A method for preparing an N-arylpyrazole compound

Abstract

This invention discloses a method for preparing N-arylpyrazole compounds. Using low-cost arylhydrazine hydrochloride and β-dicarbonyl compounds as raw materials, a cyclization reaction occurs under mild conditions in a eutectic solvent formed by choline chloride and urea, efficiently preparing N-arylpyrazole compounds. This eutectic solvent is characterized by simple preparation, low volatility, and good biocompatibility. After the reaction, water can be evaporated for recovery and recycling, significantly reducing waste emissions and production costs. The method of this invention is simple to operate, requiring no metal catalysts, toxic reagents, or traditional organic solvents, making it environmentally friendly and operator-friendly. It has broad substrate applicability, high product yield, a simple process route, and convenient post-processing, conforming to green chemistry principles and suitable for the batch, large-scale, and green production of pyrazole active pharmaceutical ingredients and intermediates.

Description

Technical Field

[0001] This invention belongs to the field of biopharmaceutical manufacturing and chemical pharmaceutical raw material manufacturing technology, specifically relating to a method for preparing N-arylpyrazole compounds, a key structural unit of drugs and bioactive molecules. Background Technology

[0002] Pyrazole compounds, as key structural units in various drugs and bioactive molecules, are widely used in the manufacture of biopharmaceuticals and chemical pharmaceutical raw materials and formulations. These compounds exhibit a variety of pharmacological activities, including anti-inflammatory, antiviral, antitumor, anticoagulant, and antifungal effects, and form the core framework of many marketed drugs. For example, the anti-inflammatory drug celecoxib, as the world's first selective cyclooxygenase-2 inhibitor, has become a classic drug for treating rheumatoid arthritis and osteoarthritis; the anticoagulant apixaban also contains a pyrazole structure, further demonstrating the important role of this class of compounds in drug development and production. Given the crucial role of pyrazole compounds in drug development, the development of efficient, green, and drug-compatible synthetic methods for pyrazoles has attracted widespread attention.

[0003] Among various synthetic routes, the condensation reaction of hydrazine with β-dicarbonyl compounds has become one of the most commonly used methods in laboratory and potential industrial preparations due to the readily available raw materials and direct operation. However, this route still faces severe challenges in terms of efficiency, cost, and environmental impact when applied to large-scale, compliant production of active pharmaceutical ingredients. Various reported metal catalyst systems (such as Sc(OTf)3, [Ce(L-Pro)2]2(Oxa), Zn[(L)proline]2, Cu...) 1.5 PMo 12 O 40 Although catalysts (such as those used in pharmaceutical manufacturing) can promote reactions, they have problems such as complex catalyst preparation, high risk of metal residue, cumbersome post-processing, and high cost, making it difficult to meet the strict requirements for purity and safety in pharmaceutical production.

[0004] CN104974091A discloses a method for preparing 3-methyl-1,5-diarylpyrazole compounds by catalytic cyclization of aryl hydrazine hydrochloride and aryl-1,3-butanedione in ethanol solvent with anhydrous sodium acetate as an additive. However, this method has limited reaction yields, hindering cost reduction and process efficiency. While CN114292234A achieves the synthesis of pyrazole derivatives from aryl hydrazine derivatives and alkyl dione derivatives without metals or additives, this method requires a large amount of acetonitrile, an organic solvent with high toxicity, environmental and operator risks, and increased difficulty and cost in subsequent solvent recovery and waste disposal, making it difficult to meet the requirements of green pharmaceuticals and sustainable production. Furthermore, when the aromatic ring has an electron-donating group (such as methoxy or tert-butyl) or the pyrazole ring has an alkyl derivative at the 4-position, the reaction yield decreases significantly (e.g., the yield of p-methoxyphenylhydrazine is only 46%), indicating that substrate universality needs improvement. Therefore, in the fields of biopharmaceutical manufacturing and chemical active pharmaceutical ingredient (API) production, there is an urgent need to develop a high-efficiency synthetic process for pyrazole compounds that is mild, easy to operate, environmentally friendly, and suitable for large-scale preparation. This would improve the efficiency, economy, and compliance of API production, meeting increasingly stringent drug quality and green production standards. Consequently, in the fields of biopharmaceutical and chemical API manufacturing, there is an urgent need to develop a novel synthetic strategy that simultaneously considers synthetic efficiency, structural flexibility, operational safety, and environmental friendliness. Summary of the Invention

[0005] This invention aims to overcome the shortcomings of existing pyrazole compound synthesis technologies, such as poor environmental friendliness, insufficient economic efficiency, low operational safety, and low yield. It provides a general preparation method for N-arylpyrazole compounds that is mild, simple in procedure, high in yield, environmentally friendly, allows for solvent recycling and reuse, and allows for flexible control of product structure. This provides a practical solution for the green, economical, and large-scale production of related active pharmaceutical ingredients.

