Improved process for the synthesis of difluoromethyl triazolinones

Abstract

This invention relates to an improved method for the synthesis of difluoromethyltriazolinone: 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one (triazolinone) metal salt is dispersed in a composite solvent, a catalyst is added, and difluorochloromethane is introduced to prepare difluoromethyltriazolinone. This invention features simple operation, high conversion rate, good product quality, and high yield.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to an improved method for synthesizing difluoromethyltriazolone. Background Technology

[0002] 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one is an important intermediate in the synthesis of the highly effective herbicide cyclohexane and has wide applications in herbicide production. Currently, the commonly used process uses 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one as raw material, N,N-dimethylformamide solvent, potassium carbonate as an acid-binding agent, and difluorochloromethane under reflux. After the reaction, the product is obtained through centrifugation to remove salt, solvent concentration, hydrolysis, centrifugation to obtain a crude wet product, followed by purification, centrifugation, and drying to obtain the final product, 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The process is complicated, generates a large amount of wastewater, DMF is easily decomposed, and the product is easily polymerized, resulting in low yield. This leads to large equipment investment and significant environmental pressure, which are not conducive to large-scale production.

[0003] WO2024012537A1 discloses a class of compounds as shown in the figure below and their application as herbicides.

[0004] The method for preparing intermediate A-4 from intermediate A-3 is disclosed in Preparation Example 1 of the specification: The reaction uses tetrahydrofuran as the reaction solvent, with 2 equivalents of KOH and 5 equivalents of tetrabutylammonium bromide added. Monochlorodifluoromethane is introduced under reflux conditions. The raw material consumption is large, the oxoisomer is large, the effective conversion rate of raw materials is low, the product purification is difficult, and the yield is low.

[0005] US5756755A discloses a method for preparing 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one using polyethers as solvents: The specification discloses in Examples 1-8 a method for preparing 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one using solvents such as tetraethylene glycol dimethyl ether and diethylene glycol dimethyl ether. The reaction temperature is ≥190℃, the reaction rate is slow, a large amount of difluorochloromethane decomposes, and the reaction conditions are harsh, resulting in high requirements for production equipment, high energy consumption, and is not conducive to industrial production.

[0006] US5438149A discloses a reaction method using difluorochloromethane as the difluoromethylating agent, potassium carbonate as the acid-binding agent, and DMF as the reaction solvent, in a closed high-pressure reactor at a temperature of 160-200°C. This method involves a closed, high-pressure reaction, increasing reaction risk and making industrial implementation difficult. High-temperature fluorine infusion leads to rapid reaction rates, temperature runaway, rapid pressure increases, and an inability to achieve a stable reaction, increasing safety risks for industrial application. The reaction is also difficult to control, resulting in numerous impurities in the product and low product quality and yield.

[0007] CN107935948A discloses a method for synthesizing pyrazosulfuron-methyl, wherein Example 2 of the specification specifically discloses a method for preparing intermediate III from intermediate II: The reaction uses DMF as a solvent and potassium carbonate as an acid-binding agent, with dichlorofluoromethane gas passed through under reflux. The large amount of potassium carbonate used causes the potassium bicarbonate obtained from the reaction to decompose at reflux temperature, producing water. This water hydrolyzes DMF and Freon under the same temperature and alkaline system, generating impurities such as potassium fluoride and dimethylamine. These impurities continue to participate in the reaction, producing a large amount of tar-like substances, resulting in poor product color, low content, and low yield.

[0008] CN103965124A discloses a method for synthesizing triazolinone: The specification details the industrial-scale difluoromethylation process, which still uses DMF as the reaction solvent, potassium carbonate as the acid-binding agent, and difluorochloromethane gas at 115°C. The low reaction temperature leads to a significant increase in oxygen isomer impurities, resulting in increased impurities in the product, making purification more difficult and reducing the yield.

