Synthesis method of 1-methyl-3-difluoromethyl-4-pyrazole acid ester

Abstract

The invention provides a synthesis method of 1-methyl-3-difluoromethyl-4-pyrazole acid ester, which comprises the following steps of: reacting pyruvic acid (methyl) ethyl ester with difluoroacetyl halide or difluoroacetate compound in an aprotic organic solvent in the presence of alkali to obtain a first intermediate; then reacting with hydrazine hydrate to obtain a cyclization intermediate, and finally performing methylation reaction on the cyclization intermediate and dimethyl sulfate to obtain a target product. The faint yellow 1-methyl-3-difluoromethyl-4-pyrazole acid ester product is synthesized through the steps, the content is 98.1%-99.0%, the total yield of the reaction is 92.0%-95.0%, meanwhile, no isomer of the product is generated in the synthesis route, and the selectivity is high. The preparation method disclosed by the invention is safe in process operation, mild in synthesis condition and high in target product yield, and can be applied to industrial amplification practical application.

Description

Technical Field

[0001] The invention relates to the synthesis of fluorine-containing intermediates, in particular to the synthesis of 1-methyl-3-difluoromethyl-4-pyrazole ester, and belongs to the field of chemical synthesis. Background Art

[0002] 1-Methyl-3-difluoromethyl-4-pyrazole ester is a fluorinated pharmaceutical and pesticide intermediate. Its hydrolysis product, 1-methyl-3-difluoromethyl-pyrazole-4-carboxylic acid, is a key intermediate in the synthesis of SDHI fungicides. It is primarily used in the synthesis of various succinate dehydrogenase inhibitors, including isopyrazam, fluxapyroxad, bixafen, flurazine, and benzoene fluconazole. These pesticides have been a hot topic in pesticide research in recent years. As SDHI fungicides, pyrazoleamide fungicides possess a unique mechanism of action and are highly effective and low in toxicity, making them suitable for controlling a wide range of crop diseases.

[0003] There are many methods for synthesizing 1-methyl-3-difluoromethyl-4-pyrazole ester, among which the common process routes are as follows: (1) Patent document EP2008996A discloses a five-step synthesis using dichloroacetyl chloride, vinyl ether compounds, methylhydrazine and other raw materials through condensation, cyclization, fluorination and other reactions: the reaction conditions of this synthesis route are relatively harsh, in which dichloroacetyl chloride and vinyl ether compounds need to react at -40℃ to -20℃; the reaction temperature in the catalytic pressure reaction of carboxyl group needs to be 150℃, and the pressure needs to be changed continuously during the process, which is inconvenient to operate, and the isomers are difficult to separate, making it unsuitable for industrial production. (2) Patent document EP2008996A discloses a three-step synthesis using 1,1-difluoroacetone, methylhydrazine and phosphorus oxychloride as raw materials. The raw material 1,1-difluoroacetone of this synthesis route is expensive, the yield is low at only 53%, and the isomers are difficult to separate. At the same time, a large amount of wastewater containing phosphorus and DMF is generated, which is not suitable for industrial production. (3) Patent document EP1997808A discloses a four-step reaction synthesis using difluoroacetoacetic acid ethyl ester, triethyl orthoformate, acetic anhydride, and methylhydrazine as raw materials. This synthetic route has simple steps and low waste production, but the raw material difluoroacetoacetic acid ethyl ester is expensive (600,000 / ton), and the reaction system has strict requirements on water content, which is not suitable for industrial production. (4) Patent document EP2008996A discloses a synthesis using difluoroacetic acid ethyl ester, ethyl propiolate, and methylhydrazine as raw materials. Although it has certain advantages in cost, the key step of the reaction between difluoroacetoacetic acid ethyl ester and ethyl propiolate requires high temperature reaction, ethyl propiolate has high requirements on system water content, and there is no yield report, which is not suitable for industrial production. (5) Patent document CN1021720317A discloses a reaction synthesis using 1,1,2,2-tetrafluoroethyldimethylamine, 3-methoxyacrylate, and methylhydrazine as raw materials. The problems with this route are that the raw materials are not easy to obtain, the fluorination reagent used is relatively dangerous, and isomers are generated, resulting in a low reaction yield. (6) Li Lifeng's master's thesis, "Study on the Synthesis Process of 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic Acid," discloses a reaction synthesis using propargyl alcohol, sodium hypochlorite, acyl chloride, dimethylamine, difluoroacetic acid, and hydrazine hydrate as raw materials. The raw materials of this route are cheap and readily available, the yield is high, and the reaction conditions are mild. However, the raw materials are highly toxic and the synthesis steps are long. (7) Patent document CN1871204A discloses a reaction synthesis using difluoroacetyl chloride or difluoroacetyl fluoride, dimethylaminoethyl acrylate, and methylhydrazine as raw materials. The problems of this route are that the raw materials difluoroacetyl chloride and dimethylaminoethyl acrylate are both difficult to obtain, the reaction conditions are relatively harsh (reaction temperature -30 to -50°C), and a mixture of two isomers is obtained. The proportion of the unwanted isomer is large and the isomers are difficult to separate, making it unsuitable for industrial production.

