Method for synthesizing pyroxasulfone intermediate

Abstract

The invention relates to the technical field of organic synthesis, and discloses a method for synthesizing a pyroxasulfone intermediate. In the presence of a first solvent and a first catalyst, carrying out first reaction on the compound shown in the formula IV and a chloromethylation reagent to obtain a compound shown in a formula III; in the presence of a third solvent, carrying out third reaction on the compound shown in the formula III and a sulfur compound to obtain a compound shown in a formula II; and in the presence of a fourth solvent, a second catalyst and a second alkali, carrying out fourth reaction on the compound in the formula II and a halogenated isoxazoline derivative to obtain the compound in the formula I. The method for synthesizing the pyroxasulfone intermediate provided by the invention solves the problems of high risk, environmental pollution and the like in the prior art, the reaction route is short, the whole process is mild in reaction condition, simple to operate and short in reaction time, and the product obtained by the reaction is high in purity, easy to separate, high in yield, low in discharge of three wastes, environment-friendly, low in production cost and suitable for industrial production. The method is suitable for industrial mass production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing a sulfonepyraclostrobin intermediate. Background Art

[0002] Pyroxasulfone (CAS: 447399-55-5) is a white crystalline powder at room temperature. It is a new type of pyrazole selective herbicide, launched in 2011. It is a novel pre-emergence herbicide. Its mechanism of action is that after being absorbed by weed roots and shoots, it destroys the seedling meristem and coleoptile, inhibiting the synthesis of very-long-chain fatty acids in the weed plant, thereby inhibiting the early growth of weed seedlings. Pyroxasulfone is widely used in a variety of crops, including corn, soybeans, wheat, cotton, sunflowers, potatoes, and peanuts, to control annual grass weeds and broadleaf weeds. Its structure is as follows:

[0003]

[0004] 3-(5-Difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline (compound of formula I) is an important intermediate for the synthesis of sulfone metabendazole.

[0005]

[0006] WO2004 / 013106A1 reports a method for preparing a compound of formula I. However, the method in this patent is limited in terms of time and method for purifying the intermediate, and thus has problems in industrial implementation.

[0007] WO2005 / 095352A1 reports the following reaction route:

[0008]

[0009] The intermediates before the etherification reaction in this route have allergic problems and place strict requirements on equipment. CN112969697A improves the above problems. The main route is:

[0010]

[0011] However, this process has problems in industrial production, such as long reaction time, low yield and content.

[0012] CN116761802A reports the following reaction scheme:

[0013]

[0014] However, this route has a low yield and a long condensation reaction time when preparing 5-difluoromethoxy-4-halomethyl-1-methyl-3-trifluoromethylpyrazole.

[0015] In addition, in the reaction routes disclosed in the above-mentioned documents and other existing technologies, 5-difluoromethoxy-4-halomethyl-1-methyl-3-trifluoromethylpyrazole is its main intermediate. However, when preparing this intermediate, carbon tetrachloride and other reagents that are not conducive to the ecological environment are mainly used, and the yield is low, which restricts the industrialization of this product. Summary of the Invention

[0016] The purpose of the present invention is to overcome the problems existing in the prior art and provide a method for synthesizing a sulfonepyraclostrobin intermediate.

[0017] In order to achieve the above-mentioned object, the first aspect of the present invention provides a method for synthesizing a sulfonepyraclostrobin intermediate represented by formula III, wherein the method comprises: in the presence of a first solvent and a catalyst, reacting a compound of formula IV with a chloromethylating agent to obtain a compound of formula III;

[0018]

[0019] The second aspect of the present invention provides a method for synthesizing the sulfonepyraclostrobin intermediate shown in Formula I, wherein the method comprises the following steps:

[0020] (1) obtaining a compound of formula III by the method described in the first aspect;

[0021] (2) in the presence of a third solvent, subjecting the compound of formula III to a third reaction with a sulfur compound to obtain a compound of formula II;

[0022] (3) reacting the compound of formula II with a halogenated isoxazoline derivative in the presence of a fourth solvent, a second catalyst, and a second base to obtain a compound of formula I;

[0023]

[0024] Through the above technical solution, the beneficial technical effects achieved by the present invention are as follows:

[0025] The method for synthesizing a sulfonepyraclostrobin intermediate provided by the present invention solves the problems of high risk and environmental pollution in the prior art. The reaction route is short, and the reaction conditions in the entire process are mild, the operation is simple, the reaction time is short, the product obtained by the reaction is high in purity and easy to separate, the yield is high, the amount of three wastes discharged is small, the method is environmentally friendly, the production cost is low, and the method is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is the liquid phase tracking spectrum of the reaction in Examples 1-3 of the present invention;

[0027] Figure 2 is the liquid phase tracking spectrum of the reaction in Example 2-4 of the present invention;

[0028] Figure 3 is the liquid phase spectrum of the compound of formula I in Example 4-1 of the present invention;

[0029] Figure 4 This is the MS spectrum of the compound of formula I in Example 4-1 of the present invention. DETAILED DESCRIPTION

[0030] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0031] A first aspect of the present invention provides a method for synthesizing a sulfonepyraclostrobin intermediate represented by formula III, wherein the method comprises: reacting a compound of formula IV with a chloromethylating agent in the presence of a first solvent and a catalyst to obtain a compound of formula III;

[0032]

[0033] The present invention uses a compound of formula IV (5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole) as a raw material, and chloromethylates it to obtain a compound of formula III (5-difluoromethoxy-4-chloromethyl-1-methyl-3-trifluoromethylpyrazole).