[0009] CN103819418A discloses a method for synthesizing cyclohexane and cyclohexane intermediates: The specification, in Example 1, specifically discloses a method for preparing 1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-3-methyl-1H-1,2,4-triazol-5-one from 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-one: DMF is used as the reaction solvent, potassium carbonate is used as the acid-binding agent, tetrabutylammonium bromide is added, the water generated in the reaction is removed by heating and negative pressure, and difluorochloromethane gas is introduced at reflux temperature. Although this method increases the conversion rate of the product and the conversion rate of tar and impurities, it does not fundamentally solve the problems caused by the decomposition of DMF and Freon, and the quality and yield of the product are not significantly improved.

[0010] CN104326992A discloses a method for synthesizing difluoromethyltriazolinone and mesotrione: The method for preparing the product from l-(4-chloro-2-fluorophenyl)-methyl-1,2,4-triazolin-5-one is specifically disclosed in Examples 1-6 of the specification. Toluene is first used as a salt solvent, and potassium carbonate and potassium hydroxide aqueous solutions are added to react. Water is removed by reflux of toluene and toluene is distilled off. Then DMF or DMSO is added for subsequent difluoromethylation reaction. This operation has many disadvantages in industrialization: (1) After the raw material is salted, it is completely dissolved in water, and toluene cannot be effectively removed; (2) Toluene is not soluble in the raw material salt, and water is removed later, resulting in severe material expansion, making it impossible to carry out water removal operation; (3) Using DMF or DMSO as a solvent and passing Freon for reaction results in poor reaction, low yield and low quality.

[0011] The paper "Study on the Synthesis Process of 4,5-dihydro-3-methyl-1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-1,2,4-triazol-5(1H)one" was published in Fine Petrochemicals (2012), 29(1), 63-65. The reaction used N-methylpyrrolidone as solvent, the reaction temperature was 165℃, and the reaction yield was ≥56%. However, the reaction had problems such as poor conversion rate, severe tar formation, and low yield.

[0012] The article "Synthetic Method of 4,5-Dihydro-3-methyl-1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-1,2,4-triazol-5(1H)one" was published in the 2007 issue 03 of *Anhui Chemical Industry*. The reaction used N,N-dimethylformamide as a solvent and employed a high-temperature fluorination method to prepare the target compound. However, the reaction process resulted in severe tar formation, with a yield <75%. Problems included low yield and poor color.

[0013] Most existing technologies use 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one as raw material, N,N-dimethylformamide as solvent, and potassium carbonate as alkali. Difluorochloromethane is introduced and the reaction is carried out at reflux temperature. After the reaction, the product is obtained through centrifugation to remove salt, solvent concentration, hydrolysis, centrifugation to obtain a crude wet product, followed by purification, centrifugation, and drying to obtain the final product, 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. This process is cumbersome, generates large amounts of wastewater, and N,N-dimethylformamide is prone to decomposition during the reaction, resulting in numerous side reactions, severe tar formation leading to low yield, complicated post-treatment, and difficulties in treating waste.

[0014] This invention utilizes a composite solvent to replace the solvents used in existing technologies, and employs a catalyst to effectively lower the reaction temperature and accelerate the raw material conversion rate, while also reducing equipment investment and energy consumption, and improving the effective conversion rate. This method also reduces the decomposition ratio of dichlorofluoromethane, and features high yield, good quality, low waste, and low environmental impact, greatly increasing the feasibility of industrial scale-up. Summary of the Invention

[0015] The purpose of this invention is to overcome the problems existing in the prior art and provide an improved method for the synthesis of difluoromethyltriazolinone: 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one (triazolinone) metal salt is dispersed in a composite solvent, a catalyst is added, and difluorochloromethane is introduced to prepare difluoromethyltriazolinone. This invention features simple operation, high conversion rate, good product quality, and high yield.

