Synthesis process of isoxazoline derivative

Abstract

The invention provides a synthesis process of an isoxazoline derivative, which comprises the following steps: (1) carrying out reaction on ethyl difluoroacetoacetate and methylhydrazine in a solvent to obtain an intermediate product 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole; (2) reacting 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole, formaldehyde and 5, 5-dimethyl-4, 5-dihydroisoxazole-3-sulfenyl methylimidazole salt in an aqueous solution in the presence of inorganic alkali, so as to obtain an intermediate A; (3) reacting the intermediate A with a difluoromethylation reagent in the presence of a solvent and alkali to prepare an intermediate B; and (4) in the presence of hydrogen peroxide, a solvent and sodium tungstate, carrying out oxidation reaction on the intermediate B to prepare the isoxazoline derivative C. The synthesis process is simple to operate, the raw materials are simple and easy to obtain, the product yield is relatively high, the emission of three wastes is less, and the method is suitable for process production.

Description

Technical Field

[0001] The invention belongs to the technical field of herbicides, and particularly relates to a synthesis process of isoxazoline derivatives. Background Art

[0002] Isoxazoline compounds are a class of compounds with excellent biological activity and can be used as herbicides. Chinese patent CN111574509A discloses an isoxazoline derivative, wherein compound C has a good control effect on broadleaf weeds (such as velvetleaf, Amaranthus retroflexus, and Caragana chinensis) and gramineous weeds (such as crabgrass, barnyard grass, and foxtail grass), is safe for crops, and has a better control effect on weeds than commercial herbicides and isoxazoline compounds with similar structures such as sulfonepyraclostrobin, and has excellent application prospects.

[0003] The current synthesis process of compound C is as follows:

[0004]

[0005] The specific preparation method comprises the following steps:

[0006] (1) reacting ethyl difluoroacetoacetate with methylhydrazine to obtain an intermediate product, 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole;

[0007] (2) reacting the intermediate 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole with ClCF2CO2Me in the presence of a solvent and a base to obtain intermediate I;

[0008] (3) in the presence of the first acid catalyst and the second acid catalyst, the intermediate I reacts with formaldehyde to generate the intermediate II;

[0009] (4) In the presence of an inorganic base, intermediate II reacts with 5,5-dimethyl-4,5-dihydroisoxazole-3-thiomethylimidazolium salt to obtain intermediate III;

[0010] (5) In the presence of hydrogen peroxide, a solvent and sodium tungstate, the intermediate III is subjected to an oxidation reaction to obtain an isoxazoline derivative C.

[0011] However, the synthesis process of the above compound C is complicated and has a low yield, which is not suitable for industrial production. Summary of the invention

[0012] The purpose of the present invention is to provide a synthesis process of isoxazoline derivatives to solve the problems of complex synthesis process and low product yield of the above-mentioned isoxazoline derivatives (that is, compound C).

[0013] In order to achieve the above object, the present invention provides the following technical solutions:

[0014] A synthesis process of an isoxazoline derivative comprises the following steps:

[0015] (1) reacting ethyl difluoroacetoacetate and methylhydrazine in a solvent to obtain an intermediate product, 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole;

[0016] (2) In an aqueous solution, in the presence of an inorganic base, 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole, formaldehyde and 5,5-dimethyl-4,5-dihydroisoxazole-3-thiomethylimidazolium salt react to prepare intermediate A;

[0017] (3) reacting intermediate A with a difluoromethylating agent in the presence of a solvent and a base to obtain intermediate B;

[0018] (4) In the presence of hydrogen peroxide, a solvent and sodium tungstate, the intermediate B is subjected to an oxidation reaction to obtain an isoxazoline derivative C.

[0019] Reaction equation of the present invention is as follows:

[0020]

[0021] Preferably, in step (1), the reaction temperature is 20-80° C., the reaction time is 12-20 h, and the solvent is one or more of ethanol, methyl tert-butyl ether, and tetrahydrofuran.

