A method for synthesizing difluoropyrazole acid, a pesticide intermediate

Abstract

The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing difluoropyrazole acid, a pesticide intermediate. The difluoropyrazole acid is prepared by subjecting 3-difluoromethyl-1-methylpyrazole to a CO2 carboxylation reaction. The method does not require a bromination reaction, thereby reducing the generation of toxic waste liquid, and has relatively high reaction yield and product purity. The method has certain industrial application prospects, and fully utilizes CO2, thereby contributing to reducing CO2 emissions and alleviating the greenhouse effect.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing difluoropyrazole acid, a pesticide intermediate. Background Art

[0002] As we all know, fluorine- and nitrogen-containing heterocyclic compounds have good biological activity, especially fluorine-containing pyrazole carboxamide compounds. Many new varieties with insecticidal, fungicidal and herbicidal activities have been reported at home and abroad. Their development and application prospects have been favored by scientific researchers. Pyrazole derivatives are not only widely used in medicine, but also perform very well in the field of pesticides. In the 21st century, Syngenta launched pyraclostrobin and cypermethrin, BASF and Bayer launched fluphenazine and bixafen respectively, which have unique mechanisms and high-efficiency characteristics and have very broad application prospects.

[0003] Difluoropyrazole acid, i.e., 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, is an important intermediate for the synthesis of amide-based low-toxic and highly effective fungicides such as pyrazolpyralid. One of the synthetic routes disclosed in the prior art is to use dichloroacetyl chloride, vinyl ether compounds, and methylhydrazine as raw materials to synthesize 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid in five steps. For details, see Figure 1 Although this route has certain advantages in cost control, the reaction conditions are relatively harsh. The intermediate product 3-difluoromethyl-1-methylpyrazole must be brominated first and then catalytically pressurized to add a carboxyl group. This not only causes serious pollution and high operating requirements, but also the by-products are difficult to separate, limiting the prospects for industrial application. Summary of the invention

[0004] Purpose of the invention: In view of the above technical problems, the present invention proposes a method for synthesizing difluoropyrazole acid, a pesticide intermediate.

[0005] The technical solutions adopted are as follows:

[0006] A method for synthesizing difluoropyrazole acid, a pesticide intermediate:

[0007] The difluoropyrazole acid is prepared by reacting 3-difluoromethyl-1-methylpyrazole with CO 2 Produced by carboxylation reaction.

[0008] Furthermore, the synthesis method of the above pesticide intermediate difluoropyrazole acid is as follows:

[0009] 3-Difluoromethyl-1-methylpyrazole and the catalyst were added to a high-pressure reactor, xylene was used as the reaction medium, and the high-pressure reactor was sealed and introduced with CO 2 The pressure in the autoclave is 1-2MPa, the temperature is raised to 140-180℃, and the reaction is carried out for 1-5h. After the reaction is completed, the autoclave is cooled to room temperature and the CO in the autoclave is vented.2 gas, filter the reaction solution, add deionized water to the collected filtrate, mix thoroughly and let stand to separate the layers, separate the aqueous phase, adjust the pH of the aqueous phase to 1-2 to allow crystallization, filter again, collect the precipitated product, wash it with deionized water and then dry it.

[0010] Further, the catalyst is M 2 CO 3 / ABO 3 , where M is a group IA element, A is a group IIA element, and B is a transition metal element.

[0011] Furthermore, M is K and / or Cs.

[0012] Furthermore, A is any one of Ca, Sr, and Ba, or a combination of two or more thereof.

[0013] Furthermore, B is any one of Ti, Fe, Co, Cr and Mn, or a combination of two or more thereof.

[0014] Furthermore, the ABO 3 CaTiO 3 .

[0015] Furthermore, the preparation method of the catalyst is as follows:

[0016] Preparation of CaTiO by sol-gel method 3 , M 2 CO 3 After dissolving in water, CaTiO 3 Add and stir to mix evenly, then heat to remove water.

[0017] Furthermore, the M 2 CO 3 and CaTiO 3 The mass ratio is 1:1-10.

[0018] Furthermore, the mass ratio of the 3-difluoromethyl-1-methylpyrazole to the catalyst is 1-10:1.