[0004] In summary, as an important intermediate for the synthesis of SDHI fungicides, 1-methyl-3-difluoromethyl-4-pyrazole ester has a large demand and broad market prospects. However, in the current synthesis methods of 1-methyl-3-difluoromethyl-4-pyrazole ester, the isomer content of the cyclization intermediate is high and difficult to separate, with the lowest being around 10.9-12.7%; the product yield is low, generally around 25-65%; the raw materials are difficult to obtain and the cost is high; or the reaction conditions are harsh and the amount of three wastes is large. Therefore, it is necessary to develop a new synthesis route for 1-methyl-3-difluoromethyl-4-pyrazole ester with low cost, high reaction yield, low isomer content, mild reaction conditions, and a process suitable for industrial use. Summary of the Invention

[0005] In order to solve the above technical problems, the present invention provides a method for synthesizing 1-methyl-3-difluoromethyl-4-pyrazole ester, which has high product selectivity, high yield, mild reaction conditions, and is suitable for industrial production.

[0006] To achieve the above objectives, the main technical solutions adopted by the present invention include:

[0007] A method for preparing 1-methyl-3-difluoromethyl-4-pyrazole ester, wherein the structure of the 1-methyl-3-difluoromethyl-4-pyrazole ester is shown in (1).

[0008]

[0009] The preparation method comprises the following steps:

[0010] Step (1): Step (1): methyl pyruvate or ethyl pyruvate is reacted with a base in an aprotic organic solvent at a temperature suitable for the reaction, and then difluoroacetyl halide or difluoroacetic acid ester compound is added to continue the reaction, and the obtained reaction solution is slowly added with formic acid to acidify, and the pH is controlled between 5-6, and then the base used for the reaction is added to adjust the pH between 7-8 to obtain a reaction solution of the first intermediate (2), and then ice water at 0-10°C is added to separate the liquids, and the organic layer is the product layer; further, the aqueous layer can be continuously extracted twice with a small amount of reaction solvent, and the organic layers are combined;

[0011] Step (2): Step (2): The organic layer containing the first intermediate (2) obtained in step (1) is slowly added to hydrazine hydrate at a temperature suitable for the reaction to obtain a cyclized intermediate (3), and then the temperature is raised to room temperature, the liquid is separated, and the organic layer is subjected to the next reaction;

[0012] Step (3): the cyclization intermediate (3) obtained in step (2) is reacted with dimethyl sulfate in the presence of a base at a temperature suitable for the reaction to undergo a methylation reaction to obtain a reaction solution of the target product (1). After the reaction is completed, the temperature is lowered and the pH is adjusted to between 7 and 8. The liquids are separated and the organic layer is concentrated under reduced pressure to obtain the target product (1);

[0013] According to the above steps, the total yield of the reaction is 92.0% to 95.0% (calculated as pyruvate).

[0014] The reaction formula is as follows:

[0015]

[0016] In step (1) of the present invention, the aprotic organic solvent is immiscible with water and is selected from at least one of benzene, toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, n-hexane, cyclohexane, and petroleum ether, preferably toluene or dichloroethane; the difluoroacetyl halide is at least one of difluoroacetyl chloride, difluoroacetyl fluoride, and difluoroacetyl bromide, preferably difluoroacetyl chloride or difluoroacetyl fluoride; the difluoroacetate is at least one of difluoroacetate compounds, preferably methyl difluoroacetate and ethyl difluoroacetate; the base is an inorganic base or a non-nucleophilic organic base, preferably sodium ethoxide or sodium methoxide or 1,8-diazabicyclo[5.4.0]undec-7-ene, referred to as DBU.

[0017] In step (1) of the present invention, the suitable reaction temperature is -30°C to 30°C, and the preferred reaction temperature is -5°C to 10°C; the molar ratio of the methyl pyruvate or ethyl pyruvate to the base used in the reaction is 1:1.0 to 3.0, and the preferred molar ratio is 1:1.0 to 1.8; the molar ratio of the methyl pyruvate or ethyl pyruvate to the difluoroacetyl halide or difluoroacetate compound is 1:1.0 to 2.0, and the preferred molar ratio is 1:1.0 to 1.3.

[0018] The reaction in step (1) of the present invention can be carried out under normal pressure or under pressure. However, trifluoroacetyl halide is a gas. During the introduction of trifluoroacetyl halide, the reaction can be carried out under pressure. The appropriate reaction pressure is 0 MPa to 1.0 MPa, and the preferred reaction pressure is 0.1 MPa to 0.3 MPa.

[0019] In step (2) of the present invention, the organic layer containing the first intermediate (2) is slowly added to a mixture containing hydrazine hydrate and the same aprotic organic solvent used in step (1) at a temperature suitable for the reaction.

[0020] In step (2) of the present invention, the suitable reaction temperature is -30°C to 10°C, and the preferred reaction temperature is -5°C to 5°C; the molar ratio of methyl pyruvate or ethyl pyruvate to hydrazine is 1:1.0 to 2.0, and the preferred molar ratio is 1:1.0 to 1.3.

