3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic acid
By using inexpensive difluorochloromethane and carbon monoxide as raw materials, and combining carbonyl insertion, halogenation, and pericyclic reactions, the synthetic route of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was simplified, solving the problems of expensive raw materials and excessive waste, and realizing low-cost, highly selective industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANDONG RUNBO BIOTECH CO LTD
- Filing Date
- 2023-09-28
- Publication Date
- 2026-07-03
Smart Images
Figure CN117304112B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic compound synthesis, specifically a method for synthesizing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. Background Technology
[0002] 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is an important pharmaceutical and pesticide intermediate, commonly used in the synthesis of SDHI (succinate dehydrogenase inhibitor) fungicides. In recent years, SDHI fungicides have experienced rapid growth, primarily driven by the strong launch of new products, especially after 2000, which saw the emergence of many blockbuster and high-potential products. For example, fluopyram and benzimidazole, with their broad-spectrum fungicidal activity, have annual sales exceeding $300 million. Fluopyram has achieved breakthrough control of wheat scab and significantly reduced DON toxin content. Fluopyram aniline and fluopyram play important roles in the seed treatment field, such as pyraclostrobin, fluopyram, benzimidazole, bifenthiophanate, and fluopyram.
[0003] The reported synthesis methods mainly include:
[0004] (1) Patent EP1997808A discloses a method that uses ethyl difluoroacetate as a raw material to react with methyl orthoformate and acetic anhydride to generate intermediate ethyl 4,4-difluoro-2-(ethoxymethylene)-3-oxobutyrate. Then, the intermediate is cyclized with methylhydrazine and hydrolyzed under alkaline conditions to generate 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. This method is simple and produces less waste, but the raw materials required are expensive and difficult to obtain, and the product has poor selectivity.
[0005] (2) Patent CN101687806A and patent CN101679282A disclose a five-step reaction to synthesize 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid using dichloroacetyl chloride and vinyl ether as raw materials, and methylhydrazine cyclization, bromination, potassium fluoride substitution, and carbonyl insertion. The process involves a large temperature range, and the carbonyl insertion process requires catalysis and pressure. The conditions are harsh, it is not easy to operate, and the cost is high, making it unsuitable for industrial production.
[0006] (3) Patent WO2012025469 discloses a method that uses difluorochloroacetyl chloride as a raw material, reacts with ketene to obtain ethyl difluorochloroacetoacetate, and after cyclization with methylhydrazine, it is dechlorinated by hydrogenation to obtain ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. Under alkaline conditions, it is hydrolyzed to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. This method has a long route, the raw materials are not easy to obtain, the hydrogenation dechlorination step is complicated to operate, the cost is high, and a lot of waste is generated. Summary of the Invention
[0007] In most existing technologies, the synthesis of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid involves the construction of a difluoromethyl group, primarily obtained from difluoroacetic acid. However, the preparation of difluoroacetyl chloride and difluoroethyl acetate from difluoroacetic acid results in excessive wastewater and severe equipment corrosion. Furthermore, existing processes are complex and generate numerous wastes. This invention provides a novel method for synthesizing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid using inexpensive and readily available difluorochloromethane as the starting material. Through carbonylation, halogenation, and pericyclic reactions, this method utilizes even cheaper difluorochloromethane, has fewer steps, is simpler, more operable, and possesses significant industrial practical value.
[0008] The structural formula of the 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid synthesized in this invention is shown in formula (VII):
[0009] .
[0010] The technical solution adopted by the present invention to achieve the above objectives is as follows:
[0011] This invention provides a method for synthesizing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, comprising the following steps:
[0012] (A) Carbonylation reaction: Carbonylation reaction occurs between difluorochloromethane, carbon monoxide and methylhydrazine in the presence of a catalyst and sodium formate to obtain intermediate formula (I);
[0013]
[0014] (B) Halogenation reaction: The reaction solution of the intermediate shown in formula (I) is halogenated with a halogenating agent to obtain the intermediate of formula (II);
[0015]
[0016] (C) Pericyclic reaction: The intermediate shown in formula (II), the base and propynic acid react to undergo a pericyclic reaction to 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid as shown in (V);
[0017] .
[0018] Further, in step (A), the catalyst is one or both of palladium salt and phosphine ligand; the palladium salt is Pd(CH3CN)Cl2, Pd(dppf)Cl2, Pd(OAc)2, Pd(PPh3)2Cl2, Pd(acac)2 or PdCl2; the phosphine ligand is 1,2-bis(diisopropylphosphine)ethane, BINAP, Xantphos, 1,3-bis(diphenylphosphine)propane or 1,2-bis(dimethylphosphine)ethane.
[0019] Further, in step (A), the molar ratio of difluorochloromethane, catalyst, and ligand is 1:0.02%–1%:0.02%–1%; the molar ratio of difluorochloromethane to sodium formate is 1:1.03–4; the molar ratio of difluorochloromethane to methylhydrazine is 1:1.05; and the amount of carbon monoxide introduced is such that the pressure of the reaction system is maintained at 50 psi.
