Synthesis process of tetrafluoroisoxazoline herbicide

Abstract

The invention provides a synthesis process of a tetrafluoroisoxazoline herbicide, which comprises the following steps: (1) preparing an intermediate product 5, 5-dimethyl-3-(methylthio)-4, 5-dihydroisoxazole; (2) preparing an intermediate 3-((chloromethyl) thio)-5, 5-dimethyl-4, 5-dihydroisoxazole; (3) preparing an intermediate, namely 1, 4-di-tert-butoxy-2, 3, 5, 6-tetrafluorobenzene; (4) preparing 2, 3, 5, 6-tetrafluoro-1, 4-hydroquinone; (5) preparing 2, 3, 5, 6-tetrafluoro-4-methoxyphenol, and preparing 2, 3, 5, 6-tetrafluoro-4-methoxyphenol; (6) preparing 3-(((4-(methoxyl)-2, 3, 5, 6-tetrafluorophenoxyl) methyl) sulfenyl)-5, 5-dimethyl-4, 5-dihydroisoxazole, and (7) preparing the 3-(((4-(methoxyl)-2, 3, 5, 6-tetrafluorophenoxyl) methyl) sulfenyl)-5, 5-dimethyl-4, 5-dihydroisoxazole; and (7) preparing the herbicide. 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 a tetrafluoroisoxazoline herbicide. Background Art

[0002] Isoxazoline compounds are a class of compounds with excellent biological activity and can be used as herbicides. Chinese Patent CN 112225707 A discloses an isoxazoline derivative, of which Compound C exhibits excellent control effects against grass weeds (such as barnyardgrass, foxtail grass, Leptochloa chinensis, and crabgrass). It is safe for crops and demonstrates superior weed control effectiveness compared to commercially available herbicides and similarly structured isoxazoline compounds, demonstrating its excellent application prospects.

[0003] The current synthesis process of the compound 3-(((4-(methoxy)-2,3,5,6-tetrafluorophenoxy)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole is as follows:

[0004]

[0005] The isoxazoline derivative 3-(((4-(methyloxy)-2,3,5,6-tetrafluorophenoxy)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole is prepared according to the process in the background art, specifically comprising the following steps:

[0006] (1) 3-Chloro-5,5-dimethyl-4,5-dihydroisoxazole reacts with an aqueous solution of sodium thiomethoxide to obtain the intermediate 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole.

[0007] (2) 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole reacts with NCS to obtain the intermediate 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole.

[0008] (3) Pentafluorophenol is reacted with 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole in the presence of potassium tert-butoxide and NaI to obtain the intermediate 5,5-dimethyl-3-(((perfluorophenoxy)methyl)thio)-4,5-dihydroisoxazole.

[0009] (4) 5,5-dimethyl-3-(((perfluorophenoxy)methyl)thio)-4,5-dihydroisoxazole is reacted with sodium methoxide to obtain the intermediate 3-(((4-(methyloxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole.

[0010] (5) Oxidizing 3-(((4-(methyloxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole with m-chloroperbenzoic acid to obtain the final product 3-(((4-(methyloxy)-2,3,5,6-tetrafluorophenoxy)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole.

[0011] However, the synthesis process of the above compounds is complicated and has low yield, making them unsuitable for industrial production. Summary of the Invention

[0012] The present invention aims to provide a synthesis process for a tetrafluoroisoxazoline herbicide to solve the problems of complex synthesis process and low product yield of the above-mentioned isoxazoline derivative (i.e., the compound 3-(((4-(methyloxy)-2,3,5,6-tetrafluorophenoxy)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole).

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

[0014] A synthesis process for a tetrafluoroisoxazoline herbicide comprises the following steps:

[0015] Step (1) reacting 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole and a methyl mercaptan reagent in a solvent to obtain an intermediate product, 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole;

[0016] Step (2) reacting 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole with a chlorination reagent in a solvent to prepare an intermediate 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole;

[0017] Step (3) reacting hexafluorobenzene with tert-butanol or tert-butoxide in the presence of a solvent to obtain the intermediate 1,4-di-tert-butoxy-2,3,5,6-tetrafluorobenzene;

[0018] Step (4) adding the intermediate 1,4-di-tert-butoxy-2,3,5,6-tetrafluorobenzene prepared above to a solvent and removing the tert-butyl group under acidic conditions to obtain 2,3,5,6-tetrafluoro-1,4-hydroquinone;