[0021] The hydrazine hydrate in step (2) of the present invention can be pure hydrazine or a hydrazine hydrate solution in different solution forms, such as a commercially available hydrazine hydrate solution, preferably a 40%-80% hydrazine hydrate solution.

[0022] The base in step (3) of the present invention is at least one of an inorganic base or an organic tertiary amine base. Preferably, the inorganic base is selected from one, two or more of alkali metal carbonates and alkaline earth metal carbonates, and potassium carbonate and sodium carbonate are further preferred. The organic tertiary amine base is preferably triethylamine or pyridine.

[0023] The suitable reaction temperature in step (3) of the present invention is 40°C to 100°C, and the preferred reaction temperature is 60°C to 90°C; the molar ratio of methyl pyruvate or ethyl pyruvate to dimethyl sulfate is 1:1.0 to 2.0, and the preferred molar ratio is 1:1.0 to 1.3.

[0024] The 1-methyl-3-difluoromethyl-4-pyrazole ester prepared by the steps of the present invention has a content of 98.1% to 99.0% (gas chromatography, external standard method), a total yield of 92.0% to 95.0% (calculated as pyruvate), and no isomers of the product are found in the synthetic route, indicating high selectivity. The preparation method of the present invention has safe process operation, mild synthesis conditions, and a high yield of the target product, and can be used for industrial scale-up and practical application.

[0025] Compared with the prior art, the present invention has the following advantages:

[0026] (1) The process is simple to operate. Each step of the reaction does not require a complex purification process. Only a simple extraction and separation operation is required, and the organic layer is directly used for the next reaction. Only the same solvent is used in the entire step.

[0027] (2) The process is highly selective and no isomers are produced;

[0028] (3) The process has mild reaction conditions and does not require very low temperatures. Other processes require -15°C or even lower temperatures to control the content of isomers. It has low energy consumption and is suitable for industrial production.

[0029] (4) The process has a high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] One or more embodiments are illustrated by way of examples in the accompanying drawings, and these exemplary illustrations do not constitute limitations on the embodiments.

[0031] Figure 1 : After the reaction of step (3) of Example 1 of the present invention is completed, the organic layer is subjected to gas chromatography analysis: the solvent peak toluene has been deducted, of which 11.032 minutes is the product peak

[0032] Figure 2: The organic layer reaction liquid of Comparative Example 1 of the present invention was subjected to gas chromatography analysis after the reaction was completed: the solvent peak of toluene was deducted, wherein 11.041 minutes was the product peak, 9.399 minutes was the isomer peak, and 9.948 minutes was the peak of the raw material N, N-dimethylamino ethyl acrylate. DETAILED DESCRIPTION

[0033] The present invention will be further described below with reference to specific embodiments, but the present invention is not limited to these specific embodiments. Those skilled in the art should recognize that the present invention covers all possible alternatives, improvements and equivalents within the scope of the claims.

[0034] Analytical instrument: Shimadzu GC-2014 gas chromatograph, CP-Sil 8CB chromatographic column (length 30.0 m, inner diameter 0.32 mm, film thickness 0.25 μm).

[0035] Analysis conditions: initial temperature 40°C, hold for 5 min, heat to 220°C at a rate of 5°C / min, hold for 5 min; injection port temperature: 220°C; carrier gas: nitrogen; split ratio: 30.0; column flow rate: 0.73 ml / min; detector: FID; detector temperature: 220°C.

[0036] In the following examples, the GC spectra of the esters are shown, i.e., gas chromatography detection.

[0037] Example 1

[0038] Step (1): 170 g (1.0 mol) of ethyl trifluoropyruvate was added to a 1 L three-necked flask, 250 g of toluene was added, stirring was started, and the temperature was cooled to -5 ° C. 81.6 g (1.2 mol) of sodium ethoxide was slowly added to the three-necked flask, the temperature was controlled not to exceed 0 ° C. The reaction was completed for 1 hour, and then 136.4 g (1.1 mol) of ethyl difluoroacetate was dropwise added, the temperature was controlled between -5 and 0 ° C during the dropwise addition, and the reaction was kept at 0 ° C for 1 hour after the dropwise addition was completed. Formic acid was slowly added to acidify and the pH was controlled between 5 and 6. Sodium ethoxide was then added to adjust the pH to about 7. Then 150 ml of ice water at 0 to 10 ° C was added, and the solution was allowed to stand for separation. The organic layer was the product layer. The aqueous layer was further extracted twice with a small amount of toluene. The organic layers were combined and the organic layer was subjected to the next step of reaction. The organic layer was subjected to gas chromatography analysis, and the product purity was 98.1% (after deducting the solvent).

[0039] Step (2): 88 g (1.1 mol) of 40% hydrazine hydrate and 50 g of toluene were added to a 1 L three-necked flask, cooled to -5°C, and the organic layer obtained in step (1) was slowly added dropwise to the hydrazine hydrate, controlling the temperature between -5 and 5°C during the addition. After the addition was complete, the mixture was reacted for 1 hour, raised to room temperature, and allowed to stand for separation. The organic layer was the product layer and was used for the next reaction. The organic layer was subjected to gas chromatography analysis, and the purity of the product was 99.1% (after deducting the solvent).

