column chromatography to obtain compound (I); More preferably, the molar ratio of 5-chloro-4-fluoro-2-(nitrosomethyl)phenyl-4-alkyl-1,3-oxazol-5-one, methyl methacrylate, triethylamine, and sodium hypochlorite is 1.2:1:0.6:5; the reaction temperature is room temperature, and the reaction time is overnight; the eluent used for column chromatography is petroleum ether:ethyl acetate = 3:

1.

9. The compound prepared by the method according to any one of claims 1-8, characterized in that, The compound has the following structural formula: Ethyl 5-chloro-4-fluoro-2-[5-methyl-5-carboxy-3-(1,3-oxazol-4-yl)]phenyl-1,3-oxazol-4-carboxylate.

10. The compound prepared by the method according to any one of claims 1-8, characterized in that, The compound has the following structural formula: 5-Chloro-4-fluoro-2-[5-methyl-5-carboxy-3-(1,3-oxazol-4-yl)]phenyl-1,3-oxazol-4-carboxylic acid.

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