[0019] Step (5) adding the above-prepared 2,3,5,6-tetrafluoro-1,4-hydroquinone and a methylating agent into a solvent, and reacting under the action of a base to obtain 2,3,5,6-tetrafluoro-4-methoxyphenol;

[0020] Step (6) adding 2,3,5,6-tetrafluoro-4-methoxyphenol obtained in the above reaction and 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole to a solvent and reacting in the presence of a base to obtain 3-(((4-(methoxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole;

[0021] Step (7) In the presence of an oxidant and a solvent, the synthesized intermediate 3-(((4-(methyloxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole is subjected to an oxidation reaction to prepare a tetrafluoroisoxazoline herbicide.

[0022] Reaction equation of the present invention is as follows:

[0023]

[0024] Preferably, in step (1), the reaction conditions are: reaction temperature is 20-80° C., reaction time is 4-24 h; and the solvent includes one or more of water, ethanol, tetrahydrofuran, and toluene.

[0025] More preferably, in step (1), the reaction temperature is 60-70° C. and the solvent is toluene.

[0026] Preferably, in step (1), the methyl mercaptan reagent comprises one or more of methyl mercaptan, potassium methyl mercaptan and sodium methyl mercaptan; and the molar ratio of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole to potassium methyl mercaptan is 1:(1-2).

[0027] More preferably, in step (1), the methyl mercaptan reagent is potassium methyl mercaptan.

[0028] Preferably, in step (2), the chlorination reagent includes one or more of chlorine, phosphorus oxychloride, thionyl chloride and NCS; the molar ratio of 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole to the chlorination reagent is 1:(1-3); the solvent includes one or more of toluene, methylcyclohexane and 1,2-dichloroethane; the reaction temperature is 15-50° C., and the reaction time is 5-12 h.

[0029] More preferably, in step (2), the chlorination agent is thionyl chloride; the molar ratio of 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole to the chlorination agent is 1:(1-2); the reaction temperature is 40-50° C.; and the solvent comprises one or more of methylcyclohexane and 1,2-dichloroethane.

[0030] Preferably, in step (3), the tert-butoxide salt includes one or more of potassium tert-butoxide and sodium tert-butoxide; the molar ratio of hexafluorobenzene to tert-butanol or tert-butoxide salt is 1:(2-3); the solvent includes one or more of toluene, tetrahydrofuran, methylcyclohexane, and 1,2-dichloroethane; and the reaction conditions are: the reaction temperature is 15-50° C. and the reaction time is 10-18 h.

[0031] More preferably, in step (3), the molar ratio of hexafluorobenzene to tert-butanol or tert-butoxide is 1:3.

[0032] More preferably, in step (3), the tert-butoxide salt is potassium tert-butoxide; and the solvent is 1,2-dichloroethane.

[0033] Preferably, in step (4), the acid comprises one or more of concentrated sulfuric acid, dilute sulfuric acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and concentrated hydrochloric acid.

[0034] More preferably, in step (4), the acid comprises one or more of concentrated sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and concentrated hydrochloric acid.

[0035] More preferably, in step (4), the acid is trifluoroacetic acid.

[0036] Preferably, in step (4), the solvent includes one or more of tetrahydrofuran, methyltetrahydrofuran, toluene, 1,2-dichloroethane and dichloromethane; the reaction conditions are: reaction temperature of 30-60° C., and reaction time of 10-18 h.

[0037] More preferably, in step (4), the solvent comprises one or more of tetrahydrofuran, toluene, and 1,2-dichloroethane.

[0038] Preferably, in step (5), the methylating agent includes one or more of methyl iodide, methyl chloride, methyl bromide, dimethyl sulfate and dimethyl carbonate; the base includes one or more of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate and sodium amide.

[0039] More preferably, in step (5), the methylating agent includes one or more of dimethyl sulfate, methyl iodide, and dimethyl carbonate; and the base includes one or more of potassium carbonate, potassium hydroxide, and sodium carbonate.

[0040] More preferably, in step (5), the methylating agent is dimethyl carbonate; and the base is potassium hydroxide.

