Method for synthesizing pyrazoline by catalyzing ketazine internal cyclization through zinc-based catalyst

Abstract

The invention discloses a method for synthesizing pyrazoline by catalyzing ketazine internal cyclization with a zinc-based catalyst, which comprises the following steps: sequentially adding a ketazine compound and the zinc-based catalyst into a device, and stirring for reaction to obtain a pyrazoline compound. The preparation method disclosed by the invention is simple in process condition and high in yield, and the Zn-based catalyst is easy to obtain, easy in product separation and convenient to recycle; few three wastes are generated in the synthesis process, the method is suitable for industrial amplification, and the obtained target product pyrazoline is diversified and unique in structure and meets the requirement of serving as a biological medicine intermediate in the aspect of biological medicine; in the optical aspect, the compound can be used for fluorescent materials or fluorescent probes, and the industrial application prospect is very wide.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing pyrazoline by catalyzing the internal ring reaction of ketazine with a zinc-based catalyst. Background Art

[0002] Pyrazolines, a class of five-membered nitrogen heterocyclic compounds, have been extensively studied due to their unique chemical, biological, agrochemical, and pharmacological properties. They have found applications in a wide range of scientific fields. For example, in the biopharmaceutical field, pyrazolines exhibit a variety of biological activities, including anti-inflammatory, anticonvulsant, anticancer, and antiviral activities. They are recognized as the most effective corrosion inhibitors in the field of preservative materials. In agrochemistry, they exhibit antibacterial, antifungal, and antiamoeba activities. Therefore, the synthesis, research, and analysis of pyrazoline compounds are of great significance.

[0003] According to literature reports, common synthetic routes for pyrazoline include the oxalic acid-catalyzed ketazine to pyrazoline (Dokl. Akad. Nauk SSSR 1960, 130, 779-781). However, this method currently suffers from drawbacks such as corrosion to equipment, harsh operating conditions, and difficulty in product separation. Patent document CN120004800A also mentions the use of solid superacid catalysts for the synthesis of pyrazoline compounds, while patent document CN118994012A provides for the use of ZSM-5 molecular sieve catalysts for the synthesis of pyrazoline compounds. However, the catalysts used in these documents suffer from drawbacks such as difficult post-processing (e.g., solid superacid catalysts) and relatively high reaction temperatures (140-220°C).

[0004] Zinc-based catalysts are widely used catalysts with advantages such as strong controllability and mild reaction conditions. They can also form deep eutectic solvents with ionic liquids, enhancing catalytic efficiency. However, their application in pyrazoline synthesis has not yet been seen.

[0005] In view of this, the present invention is proposed. Summary of the Invention

[0006] In view of the shortcomings of the existing technology, the purpose of the present invention is to provide a method for synthesizing pyrazoline by catalyzing the internal ring reaction of ketazine with a zinc-based catalyst. Based on the use of the zinc-based catalyst, the reaction conversion rate and yield are high, and the reaction conditions are mild. The reaction efficiency can still be maintained at a high level after 10 cycles.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions: In a first aspect, the present invention provides a method for synthesizing pyrazoline by catalyzing the internal cyclization of ketazine with a zinc-based catalyst, comprising the following steps: sequentially adding a ketazine compound and a zinc-based catalyst into a device, and stirring the reaction to obtain a pyrazoline compound.

[0008] In the above technical solution, the Zn-based catalyzed ketone azo inner ring reaction to prepare pyrazoline can be carried out at normal pressure. Its operating process conditions are simple, avoiding the stringent requirements of existing synthesis methods on reaction conditions, thereby reducing the requirements for reaction equipment. It is suitable for industrial production, and the reaction process produces less three wastes, avoiding environmental pollution problems, which is in line with the concept of green development.

[0009] As a preferred embodiment of the technical solution of the present invention, the ketone azine compound is selected from one of acetonazine, 2-butanone azine, 2-pentanone azine, methyl isopropyl ketone azine, 2-hexanone azine, 3,3-dimethyl-2-butanone azine, and cyclopropyl methyl ketone azine.

