Preparation method of pyroxasulfone intermediate 5, 5-dimethyl-4, 5-dihydroisoxazole-3-thioformamidine hydrochloride

Abstract

The invention belongs to the technical field of organic synthesis, and mainly relates to a synthesis method of pyroxasulfone intermediate 5, 5-dimethyl-4, 5-dihydroisoxazole-3-thioformamidine hydrochloride, which comprises the following steps: reacting a compound IV with hydroxyurea under alkaline conditions to obtain a compound III; directly reacting the compound III with a chlorination reagent under an acidic condition without purification to obtain a compound II; reacting the compound II with thiourea in the presence of inorganic acid to obtain a compound I; according to the method provided by the invention, 3, 3-methyl dimethacrylate is used as a raw material, so that compared with 3, 3-ethyl dimethacrylate used in similar methods, the cost is lower, and the cyclization yield is higher; meanwhile, phosphoric acid is added as a catalyst, so that the generation of by-products is greatly reduced; finally, the compound I is prepared by directly reacting with thiourea in the presence of inorganic acid, the yield of a finished product is up to 86% or above, the purity can reach 98%, most of used solvents can be recycled and reused, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and mainly relates to the preparation of sulfonepyraclostrobin intermediate 5,5-dimethyl-4,5-dihydroisoxazole-3-thiocarboxamidine hydrochloride. Background Art

[0002] 5,5-Dimethyl-4,5-dihydroisoxazole-3-thiocarboxamidine hydrochloride I is a key intermediate in the synthesis of the herbicide pyraclostrobin, which is a pre-emergence soil treatment herbicide developed by Kumizu Chemical and Ibara Chemical Co., Ltd. of Japan that can act on most crop fields. In general, pyraclostrobin is basically harmless to organic matter in the environment, has low water solubility, and is less likely to pollute groundwater.

[0003] Studying the important synthetic intermediate I of sulfonepyraclostrobin and developing a synthetic process with high product content, good quality, high yield and environmental friendliness are of great significance for the further development of subsequent sulfonepyraclostrobin synthetic methods.

[0004] At present, there are three main methods for preparing 5,5-dimethyl-4,5-dihydroisoxazole-3-thiocarboxamidine hydrochloride: The first method is to synthesize dichloroformaldehyde oxime from glyoxylic acid in two steps, then react dichloroformaldehyde oxime with isobutylene to prepare 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole, and then react the compound with thiourea in the presence of hydrochloric acid to form a salt to prepare compound I. In this method, the intermediate dichloroformaldehyde oxime is unstable, easily deteriorated, highly corrosive, and a dangerous substance; the use of isobutylene gas has high requirements for the reactor and low yield; it is not conducive to large-scale industrial production.

[0005] .

[0006] The second method is to directly chlorinate 5,5-dimethyl-4,5-dihydroisoxazole, and then react the obtained compound with thiourea under acidic conditions to prepare 5,5-dimethyl-4,5-dihydroisoxazole-3-thiocarboxamidine hydrochloride. This method has a high yield, but the reaction conditions are relatively harsh and the solvent is difficult to apply.

[0007] .

[0008] The third method is to prepare 5,5-dimethyl-isoxazoline-3-one by reacting hydroxyurea with ethyl 3,3-dimethacrylate, and then chlorinating it with phosphorus oxychloride to obtain compound II, and finally reacting it with thiourea under acidic conditions to synthesize 5,5-dimethyl-4,5-dihydroisoxazole-3-thiocarboxamidine hydrochloride. The cyclization and chlorination yields of this method are low, and phosphorus oxychloride is used in the chlorination without any acid binding agent, resulting in more by-products and difficulty in industrialization.

[0009] . Summary of the invention

[0010] The technical problem to be solved by the present invention is to provide a method for preparing sulfonepyraclostrobin intermediate 5,5-dimethyl-4,5-dihydroisoxazole-3-thiocarboxamidine hydrochloride, which has relatively low cost, short reaction time, low operation difficulty, simple three waste treatment, high total yield and is suitable for industrial production.