[0040] Step (3): the organic layer obtained in step (2) is added into a 1L three-necked flask, 138.6g (1.1mol) of dimethyl sulfate and 116.6g (1.1mol) of sodium carbonate are added, and the mixture is heated to 70°C. At this temperature, the mixture is reacted for 3 hours. The reaction is completed. After cooling, 10% sodium hydroxide solution is added, and the pH value is adjusted between 7 and 8. The separation is allowed to stand, and the organic layer reaction solution is subjected to gas chromatography detection, which shows no isomer peak. The mixture is concentrated under reduced pressure to obtain a light yellow product, which is then dried to obtain 187.7 grams of 1-methyl-3-difluoromethyl-4-pyrazole acid ethyl ester with a content of 98.7% (gas chromatography, external standard method). The total yield of the reaction is 92.0%.

[0041] Comparative Example 1

[0042] According to a traditional synthesis process, difluoroacetyl fluoride and ethyl N,N-dimethylaminoacrylate are used as starting materials to react to obtain an intermediate reaction solution, which is then cyclized with aqueous methylhydrazine to produce 3-difluoromethylpyrazolecarboxylate. 250g of N,N-dimethylaminoacrylate and 155g of triethylamine are added to a 2000ml three-necked flask, and 660g of toluene is added to dissolve. The mixture is cooled to -5-0°C by refrigeration, and 159g of difluoroacetyl fluoride is introduced. The reaction is allowed to proceed for 3 hours, and the temperature is slowly raised to 10°C for 5 hours. After completion of the reaction, GC monitoring is performed, and the triethylamine hydrofluoride salt is washed dropwise with water after refrigeration and cooling to 0°C. The liquids are separated by stirring, and the organic layer is directly used in the next step. 183 g of 40% methylhydrazine was added to a three-necked flask, 220 g of toluene was added for dilution, and the temperature was cooled to -20 ° C with stirring. The organic layer of the previous reaction was cooled to -5 ° C and slowly added dropwise to the methylhydrazine solution. The temperature was controlled well. The reaction was completed for 1 hour and then raised to room temperature of 20 ° C. The precipitated product in the reaction system was completely dissolved. The reaction was completed by GC detection. The liquid was separated and the organic layer reaction liquid was subjected to gas chromatography detection. The isomer peak: product peak was approximately 1:10.

[0043] Example 2

[0044] Step (1): 170 g (1.0 mol) of ethyl trifluoropyruvate was added to a 1 L three-necked flask, 250 g of toluene was added, stirring was started, and the temperature was cooled to -5 ° C. 122.4 g (1.8 mol) of sodium ethoxide was slowly added to the three-necked flask, the temperature was controlled not to exceed 0 ° C. The reaction was completed for 1 hour, and then 136.4 g (1.1 mol) of ethyl difluoroacetate was dropwise added, the temperature was controlled between -5 and 0 ° C during the dropwise addition, and the reaction was kept at 0 ° C for 1 hour after the dropwise addition was completed. Formic acid was slowly added to acidify, the pH was controlled between 5 and 6, and then sodium ethoxide was added to adjust the pH to about 7. Then 150 ml of ice water at 0 to 10 ° C was added, and the solution was allowed to stand for separation. The organic layer was the product layer, and the aqueous layer was extracted twice with a small amount of toluene. The organic layers were combined and the organic layer was subjected to the next step of reaction. The organic layer was subjected to gas chromatography analysis, and the product purity was 98.9% (after deducting the solvent);

[0045] Step (2): 88 g (1.1 mol) of 40% hydrazine hydrate and 50 g of toluene were added to a 1 L three-necked flask, cooled to -5°C, and the organic layer obtained in step (1) was slowly added dropwise to the hydrazine hydrate, controlling the temperature between -5 and 5°C during the addition. After the addition was complete, the mixture was reacted for 1 hour, raised to room temperature, and allowed to stand for separation. The organic layer was the product layer and was used for the next reaction. The organic layer was subjected to gas chromatography analysis, and the purity of the product was 99.4% (after deducting the solvent).

[0046] Step (3): the organic layer obtained in step (2) is added into a 1L three-necked flask, 138.6g (1.1mol) of dimethyl sulfate and 116.6g (1.1mol) of sodium carbonate are added, and the mixture is heated to 70°C. At this temperature, the mixture is reacted for 3 hours. The reaction is completed. After cooling, 10% sodium hydroxide solution is added, and the pH value is adjusted between 7 and 8. The organic layer reaction solution is allowed to stand for separation, and gas chromatography detection is performed to find no isomer peaks. The mixture is concentrated under reduced pressure to obtain a light yellow product, which is then dried to give 190.9 grams of 1-methyl-3-difluoromethyl-4-pyrazole acid ethyl ester with a content of 98.8% (gas chromatography, external standard method). The total yield of the reaction is 93.6%.

