A method for synthesizing 2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole

Abstract

The application discloses a synthesis method of 2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole, and has the beneficial effect that a clean and environment-friendly synthesis route is provided to prepare a key intermediate 1,3,4-thiadiazole compound of fluthiacet-methyl, the synthesis method is simple, the process condition is not harsh, the environment pollution is small, the yield is higher than that of the prior art, and some defects related to the prior art are avoided. The application avoids using difficult-to-handle reagents such as CS2 and POCl3, and the by-product urea generated in the reaction can be recycled, so that the complexity and cost related to the process steps are reduced, and the application is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of fine chemicals, and more particularly to a method for synthesizing 2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole. Background Technology

[0002] Fluthiamide (4'-fluoro-N-isopropyl-2-(5-trifluoromethyl-1,3,4-thiadiazol-2-yloxy)acetanilide) is a herbicide discovered by Bayer Crop Science. Like bensulfuron-methyl, its active ingredient belongs to the aryloxyacetamide class of compounds and has a similar weed control spectrum to chloroacetamide herbicides, effectively controlling a wide range of annual grasses, sedges, and some small broadleaf weeds.

[0003]

[0004] The synthesis of fluthiamethoxam mainly involves two processes: the first is the condensation of 2-chloro-5-trifluoromethyl-1,3,4-thiadiazole with 2-hydroxy-N-(4-fluoroaniline)-N-(1-methylethyl)acetamide to produce fluthiamethoxam; the second is the condensation of 2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole with 2-hydroxy-N-(4-fluoroaniline)-N-(1-methylethyl)acetamide to produce fluthiamethoxam.

[0005] Among them, 1,3,4-thiadiazole compounds are an important intermediate in the synthesis of fluthiamethoxam, and their synthesis methods are roughly as follows:

[0006] First, the article "Modern Pesticides [J]., 2002(02):8-10" mentions that carbon disulfide is used as a raw material to react with hydrazine hydrate and dimethyl sulfate to produce methyl hydrazine dithiocarbamate, which is then cyclized with trifluoroacetic acid and oxidized with hydrogen peroxide to obtain 2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole. The large amount of foul-smelling CS2 waste gas generated during production and use is highly toxic, flammable, and explosive, posing a significant threat to the environment and human health. Simultaneously, CS2 slowly hydrolyzes to generate hydrogen sulfide, corroding production equipment and causing economic losses. Therefore, the requirements for the materials and airtightness of the production equipment, as well as the supporting exhaust gas treatment equipment, are extremely high in the steps involving CS2 in this process.

[0007]

[0008] Second, CN105646397A mentions that 2-chloro-5-trifluoromethyl-1,3,4-thiadiazole is obtained by diazotization after cyclization using aminothiourea as a raw material with phosphorus oxychloride. Heating in the presence of trifluoroacetic acid and phosphorus oxychloride results in dehydration and cyclization, but phosphorus oxychloride decomposes in water to produce a large amount of HCl gas. This synthesis method requires sophisticated equipment, and the large amount of phosphorus-containing wastewater generated during the production process is difficult to treat.

[0009] Summary of the Invention

[0010] Therefore, there is a need to provide a method for synthesizing 2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole, avoiding the use of difficult-to-handle reagents such as CS2 and POCl3, and solving the problems of cumbersome synthesis methods, harsh process conditions, significant environmental pollution, and poor yield in existing methods.

[0011] To achieve the above objectives, the present invention provides a method for synthesizing 2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole, comprising,

[0012] Cyclization reaction: At room temperature, methylthioformylhydrazide and toluene were added to the first reaction vessel, and stirring was started. A toluene solution of trifluoroacetyl chloride was added to the reaction vessel. After the addition was completed, the mixture was stirred for 2-4 hours. Then, the temperature was raised to the first temperature and the mixture was refluxed to carry water. After the reaction was completed, the solution was removed and distilled to obtain 2-methylthio-5-trifluoromethyl-1,3,4-oxadiazole.

[0013] Substitution reaction: 2-methylthio-5-trifluoromethyl-1,3,4-oxadiazole, toluene and thiourea were added to a sealed second reaction vessel. The temperature was raised to the second temperature and kept at the temperature for 12-16 h. After the reaction was completed, the mixture was washed and separated to obtain 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole.