[0016] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: An improved method for synthesizing difluoromethyltriazolinone includes the following steps: Compound (II) is reacted with ClCF₂H in a mixed solvent consisting of solvent A and solvent B, the weight of which is 8-15 times the weight of compound (II), in the presence of a catalyst to obtain compound (I); wherein M is selected from K or Na; the catalyst is selected from at least one of a quaternary ammonium salt compound, a crown ether compound, or polyethylene glycol; and solvent A is selected from C1-C2 alkyl-[OCH₂CH₂]. n -OH or C1-C2 alkyl-[OCH2CH2] n -O-C1-C2 alkyl, n is selected from 1, 2, 3 or 4, solvent B is selected from at least one of N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, N,N-dimethylformamide or N,N-dimethylacetamide, and the reaction formula is as follows: .

[0017] Preferably, the improved synthesis method includes the following steps: dissolving the metal salt of 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one (abbreviated as triazolone) in a composite solvent (i.e., a mixed solvent), adding a catalyst, heating and introducing difluorochloromethane until the reaction is complete; cooling and filtering to remove the solid salt, recovering the solvent from the mother liquor, adding a crystallization solvent to disperse, filtering and drying to obtain 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one (abbreviated as difluoromethyltriazolone).

[0018]

[0019] Preferably, the weight of the mixed solvent is 9-12 times the weight of the compound of formula (II).

[0020] Preferably, the mass ratio of solvent A to solvent B in the composite solvent is 1~10:1, more preferably 8~10:1.

[0021] Preferably, the catalyst is selected from tetrabutylphosphine bromide or 18-crown ether-6; the mass of the catalyst is 1 to 10% of the mass of the raw material 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one, preferably 1 to 5%.

[0022] Preferably, the molar ratio of ClCF2H to the compound of formula (II) is 1.5-2 mol: 1 mol.

[0023] Preferably, M is selected from K; the catalyst is selected from at least one of tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium chloride, tetraethylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylphosphine bromide, 15-crown ether-5, 18-crown ether-6, or polyethylene glycol; and the solvent A is selected from C1-C2 alkyl-[OCH2CH2]. n -O-C1-C2 alkyl, n is selected from 1 or 2; solvent B is selected from at least one of N-methylpyrrolidone, sulfolane, N,N-dimethylformamide or N,N-dimethylacetamide.

[0024] Preferably, solvent A is selected from at least one of ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, tri(ethylene glycol) monoethyl ether, tetraethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol diethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, or tetraethylene glycol dimethyl ether.

[0025] In this invention, if there is a conflict between the Chinese name and the structural formula of a compound, the structural formula shall prevail, unless the structural formula is obviously incorrect.

[0026] The beneficial effects of this invention are as follows: The 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one synthesized by this invention has a yield ≥92% based on the potassium salt of the raw material 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one; the effective content of the product is ≥98%. The method of this invention reduces equipment requirements, simplifies operation steps, reduces the decomposition of dichloromethane, and improves the conversion rate of raw materials and the reaction yield.

[0027] This invention overcomes the drawbacks of traditional methods and has the following advantages: ① mild reaction and low equipment investment; ② high reaction conversion rate, small by-products, high yield and good quality; ③ less waste, less pollution and less environmental pressure. Detailed Implementation

[0028] The present invention is illustrated below with reference to examples, but is not intended to limit the invention. Any simple substitutions or modifications made to the present invention by those skilled in the art are within the scope of the technical solutions protected by this invention. Example 1:

[0029] Add 1320 g of diethylene glycol diethyl ether and 140 g of N-methylpyrrolidone to a 3000 mL four-necked flask, start stirring, add 140.9 g of 99% 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one potassium salt (0.527 mol) and 5.6 g of 18-crown-6, heat to 140~150℃, and introduce 72.5 g of difluorochloromethane (0.843 mol). HPLC analysis of the sample revealed the following: 0.43% for 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one, 1.14% for 1-(4-chloro-2-fluorophenyl)-5(difluoromethoxy)-3-methyl-1H-1,2,4-triazol (impurity), and 98.3% for 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was cooled to 60-70℃ and filtered to obtain an organic phase containing 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was kept under negative pressure of 0.099 MPa and at a temperature of 90-150℃, and the mixed solvent was recovered. The mixture was then cooled to 80-90℃ and 400 g of 50% isopropanol aqueous solution was added. The mixture was stirred at 60-70℃ for 1 hour, cooled to 5-10℃, filtered, and dried to obtain 144.87 g of 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one, with a purity of 98.7% and a yield of 94.3%.