[0034] The reaction route is as follows:

[0035]

[0036] In some embodiments of the present invention, the first solvent is selected from at least one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate and tetrahydrofuran, preferably dichloromethane.

[0037] In some embodiments of the present invention, the first catalyst is selected from at least one of zinc chloride, zinc bromide, zinc iodide, tin tetrachloride and aluminum trichloride, preferably zinc chloride.

[0038] In some embodiments of the present invention, the molar ratio of the compound of formula IV to the first catalyst is 1:0.02-0.1, preferably 1:0.02-0.05, and more preferably 1:0.03.

[0039] In some embodiments of the present invention, the chloromethylation agent is a mixture of dimethoxymethane and chlorosulfonic acid. Under preferred conditions, the molar ratio of dimethoxymethane to chlorosulfonic acid is 1:1.

[0040] In some embodiments of the present invention, the molar ratio of the compound of formula IV, dimethoxymethane and chlorosulfonic acid is 1:1-1.5:1-1.5, preferably 1:1.2:1.2.

[0041] In some embodiments of the present invention, the chloromethylation agent is a mixture of paraformaldehyde and concentrated hydrochloric acid. The concentration of paraformaldehyde can be 90%, and the concentration of concentrated hydrochloric acid can be 37%.

[0042] In some embodiments of the present invention, the molar ratio of the compound of formula IV to paraformaldehyde and concentrated hydrochloric acid is 1:1-1.5:2-4, preferably 1:1.2:3.

[0043] In some embodiments of the present invention, the addition temperature of dimethoxymethane and the compound of formula IV is -15 to 0°C, preferably -10°C.

[0044] In the present invention, dimethoxymethane is added dropwise to a system containing chlorosulfonic acid. The two react at -15 to 0°C to form a chloromethylation reagent. This process is exothermic, and maintaining a low temperature can reduce the generation of impurities. Alternatively, the compound of Formula IV can be added dropwise at the same low temperature to prevent the generation of impurities due to the exothermic addition process. After the addition is complete, the reaction temperature is slightly increased to ensure a more complete reaction and shorten the reaction cycle.

[0045] In some embodiments of the present invention, the temperature of the first reaction is 0-50°C, preferably 5-10°C.

[0046] In some embodiments of the present invention, the time of the first reaction is 0.5-3 hours, preferably 2 hours.

[0047] In some embodiments of the present invention, the method further comprises: reacting 5-hydroxy-1-methyl-3-trifluoromethylpyrazole with chlorodifluoromethane in the presence of a second solvent and a first base to obtain a compound of formula IV.

[0048] The reaction route is as follows:

[0049]

[0050] The present invention uses 5-hydroxy-1-methyl-3-trifluoromethylpyrazole as a starting material and obtains the compound of formula III through two-step reactions.

[0051] In some embodiments of the present invention, the second solvent is water. Not using an organic solvent can reduce production costs.

[0052] In some embodiments of the present invention, the first base is sodium hydroxide and / or potassium hydroxide, preferably sodium hydroxide.

[0053] In some embodiments of the present invention, the molar ratio of 5-hydroxy-1-methyl-3-trifluoromethylpyrazole to the first base is 1:1-2, preferably 1:1.2.

[0054] In some embodiments of the present invention, the second reaction is performed in the presence of a phase transfer catalyst.

[0055] In some embodiments of the present invention, the phase transfer catalyst is selected from at least one of tetrabutylammonium bromide, 18-crown-6, benzyltriethylammonium chloride and tetrabutylammonium chloride, preferably 18-crown-6.

[0056] In some embodiments of the present invention, the molar ratio of the 5-hydroxy-1-methyl-3-trifluoromethylpyrazole to the phase transfer catalyst is 1:0.002-0.005, preferably 1:0.003.

[0057] In some embodiments of the present invention, the molar ratio of 5-hydroxy-1-methyl-3-trifluoromethylpyrazole to chlorodifluoromethane is 1:1-1.5, preferably 1:1.2.

[0058] In some embodiments of the present invention, the temperature of the second reaction is 25-30°C.

[0059] In some embodiments of the present invention, the second reaction time is 1.5-4 hours, preferably 2 hours.

[0060] The second aspect of the present invention provides a method for synthesizing the sulfonepyraclostrobin intermediate shown in Formula I, wherein the method comprises the following steps:

[0061] (1) obtaining a compound of formula III by the method described in the first aspect;

[0062] (2) in the presence of a third solvent, subjecting the compound of formula III to a third reaction with a sulfur compound to obtain a compound of formula II;

[0063] (3) reacting the compound of formula II with a halogenated isoxazoline derivative in the presence of a fourth solvent, a second catalyst, and a second base to obtain a compound of formula I;

[0064]

[0065] The compound of formula I is 3-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline.

[0066] The reaction route is as follows:

[0067]

[0068] In some embodiments of the present invention, in step (2), the third solvent is selected from at least one of methanol, ethanol, dichloromethane, 1,2-dichloroethane, toluene, chlorobenzene, acetonitrile and N,N-dimethylformamide, preferably selected from at least one of methanol, ethanol and acetonitrile, and more preferably methanol.

[0069] In some embodiments of the present invention, the sulfur compound is thiourea.