[0041] Preferably, in step (5), the molar ratio of 2,3,5,6-tetrafluoro-1,4-hydroquinone to the methylating agent is 1:(0.5-1.5); the solvent comprises one or more of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, dichloroethane, and toluene; and the reaction conditions are: reaction temperature of 60-100°C, and reaction time of 10-18 hours.

[0042] More preferably, in step (5), the molar ratio of 2,3,5,6-tetrafluoro-1,4-hydroquinone to the methylating agent is 1:1; and the solvent comprises one or more of acetonitrile, N,N-dimethylformamide, dichloromethane, and toluene.

[0043] More preferably, in step (5), the solvent is toluene.

[0044] Preferably, in step (6), the solvent is one or more of tetrahydrofuran, toluene, 1,2-dichloroethane, acetonitrile, and N,N-dimethylformamide; the base includes one or more of potassium carbonate, potassium hydroxide, sodium hydroxide, and sodium carbonate; the molar ratio of 2,3,5,6-tetrafluoro-4-methoxyphenol to 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole is (1:1-2); and the reaction conditions are: the reaction temperature is 20-100°C and the reaction time is 10-18h.

[0045] More preferably, in step (6), the solvent is tetrahydrofuran; the base is sodium hydroxide; and the molar ratio of 2,3,5,6-tetrafluoro-4-methoxyphenol to 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole is (1:1-1.3).

[0046] Preferably, in step (7), the oxidant includes one or more of sodium tungstate, potassium permanganate, hydrogen peroxide, sodium peroxide and m-chloroperbenzoic acid; the molar ratio of 3-(((4-(methyloxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole to the oxidant is 1:(0.05-2.5); and the organic solvent includes one or more of methanol, ethanol, acetonitrile, dichloromethane and dichloroethane.

[0047] More preferably, in step (7), the oxidant is a mixture of sodium tungstate and hydrogen peroxide, and the molar ratio of 3-(((4-(methyloxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole, hydrogen peroxide, and sodium tungstate is 1:2:(0.01-0.2).

[0048] More preferably, in step (7), the molar ratio of 3-(((4-(methyloxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole, hydrogen peroxide, and sodium tungstate is 1:2:0.05.

[0049] Preferably, in step (7), the oxidation reaction temperature is 20 to 60° C.; and the oxidation reaction time is 5 to 10 hours.

[0050] More preferably, in step (7), the temperature of the oxidation reaction is 30-40°C.

[0051] Compared with the prior art, the advantages and beneficial effects of the present invention are:

[0052] The present invention synthesizes an isoxazoline herbicide. By changing the intermediates and raw materials in the reaction, the synthesis time is shortened and the occurrence of side reactions is reduced. The synthesis process of the present invention is simple to operate, the raw materials are readily available, the product yield is high, and the discharge of three wastes is reduced, making it suitable for process production. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 This is the H NMR spectrum of the intermediate product 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole;

[0054] Figure 2 This is the H NMR spectrum of the intermediate 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole;

[0055] Figure 3 This is the H NMR spectrum of tetrafluoroisoxazoline herbicide. DETAILED DESCRIPTION

[0056] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0057] Step (1): The reaction equation for synthesizing the intermediate product 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole is as follows:

[0058]

[0059] Example 1

[0060] This embodiment provides a synthesis process of 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole, comprising the following steps:

[0061] 270 g of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was added to 500 mL of toluene, and then 880 g of a 20 wt% aqueous solution of potassium methyl mercaptan was added dropwise. The mixture was stirred at 60° C. for 24 h. After completion of the reaction, the layers were separated and the mixture was concentrated under reduced pressure to obtain 292 g of a crude product with a GC content (gas chromatographic purity) of 95% and a yield of 95.5%.

[0062] Example 2

[0063] This embodiment provides a synthesis process of 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole, comprising the following steps:

[0064] 270 g of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was added to 500 mL of toluene, and 1323 g of a 20 wt% aqueous solution of sodium methyl mercaptide was added dropwise. The mixture was stirred at 80° C. for 24 h. After completion of the reaction, the layers were separated and the mixture was concentrated under reduced pressure to obtain 290 g of a crude product with a GC content of 89% and a yield of 88.0%.

[0065] Figure 1 This is the nuclear magnetic hydrogen spectrum of the intermediate 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole. It can be seen from the figure that 1 H NMR (400 MHz, Chloroform-d) δ 2.78 (s, 2H), 2.47 (s, 3H), 1.40 (s, 6H), demonstrating that the intermediate 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole had been successfully synthesized.