[0011] The technical solution of the present invention to solve the above technical problems is as follows: A method for preparing sulfonepyraclostrobin intermediate 5,5-dimethyl-4,5-dihydroisoxazole-3-thiocarboxamidine hydrochloride comprises the following steps: (1) Compound IV reacts with hydroxyurea under alkaline conditions to obtain compound III; (2) Compound III is directly reacted with a chlorinating agent under acidic conditions without purification to obtain compound II; (3) Compound II reacts with thiourea in the presence of an inorganic acid to obtain compound I, i.e., the target product sulfonepyraclostrobin intermediate; the specific reaction structure is shown below: .

[0012] In the technical solution of the present invention, step (1) inevitably includes a post-processing step well known to those skilled in the art. Post-processing steps include filtration, extraction and drying.

[0013] Step (2) inevitably includes post-processing steps well known to those skilled in the art. Post-processing steps include filtration, extraction and drying.

[0014] Step (3) inevitably includes post-processing steps well known to those skilled in the art. Post-processing steps include filtration, washing, crystallization and drying.

[0015] Preferably, the base described in step (1) can be sodium methoxide or potassium methoxide; further, preferably, the base in step (1) is sodium methoxide. More preferably, the base in step (1) is a methanol solution of sodium methoxide. When sodium methoxide solid is used as a base to participate in the reaction, the entire reaction system will become complicated, thereby affecting the next step of the reaction.

[0016] Preferably, the molar ratio of compound IV to sodium methoxide in step (1) is 1:1.0-1:5.0; further, preferably, the molar ratio of compound IV to the methanol solution of sodium methoxide in step (1) is 1:1.5-1:3.0; further, the molar ratio of compound IV to the methanol solution of sodium methoxide in step (1) is 1:1.8-1:2.5.

[0017] Preferably, the molar ratio of compound IV to hydroxyurea in step (1) is 1:1.0 to 1:2.0; further, preferably, the molar ratio of compound IV to hydroxyurea in step (1) is 1:1.1 to 1:1.5; further, the molar ratio of compound IV to hydroxyurea in step (1) is 1:1.1 to 1:1.2. A small excess of hydroxyurea is required, which is conducive to the thorough reaction of the raw material 3,3-dimethacrylate methyl ester and shortens the reaction time.

[0018] Preferably, the organic solvent used in step (1) is methanol, and the selection of the solvent is related to the use of sodium methoxide as a base.

[0019] Preferably, the mass ratio of compound IV to solvent methanol in step (1) is 1:1.0~1:10; further, preferably, the mass ratio of compound IV to solvent methanol in step (1) is 1:2.0~1:8.0; further, the mass ratio of compound IV to solvent methanol in step (1) is 1:3.0~1:5.0.

[0020] Preferably, the reaction temperature in step (1) is 20-100°C; further, preferably, the reaction temperature in step (1) is 40-80°C; further, preferably, the reaction temperature in step (1) is 50-60°C.

[0021] Preferably, the reaction time of step (1) is 0.5-24 hours; further, the reaction time of step (1) is 3-5 hours. Compared with other methods for synthesizing compound III, the reaction time of step (1) is shorter and the output is higher within a certain period of time.

[0022] Preferably, the acid in step (2) may be an inorganic acid or an organic acid; further, preferably, the acid in step (2) is an inorganic acid; further, further, the acid in step (2) is phosphoric acid.

[0023] Preferably, the molar ratio of compound III to phosphoric acid in step (2) is 1:0.01 to 1:0.05. The amount of phosphoric acid as an additive plays a crucial role in the reaction. Only a suitable ratio of phosphoric acid can inhibit the formation of by-products in step (2). By controlling a suitable ratio of phosphoric acid, a compound II with very high purity can be obtained.

[0024] Preferably, the chlorination agent in step (2) is phosphorus pentachloride, phosphorus oxychloride, or phosphorus trichloride; further, preferably, the chlorination agent in step (2) is phosphorus pentachloride or phosphorus oxychloride; further, further, the chlorination agent in step (2) is phosphorus oxychloride.

[0025] Preferably, the molar ratio of compound III to phosphorus oxychloride in step (2) is 1:0.3-1:2.0; further, preferably, the molar ratio of compound III to phosphorus oxychloride in step (2) is 1:0.4-1:1.2; further, the molar ratio of compound III to phosphorus oxychloride in step (2) is 1:0.5-1:0.8.

