A method for synthesizing nitrogen-containing heterocyclic compounds having maleimide structural units and pyrazolone rings

Abstract

This invention discloses a method for synthesizing nitrogen-containing heterocyclic compounds with a maleimide structural unit and a pyrazolone ring. The method includes the following steps: N-phenylmaleimide olefin and pyrazolone olefin are reacted with 4-dimethylaminopyridine in dichloromethane at a reflux temperature of dichloromethane. After the reaction, saturated brine is added to quench the reaction, followed by extraction with ethyl acetate, removal of the solvent by rotary evaporation under reduced pressure, and separation by forward silica gel column chromatography to obtain nitrogen-containing heterocyclic compounds with a maleimide structural unit and a pyrazolone ring. This invention utilizes optimal reaction conditions for substrate expansion, introducing methyl, methoxy, and chlorine atoms at the ortho, meta, and para positions on the benzene ring of N-phenylmaleimide olefin, constructing a series of nitrogen-containing heterocyclic compounds simultaneously containing a maleimide structural unit and a pyrazolone ring in yields up to 90%. The reaction method of this invention has a fast reaction rate and high yield.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and specifically relates to a method for synthesizing nitrogen-containing heterocyclic compounds having maleimide structural units and pyrazolone rings. Background Technology

[0002] Currently, N-phenylmaleimide alkenes participate in relatively few reactions, and their reactions with azodicarbonate esters and pyrazolone alkenes have not been reported. Therefore, a synthetic method for nitrogen-containing heterocyclic compounds with maleimide structural units and pyrazolone rings is urgently needed. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention provides a method for synthesizing nitrogen-containing heterocyclic compounds having maleimide structural units and pyrazolone rings.

[0004] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0005] This invention provides a method for synthesizing nitrogen-containing heterocyclic compounds having a maleimide structural unit and a pyrazolone ring, the synthetic route of which is shown below:

[0006]

[0007] Specifically, the steps include: using N-phenylmaleimide and pyrazolone as reactants at the reflux temperature of dichloromethane, 4-dimethylaminopyridine is added to dichloromethane for reaction. After the reaction is completed, saturated brine is added to quench the reaction, followed by extraction with ethyl acetate, removal of solvent by rotary evaporation under reduced pressure, and separation by forward silica gel column chromatography to obtain a nitrogen-containing heterocyclic compound with maleimide structural units and a pyrazolone ring.

[0008] Preferably, the mass ratio of N-phenylmaleimide to pyrazolone is 1:1.5 to 1:2; the 4-dimethylaminopyridine is 20 mol%; and the silica gel column chromatography forward separation uses PE / EA = 20 / 1 to 6 / 1 as the eluent.

[0009] Preferably, the synthesis of N-phenylmaleimide ene includes the following steps: adding dichloromethane as a reaction solvent to benzaldehyde, N-phenylmaleimide and triphenylphosphine, stirring the reaction at room temperature, quenching with saturated brine after the reaction is complete, extracting with EA, and then removing the solvent by rotary evaporation under reduced pressure to obtain a crude product; dissolving the crude product in dichloromethane, adding silica gel powder and mixing the sample, and then separating by forward silica gel column chromatography to obtain a white blocky solid, which is N-phenylmaleimide ene.

[0010] Preferably, the mass ratio of benzaldehyde, N-phenylmaleimide, and triphenylphosphine is 1.2:1.0:1.0; the reaction time is 24-26 hours, and the reaction progress is monitored by thin-layer chromatography; the silica gel powder is 100-200 mesh, and the forward separation of silica gel column chromatography uses PE / EA = 20 / 1-6 / 1 as the eluent.

[0011] Preferably, the synthesis of the pyrazolone ether includes the following steps: using ethyl acetoacetate and phenylhydrazine as reactants, adding glacial acetic acid as a reaction solvent, heating the water bath to 125°C to start the reflux reaction, and observing that the reaction solution gradually turns yellow; after reacting for 8-10 hours, stopping the heating, cooling to room temperature, adding DCM and water to extract the reaction system, combining the organic phases, adding anhydrous sodium sulfate and letting it stand, removing sodium sulfate by suction filtration, and removing the solvent DCM by rotary evaporation under reduced pressure to obtain a brownish-yellow intermediate;

[0012] Benzaldehyde and sodium acetate were added to the intermediate, and glacial acetic acid was used as the reaction solvent. The mixture was heated to 30°C and stirred until the reaction was complete. Heating was stopped and the mixture was cooled to room temperature. Water was added, followed by ethyl acetate, and the mixture was shaken vigorously. A large amount of flocculent material appeared. Ethyl acetate was added again, and the flocculent material gradually disappeared. The mixture was allowed to stand until the solution separated into layers. The organic phase was collected, and the operation was repeated. Anhydrous sodium sulfate was added to the ethyl acetate layer and allowed to stand to remove residual water. The sodium sulfate was removed by filtration, and the ethyl acetate was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was completely dissolved in dichloromethane, and silica gel powder was added and rotary evaporated to make the crude product uniformly adhere to the silica gel powder while removing the solvent. The product was separated by forward silica gel column chromatography to obtain a red powdery solid, which is pyrazolone ene.