[0066] Step (2): The reaction equation for synthesizing the intermediate 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole is as follows:

[0067]

[0068] Example 3

[0069] This embodiment provides a synthesis process of an intermediate 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole, comprising the following steps:

[0070] 290 g of 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole was dissolved in 1 L of methylcyclohexane, and 240 g of thionyl chloride was added. The mixture was stirred at 45° C. for 6 h. GC detection showed that the reaction of 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole was complete. The reaction was stopped. After the reaction was completed, the mixture was cooled at 0° C. and then filtered. The filter cake was washed twice with methylcyclohexane. The filtrate was collected and concentrated to obtain a yellow liquid. The product was distilled under reduced pressure to obtain 350 g of the product with a GC content of 90% and a yield of 87.7%.

[0071] Example 4

[0072] This embodiment provides a synthesis process of an intermediate 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole, comprising the following steps:

[0073] 290 g of 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole was dissolved in 1 L of 1,2-dichloroethane, and 270 g of NCS was added. The mixture was stirred at 50° C. for 6 h. GC detection showed that the reaction of 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole was complete. The reaction was stopped and cooled at 0° C. after completion of the reaction. The mixture was then filtered with suction, and the filter cake was rinsed twice with 1,2-dichloroethane, filtered, and the filtrate was concentrated to obtain a yellow liquid. The product was distilled under reduced pressure to obtain 220 g of the product with a GC content of 91% and a yield of 57.0%.

[0074] Figure 2 This is the nuclear magnetic hydrogen spectrum of the intermediate 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole. It can be seen from the figure that 1 H NMR (400 MHz, Chloroform-d) δ 5.00 (s, 2H), 2.86 (s, 2H), 1.44 (s, 7H), demonstrating that the intermediate 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole had been successfully synthesized.

[0075] Step (3): The reaction equation for synthesizing the intermediate 1,4-di-tert-butoxy-2,3,5,6-tetrafluorobenzene is as follows:

[0076]

[0077] Example 5

[0078] This embodiment provides a synthesis process of an intermediate 1,4-di-tert-butoxy-2,3,5,6-tetrafluorobenzene, comprising the following steps:

[0079] 170 g of potassium tert-butoxide was dissolved in 250 mL of 1,2-dichloroethane, and 94 g of hexafluorobenzene was added dropwise. After the addition was complete, the reaction was kept at 20° C. for 12 h. The GC content was controlled to be less than 2% by hexafluorobenzene. Water was added to the system to quench the reaction, followed by desolventization and extraction twice with 1,2-dichloroethane. The organic phases were combined and concentrated to obtain 122 g of crude 1,4-di-tert-butoxy-2,3,5,6-tetrafluorobenzene with a GC content of 94% and a yield of 78%.

[0080] Step (4): The reaction equation for synthesizing 2,3,5,6-tetrafluoro-1,4-hydroquinone is as follows:

[0081]

[0082] Example 6

[0083] This embodiment provides a method for preparing 2,3,5,6-tetrafluoro-1,4-hydroquinone, comprising the following steps:

[0084] 157 g of 1,4-di-tert-butoxy-2,3,5,6-tetrafluorobenzene was dissolved in 250 mL of 1,2-dichloroethane, and 173 g of trifluoroacetic acid was added dropwise. The mixture was kept at 40°C for 12 h, during which time a large amount of product precipitated in the reaction solution. 2,3,5,6-tetrafluoro-1,4-hydroquinone was obtained by filtration and dried and weighed to obtain 76 g of a crude product with a GC content of 96% and a yield of 81%.

[0085] Example 7

[0086] This embodiment provides a method for preparing 2,3,5,6-tetrafluoro-1,4-hydroquinone, comprising the following steps:

[0087] 157 g of 1,4-di-tert-butoxy-2,3,5,6-tetrafluorobenzene was dissolved in 250 mL of 1,2-dichloroethane, and 152 g of trifluoromethanesulfonic acid was added dropwise. The mixture was kept at 40°C for 12 h, during which time a large amount of white solid precipitated in the reaction solution. 2,3,5,6-tetrafluoro-1,4-hydroquinone was obtained by filtration and dried and weighed to obtain 74 g of a crude product with a GC content of 94% and a yield of 76%.