[0026] Preferably, the organic solvent in step (2) is acetonitrile, carbon tetrachloride, chloroform, dichloromethane, or dichloroethane; further, the organic solvent in step (2) is carbon tetrachloride, chloroform, or dichloroethane; further, the organic solvent in step (2) is dichloroethane. Chlorine-containing organic solvents have a better effect on the chlorination reaction, and dichloroethane has the best effect on the reaction.

[0027] Preferably, the mass ratio of compound III to solvent dichloroethane in step (2) is 1:1.0-1:10; further, the mass ratio of compound III to solvent dichloroethane in step (2) is 1:3.0-1:8.0; further, the mass ratio of compound III to solvent dichloroethane in step (2) is 1:5.0-1:7.0.

[0028] Preferably, the reaction temperature in step (2) is 20-100°C; further, the reaction temperature in step (2) is 40-80°C; further, the reaction temperature in step (2) is 50-60°C.

[0029] Preferably, the reaction time in step (2) is 0.5 to 24 hours; further, the reaction time in step (2) is 1 to 3 hours. This step reacts very quickly, and compound III is completely consumed, which has great advantages in industrial production.

[0030] Preferably, the inorganic acid described in step (3) is sulfuric acid, nitric acid, or hydrochloric acid; further, the inorganic acid described in step (2) is sulfuric acid or hydrochloric acid; further, the inorganic acid described in step (2) is hydrochloric acid.

[0031] Preferably, the mass fraction of hydrochloric acid in step (3) is 5% to 38%; further, the mass fraction of hydrochloric acid in step (3) is 10% to 38%; further, the mass fraction of hydrochloric acid in step (3) is 20% to 30%.

[0032] Preferably, the molar ratio of compound II to the aqueous hydrochloric acid solution in step (3) is 1:0.1 to 1:1.5; further, the molar ratio of compound II to the aqueous hydrochloric acid solution in step (3) is 1:0.5 to 1:1.0; further, the molar ratio of compound II to the aqueous hydrochloric acid solution in step (3) is 1:0.7 to 1:0.9. The amount of aqueous hydrochloric acid solution is reduced, the reaction can proceed normally, and compound II can be basically consumed completely, but at the same time the water content in the system will also be reduced, and the product is easy to precipitate in the reaction system, which is not conducive to the subsequent product purification.

[0033] Preferably, the molar ratio of compound II to thiourea in step (3) is 1:1.0-1:2.0; further, the molar ratio of compound II to thiourea in step (3) is 1:1.2-1:1.8; further, the molar ratio of compound II to thiourea in step (3) is 1:1.4-1:1.6.

[0034] Preferably, the organic solvent in step (3) is acetonitrile or tert-butanol; further, the organic solvent in step (3) is acetonitrile.

[0035] Preferably, the mass ratio of compound II to solvent acetonitrile in step (3) is 1:1.0-1:10; further, the mass ratio of compound II to solvent acetonitrile in step (3) is 1:2.0-1:5.0; further, the mass ratio of compound II to solvent acetonitrile in step (3) is 1:3.0-1:4.0.

[0036] Preferably, the reaction temperature in step (3) is 20-100°C; further, the reaction temperature in step (3) is 30-50°C.

[0037] Preferably, the reaction time in step (3) is 0.5 to 24 hours; further, the reaction time in step (3) is 3 to 5 hours, which is conducive to industrial production.

[0038] The method provided by the present invention uses methyl 3,3-dimethacrylate as a raw material, which has lower cost and higher cyclization yield than ethyl 3,3-dimethacrylate used in similar methods; phosphorus oxychloride is chlorinated, and phosphoric acid is added as a catalyst, which greatly reduces the generation of by-products; finally, in the presence of an inorganic acid, it directly reacts with thiourea to prepare compound I, and the yield of the finished product is as high as more than 86%, more preferably more than 90%, more preferably more than 92%, and more preferably more than 95%; the purity can reach more than 90%, more preferably more than 95%, and more preferably more than 98%, and most of the used solvent can be recovered and reused, which is suitable for industrial production. DETAILED DESCRIPTION

[0039] The present invention is described below with reference to examples, but the present invention is not limited thereto. In the art, simple replacement or improvement made by technicians in the field to the present invention belongs to the technical solution protected by the present invention.