[0006] The method for preparing N-arylpyrazole compounds provided by the present invention is as follows: aryl hydrazine hydrochloride shown in Formula I and β-dicarbonyl compound shown in Formula II are added to a eutectic solvent of choline chloride and urea, and the mixture is stirred and reacted at 60-100 °C. After the reaction is complete, the mixture is cooled to room temperature, water is added, and the mixture is separated and purified to obtain N-arylpyrazole compounds shown in Formula III.

[0007]

[0008] In the formula, R 1 Represents any one of phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, halophenyl, nitro-substituted phenyl, cyano-substituted phenyl, carboxyl-substituted phenyl, naphthyl, pyridyl, pyrazinyl, and quinolinyl; R 2 R 4Each independently represents any one of C1-C4 alkyl, phenyl, or C3-C6 cycloalkyl; R 3 It represents any one of hydrogen, C1 to C4 alkyl groups, or halogens.

[0009] In the above-mentioned eutectic solvent, the molar ratio of choline chloride to urea is 1:1 to 5, preferably 1:2 to 3. The eutectic solvent is prepared by mixing choline chloride and urea, and heating and stirring at 60 to 90 °C until it melts into a homogeneous, stable, and transparent solution.

[0010] In the above preparation method, the molar ratio of arylhydrazine hydrochloride to β-dicarbonyl compound is 1:0.5 to 2, preferably 1:1 to 1.5.

[0011] In the above preparation method, the preferred feeding ratio of the arylhydrazine hydrochloride to the eutectic solvent is 1 mmol: 0.25-3 mL.

[0012] In the above preparation method, it is preferable to stir the reaction at 75–85 °C for 2–6 hours.

[0013] In the above preparation method, if a solid precipitates after adding water, it is directly filtered, and the solid is the target product N-arylpyrazole compound. The filtrate is distilled to remove water and then recycled as a eutectic solvent. If no solid precipitates after adding water, it is extracted with ethyl acetate. The organic phase is dried with anhydrous Na2SO4, purified by vacuum distillation and column chromatography to obtain the target product N-arylpyrazole compound. The aqueous phase is distilled to remove water and then recycled as a eutectic solvent.

[0014] The beneficial effects of this invention are as follows:

[0015] This invention utilizes inexpensive arylhydrazine hydrochloride and β-dicarbonyl compounds as raw materials, undergoing a cyclization reaction in a eutectic solvent formed by choline chloride and urea to efficiently prepare N-arylpyrazole compounds. The eutectic solvent used in this invention is simply prepared by mixing the raw materials, resulting in low cost and complete conversion. Its low volatility and good biocompatibility significantly reduce harm to the environment and operators. The reaction conditions are mild, allowing for smooth operation without the need for inert gas protection, metal catalysts, or complex additives, simplifying the operation process and equipment requirements. This invention exhibits good adaptability to various arylhydrazine hydrochloride and β-dicarbonyl substrate structures, achieving high yields of the target products and overcoming the limitations of existing methods, such as low yields and insufficient substrate universality. After the reaction, the eutectic solvent can be efficiently recovered and recycled by simple evaporation of water, significantly reducing raw material consumption and waste disposal costs. By selecting low-cost reaction raw materials, this invention provides an efficient method for constructing structurally diverse N-arylpyrazole skeletons, which is beneficial for the discovery and optimization of drug lead compounds. The present invention features a simple process route, convenient post-processing, and recyclable solvents, making it highly suitable for large-scale production. It provides a key technical solution with industrial potential for the green, economical, and safe manufacturing of pyrazole active pharmaceutical ingredients and intermediates. Attached Figure Description

[0016] Figure 1 This is the 1H NMR spectrum of the yellow oily liquid product from Example 1.