[0088] Step (5): The reaction equation for synthesizing 2,3,5,6-tetrafluoro-4-methoxyphenol is as follows:

[0089]

[0090] Example 8

[0091] This embodiment provides a method for preparing 2,3,5,6-tetrafluoro-4-methoxyphenol, comprising the following steps:

[0092] 95 g of 2,3,5,6-tetrafluoro-1,4-hydroquinone was dissolved in 200 mL of toluene, and 46 g of dimethyl carbonate and 31 g of potassium hydroxide were added in sequence. The reaction temperature was then raised to 80°C and the reaction was carried out for 12 h. After the reaction, 400 mL of water was added to the reaction solution, and the mixture was extracted twice with 400 mL of ethyl acetate. The organic phase was concentrated and subjected to column chromatography to obtain 90 g of 2,3,5,6-tetrafluoro-4-methoxyphenol with a GC content of 94% and a yield of 86.3%.

[0093] 95 g of 2,3,5,6-tetrafluoro-1,4-hydroquinone was dissolved in 200 mL of N,N-dimethylformamide, and 72 g of iodomethane and 70 g of potassium carbonate were added in sequence. The mixture was reacted at 20°C for 12 h. After the reaction, 400 mL of water was added to the reaction solution, and the mixture was extracted twice with 400 mL of ethyl acetate. The organic phase was concentrated and subjected to column chromatography to obtain 65 g of 2,3,5,6-tetrafluoro-4-methoxyphenol with a GC content of 92% and a yield of 61%.

[0094] Step (6): The reaction equation for synthesizing 3-(((4-(methoxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole is as follows:

[0095]

[0096] Example 10

[0097] This embodiment provides a method for preparing 3-(((4-(methoxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole, comprising the following steps:

[0098] 104 g of 2,3,5,6-tetrafluoro-4-methoxyphenol was dissolved in 200 mL of acetonitrile, and 100 g of 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole and 70 g of potassium carbonate were added in sequence. The mixture was reacted at 20° C. for 16 h. After the reaction, the acetonitrile was evaporated, and 400 mL of water was added. The mixture was extracted twice with 400 mL of ethyl acetate. The organic phase was concentrated and subjected to column chromatography to obtain 120 g of 3-(((4-(methoxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole with a GC content of 92% and a yield of 65%.

[0099] Example 11

[0100] 104 g of 2,3,5,6-tetrafluoro-4-methoxyphenol was dissolved in 200 mL of tetrahydrofuran, and 100 g of 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole and 20 g of sodium hydroxide were added in sequence. The reaction was carried out at 20° C. for 16 h. After the reaction, the tetrahydrofuran was evaporated, and then 400 mL of water was added. The mixture was extracted twice with 400 mL of ethyl acetate. The organic phase was concentrated and weighed to obtain 151 g of crude 3-(((4-(methoxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole with a content of 93% and a yield of 82.7%.

[0101] Step 7: The reaction equation for synthesizing 3-(((4-(methyloxy)-2,3,5,6-tetrafluorophenoxy)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole is as follows:

[0102]

[0103] Example 12

[0104] This embodiment provides a method for preparing 3-(((4-(methoxy)-2,3,5,6-tetrafluorophenoxy)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole, comprising the following steps:

[0105] 700 mL of methanol solvent and 1.7 g of sodium tungstate dihydrate were added to 182 g of 3-(((4-(methyloxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole, and then 170 g of 20 wt% hydrogen peroxide was added dropwise. The mixture was kept at 40° C. for 6 h. After the reaction was completed, a white solid was precipitated, which was filtered and the filter cake was dried to obtain 171 g of the final product with a GC content of 97% and a yield of 89.3%.

[0106] Figure 3 This is the H NMR spectrum of tetrafluoroisoxazoline herbicide. As can be seen from the figure, 1H NMR (400 MHz, Chloroform-d) δ 5.32 (s, 2H), 4.03 (s, 3H), 3.17 (s, 2H), 1.51 (s, 6H), proving that tetrafluoroisoxazoline herbicide has been successfully synthesized.

