A method for synthesizing difluoromethyl alkyl pyrazole carboxylic acids

Abstract

The application belongs to the technical field of pesticide intermediate synthesis, and particularly relates to a preparation method of difluoromethyl alkyl pyrazole carboxylic acid. The method directly obtains the product by removing fluorine under direct current electrolysis by taking trifluoromethyl alkyl pyrazole carboxylic acid as raw material. The process is simple, the cost is low, the safety is high, the waste is less, and the industrial production is easy.

Description

Technical Field

[0001] This invention belongs to the field of pesticide intermediate synthesis technology, specifically relating to a method for preparing difluoromethylalkylpyrazole carboxylic acid. Background Technology

[0002] Difluoromethylalkylpyrazole carboxylic acid is a key intermediate in the synthesis of more than ten novel amide fungicides, including benzo[a]fluopyram, fluopyram, fluopyram, fluopyram aniline, fluopyram, bifenthionil, and pyraclostrobin. These novel fungicides possess advantages such as high activity, low residue, environmental friendliness, and good safety, and have been widely developed and utilized in the pesticide and other fields. However, existing synthesis processes often use expensive difluorocarboxylic acids or difluorocarboxylic acid esters and hydrazine as raw materials, obtaining the difluoromethylalkylpyrazole carboxylic acid product through multiple steps, resulting in complex processes and difficult post-processing.

[0003]

[0004] The above route is a common route for synthesizing difluoro or trifluoromethylalkylpyrazole carboxylic acids. The starting material difluoroacetic acid is about ten times more expensive than trifluoroacetic acid, which results in the product difluoromethylalkylpyrazole carboxylic acid being several times more expensive than trifluoromethylalkylpyrazole carboxylic acid.

[0005] Therefore, finding a low-cost route that is more suitable for industrialization is particularly important. Summary of the Invention

[0006] To address the problems of complex synthesis processes, harsh conditions, high costs, and difficult isomer separation in existing difluoromethylalkylpyrazole carboxylic acid synthesis technologies, this invention provides a simple and efficient method for synthesizing difluoromethylalkylpyrazole carboxylic acid. This method is simple, low-cost, safe, produces less waste, is easy to industrialize, requires no addition of excessive complex catalysts, and has simple post-processing.

[0007] The technical solution of the present invention is as follows:

[0008] A method for synthesizing difluoromethylalkylpyrazole carboxylic acid, using trifluoromethylalkylpyrazole carboxylic acid as a raw material, involves direct defluorination under direct current electrolysis to obtain the product, as shown in the following reaction formula:

[0009]

[0010] R is a hydrogen atom or an alkyl group with 1-6 carbon atoms; R is attached to the nitrogen atom of the pyrazole ring or to the carbon atom adjacent to the carboxyl group;

[0011] The specific reaction formula is as follows:

[0012]

[0013] Preferably, the specific synthesis method is as follows: high-purity nitrogen gas is introduced into the electrolytic cell for protection, alkali is added to the cathode chamber, and then the raw material trifluoromethylalkylpyrazole carboxylic acid is added to the cathode chamber and the catalyst is added to the anode chamber; then anhydrous solvent is added to the two electrode chambers, and electrolysis is carried out under constant voltage; after electrolysis, the cathode electrolyte is post-treated to obtain the product difluoromethylalkylpyrazole carboxylic acid.

[0014] More preferably, the molar ratio of raw material to alkali is 1:1-3; the molar ratio of raw material to catalyst is 1:0.1-1.0. When there is too much raw material, trifluoromethylalkylpyrazole carboxylic acid cannot be completely converted into carboxylate, the conductivity will be poor, the reaction will be slowed down, and the reaction will be incomplete. When there is too little raw material, it will cause waste of materials.

[0015] More preferably, the anhydrous solvent is: acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N,N-diethylacetamide, 1,4-dioxane, dimethyl sulfoxide, ethanol, methanol, propanol, butanol, and the mass-to-volume ratio (g / mL) of the raw material to the anhydrous solvent is 1:6-30.

[0016] More preferably, the electrode is a palladium, platinum, nickel, chromium, graphite, or other electrode.

[0017] More preferably, the constant voltage is 1-10V. When the voltage is too low, the reaction will slow down or stop; while when the voltage is too high, the reaction will be too fast, the selectivity will be poor, and it will be difficult to control the formation of only the target product.