[0010] As a preferred embodiment of the technical solution of the present invention, the zinc-based catalyst is selected from a zinc-based salt or a zinc-based ionic liquid.

[0011] As a preferred embodiment of the technical solution of the present invention, the zinc-based salt is selected from one of zinc lactate, zinc nitrate, zinc sulfate, zinc chloride, zinc citrate, and zinc iodide.

[0012] As a preferred embodiment of the technical solution of the present invention, the zinc-based ionic liquid is selected from one of [Emim]Cl-xZnCl2, [Pmim]Cl-xZnCl2, [Bmim]Cl-xZnCl2, [HO3S-(CH2)x-mim]Cl-yZnCl2, and [HO3S-(CH2)x-mim]CF3SO3-yZnCl2. [Emim]Cl-xZnCl2 is an ionic liquid composed of 1-ethyl-3-methylimidazolium chloride ([Emim]Cl) and ZnCl2, where "x" can be 0.5, 1, or 2, etc., and the specific value depends on the molar fraction of ZnCl2; [Pmim]Cl-xZnCl2 is an ionic liquid composed of 1-propyl-3-methylimidazolium chloride ([Pmim]Cl) and ZnCl2, where "x" can be 0.5, 1, etc., and the specific value depends on the molar fraction of ZnCl2; [Bmim]Cl-xZnCl2 is an ionic liquid composed of 1-butyl-3-methylimidazolium chloride ([Bmim]Cl) and ZnCl2. The ionic liquid is composed of imidazolium chloride ([Bmim]Cl) and ZnCl2, wherein "x" can be 0.5, 1, or 2, etc., and the specific value depends on the molar fraction of ZnCl2; [HO3S-(CH2)x-mim]Cl-yZnCl2 is a sulfonic acid functionalized chlorozinc acid ionic liquid, wherein "x" can be 3, 4, etc., and "y" can be 0.5, 1, or 2, etc., and the specific value depends on the molar fraction of ZnCl2; [HO3S-(CH2)x-mim]CF3SO3-yZnCl2 is based on the traditional ionic liquid [HO3S-(CH2) x-mim]Cl-1yZnCl2, where "x" can be 3, etc., and "y" can be 1.5, etc., and the specific values ​​are also determined by the molar fraction of ZnCl2.

[0013] As a preferred embodiment of the technical solution of the present invention, the reaction temperature is 0-150°C, preferably 80-120°C; the reaction time is 1-12 h, preferably 6-10 h, and the reaction pressure is normal pressure.

[0014] As a preferred embodiment of the technical solution of the present invention, the reaction is carried out under atmospheric conditions, and the atmosphere is selected from nitrogen, argon or helium.

[0015] As a preferred embodiment of the technical solution of the present invention, the molar ratio of the ketazine compound to the zinc-based catalyst is 1:(0.001~0.02).

[0016] As a preferred embodiment of the technical solution of the present invention, the pyrazoline compound is one of 3,5,5-trimethyl-2-pyrazoline, 3,5-diethyl-5-methyl-2-pyrazoline, 3,5-dipropyl-5-methyl-2-pyrazoline, 3,5-diisopropyl-5-methyl-2-pyrazoline, 3,5-dibutyl-5-methyl-2-pyrazoline, 3,5-diisobutyl-5-methyl-2-pyrazoline, and 3,5-dicyclopropyl-5-methyl-2-pyrazoline.

[0017] In a second aspect, the present invention also seeks to protect the pyrazoline compound prepared by the above method.

[0018] In the present invention, the structural formula of the above-mentioned ketazine compound is as follows: Among them, the R group can be one of -CH3, -CH2CH3, -CH2CH2CH3, -CH3CHCH3, -CH2CH2CH2CH3, -CH3CHCH2CH3, -CHCH2CH2.