[0022] More preferably, in step (1), the reaction temperature is 20° C. and the solvent is tetrahydrofuran.

[0023] Preferably, in step (1), the molar ratio of ethyl difluoroacetoacetate to methylhydrazine is 1:(1-2).

[0024] Preferably, in step (2), the inorganic base is one or more of sodium hydroxide, potassium hydroxide, and sodium carbonate, and the reaction temperature is 35-50°C.

[0025] More preferably, in step (2), the inorganic base is sodium hydroxide.

[0026] Preferably, in step (2), the molar ratio of the inorganic base, 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole, formaldehyde and 5,5-dimethyl-4,5-dihydroisoxazole-3-thiomethimide salt is 1:(0.3-0.8):1:(0.3-0.8).

[0027] Preferably, in step (3), the solvent is one or more of tetrahydrofuran, methanol, and acetonitrile; and the base is one or more of potassium carbonate, potassium hydroxide, and sodium carbonate.

[0028] More preferably, in step (3), the solvent is acetonitrile and the base is potassium hydroxide.

[0029] Preferably, in step (3), the difluoromethylating agent is one or more of ethyl bromodifluoroacetate, ethyl chlorodifluoroacetate, and sodium chlorodifluoroacetate.

[0030] Preferably, in step (3), the molar ratio of intermediate A to difluoromethylating agent is (0.8-1.2): (0.8-1.2).

[0031] More preferably, in step (3), the molar ratio of intermediate A to difluoromethylating agent is 1:1.

[0032] Preferably, in step (4), the molar ratio of intermediate B, hydrogen peroxide and sodium tungstate is 1:2:(0.01-0.2).

[0033] More preferably, in step (4), the molar ratio of intermediate B, hydrogen peroxide and sodium tungstate is 1:2:0.2.

[0034] Preferably, in step (4), the temperature of the oxidation reaction is 20 to 60°C.

[0035] Compared with the prior art, the advantages and beneficial effects of the present invention are:

[0036] 1. The present invention simplifies the process flow, and reacts 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole, formaldehyde and 5,5-dimethyl-4,5-dihydroisoxazole-3-thiomethylimidazole salt simultaneously in an aqueous solution to generate intermediate A, which not only shortens the synthesis time, but also reduces the occurrence of side reactions and improves the yield of the target product.

[0037] 2. The solvents and raw materials used in the present invention are low-toxic reagents, which are easy to obtain, convenient for post-processing, and environmentally friendly.

[0038] 3. The process steps of the present invention are simple, and it is easier to transfer from laboratory scale to industrial production. The preparation process is scalable and suitable for process production.

[0039] 4. The isoxazoline derivative compound C prepared by the present invention has a higher yield.

[0040] 5. The preparation process of the present invention has less three wastes discharged. In step (2) of the present invention, an aqueous solution is used for reaction. Since water is used as the main solvent, the dependence on organic solvents is reduced, thereby reducing the cost and complexity of solvent recovery and treatment, which not only saves resources, but also reduces environmental pollution that may be caused by improper solvent treatment. The present invention uses low-volatile reagents to reduce the generation of waste gas. The present invention improves the yield and selectivity of the target product by accurately controlling the reaction conditions, and reduces the residue of unreacted raw materials and by-products, which not only improves resource utilization, but also reduces the generation of waste residues. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 This is the H NMR spectrum of the intermediate product 5-(hydroxy)-1-methyl-3-(difluoromethyl)-1H-pyrazole;

[0042] Figure 2 is the H NMR spectrum of intermediate A;

[0043] Figure 3 is the H NMR spectrum of intermediate B;

[0044] Figure 4 This is the H NMR spectrum of isoxazoline derivative C. DETAILED DESCRIPTION

[0045] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. 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.