[0047] Example 3

[0048] Step (1): 170 g (1.0 mol) of ethyl trifluoropyruvate was added to a 1 L three-necked flask, 250 g of dichloroethane was added, stirring was started, and the temperature was cooled to -5 ° C. 122.4 g (1.8 mol) of sodium ethoxide was slowly added to the three-necked flask, the temperature was controlled not to exceed 0 ° C. The reaction was completed for 1 hour, and then 136.4 g (1.1 mol) of ethyl difluoroacetate was dropwise added, the temperature was controlled between -5 and 0 ° C during the dropwise addition, and the reaction was kept at 0 ° C for 1 hour after the dropwise addition was completed. Formic acid was slowly added to acidify, the pH was controlled between 5 and 6, and then sodium ethoxide was added to adjust the pH to about 7. Then 150 ml of ice water at 0 to 10 ° C was added, and the mixture was allowed to stand for separation. The organic layer was the product layer, and the aqueous layer was continuously extracted twice with a small amount of dichloroethane. The organic layers were combined and the organic layer was subjected to the next step of reaction. The organic layer was subjected to gas chromatography analysis, and the product purity was 98.1% (after deducting the solvent);

[0049] Step (2): 52 g (1.3 mol) of 80% hydrazine hydrate and 50 g of dichloroethane were added to a 1 L three-necked flask, cooled to -5°C, and the organic layer obtained in step (1) was slowly added dropwise to the hydrazine hydrate. The temperature was controlled between -5°C and 5°C during the addition. After the addition was complete, the mixture was reacted for 1 hour, heated to room temperature, and allowed to stand for separation. The organic layer was the product layer and was used for the next reaction. The organic layer was subjected to gas chromatography analysis, and the purity of the product was 98.6% (after deducting the solvent).

[0050] Step (3): the organic layer obtained in step (2) is added into a 1L three-necked flask, 138.6g (1.1mol) of dimethyl sulfate and 116.6g (1.1mol) of sodium carbonate are added, and the mixture is heated to 70°C. At this temperature, the mixture is reacted for 3 hours. The reaction is completed. After cooling, 10% sodium hydroxide solution is added, and the pH value is adjusted between 7 and 8. The separation is allowed to stand, and the organic layer reaction solution is subjected to gas chromatography detection, which shows no isomer peak. The mixture is concentrated under reduced pressure to obtain a light yellow product, which is then dried to obtain 194.4 grams of 1-methyl-3-difluoromethyl-4-pyrazole acid ethyl ester with a content of 99.1% (gas chromatography, external standard method). The total yield of the reaction is 95.3%.

[0051] Example 4

[0052] Step (1): 170 g (1.0 mol) of ethyl trifluoropyruvate was added to a 1 L three-necked flask, 250 g of toluene was added, stirring was started, and the temperature was cooled to -5 ° C. 122.4 g (1.8 mol) of sodium ethoxide was slowly added to the three-necked flask, the temperature was controlled not to exceed 0 ° C. The reaction was completed for 1 hour, and then 117.6 g (1.2 mol) of difluoroacetyl fluoride was slowly introduced, the temperature was controlled between -5 and 0 ° C during the addition, and the reaction was kept at 0 ° C for 1 hour after the dropwise addition was completed. Formic acid was slowly added to acidify, the pH was controlled between 5 and 6, and then sodium ethoxide was added to adjust the pH to about 7. Then 150 ml of ice water at 0 to 10 ° C was added, and the organic layer was allowed to stand for separation. The organic layer was the product layer, and the aqueous layer was further extracted with a small amount of toluene twice. The organic layers were combined and the organic layer was subjected to the next step of reaction. The organic layer was subjected to gas chromatography analysis, and the product purity was 98.8% (after deducting the solvent);

[0053] Step (2): 52 g (1.3 mol) of 80% hydrazine hydrate and 50 g of toluene were added to a 1 L three-necked flask, and the temperature was cooled to -5°C. The organic layer obtained in step (1) was slowly added dropwise to the hydrazine hydrate, and the temperature was controlled between -5 and 5°C during the addition. After the addition was complete, the mixture was reacted for 1 hour, and the temperature was raised to room temperature. The mixture was allowed to stand for separation, and the organic layer was the product layer, which was used for the next reaction. The organic layer was subjected to gas chromatography analysis, and the purity of the product was 98.4% (after deducting the solvent).

[0054] Step (3): the organic layer obtained in step (2) is added into a 1L three-necked flask, 138.6g (1.1mol) of dimethyl sulfate and 116.6g (1.1mol) of sodium carbonate are added, and the mixture is heated to 70°C. At this temperature, the mixture is reacted for 3 hours. The reaction is completed. After cooling, 10% sodium hydroxide solution is added, and the pH value is adjusted between 7 and 8. The separation is allowed to stand, and the organic layer reaction solution is subjected to gas chromatography detection, which shows no isomer peak. The mixture is concentrated under reduced pressure to obtain a light yellow product, which is then dried to obtain 192.0 grams of 1-methyl-3-difluoromethyl-4-pyrazole acid ethyl ester with a content of 98.5% (gas chromatography, external standard method). The total yield of the reaction is 94.1%.