[0070] In some embodiments of the present invention, the molar ratio of the compound of formula III to the sulfur compound is 1:1-1.1, preferably 1:1.05.

[0071] In some embodiments of the present invention, the third reaction temperature is reflux temperature.

[0072] In some embodiments of the present invention, the third reaction time is 2-5 hours, preferably 3 hours.

[0073] In some embodiments of the present invention, in step (3), the fourth solvent is selected from one or more of ethanol, acetonitrile, tetrahydrofuran, DMF and acetone, preferably ethanol.

[0074] In some embodiments of the present invention, the second base is selected from at least one of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, preferably potassium carbonate.

[0075] In some embodiments of the present invention, the molar ratio of the compound of formula II to the second base is 1:2-6, preferably 1:2.05.

[0076] In some embodiments of the present invention, the structural formula of the halogenated isoxazole ring derivative is X is chlorine or bromine.

[0077] In some embodiments of the present invention, the second catalyst is tungsten hexacarbonyl.

[0078] In some embodiments of the present invention, the amount of the second catalyst is 3-5‰, preferably 3‰, based on the mass of the compound of formula II.

[0079] In some embodiments of the present invention, the molar ratio of the compound of formula II to the halogenated isoxazole ring derivative is 1:1.

[0080] In some embodiments of the present invention, the temperature of the fourth reaction is 5-15°C, preferably 10°C.

[0081] In some embodiments of the present invention, the fourth reaction time is 1.5-4 hours, preferably 2 hours.

[0082] The present invention will be described in detail below through examples.

[0083] In the following examples and comparative examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or those recommended by the manufacturer. All reagents and instruments used, if no manufacturer is specified, are commercially available conventional products.

[0084] Example 1-1

[0085] This example is used to illustrate the synthesis of compound IV using 5-hydroxy-1-methyl-3-trifluoromethylpyrazole as a raw material.

[0086]

[0087] To a 250 mL autoclave were added, in sequence, 30% sodium hydroxide solution (8.2 g, 0.06 mol, 1.2 eq), 5-hydroxy-1-methyl-3-trifluoromethylpyrazole (8.3 g, 0.05 mol, 1 eq), and 18-crown-6 (0.04 g, 0.15 mmol, 0.003 eq) under stirring. Chlorodifluoromethane gas (5.2 g, 0.06 mol, 1.2 eq) was introduced into the autoclave at 25°C using a weight-loss method. After 2 h, a sample was taken for HPLC analysis, confirming complete conversion of 5-hydroxy-1-methyl-3-trifluoromethylpyrazole. The feed solution was transferred to a 500 mL four-necked flask, the pH was adjusted to about 2 with hydrochloric acid, ethyl acetate was added for extraction (100 mL × 3), the organic phases were combined, the organic phases were washed with water until neutral (50 mL × 3), dried over anhydrous sodium sulfate, and desolvated under negative pressure to obtain the compound of formula IV (10.56 g, yield 96.0%, purity 98.2%).

[0088] Example 1-2

[0089] This example is used to illustrate the synthesis of compound IV using 5-hydroxy-1-methyl-3-trifluoromethylpyrazole as a raw material.

[0090] To a 250 mL autoclave were added, in sequence, 30% potassium hydroxide solution (11.2 g, 0.06 mol, 1.2 eq), 5-hydroxy-1-methyl-3-trifluoromethylpyrazole (8.3 g, 0.05 mol, 1 eq), and 18-crown-6 (0.04 g, 0.15 mmol, 0.003 eq) under stirring. Chlorodifluoromethane gas (5.2 g, 0.06 mol, 1.2 eq) was introduced into the autoclave at 25°C using a weight-loss method. After 2 h, a sample was taken for HPLC analysis, confirming complete conversion of 5-hydroxy-1-methyl-3-trifluoromethylpyrazole. The feed solution was transferred to a 500 mL four-necked flask, the pH was adjusted to about 2 with hydrochloric acid, ethyl acetate was added for extraction (100 mL × 3), the organic phases were combined, the organic phases were washed with water until neutral (50 mL × 3), dried over anhydrous sodium sulfate, and desolvated under negative pressure to obtain the compound of formula IV (10.53 g, yield 95.8%, purity 98.2%).

[0091] It can be seen that after the base type is replaced by sodium hydroxide and potassium hydroxide, the yield and purity of the product remain basically unchanged.

[0092] Examples 1-3

[0093] This example is used to illustrate the synthesis of compound IV using 5-hydroxy-1-methyl-3-trifluoromethylpyrazole as a raw material.

[0094] To a 250 mL autoclave were added, in sequence, 30% sodium hydroxide solution (8.2 g, 0.06 mol, 1.2 eq), 5-hydroxy-1-methyl-3-trifluoromethylpyrazole (8.3 g, 0.05 mol, 1 eq), and tetrabutylammonium bromide (0.05 g, 0.15 mmol, 0.003 eq) under stirring. Chlorodifluoromethane gas (5.2 g, 0.06 mol, 1.2 eq) was introduced into the autoclave at 25°C using a weight-loss method. After 2 h, a sample was taken for HPLC analysis, revealing approximately 7% of 5-hydroxy-1-methyl-3-trifluoromethylpyrazole remaining. The reaction was continued for another 2 h, but conversion was still incomplete. The feed solution was transferred to a 500 mL four-necked flask, the pH was adjusted to about 2 with hydrochloric acid, ethyl acetate was added for extraction (100 mL × 3), the organic phases were combined, the organic phases were washed with water until neutral (50 mL × 3), dried over anhydrous sodium sulfate, and desolvated under negative pressure to obtain the compound of formula IV (10.54 g, yield 93.1%, purity 95.3%).