[0019] Beneficial effects of the present invention:

[0020] The present invention provides a method for synthesizing difluoropyrazole acid, a pesticide intermediate. 2 There are reports on the preparation of aromatic acids by carboxylation, but there are few reports on its application in pyrazoles. How to efficiently and selectively achieve the carboxylation of the CH bond in pyrazoles is a more difficult problem. In this application, carbonate can destroy the CH bond in the substrate, 3-difluoromethyl-1-methylpyrazole, to form a carbon anion, which in turn acts as a nucleophile to attack the weakly electrophilic CO 2Forming CC bonds to achieve carboxylation, the catalyst M in this application 2 CO 3 / ABO 3 With its strong alkalinity, it can successfully achieve the carboxylation reaction of CH bonds without adding small molecule carboxylates. 3 As a carrier, carbonate can be evenly distributed on its surface, achieving direct and sufficient contact between carbonate and substrate, and significantly reducing the inability of carbonate in the bulk phase to interact with CO due to product deposition. 2 The contact affects the reaction, which greatly improves the utilization rate of carbonates, and the ABO perovskite structure 3 The catalytic effect may reduce the activation energy barrier of the CH bond on the pyrazole ring to a certain extent, increase the reactivity of the reaction substrate, thereby increasing the reaction yield and showing better selectivity. The method of the present invention does not require bromination reaction, reduces the generation of toxic waste liquid, and has a relatively high reaction yield and product purity. It has a certain industrial application prospect and makes full use of CO 2 , for reducing CO 2 emissions and contribute to mitigating the greenhouse effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The synthetic route of difluoropyrazole acid disclosed in the prior art;

[0022] Figure 2 This is the synthetic route of difluoropyrazole acid in Example 1 of the present invention. DETAILED DESCRIPTION

[0023] If the specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or the conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially. The techniques not mentioned in the present invention are all referenced to the prior art. Unless otherwise specified, the following examples and comparative examples are parallel experiments, using the same processing steps and parameters.

[0024] Embodiment 1:

[0025] This embodiment provides a method for synthesizing difluoropyrazole acid, a pesticide intermediate:

[0026] 13.21 g of 3-difluoromethyl-1-methylpyrazole and 1.5 g of Cs 2 CO 3 / CaTiO 3 The catalyst was added into the autoclave, 100 ml of xylene was used as the reaction medium, the autoclave was sealed and CO was introduced. 2The pressure in the kettle was 1.5 MPa, and the temperature was raised to 180°C and kept for 5 hours. After the reaction, it was naturally cooled to room temperature and the exhaust valve was opened to exhaust the CO in the kettle. 2 gas, filter the reaction solution with a 200-mesh filter cloth, add 100 ml of deionized water to the collected filtrate, mix well and let stand to separate the layers, separate the aqueous phase, adjust the pH of the aqueous phase to 1 with 1 mol / L dilute sulfuric acid to acidify and crystallize, filter again with a 200-mesh filter cloth, collect the precipitated product, wash it with deionized water and then dry it to obtain difluoropyrazole acid with a yield of 66.9% and a content of 98.6% (HPLC).

[0027] Among them, Cs 2 CO 3 / CaTiO 3 The preparation method of the catalyst is as follows:

[0028] 170.18g of tetrabutyl titanate was mixed with 150ml of anhydrous ethanol and stirred evenly. Then, 3g of concentrated nitric acid with a mass concentration of 68% was slowly dripped to form a yellow transparent solution A. 118.08g of calcium nitrate tetrahydrate was mixed with 150ml of anhydrous ethanol and stirred evenly to obtain solution B. Solution B was slowly dripped into solution A. At the same time, 1g of concentrated nitric acid and 100ml of acetic acid were added to adjust the pH of the mixed solution to 2.5. Then, 10g of PEG1000 was added to the mixed solution as a dispersant. After stirring and mixing evenly, a colorless transparent sol was formed. The sol was placed in a 60℃ water bath to react for 20h to obtain a transparent gel. The gel was dried at 80℃ for 24h to obtain a loose dry powder. Then, the dry powder was placed in a muffle furnace and calcined at 800℃ for 2h to obtain CaTiO 3 , 2gCs 2 CO 3 Dissolve 10g CaTiO in 20ml deionized water. 3 Add and stir to mix evenly, then place in an oven at 80℃ to heat and remove water to obtain Cs 2 CO 3 / CaTiO 3 catalyst.