[0055] Example 5

[0056] Step (1): 156 g (1.0 mol) of methyl trifluoropyruvate was added to a 1 L three-necked flask, 250 g of toluene was added, stirring was started, and the temperature was cooled to -5 ° C. 102 g (1.5 mol) of sodium ethoxide was slowly added to the three-necked flask, the temperature was controlled not to exceed 0 ° C. The reaction was completed for 1 hour, and then 136.8 g (1.2 mol) of difluoroacetyl chloride was slowly introduced, the temperature was controlled between -5 and 0 ° C during the dropwise addition, and the reaction was kept at 0 ° C for 1 hour after the dropwise addition was completed. Formic acid was slowly added to acidify, the pH was controlled between 5 and 6, and then sodium ethoxide was added to adjust the pH to about 7. Then 150 ml of ice water at 0 to 10 ° C was added, and the solution was allowed to stand for separation. The organic layer was the product layer, and the aqueous layer was continuously extracted twice with a small amount of toluene. The organic layers were combined and the organic layer was subjected to the next step of reaction. The organic layer was subjected to gas chromatography analysis, and the product purity was 98.0% (after deducting the solvent);

[0057] Step (2): 52 g (1.3 mol) of 80% hydrazine hydrate and 50 g of toluene were added to a 1 L three-necked flask, and the temperature was cooled to -5°C. The organic layer obtained in step (1) was slowly added dropwise to the hydrazine hydrate, and the temperature was controlled between -5 and 5°C during the addition. After the addition was complete, the mixture was reacted for 1 hour, the temperature was raised to room temperature, and the mixture was allowed to stand for separation. The organic layer was the product layer and was used for the next reaction. The organic layer was subjected to gas chromatography analysis, and the purity of the product was 98.1% (after deducting the solvent).

[0058] Step (3): the organic layer obtained in step (2) is added into a 1L three-necked flask, 138.6g (1.1mol) of dimethyl sulfate and 151.8g (1.1mol) of potassium carbonate are added, and the mixture is heated to 80°C. At this temperature, the mixture is reacted for 3 hours. The reaction ends. After cooling, 10% sodium hydroxide solution is added, the pH value is adjusted between 7 and 8, and the separation is allowed to stand. The organic layer reaction solution is subjected to gas chromatography detection, and no isomer peak is observed. The mixture is concentrated under reduced pressure to obtain a pale yellow product, which is then dried to give 176.5 grams of 1-methyl-3-difluoromethyl-4-pyrazole acid methyl esters with a content of 98.1% (gas chromatography, external standard method). The total yield of the reaction is 92.9%.

[0059] Example 6

[0060] Step (1): 170 g (1.0 mol) of ethyl trifluoropyruvate was added to a 1 L three-necked flask, 250 g of toluene was added, stirring was started, and the temperature was cooled to -5°C. 273.6 g (1.8 mol) of DBU was slowly added to the three-necked flask, the temperature was controlled not to exceed 0°C, and the reaction was completed for 1 hour. Then 136.4 g (1.1 mol) of ethyl difluoroacetate was added dropwise, and the temperature was controlled between -5 and 0°C during the addition. After the dropwise addition was completed, the reaction was kept at 0°C for 1 hour, formic acid was slowly added to acidify, and the pH was controlled between 5 and 6. Then sodium ethoxide was added to adjust the pH to about 7. Then 150 ml of ice water at 0 to 10°C was added, and the mixture was allowed to stand for separation. The organic layer was the product layer, and the aqueous layer was further extracted twice with a small amount of toluene. The organic layers were combined and the organic layer was subjected to the next step of reaction. The organic layer was subjected to gas chromatography analysis, and the product purity was 98.9% (after deducting the solvent);

[0061] Step (2): 52 g (1.3 mol) of 80% hydrazine hydrate and 50 g of toluene were added to a 1 L three-necked flask, and the temperature was cooled to -5°C. The organic layer obtained in step (1) was slowly added dropwise to the hydrazine hydrate, and the temperature was controlled between -5 and 5°C during the addition. After the addition was complete, the mixture was reacted for 1 hour, and the temperature was raised to room temperature. The mixture was allowed to stand for separation, and the organic layer was the product layer, which was used for the next reaction. The organic layer was subjected to gas chromatography analysis, and the purity of the product was 99.0% (after deducting the solvent).

[0062] Step (3): the organic layer obtained in step (2) is added into a 1L three-necked flask, 138.6g (1.1mol) of dimethyl sulfate and 116.6g (1.1mol) of sodium carbonate are added, and the mixture is heated to 90°C. At this temperature, the mixture is reacted for 3 hours. The reaction is completed. After cooling, 10% sodium hydroxide solution is added, and the pH value is adjusted between 7 and 8. The separation is allowed to stand, and the organic layer reaction solution is subjected to gas chromatography detection, which shows no isomer peak. The mixture is concentrated under reduced pressure to obtain a light yellow product, which is then dried to obtain 189.7 grams of 1-methyl-3-difluoromethyl-4-pyrazole acid ethyl ester with a content of 99.1% (gas chromatography, external standard method). The total yield of the reaction is 93.0%.