[0095] It can be seen that the effect of using tetrabutylammonium bromide as a phase catalyst is worse than that of 18-crown-6, resulting in poor reaction conversion rate, increased by-products, and reduced product purity and yield.

[0096] like Figure 1In the reaction trace shown, the peak of the raw material 5-hydroxy-1-methyl-3-trifluoromethylpyrazole is at 1.035 min, with a content of about 7.339%; the peak of the compound of formula IV is at 2.627 min, and the remaining peaks are impurity peaks.

[0097] Examples 1-4

[0098] Under stirring, a 30% sodium hydroxide solution (0.82 kg, 6 mol, 1.2 eq), 5-hydroxy-1-methyl-3-trifluoromethylpyrazole (0.83 kg, 5 mol, 1 eq), and 18-crown-6 (4 g, 15 mmol, 0.003 eq) were added sequentially to a 5 L autoclave. Chlorodifluoromethane gas (0.52 kg, 6 mol, 1.2 eq) was introduced into the autoclave at 25°C using a weight-loss method. After 2 h, a sample was taken for HPLC analysis, confirming complete conversion of 5-hydroxy-1-methyl-3-trifluoromethylpyrazole. The resulting solution was transferred to a 10 L four-necked flask, the pH adjusted to approximately 2 with hydrochloric acid, and extracted with ethyl acetate (1 L x 3). The organic phases were combined, washed with water until neutral (1 L x 3), dried over anhydrous sodium sulfate, and desolvated under reduced pressure to yield compound IV (1.062 kg, 96.5% yield, 98.2% purity).

[0099] Example 2-1

[0100] This example is used to illustrate the synthesis of compound III using compound IV as raw material.

[0101]

[0102] To a 2L reaction flask, zinc chloride (1.8 g, 13.5 mmol, 0.03 eq), chlorosulfonic acid (62.9 g, 540 mmol, 1.2 eq), and 450 mL of dichloromethane were added sequentially. The system was cooled to -10°C. At this temperature, dimethoxymethane (41.1 g, 540 mmol, 1.2 eq) was added dropwise. After incubation at -10°C for 30 min, a solution of the compound of Formula IV (99.0 g, 450 mmol, 1 eq) obtained in Example 1-4 in dichloromethane (75 mL) was slowly added dropwise. After the addition was complete, the mixture was reacted at 10°C for 2 h. Samples were taken for HPLC analysis, confirming complete conversion of the compound of Formula IV. The reaction solution was poured into 150 mL of ice water and extracted with dichloromethane (300 mL × 3). The organic phases were combined and washed sequentially with 5% sodium carbonate solution (150 mL × 2) and water (150 mL × 2), dried over anhydrous sodium sulfate, and desolvated under negative pressure to obtain a compound of formula III (118.7 g, yield 96.8%, purity 97.1%).

[0103] Example 2-2

[0104] This example is used to illustrate the synthesis of compound III using compound IV as raw material.

[0105] Zinc iodide (4.35 g, 13.5 mmol, 0.03 eq), chlorosulfonic acid (62.9 g, 540 mmol, 1.2 eq), and 450 mL of dichloromethane were sequentially added to a 2 L reaction flask. The system was cooled to -10°C. At this temperature, dimethoxymethane (41.1 g, 540 mmol, 1.2 eq) was added dropwise. After incubation at -10°C for 30 min, a solution of the compound of Formula IV (99.0 g, 450 mmol, 1 eq) obtained in Example 1-4 in dichloromethane (75 mL) was slowly added dropwise. After the addition was complete, the mixture was reacted at 10°C for 2 h. Samples were taken for HPLC analysis, indicating that the conversion of the raw material was complete. The reaction solution was poured into 150 mL of ice water and extracted with dichloromethane (300 mL × 3). The organic phases were combined and washed sequentially with 5% sodium carbonate solution (150 mL × 2) and water (150 mL × 2), dried over anhydrous sodium sulfate, and desolvated under negative pressure to obtain a compound of formula III (120.2 g, yield 98.0%, purity 97.1%).

[0106] From the comparison between Example 2-1 and Example 2-2, it can be seen that the catalytic effect of zinc iodide is better than that of zinc chloride. However, due to its high price and the fact that its catalytic effect is not significantly improved compared with zinc chloride, zinc chloride is preferred in terms of production cost.

[0107] Example 2-3

[0108] At room temperature, the compound of formula IV obtained in Example 1-4 (99 g, 450 mmol, 1 eq), 450 mL of dichloromethane, zinc chloride (1.8 g, 13.5 mmol, 0.03 eq), paraformaldehyde (18.0 g, 540 mmol, 90%, 1.2 eq) and concentrated hydrochloric acid (134.0 g, 37%, 1.35 mol, 3 eq) were added to a 2 L reaction flask in sequence. The reaction was allowed to proceed for 3 h. After sampling and HPLC detection, the conversion of the raw materials and the hydroxymethyl intermediate was complete. The reaction solution was poured into 150 mL of ice water and extracted with dichloromethane (300 mL × 3). The organic phases were combined and washed with 5% sodium carbonate solution (150 mL × 2) and water (150 mL × 2) in sequence. The organic phases were dried over anhydrous sodium sulfate and desolvated under negative pressure to obtain a compound of formula III (117.8 g, yield 96.5%, purity 97.0%).

