Preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-ethyl formate
Through microwave heating reaction between microwave chemical reactor and specific solvent system, the problem of low synthesis yield caused by isomer formation in the prior art is solved, and the preparation of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-formate with high efficiency and low energy consumption is achieved, which is suitable for industrial applications.
Patent Information
- Application Number
- CN202510707216.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-29
- Publication Date
- 2025-08-26
AI Technical Summary
In the existing methods for synthesizing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, the isomer generation ratio is high, resulting in low synthesis yield and long purification time, making it difficult to meet industrial needs.
The isomers are converted by microwave chemical reactors and specific solvent systems by microwave heating reaction and under-pressure distillation. The specific solvents include esters, ketones, amides, ethers or sulfones, and the reaction time and power are controlled within a suitable range.
It significantly improves the synthesis efficiency, has a yield of more than 80%, has low energy consumption, is suitable for industrial production, and solves the problem of isomer generation.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of pesticide intermediate synthesis, and particularly relates to a method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate. Background Art
[0002] As important pyrazole pesticide intermediates, difluoropyraclostrobin and trifluoropyraclostrobin play a very important role in the synthesis of many new pesticide varieties. They can be used in the synthesis of various fungicides and pesticides, such as SDHI fungicides such as penthiopyrad, fluopyram, pyraclostrobin, fluopyram, bixafen, and fluopyram.
[0003] 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester is an important intermediate for the synthesis of difluoropyrazole acid. In existing synthesis methods, most use methylhydrazine as a raw material for cyclization reaction. In this way, 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester is inevitably produced during the reaction process. The proportion of isomers accounts for 15%-20% of the total product. This results in the need to spend more time for purification, and most importantly, the generation of isomers will greatly reduce the synthesis yield.
[0004] Therefore, it is necessary to develop an efficient and simple method for converting isomers into ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate. Based on this, the present application was developed. Summary of the Invention
[0005] The present invention aims to overcome the defects of the prior art and provide a novel preparation method of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, which avoids the shortcomings of the current synthesis methods and has the advantages of low energy consumption, high synthesis efficiency and suitability for industrial production.
[0006] To achieve the above object, the present invention adopts the following technical solutions: A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, comprising the following steps: (1) Solution preparation: Prepare a solvent solution containing ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate; (2) Reaction: The solution of step (1) is added to a microwave chemical reactor, reacted for a certain period of time, and then subjected to reduced pressure distillation to obtain ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate. The synthetic reaction formula is shown below.
[0007] .
[0008] Specifically, in step (1), the solvent includes but is not limited to esters, ketones, amides, ethers or sulfones.
[0009] Furthermore, the esters include one or more of diformate, ethyl benzoate, trimethyl phosphate, etc. Furthermore, the ketone is isophorone, etc., and the amide includes one or two of 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone, etc.
[0010] Furthermore, the ether is diphenyl ether, and the sulfone includes one or two of dimethyl sulfoxide, sulfolane, etc.
[0011] Furthermore, in step (1), the amount of the solvent is preferably more than 10% of the total weight of the raw materials.
[0012] Specifically, in step (2), the power of the microwave chemical reactor is set at 500-1000W, and the retention time of the material in the microwave chemical reactor is 30-60min.
[0013] Compared with the prior art, the preparation method of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate provided by the present invention has the following advantages and beneficial effects: 1) The method of the present invention can convert isomers in conventional synthetic routes into ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate; 2) In the method of the present invention, the non-thermal effect of microwaves greatly accelerates the reaction rate; 3) The preparation method of the present invention has the advantages of low energy consumption, fast reaction rate, high synthesis efficiency (yield of more than 80%, up to 88.7%), and is suitable for industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Figure 1 This is the H NMR spectrum of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate prepared in Example 1. DETAILED DESCRIPTION
[0015] The technical solution of the present invention is further described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited thereto.
[0016] A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, comprising the following steps: (1) preparing a solvent solution containing ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate; (2) The solution of step (1) was added to a microwave chemical reactor, reacted for a certain period of time, and then distilled under reduced pressure to obtain ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate.