[0040] Embodiment 1: In a 1000ml dry four-necked bottle, add 500g of methanol, stir and drop 324g (1.8mol) of 30% sodium methoxide methanol solution, add 84g (1.1mol) of hydroxyurea in batches, continue stirring to completely dissolve the hydroxyurea, then stir and drop 114.14g (1.0mol) of 3,3-methyl dimethacrylate, and a white solid precipitates. After the addition is complete, the temperature is raised to 50°C for reaction. The raw material 3,3-methyl dimethacrylate disappears in liquid phase monitoring. The reaction solution is cooled to room temperature, filtered, and the filtrate is dried by rotation. 500g of water is added to dissolve the solid, and 30% hydrochloric acid aqueous solution is added dropwise with stirring in an ice bath to adjust the solution pH to 2. Extract with 300g of dichloroethane for 6 times, combine the organic phases, and spin dry to obtain 103.62g of white solid compound III with a yield of 90.0% and a purity of >99%.

[0041] The above 103.62g (0.9mol) of white solid compound III was transferred to a 1000ml dry four-necked bottle, 600g of dichloroethane was added, stirring was started, and 0.9g (0.009mol) of phosphoric acid was added dropwise under a nitrogen atmosphere. The color of the reaction solution will deepen, and the temperature was lowered to 0-5°C. 83g (0.54mol) of phosphorus oxychloride was slowly added dropwise. A large amount of white smoke was generated during the addition and heat was released violently. It was necessary to pay attention to control the temperature to prevent heat accumulation. After the addition was completed, the temperature was raised to 50°C for reaction. A large amount of white flocculent solids were generated during the process. The raw material compound III disappeared in the liquid phase monitoring. The reaction solution was cooled to room temperature, 500g of water was added to the reaction system to dissolve the solid, triethylamine was added dropwise under an ice bath to adjust the pH to 8, and 300g of dichloroethane was used for extraction 3 times. The organic phases were combined and spin-dried to obtain 120.22g of yellow liquid compound II with a yield of>99% and a purity of>99%. In this reaction, the use of phosphoric acid makes the reaction system very clean, with almost no by-products generated.

[0042] In a 1000ml dry four-necked bottle, add 96g (1.26mol) of thiourea and 400g of acetonitrile, add 88g (0.72mol) of 30% hydrochloric acid aqueous solution dropwise with stirring, stir at room temperature for 40 minutes, add 120.22g (0.9mol) of the above-mentioned yellow liquid compound II dropwise, heat to 40°C for reaction, liquid phase monitoring shows that the raw material compound II disappears, the reaction liquid is cooled to room temperature, filtered, the filtrate is spin-dried and then crystallized and washed with ethyl acetate to obtain 173.62g of white solid compound I with a yield of 92.5% and a purity of 98.0%.

[0043] Embodiment 2: In a 1000ml dry four-necked bottle, add 500g of methanol, stir and drop 360g (2.0mol) of 30% sodium methoxide methanol solution, add 84g (1.1mol) of hydroxyurea in batches, continue stirring to completely dissolve the hydroxyurea, then stir and drop 114.14g (1.0mol) of 3,3-methyl dimethacrylate, and a white solid precipitates. After the addition is complete, the temperature is raised to 60°C for reaction. The raw material 3,3-methyl dimethacrylate disappears in liquid phase monitoring. The reaction solution is cooled to room temperature, filtered, and the filtrate is dried by rotation. 500g of water is added to dissolve the solid, and 30% hydrochloric acid aqueous solution is added dropwise with stirring in an ice bath to adjust the solution pH to 2. Extract with 300g of dichloroethane for 6 times, combine the organic phases, and spin dry to obtain 105.92g of white solid compound III with a yield of 92.0% and a purity of >99%.