[0109] Examples 2-4

[0110] The compound of formula III was synthesized according to the method of Example 2-1, except that after the compound of formula IV was added dropwise, the reaction was carried out at 25° C. to obtain the compound of formula III (118.1 g, yield 90.8%, purity 91.6%).

[0111] It can be seen that increasing the reaction temperature increases the amount of impurities during the reaction, which reduces the purity and yield of the final product. Figure 2 The reaction tracing diagram of the compound of formula III shown shows multiple impurity peaks.

[0112] Examples 2-5

[0113] The compound of formula III was synthesized according to the method of Example 2-1, except that 0.025 eq of zinc chloride was used to obtain the compound of formula III (118.1 g, yield 93.8%, purity 95.6%).

[0114] It can be seen that the product contains unreacted raw material compound of formula IV, which affects the yield and purity. Therefore, it can be seen that reducing the amount of zinc chloride will not completely convert the raw material.

[0115] Examples 2-6

[0116] The compound of formula III was synthesized according to the method of Example 2-1, except that dichloromethane was replaced by 1,2-dichloroethane to obtain the compound of formula III (118.2 g, yield 96.3%, purity 97.0%).

[0117] It can be seen that the use of 1,2-dichloroethane can achieve an effect close to that of using dichloromethane. Considering the recovery and production cost factors, dichloromethane is preferred.

[0118] Examples 2-7

[0119] This example is used to illustrate the synthesis of compound III using compound IV as raw material.

[0120] Zinc chloride (1.8 g, 13.5 mmol, 0.03 eq), chlorosulfonic acid (58.5 g, 495 mol, 1.1 eq), and 450 mL of dichloromethane were added sequentially to a 2 L reaction flask, and the system was cooled to -10°C. At this temperature, dimethoxymethane (37.5 g, 495 mmol, 1.1 eq) was added dropwise. After incubation at -10°C for 30 min, a solution of the compound of formula IV (99 g, 30 mmol, 1 eq) obtained in Example 1-4 in dichloromethane (75 mL) was slowly added dropwise. After the addition was complete, the reaction was continued at 10°C for 2 h. Samples were taken for HPLC analysis. If there was residual compound of formula IV, the reaction was continued for 1 h, and the conversion of compound of formula IV was complete. The reaction solution was poured into 150 mL of ice water and extracted with dichloromethane (300 mL × 3). The organic phases were combined and washed with 5% sodium carbonate solution (150 mL × 2) and water (150 mL × 2) in sequence, dried over anhydrous sodium sulfate, and desolvated under negative pressure to obtain the compound of formula III (115.8 g, yield 92.8%, purity 95.4%).

[0121] It can be seen that reducing the amount of chloromethylation reagent will prolong the reaction time and reduce the product purity and yield.

[0122] Example 3-1

[0123] This example is used to illustrate the synthesis of compound II using compound III as raw material.

[0124]

[0125] To a 500 mL reaction flask was added the compound of formula III obtained in Example 2-1 (31.4 g, 115 mmol, 1 eq) and 150 mL of methanol. Thiourea (9.2 g, 121 mmol, 1.05 eq) was added under stirring. The reaction solution was heated to reflux for 3 h. After sampling and HPLC analysis, the conversion of the compound of formula III was complete. After completion of the reaction, the temperature was lowered, the solvent was removed under negative pressure, and n-hexane was added to the residue in the flask for crystallization and purification. The mixture was filtered to obtain the compound of formula II (38.4 g, 96.5% yield, 99.1% purity).

[0126] Example 3-2

[0127] This example is used to illustrate the synthesis of the compound of formula I using the compound of formula III as a raw material.

[0128] To a 500 mL reaction flask was added the compound of formula III obtained in Example 2-1 (31.4 g, 115 mmol, 1 eq) and 150 mL of methanol. Thiourea (8.75 g, 115 mmol, 1 eq) was added while stirring. The reaction solution was heated to reflux for 3 h. After sampling and HPLC analysis, 2.1% of the compound of formula III remained. After completion of the reaction, the temperature was lowered, the solvent was removed under negative pressure, and n-hexane was added to the residue in the flask for crystallization and purification. Filtering afforded the compound of formula II (37.4 g, 94.1% yield, 98.9% purity).

[0129] It can be seen that reducing the amount of thiourea will result in excess raw materials and a lower yield.

[0130] Example 3-3

[0131] This example is used to illustrate the synthesis of the compound of formula I using the compound of formula III as a raw material.

[0132] To a 500 mL reaction flask was added the compound of formula III obtained in Example 2-1 (31.4 g, 115 mmol, 1 eq) and 150 mL of ethanol. Thiourea (9.2 g, 121 mmol, 1.05 eq) was added under stirring. The reaction solution was heated to reflux for 3 h. After sampling and HPLC analysis, the conversion of formula III was complete. After completion of the reaction, the temperature was lowered, the solvent was removed under negative pressure, and n-hexane was added to the residue in the flask for crystallization and purification. Filtering afforded the compound of formula II (38.2 g, 95.7% yield, 98.7% purity).

[0133] It can be seen that when ethanol is used as the solvent, the reaction reflux temperature is high, the by-products increase, and the yield and purity tend to decrease.

[0134] Example 4-1

[0135] This example is used to illustrate the synthesis of the compound of formula I using the compound of formula II as a raw material.