[0018] More preferably, the electrolysis temperature is 10-50℃. Low temperatures will slow down or stop the reaction, while excessively high temperatures will lead to the generation of other impurities, affecting the yield and content.

[0019] More preferably, the electrolysis time is 1-24 hours. A shorter reaction time will result in an incomplete reaction, while a longer reaction time will lead to the generation of other impurities, affecting the yield and content of the product.

[0020] More preferably, the catalyst is one of tetramethylammonium chloride, tetraethylammonium chloride, tetrapropylammonium chloride, tetrabutylammonium chloride, tetramethylammonium bromide, tetraethylammonium bromide, tetrapropylammonium bromide, tetrabutylammonium bromide, and methyltrioctylammonium chloride.

[0021] More preferably, the alkali is one of the following: sodium hydroxide, potassium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium hydrogen hydride, sodium tert-butoxide, potassium tert-butoxide, sodium isopropoxide, potassium isopropoxide, lithium diisopropylamino, triethylamine, and diisopropylethylamine.

[0022] More preferably, the post-treatment involves: the electrolyte being successively concentrated under reduced pressure to remove the solvent, dissolved in water, filtered to remove insoluble matter, acid added to adjust the pH of the filtrate to 2-3, filtered again, and dried to obtain difluoromethylalkylpyrazole carboxylic acid. The acid is one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or hydrobromic acid.

[0023] This invention provides a method for synthesizing difluoromethylalkylpyrazole carboxylic acid. This method is simple, low-cost, safe, and produces little waste. It is easy to industrialize, requires no complex catalysts, and has simple post-processing. It can also produce difluoromethylalkylpyrazole carboxylic acid products with high yield and high content, and has high promotion value. Attached Figure Description

[0024] Figure 1 The HPLC chromatogram of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid in Example 1 is shown below.

[0025] Figure 2 The HPLC chromatogram of 3-difluoromethyl-1H-pyrazole-4-carboxylic acid in Example 2;

[0026] Figure 3 The 1H NMR spectrum of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid in Example 1;

[0027] Figure 4 The image shows the 1H NMR spectrum of 3-difluoromethyl-1H-pyrazole-4-carboxylic acid in Example 2. Detailed Implementation

[0028] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions of the embodiments of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.

[0029] Example 1

[0030] Synthetic method of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid:

[0031]

[0032] After drying, the electrolytic cell was purged with high-purity nitrogen for drying protection. Sodium hydroxide (2.0 mol, 80.0 g, 2.0 equiv.) was added to the cathode chamber, followed by the introduction of 3-trifluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (1.0 mol, 194.1 g, 1.0 equiv.) into the cathode chamber. Tetrabutylammonium chloride (0.3 mol, 83.4 g, 0.3 equiv.) was added to the anode chamber. Then, non-acidic nitrogen was added to both electrode chambers. The mixture was prepared in 4.0 L of water and methanol, with nickel foil and chromium wire electrodes used as the cathode and anode, respectively. The voltage was controlled at 5.5 V and electrolysis was carried out at 25 °C for 6 hours. After electrolysis, the cathode electrolyte was concentrated under reduced pressure to remove the solvent, dissolved in 500 mL of water, filtered to remove insoluble matter, and the pH of the filtrate was adjusted to 2 with hydrochloric acid. The product was collected by filtration and dried to obtain 146.5 g of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, with a purity of 99.4% and a yield of 82.7%. 1 H NMR (400MHz, DMSO-d6) δ12.84 (s, 1H), 8.34 (s, 1H), 7.21 (t, J = 53.8Hz, 1H), 3.92 (s, 3H).

[0033] Example 2

[0034] Synthetic method of 3-difluoromethyl-1H-pyrazole-4-carboxylic acid:

[0035]