[0044] The above 105.92g (0.92mol) of white solid compound III was transferred to a 1000ml dry four-necked bottle, 600g of dichloroethane was added, stirring was started, and 1.8g (0.018mol) of phosphoric acid was added dropwise under a nitrogen atmosphere. The color of the reaction solution will deepen, and the temperature was lowered to 0-5°C. 99g (0.644mol) of phosphorus oxychloride was slowly added dropwise. A large amount of white smoke was generated during the addition and heat was released violently. It was necessary to pay attention to control the temperature to prevent heat accumulation. After the addition was completed, the temperature was raised to 60°C for reaction. A large amount of white flocculent solids were generated during the process. The raw material compound III disappeared in the liquid phase monitoring. The reaction solution was cooled to room temperature, 500g of water was added to the reaction system to dissolve the solid, triethylamine was added dropwise under an ice bath to adjust the pH to 8, and 300g of dichloroethane was used for extraction 3 times. The organic phases were combined and spin-dried to obtain 122.89g of yellow liquid compound II with a yield of>99% and a purity of>99%. In this reaction, the use of phosphoric acid makes the reaction system very clean, with almost no by-products generated.

[0045] In a 1000ml dry four-necked bottle, add 105g (1.38mol) of thiourea and 400g of acetonitrile, add 78g (0.644mol) of 30% hydrochloric acid aqueous solution dropwise with stirring, stir at room temperature for 40 minutes, add 122.89g (0.92mol) of the above-mentioned yellow liquid compound II dropwise, heat to 40°C for reaction, and the raw material compound II disappears after liquid phase monitoring. The reaction liquid is cooled to room temperature and filtered. The filtrate is spin-dried and then crystallized and washed with ethyl acetate to obtain 181.34g of white solid compound I with a yield of 94.5% and a purity of 96.8%.

[0046] Embodiment 3: In a 1000ml dry four-necked bottle, add 500g of methanol, stir and drop 324g (1.8mol) of 30% sodium methoxide methanol solution, add 91g (1.2mol) of hydroxyurea in batches, continue stirring to completely dissolve the hydroxyurea, then stir and drop 114.14g (1.0mol) of 3,3-methyl dimethacrylate, and a white solid precipitates. After the addition is complete, the temperature is raised to 50°C for reaction. The raw material 3,3-methyl dimethacrylate disappears after liquid phase monitoring. The reaction solution is cooled to room temperature, filtered, and the filtrate is dried by rotation. 500g of water is added to dissolve the solid, and 30% hydrochloric acid aqueous solution is added dropwise with stirring under an ice bath to adjust the solution pH to 2. Extract with 300g of dichloroethane for 6 times, combine the organic phases, and spin dry to obtain 103.62g of white solid compound III with a yield of 90.0% and a purity of 95.4%.

[0047] The above 103.62g (0.9mol) of white solid compound III was transferred to a 1000ml dry four-necked bottle, 600g of dichloroethane was added, stirring was started, and 4.4g (0.045mol) of phosphoric acid was added dropwise under a nitrogen atmosphere. The color of the reaction solution will deepen, and the temperature will be lowered to 0~5°C. 69g (0.45mol) of phosphorus oxychloride was slowly added dropwise. A large amount of white smoke will be generated during the addition, and heat will be released violently. It is necessary to pay attention to control the temperature to prevent heat accumulation. After the addition is completed, the temperature is raised to 50°C for reaction. A large amount of white flocculent solid will be generated during the process. The raw material compound III disappears in the liquid phase monitoring. The reaction solution is cooled to room temperature, 500g of water is added to the reaction system to dissolve the solid, triethylamine is added dropwise under an ice bath to adjust the pH to 8, and 300g of dichloroethane is used for extraction 3 times. The organic phases are combined and spin-dried to obtain 120.22g of yellow liquid compound II with a yield of> 99% and a purity of 94.6%. In this reaction, the use of phosphoric acid makes the reaction system very clean, with almost no by-products generated.