[0017] In the step (1), the solvent includes esters, ketones, amides, ethers or sulfones, etc., the esters include one or more of diformic acid esters, ethyl benzoate, trimethyl phosphate, etc., the ketones are isophorone, the amides include one or two of 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone, etc., the ethers are diphenyl ether, and the sulfones include one or two of dimethyl sulfoxide, cyclopentane sulfone, etc.
[0018] In the step (1), the amount of the solvent used is more than 10% of the total weight of the raw materials.
[0019] The reaction equation of step (2) is as follows.
[0020] .
[0021] In step (2), the power of the microwave chemical reactor is set at 500-1000W, and the retention time of the material in the microwave chemical reactor is 30-60 minutes.
[0022] The present invention will be further described below with reference to the embodiments.
[0023] Example 1 A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, comprising the following steps: 1) Prepare the reaction raw materials: Add 204 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate and 102 g of dimethyl sulfoxide to a reaction kettle, stir well, and set aside.
[0024] 2) Reaction: The solution from step 1) was added to a microwave chemical reactor. The stirring speed was set at 200 rpm, the power at 900 W, and the reaction time was 60 min. After the reaction, 88 g of solvent and 177 g of the product, ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, were recovered by vacuum distillation, yielding 86.8%.
[0025] The H NMR spectrum of the product 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester prepared in this example is as follows Figure 1 shown.
[0026] Example 2 A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, comprising the following steps: 1) Prepare the reaction raw materials: Add 204 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate and 102 g of trimethyl phosphate to a reaction kettle, stir well, and set aside.
[0027] 2) Reaction: Add the solution from step 1) to a microwave chemical reactor. Set the stirring speed to 200 rpm, the power to 900 W, and the reaction time to 60 min. After the reaction, vacuum distillation was performed to recover 90 g of solvent and 173 g of the product, ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, for a yield of 84.8%.
[0028] Example 3 A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, comprising the following steps: 1) Prepare the reaction raw materials: Add 204 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate and 102 g of N-methylpyrrolidone to a reaction kettle, stir well, and set aside.
[0029] 2) Reaction: The solution from step 1) was added to a microwave chemical reactor. The stirring speed was set at 200 rpm, the power at 900 W, and the reaction time was 60 min. After the reaction, 92 g of solvent and 181 g of the product, ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, were recovered by vacuum distillation, yielding 88.7%.
[0030] Example 4 A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, comprising the following steps: 1) Prepare the reaction raw materials: Add 204 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate and 102 g of diphenyl ether to a reaction kettle, stir well, and set aside.
[0031] 2) Reaction: The solution from step 1) was added to a microwave chemical reactor. The stirring speed was set at 200 rpm, the power at 900 W, and the reaction time was 60 min. After the reaction, 96 g of solvent and 165 g of the product, ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, were recovered by vacuum distillation, yielding 80.9%.
[0032] Example 5 A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, comprising the following steps: 1) Prepare the reaction raw materials: Add 204 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate and 102 g of N-methylpyrrolidone to a reaction kettle, stir well, and set aside.
[0033] 2) Reaction: Add the solution from step 1) to a microwave chemical reactor. Set the stirring speed to 200 rpm, the power to 1000 W, and the reaction time to 30 min. After the reaction, vacuum distillation was performed to recover 96 g of solvent and 180 g of the product, ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, for a yield of 88.2%.
[0034] Example 6 A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, comprising the following steps: 1) Prepare the reaction raw materials: Add 204 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate and 102 g of isophorone to a reaction kettle, stir well, and set aside.
[0035] 2) Reaction: Add the solution from step 1) to a microwave chemical reactor. Set the stirring speed to 200 rpm, the power to 1000 W, and the reaction time to 30 min. After the reaction, vacuum distillation was performed to recover 97 g of solvent and 171 g of the product, ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, for a yield of 83.8%.
[0036] Example 7 A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, comprising the following steps: 1) Prepare the reaction raw materials: Add 204 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate and 102 g of ethyl benzoate to a reaction kettle, stir well, and set aside.