[0036] After drying, the electrolytic cell was purged with high-purity nitrogen for drying protection. Sodium methoxide (2.5 mol, 135.1 g, 2.5 equiv.) was added to the cathode chamber, followed by the feedstock 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (1.0 mol, 180.1 g, 1.0 equiv.) to the cathode chamber. Tetramethylammonium chloride (0.2 mol, 21.9 g, 0.2 equiv.) was added to the anode chamber. Anhydrous acetonitrile (3 L) was then added to both electrode chambers. Platinum wire and chromium wire electrodes were used as the cathode and anode, respectively. Finally, the voltage was controlled at 6.0 V and electrolysis was carried out at 15 °C for 4 hours. After electrolysis, the cathode electrolyte was concentrated under reduced pressure to remove the solvent, dissolved in 400 mL of water, filtered to remove insoluble matter, and the pH of the filtrate was adjusted to 2 with hydrochloric acid. The product was collected by filtration and dried to obtain 141.7 g of 3-difluoromethyl-1H-pyrazole-4-carboxylic acid, with a purity of 99.7% and a yield of 87.1%. 1 H NMR (400MHz, DMSO-d6) δ 13.77 (brs, 1H), 12.85 (brs, 1H), 8.36 (s, 1H), 7.25 (t, J = 53.8Hz, 1H).

[0037] Example 3

[0038] Synthetic method of 3-difluoromethyl-5-methyl-1H-pyrazole-4-carboxylic acid:

[0039]

[0040] After drying, the electrolytic cell was purged with high-purity nitrogen for drying protection. Triethylamine (3.0 mol, 303.6 g, 3.0 equiv.) was added to the cathode chamber, followed by the addition of 3-trifluoromethyl-5-methyl-1H-pyrazole-4-carboxylic acid (1.0 mol, 194.1 g, 1.0 equiv.) to the cathode chamber. Tetrabutylammonium bromide (0.4 mol, 128.9 g, 0.4 equiv.) was added to the anode chamber. Then, additives were added to both electrode chambers. Anhydrous ethanol (2L) was used, with nickel foil and platinum wire electrodes serving as the cathode and anode, respectively. The voltage was controlled at 3.0V, and electrolysis was performed at 40℃ for 12 hours. After electrolysis, the cathode electrolyte was concentrated under reduced pressure to remove the solvent, dissolved in 500mL of water, filtered to remove insoluble matter, and the pH of the filtrate was adjusted to 2 with nitric acid. The product was collected by filtration and dried to obtain 164.9g of 3-difluoromethyl-5-methyl-1H-pyrazole-4-carboxylic acid, with a purity of 97.5% and a yield of 91.3%.

[0041] Example 4

[0042] Synthetic method of 5-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid:

[0043]

[0044] After drying, the electrolytic cell was purged with high-purity nitrogen for drying protection. Potassium tert-butoxide (2.0 mol, 224.4 g, 2.0 equiv.) was added to the cathode chamber, followed by the addition of 5-trifluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (1.0 mol, 194.1 g, 1.0 equiv.) to the cathode chamber. Tetramethylammonium bromide (0.5 mol, 77.0 g, 0.5 equiv.) was added to the anode chamber. Anhydrous nitrogen was then added to both electrode chambers. N-Dimethylformamide (3L) was used, with nickel foil electrode and graphite rod electrode serving as the cathode and anode, respectively. The voltage was controlled at 8.0V, and electrolysis was performed at 50℃ for 2 hours. After electrolysis, the cathode electrolyte was concentrated under reduced pressure to remove the solvent, dissolved in 500mL of water, filtered to remove insoluble matter, and sulfuric acid was added to adjust the pH of the filtrate to 2. The product was then collected by filtration and dried to obtain 155.7g of 5-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, with a purity of 95.1% and a yield of 84.1%.

[0045] Example 5

[0046] Synthetic method of 3-difluoromethyl-1-isopropyl-1H-pyrazole-4-carboxylic acid:

[0047]

[0048] After drying, the electrolytic cell is purged with high-purity nitrogen for drying protection. Potassium hydroxide (3.0 mol, 168.3 g, 3.0 equiv.) is added to the cathode chamber, followed by the introduction of raw material 3-trifluoromethyl-1-isopropyl-1H-pyrazole-4-carboxylic acid (1.0 mol, 222.0 g, 1.0 equiv.) into the cathode chamber, and tetrapropylammonium bromide (0.6 mol, 159.7 g, 0.6 equiv.) into the anode chamber. Next, anhydrous propionitrile (3.5 L) was added to the two electrode chambers, and the palladium electrode and chromium wire electrode were used as the cathode and anode, respectively. Finally, the voltage was controlled at 1.5 V and electrolysis was carried out at 50 °C for 20 hours. After electrolysis, the cathode electrolyte was concentrated under reduced pressure to remove the solvent, dissolved in 800 mL of water, filtered to remove insoluble matter, and sulfuric acid was added to adjust the pH of the filtrate to 2. The product was collected by filtration and dried to obtain 183.6 g of product 3-difluoromethyl-1-isopropyl-1H-pyrazole-4-carboxylic acid, with a purity of 88.9% and a yield of 80.4%.