[0020] In step (A) of the present invention, the carbonylation reaction is carried out in a solvent; the solvent is water, an alcohol solvent, an ether solvent, or an amide solvent.
[0021] The solvents mentioned above are methanol, N,N-dimethylformamide, ethanol, isopropanol, tetrahydrofuran, isopropyl ether, or methyltetrahydrofuran.
[0022] Furthermore, in step (A), the carbonyl insertion reaction is carried out at a temperature of -5 to 30°C for 3 to 6 hours.
[0023] Furthermore, in step (B), the molar ratio of the intermediate shown in formula (I) to the halogenating reagent is 1:1.03 to 1.5; the halogenation reaction is carried out at -5 to 25°C for 3 hours.
[0024] Furthermore, the halogenating agent is Cl2, Br2, NBS, NCS, TCCA, dibromohydantoin, or dichlorohydantoin.
[0025] Furthermore, in step (C), the molar ratio of the intermediate shown in formula (II) to propynic acid is 1:1.03-2; the molar ratio of propynic acid to base is 1:1.8-2.0; the reaction temperature is -5 to 25℃, and the time is 2-4h.
[0026] Furthermore, in step (C), the base includes, but is not limited to, at least one of triethylamine, potassium bicarbonate, DBU, sodium bicarbonate, sodium hydroxide, sodium carbonate, potassium carbonate, and potassium hydroxide.
[0027] Compared with the prior art, the present invention has the following advantages:
[0028] 1. This invention provides a novel method for synthesizing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, which uses inexpensive propynic acid as a reactant and has a simple synthesis method.
[0029] 2. This invention is the first to use difluorochloromethane and carbon monoxide, which are cheaper, to synthesize 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. It is inexpensive, has high reaction selectivity, generates less waste, and has high economic and environmental value, making it more suitable for industrial production. Attached Figure Description
[0030] Figure 1 The hydrogen spectrum of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid;
[0031] Figure 2 The carbon spectrum of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. Detailed Implementation
[0032] The present invention will be further described below with reference to specific embodiments. The following description is merely exemplary and does not limit the scope of protection. Other embodiments obtained by those skilled in the art without creative effort, without departing from the inventive concept of the present invention, are also within the scope of protection.
[0033] Unless otherwise specified, all raw materials used in the following embodiments are commercially available products.
[0034] Unless otherwise specified, all concentrations mentioned in the following examples are mass percentage concentrations.
[0035] In the following examples, yield = actual product mass × purity / theoretical product mass.
[0036] Example 1
[0037] Carbonylation reaction: At room temperature, 50 mL of N,N-dimethylformamide was added to an autoclave, followed by 43.23 g (0.500 mol) of difluorochloromethane, then 37.4 g (0.550 mol) of sodium formate, 20.22 g (0.001 mol) of Pd(OAc) catalyst, 0.26 g (0.001 mol) of dippp, 2-bis(di-isopropylphosphino)ethane ligand, and 60.47 g (0.525 mol) of aqueous methylhydrazine solution. CO was then introduced into the autoclave at room temperature to maintain a pressure of 50 psi. After 4 h of reaction, the reaction was stopped, yielding an N,N-dimethylformamide solution of intermediate I.
[0038] Halogenation reaction: The N,N-dimethylformamide solution of the above intermediate I was added to a four-necked flask and placed at -5-0℃. 82.96 g (0.519 mol) of bromine was slowly added dropwise. After the addition was completed in 2 hours, the mixture was kept at -5-0℃ and stirred for 2 hours. The temperature was then raised to room temperature and stirred for 1 hour to obtain the bromination reaction solution.
[0039] Pericyclic reaction: 34.83 g (0.497 mol) of propynyl acid was added to the above bromination reaction solution, followed by the dropwise addition of 128.74 g (0.965 mol) of 30% liquid alkali. After the addition was completed over 2 hours, the mixture was stirred at room temperature for 2 hours. Under HPLC control, no raw material remained. 15% hydrochloric acid was added to adjust the pH to 6, and the mixture was stirred and cooled to -5°C to crystallize. The crystals were filtered, collected, and dried to obtain a white solid, 76.83 g (0.431 mol) of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, with a purity of 98.8% and a yield of 86.2% based on difluorochloromethane.
[0040] The proton NMR spectrum of the synthesized final product, 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, is shown below. Figure 1 As shown; carbon spectrum as shown Figure 2 As shown:
[0041] 1 H NMR (400 MHz, DMSO- d 6) δ 12.82 (s, 1H), 8.33 (s, 1H), 7.20 (t, J =53.8 Hz, 1H), 3.91 (s, 3H).
[0042] 13 C NMR (101 MHz, DMSO- d 6) δ 163.0, 145.1 (t, J = 23.8 Hz), 136.2, 113.0(t, J = 3.3 Hz), 109.6 (t, J = 234.7 Hz). 39.3.
[0043] Example 2
[0044] 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method in Example 1, except that 0.26 g of Pd(CH3CN)2Cl2 was added to 50 mL of tetrahydrofuran as a solvent and used as a catalyst in the carbonylation step; the other steps remained unchanged. A white solid of 74.66 g, namely 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, was finally obtained. The purity was determined to be 98.5%, and the yield, based on difluorochloromethane, was 83.51%.