[0013] Preferably, the mass ratio of ethyl acetoacetate to phenylhydrazine is 1:1.2; and the standing time is 5 to 8 minutes.

[0014] Preferably, the mass ratio of benzaldehyde to sodium acetate is 1.0:1.5; the reaction is carried out at 30°C with stirring for 3 to 4 hours; the operation is repeated at least 3 times; anhydrous sodium sulfate is added to the ethyl acetate layer and allowed to stand for 10 to 12 minutes; the silica gel powder is 100 to 200 mesh; and the eluent ratio for forward separation in silica gel column chromatography is PE / EA = 20 / 1-6 / 1.

[0015] Compared with the prior art, the present invention has the following beneficial effects:

[0016] This invention expands the substrate under optimal reaction conditions by introducing methyl, methoxy, and chlorine atoms at the ortho, meta, and para positions on the benzene ring of N-phenylmaleimide, constructing a series of nitrogen-containing heterocyclic compounds containing both maleimide structural units and pyrazolone rings in yields up to 90%. The reaction method of this invention is fast and yield-efficient. This atom-economical reaction provides a new approach for constructing nitrogen-containing heterocyclic compounds containing both maleimide structural units and pyrazolone rings.

[0017] The pyrazolone ring is a structural core with anticancer, anti-inflammatory, analgesic, bactericidal, and insecticidal activities. Compounds containing pyrrole, piperazine, phthalazine, and pyrazolone skeletons have been widely used in pesticides, pharmaceuticals, and food.

[0018] This invention utilizes a base as a catalyst to achieve the Michael addition reaction involving N-phenylmaleimide olefins and pyrazolone olefins, and systematically optimizes the reaction conditions. Detailed Implementation

[0019] The preferred embodiments of the present invention will be described below. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0020] Example 1:

[0021] (1) Synthesis of N-phenylmaleimide with different substitutions.

[0022]

[0023] Synthesis of N-phenylmaleimide 3-1a: Benzaldehyde (3.54 g, 1.2 eq), N-phenylmaleimide (3.46 g, 1.0 eq), and triphenylphosphine (5.24 g, 1.0 eq) were added to a clean, dry 250 mL round-bottom flask. 60 mL of dichloromethane was added as the reaction solvent. The mixture was stirred at room temperature for 24 hours, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, saturated brine was added to quench the reaction. The mixture was extracted three times with EA, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was dissolved in dichloromethane, and after mixing with 100-200 mesh silica gel powder, it was separated by forward silica gel column chromatography (using PE / EA = 20 / 1-6 / 1 as the eluent) to obtain a white, lumpy solid with a yield of 80%.

[0024] (2) Synthesis of pyrazolone ether.

[0025]

[0026] Synthesis of pyrazolone 3-2: Ethyl acetoacetate (3.60 g, 1 eq) and phenylhydrazine (3.59 g, 1.2 eq) were added as reactants to a clean, dry 250 mL round-bottom flask, along with 40 mL of glacial acetic acid as the solvent. The mixture was heated to 125 °C in a water bath and refluxed until the reaction solution gradually turned yellow. After 8 hours of reaction, heating was stopped, the round-bottom flask was removed and cooled to room temperature, and the reaction system was extracted three times with DCM and water. The organic phases were combined, anhydrous sodium sulfate was added, and the mixture was allowed to stand for 5 min. The sodium sulfate was removed by filtration, and the solvent DCM was removed by rotary evaporation under reduced pressure to obtain a brownish-yellow intermediate.

[0027] The intermediate obtained in the previous step was added to a 250 mL round-bottom flask along with benzaldehyde (3.12 g, 1.0 eq) and sodium acetate (3.41 g, 1.5 eq). Using 40 mL of glacial acetic acid as the reaction solvent, the mixture was heated to 30 °C and stirred for 3 hours. After the reaction was complete, heating was stopped, and the flask was removed and cooled to room temperature. Water was added, followed by ethyl acetate, and the mixture was vigorously shaken. A large amount of flocculent material appeared. Ethyl acetate was continued to be added, and the flocculent material gradually disappeared. The mixture was allowed to stand until the solution separated into layers, and the organic phase was collected. This operation was repeated three times. Anhydrous sodium sulfate was added to the ethyl acetate layer, and the mixture was allowed to stand for 10 minutes to remove residual water. The sodium sulfate was then removed by filtration, and the ethyl acetate was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was completely dissolved in dichloromethane, and 100-200 mesh silica gel powder was added. Rotary evaporation was then performed to ensure the crude product adhered uniformly to the silica gel powder while removing the solvent. The product was then separated by forward silica gel column chromatography (eluent ratio PE / EA = 20 / 1-6 / 1) to obtain a red powdery solid with a yield of 65%.