[0107] Comparative Example 1

[0108] The isoxazoline derivative 3-(((4-(methyloxy)-2,3,5,6-tetrafluorophenoxy)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole is prepared according to the process in the background art, specifically comprising the following steps:

[0109] (1) 40 g of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was dissolved in 150 mL of N,N-dimethylformamide, and 210 g of a 20 wt% aqueous solution of sodium methyl mercaptide was added dropwise. The mixture was stirred at room temperature for 12 h. After the reaction was completed, 200 mL of water was added to the reaction mixture and stirred. The mixture was extracted with 200 mL of ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed and the mixture was separated by column chromatography to obtain 23.3 g of a yellow liquid with a yield of 53.5%.

[0110] (2) 23.30 g of 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole was dissolved in 250 mL of carbon tetrachloride. 23.57 g of NCS was added to the mixture and stirred at room temperature for 6 h. After the reaction was completed, the mixture was cooled to 0°C, filtered, and the filtrate was concentrated and separated by column chromatography to obtain 21.6 g of a yellow liquid with a yield of 75.0%.

[0111] (3) 13.00 g of pentafluorophenol and 9.51 g of potassium tert-butoxide were dissolved in 200 mL of N,N-dimethylformamide and stirred at 25°C for 30 min. Then, 15.23 g of 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole was added to the above system. After completion, 0.1 g of NaI was added, and the temperature was raised to 80°C and stirred for 8 h to stop the reaction. The above mixture was washed with 400 mL of water and extracted with ethyl acetate (120 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 16.56 g of a yellow liquid with a yield of 71.6%.

[0112] (4) 0.65 g of 5,5-dimethyl-3-(((perfluorophenoxy)methyl)thio)-4,5-dihydroisoxazole was dissolved in 30 mL of anhydrous methanol, 0.11 g of sodium methoxide was added, the temperature was raised to 70°C and stirred for 14 h, the reaction was stopped, the methanol was removed under reduced pressure, and the reaction mixture was washed with 100 mL of water and extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 0.56 g of a yellow liquid with a yield of 82.0%.

[0113] (5) 0.56 g of 3-(((4-(methyloxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole was dissolved in 20 mL of dichloromethane, and 0.76 g of 75% m-chloroperbenzoic acid was added. After stirring at 25° C. for 8 h, the reaction was stopped. The mixture was washed with 20 mL of saturated sodium bisulfite solution and then with 100 mL of saturated sodium bicarbonate solution, and then extracted with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 0.30 g of a white solid with a yield of 49.2%.

[0114] In Comparative Example 1, the synthesis of the isoxazoline derivative 3-(((4-(methoxy)-2,3,5,6-tetrafluorophenoxy)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole was carried out from 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole, requiring five reaction steps with a total yield of 11.6%. In the present invention, the synthesis of the tetrafluoroisoxazoline herbicide (3-(((4-(methoxy)-2,3,5,6-tetrafluorophenoxy)methyl)sulfanyl)-5,5-dimethyl-4,5-dihydroisoxazole) was carried out from 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole, requiring six steps with a total process yield of 23%. The yield of the product in the present invention is higher than that of the product in Comparative Example 1.

[0115] 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 within the scope of protection of the present invention.

Claims

1. A synthesis process for a tetrafluoroisoxazoline herbicide, characterized in that: The following steps are involved: Step (1) reacting 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole and a methyl mercaptan reagent in a solvent to obtain an intermediate product, 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole; Step (2) reacting 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole with a chlorination reagent in a solvent to obtain an intermediate 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole; Step (3) reacting hexafluorobenzene with tert-butanol or tert-butoxide in the presence of a solvent to obtain the intermediate 1,4-di-tert-butoxy-2,3,5,6-tetrafluorobenzene; Step (4) adding the intermediate 1,4-di-tert-butoxy-2,3,5,6-tetrafluorobenzene prepared above to a solvent and removing the tert-butyl group under acidic conditions to obtain 2,3,5,6-tetrafluoro-1,4-hydroquinone; Step (5) adding the above-prepared 2,3,5,6-tetrafluoro-1,4-hydroquinone and a methylating agent into a solvent, and reacting them under the action of a base to obtain 2,3,5,6-tetrafluoro-4-methoxyphenol; Step (6) adding 2,3,5,6-tetrafluoro-4-methoxyphenol obtained in the above reaction and 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole to a solvent, and reacting in the presence of a base to obtain 3-(((4-(methoxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole; Step (7) In the presence of an oxidant and an organic solvent, the synthesized 3-(((4-(methyloxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole is subjected to an oxidation reaction to prepare a tetrafluoroisoxazolinyl herbicide.

