Preparation method of 3, 4-dimethylpyrazole and phosphate thereof

Abstract

The invention discloses a preparation method of 3, 4-dimethyl pyrazole and phosphate thereof, and belongs to the technical field of agricultural chemistry. The preparation method comprises the following steps: carrying out dehydration condensation on 2-butanone and formylhydrazine, carrying out cyclization under an alkaline condition to obtain 3, 4-dimethyl pyrazole, and salifying with phosphoric acid to generate 3, 4-dimethyl pyrazole phosphate. The method disclosed by the invention is simple to operate, the two-step reaction can be continuously carried out, the used materials are sufficient in market supply, the use of high-activity metals such as hydrazine hydrate of a pipe product or metallic sodium of a dangerous article is avoided, and the product obtained by adopting the method has relatively strong market competitiveness.

Description

Technical Field

[0001] This invention belongs to the field of agricultural chemistry and relates to a method for preparing 3,4-dimethylpyrazole and its phosphate. Background Technology

[0002] 3,4-Dimethylpyrazole phosphate (DMPP) is a nitrogen fertilizer nitrifying enzyme inhibitor developed by BASF in Germany. It is characterized by high efficiency, non-toxicity, stability, and specificity. Studies have shown that DMPP can significantly inhibit soil NH4+. 4+ -N to NO 3- The -N conversion exhibits a significant nitrification inhibition effect, far superior to similar products (Reference: Journal of Plant Nutrition and Fertilizers, 2017, 23, 54). Since its application trials in Germany and Europe in 1999, it has been successfully commercialized and widely used in agricultural production. Therefore, it is also known as the most promising new generation of slow-release fertilizer in the 21st century, with broad application prospects.

[0003] 3,4-Dimethylpyrazole is an important intermediate in the synthesis of 3,4-dimethylpyrazole phosphate. Currently, the main methods reported in the literature for its synthesis include:

[0004] A. Noyce obtained an intermediate by reacting butanone with isopropyl formate in the presence of sodium isopropoxide, and then cyclized it with hydrazine hydrate to obtain 3,4-dimethylpyrazole. The reaction requires diethyl ether as a solvent, which is not suitable for large-scale industrial production. However, the preparation method of 3,4-dimethylpyrazole phosphate was not reported at the same time (J. Org. Chem., 1955, 20, 1681).

[0005] B. BASF's patent US6022979A discloses that 2-butanone and methyl formate react in the presence of sodium methoxide to obtain the intermediate sodium 2-methyl-3-oxobutyraldehyde. The reaction time is relatively long (16 hours). The separated intermediate then undergoes a cyclization reaction with hydrazine hydrate under sulfuric acid catalysis to produce 3,4-dimethylpyrazole.

[0006] C. BASF's patent US6229022B discloses a method involving the direct cyclization of 2-methyl-2-butenal with hydrazine hydrate, followed by aromatization under concentrated sulfuric acid / sodium iodide catalysis to yield 3,4-dimethylpyrazole. This method suffers from drawbacks such as high raw material costs and significant side reactions, making it unsuitable for large-scale production.

[0007] D. Lu Ran used sodium metal to react with 2-butanone and ethyl formate to generate sodium 2-methyl-3-oxobutyraldehyde, which was then used to prepare 3,4-dimethylpyrazole phosphate (CN102558054A) through cyclization and salt formation. However, this method uses highly reactive sodium metal, which is easily flammable, and quenching poses a safety hazard. The process cannot meet the needs of large-scale production.

[0008] E. Lin Wenbin and Chen Zhiwei reacted 2-butanone and paraformaldehyde under alkaline or protic acid conditions, which then underwent a cyclization reaction with hydrazine hydrate to prepare 3,4-dimethylpyrazole, which was finally salted to obtain the product (CN102311388A and CN102911119A). In this method, paraformaldehyde slowly releases formaldehyde gas, a highly toxic and carcinogenic substance, posing serious challenges to occupational health and environmental pollution during industrialization.