[0037] 2) Reaction: Add the solution from step 1) to a microwave chemical reactor. Set the stirring speed to 200 rpm, the power to 1000 W, and the reaction time to 30 min. After the reaction, vacuum distillation was performed to recover 95 g of solvent and 167 g of the product, ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, for a yield of 81.9%.
[0038] Example 8 A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, comprising the following steps: 1) Prepare the reaction raw materials: Add 204 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate and 102 g of 1,3-dimethyl-2-imidazolidinone to a reaction kettle, stir well, and set aside.
[0039] 2) Reaction: Add the solution from step 1) to a microwave chemical reactor. Set the stirring speed to 200 rpm, the power to 1000 W, and the reaction time to 30 min. After the reaction, vacuum distillation was performed to recover 99 g of solvent and 179 g of the product, ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, for a yield of 87.5%.
[0040] Example 9 A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, comprising the following steps: 1) Prepare the reaction raw materials: Add 204 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate and 51 g of N-methylpyrrolidone to a reaction kettle, stir well, and set aside.
[0041] 2) Reaction: Add the solution from step 1) to a microwave chemical reactor. Set the stirring speed to 200 rpm, the power to 1000 W, and the reaction time to 30 min. After the reaction, vacuum distillation was performed to recover 42 g of solvent and 175 g of the product, ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, for a yield of 85.9%.
[0042] Example 10 A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, comprising the following steps: 1) Prepare the reaction raw materials: Add 204 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate and 136 g of N-methylpyrrolidone to a reaction kettle, stir well, and set aside.
[0043] 2) Reaction: Add the solution from step 1) to a microwave chemical reactor. Set the stirring speed to 200 rpm, the power to 1000 W, and the reaction time to 30 min. After the reaction, vacuum distillation was performed to recover 129 g of solvent and 179 g of the product, ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, for a yield of 87.7%.
[0044] Example 11 A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, comprising the following steps: 1) Prepare the reaction raw materials: Add 204 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate and 204 g of N-methylpyrrolidone to a reaction kettle, stir well, and set aside.
[0045] 2) Reaction: The solution from step 1) was added to a microwave chemical reactor. The stirring speed was set at 200 rpm, the power at 1000 W, and the reaction time was 30 min. After the reaction, 196 g of solvent and 181 g of the product, ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, were recovered by vacuum distillation, yielding 88.7%.
[0046] Comparative Example A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, comprising the following steps: 1) Prepare the reaction raw materials: Add 204 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate and 102 g of dimethyl sulfoxide to a reaction kettle, stir well and set aside.
[0047] 2) Reaction: The solution from step 1) was added to a reactor equipped with oil bath heating. The stirring speed was set at 200 rpm, the temperature was 190°C, and the reaction time was 420 min. After the reaction, 86 g of solvent and 106 g of the product, ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, were recovered by vacuum distillation, with a yield of 52.0%.
[0048] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not limited to the embodiments shown herein but is intended to conform to the widest scope consistent with the principles and novel features disclosed herein.
Claims
1. A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, characterized in that: The following steps are involved: (1) preparing a solvent solution containing ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate; (2) The solution of step (1) is added to a microwave chemical reactor, reacted for a certain period of time, and then distilled under reduced pressure to obtain ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate.
2. The method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate according to claim 1, wherein In step (1), the solvent includes esters, ketones, amides, ethers or sulfones.
3. The method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate according to claim 2, wherein: The esters include one or more of diformate, ethyl benzoate, and trimethyl phosphate.
4. The method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate according to claim 2, wherein: The ketone is isophorone, and the amides include one or both of 1,3-dimethyl-2-imidazolidinone and N-methylpyrrolidone.
5. The method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate according to claim 2, wherein: The ether is diphenyl ether, and the sulfone includes one or both of dimethyl sulfoxide and sulfolane.
6. The method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate according to claim 1, wherein: In step (1), the amount of the solvent used is more than 10% of the total weight of the raw materials.
7. The method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate according to claim 1, wherein: In step (2), the power of the microwave chemical reactor is set at 500-1000W, and the retention time of the material in the microwave chemical reactor is 30-60min.