[0014] Oxidation reaction: 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole, toluene, acetic acid and sodium molybdate were added to the third reaction vessel. The mixture was stirred and heated to the third temperature. Hydrogen peroxide was slowly added dropwise. After the addition was completed, the mixture was kept at the temperature for further reaction. After the reaction was completed, the temperature was slowly lowered to allow crystals to precipitate. The crystals were then filtered and washed to obtain 2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole.

[0015] Furthermore, in the cyclization reaction, the molar ratio of trifluoroacetyl chloride to methylthioformylhydrazine is 1.5-2:1.

[0016] Furthermore, in the substitution reaction, the molar ratio of thiourea to 2-methylthio-5-trifluoromethyl-1,3,4-oxadiazole is 1.2-2.5:1.

[0017] Furthermore, in the oxidation reaction, the molar ratio of acetic acid to 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole is 0.5:1.

[0018] Furthermore, in the oxidation reaction, the molar ratio of sodium molybdate to 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole is 0.001-0.005:1.

[0019] Furthermore, in the oxidation reaction, the molar ratio of hydrogen peroxide to 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole is 2-4:1.

[0020] Further, the first temperature is 100-105°C; and / or

[0021] The second temperature is 100-110℃; and / or

[0022] The third temperature is 70-80℃.

[0023] Unlike existing technologies, the above-mentioned technical solution uses trifluoroacetyl compounds as the starting point for synthesis, and sequentially proceeds through cyclization, substitution, and oxidation reactions to prepare the key intermediate 1,3,4-thiadiazole compounds for fluthiamethoxam via an environmentally friendly synthetic route. The synthesis method of this invention is simple and the process conditions are not demanding, resulting in less environmental pollution. It also offers higher yields compared to existing technologies and avoids some of the drawbacks associated with existing methods. This invention avoids the use of difficult-to-handle reagents such as CS2 and POCl3, and the byproduct urea produced in the reaction can be recovered, reducing the complexity and cost of the process steps and making it suitable for industrial production. Detailed Implementation

[0024] To explain in detail the technical content, structural features, objectives, and effects of the technical solution, the following detailed description is provided in conjunction with specific embodiments.

[0025] In this document, the term "embodiment" means that a specific feature, structure, or characteristic described in connection with an embodiment may be included in at least one embodiment of this application. The term "embodiment" appearing in various places throughout the specification does not necessarily refer to the same embodiment, nor does it specifically limit its independence or connection with other embodiments. In principle, in this application, as long as there are no technical contradictions or conflicts, the technical features mentioned in each embodiment can be combined in any way to form corresponding implementable technical solutions.

[0026] Unless otherwise defined, the technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains; the use of related terms herein is merely for the purpose of describing particular embodiments and is not intended to limit this application.

[0027] In the description of this application, the term "and / or" is used to describe the logical relationship between objects, indicating that three relationships can exist. For example, A and / or B means: A exists, B exists, and A and B exist simultaneously. Additionally, the character " / " in this document generally indicates that the preceding and following objects have an "or" logical relationship.

[0028] In this application, terms such as “first” and “second” are used only to distinguish one entity or operation from another, and do not necessarily require or imply any actual quantity, hierarchy or order relationship between these entities or operations.

[0029] Unless otherwise specified, the use of terms such as “comprising,” “including,” “having,” or other similar expressions in this application is intended to cover non-exclusive inclusion, which does not exclude the presence of additional elements in a process, method, or product that includes the stated elements, such that a process, method, or product that includes a list of elements may include not only those defined elements but also other elements not expressly listed, or elements inherent to such a process, method, or product.

[0030] Similar to the understanding in the Examination Guidelines, in this application, expressions such as "greater than," "less than," and "exceeding" are understood to exclude the stated number; expressions such as "above," "below," and "within" are understood to include the stated number. Furthermore, in the description of the embodiments in this application, "multiple" means two or more (including two), and similar expressions related to "multiple" are also understood in this way, such as "multiple groups" and "multiple times," unless otherwise explicitly specified.

[0031] The following is the specific synthetic route of the synthetic method described in this invention.

[0032]

[0033] R = F, Cl, OH, OMe or OEt

[0034] in:

[0035]

[0036] Formula I: a trifluoroacetyl compound, wherein R = F, Cl, OH, OMe, OEt

[0037]

[0038] Formula II: 2-Methylthio-5-trifluoromethyl-1,3,4-oxadiazole

[0039]

[0040] Formula III: 2-Methylthio-5-trifluoromethyl-1,3,4-thiadiazole

[0041]

[0042] Formula IV: 2-Methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole

[0043] The following are specific examples. For ease of explanation, please refer to the preceding text and use Formulas I-IV to refer to the corresponding chemical formulas.