[0019] Correspondingly, the structural formula of the pyrazoline compound is as follows: Among them, the R group can be one of -CH3, -CH2CH3, -CH2CH2CH3, -CH3CHCH3, -CH2CH2CH2CH3, -CH3CHCH2CH3, -CHCH2CH2.

[0020] Compared with the prior art, the present invention has the following beneficial effects: (1) The preparation of pyrazoline by the internal cyclization of ketazine is a complex cascade reaction that is prone to side reactions. The target product pyrazoline is an unstable product in this cascade reaction. The Zn-based catalyst provided by the present invention has the characteristics of high conversion rate and high selectivity, and can control the reaction to proceed in the direction of synthesizing pyrazoline; (2) The Zn-based catalyst used in the present invention can catalyze a series of ketone-azine compounds, not just a single ketone-azine, and has universal applicability; the Zn-based catalyst has a long lifespan, which can avoid the problem of catalyst deactivation during the synthesis process. After the reaction is completed, the Zn-based catalyst can be filtered and recycled. The yield of pyrazoline is still considerable after 10 cycles, and the catalytic activity is maintained at a high level. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the H NMR spectrum of 3,5,5-trimethyl-2-pyrazoline in Example 1; Figure 2 This is the infrared spectrum of 3,5,5-trimethyl-2-pyrazoline in Example 1; Figure 3 They are respectively the H NMR spectra of 3,5-diethyl-5-methyl-2-pyrazoline in Example 6; Figure 4 They are respectively the C NMR spectra of 3,5-diethyl-5-methyl-2-pyrazoline in Example 6; Figure 5 They are respectively the infrared spectra of 3,5-diethyl-5-methyl-2-pyrazoline in Example 6; Figure 6 They are respectively the H NMR spectra of 3,5-dipropyl-5-methyl-2-pyrazoline in Example 15; Figure 7 They are respectively the C NMR spectra of 3,5-dipropyl-5-methyl-2-pyrazoline in Example 15; Figure 8 They are respectively the infrared spectra of 3,5-dipropyl-5-methyl-2-pyrazoline in Example 15; Figure 9 They are respectively the H NMR spectra of 3,5-diisopropyl-5-methyl-2-pyrazoline in Example 7; Figure 10 They are respectively the C NMR spectra of 3,5-diisopropyl-5-methyl-2-pyrazoline in Example 7; Figure 11 They are respectively the H NMR spectra of 3,5-dibutyl-5-methyl-2-pyrazoline in Example 16; Figure 12 They are respectively the C NMR spectra of 3,5-dibutyl-5-methyl-2-pyrazoline in Example 16. DETAILED DESCRIPTION

[0022] In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the embodiments. Of course, the specific embodiments described here are only used to explain the present invention and are not used to limit the present invention.

[0023] Although the steps in the present invention are arranged with numbers, they are not intended to limit the order of the steps. Unless the order of the steps is clearly stated or the execution of a step requires other steps as a basis, the relative order of the steps can be adjusted. It is understood that the term "and / or" used herein refers to and covers any and all possible combinations of one or more of the associated listed items.

[0024] Example 1 A method for synthesizing pyrazoline by catalyzing the internal cyclization of ketazine with a zinc-based catalyst comprises the following steps: 1 mol of acetone azide was placed in a 500 mL three-necked flask with a heating mantle set to 500 rpm. 0.01 mol of zinc chloride catalyst was then added, and the air in the flask was replaced with nitrogen. The temperature was then raised to 95°C. The reaction was terminated after 8 hours. The product was filtered, and the liquid phase was analyzed. The solid catalyst was washed and recycled. The raw materials and products were analyzed by Agilent gas chromatography using an HP-5 column. The contents of various compounds were calculated using an internal standard method based on a standard curve. The resulting pyrazoline product was purified by distillation and further characterized by infrared spectroscopy and nuclear magnetic resonance spectroscopy to confirm the compound's structure. The acetone azide conversion was 81.7%, the selectivity for 3,5,5-trimethyl-2-pyrazoline was 98.9%, and the yield was 80.8%.