[0063] Example 7

[0064] Step (1): 170 g (1.0 mol) of ethyl trifluoropyruvate was added to a 1 L three-necked flask, 250 g of toluene was added, stirring was started, and the temperature was cooled to -5 ° C. 122.4 g (1.8 mol) of sodium ethoxide was slowly added to the three-necked flask, the temperature was controlled not to exceed 0 ° C. The reaction was completed for 1 hour, and then 136.4 g (1.1 mol) of ethyl difluoroacetate was dropwise added, the temperature was controlled between -5 and 0 ° C during the dropwise addition, and the reaction was kept at 0 ° C for 1 hour after the dropwise addition was completed. Formic acid was slowly added to acidify, the pH was controlled between 5 and 6, and then sodium ethoxide was added to adjust the pH to about 7. Then 150 ml of ice water at 0 to 10 ° C was added, and the solution was allowed to stand for separation. The organic layer was the product layer, and the aqueous layer was continuously extracted twice with a small amount of toluene. The organic layers were combined and the organic layer was subjected to the next step of reaction. The organic layer was subjected to gas chromatography analysis, and the product purity was 98.1% (after deducting the solvent);

[0065] Step (2): 52 g (1.3 mol) of 80% hydrazine hydrate and 50 g of toluene were added to a 1 L three-necked flask, and the temperature was cooled to -5°C. The organic layer obtained in step (1) was slowly added dropwise to the hydrazine hydrate, and the temperature was controlled between -5 and 5°C during the addition. After the addition was complete, the mixture was reacted for 1 hour, and the temperature was raised to room temperature. The mixture was allowed to stand for separation, and the organic layer was the product layer, which was used for the next reaction. The organic layer was subjected to gas chromatography analysis, and the purity of the product was 98.4% (after deducting the solvent).

[0066] Step (3): the organic layer obtained in step (2) is added into a 1L three-necked flask, 138.6g (1.1mol) of dimethyl sulfate and 111.1g (1.1mol) of triethylamine are added, and the mixture is heated to 80°C. At this temperature, the reaction is carried out for 3 hours. The reaction ends. After cooling, 10% sodium hydroxide solution is added, the pH is adjusted between 7 and 8, and the separation is allowed to stand. The organic layer reaction solution is subjected to gas chromatography detection and has no isomer peak. The product is concentrated under reduced pressure to obtain a light yellow product, which is then dried to obtain 189.3 grams of 1-methyl-3-difluoromethyl-4-pyrazole acid ethyl ester with a content of 98.7% (gas chromatography, external standard method). The total yield of the reaction is 92.8%.

[0067] Example 8

[0068] Step (1): 156 g (1.0 mol) of methyl trifluoropyruvate was added to a 1 L three-necked flask, 250 g of toluene was added, stirring was started, and the temperature was cooled to -5 ° C. 122.4 g (1.8 mol) of sodium ethoxide was slowly added to the three-necked flask, the temperature was controlled not to exceed 0 ° C. The reaction was completed for 1 hour, and then 136.8 g (1.2 mol) of difluoroacetyl chloride was slowly introduced, the temperature was controlled between -5 and 0 ° C during the addition process, and the reaction was kept at 0 ° C for 1 hour after the dropwise addition was completed. Formic acid was slowly added to acidify, the pH was controlled between 5 and 6, and then sodium ethoxide was added to adjust the pH to about 7. Then 150 ml of ice water at 0 to 10 ° C was added, and the solution was allowed to stand for separation. The organic layer was the product layer, and the aqueous layer was further extracted twice with a small amount of toluene. The organic layers were combined and the organic layer was subjected to the next step of reaction. The organic layer was subjected to gas chromatography analysis, and the product purity was 98.6% (after deducting the solvent);

[0069] Step (2): 52 g (1.3 mol) of 80% hydrazine hydrate and 50 g of toluene were added to a 1 L three-necked flask, cooled to -5°C, and the organic layer obtained in step (1) was slowly added dropwise to the hydrazine hydrate, controlling the temperature between -5 and 5°C during the addition. After the addition was complete, the mixture was reacted for 1 hour, raised to room temperature, and allowed to stand for separation. The organic layer was the product layer and was used for the next reaction. The organic layer was subjected to gas chromatography analysis, and the product purity was 98.3% (after deducting the solvent).

[0070] Step (3): the organic layer obtained in step (2) is added into a 1L three-necked flask, 138.6g (1.1mol) of dimethyl sulfate and 87.0g (1.1mol) of pyridine are added, and the mixture is heated to 90°C. At this temperature, the reaction is carried out for 3 hours. The reaction ends. After cooling, 10% sodium hydroxide solution is added, and the pH value is adjusted between 7 and 8. The separation is allowed to stand. The organic layer reaction solution is subjected to gas chromatography detection, and no isomer peak is observed. The product is concentrated under reduced pressure to obtain a light yellow product, which is then dried to obtain 175.2 grams of 1-methyl-3-difluoromethyl-4-pyrazole acid methyl esters with a content of 98.5% (gas chromatography, external standard method). The total yield of the reaction is 92.2%.