[0017] Figure 2 This is the carbon NMR spectrum of the yellow oily liquid product in Example 1.

[0018] Figure 3 This is a high-resolution mass spectrum of the yellow oily liquid product from Example 1.

[0019] Figure 4 This is a graph showing the relationship between the number of times the eutectic solvent was used and the yield of 3,5-dimethyl-1-phenylpyrazole in Example 1. Detailed Implementation

[0020] To determine the process conditions of this invention, the inventors conducted a large number of laboratory research experiments using phenylhydrazine hydrochloride (trade name phenylhydrazine hydrochloride) and acetylacetone as model reactions. As shown in Table 1, different solvents were used to stir phenylhydrazine hydrochloride (2.0 mmol) and acetylacetone at different molar ratios at different temperatures for different times to investigate the effect of reaction conditions on the yield of 3,5-dimethyl-1-phenylpyrazole.

[0021] Table 1

[0022]

[0023]

[0024] Note: In the table, ethanol-sodium acetate uses ethanol as the solvent and sodium acetate as the additive, with an ethanol volume of 97 mL and a sodium acetate volume of 2 mmol; ChCl / 2Urea is a eutectic solvent with a molar ratio of choline chloride to urea of ​​1:2; 2ChCl / TsOH is a eutectic solvent with a molar ratio of choline chloride to p-toluenesulfonic acid of 2:1; ChCl / 4EG is a eutectic solvent with a molar ratio of choline chloride to ethylene glycol of 1:4; ChCl / OA is a eutectic solvent with a molar ratio of choline chloride to oxalic acid of 1:1, and so on.

[0025] As shown in Table 1, the yield of 3,5-dimethyl-1-phenylpyrazole produced by the reaction of phenylhydrazine hydrochloride with acetylacetone using the method in CN104974091A with ethanol as solvent and anhydrous sodium acetate as base is low, only 75.24%. While the yield of 3,5-dimethyl-1-phenylpyrazole is high using the method in CN114292234A with acetonitrile as solvent, acetonitrile is highly toxic and requires a large amount, which is unfriendly to the environment and operators. When using eutectic solvents such as ChCl / TsOH, ChCl / EG, and ChCl / OA, the reaction does not occur. However, when using eutectic solvents formed by choline chloride and urea in different molar ratios, the yield of 3,5-dimethyl-1-phenylpyrazole produced by the reaction of phenylhydrazine hydrochloride and acetylacetone can reach over 95% at reaction temperatures of 60–100℃. Therefore, this invention selects eutectic solvents of choline chloride and urea.

[0026] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the scope of protection of the present invention is not limited to these embodiments.

[0027] Example 1

[0028] 2.7924 g (20 mmol) of choline chloride and 2.4024 g (40 mmol) of urea were added to a 50 mL dry round-bottom flask. The mixture was heated and stirred at 80 °C until it melted into a homogeneous, stable, and transparent solution to obtain a eutectic solvent. 0.2892 g (2.0 mmol) of phenylhydrazine hydrochloride and 0.2 g (2.0 mmol) of acetylacetone were added sequentially to 3 mL of the eutectic solvent. The mixture was stirred at 80 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, and purified by column chromatography after removing ethyl acetate by vacuum distillation to obtain a yellow oily liquid product, 3,5-dimethyl-1-phenylpyrazole, in 98.99% yield.

[0029] The 1H NMR spectrum, 1C NMR spectrum, and high-resolution mass spectrum of the 3,5-dimethyl-1-phenylpyrazole prepared in this embodiment are shown below. Figures 1-3 As shown, the specific data is as follows: 1 H NMR (400 MHz, CDCl3) δ 7.46-7.41 (m, 4H), 7.35-7.31 (m, 1H), 5.99 (s, 1H), 2.30 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ148.96, 139.97, 139.37, 128.97, 127.22, 124.78, 106.90, 13.50, 12.36; HRMSC 11 H 13 N2[M+H] + Theoretical value: 173.1079, measured value: 173.1083. According to... Figures 1-3 It can be seen that 3,5-dimethyl-1-phenylpyrazole was successfully prepared in this embodiment.