[0046] The reaction equation for the synthesis of the intermediate product 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole is as follows:

[0047]

[0048] Example 1

[0049] This embodiment provides a synthesis process of 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole, comprising the following steps:

[0050] Ethyl difluoroacetoacetate (CAS: 352-24-9) (83.06 g, 99%, 0.5 mol) was dissolved in anhydrous ethanol (200 mL), and 86.25 g of methylhydrazine aqueous solution (40 wt% aqueous solution, 0.75 mol) was added, and the mixture was reacted at 20°C for 4 h, and then the mixture was heated to 80°C for 12 h. After the reaction, saturated sodium bicarbonate was added to neutralize the reaction solution, the solvent was evaporated under reduced pressure, and the mixture was dissolved in ethyl acetate (150 mL), washed with water, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to obtain 42.8 g of a light yellow solid with a content of 99% and a yield of 58.0%.

[0051] Figure 1 is the H NMR spectrum of 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole, from Figure 1 It can be seen that 1HNMR (300MHz, DMSO-d6)δ11.36(s,1H),6.70(t,J=54.8Hz,1H),5.55(s,1H),3.54(s,3H). This proves that the intermediate product 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole has been successfully synthesized.

[0052] Example 2

[0053] This embodiment provides a synthesis process of 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole, comprising the following steps:

[0054] Ethyl difluoroacetoacetate (CAS: 352-24-9) (83.06 g, 99%, 0.5 mol) was dissolved in methyl tert-butyl ether (200 mL), and 86.25 g of methyl hydrazine aqueous solution (40 wt% aqueous solution, 0.75 mol) was added, and the mixture was reacted at 20°C for 12 h. After the reaction, saturated sodium bicarbonate was added to neutralize the reaction solution, and the solvent was evaporated under reduced pressure, and the mixture was dissolved in ethyl acetate (150 mL), washed with water, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 64.0 g of a light yellow solid with a content of 97% and a yield of 84.0%.

[0055] Example 3

[0056] This embodiment provides a synthesis process of 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole, comprising the following steps:

[0057] Ethyl difluoroacetoacetate (CAS: 352-24-9) (83.06 g, 99%, 0.5 mol) was dissolved in tetrahydrofuran (200 mL), and 86.25 g of methylhydrazine aqueous solution (40 wt% aqueous solution, 0.75 mol) was added, and the mixture was reacted at 20°C for 12 h. After the reaction, saturated sodium bicarbonate was added to neutralize the reaction solution, and the solvent was evaporated under reduced pressure, and the mixture was dissolved in ethyl acetate (150 mL), washed with water, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to obtain 55.3 g of a light yellow solid with a content of 95% and a yield of 71.0%.

[0058] It can be seen from Examples 1 to 3 that the yields of the intermediate product 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole are different when different solvents are used for the reaction, among which the yield is the highest when methyl tert-butyl ether is used as the solvent for the reaction.

[0059] The reaction equation for the synthesis of intermediate A is as follows:

[0060]

[0061] Example 4

[0062] This embodiment provides a synthesis process of intermediate A, comprising the following steps:

[0063] To the reaction bottle, add the prepared 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole (74 g, 99%, 0.5 mol), 200 g of water, KOH (56 g, 99%, 1.0 mol), and then add an aqueous solution (37 wt%) containing 81 g (1 mol) of formaldehyde, and stir at room temperature. HPLC detection shows that the 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole has reacted completely; then add 5,5-dimethyl-4,5-dihydroisoxazole -3-Mercaptomethylimidazole salt (CAS: 869002-97-1) (110 g, 95%, 0.5 mol), stirred at 40 ° C for reaction, HPLC detected that 5,5-dimethyl-4,5-dihydroisoxazole-3-mercaptomethylimidazole salt had reacted completely, stopped the reaction, added hydrochloric acid and water to the reaction solution, adjusted pH = 7; then filtered, rinsed the filter cake twice with water; the filter cake was placed in a 45 ° C oven for drying, and after drying, it was taken out and weighed 100 g, with a content of 95% and a yield of 65%.