[0029] Embodiment 2:

[0030] This embodiment provides a method for synthesizing difluoropyrazole acid, a pesticide intermediate:

[0031] 13.21 g of 3-difluoromethyl-1-methylpyrazole and 1.5 g of K 2 CO 3 / CaTiO 3 The catalyst was added into the autoclave, 100 ml of xylene was used as the reaction medium, the autoclave was sealed and CO was introduced. 2The pressure in the kettle was 1.5 MPa, and the temperature was raised to 180°C and kept for 5 hours. After the reaction, it was naturally cooled to room temperature and the exhaust valve was opened to exhaust the CO in the kettle. 2 gas, filter the reaction solution with a 200-mesh filter cloth, add 100 ml of deionized water to the collected filtrate, mix well and let stand for stratification, separate the aqueous phase, adjust the pH of the aqueous phase to 1 with 1 mol / L dilute sulfuric acid to acidify and crystallize, filter again with a 200-mesh filter cloth, collect the precipitated product, wash it with deionized water and then dry it to obtain difluoropyrazole acid with a yield of 54.3% and a content of 96.7% (HPLC).

[0032] Among them, K 2 CO 3 / CaTiO 3 The preparation method of the catalyst is as follows:

[0033] 170.18g of tetrabutyl titanate was mixed with 150ml of anhydrous ethanol and stirred evenly. Then, 3g of concentrated nitric acid with a mass concentration of 68% was slowly dripped to form a yellow transparent solution A. 118.08g of calcium nitrate tetrahydrate was mixed with 150ml of anhydrous ethanol and stirred evenly to obtain solution B. Solution B was slowly dripped into solution A. At the same time, 1g of concentrated nitric acid and 100ml of acetic acid were added to adjust the pH of the mixed solution to 2.5. Then, 10g of PEG1000 was added to the mixed solution as a dispersant. After stirring and mixing evenly, a colorless transparent sol was formed. The sol was placed in a 60℃ water bath to react for 20h to obtain a transparent gel. The gel was dried at 80℃ for 24h to obtain a loose dry powder. Then, the dry powder was placed in a muffle furnace and calcined at 800℃ for 2h to obtain CaTiO 3 , 2gK 2 CO 3 Dissolve 10g CaTiO in 20ml deionized water. 3 Add and stir to mix evenly, then place in an oven at 80℃ to heat and remove water to obtain K 2 CO 3 / CaTiO 3 catalyst.

[0034] Embodiment 3:

[0035] This embodiment provides a method for synthesizing difluoropyrazole acid, a pesticide intermediate:

[0036] 13.21 g of 3-difluoromethyl-1-methylpyrazole and 1.5 g of Cs 2 CO 3 / CaTiO 3 The catalyst was added into the autoclave, 100 ml of xylene was used as the reaction medium, the autoclave was sealed and CO was introduced. 2The pressure in the kettle was 1MPa, and the temperature was raised to 180℃ and kept for 5h. After the reaction, it was naturally cooled to room temperature and the exhaust valve was opened to exhaust the CO in the kettle. 2 gas, filter the reaction solution with a 200-mesh filter cloth, add 100 ml of deionized water to the collected filtrate, mix well and let stand for stratification, separate the aqueous phase, adjust the pH of the aqueous phase to 1 with 1 mol / L dilute sulfuric acid to acidify and crystallize, filter again with a 200-mesh filter cloth, collect the precipitated product, wash it with deionized water and then dry it to obtain difluoropyrazole acid with a yield of 60.2% and a content of 98.1% (HPLC).

[0037] Among them, Cs 2 CO 3 / CaTiO 3 The preparation method of the catalyst is the same as that of Example 1.