[0030] In this embodiment, the aqueous phase after extraction with ethyl acetate was distilled to remove water, and a eutectic solvent prepared by choline chloride and urea in a molar ratio of 1:2 was added to a final volume of 3 mL for the second reaction. This process was repeated for the third, fourth, and fifth reactions, with the results shown below. Figure 4 As shown. According to Figure 4 It can be seen that the product yield of the first reaction was 98.99%, the product yield of the second reaction was 98.96%, and the product yields of the third, fourth and fifth reactions were 98.94%, 98.91% and 98.89%, respectively. After the eutectic solvent was used five times, the product yield did not decrease significantly, which proves that the preparation method of the present invention can recycle the eutectic solvent.

[0031] Example 2

[0032] In this embodiment, equimolar amounts of 2-methylphenylhydrazine hydrochloride were used to replace the phenylhydrazine hydrochloride in Example 1. The other steps were the same as in Example 1, and a colorless and transparent liquid product, 3,5-dimethyl-1-(2-tolyl)pyrazole, with the following structural formula was obtained, with a yield of 90.27%.

[0033]

[0034] The structural characterization data of the obtained 3,5-dimethyl-1-(2-tolyl)pyrazole are as follows: 1H NMR (400 MHz, CDCl3) δ 7.39-7.13 (m, 4H), 5.96 (s, 1H), 2.29 (s, 3H), 2.05 (s, 6H); 13 HRMS C 12 H 15 N2 [M+H]+: Theoretical value 187.1235, measured value 187.1237.

[0035] Example 3

[0036] In this embodiment, equimolar amounts of 3-methylphenylhydrazine hydrochloride were used to replace the phenylhydrazine hydrochloride in Example 1, and the other steps were the same as in Example 1, to obtain a yellow oily liquid product 3,5-dimethyl-1-(3-tolyl)pyrazole with the following structural formula, with a yield of 91.79%.

[0037]

[0038] The structural characterization data of the obtained 3,5-dimethyl-1-(3-tolyl)pyrazole are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 7.7 Hz, 1H), 7.27 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 5.98 (s, 1H), 2.40 (s, 3H), 2.29 (s, 3H), 2.29 (s,3H); 13 HRMS C 12 H 15 N2 [M+H] + Theoretical value: 187.1235, measured value: 187.1237.

[0039] Example 4

[0040] In this embodiment, equimolar amounts of 4-methylphenylhydrazine hydrochloride were used to replace the phenylhydrazine hydrochloride in Example 1, and the other steps were the same as in Example 1, to obtain a yellow oily liquid product 3,5-dimethyl-1-(4-tolyl)pyrazole with the following structural formula, with a yield of 92.87%.

[0041]

[0042] The structural characterization data of the obtained 3,5-dimethyl-1-(4-tolyl)pyrazole are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 5.97 (s, 1H), 2.39 (s, 3H), 2.29 (s, 3H), 2.27 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 148.67,139.32, 137.51, 137.11, 129.51, 124.70, 106.56, 21.05, 13.49, 12.27; HRMSC 12 H 15 N2 [M+H] + Theoretical value: 187.1235, measured value: 187.1239.

[0043] Example 5

[0044] In this embodiment, equimolar amounts of 2-methoxyphenylhydrazine hydrochloride were used to replace the phenylhydrazine hydrochloride in Example 1, and the other steps were the same as in Example 1, to obtain a yellow oily liquid product 1-(2-methoxyphenyl)-3,5-dimethylpyrazole with the following structural formula, with a yield of 88.17%.

[0045]

[0046] The structural characterization data of the obtained 1-(2-methoxyphenyl)-3,5-dimethylpyrazole are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.37 (td, J = 8.0, 1.7 Hz, 1H), 7.32 (dd, J = 7.7, 1.6 Hz, 1H), 7.02(m, 2H), 5.96 (s, 1H), 3.79 (s, 3H), 2.30 (s, 3H), 2.09 (s, 3H); 13HRMS C 12 H 15 N2O [M+H] + Theoretical value: 203.1184, measured value: 203.1188.

[0047] Example 6

[0048] In this embodiment, equimolar amounts of 3-methoxyphenylhydrazine hydrochloride were used to replace the phenylhydrazine hydrochloride in Example 1, and the other steps were the same as in Example 1, to obtain a yellow oily liquid product 1-(3-methoxyphenyl)-3,5-dimethylpyrazole with the following structural formula, with a yield of 89.73%.