[0030] H NMR (400MHz, CDCl3, 6ppm): 2.48 (s, 3H), 7.26 (s, 1H), 7.02 (t, J = 58.0Hz, 1H), 7.35 (d, J = 9.6Hz, 1H), 7.97 (d, J = 7.8HZ, 1H) Example 2:

[0031] Add 1150 g of diethylene glycol diethyl ether and 300 g of N-methylpyrrolidone to a 3000 mL four-necked flask, start stirring, add 140.9 g of 99% 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one potassium salt (0.527 mol), 5.6 g of 18-crown-6, heat to 140-150 °C, and introduce 72.5 g of difluorochloromethane (0.843 mol). HPLC analysis of the sample: 0.23% of 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one, 2.74% of 1-(4-chloro-2-fluorophenyl)-5(difluoromethoxy)-3-methyl-1H-1,2,4-triazol (impurity), and 96.5% of 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was cooled to 60-70℃ and filtered to obtain an organic phase containing 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was kept under negative pressure of 0.099 MPa and at a temperature of 90-150℃, and the mixed solvent was recovered. The mixture was then cooled to 80-90℃ and 400 g of 50% isopropanol aqueous solution was added. The mixture was stirred at 60-70℃ for 1 hour, cooled to 5-10℃, filtered, and dried to obtain 139.63 g of 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one, with a purity of 98.1% and a yield of 93.6%.

[0032] H NMR (400MHz, CDCl3, 6ppm): 2.48 (s, 3H), 7.26 (s, 1H), 7.02 (t, J = 58.0Hz, 1H), 7.35 (d, J = 9.6Hz, 1H), 7.97 (d, J = 7.8HZ, 1H) Example 3:

[0033] Add 1320 g of diethylene glycol diethyl ether and 140 g of N-methylpyrrolidone to a 3000 mL four-necked flask, start stirring, add 140.9 g of 99% 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one potassium salt (0.527 mol) and 5.6 g of tetrabutylphosphine bromide, heat to 140-150 °C, and introduce 72.5 g of difluorochloromethane (0.843 mol). HPLC analysis of the sample: 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one 2.13%, 1-(4-chloro-2-fluorophenyl)-5(difluoromethoxy)-3-methyl-1H-1,2,4-triazol (impurity) 1.58%, 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one 95.98%. The mixture was cooled to 60-70℃ and filtered to obtain an organic phase containing 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was kept under a negative pressure of 0.099 MPa and a temperature of 90-150℃ to recover the mixed solvent. The mixture was then cooled to 80-90℃ and 400 g of 50% isopropanol aqueous solution was added. The temperature was maintained at 60-70℃ and stirred for 1 hour. The mixture was then cooled to 5-10℃, filtered, and dried to obtain 139.17 g of 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one, with a purity of 98.0% and a yield of 93.2%.