[0009] F. Patent CN101781222A discloses a method for obtaining an enolate by formylation of an enolate intermediate with two substituents on its nitrogen atom, using an α-methyl or α-methylene ketone compound as a substrate; the enolate then undergoes a dehydration condensation reaction with dimethylamine hydrochloride to yield the enolate compound. This method uses flammable alkali metal sodium, posing an extremely high risk and is unsuitable for large-scale scaling. Furthermore, the use of diethyl ether further limits the method's applicability.

[0010] While numerous synthetic routes have been publicly reported, they all suffer from several drawbacks, including high raw material costs, demanding reaction conditions, the use of highly flammable and hazardous reagents, and severe environmental pollution, hindering large-scale industrial production. Therefore, developing a novel method for synthesizing 3,4-dimethylpyrazole and its phosphates is of significant practical and commercial value. Summary of the Invention

[0011] To overcome the aforementioned technical deficiencies, this invention provides a method for preparing 3,4-dimethylpyrazole and its phosphate. The method involves first dehydrating and condensing 2-butanone with formyl hydrazine, followed by cyclization under alkaline conditions to obtain 3,4-dimethylpyrazole, which is then reacted with phosphate to form 3,4-dimethylpyrazole phosphate. The method described in this invention is simple to operate, the two-step reaction can be carried out continuously, the materials used are readily available in the market, and it avoids the use of controlled substances such as hydrazine hydrate or highly reactive metals such as hazardous sodium. The product obtained using this method has strong market competitiveness.

[0012] The present invention discloses a method for synthesizing 3,4-dimethylpyrazole, employing a two-step continuous reaction process, comprising the following steps: first, dehydration condensation of 2-butanone with formyl hydrazine, followed by cyclization under alkaline conditions to obtain 3,4-dimethylpyrazole. The process is represented by the following reaction equation:

[0013]

[0014] Furthermore, in the above technical solution, the solvent for the first step reaction is selected from methanol, ethanol, tert-butanol, tetrahydrofuran, or acetonitrile.

[0015] Furthermore, in the above technical solution, the molar ratio of 2-butanone to formyl hydrazine in the first step is 1:1-1.2.

[0016] Furthermore, in the above technical solution, the reaction temperature in the first step is 10-60℃.

[0017] Furthermore, in the above technical solution, the alkali mentioned in the second step is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, or a 30% sodium methoxide-methanol solution.

[0018] Furthermore, in the above technical solution, the molar ratio of the alkali to 2-butanone in the second step is 1-1.6:1.

[0019] Furthermore, in the above technical solution, the reaction temperature in the second step is 10-30℃.

[0020] Based on the aforementioned method for synthesizing 3,4-dimethylpyrazole, this invention also provides a method for synthesizing 3,4-dimethylpyrazole phosphate, comprising the following steps: adding pure 3,4-dimethylpyrazole or a solution containing 3,4-dimethylpyrazole to phosphate to form a salt, thereby obtaining 3,4-dimethylpyrazole phosphate.

[0021] Furthermore, in the above technical solution, the molar ratio of phosphoric acid to 3,4-dimethylpyrazole is 1-1.5:1.

[0022] Furthermore, in the above technical solution, after the salt formation is completed, a white solid product can be obtained by filtration and drying.

[0023] The method described in this invention is simple to operate, the two-step reaction can be carried out continuously, the materials used are readily available in the market, and the use of highly reactive metals such as hydrazine hydrate or sodium metal, which are hazardous materials, is avoided. The products obtained by this method have strong market competitiveness. Detailed Implementation

[0024] The present invention will now be described in detail and specifically through specific embodiments to enable a better understanding of the invention. However, the following embodiments do not limit the scope of the invention.