[0064] Figure 2 is the nuclear magnetic hydrogen spectrum of intermediate A. It can be seen from the figure that 1 H NMR (300 MHz, DMSO-d6) δ11.24 (s, 1H), 6.80 (t, J = 53.9 Hz, 1H), 4.12 (s, 2H), 3.55 (t, J = 1.2 Hz, 3H), 2.87 (s, 2H), 1.31 (s, 6H). This proves that intermediate A has been successfully synthesized.

[0065] Example 5

[0066] This embodiment provides a synthesis process of intermediate A, comprising the following steps:

[0067] Under ice bath, weigh Na2CO3 (106 g, 99%, 1.0 mol) and slowly add it into 200 g water. After stirring to dissolve, add the prepared 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole (74 g, 99%, 0.5 mol) into the alkali solution. Then, an aqueous solution (37 wt%) containing 81 g (1 mol) of formaldehyde was slowly added, and the mixture was stirred at room temperature. HPLC detected that 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole had reacted completely. Then, 5,5-dimethyl-4,5-dihydroisoxazole-3-mercaptomethylimidazole salt (CAS: 869002-97-1) (110 g, 95%, 0.5 mol) was added, and the mixture was stirred and reacted at 40° C. HPLC detected that 5,5-dimethyl-4,5-dihydroisoxazole-3-mercaptomethylimidazole salt had reacted completely. The reaction was stopped, and hydrochloric acid and water were added to the reaction solution to adjust the pH to 7. Then, the mixture was filtered and the filter cake was rinsed twice with water. The filter cake was dried in an oven at 45° C. After drying, the cake was taken out and weighed 86.7 g, with a content of 94% and a yield of 56%.

[0068] Example 6

[0069] This embodiment provides a synthesis process of intermediate A, comprising the following steps:

[0070] To the reaction bottle, the prepared 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole (74 g, 99%, 0.5 mol), 200 g of water, and NaOH (40 g, 99%, 1.0 mol) were added, and then an aqueous solution (37 wt%) containing 81 g (1 mol) of formaldehyde was added, and stirred at room temperature. HPLC detected that the 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole had reacted completely; then 5,5-dimethyl-4,5-dihydroisoxane was added. 5,5-dimethyl-4,5-dihydroisoxazole-3-mercaptomethylimidazole salt (CAS: 869002-97-1) (110 g, 95%, 0.5 mol) was stirred at 40 ° C for reaction. HPLC detected that 5,5-dimethyl-4,5-dihydroisoxazole-3-mercaptomethylimidazole salt had reacted completely, and the reaction was stopped. Hydrochloric acid and water were added to the reaction solution to adjust the pH to 7; then the solution was filtered and the filter cake was washed twice with water; the filter cake was placed in a 45 ° C oven for drying, and after drying, it was taken out and weighed 110 g, with a content of 95% and a yield of 72%.

[0071] The reaction equation for the synthesis of intermediate B is as follows:

[0072]

[0073] Example 7

[0074] This embodiment provides a synthesis process of intermediate B, comprising the following steps:

[0075] The prepared intermediate A (153 g, 95%, 0.5 mol) and 56 g KOH (99%, 1.0 mol) were added in sequence to a reaction bottle equipped with a stirrer, and then 1 L of acetonitrile was added, and BrCF2CO2Et (CAS: 667-27-6) (101 g, 99%, 0.5 mol) was slowly added dropwise for 1 h; then the temperature was raised to reflux, and the reaction was detected by HPLC until the end; the solvent was concentrated, the aqueous phase was extracted with ethyl acetate, the organic phase was collected and evaporated under reduced pressure, and petroleum ether was added for pulping to obtain 89 g of intermediate B with a content of 96% and a yield of 50%.

[0076] Figure 3 is the nuclear magnetic hydrogen spectrum of intermediate B. It can be seen from the figure that 1 H NMR (400 MHz, DMSO-d6) δ7.46–7.14 (m, 1H), 7.09–6.87 (m, 1H), 4.75 (s, 2H), 3.79 (s, 3H), 3.15 (s, 2H), 1.42 (s, 6H). This proved that intermediate B had been successfully synthesized.