[0071] The embodiments described above are intended to illustrate the present invention in detail by way of preferred embodiments and are not intended to limit the scope of the present invention. Any person skilled in the art may make modifications without departing from the scope of the present invention. Any equivalent modifications made in accordance with the present invention are intended to be encompassed by the scope of the present invention.

Claims

1. A method for synthesizing 1-methyl-3-difluoromethyl-4-pyrazole ester, characterized in that: The following steps are involved: Step (1): methyl pyruvate or ethyl pyruvate is reacted with a base in an aprotic organic solvent at a temperature suitable for the reaction, and then difluoroacetyl halide or difluoroacetic acid ester compound is added to continue the reaction. Formic acid is slowly added to the obtained reaction solution to acidify the pH to control the pH between 5 and 6. Then, a base used for the reaction is added to adjust the pH to between 7 and 8 to obtain a reaction solution of the first intermediate (2). Ice water at 0 to 10° C. is then added to separate the liquids, and the organic layer is the product layer. Step (2): The organic layer containing the first intermediate (2) obtained in step (1) is slowly added to hydrazine hydrate at a temperature suitable for the reaction to obtain a cyclized intermediate (3), and then the temperature is raised to room temperature, the liquid is separated, and the organic layer is subjected to the next reaction; Step (3): the cyclization intermediate (3) obtained in step (2) is reacted with dimethyl sulfate in the presence of a base at a temperature suitable for the reaction to undergo a methylation reaction to obtain a reaction solution of the target product (1). After the reaction is completed, the temperature is lowered and the pH is adjusted to between 7 and 8. The liquids are separated and the organic layer is concentrated under reduced pressure to obtain the target product (1); The reaction formula is as follows:

2. The synthesis method according to claim 1, characterized in that In the step (1), the aprotic organic solvent is immiscible with water and is selected from at least one of benzene, toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, n-hexane, cyclohexane, and petroleum ether, preferably toluene or dichloroethane; in the step (2), the organic layer containing the first intermediate (2) is slowly added to a mixed solution containing hydrazine hydrate and the same aprotic organic solvent used in the step (1) at a temperature suitable for the reaction.

3. The synthesis method according to claim 1, wherein In the step (1), the difluoroacetyl halide is at least one of difluoroacetyl chloride, difluoroacetyl fluoride, and difluoroacetyl bromide, preferably difluoroacetyl chloride or difluoroacetyl fluoride.

4. The synthesis method according to claim 1, characterized in that In the step (1), the difluoroacetate is at least one of difluoroacetate compounds, preferably methyl difluoroacetate and ethyl difluoroacetate; the base is an inorganic base or a non-nucleophilic organic base, preferably sodium ethoxide or sodium methoxide or 1,8-diazabicyclo[5.4.0]undec-7-ene.

5. The synthesis method according to claim 1, wherein In the step (1), the suitable reaction temperature is -30°C to 30°C, and the preferred reaction temperature is -5°C to 10°C; the molar ratio of the methyl pyruvate or ethyl pyruvate to the base used in the reaction is 1:1.0 to 3.0, preferably 1:1.0 to 1.8; the molar ratio of the methyl pyruvate or ethyl pyruvate to the difluoroacetyl halide or difluoroacetate compound is 1:1.0 to 2.0, preferably 1:1.0 to 1.

3.

6. The synthesis method according to claim 1, characterized in that In the step (1), the reaction is carried out at normal pressure or under pressure, but trifluoroacetyl halide is a gas. During the introduction of difluoroacetyl halide, the reaction can be carried out under pressure. The appropriate reaction pressure is 0 MPa to 1.0 MPa, and the preferred reaction pressure is 0.1 MPa to 0.3 MPa.

7. The synthesis method according to claim 1, characterized in that In the step (2), the suitable reaction temperature is -30°C to 10°C, and the preferred reaction temperature is -5°C to 5°C; the molar ratio of methyl pyruvate or ethyl pyruvate to hydrazine is 1:1.0 to 2.0, and the preferred molar ratio is 1:1.0 to 1.

3.

8. The synthesis method according to claim 1, characterized in that In the step (2), the hydrazine hydrate is pure hydrazine, or a hydrazine hydrate solution in different solution forms, preferably a 40%-80% hydrazine hydrate solution.

9. The synthesis method according to claim 1, characterized in that In the step (3), the base is at least one of an inorganic base or an organic tertiary amine base. Preferably, the inorganic base is selected from one, two or more of alkali metal carbonates and alkaline earth metal carbonates, and potassium carbonate and sodium carbonate are further preferred. The organic tertiary amine base is preferably triethylamine or pyridine.

10. The synthesis method according to claim 1, characterized in that In the step (3), the suitable reaction temperature is 40°C to 100°C, and the preferred reaction temperature is 60°C to 90°C; the molar ratio of methyl pyruvate or ethyl pyruvate to dimethyl sulfate is 1:1.0 to 2.0, and the preferred molar ratio is 1:1.0 to 1.3.

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