2. The synthesis process of tetrafluoroisoxazoline herbicide according to claim 1, wherein In step (1), the reaction conditions are: reaction temperature is 20-80°C, reaction time is 4-24h; the solvent includes one or more of water, ethanol, tetrahydrofuran, and toluene.

3. The synthesis process of tetrafluoroisoxazoline herbicide according to claim 1, wherein In step (1), the methyl mercaptan reagent includes one or more of methyl mercaptan, potassium methyl mercaptan and sodium methyl mercaptan; and the molar ratio of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole to the methyl mercaptan reagent is 1:(1~2).

4. The synthesis process of tetrafluoroisoxazoline herbicide according to claim 1, wherein In step (2), the solvent includes one or more of toluene, methylcyclohexane and 1,2-dichloroethane; the chlorination reagent includes one or more of chlorine, phosphorus oxychloride, thionyl chloride and N-chlorosuccinimide (NCS); the molar ratio of 5,5-dimethyl-3-(methylthio)-4,5-dihydroisoxazole to the chlorination reagent is 1:(1-3); the reaction conditions are: the reaction temperature is 15-50°C, and the reaction time is 5-12h.

5. The synthesis process of tetrafluoroisoxazoline herbicide according to claim 1, characterized in that, In step (3), the tert-butoxide salt includes one or more of potassium tert-butoxide and sodium tert-butoxide, the molar ratio of hexafluorobenzene to tert-butanol or tert-butoxide salt is 1:(2-3); the solvent includes one or more of toluene, tetrahydrofuran, methylcyclohexane and 1,2-dichloroethane; the reaction conditions are: the reaction temperature is 15-50°C, and the reaction time is 10-18h.

6. The synthesis process of tetrafluoroisoxazoline herbicide according to claim 1, characterized in that, In step (4), the acid includes one or more of concentrated sulfuric acid, dilute sulfuric acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and concentrated hydrochloric acid; the solvent includes one or more of tetrahydrofuran, methyltetrahydrofuran, toluene, 1,2-dichloroethane and dichloromethane; the reaction conditions are: the reaction temperature is 30-60°C, and the reaction time is 10-18 hours.

7. The synthesis process of tetrafluoroisoxazoline herbicide according to claim 1, characterized in that, In step (5), the methylating agent includes one or more of iodomethane, chloromethane, bromomethane, dimethyl sulfate and dimethyl carbonate; the base includes one or more of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate and sodium amide; the reaction conditions are: the reaction temperature is 60-100°C, and the reaction time is 10-18h.

8. The synthesis process of tetrafluoroisoxazoline herbicide according to claim 1, characterized in that, In step (5), the molar ratio of 2,3,5,6-tetrafluoro-1,4-hydroquinone to the methylating agent is 1:(0.5~1.5); the solvent includes acetonitrile, N, N - one or more of dimethylformamide, dimethyl sulfoxide, dichloromethane, dichloroethane and toluene.

9. The synthesis process of tetrafluoroisoxazoline herbicide according to claim 1, characterized in that, In step (6), the solvent includes tetrahydrofuran, toluene, 1,2-dichloroethane, acetonitrile, N,N -one or more of dimethylformamide; the base includes one or more of potassium carbonate, potassium hydroxide, sodium hydroxide, and sodium carbonate; the molar ratio of 2,3,5,6-tetrafluoro-4-methoxyphenol to 3-((chloromethyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole is (1:1-2); the reaction conditions are: the reaction temperature is 20-100°C, and the reaction time is 10-18h.

10. The synthesis process of the tetrafluoroisoxazoline herbicide according to claim 1, characterized in that: In step (7), the oxidant includes one or more of sodium tungstate, potassium permanganate, hydrogen peroxide, sodium peroxide and m-chloroperbenzoic acid; the organic solvent includes one or more of methanol, ethanol, acetonitrile, dichloromethane and dichloroethane; the molar ratio of 3-(((4-(methoxy)-2,3,5,6-tetrafluorophenoxy)methyl)thio)-5,5-dimethyl-4,5-dihydroisoxazole to the oxidant is 1:(0.05-2.5); the oxidation reaction conditions are: the oxidation reaction temperature is 20-60°C, and the oxidation reaction time is 5-10 hours.

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