[0049]

[0050] The structural characterization data of the obtained 1-(3-methoxyphenyl)-3,5-dimethylpyrazole are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.35-7.31(m, 1H), 7.00-6.98 (m, 2H), 6.90-6.87 (m, 1H), 5.99 (s,1H), 3.84 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H); 13 HRMS C 12 H 15 N2O [M+H] + Theoretical value: 203.1184, measured value: 203.1189.

[0051] Example 7

[0052] In this embodiment, equimolar amounts of 4-methoxyphenylhydrazine hydrochloride were used to replace the phenylhydrazine hydrochloride in Example 1, and the other steps were the same as in Example 1, to obtain a yellow oily liquid product 1-(4-methoxyphenyl)-3,5-dimethylpyrazole with the following structural formula, with a yield of 90.47%.

[0053]

[0054] The structural characterization data of the obtained 1-(4-methoxyphenyl)-3,5-dimethylpyrazole are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.33-7.29 (m, 2H), 6.96-6.93 (m, 2H), 5.95 (s, 1H), 3.83 (s, 3H), 2.28 (s, 3H), 2.23 (s, 3H); 13 HRMS C 12 H 15 N2O [M+H] + Theoretical value: 203.1184, measured value: 203.1187.

[0055] Example 8

[0056] In this embodiment, equimolar amounts of 4-tert-butylphenylhydrazine hydrochloride were used to replace the phenylhydrazine hydrochloride in Example 1, and the other steps were the same as in Example 1, to obtain a yellow oily liquid product 1-(4-tert-butylphenyl)-3,5-dimethylpyrazole with the following structural formula, with a yield of 88.66%.

[0057]

[0058] The structural characterization data of the obtained 1-(4-tert-butylphenyl)-3,5-dimethylpyrazole are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 5.97 (s, 1H), 2.29 (s, 6H), 1.34 (s, 9H); 13 HRMS C 15 H 21 N2 [M+H] + Theoretical value: 229.1705, measured value: 229.1707.

[0059] Example 9

[0060] In this embodiment, equimolar amounts of 4-fluorophenylhydrazine hydrochloride were used to replace the phenylhydrazine hydrochloride in Example 1. The other steps were the same as in Example 1, and a yellow oily liquid product 1-(4-fluorophenyl)-3,5-dimethylpyrazole with the following structural formula was obtained with a yield of 89.94%.

[0061]

[0062] The structural characterization data of the obtained 1-(4-fluorophenyl)-3,5-dimethylpyrazole are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.43-7.33 (m, 2H), 7.18-7.07 (m, 2H), 5.98 (s, 1H), 2.29 (s, 3H), 2.27 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 161.62 (d, J = 245 Hz), 149.02,139.47, 136.05, 126.63 (d, J = 9 Hz), 115.84 (d, J = 22 Hz), 106.85, 13.44,12.20; HRMS C 11 H 12 N2F [M+H] + Theoretical value: 191.0985, measured value: 191.0985.

[0063] Example 10

[0064] In this embodiment, equimolar amounts of 4-chlorophenylhydrazine hydrochloride were used to replace the phenylhydrazine hydrochloride in Example 1, and the other steps were the same as in Example 1, to obtain a yellow oily liquid product 1-(4-chlorophenyl)-3,5-dimethylpyrazole with the following structural formula, with a yield of 92.56%.

[0065]

[0066] The structural characterization data of the obtained 1-(4-chlorophenyl)-3,5-dimethylpyrazole are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.42-7.36 (m, 4H), 5.99 (s, 1H), 2.29 (s, 3H), 2.28 (s, 3H); 13 HRMS C11 H 12 ClN2[M+H] + Theoretical value: 207.0689, measured value: 207.0685.

[0067] Example 11

[0068] In this embodiment, equimolar amounts of 4-bromophenylhydrazine hydrochloride were used to replace the phenylhydrazine hydrochloride in Example 1. The other steps were the same as in Example 1, and a yellow oily liquid product 1-(4-bromophenyl)-3,5-dimethylpyrazole with the following structural formula was obtained with a yield of 89.89%.

[0069]

[0070] The structural characterization data of the obtained 1-(4-bromophenyl)-3,5-dimethylpyrazole are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 6.00 (s, 1H), 2.30 (s, 3H), 2.28 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 149.41, 139.37, 139.01,132.10, 126.06, 120.72, 107.42, 13.46, 12.41; HRMS C 11 H 12 N2Br[M+H] + Theoretical value: 251.0184, measured value: 251.0185.