[0048] In a 1000ml dry four-necked bottle, add 96g (1.26mol) of thiourea and 400g of acetonitrile, add 131g (0.72mol) of 20% hydrochloric acid aqueous solution dropwise with stirring, stir at room temperature for 40 minutes, add 120.22g (0.9mol) of the above-mentioned yellow liquid compound II dropwise, heat to 40°C for reaction, liquid phase monitoring shows that the raw material compound II disappears, the reaction liquid is cooled to room temperature, filtered, the filtrate is spin-dried and then crystallized and washed with ethyl acetate to obtain 173.62g of white solid compound I with a yield of 92.6% and a purity of 96.4%.

[0049] Embodiment 4: In a 1000ml dry four-necked bottle, add 500g of methanol, stir and drop 324g (1.8mol) of 30% sodium methoxide methanol solution, add 91g (1.2mol) of hydroxyurea in batches, continue stirring to completely dissolve the hydroxyurea, then stir and drop 114.14g (1.0mol) of 3,3-methyl dimethacrylate, and a white solid precipitates. After the dropwise addition is completed, the temperature is raised to 50°C for reaction. The raw material 3,3-methyl dimethacrylate disappears after liquid phase monitoring. The reaction solution is cooled to room temperature, filtered, and the filtrate is spin-dried. 500g of water is added to dissolve the solid, and 30% hydrochloric acid aqueous solution is added dropwise with stirring under an ice bath to adjust the solution pH to 2. Extract with 300g of dichloroethane for 6 times, combine the organic phases, and spin-dry to obtain 103.62g of white solid compound III with a yield of 90.0% and a purity of 95.8%.

[0050] The above 103.62g (0.9mol) of white solid compound III was transferred to a 1000ml dry four-necked bottle, 600g of dichloroethane was added, stirring was started, 5.5g (0.045mol) of 30% hydrochloric acid aqueous solution was added dropwise under a nitrogen atmosphere, the temperature was lowered to 0~5°C, and 69g (0.45mol) of phosphorus oxychloride was slowly added dropwise. It is necessary to pay attention to control the temperature to prevent heat accumulation. After the addition is completed, the temperature is raised to 50°C for reaction. The raw material compound III disappears in liquid phase monitoring. The reaction liquid is cooled to room temperature, 500g of water is added to the reaction system to dissolve the solid, triethylamine is added dropwise under an ice bath to adjust the pH to 8, and 300g of dichloroethane is used for extraction 3 times. The organic phases are combined and spin-dried to obtain 120.22g of yellow liquid compound II with a yield of>99% and a purity of 83.3%. Some by-products are generated.

[0051] In a 1000ml dry four-necked bottle, add 96g (1.26mol) of thiourea and 400g of acetonitrile, add 131g (0.72mol) of 20% hydrochloric acid aqueous solution dropwise with stirring, stir at room temperature for 40 minutes, add 120.22g (0.9mol) of the above-mentioned yellow liquid compound II dropwise, heat to 40°C for reaction, liquid phase monitoring shows that the raw material compound II disappears, the reaction liquid is cooled to room temperature, filtered, the filtrate is spin-dried and then crystallized and washed with ethyl acetate to obtain 160.41g of white solid compound I with a yield of 85.5% and a purity of 80.6%.

[0052] Embodiment 5: In a 1000ml dry four-necked bottle, 500g of methanol was added, and 324g (1.8mol) of 30% sodium methoxide methanol solution was added dropwise with stirring. 91g (1.2mol) of hydroxyurea was added in batches, and stirring was continued to dissolve the hydroxyurea completely. Then 114.14g (1.0mol) of 3,3-dimethacrylate was added dropwise with stirring, and a white solid precipitated. After the addition was completed, the temperature was raised to 50°C for reaction. The raw material 3,3-dimethacrylate disappeared after liquid phase monitoring. The reaction solution was cooled to room temperature, filtered, and the filtrate was dried by rotation. 500g of water was added to dissolve the solid. 30% hydrochloric acid aqueous solution was added dropwise with stirring under an ice bath to adjust the solution pH to 2. The solution was extracted 6 times with 300g of dichloroethane. The organic phases were combined and dried to obtain 103.62g of white solid compound III with a yield of 90.0% and a purity of 95.7%.