[0044] Example 1:

[0045] Step 1 Cyclization reaction: At room temperature, methylthioformylhydrazine (106 g, 1 mol) and toluene (106 g, 1 m / m) were added to the reaction vessel, and stirring was started. A toluene solution of trifluoroacetyl chloride (198.7 g, 1.5 mol; toluene 106 g, 1 m / m) was added to the reaction vessel, and the dropping temperature did not exceed 35 °C. After the dropping was completed, the mixture was stirred for 2 h, and then the temperature was raised to 100-105 °C and refluxed to react with water. After the reaction was completed, the solvent was removed, and simple distillation was performed to obtain 151 g of Formula II (2-methylthio-5-trifluoromethyl-1,3,4-oxadiazole) (yield 82%, liquid phase purity 97.2%).

[0046] The second step of the substitution reaction: Formula II (151 g, 0.82 mol), toluene (151 g, 1 m / m), and thiourea (74.9 g, 0.98 mol) were added to a closed reaction vessel, the temperature was raised to 100-110 °C, and the reaction was maintained at this temperature for 16 h. After the reaction was completed, water was added to the reaction system for washing and separation to obtain 133.8 g of Formula III (2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole) (yield 81.5%, liquid phase purity 96.5%).

[0047] The third step of the oxidation reaction: Formula III (133.8 g, 0.67 mol), toluene (133.8 g, 1 m / m), and acetic acid (20.1 g, 0.33 mol) were added to the reactor, along with the catalyst sodium molybdate (0.14 g). The mixture was stirred and heated to 70-80 °C, and hydrogen peroxide (45.6 g, 1.34 mol) was slowly added dropwise. After the addition was completed, the mixture was kept at the same temperature for the reaction. After the reaction was completed, the temperature was slowly lowered to 0-5 °C to crystallize. The crystals were filtered and washed to obtain 136.9 g of Formula IV (2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole) (yield 88%, liquid phase purity 98.8%).

[0048] Example 2:

[0049] Step 1 Cyclization reaction: At room temperature, methylthioformylhydrazine (106 g, 1 mol) and toluene (106 g, 1 m / m) were added to the reaction vessel, and stirring was started. A toluene solution of trifluoroacetyl fluoride (174.02 g, 1.5 mol; toluene 106 g, 1 m / m) was added to the reaction vessel, and the dropwise addition temperature did not exceed 35 °C. After the dropwise addition was completed, the mixture was stirred for 2 h, and then heated to 100-105 °C and refluxed to remove water. After the reaction was completed, the solution was removed, and simple distillation was performed to obtain 158.5 g of Formula II (2-methylthio-5-trifluoromethyl-1,3,4-oxadiazole) (yield 86.1%, liquid phase purity 96.8%).

[0050] The second step of the substitution reaction: Formula II (158.5 g, 0.86 mol), toluene (158.5 g, 1 m / m), and thiourea (98.2 g, 1.29 mol) were added to a closed reaction vessel. The temperature was raised to 100-110 °C and the reaction was maintained for 14 h. After the reaction was completed, water was added to the reaction system for washing and separation to obtain 148.1 g of Formula III (2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole) (yield 86%, liquid phase purity 98.4%).

[0051] The third step of the oxidation reaction: Formula III (148.1 g, 0.74 mol), toluene (148.1 g, 1 m / m), and acetic acid (22.2 g, 0.37 mol) were added to the reactor, along with the catalyst sodium molybdate (0.49 g). The mixture was stirred and heated to 70-80 °C, and hydrogen peroxide (62.9 g, 1.85 mol) was slowly added dropwise. After the addition was completed, the mixture was kept at the same temperature for the reaction. After the reaction was completed, the temperature was slowly lowered to 0-5 °C to crystallize. The crystals were filtered and washed to obtain 152.4 g of Formula IV (2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole) (yield 88.7%, liquid phase purity 98.8%).