[0077] Example 8

[0078] This embodiment provides a synthesis process of intermediate B, comprising the following steps:

[0079] The prepared intermediate A (153 g, 95%, 0.5 mol) and 106 g Na2CO3 (99%, 1.0 mol) were added in sequence to a reaction bottle equipped with a stirring bar, and then 1 L of tetrahydrofuran was added, and BrCF2CO2Et (CAS: 667-27-6) (101 g, 99%, 0.5 mol) was slowly added dropwise for 1 hour; then the temperature was raised to reflux and the reaction was detected by HPLC until the end; the solvent was concentrated, the aqueous phase was extracted with ethyl acetate, the organic phase was collected and evaporated under reduced pressure, and petroleum ether was added for pulping to obtain 80 g of intermediate B with a content of 96% and a yield of 45%.

[0080] Example 9

[0081] This embodiment provides a synthesis process of intermediate B, comprising the following steps:

[0082] The prepared intermediate A (153 g, 95%, 0.5 mol) and 56 g KOH (99%, 1.0 mol) were added in sequence to a reaction bottle equipped with a stirrer, and then 1 L of acetonitrile was added, and ClCF2CO2Et (CAS: 383-62-0) (80 g, 99%, 0.5 mol) was slowly added dropwise for 1 h; then the temperature was raised to reflux, and the reaction was detected by HPLC until the end; the solvent was concentrated, the aqueous phase was extracted with ethyl acetate, the organic phase was collected and evaporated under reduced pressure, and petroleum ether was added for pulping to obtain 100.6 g of intermediate B with a content of 95% and a yield of 56%.

[0083] Example 10

[0084] This embodiment provides a synthesis process of intermediate B, comprising the following steps:

[0085] The prepared intermediate A (153 g, 95%, 0.5 mol) and 56 g KOH (99%, 1.0 mol) were added in sequence to a reaction bottle equipped with a stirrer, and then 1 L of acetonitrile was added, and ClF2CO2Na (CAS: 1895-39-2) (77 g, 99%, 0.5 mol) was slowly added dropwise for 1 h; then the temperature was raised to reflux and the reaction was detected by HPLC until the end; the solvent was concentrated, the aqueous phase was extracted with ethyl acetate, the organic phase was collected and evaporated under reduced pressure, and petroleum ether was added for pulping to obtain 71 g of intermediate B with a content of 96% and a yield of 40%.

[0086] The reaction equation for synthesizing isoxazoline derivative C is as follows:

[0087]

[0088] Embodiment 11

[0089] This embodiment provides a method for preparing an isoxazoline derivative C, comprising the following steps:

[0090] Add the prepared intermediate B (177g, 96%, 0.5mol), 1L methanol, sodium tungstate (16.5g, 99%, 0.05mol) to the reaction bottle, stir at 20℃ for 1h, then heat to 60℃, slowly drop hydrogen peroxide (113g, 30wt% aqueous solution, 1.0mol), keep warm for 30min after dripping, and the reaction is complete by HPLC detection; add water, cool to 5℃, and a large amount of white solid precipitates. Quench the excess hydrogen peroxide in the filtrate with 20% sodium sulfite aqueous solution until the starch potassium iodide test paper does not turn blue, and filter with suction. The filter cake is the isoxazoline derivative C, which is weighed and measured after drying. The product mass is 184g, the content is 91%, and the yield is 90%.

[0091] Figure 4 is the NMR hydrogen spectrum of the product isoxazoline derivative C, from Figure 4 It can be seen that 1 H NMR (400 MHz, Chloroform-d) δ7.00–6.60 (m, 2H), 4.59 (s, 2H), 3.83 (s, 3H), 3.10 (s, 2H), 1.51 (s, 6H). This proved that the product isoxazoline derivative C had been successfully synthesized.