[0136]

[0137] At room temperature, the compound of Formula II obtained in Example 3-1 (6.86 g, 99.1%, 20 mmol, 1 eq), 70 mL of ethanol, and a 30% potassium carbonate solution (18.89 g, 41 mmol, 2.05 eq) were added sequentially to a reaction flask. After stirring for 15 minutes, tungsten hexacarbonyl (0.0204 g, 3‰) was added. The reaction solution was cooled to 10°C in an ice-water bath, and then a solution of 3-chloro-5,5-dimethyl-2-isoxazoline (2.7 g, 20 mmol, 1 eq) in ethanol (5 mL) was added dropwise. The system temperature was maintained at approximately 10°C during the addition. After the addition was complete, the reaction was continued at 10°C for 2 hours. Samples were taken for HPLC analysis, confirming complete conversion of the raw material. The solvent was removed under negative pressure, and then water (30 mL) and toluene (70 mL) were added to the bottle. After stirring for 10 min, the liquid was separated, and the organic phase was collected and washed with water (40 mL×2). The organic phase was desolvated to obtain the compound of formula I (7.18 g, yield 98.2%, purity 98.3%).

[0138] Example 4-2

[0139] This example is used to illustrate the synthesis of the compound of formula I using the compound of formula II as a raw material.

[0140] At room temperature, compound II obtained in Example 3-1 (6.86 g, 99.1%, 20 mmol, 1 eq), 70 mL of acetonitrile, and a 30% potassium carbonate solution (18.89 g, 41 mmol, 2.05 eq) were added sequentially to a reaction flask. After stirring for 15 minutes, tungsten hexacarbonyl (0.0204 g, 3‰) was added. The reaction solution was cooled to 10°C in an ice-water bath, and then a solution of 3-chloro-5,5-dimethyl-2-isoxazoline (2.7 g, 20 mmol, 1 eq) in acetonitrile (5 mL) was added dropwise. The system temperature was maintained at approximately 10°C during the addition. After the addition was complete, the reaction was continued at 10°C for 2 hours. Samples were taken for HPLC analysis, confirming complete conversion of the raw material. The solvent was removed under negative pressure, and then water (30 mL) and toluene (70 mL) were added to the bottle. After stirring for 10 min, the liquid was separated, and the organic phase was collected and washed with water (40 mL×2). The organic phase was desolvated to obtain the compound of formula I (7.18 g, yield 98.3%, purity 98.4%).

[0141] It can be seen that the product yields obtained by using ethanol and acetonitrile are not much different. Considering the production cost, ethanol is preferred.

[0142] Example 4-3

[0143] This example is used to illustrate the synthesis of the compound of formula I using the compound of formula II as a raw material.

[0144] At room temperature, the compound of Formula II obtained in Example 3-1 (6.86 g, 99.1%, 20 mmol, 1 eq), 70 mL of ethanol, and a 30% potassium carbonate solution (18.89 g, 41 mmol, 2.05 eq) were added sequentially to a reaction flask. After stirring for 15 minutes, tungsten hexacarbonyl (0.0136 g, 2‰) was added. The reaction solution was cooled to 10°C in an ice-water bath, and then a solution of 3-chloro-5,5-dimethyl-2-isoxazoline (2.7 g, 20 mmol, 1 eq) in ethanol (5 mL) was added dropwise. The temperature of the system was maintained at approximately 10°C during the addition. After the addition was complete, the reaction was continued at 10°C for 2 hours. Samples were taken for HPLC analysis, indicating residual starting material. Stirring was continued for 2 hours, and residual starting material was still present. The solvent was removed under negative pressure, and then water (30 mL) and toluene (70 mL) were added to the bottle. After stirring for 10 min, the liquid was separated, and the organic phase was collected and washed with water (40 mL×2). The organic phase was desolvated to obtain the compound of formula I (7.04 g, yield 92.4%, purity 94.3%).

[0145] It can be seen that reducing the amount of catalyst will result in incomplete conversion of raw materials, affecting the content and yield of the product.

[0146] Example 4-4

[0147] This example is used to illustrate the synthesis of the compound of formula I using the compound of formula II as a raw material.

[0148] At room temperature, the compound of Formula II obtained in Example 3-1 (6.86 g, 99.1%, 20 mmol, 1 eq), 70 mL of ethanol, and a 30% potassium carbonate solution (18.89 g, 41 mmol, 2.05 eq) were added sequentially to a reaction flask. After stirring for 15 minutes, tungsten hexacarbonyl (0.034 g, 5‰) was added. The reaction solution was cooled to 10°C in an ice-water bath, and then a solution of 3-chloro-5,5-dimethyl-2-isoxazoline (2.7 g, 20 mmol, 1 eq) in ethanol (5 mL) was added dropwise. The system temperature was maintained at approximately 10°C during the addition. After the addition was complete, the reaction was continued at 10°C for 2 hours. Samples were taken for HPLC analysis, confirming complete conversion of the raw material. The solvent was removed under negative pressure, and then water (30 mL) and toluene (70 mL) were added to the bottle. After stirring for 10 min, the liquid was separated, and the organic phase was collected and washed with water (40 mL×2). The organic phase was desolvated to obtain the compound of formula I (7.18 g, yield 98.3%, purity 98.4%).

[0149] Increasing the amount of catalyst did not improve the content and yield of the product.

[0150] Examples 4-5

[0151] This example is used to illustrate the synthesis of the compound of formula I using the compound of formula II as a raw material.