[0025] Example 2 The difference from Example 1 is that the amount of zinc chloride catalyst used is 0.02 mol. The catalytic performance evaluation results show that the conversion of acetone azine is 87.5%, the selectivity of 3,5,5-trimethyl-2-pyrazoline is 98.5%, and the yield is 86.2%.

[0026] Example 3 The difference from Example 1 is that the reaction time is 7 h. The catalytic performance evaluation results show that the conversion of acetone azine is 79.3%, the selectivity of 3,5,5-trimethyl-2-pyrazoline is 99.2%, and the yield is 78.7%.

[0027] Example 4 The difference from Example 1 is that the reaction temperature is 90° C. The catalytic performance evaluation results show that the conversion rate of acetone azine is 78.8%, the selectivity of 3,5,5-trimethyl-2-pyrazoline is 99.1%, and the yield is 78.1%.

[0028] Example 5 The difference from Example 2 is that the reaction temperature is 100° C. The catalytic performance evaluation results show that the conversion rate of acetone azine is 88.4%, the selectivity of 3,5,5-trimethyl-2-pyrazoline is 98.3%, and the yield is 86.9%.

[0029] Example 6 The difference from Example 2 is that the reactant is 2-butanone azine. The catalytic performance evaluation results show that the conversion rate of 2-butanone azine is 76%, the selectivity of 3,5-diethyl-5-methyl-2-pyrazoline is 98.4%, and the yield is 74.8%.

[0030] Example 7 The difference from Example 2 is that the reactant is methyl isopropyl ketone azide. The catalytic performance evaluation results show that the conversion rate of methyl isopropyl ketone azide is 38.1%, the selectivity of 3,5-diisopropyl-5-methyl-2-pyrazoline is 85.7%, and the yield is 32.7%.

[0031] Example 8 The difference from Example 1 is that zinc nitrate catalyst was used. The catalytic performance evaluation results showed that the conversion rate of acetone azine was 78.6%, the selectivity of 3,5,5-trimethyl-2-pyrazoline was 98.8%, and the yield was 77.7%.

[0032] Example 9 The difference from Example 8 is that the reaction time is 9 h. The catalytic performance evaluation results show that the conversion of acetone azine is 79.9%, the selectivity of 3,5,5-trimethyl-2-pyrazoline is 98.2%, and the yield is 78.5%.

[0033] Example 10 The difference from Example 8 is that the amount of zinc nitrate catalyst used is 0.02 mol. The catalytic performance evaluation results show that the conversion of acetone azine is 85.4%, the selectivity of 3,5,5-trimethyl-2-pyrazoline is 94.2%, and the yield is 80.4%.

[0034] Example 11 The difference from Example 8 is that the reaction temperature is 115° C. The catalytic performance evaluation results show that the conversion of acetone azine is 87.2%, the selectivity of 3,5,5-trimethyl-2-pyrazoline is 91.5%, and the yield is 79.8%.

[0035] Example 12 In this example, an ionic liquid was first prepared, comprising the following steps: in an N2 atmosphere, n-heptane was used as the reaction solvent, [Bmim]Cl ionic liquid and zinc chloride were mixed at different molar ratios (1:2), the temperature was raised to 80°C, and the reaction was carried out for 48 hours. The resulting liquid was washed several times with ethyl acetate and dried in a vacuum drying oven for 24 hours to finally obtain a Zn-based ionic liquid catalyst.

[0036] The Zn-based ionic liquid catalyst prepared above was used to catalyze a synthesis reaction, comprising the following steps: 1 mol of acetone azine was placed in a 500 mL three-necked flask, stirred at 500 rpm using a heating mantle, and then 0.01 mol of the Zn-based ionic liquid catalyst was added. The air in the flask was replaced with nitrogen, and the temperature was raised to 85°C. The reaction was terminated after 9 hours, and the product was filtered and analyzed. The raw materials and products were analyzed by Agilent gas chromatography using an HP-5 column. The contents of various compounds were calculated using the internal standard method based on a standard curve. The acetone azine conversion was 85.6%, the selectivity for 3,5,5-trimethyl-2-pyrazoline was 98.4%, and the yield was 84.2%.