[0038] Embodiment 4:

[0039] This embodiment provides a method for synthesizing difluoropyrazole acid, a pesticide intermediate:

[0040] 13.21 g of 3-difluoromethyl-1-methylpyrazole and 1.5 g of Cs 2 CO 3 / CaTiO 3 The catalyst was added into the autoclave, 100 ml of xylene was used as the reaction medium, the autoclave was sealed and CO was introduced. 2 The pressure in the kettle was 2MPa, and the temperature was raised to 180℃ and kept for 5h. After the reaction, it was naturally cooled to room temperature and the exhaust valve was opened to exhaust the CO in the kettle. 2 gas, filter the reaction solution with a 200-mesh filter cloth, add 100 ml of deionized water to the collected filtrate, mix well and let stand for stratification, separate the aqueous phase, adjust the pH of the aqueous phase to 1 with 1 mol / L dilute sulfuric acid to acidify and crystallize, filter again with a 200-mesh filter cloth, collect the precipitated product, wash it with deionized water and then dry it to obtain difluoropyrazole acid with a yield of 63.8% and a content of 98.3% (HPLC).

[0041] Among them, Cs 2 CO 3 / CaTiO 3 The preparation method of the catalyst is the same as that of Example 1.

[0042] Embodiment 5:

[0043] This embodiment provides a method for synthesizing difluoropyrazole acid, a pesticide intermediate:

[0044] 13.21 g of 3-difluoromethyl-1-methylpyrazole and 1.5 g of Cs 2 CO3 / CaTiO 3 The catalyst was added into the autoclave, 100 ml of xylene was used as the reaction medium, the autoclave was sealed and CO was introduced. 2 The pressure in the kettle was 1.5 MPa, and the temperature was raised to 140°C and kept for 5 hours. After the reaction, it was naturally cooled to room temperature and the exhaust valve was opened to exhaust the CO in the kettle. 2 gas, filter the reaction solution with a 200-mesh filter cloth, add 100 ml of deionized water to the collected filtrate, mix well and let stand to separate the layers, separate the aqueous phase, adjust the pH of the aqueous phase to 1 with 1 mol / L dilute sulfuric acid to acidify and crystallize, filter again with a 200-mesh filter cloth, collect the precipitated product, wash it with deionized water and then dry it to obtain difluoropyrazole acid with a yield of 44.9% and a content of 97.8% (HPLC).

[0045] Among them, Cs 2 CO 3 / CaTiO 3 The preparation method of the catalyst is the same as that of Example 1.

[0046] Comparative Example 1:

[0047] The same as Example 1, except that Cs 2 CO 3 As a catalyst.

[0048] This comparative example provides a method for synthesizing difluoropyrazole acid, a pesticide intermediate:

[0049] 13.21 g of 3-difluoromethyl-1-methylpyrazole and 1.5 g of Cs 2 CO 3 The catalyst was added into the autoclave, 100 ml of xylene was used as the reaction medium, the autoclave was sealed and CO was introduced. 2 The pressure in the kettle was 1.5 MPa, and the temperature was raised to 180°C and kept for 5 hours. After the reaction, it was naturally cooled to room temperature and the exhaust valve was opened to exhaust the CO in the kettle. 2 gas, filter the reaction solution with a 200-mesh filter cloth, add 100 ml of deionized water to the collected filtrate, mix thoroughly and evenly, let stand to separate, separate the aqueous phase, adjust the pH of the aqueous phase to 1 with 1 mol / L dilute sulfuric acid to acidify and crystallize, filter again with a 200-mesh filter cloth, collect the precipitated product, wash it with deionized water and dry it to obtain difluoropyrazole acid, with a yield of 37.5% and a content of 94.9% (HPLC);

[0050] By comparing Example 1 with Comparative Example 1, it can be seen that compared with using Cs 2 CO 3 As a catalyst, Cs used in Example 12 CO 3 / CaTiO 3 Catalysts can effectively improve reaction yield and product yield.

[0051] Comparative Example 2:

[0052] The same as Example 1, except that Cs 2 CO 3 As a catalyst.

[0053] This comparative example provides a method for synthesizing difluoropyrazole acid, a pesticide intermediate:

[0054] 13.21 g of 3-difluoromethyl-1-methylpyrazole and 0.3 g of Cs 2 CO 3 The catalyst was added into the autoclave, 100 ml of xylene was used as the reaction medium, the autoclave was sealed and CO was introduced. 2 The pressure in the kettle was 1.5 MPa, and the temperature was raised to 180°C and kept for 5 hours. After the reaction, it was naturally cooled to room temperature and the exhaust valve was opened to exhaust the CO in the kettle. 2 gas, filter the reaction solution with a 200-mesh filter cloth, add 100 ml of deionized water to the collected filtrate, mix thoroughly and evenly, let stand to separate, separate the aqueous phase, adjust the pH of the aqueous phase to 1 with 1 mol / L dilute sulfuric acid to acidify and crystallize, filter again with a 200-mesh filter cloth, collect the precipitated product, wash it with deionized water and dry it to obtain difluoropyrazole acid, with a yield of 34.2% and a content of 94.1% (HPLC);

[0055] By comparing Comparative Example 1 with Comparative Example 2, it can be seen that the reaction yield and product yield are similar to those of the catalyst Cs 2 CO 3 The dosage is positively correlated.