[0025] Example 13. Synthesis of 4-dimethylpyrazole phosphate

[0026] 72 g (1.0 mol) of 2-butanone, 66 g (1.1 mol) of formyl hydrazine, and 100 g of methanol were added to a reaction flask. The mixture was then heated to 40-50 °C and stirred for 3-5 hours. The temperature was lowered to 0-10 °C, and 270 g (1.5 mol) of 30% sodium methoxide-methanol solution was added dropwise. The mixture was then reacted at 15-25 °C for 14 hours. After the reaction, hydrochloric acid was added to adjust the pH to 1-3, and the mixture was refluxed for 4 hours (3,4-dimethylpyrazole / 3-ethylpyrazole ratio 98.2 / 1.8). The methanol was concentrated and recovered. A 10% sodium hydroxide aqueous solution was added to adjust the pH to 7-9. Toluene was added for extraction twice. Phosphoric acid was added dropwise to the combined organic phases, resulting in the precipitation of a solid. The mixture was stirred at 0-10 °C for 30 minutes and then filtered. After drying, 177.6 g of a white solid was obtained, with a yield of 91.6% and a purity of 99.8% (2-ethylpyrazole was not detected).

[0027] Example 23: Synthesis of 4-dimethylpyrazole phosphate

[0028] 72 g (1.0 mol) of 2-butanone, 62 g (1.03 mol) of formyl hydrazine, and 160 g of methanol were added to a reaction flask. The mixture was then heated to 40-50 °C and stirred for 3-5 hours. The temperature was lowered to 0-10 °C, and 63 g (1.17 mol) of solid sodium methoxide was added in portions. The mixture was then reacted at 15-25 °C for 14 hours. After the reaction, hydrochloric acid was added to adjust the pH to 1-3, and the mixture was refluxed for 4 hours (3,4-dimethylpyrazole / 3-ethylpyrazole ratio 98.9 / 1.1). The methanol was concentrated and recovered. The pH was adjusted to 7-9 using a 10% sodium hydroxide aqueous solution. Toluene was added for extraction twice. Phosphoric acid was added dropwise to the combined organic phases, resulting in the precipitation of a solid. The mixture was stirred at 0-10 °C for 30 minutes and then filtered. After drying, 166.9 g of a white solid was obtained, with a yield of 86.1% and a purity of 99.5% (2-ethylpyrazole was not detected).

[0029] Example 33: Synthesis of 3,4-dimethylpyrazole phosphate

[0030] 72 g (1.0 mol) of 2-butanone, 62 g (1.03 mol) of formylhydrazine, and 160 g of ethanol were added to a reaction flask. The mixture was then heated to 20-30 °C and stirred for 3-5 hours. The temperature was lowered to 0-10 °C, and 102 g (1.5 mol) of solid sodium ethoxide was added in portions. The mixture was then reacted at 15-25 °C for 14 hours. After the reaction was complete, hydrochloric acid was added to adjust the pH to 1-3, and the mixture was refluxed for 4 hours (3,4-dimethylpyrazole / 3-ethylpyrazole ratio 99.3 / 0.7). The ethanol was concentrated and recovered. The pH was adjusted to 7-9 using a 10% sodium hydroxide aqueous solution. Toluene was added for extraction twice. Phosphoric acid was added dropwise to the combined organic phases, resulting in the precipitation of a solid. The mixture was stirred at 0-10 °C for 30 minutes and then filtered. After drying, 180.7 g of a white solid was obtained, with a yield of 93.2% and a purity of 99.7% (2-ethylpyrazole was not detected).