[0037] Example 13 The difference from Example 12 is that the amount of Zn-based ionic liquid catalyst used is 0.02 mol. The catalytic performance evaluation results show that the conversion of acetone azine is 93.4%, the selectivity of 3,5,5-trimethyl-2-pyrazoline is 97.7%, and the yield is 91.3%.

[0038] Example 14 The difference from Example 12 is that the reaction temperature is 105° C. Catalytic performance evaluation showed that the conversion of acetone azide was 90.7%, the selectivity of 3,5,5-trimethyl-2-pyrazoline was 98.1%, and the yield was 89%.

[0039] Example 15 Unlike Example 14, 2-pentanone azine was used as the reactant. Catalytic performance evaluation results showed a 2-pentanone azine conversion rate of 78.3%, a 3,5-dipropyl-5-methyl-2-pyrazoline selectivity of 98.4%, and a yield of 77%.

[0040] Example 16 Unlike Example 14, the reactant ketazine was 2-hexanone azine. Catalytic performance evaluation results showed that the conversion of 2-hexanone azine was 64.6%, the selectivity for 3,5-dibutyl-5-methyl-2-pyrazoline was 91.8%, and the yield was 59.3%.

[0041] Example 17 In this embodiment, an ionic liquid is first prepared, comprising the following steps: N-methylimidazole and sultone in a molar ratio of 1:1 are mixed in a flask, the temperature is raised to 60°C and the reaction is carried out for 12 hours, hydrochloric acid is added dropwise using a separatory funnel at room temperature, the temperature is raised and stirred for reaction, the resulting crude product is washed with ether, and vacuum dried to obtain an ionic liquid, zinc salt is added in batches at a molar ratio of (1:2) at room temperature, the mixture is stirred for half an hour, and the mixture is reacted in an oil bath at 100°C for 48 hours to finally obtain a Zn-based ionic liquid catalyst.

[0042] The Zn-based ionic liquid catalyst prepared above was used to catalyze a synthesis reaction, comprising the following steps: 1 mol of acetone azine was placed in a 500 mL three-necked flask, stirred at 500 rpm using a heating mantle, and then 0.01 mol of the Zn-based ionic liquid catalyst was added. The air in the flask was replaced with nitrogen, and the temperature was raised to 90°C. The reaction was terminated after 9 hours, and the product was filtered and analyzed. The raw materials and products were analyzed by Agilent gas chromatography using an HP-5 column. The contents of various compounds were calculated using the internal standard method based on a standard curve. The acetone azine conversion was 89.4%, the selectivity for 3,5,5-trimethyl-2-pyrazoline was 99.6%, and the yield was 89%.

[0043] Example 18 The difference from Example 17 is that the amount of Zn-based ionic liquid catalyst used is 0.02 mol. The catalytic performance evaluation results show that the conversion of acetone azine is 92.5%, the selectivity of 3,5,5-trimethyl-2-pyrazoline is 99.5%, and the yield is 92%.

[0044] Example 19 The difference from Example 18 is that the reaction temperature is 110° C. The catalytic performance evaluation results show that the conversion of acetone azine is 93.4%, the selectivity of 3,5,5-trimethyl-2-pyrazoline is 98.5%, and the yield is 92%.

[0045] Example 20 The difference from Example 18 is that the reaction time is 12 h. The catalytic performance evaluation results show that the conversion of acetone azine is 95.7%, the selectivity of 3,5,5-trimethyl-2-pyrazoline is 91.6%, and the yield is 87.7%.

[0046] Example 21 The difference from Example 18 is that the raw material is cyclopropyl methyl ketazine. The catalytic performance evaluation results show that the conversion rate of cyclopropyl methyl ketazine is 50.2%, the selectivity of 3,5-dicyclopropyl-5-methyl-2-pyrazoline is 85.3%, and the yield is 42.8%.