[0056] Comparative Example 3:

[0057] It is basically the same as Example 1, except that Cs 2 CO 3 / TiO 2 Catalyst instead of Cs 2 CO 3 / CaTiO 3 catalyst.

[0058] This comparative example provides a method for synthesizing difluoropyrazole acid, a pesticide intermediate:

[0059] 13.21 g of 3-difluoromethyl-1-methylpyrazole and 1.5 g of Cs 2 CO 3 / TiO 2The catalyst was added into the autoclave, 100 ml of xylene was used as the reaction medium, the autoclave was sealed and CO was introduced. 2 The pressure in the kettle was 1.5 MPa, and the temperature was raised to 180°C and kept for 5 hours. After the reaction, it was naturally cooled to room temperature and the exhaust valve was opened to exhaust the CO in the kettle. 2 gas, filter the reaction solution with a 200-mesh filter cloth, add 100 ml of deionized water to the collected filtrate, mix thoroughly and evenly, let stand to separate, separate the aqueous phase, adjust the pH of the aqueous phase to 1 with 1 mol / L dilute sulfuric acid to acidify and crystallize, filter again with a 200-mesh filter cloth, collect the precipitated product, wash it with deionized water and dry it to obtain difluoropyrazole acid, with a yield of 43.8% and a content of 95.5% (HPLC);

[0060] Among them, Cs 2 CO 3 / TiO 2 The preparation method of the catalyst is as follows:

[0061] 2g Cs 2 CO 3 Dissolve 10g TiO in 20ml deionized water. 2 (particle size 1-10nm, Hangzhou Jikang New Materials Co., Ltd.) Add and stir to mix evenly, then place in an oven at 80℃ to heat and remove water to obtain Cs 2 CO 3 / TiO 2 catalyst.

[0062] By comparing Example 1 with Comparative Example 3, it can be seen that Cs 2 CO 3 / CaTiO 3 The catalyst has a better effect on improving the reaction yield and product yield than Cs 2 CO 3 / TiO 2 catalyst.

[0063] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing difluoropyrazole acid, a pesticide intermediate, characterized in that: The details are as follows: Add 3-difluoromethyl-1-methylpyrazole and a catalyst into a high-pressure reactor, use xylene as a reaction medium, seal the high-pressure reactor, introduce CO2 gas to make the pressure in the reactor 1-2MPa, maintain the pressure and heat to 140-180°C, and then keep the temperature for reaction for 1-5h. After the reaction is completed, cool to room temperature, exhaust the CO2 gas in the reactor, filter the reaction liquid, add deionized water to the collected filtrate, mix well and stand for stratification, separate the water phase, adjust the pH of the water phase to 1-2 to crystallize, filter again, collect the precipitated product, wash it with deionized water and then dry it; The catalyst is K2CO3 / CaTiO3 or Cs2CO3 / CaTiO3.

2. The method for synthesizing the pesticide intermediate difluoropyrazole acid as claimed in claim 1, characterized in that: The preparation method of the catalyst is as follows: CaTiO3 is prepared by the sol-gel method. K2CO3 or Cs2CO3 is dissolved in water, and then CaTiO3 is added, stirred and mixed evenly, and then heated to remove water.

3. The method for synthesizing the pesticide intermediate difluoropyrazole acid as claimed in claim 2, characterized in that: The mass ratio of K2CO3 or Cs2CO3 and CaTiO3 is 1:1-10.

4. The method for synthesizing the pesticide intermediate difluoropyrazole acid as claimed in claim 1, characterized in that: The mass ratio of the 3-difluoromethyl-1-methylpyrazole to the catalyst is 1-10:1.

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