[0152] At room temperature, the compound of Formula II obtained in Example 3-1 (6.86 g, 99.1%, 20 mmol, 1 eq), 70 mL of ethanol, and a 30% potassium carbonate solution (18.89 g, 41 mmol, 2.05 eq) were added sequentially to a reaction flask. After stirring for 15 minutes, tungsten hexacarbonyl (0.0204 g, 3‰) was added. The reaction solution was cooled to 10°C in an ice-water bath, and then a solution of 3-bromo-5,5-dimethyl-2-isoxazoline (3.6 g, 20 mmol, 1 eq) in ethanol (5 mL) was added dropwise. The system temperature was maintained at approximately 10°C during the addition. After the addition was complete, the reaction was continued at 10°C for 1.5 hours. Samples were taken for HPLC analysis, confirming complete conversion of the raw material. The solvent was removed under negative pressure, and then water (30 mL) and toluene (70 mL) were added to the bottle. After stirring for 10 min, the liquid was separated, and the organic phase was collected and washed with water (40 mL×2). The organic phase was desolvated to obtain the compound of formula I (7.22 g, yield 98.6%, purity 98.1%).

[0153] By using a brominated isoxazoline compound, the reaction time is shortened due to the high reactivity of the bromide, and the catalyst achieves the same effect.

[0154] Comparative Example 1

[0155] This comparative example is used to illustrate the synthesis of 5-difluoromethoxy-4-chloromethyl-1-methyl-3-trifluoromethylpyrazole (ie, compound of formula III) using 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole as a raw material.

[0156]

[0157] To a solution of 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole (11.5 g, 50 mmol) in 50 mL of carbon tetrachloride were added sulfonyl chloride (10.1 g, 75 mmol) and α,α'-azobisisobutyronitrile (0.8 g, 5 mmol), followed by heating under reflux with stirring. The reaction solution was irradiated with external light for 11 hours. After confirming the completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The resulting organic layer was washed with water and brine in sequence and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain an anhydrous, transparent liquid 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole (6.51 g, 42.5% yield, 86.3% purity).

[0158] Comparative Example 2

[0159] This comparative example is used to illustrate the synthesis of 5-difluoromethoxy-4-chloromethyl-1-methyl-3-trifluoromethylpyrazole (ie, compound of formula III) using 5-hydroxy-1-methyl-3-trifluoromethylpyrazole as a raw material.

[0160]

[0161] Referring to patent CN1013845568A, 5-hydroxy-1-methyl-3-trifluoromethylpyrazole was subjected to hydroxymethylation and etherification (one-pot method). The specific operation is as follows:

[0162] 5-Hydroxy-1-methyl-3-trifluoromethylpyrazole (16.6 g, 0.10 mol) was dissolved in a 24% potassium hydroxide aqueous solution (35.0 g, 0.15 mol). The solution was stirred at room temperature, and a 37% formalin solution (9.7 g, 0.12 mol) was added dropwise, followed by stirring at the same temperature for 1 hour. Then, a 24% potassium hydroxide aqueous solution (70.0 g, 0.3 mol) and 100 mL of acetonitrile were added. At room temperature, monochlorodifluoromethane (17.3 g, 0.2 mol) was blown into the solution over a period of 2 hours, followed by stirring at room temperature for 2 hours to react. After the reaction, the organic layer that emerged through separation was concentrated under reduced pressure to obtain 24.8 g of a crude product with a purity of 84.1% and a yield of 84.7%. The crude product was subjected to reduced pressure distillation to obtain a product of higher purity (purity ≥ 97%).

[0163] Refer to CN117545741A to continue the chlorination reaction. The specific operation is as follows:

[0164] Under nitrogen, 5-difluoromethoxy-4-hydroxymethyl-1-methyl-3-trifluoromethylpyrazole (9.86 g, 97% purity, 38.9 mmol, 1 eq) was added to a reaction flask and dissolved in 16 mL of acetonitrile. Sulfenyl chloride (5.35 g, 45 mmol, 1.16 eq) was added dropwise to the mixture at an internal temperature of 15°C over 25 minutes. The reaction was maintained at an internal temperature of 25°C for 1.5 hours.

[0165] After the reaction, the mixture was diluted with 40 mL of ethyl acetate, washed successively with 30 mL of aqueous sodium carbonate solution, 30 mL of water and 30 mL of brine, and the organic layer was dried over anhydrous magnesium sulfate and desolvated under reduced pressure to give 10.83 g of 5-difluoromethoxy-4-chloromethyl-1-methyl-3-trifluoromethylpyrazole (i.e., compound of formula III) as an oil with a purity of 90.6% and a yield of 95.3%.

[0166] Comparative Example 3

[0167] This comparative example is used to illustrate the synthesis of the compound of formula I.

[0168]

[0169] To a 10 mL solution of (5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)isothiourea hydrobromide (1.93 g, 5.00 mmol) in ethanol, sodium hydroxide (0.48 g, 12 mmol) and 10 mL of water were added, and the mixture was stirred at room temperature for 30 minutes. 3-Chloro-5,5-dimethyl-2-isoxazoline (0.67 g, 5 mmol) was added at room temperature, and the mixture was stirred at reflux for 12 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure. The resulting residue was added to water and extracted with ethyl acetate. The resulting organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.22 g of the target compound (Formula I) with a yield of 63.2% and a purity of 93.2%.