[0047] Example 22 After the reaction, the Zn-based catalyst in Example 2 was filtered, the solid was washed 2-3 times with anhydrous ethanol, and dried in a forced air drying oven at 100°C for 12 hours to obtain a Zn-based catalyst for reuse. After 10 reuses, the catalyst still exhibited high catalytic activity, achieving a yield of 77% for 3,5,5-trimethyl-2-pyrazoline. The specific results are shown in Table 1.

[0048] Table 1 Effect of catalyst cycle times on the yield of butanone pyrazoline While the present invention is illustrated by the aforementioned embodiments, the present invention is not limited to these embodiments, nor does it necessarily rely on these embodiments for implementation. Those skilled in the art will appreciate that any improvements to the present invention, equivalent replacements for individual raw materials in the present invention, additions of auxiliary ingredients, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

Claims

1. A method for synthesizing pyrazoline by catalyzing the internal ring reaction of ketazine with a zinc-based catalyst, characterized in that: The method comprises the following steps: sequentially adding a ketazine compound and a zinc-based catalyst into a device, and stirring and reacting the mixture to obtain a pyrazoline compound.

2. The method for synthesizing pyrazoline by catalyzing the internal ring reaction of ketazine with a zinc-based catalyst according to claim 1, characterized in that: The ketazine compound is selected from one of acetonazine, 2-butanone azine, 2-pentanone azine, methyl isopropyl ketazine, 2-hexanone azine, 3,3-dimethyl-2-butanone azine, and cyclopropyl methyl ketazine.

3. The method for synthesizing pyrazoline by catalyzing the internal ring reaction of ketazine with a zinc-based catalyst according to claim 1, characterized in that: The zinc-based catalyst is selected from a zinc-based salt or a zinc-based ionic liquid.

4. The method for synthesizing pyrazoline by catalyzing the internal ring reaction of ketazine with a zinc-based catalyst according to claim 3, characterized in that: The zinc-based salt is selected from one of zinc lactate, zinc nitrate, zinc sulfate, zinc chloride, zinc citrate and zinc iodide.

5. The method for synthesizing pyrazoline by catalyzing ketazine internal ring reaction with a zinc-based catalyst according to claim 3, characterized in that: The zinc-based ionic liquid is selected from one of [Emim]Cl-xZnCl2, [Pmim]Cl-xZnCl2, [Bmim]Cl-xZnCl2, [HO3S-(CH2)x-mim]Cl-yZnCl2, and [HO3S-(CH2)x-mim]CF3SO3-yZnCl2.

6. The method for synthesizing pyrazoline by catalyzing the internal ring reaction of ketazine with a zinc-based catalyst according to claim 1, characterized in that: The reaction temperature is 80~120 ℃, the reaction time is 6~10 h, and the reaction pressure is normal pressure.

7. The method for synthesizing pyrazoline by catalyzing the internal ring reaction of ketazine with a zinc-based catalyst according to claim 1, characterized in that: The reaction is carried out under an atmosphere selected from nitrogen, argon or helium.

8. The method for synthesizing pyrazoline by catalyzing the internal cyclization of ketazine with a zinc-based catalyst according to claim 1, characterized in that: The molar ratio of the ketazine compound to the zinc-based catalyst is 1:(0.001~0.02).

9. The method for synthesizing pyrazoline by catalyzing the internal ring reaction of ketazine with a zinc-based catalyst according to claim 1, characterized in that: The pyrazoline compound is one of 3,5,5-trimethyl-2-pyrazoline, 3,5-diethyl-5-methyl-2-pyrazoline, 3,5-dipropyl-5-methyl-2-pyrazoline, 3,5-diisopropyl-5-methyl-2-pyrazoline, 3,5-dibutyl-5-methyl-2-pyrazoline, 3,5-diisobutyl-5-methyl-2-pyrazoline and 3,5-dicyclopropyl-5-methyl-2-pyrazoline.

10. A pyrazoline compound prepared by the method according to any one of claims 1 to 9.

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