[0034] H NMR (400MHz, CDCl3, 6ppm): 2.48 (s, 3H), 7.26 (s, 1H), 7.02 (t, J = 58.0Hz, 1H), 7.35 (d, J = 9.6Hz, 1H), 7.97 (d, J = 7.8HZ, 1H) Example 4:

[0035] Add 1320 g of diethylene glycol dimethyl ether and 140 g of N-methylpyrrolidone to a 3000 mL four-necked flask, start stirring, add 140.9 g of 99% 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one potassium salt (0.527 mol) and 5.6 g of tetrabutylphosphine bromide, heat to 140-150 °C, and introduce 72.5 g of difluorochloromethane (0.843 mol). HPLC analysis of the sample: 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one 2.92%, 1-(4-chloro-2-fluorophenyl)-5(difluoromethoxy)-3-methyl-1H-1,2,4-triazol (impurity) 2.32%, 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one 93.24%. The mixture was cooled to 60-70℃ and filtered to obtain an organic phase containing 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was kept under a negative pressure of 0.099 MPa and a temperature of 90-130℃, and the mixed solvent was recovered. The mixture was then cooled to 80-90℃ and 400 g of 50% isopropanol aqueous solution was added. The temperature was maintained at 60-70℃ and stirred for 1 hour. The mixture was then cooled to 5-10℃, filtered, and dried to obtain 136.64 g of 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one, with a purity of 98.1% and a yield of 92.6%.

[0036] H NMR (400MHz, CDCl3, 6ppm): 2.48 (s, 3H), 7.26 (s, 1H), 7.02 (t, J = 58.0Hz, 1H), 7.35 (d, J = 9.6Hz, 1H), 7.97 (d, J = 7.8HZ, 1H) Example 5:

[0037] Add 1320 g of diethylene glycol diethyl ether and 140 g of N,N-dimethylformamide to a 3000 mL four-necked flask, start stirring, add 140.9 g of 99% 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-ketone potassium salt (0.527 mol) and 5.6 g of 18-crown-6, heat to 140~150℃, and introduce 72.5 g of difluorochloromethane (0.843 mol). HPLC analysis of the sample revealed the following: 0.36% for 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one, 2.94% for 1-(4-chloro-2-fluorophenyl)-5(difluoromethoxy)-3-methyl-1H-1,2,4-triazol (impurity), and 95.87% for 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was cooled to 60-70℃ and filtered to obtain an organic phase containing 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was kept under a negative pressure of 0.099 MPa and a temperature of 90-150℃, and the mixed solvent was recovered. The mixture was then cooled to 80-90℃ and 400 g of 50% isopropanol aqueous solution was added. The temperature was maintained at 60-70℃ and stirred for 1 hour. The mixture was then cooled to 5-10℃, filtered, and dried to obtain 141.5 g of 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one, with a purity of 98.2% and a yield of 95.0%.

[0038] H NMR (400MHz, CDCl3, 6ppm): 2.48 (s, 3H), 7.26 (s, 1H), 7.02 (t, J = 58.0Hz, 1H), 7.35 (d, J = 9.6Hz, 1H), 7.97 (d, J = 7.8HZ, 1H) Compare with Example 1: Add 1450 g of diethylene glycol diethyl ether to a 3000 mL four-necked flask, start stirring, add 140.9 g of 99% 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one potassium salt (0.527 mol) and 5.6 g of 18-crown-6, heat to 140-150 °C, and introduce 72.5 g of difluorochloromethane (0.843 mol). Take a sample for HPLC analysis. Analysis: 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one 35.3%, 1-(4-chloro-2-fluorophenyl)-5(difluoromethoxy)-3-methyl-1H-1,2,4-triazol (impurity) 3.87%, 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one 60.25%.

[0039] Compare with Example 2: Add 1450 g of N-methylpyrrolidone to a 3000 mL four-necked flask, start stirring, add 140.9 g of 99% 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one potassium salt (0.527 mol) and 5.6 g of 18-crown-6, heat to 140-150 °C, and introduce 72.5 g of difluorochloromethane (0.843 mol). Take a sample for HPLC analysis: 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one potassium salt. 0.12% of 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one, 7.32% of 1-(4-chloro-2-fluorophenyl)-5-(difluoromethoxy)-3-methyl-1H-1,2,4-triazol (impurity), 7.53% of unknown impurities, and 83.56% of 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was cooled to 60-70℃ and filtered to obtain an organic phase containing 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The solvent was recovered under a negative pressure of 0.099 MPa and a temperature of 120-170℃. The mixture was then cooled to 80-90℃ and 400 g of 50% isopropanol aqueous solution was added. The mixture was stirred at 60-70℃ for 1 hour, cooled to 5-10℃, filtered, and dried to obtain 125.68 g of 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one, with a purity of 91.4% and a yield of 78.5%.