[0049] Example 6

[0050] Synthetic method of 3-difluoromethyl-5-tert-butyl-1H-pyrazole-4-carboxylic acid:

[0051]

[0052] After drying, the electrolytic cell was purged with high-purity nitrogen for drying protection. Diisopropylaminolithium (1.5 mol, 163.7 g, 1.5 equiv.) was added to the cathode chamber, followed by the introduction of 3-trifluoromethyl-5-tert-butyl-1H-pyrazole-4-carboxylic acid (1.0 mol, 236.1 g, 1.0 equiv.) into the cathode chamber. Tetrapropylammonium chloride (0.7 mol, 155.3 g, 0.7 equiv.) was added to the anode chamber. Then, the two electrode chambers were... Anhydrous propanol (2.0 L) was added, and chromium wire and platinum wire electrodes were used as cathode and anode, respectively. The voltage was controlled at 4.5 V and electrolysis was carried out at 30 °C for 7 hours. After electrolysis, the cathode electrolyte was concentrated under reduced pressure to remove solvent, dissolved in 1.0 L of water was added, filtered to remove insoluble matter, hydrobromic acid was added to adjust the pH of the filtrate to 3, the product was collected by filtration and dried to obtain 180.7 g of product 3-difluoromethyl-5-tert-butyl-1H-pyrazole-4-carboxylic acid, with a purity of 85.2% and a yield of 70.9%.

[0053] Comparative Example 1

[0054] Synthetic methods for 3-difluoromethyl-1H-pyrazole-4-carboxylic acid and 3-monofluoromethyl-1H-pyrazole-4-carboxylic acid:

[0055]

[0056] After drying, the electrolytic cell is purged with high-purity nitrogen for drying protection. Sodium methoxide (2.5 mol, 135.1 g, 2.5 equiv.) is added to the cathode chamber, followed by the introduction of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (1.0 mol, 180.1 g, 1.0 equiv.) into the cathode chamber, and tetramethylammonium chloride (3.0 mol, 328.8 g, 3.0 equiv.) into the anode chamber. Next, anhydrous acetonitrile (3L) was added to the two electrode chambers, and platinum wire and chromium wire electrodes were used as the cathode and anode, respectively. Finally, the voltage was controlled at 10.0V and electrolysis was carried out at 65℃ for 10 hours. After electrolysis, the cathode electrolyte was concentrated under reduced pressure to remove the solvent, dissolved in 400mL of water, filtered to remove insoluble matter, and the pH of the filtrate was adjusted to 2 with hydrochloric acid. The product was collected by filtration and dried to obtain a mixture of 115.1g, of which the content of 3-difluoromethyl-1H-pyrazole-4-carboxylic acid was 42.5% (yield 30.2%) and the content of 3-monofluoromethyl-1H-pyrazole-4-carboxylic acid was 35.8% (yield 28.6%).

[0057] Comparative Example 2

[0058] Synthetic method of 3-difluoromethyl-1H-pyrazole-4-carboxylic acid:

[0059]

[0060] After drying, the electrolytic cell was purged with high-purity nitrogen for drying protection. Sodium methoxide (2.5 mol, 135.1 g, 2.5 equiv.) was added to the cathode chamber, followed by the addition of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (1.0 mol, 180.1 g, 1.0 equiv.) to the cathode chamber. Tetramethylammonium chloride (5.0 mol, 548.0 g, 5.0 equiv.) was added to the anode chamber. Anhydrous acetonitrile (3 L) was then added to both electrode chambers, with platinum wire and chromium wire electrodes serving as the cathode and anode, respectively. Finally, the process was controlled... Electrolysis was performed at 15.0V and 70℃ for 17 hours. After electrolysis, the cathode electrolyte was concentrated under reduced pressure to remove the solvent, dissolved in 400mL of water, filtered to remove insoluble matter, and the pH of the filtrate was adjusted to 2 with hydrochloric acid. The product was collected by filtration and dried to obtain a mixture of 108.6g, of which 3-difluoromethyl-1H-pyrazole-4-carboxylic acid content was 18.4% (yield 12.3%), 3-monofluoromethyl-1H-pyrazole-4-carboxylic acid content was 23.2% (yield 17.5%), and 3-methyl-1H-pyrazole-4-carboxylic acid content was 3.7% (yield 3.2%).