[0028] (3) Michael addition reaction of N-phenylmaleimide and pyrazolone with different substitutions.

[0029]

[0030] The reaction solvent was dichloromethane, and the temperature was the reflux temperature of dichloromethane. Maleimide olefin 3-1a and pyrazolone olefin 3-2 were reacted with 20 mol% 4-dimethylaminopyridine as catalyst with a feed ratio of 1 / 1.5 for 2 hours.

[0031] According to the reaction route, a dry and clean reaction tube was taken, and N-phenylmaleimide 3-1a (1.0 eq) and pyrazolone 3-2 (1.5 eq) with different substitutions were used as reaction raw materials at the reflux temperature of dichloromethane. 20 mol% of 4-dimethylaminopyridine was added to 1 mL of dichloromethane for reaction. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, saturated brine was added to quench the reaction and ethyl acetate was used for extraction three times. The solvent was then removed by rotary evaporation under reduced pressure. Finally, the target product was obtained by forward separation by silica gel column chromatography (using PE / EA = 20 / 1-6 / 1 as eluent).

[0032] (4) Investigation of bioactivity.

[0033]

[0034]

[0035] Common pathogenic fungi that are mainly found in the human digestive and urinary systems include Candida albicans; foodborne pathogenic bacteria that commonly parasitize human skin, oral cavity, and nasal cavity include Staphylococcus aureus.

[0036] Take a 96-well culture plate, dilute the sample to be tested, add bacterial (fungal) culture to each well, and the final concentration is 5×10⁵ CFU / mL; incubate at 28℃ (37℃) for 24 hours, and detect the absorbance at 625nm using an ELISA reader. The experiment also included a culture medium blank control group, a bacterial control group, and a penicillin G sodium (amphotericidal B) positive control group.

[0037] The antifungal and antibacterial activities of compound 3-3a were tested using Staphylococcus aureus and Candida albicans. A blank culture medium and a positive control group were included in the experiment. For bacteria, the inhibitory effect of penicillin G sodium served as a positive control, and for fungi, the inhibitory effect of amphotericin B served as a positive control.

[0038] Table 2: Antibacterial effects of target compounds against different bacterial species

[0039]

[0040] Compound 3-3a exhibited significantly different antifungal and antibacterial effects against fungi and bacteria. Penicillin G sodium and amphotericin B were selected as positive controls for compound 3-3a against Staphylococcus aureus and Candida albicans, respectively: penicillin G sodium showed an inhibition rate of approximately 99.958% against Staphylococcus aureus, while compound 3-3a showed an inhibition rate of approximately 29.903%; amphotericin B showed an inhibition rate of almost 100% against Candida albicans, while compound 3-3a showed an inhibition rate of approximately -5.053% against Candida albicans.

[0041] Studies on the antibacterial activity of compound 3-3a against two bacteria revealed that at a concentration of 100 μM, the sample exhibited a certain inhibitory effect on Staphylococcus aureus but no inhibitory effect on Candida albicans.

[0042] Comparative Example 1: Effect of catalyst on reaction (the rest is the same as in Example 1, except for the composition of the catalyst).

[0043] Organic bases such as triethylenediamine, triethylamine, 4-dimethylaminopyridine, imidazole and pyridine, and inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide were screened, and 4-dimethylaminopyridine was determined to be the optimal catalyst for the reaction (results are shown in Table 1).

[0044] Table 1: Reaction results with different catalysts.

[0045]

[0046] Comparative Example 2: The effect of the reaction solvent on the reaction (the rest is the same as in Example 1).

[0047] Fourteen solvents were tested, including dichloromethane, trichloromethane, 1,2-dibromoethane, bromoethane, ethanol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, toluene, tetrahydrofuran, petroleum ether, diethyl ether, dimethyl tert-butyl ether, and 1,4-dioxane. The optimal solvent for this reaction was found to be dichloromethane (results are shown in Table 2).

[0048] Table 2: Reaction results with different reaction solvents.

[0049]

[0050] Comparative Example 3: Reaction temperature (the rest is the same as in Example 1).

[0051] The reaction temperature range was from 0℃ to the reflux temperature of dichloromethane. After considering the reaction yield and reaction time, the reflux temperature of dichloromethane was determined to be the optimal temperature for the reaction (results are shown in Table 3).