[0053] The above 103.62g (0.9mol) of white solid compound III was transferred to a 1000ml dry four-necked bottle, 600g of dichloroethane was added, stirring was started, no additives were added, the temperature was lowered to 0~5°C, 69g (0.45mol) of phosphorus oxychloride was slowly added dropwise, and the temperature should be controlled to prevent heat accumulation. After the addition was completed, the temperature was raised to 50°C for reaction, and the liquid phase was monitored. The raw materials could not react completely even if the time was extended. The reaction liquid was cooled to room temperature, 500g of water was added to the reaction system to dissolve the solid, triethylamine was added dropwise in an ice bath to adjust the pH to 8, and 300g of dichloroethane was used for extraction 3 times. The organic phases were combined and dried to obtain 120.22g of yellow liquid compound II, with a yield of>99% and a purity of 50%. The crude product contained unreacted raw materials and generated by-products, so the purity was low. When phosphoric acid and hydrochloric acid are used as additives, the hydrolysis of the chlorination reagent phosphorus oxychloride can be inhibited, the formation of by-products can be reduced, and the reaction effect is better. Phosphoric acid is weaker in acidity than hydrochloric acid, which avoids damage to other substances in the system. Therefore, phosphoric acid has the best reaction effect as an additive.

[0054] In a 1000ml dry four-necked bottle, add 96g (1.26mol) of thiourea and 400g of acetonitrile, add 131g (0.72mol) of 20% hydrochloric acid aqueous solution dropwise with stirring, stir at room temperature for 40 minutes, add 120.22g (0.9mol) of the above-mentioned yellow liquid compound II dropwise, heat to 40°C for reaction, liquid phase monitoring shows that the raw material compound II disappears, the reaction liquid is cooled to room temperature, filtered, the filtrate is spin-dried and then crystallized and washed with ethyl acetate to obtain 113.2g of white solid compound I with a yield of 60.9% and a purity of 70.2%.

Claims

1. A method for synthesizing 5,5-dimethyl-4,5-dihydroisoxazole-3-thiocarboxamidine hydrochloride as a sulfonepyraclostrobin intermediate, comprising the following steps: (1) Compound IV reacts with hydroxyurea under alkaline conditions to obtain compound III; (2) Compound III reacts with a chlorinating agent under acidic conditions to obtain compound II; (3) Compound II reacts with thiourea in the presence of an inorganic acid to obtain compound I, i.e., the target product sulfonepyraclostrobin intermediate; the specific reaction structure is shown below: 。 2. The method for preparing a sulfonepyraclostrobin intermediate according to claim 1, characterized in that: In step (1), the molar ratio of compound IV to hydroxyurea is 1:1.0-1:2.0; the alkaline condition is an alcohol solution of sodium methoxide, and the alcohol solution is any one of methanol, ethanol, propanol and butanol, wherein the molar ratio of compound IV to sodium methoxide is 1:1.0-1:5.

0.

3. The method for preparing a sulfonepyraclostrobin intermediate according to claim 1, characterized in that: The chlorination reagent described in step (2) is phosphorus oxychloride, wherein the molar ratio of compound III to phosphorus oxychloride is 1:0.3-2.

0.

4. The method for preparing a sulfonepyraclostrobin intermediate according to claim 3, characterized in that: The acidic environment is an acidic environment after adding phosphoric acid, wherein the molar ratio of compound III to phosphoric acid is 1:0.01-1:0.

05.

5. The method for preparing a sulfonepyraclostrobin intermediate according to claim 1, characterized in that: During the reaction of step (2), a solvent is added, wherein the solvent includes dichloroethane and chloroform; the reaction temperature is 20-100° C.; and the reaction time is 0.5-24 h.

6. The method for preparing a sulfonepyraclostrobin intermediate according to claim 1, characterized in that: The mass fraction of hydrochloric acid in step (3) is 5% to 38%; the molar ratio of compound II, hydrochloric acid and thiourea is 1:0.1 to 1.5:1.0 to 12.

0.

7. The method for preparing a sulfonepyraclostrobin intermediate according to claim 1, characterized in that: The step (3) further comprises a reaction solvent, wherein the solvent comprises acetonitrile; the reaction temperature is 20-100° C.; and the reaction time is 0.5-24 h.

Images