[0031] Example 43: Synthesis of 4-dimethylpyrazole phosphate

[0032] 72 g (1.0 mol) of 2-butanone, 66 g (1.1 mol) of formylhydrazine, and 160 g of tert-butanol were added to a reaction flask. The mixture was then heated to 20-30 °C and stirred for 3-5 hours. The temperature was lowered to 0-10 °C, and 120 g (1.25 mol) of solid sodium tert-butoxide was added in portions. The mixture was then reacted at 15-25 °C for 14 hours. After the reaction, hydrochloric acid was added to adjust the pH to 1-3, and the mixture was heated to 70-90 °C for 4 hours (3,4-dimethylpyrazole / 3-ethylpyrazole ratio 100 / nd). The tert-butanol was concentrated and recovered. The pH was adjusted to 7-9 using a 10% sodium hydroxide aqueous solution. The mixture was extracted twice with toluene. Phosphoric acid was added dropwise to the combined organic phases, resulting in the precipitation of a solid. The mixture was stirred at 0-10 °C for 30 minutes and then filtered. After drying, 184.3 g of a white solid was obtained, with a yield of 95.1% and a purity of 99.8% (2-ethylpyrazole was not detected).

[0033] Example 5 Synthesis of 3,4-dimethylpyrazole

[0034] 72 g (1.0 mol) of 2-butanone, 66 g (1.1 mol) of formyl hydrazine, and 100 g of methanol were added to a reaction flask. The mixture was then heated to 40-50 °C and stirred for 3-5 hours. The temperature was lowered to 0-10 °C, and 270 g (1.5 mol) of 30% sodium methoxide-methanol solution was added dropwise. The mixture was then reacted at 15-25 °C for 14 hours. After the reaction, hydrochloric acid was added to adjust the pH to 1-3, and the mixture was refluxed for 4 hours (3,4-dimethylpyrazole / 3-ethylpyrazole ratio 98.2 / 1.8). Methanol was recovered by concentration, and the pH was adjusted to 7-9 using a 10% sodium hydroxide aqueous solution. Toluene was added for extraction twice, and the organic phases were combined and the toluene was recovered under reduced pressure. The mixture was then distilled under reduced pressure and cooled to obtain 81.3 g of a light brown solid, with a yield of 84.7% and a purity of 99.9% (2-ethylpyrazole was not detected).

[0035] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. For those skilled in the art, various improvements and modifications can be made without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for synthesizing 3,4-dimethylpyrazole, comprising a two-step continuous reaction process, characterized in that, Includes the following steps: 3,4-Dimethylpyrazole was obtained by first dehydrating and condensing 2-butanone with formylhydrazine, and then cyclizing under alkaline conditions.

2. The method for synthesizing 3,4-dimethylpyrazole according to claim 1, characterized in that: In the first step, the reaction solvent is selected from methanol, ethanol, tert-butanol, tetrahydrofuran, or acetonitrile.

3. The method for synthesizing 3,4-dimethylpyrazole according to claim 1, characterized in that: In the first step, the molar ratio of 2-butanone to formylhydrazine is 1:1-1.

2.

4. The method for synthesizing 3,4-dimethylpyrazole according to claim 1, characterized in that: In the first step, the reaction temperature is 10-60℃.

5. The method for synthesizing 3,4-dimethylpyrazole according to claim 1, characterized in that: In the second step, the alkali is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, or a 30% sodium methoxide-methanol solution.

6. The method for synthesizing 3,4-dimethylpyrazole according to claim 1, characterized in that: In the second step, the molar ratio of the base to 2-butanone is 1-1.6:

1.

7. The method for synthesizing 3,4-dimethylpyrazole according to claim 1, characterized in that: In the second step, the reaction temperature is 10-30℃.

8. A method for synthesizing 3,4-dimethylpyrazole phosphate, characterized in that, The method includes the following steps: obtaining 3,4-dimethylpyrazole using any one of claims 1-7, and then adding phosphate to the pure 3,4-dimethylpyrazole or a solution containing 3,4-dimethylpyrazole to form a salt, thereby obtaining 3,4-dimethylpyrazole phosphate.

9. The method for synthesizing 3,4-dimethylpyrazole phosphate according to claim 8, characterized in that: The molar ratio of phosphoric acid to 3,4-dimethylpyrazole is 1-1.5:

1.

10. The method for synthesizing 3,4-dimethylpyrazole phosphate according to claim 8, characterized in that: After the salt formation process is complete, the product is filtered and dried to obtain a white solid product.

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