[0170] By comparison with the comparative example, it can be seen that the entire process of the present invention has mild reaction conditions, simple operation, high purity and yield of the obtained product, low discharge of three wastes, is environmentally friendly, and is suitable for large-scale industrial production.

[0171] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as disclosed in the present invention and fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing a sulfonepyraclostrobin intermediate represented by formula III, characterized in that: The method comprises: in the presence of a first solvent and a first catalyst, subjecting a compound of formula IV to a first reaction with a chloromethylation agent to obtain a compound of formula III; 2. The method according to claim 1, wherein The first solvent is selected from at least one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate and tetrahydrofuran, preferably dichloromethane; Preferably, the first catalyst is selected from at least one of zinc chloride, zinc bromide, zinc iodide, tin tetrachloride and aluminum chloride, preferably zinc chloride; Preferably, the molar ratio of the compound of formula IV to the first catalyst is 1:0.02-0.1, preferably 1:0.02-0.05, more preferably 1:0.03; Preferably, the chloromethylation agent is a mixture of dimethoxymethane and chlorosulfonic acid; Preferably, the molar ratio of dimethoxymethane to chlorosulfonic acid is 1:1; Preferably, the molar ratio of the compound of formula IV, dimethoxymethane and chlorosulfonic acid is 1:1-1.5:1-1.5, preferably 1:1.2:1.2; Preferably, the chloromethylation agent is a mixture of paraformaldehyde and concentrated hydrochloric acid; Preferably, the molar ratio of the compound of formula IV, paraformaldehyde and concentrated hydrochloric acid is 1:1-1.5:2-4, preferably 1:1.2:

3.

3. The method according to claim 1 or 2, wherein: The addition temperature of dimethoxymethane and the compound of formula IV is -15 to 0°C, preferably -10°C; Preferably, the temperature of the first reaction is 0-50°C, preferably 5-10°C; Preferably, the first reaction time is 0.5-3 h, preferably 2 h.

4. The method according to any one of claims 1 to 3, wherein The method further comprises: performing a second reaction on 5-hydroxy-1-methyl-3-trifluoromethylpyrazole and chlorodifluoromethane in the presence of a second solvent and a first base to obtain a compound of formula IV.

5. The method according to claim 4, wherein The second solvent is water; Preferably, the first base is sodium hydroxide and / or potassium hydroxide, preferably sodium hydroxide; Preferably, the molar ratio of 5-hydroxy-1-methyl-3-trifluoromethylpyrazole to the first base is 1:1-2, preferably 1:1.2; Preferably, the second reaction is carried out in the presence of a phase transfer catalyst; Preferably, the phase transfer catalyst is selected from at least one of tetrabutylammonium bromide, 18-crown-6, benzyltriethylammonium chloride and tetrabutylammonium chloride, preferably 18-crown-6; Preferably, the molar ratio of 5-hydroxy-1-methyl-3-trifluoromethylpyrazole to the phase transfer catalyst is 1:0.002-0.005, preferably 1:0.003; Preferably, the molar ratio of 5-hydroxy-1-methyl-3-trifluoromethylpyrazole to chlorodifluoromethane is 1:1-1.5, preferably 1:1.

2.

6. The method according to claim 4 or 5, wherein: The temperature of the second reaction is 25-30°C; Preferably, the second reaction time is 1.5-4 h, preferably 2 h.

7. A method for synthesizing a sulfonepyraclostrobin intermediate of formula I, characterized in that: The method comprises the following steps: (1) obtaining a compound of formula III by the method according to any one of claims 1 to 6; (2) in the presence of a third solvent, subjecting the compound of formula III to a third reaction with a sulfur compound to obtain a compound of formula II; (3) reacting the compound of formula II with a halogenated isoxazoline derivative in the presence of a fourth solvent, a second catalyst, and a second base to obtain a compound of formula I; 8. The method according to claim 7, wherein: In step (2), the third solvent is selected from at least one of methanol, ethanol, dichloromethane, 1,2-dichloroethane, toluene, chlorobenzene, acetonitrile and N,N-dimethylformamide, preferably selected from at least one of methanol, ethanol and acetonitrile, more preferably methanol; Preferably, the sulfur compound is thiourea; Preferably, the molar ratio of the compound of formula III to the sulfur compound is 1:1-1.1, preferably 1:1.

05.

9. The method according to claim 7 or 8, wherein The temperature of the third reaction is reflux temperature; Preferably, the third reaction time is 2-5 hours, preferably 3 hours.

10. The method according to any one of claims 7 to 9, wherein: In step (3), the fourth solvent is selected from at least one of ethanol, acetonitrile, tetrahydrofuran, DMF and acetone, preferably ethanol; Preferably, the second base is selected from at least one of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, preferably potassium carbonate; Preferably, the molar ratio of the compound of formula II to the second base is 1:2-6, preferably 1:2.05; Preferably, the structural formula of the halogenated isoxazole ring derivative is X is chlorine or bromine; Preferably, the second catalyst is tungsten hexacarbonyl; Preferably, the amount of the second catalyst is 3-5‰, preferably 3‰, based on the mass of the compound of formula II; Preferably, the molar ratio of the compound of formula II to the halogenated isoxazole ring derivative is 1:1; Preferably, the temperature of the fourth reaction is 5-15°C, preferably 10°C; Preferably, the fourth reaction time is 1.5-4 hours, preferably 2 hours.

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