[0092] Example 12

[0093] This embodiment provides a method for preparing an isoxazoline derivative C, comprising the following steps:

[0094] Add the prepared intermediate B (177g, 96%, 0.5mol), 1L methanol, sodium tungstate (33g, 99%, 0.1mol) to the reaction bottle, stir at 20℃ for 1h, then heat to 60℃ and reflux, slowly drop hydrogen peroxide (113g, 30wt% aqueous solution, 1.0mol), keep warm for 30min after dropping, and the reaction is complete by HPLC detection; add water, cool to 5℃, and a large amount of white solid precipitates. Quench the excess hydrogen peroxide in the filtrate with 20% sodium sulfite aqueous solution until the starch potassium iodide test paper does not turn blue, and filter with suction. The filter cake is the isoxazoline derivative C, which is weighed and measured after drying. The product mass is 193g, the content is 89%, and the yield is 92%.

[0095] Example 13

[0096] This embodiment provides a method for preparing an isoxazoline derivative C, comprising the following steps:

[0097] Add the prepared intermediate B (177g, 96%, 0.5mol), 1L methanol, sodium tungstate (33g, 99%, 0.1mol) to the reaction bottle, stir at 20℃ for 1h, slowly add hydrogen peroxide (113g, 30wt% aqueous solution, 1.0mol), keep warm for 10h after the dripping, and the reaction is completed by HPLC detection; add water, cool to 5℃, and a large amount of white solid precipitates. Quench the excess hydrogen peroxide in the filtrate with 20% sodium sulfite aqueous solution until the starch potassium iodide test paper does not turn blue, and filter with suction. The filter cake is the isoxazoline derivative C, which is weighed and measured after drying. The product mass is 182g, the content is 90%, and the yield is 88%.

[0098] Comparative Example 1

[0099] The isoxazoline derivative C is prepared according to the process in the background technology, which specifically includes the following steps:

[0100] (1) Ethyl difluoroacetoacetate (83.06 g, 0.5 mol) was dissolved in anhydrous ethanol (200 mL), placed in an ice bath, and a methylhydrazine aqueous solution (40%, 86.25 g, 0.75 mol) was added dropwise. The mixture was reacted at room temperature for 4 h, and then heated to 80°C and reacted overnight. The solvent was evaporated under reduced pressure, and the mixture was dissolved in ethyl acetate (150 mL), and the separated liquid was washed with water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 42.90 g of 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole as a light yellow solid, with a yield of 58.0%.

[0101] (2) 5-Hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole (0.74 g, 5 mmol) was dissolved in acetonitrile (50 mL), potassium carbonate (2.07 g, 15 mmol) was added, the temperature was raised to 80°C, methyl chlorodifluoroacetate (1.08 g, 7.5 mmol) was added dropwise, the temperature was raised to 100°C, stirred and reacted for 12 h, the acetonitrile was removed, the mixture was dissolved in ethyl acetate (60 mL), and the separated liquid was washed with water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 0.50 g of light yellow liquid intermediate I, with a yield of 50.5%.

[0102] (3) Dissolve intermediate I (0.50 g, 2.5 mmol) in hydrochloric acid (36%, 15 mL), add concentrated sulfuric acid (98%, 0.5 mL) dropwise, stir for 5 minutes, add paraformaldehyde (0.10 g, 3.5 mmol), heat to 80°C and react for 8 h. Dilute with water (100 mL), extract with ethyl acetate (60 mL). Dry the organic phase with anhydrous sodium sulfate, evaporate the solvent to obtain 0.50 g of light yellow liquid intermediate II, yield: 81.1%.

[0103] (4) Dissolve intermediate II (0.50 g, 2.0 mmol) and 5,5-dimethyl-4,5-dihydroisoxazol-3-yl isothiourea hydrobromide (0.62 g, 2.4 mmol) in acetonitrile (30 mL), add potassium carbonate (1.10 g, 8.0 mmol), and stir at room temperature for 12 h. Remove acetonitrile, dissolve in ethyl acetate (60 mL), and wash the separated liquid with water. Dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and obtain 0.38 g of yellow liquid intermediate III, yield: 55.9%.