[0071] Example 12

[0072] In this embodiment, equimolar amounts of 4-iodophenylhydrazine hydrochloride were used to replace the phenylhydrazine hydrochloride in Example 1. The other steps were the same as in Example 1, and a yellow oily liquid product 1-(4-iodophenyl)-3,5-dimethylpyrazole with the following structural formula was obtained with a yield of 92.55%.

[0073]

[0074] The structural characterization data of the obtained 1-(4-iodophenyl)-3,5-dimethylpyrazole are as follows: 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 5.99 (s, 1H), 2.30 (s, 3H), 2.28 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 149.40, 139.62, 139.33,138.05, 126.19, 107.48, 91.83, 13.43, 12.42; HRMS C 11 H 12 N2I [M+H] + Theoretical value: 299.0045, measured value: 299.0049.

[0075] Example 13

[0076] In this embodiment, equimolar amounts of 4-nitrophenylhydrazine hydrochloride were used to replace the phenylhydrazine hydrochloride in Example 1. After the reaction was completed, the mixture was cooled to room temperature, water was added to precipitate the solid product, and the product was filtered and washed with water to obtain the yellow solid product 3,5-dimethyl-1-(4-nitrophenyl)pyrazole with the following structural formula, with a yield of 95.97%.

[0077]

[0078] The structural characterization data of the obtained 3,5-dimethyl-1-(4-nitrophenyl)pyrazole are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 9.0 Hz, 2H), 6.08 (s, 1H), 2.43 (s, 3H), 2.30 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 150.80, 145.59, 145.03,139.81, 124.66, 123.46, 109.30, 13.46, 13.08; HRMS C 11 H 12 N3O2[M+H] + Theoretical value: 218.0930, measured value: 218.0938.

[0079] Example 14

[0080] In this embodiment, equimolar amounts of 3-cyanophenylhydrazine hydrochloride were used to replace the phenylhydrazine hydrochloride in Example 1. The other steps were the same as in Example 1, and a yellow oily liquid product 3-(3,5-dimethylpyrazolyl)benzonitrile with the following structural formula was obtained with a yield of 93.90%.

[0081]

[0082] The structural characterization data of the obtained 3-(3,5-dimethylpyrazolyl)benzonitrile are as follows: 1 H NMR (400 MHz, CDCl3)δ 7.80-7.75 (m, 1H), 7.75-7.69 (m, 1H), 7.63-7.53 (m, 2H), 6.04 (s, 1H), 2.35(s, 3H), 2.29 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 150.17, 140.74, 139.47,130.24, 129.98, 128.30, 127.41, 117.93, 113.31, 108.27, 13.43, 12.58; HRMSC 12 H 12 N3[M+H] + Theoretical value: 198.1031, measured value: 198.1033.

[0083] Example 15

[0084] In this embodiment, equimolar amounts of 4-carboxyphenylhydrazine hydrochloride were used to replace the phenylhydrazine hydrochloride in Example 1. After the reaction was completed, the mixture was cooled to room temperature, water was added to precipitate the solid product, and the product was filtered and washed with water to obtain the brownish-yellow solid product 4-(3,5-dimethylpyrazolyl)benzoic acid with the following structural formula, with a yield of 98.02%.

[0085]

[0086] The structural characterization data of the obtained 4-(3,5-dimethylpyrazolyl)benzoic acid are as follows: 1 H NMR (400 MHz, CDCl3)δ 9.97 (s, 1H), 8.19 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 6.05 (s,1H), 2.38 (s, 3H), 2.33 (s, 3H); 13HRMS C 12 H 13 N₂O₂[M+H] + Theoretical value: 217.0977, measured value: 217.0978.

[0087] Example 16

[0088] In this embodiment, equimolar amounts of 2-hydrazine hydrochloride were used to replace phenylhydrazine hydrochloride in Example 1, and the other steps were the same as in Example 1, to obtain a colorless and transparent liquid product 2-(3,5-dimethylpyrazolyl)pyridine with the following structural formula, with a yield of 93.37%.