[0052] Table 3: Reaction results at different reaction temperatures.

[0053]

[0054] Comparative Example 4: Material ratio and catalyst loading (the rest is the same as in Example 1).

[0055] The optimal material ratio for considering both reaction yield and reaction time was maleimide olefin: pyrazolone olefin = 1:1.5, and the optimal catalyst loading was 20 mol% (results are shown in Table 4).

[0056] Table 4: Reaction results with different material ratios and catalyst loading.

[0057]

[0058] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing a nitrogen-containing heterocyclic compound having a maleimide structural unit and a pyrazolone ring, characterized in that, The synthetic route is shown as follows: Specifically comprising the following steps: using N-phenyl maleimide ene and pyrazolone ene as reaction raw materials, adding 4-dimethylamino pyridine in dichloromethane at the reflux temperature of dichloromethane, adding saturated brine after the reaction is completed, extracting with ethyl acetate, removing the solvent by rotary evaporation under reduced pressure, separating by silica gel column chromatography in the forward direction to obtain a nitrogen-containing heterocyclic compound with a maleimide structural unit and a pyrazolone ring; The mass ratio of the N-phenyl maleimide ene and the pyrazolone ene is 1:1.5-1:2; the 4-dimethylamino pyridine is 20 mol%; the silica gel column chromatography in the forward direction uses PE / EA=20 / 1-6 / 1 as an eluent; The synthesis of the N-phenyl maleimide ene comprises the following steps: adding dichloromethane as a reaction solvent to benzaldehyde, N-phenyl maleimide and triphenylphosphine, stirring the reaction at room temperature, adding saturated brine after the reaction is completed, extracting with EA, and removing the solvent by rotary evaporation under reduced pressure to obtain a crude product; dissolving the crude product in dichloromethane, adding silica gel powder to the sample, and separating by silica gel column chromatography in the forward direction to obtain white blocky solid, which is the N-phenyl maleimide ene; the mass ratio of the benzaldehyde, the N-phenyl maleimide and the triphenylphosphine is 1.2:1.0:1.0; the reaction time is 24-26 hours, and the reaction progress is monitored by thin layer chromatography; the silica gel powder is 100-200 mesh, and the silica gel column chromatography in the forward direction uses PE / EA=20 / 1-6 / 1 as an eluent; The synthesis of the pyrazolone ene comprises the following steps: using ethyl acetoacetate and phenylhydrazine as reaction raw materials, adding glacial acetic acid as a reaction solvent, heating the water bath to 125℃ to start the reflux reaction, and finding that the reaction liquid gradually turns yellow; stopping heating after 8-10 hours of reaction, cooling to room temperature, extracting the reaction system with DCM and water, combining the organic phases, adding anhydrous sodium sulfate and standing, removing the sodium sulfate by suction filtration, and removing the solvent DCM by rotary evaporation under reduced pressure to obtain a brown-yellow intermediate; adding benzaldehyde and sodium acetate to the intermediate, using glacial acetic acid as a reaction solvent, heating to 30℃ for stirring reaction, stopping heating and cooling to room temperature after the reaction is completed, adding water, then adding ethyl acetate and vigorously shaking, at which time a large amount of flocculent substance appears, ethyl acetate is continuously added, the flocculent substance gradually disappears, and the solution is separated after standing, the organic phase is collected, and the operation is repeated; adding anhydrous sodium sulfate to the ethyl acetate layer, removing the residual water by standing, removing the sodium sulfate by suction filtration, and removing the ethyl acetate by rotary evaporation under reduced pressure to obtain a crude product; dissolving the crude product in dichloromethane, adding silica gel powder to the sample by rotary evaporation to make the crude product uniformly adhere to the silica gel powder while removing the solvent, and separating by silica gel column chromatography in the forward direction to obtain a red powder solid, which is the pyrazolone ene.

2. The method for synthesizing a nitrogen-containing heterocyclic compound having a maleimide structural unit and a pyrazolone ring according to claim 1, characterized in that, The mass ratio of the ethyl acetoacetate and the phenylhydrazine is 1:1.2; and the standing time is 5-8 minutes.

3. The method for synthesizing a nitrogen-containing heterocyclic compound having a maleimide structural unit and a pyrazolone ring according to claim 1, characterized in that, The mass ratio of said benzaldehyde and sodium acetate is 1.0:1.5; the stirring reaction time is 3-4 hours when heated to 30℃; the operation is repeated for at least 3 times; anhydrous sodium sulfate is added to the ethyl acetate layer and left for 10-12 minutes; the silica gel powder is 100-200 mesh; the eluent ratio of said silica gel column chromatography forward separation is PE / EA=20 / 1-6 / 1.

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