[0040] Compare with Example 3: Add 1320 g of diethylene glycol diethyl ether to a 3000 mL four-necked flask, start stirring, add 140.9 g of 99% 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one potassium salt (0.527 mol), heat to 190-200 °C, and introduce 72.5 g of difluorochloromethane (0.843 mol). Perform HPLC analysis on a sample: 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one (10.32%), 1-(4-chloro-2-fluorophenyl)-5(difluoromethoxy)-3-methyl-1H-1,2,4-triazole (impurity) (2.58%), 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)- 3-Methyl-1H-1,2,4-triazol-5(4H)-one (86.34%). The mixture was cooled to 60-70℃ and filtered to obtain an organic phase containing 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The solvent was recovered under a negative pressure of 0.099 MPa and a temperature of 90-150℃. The mixture was then cooled to 80-90℃ and 400 g of 50% isopropanol aqueous solution was added. The mixture was stirred at 60-70℃ for 1 hour, cooled to 5-10℃, filtered, and dried to obtain 1-(4-chloro-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one (138.49 g). The content was determined to be 88.12%, and the yield was 83.41%.

[0041] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. An improved method for synthesizing difluoromethyltriazolinone, characterized in that, The process includes the following steps: Compound (II) is reacted with ClCF2H in a mixed solvent consisting of solvent A and solvent B, the weight of which is 8-15 times the weight of compound (II), in the presence of a catalyst to prepare compound (I); wherein M is selected from K or Na; the catalyst is selected from at least one of quaternary ammonium salt compounds, crown ether compounds, or polyethylene glycol; and solvent A is selected from C1-C2 alkyl-[OCH2CH2]. n -OH or C1-C2 alkyl-[OCH2CH2] n -O-C1-C2 alkyl, n is selected from 1, 2, 3 or 4, solvent B is selected from at least one of N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, N,N-dimethylformamide or N,N-dimethylacetamide, and the reaction formula is as follows: 。 2. The method as described in claim 1, characterized in that, The reaction temperature is 140-150℃.

3. The method as described in claim 1, characterized in that, M is selected from K.

4. The method as described in claim 1, characterized in that, The catalyst is selected from at least one of tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium chloride, tetraethylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylphosphine bromide, 15-crown ether-5, 18-crown ether-6, or polyethylene glycol.

5. The method as described in claim 4, characterized in that, The catalyst is selected from tetrabutylphosphine bromide or 18-crown ether-6.

6. The method as described in claim 1, characterized in that, The mass of the catalyst is 1-10% of the mass of the reactant compound (II), 1-(4-chloro-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one, and the molar ratio of difluorochloromethane ClCF2H to the compound (II) is 1.5-2 mol:1 mol.

7. The method as described in claim 1, characterized in that, Solvent A is selected from C1-C2 alkyl-[OCH2CH2]. n -O-C1-C2 alkyl, n is selected from 1 or 2; solvent B is selected from at least one of N-methylpyrrolidone, sulfolane, N,N-dimethylformamide or N,N-dimethylacetamide.

8. The method as described in claim 1, characterized in that, Solvent A is selected from at least one of ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, tri(ethylene glycol) monoethyl ether, tetraethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, or tetraethylene glycol dimethyl ether.

9. The method as described in claim 1, characterized in that, The mass ratio of solvent A to solvent B is 1~10:

1.

10. The method as described in claim 1, characterized in that, The mass ratio of solvent A to solvent B is 8~10:1.

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