[0045] Example 3
[0046] 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method in Example 1, except that 70g of chlorine gas was used as the halogenating agent in the halogenation step, while the other steps remained unchanged. A white solid of 77.56g was finally obtained, which was 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. The purity was determined to be 98.9%, and the yield, based on difluorochloromethane, was 87.1%.
[0047] Example 4
[0048] 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method in Example 1, with the following differences: In the carbonylation step, 50 mL of methanol was used as the solvent and 0.732 g of Pd(dppf)Cl2 was used as the catalyst; in the halogenation step, 70 g of chlorine gas was used as the halogenating agent; and 81.1 g of sodium bicarbonate was used for the pericyclic reaction. The remaining steps remained unchanged. A white solid of 76.42 g, namely 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, was finally obtained. The purity was determined to be 98.3%, and the yield, based on difluorochloromethane, was 85.3%.
[0049] Example 5
[0050] 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method in Example 1, except that: in the carbonylation step, 50 mL of ethanol was used as the solvent, 0.177 g of PdCl2 was used as the catalyst, and 0.623 g of BINAP was used as the ligand; in the halogenation step, 92.3 g of NBS was used as the halogenating agent, and the other steps remained unchanged. A white solid of 74.96 g, namely 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, was finally obtained. The purity was determined to be 98.1%, and the yield, based on difluorochloromethane, was 83.5%.
[0051] Example 6
[0052] 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was prepared according to the method in Example 1, except that: in the carbonylation step, 50 mL of ethanol was used as the solvent and 0.578 g of Xantphos was used as the ligand; in the halogenation step, 40.2 g of TCCA was used as the halogenating agent, and the remaining steps remained unchanged. A white solid of 74.83 g, namely 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, was finally obtained. The purity was determined to be 98.2%, and the yield, based on difluorochloromethane, was 83.4%.
Claims
1. A method for synthesizing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, characterized in that, Includes the following steps: (A) Carbonylation reaction: Carbonylation occurs between difluorochloromethane, carbon monoxide and methylhydrazine in the presence of a catalyst, phosphine ligand and sodium formate to obtain intermediate formula (I); (B) Halogenation reaction: The reaction solution of the intermediate shown in formula (I) is halogenated with a halogenating agent to obtain the intermediate of formula (II); (C) Pericyclic reaction: The intermediate shown in formula (II) reacts with the base and propynic acid to undergo a pericyclic reaction to 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid shown in formula (III); ； In step (A), the catalyst is Pd(CH3CN)Cl2, Pd(dppf)Cl2, Pd(OAc)2, Pd(PPh3)2Cl2, Pd(acac)2, or PdCl2; the phosphine ligand is 1,2-bis(diisopropylphosphine)ethane, BINAP, Xantphos, 1,3-bis(diphenylphosphine)propane, or 1,2-bis(dimethylphosphine)ethane.
2. The synthesis method according to claim 1, characterized in that, In step (A), the molar ratio of difluorochloromethane, catalyst, and phosphine ligand is 1:0.02%–1%:0.02%–1%; the molar ratio of difluorochloromethane to sodium formate is 1:1.03–4; the molar ratio of difluorochloromethane to methylhydrazine is 1:1.05; and the amount of carbon monoxide introduced is such that the pressure of the reaction system is maintained at 50 psi.
3. The synthesis method according to claim 1, characterized in that, In step (A), the carbonylation reaction is carried out in a solvent; the solvent is water, an alcohol solvent, an ether solvent, or an amide solvent.
4. The synthesis method according to claim 3, characterized in that, In step (A), the solvent is methanol, N,N-dimethylformamide, ethanol, isopropanol, tetrahydrofuran, isopropyl ether, or methyltetrahydrofuran.
5. The synthesis method according to any one of claims 1-4, characterized in that, In step (A), the carbonyl insertion reaction is carried out at a temperature of -5 to 30°C for 3 to 6 hours.
6. The synthesis method according to claim 1, characterized in that, In step (B), the molar ratio of the intermediate shown in formula (I) to the halogenating reagent is 1:1.03 to 1.5; the halogenation reaction is carried out at -5 to 25°C for 3 hours.
7. The synthesis method according to claim 1 or 6, characterized in that, The halogenating agent is Cl2, Br2, NBS, NCS, TCCA, dibromohydantoin, or dichlorohydantoin.
8. The synthesis method according to claim 1, characterized in that, In step (C), the molar ratio of the intermediate shown in formula (II) to propynic acid is 1:1.03-2; the molar ratio of propynic acid to base is 1:1.8-2.0; the reaction temperature is -5 to 25℃, and the time is 2 to 4 hours.
9. The synthesis method according to claim 1 or 8, characterized in that, In step (C), the base is at least one selected from triethylamine, potassium bicarbonate, DBU, sodium bicarbonate, sodium hydroxide, sodium carbonate, potassium carbonate, and potassium hydroxide.