[0061] A comparison of the above examples and comparative examples reveals that the yield and content of the difluoromethylalkylpyrazole carboxylic acid products synthesized in Examples 1-6 are significantly higher than those in Comparative Examples 1-2. This effectively demonstrates that differences in electrolysis conditions, such as voltage, temperature, time, material ratios, and material selection, have a substantial impact on the yield and content of the final product, difluoromethylalkylpyrazole carboxylic acid. This invention selects relatively inexpensive raw materials and employs specific material ratios and electrolysis conditions to achieve high yields and contents of difluoromethylalkylpyrazole carboxylic acid. Calculations show that difluoromethylalkylpyrazole carboxylic acid is approximately ten times more expensive than trifluoromethylalkylpyrazole carboxylic acid. This invention significantly reduces the cost of synthesizing difluoromethylalkylpyrazole carboxylic acid by selecting trifluoromethylalkylpyrazole carboxylic acid as the raw material. The synthesis method of this invention is simple, low-cost, highly safe, and produces minimal waste, making it easy for industrial production. It requires no complex catalysts, has simple post-processing, and yields high-yield and high-content difluoromethylalkylpyrazole carboxylic acid products, thus possessing high promotional value.

Claims

1. A method for synthesizing difluoromethylalkylpyrazole carboxylic acid, characterized in that, The product was obtained by direct defluorination using trifluoromethylalkylpyrazole carboxylic acid as a raw material, as shown in the following reaction formula: R is a hydrogen atom or an alkyl group with 1-6 carbon atoms. The specific synthesis method is as follows: High-purity nitrogen gas is introduced into the electrolytic cell for protection. Alkali is added to the cathode chamber, and then the raw material trifluoromethylalkylpyrazole carboxylic acid is added to the cathode chamber, while the catalyst is added to the anode chamber. Next, anhydrous solvent is added to both electrode chambers, and electrolysis is carried out under a constant voltage. After electrolysis, the cathode electrolyte is post-treated to obtain the product difluoromethylalkylpyrazole carboxylic acid. The electrolysis temperature is 10-50 ℃, the electrolysis time is 1-24 h, and the constant voltage is 1-10 V; The catalyst is selected from one of tetramethylammonium chloride, tetraethylammonium chloride, tetrapropylammonium chloride, tetrabutylammonium chloride, tetramethylammonium bromide, tetraethylammonium bromide, tetrapropylammonium bromide, tetrabutylammonium bromide, and methyltrioctylammonium chloride.

2. The method for synthesizing difluoromethylalkylpyrazole carboxylic acid according to claim 1, characterized in that, The molar ratio of the raw material to the alkali is 1:1-3, and the molar ratio of the raw material to the catalyst is 1:0.1-1.

0.

3. The method for synthesizing difluoromethylalkylpyrazole carboxylic acid according to claim 1, characterized in that, The alkali is one of sodium hydroxide, potassium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium hydrogen hydride, sodium tert-butoxide, potassium tert-butoxide, sodium isopropoxide, potassium isopropoxide, diisopropylaminolithium, triethylamine, and diisopropylethylamine.

4. The method for synthesizing difluoromethylalkylpyrazole carboxylic acid according to claim 1, characterized in that, The anhydrous solvent is one of acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N,N-diethylacetamide, 1,4-dioxane, dimethyl sulfoxide, ethanol, methanol, propanol, and butanol, and the mass-to-volume ratio of the raw material to the anhydrous solvent is 1:6-30.

5. The method for synthesizing difluoromethylalkylpyrazole carboxylic acid according to claim 1, characterized in that, The post-processing involves sequentially concentrating the electrolyte under reduced pressure to remove the solvent, dissolving it in water, filtering to remove insoluble matter, adjusting the pH of the filtrate to 2-3 with acid, filtering again, and drying to obtain difluoromethylalkylpyrazole carboxylic acid.

6. The method for synthesizing difluoromethylalkylpyrazole carboxylic acid according to claim 5, characterized in that, The acid is one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and hydrobromic acid.

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