[0089]

[0090] The structural characterization data of the obtained 2-(3,5-dimethylpyrazolyl)pyridine are as follows: 1 H NMR (400 MHz, CDCl3) δ8.41 (d, J = 4.5 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.78-7.74 (m, 1H), 7.14-7.11 (m, 1H), 5.99 (s, 1H), 2.63 (s, 3H), 2.30 (s, 3H); 13 HRMS C 10 H 12 N3[M+H] + Theoretical value: 174.1031, measured value: 174.1039.

[0091] Example 17

[0092] In this embodiment, acetylacetone in Example 1 was replaced with an equimolar amount of 3,5-diheptanone, and the other steps were the same as in Example 1, to obtain a yellow oily liquid product 3,5-diethyl-1-phenylpyrazole with the following structural formula, with a yield of 97.53%.

[0093]

[0094] The structural characterization data of the obtained 3,5-diethyl-1-phenylpyrazole are as follows: 1 H NMR (400 MHz, CDCl3) δ7.44-7.39 (m, 4H), 7.35-7.29 (m, 1H), 6.05 (s, 1H), 2.72-2.66 (m, 2H), 2.65-2.61 (m, 2H), 1.28 (t, J = 7.6 Hz, 3H), 1.19 (t, J = 7.5 Hz, 3H); 13 HRMS C 13 H 17 N2 [M+H] + Theoretical value: 201.1392, measured value: 201.1392.

[0095] Example 18

[0096] In this embodiment, acetylacetone in Example 1 was replaced with an equimolar amount of 2,6-dimethyl-3,5-heptadecane, and the other steps were the same as in Example 1, to obtain a yellow oily liquid product 3,5-diisopropyl-1-phenylpyrazole with the following structural formula, with a yield of 88.33%.

[0097]

[0098] The structural characterization data of the obtained 3,5-diisopropyl-1-phenylpyrazole are as follows: 1 H NMR (400 MHz, CDCl3) δ7.45-7.39 (m, 4H), 7.37-7.32 (m, 1H), 6.03 (s, 1H), 3.01 (m, 2H), 1.30 (d, J= 7.0 Hz, 6H), 1.17 (d, J = 6.9 Hz, 6H); 13 HRMS C 15 H 21 N2 [M+H] + Theoretical value: 229.1705, measured value: 229.1709.

[0099] Example 19

[0100] In this embodiment, acetylacetone in Example 1 was replaced with an equimolar amount of 3-methylacetylacetone, and the other steps were the same as in Example 1, to obtain a yellow oily liquid product 3,4,5-trimethyl-1-phenylpyrazole with the following structural formula, with a yield of 87.87%.

[0101]

[0102] The structural characterization data of the obtained 3,4,5-trimethyl-1-phenylpyrazole are as follows: 1 H NMR (400 MHz, CDCl3) δ7.44-7.38 (m, 4H), 7.32-7.28 (m, 1H), 2.25 (s, 3H), 2.21 (s, 3H), 1.97 (s,3H); 13 HRMS C 12 H 15 N2 [M+H] + Theoretical value: 187.1235, measured value: 187.1235.

[0103] Example 20

[0104] In this embodiment, acetylacetone in Example 1 was replaced with an equimolar amount of 3-chloroacetylacetone, and the other steps were the same as in Example 1, to obtain a yellow oily liquid product 4-chloro-3,5-dimethyl-1-phenylpyrazole with the following structural formula, with a yield of 86.02%.

[0105]

[0106] The structural characterization data of the obtained 4-chloro-3,5-dimethyl-1-phenylpyrazole are as follows: 1 H NMR (400 MHz, CDCl3)δ 7.47-7.43 (m, 2H), 7.41-7.34 (m, 3H), 2.29 (s, 3H), 2.29 (s, 3H); 13 HRMS C11 H 12 N₂Cl [M+H] + Theoretical value: 207.0689, measured value: 207.0689.

[0107] Example 21

[0108] In this embodiment, acetylacetone in Example 1 was replaced with an equimolar amount of 1-cyclopropyl-1,3-butanedione, and the other steps were the same as in Example 1, to obtain a brownish-yellow oily liquid product 5-cyclopropyl-3-methyl-1-phenylpyrazole with the following structural formula, with a yield of 88.46%.