[0052] Example 3:

[0053] Step 1 Cycloning reaction: At room temperature, methylthioformylhydrazine (106 g, 1 mol) and toluene (106 g, 1 m / m) were added to the reaction vessel, and stirring was started. A toluene solution of trifluoroacetic acid (228 g, 2 mol; toluene 106 g, 1 m / m) was added to the reaction vessel, and the dropping temperature did not exceed 35 °C. After the dropping was completed, the mixture was stirred for 4 h, and then the temperature was raised to 100-105 °C and refluxed to carry the water. After the reaction was completed, the solvent was removed, and simple distillation was performed to obtain 161.9 g of Formula II (2-methylthio-5-trifluoromethyl-1,3,4-oxadiazole) (yield 87.9%, liquid phase purity 99.1%).

[0054] The second step of the substitution reaction: Formula II (161.9 g, 0.88 mol), toluene (161.9 g, 1 m / m), and thiourea (100.5 g, 1.32 mol) were added to a closed reaction vessel, the temperature was raised to 100-110 °C, and the reaction was carried out overnight for 12 h. After the reaction was completed, the reaction system was washed with water and separated to obtain 155.9 g of Formula III (2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole) (yield 88.5%, liquid phase purity 98.6%).

[0055] The third step of the oxidation reaction: Formula III (155.9 g, 0.78 mol), toluene (155.9 g, 1 m / m), and acetic acid (23.3 g, 0.39 mol) were added to the reactor, along with the catalyst sodium molybdate (0.80 g). The mixture was stirred and heated to 70-80 °C, and hydrogen peroxide (79.6 g, 2.34 mol) was slowly added dropwise. After the addition was completed, the mixture was kept at the same temperature for the reaction. After the reaction was completed, the temperature was slowly lowered to 0-5 °C to crystallize. The crystals were filtered and washed to obtain 163.2 g of Formula IV (2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole) (yield 90.1%, liquid phase purity 99.3%).

[0056] Example 4:

[0057] Step 1 Cyclization reaction: At room temperature, methylthioformylhydrazine (106 g, 1 mol) and toluene (106 g, 1 m / m) were added to the reaction vessel, and stirring was started. A toluene solution of methyl trifluoroacetate (192.1 g, 1.5 mol; toluene 106 g, 1 m / m) was added to the reaction vessel, and the dropping temperature did not exceed 35 °C. After the dropping was completed, the mixture was stirred for 4 h, and then heated to 100-105 °C and refluxed to react with water. After the reaction was completed, the solvent was removed, and simple distillation was performed to obtain 164.4 g of Formula II (2-methylthio-5-trifluoromethyl-1,3,4-oxadiazole) (yield 89.3%, liquid phase purity 98.4%).

[0058] The second step of the substitution reaction: Formula II (164.4 g, 0.89 mol), toluene (164.4 g, 1 m / m), and thiourea (135.5 g, 1.78 mol) were added to a closed reaction vessel. The temperature was raised to 100-110 °C and the reaction was maintained for 12 h. After the reaction was completed, water was added to the reaction system for washing and separation to obtain 158.4 g of Formula III (2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole) (yield 88.9%, liquid phase purity 98.3%).

[0059] The third step of the oxidation reaction: Formula III (158.4 g, 0.79 mol), toluene (158.4 g, 1 m / m), and acetic acid (23.8 g, 0.4 mol) were added to the reactor, along with the catalyst sodium molybdate (0.81 g). The mixture was stirred and heated to 70-80 °C, and hydrogen peroxide (80.6 g, 2.37 mol) was slowly added dropwise. After the addition was completed, the mixture was kept at the same temperature for the reaction. After the reaction was completed, the temperature was slowly lowered to 0-5 °C to crystallize. The crystals were filtered and washed to obtain 163.6 g of Formula IV (2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole) (yield 89.2%, liquid phase purity 99%).

[0060] Example 5:

[0061] Step 1 Cyclization reaction: At room temperature, methylthioformylhydrazine (106 g, 1 mol) and toluene (106 g, 1 m / m) were added to the reaction vessel, and stirring was started. A toluene solution of ethyl trifluoroacetate (284.2 g, 2 mol; toluene 106 g, 1 m / m) was added to the reaction vessel, and the dropping temperature did not exceed 35 °C. After the dropping was completed, the mixture was stirred for 4 h, and then the temperature was raised to 100-105 °C and refluxed to react with water. After the reaction was completed, the solvent was removed, and simple distillation was performed to obtain 165.7 g of Formula II (2-methylthio-5-trifluoromethyl-1,3,4-oxadiazole) (yield 90%, liquid phase purity 96.9%).