[0104] (5) Intermediate III (0.38 g, 1.1 mmol) was dissolved in dichloromethane (30 mL), stirred at room temperature, and then m-CPBA (0.51 g, 2.2 mmol) was added to the mixture to react for 5 h. The reaction was stopped, and then washed with saturated aqueous sodium bisulfite solution (200 mL) and saturated aqueous sodium bicarbonate solution (200 mL) in sequence, extracted with dichloromethane (100 mL), and dried over anhydrous sodium sulfate. The organic phases were combined and the solvent was removed under reduced pressure. The mixture was purified by column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain 0.18 g of white solid isoxazoline derivative C. Yield: 44.0%.

[0105] The synthesis of isoxazoline derivative C in Comparative Example 1 requires five steps of reaction, and the total yield is 5.8%. However, the process for synthesizing isoxazoline derivative C in the present invention requires only four steps, and the yield of the overall process is 31%. The yield of the product in the present invention is significantly higher than the yield of the product in Comparative Example 1.

[0106] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A synthesis process for an isoxazoline derivative, characterized in that: The following steps are involved: (1) reacting ethyl difluoroacetoacetate and methylhydrazine in a solvent to obtain an intermediate product, 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole; (2) In an aqueous solution, in the presence of an inorganic base, 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole, formaldehyde and 5,5-dimethyl-4,5-dihydroisoxazole-3-thiomethylimidazolium salt react to prepare intermediate A; (3) reacting intermediate A with a difluoromethylating agent in the presence of a solvent and a base to obtain intermediate B; (4) In the presence of hydrogen peroxide, a solvent and sodium tungstate, the intermediate B is subjected to an oxidation reaction to obtain an isoxazoline derivative C.

2. A synthesis process for an isoxazoline derivative according to claim 1, characterized in that: In step (1), the reaction temperature is 20-80° C., the reaction time is 12-20 h, and the solvent is one or more of ethanol, methyl tert-butyl ether, and tetrahydrofuran.

3. A synthesis process for an isoxazoline derivative according to claim 1, characterized in that: In step (1), the molar ratio of ethyl difluoroacetoacetate to methylhydrazine is 1:(1-2).

4. A synthesis process for an isoxazoline derivative according to claim 1, characterized in that: In step (2), the inorganic base is one or more of sodium hydroxide, potassium hydroxide, and sodium carbonate, and the reaction temperature is 35-50°C.

5. A synthesis process for an isoxazoline derivative according to claim 1, characterized in that: In step (2), the molar ratio of the inorganic base, 5-hydroxy-1-methyl-3-difluoromethyl-1H-pyrazole, formaldehyde and 5,5-dimethyl-4,5-dihydroisoxazole-3-thiomethimide salt is 1:(0.3-0.8):1:(0.3-0.8).

6. A process for synthesizing an isoxazoline derivative according to claim 1, characterized in that: In step (3), the solvent is one or more of tetrahydrofuran, methanol, and acetonitrile; and the base is one or more of potassium carbonate, potassium hydroxide, and sodium carbonate.

7. A process for synthesizing an isoxazoline derivative according to claim 1, characterized in that: In step (3), the difluoromethylating agent is one or more of ethyl bromodifluoroacetate, ethyl chlorodifluoroacetate, and sodium chlorodifluoroacetate.

8. A process for synthesizing an isoxazoline derivative according to claim 1, characterized in that: In step (3), the molar ratio of intermediate A to difluoromethylation reagent is (0.8-1.2): (0.8-1.2).

9. A process for synthesizing an isoxazoline derivative according to claim 1, characterized in that: In step (4), the molar ratio of intermediate B, hydrogen peroxide and sodium tungstate is 1:2:(0.01-0.2).

10. The synthesis process of an isoxazoline derivative according to claim 1, characterized in that: In step (4), the temperature of the oxidation reaction is 20 to 60°C.

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