[0109]

[0110] The structural characterization data of the obtained 5-cyclopropyl-3-methyl-1-phenylpyrazole are as follows: 1 H NMR (400 MHz, CDCl3)δ 7.61-7.58(m, 2H), 7.45-7.41 (m, 2H), 7.33-7.29 (m, 1H), 5.75 (s, 1H), 2.28(s, 3H), 1.78-1.75 (m, 1H), 0.96-0.92 (m, 2H), 0.75-0.71 (m, 2H); 13 C NMR (100MHz, CDCl3) δ 148.82, 146.40, 140.12, 128.79, 126.90, 124.52, 102.58, 13.48,8.77, 7.68; 13 H 15 N2 [M+H] + Theoretical value: 199.1235, measured value: 199.1239.

[0111] Example 22

[0112] In this embodiment, acetylacetone in Example 1 was replaced with an equimolar amount of benzoylacetone, and the other steps were the same as in Example 1, to obtain a yellow oily liquid product 3-methyl-1,5-diphenylpyrazole with the following structural formula, with a yield of 89.99%.

[0113]

[0114] The structural characterization data of the obtained 3-methyl-1,5-diphenylpyrazole are as follows: 1 H NMR (400 MHz, CDCl3) δ7.30-7.19 (m, 10H), 6.29 (s, 1H), 2.38 (s, 3H);13 C NMR (100 MHz, CDCl3) δ149.31, 143.59, 140.09, 130.68, 128.71, 128.52, 128.49, 128.28, 127.94,126.95, 125.02, 107.65, 13.47; HRMS C 16 H 15 N2 [M+H] + Theoretical value: 235.1235, measured value: 235.1239.

Claims

1. A method for preparing an N-arylpyrazole compound, characterized in that: The arylhydrazine hydrochloride shown in Formula I and the β-dicarbonyl compound shown in Formula II were added to the eutectic solvent of choline chloride and urea, and the reaction was stirred at 60-100 °C. After the reaction was completed, the mixture was cooled to room temperature, water was added, and the product was separated and purified to obtain the N-arylpyrazole compound shown in Formula III. In the formula, R 1 Represents any one of phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, halophenyl, nitro-substituted phenyl, cyano-substituted phenyl, carboxyl-substituted phenyl, naphthyl, pyridyl, pyrazinyl, and quinolinyl; R 2 R 4 Each independently represents any one of C1-C4 alkyl, phenyl, or C3-C6 cycloalkyl; R 3 It represents any one of hydrogen, C1 to C4 alkyl groups, or halogens.

2. The method for preparing N-arylpyrazole compounds according to claim 1, characterized in that: The molar ratio of choline chloride to urea in the eutectic solvent is 1:1 to 5.

3. The method for preparing N-arylpyrazole compounds according to claim 1, characterized in that: The molar ratio of choline chloride to urea in the eutectic solvent is 1:2 to 3.

4. The method for preparing N-arylpyrazole compounds according to any one of claims 1 to 3, characterized in that: The method for preparing the eutectic solvent is as follows: choline chloride and urea are mixed and heated and stirred at 60-90 °C until they melt into a homogeneous, stable, and transparent solution.

5. The method for preparing N-arylpyrazole compounds according to claim 1, characterized in that: The molar ratio of the arylhydrazine hydrochloride to the β-dicarbonyl compound is 1:0.5 to 2.

6. The method for preparing N-arylpyrazole compounds according to claim 1, characterized in that: The molar ratio of the arylhydrazine hydrochloride to the β-dicarbonyl compound is 1:1 to 1.

5.

7. The method for preparing N-arylpyrazole compounds according to claim 1, characterized in that: The feeding ratio of the arylhydrazine hydrochloride to the eutectic solvent is 1 mmol: 0.25–3 mL.

8. The method for preparing N-arylpyrazole compounds according to claim 1, characterized in that: Stir the reaction at 75–85 °C for 2–6 hours.

9. The method for preparing N-arylpyrazole compounds according to claim 1, characterized in that: If a solid precipitates after adding water, filter directly; the solid is the target product, an N-arylpyrazole compound. The filtrate is then distilled to remove water and recycled as a eutectic solvent. If no solid precipitates after adding water, extract with ethyl acetate. The organic phase is dried over anhydrous Na2SO4, purified by vacuum distillation and column chromatography to obtain the target product, an N-arylpyrazole compound. The aqueous phase is then distilled to remove water and recycled as a eutectic solvent.

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