[0062] The second step is the substitution reaction: Formula II (165.7 g, 0.9 mol), toluene (165.7 g, 1 m / m), and thiourea (171.27 g, 2.25 mol) are added to a closed reaction vessel. The temperature is raised to 100-110 °C and the reaction is maintained for 12 h. After the reaction is completed, water is added to the reaction system for washing and separation to obtain 157.8 g of Formula III (2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole) (yield 87.6%, liquid phase purity 98%).

[0063] The third step of the oxidation reaction: Formula III (157.8 g, 0.79 mol), toluene (157.8 g, 1 m / m), and acetic acid (23.7 g, 0.39 mol) were added to the reactor, along with the catalyst sodium molybdate (0.65 g). The mixture was stirred and heated to 70-80 °C, and hydrogen peroxide (107.5 g, 3.16 mol) was slowly added dropwise. After the addition was completed, the mixture was kept at the same temperature for the reaction. After the reaction was completed, the temperature was slowly lowered to 0-5 °C to crystallize. The crystals were filtered and washed to obtain 166.4 g of Formula IV (2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole) (yield 90.7%, liquid phase purity 98.5%).

[0064] The beneficial effects of this invention lie in providing an environmentally friendly synthetic route for preparing the key intermediate 1,3,4-thiadiazole compounds of fluthiamethoxam. The synthetic method of this invention is simple and the process conditions are not demanding, resulting in less environmental pollution. It offers higher yields compared to existing technologies and avoids some of the drawbacks associated with existing methods. This invention avoids the use of difficult-to-handle reagents such as CS2 and POCl3, and the byproduct urea produced in the reaction can be recovered, minimizing the complexity and cost associated with the process steps, making it suitable for industrial production.

[0065] It should be noted that although the above embodiments have been described herein, this does not limit the scope of patent protection for this invention. Therefore, any changes and modifications made to the embodiments described herein based on the innovative concept of this invention, or any equivalent structural or procedural transformations made using the content of this specification, directly or indirectly applying the above technical solutions to other related technical fields, are all included within the scope of patent protection for this invention.

Claims

1. A method for synthesizing 2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole, characterized in that, include, Cyclization reaction: At room temperature, methylthioformylhydrazine and toluene were added to the first reaction vessel, and stirring was started. A toluene solution of trifluoroacetyl compound was added to the reaction vessel. After the addition was completed, the mixture was stirred for 2-4 hours. Then, the temperature was raised to the first temperature and the mixture was refluxed to carry water. After the reaction was completed, the mixture was desolventized and distilled to obtain 2-methylthio-5-trifluoromethyl-1,3,4-oxadiazole. The chemical formula of the trifluoroacetyl compound is CF3COR, where R represents fluorine, chlorine, hydroxyl, methoxy or ethoxy. Substitution reaction: 2-methylthio-5-trifluoromethyl-1,3,4-oxadiazole, toluene and thiourea were added to a sealed second reaction vessel. The temperature was raised to the second temperature and kept at the temperature for 12-16 h. After the reaction was completed, the mixture was washed and separated to obtain 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole. Oxidation reaction: 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole, toluene, acetic acid and sodium molybdate were added to the third reaction vessel, stirred and heated to the third temperature, hydrogen peroxide was slowly added dropwise, and the reaction was maintained at the temperature after the addition was completed. After the reaction was completed, the temperature was slowly lowered to crystallize, filtered and washed to obtain 2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole; In the cyclization reaction, the molar ratio of trifluoroacetyl compound to methylthioformylhydrazine is 1.5-2:1; In the substitution reaction, the molar ratio of thiourea to 2-methylthio-5-trifluoromethyl-1,3,4-oxadiazole is 1.2-2.5:1; The first temperature is 100-105℃; The second temperature is 100-110℃; The third temperature is 70-80℃.

2. The method for synthesizing 2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole according to claim 1, characterized in that: In the oxidation reaction, the molar ratio of acetic acid to 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole is 0.5:

1.

3. The method for synthesizing 2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole according to claim 1, characterized in that: In the oxidation reaction, the molar ratio of sodium molybdate to 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole is 0.001-0.005:

1.

4. The method for synthesizing 2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole according to claim 1, characterized in that: In the oxidation reaction, the molar ratio of hydrogen peroxide to 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole is 2-4:1.

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