Preparation method of 1, 3, 4-trisubstituted pyrimidine

Abstract

The invention relates to the technical field of organic synthesis, and particularly discloses a preparation method of 1, 3, 4-trisubstituted pyrimidine, which comprises the following steps: uniformly mixing an amidino compound, acetylpyridine, paraformaldehyde, potassium carbonate and a solvent to obtain a mixed solution; the mixed solution is heated and subjected to a reaction, the 1, 3, 4-trisubstituted pyrimidine is obtained, and the amidino compound is selected from benzamidine hydrochloride or formamidine hydrochloride. The preparation method of the 1, 3, 4-trisubstituted pyrimidine does not need a metal catalyst and a strong oxidant, is low in reaction temperature and wide in raw material source, can effectively reduce the production cost, is mild in reaction condition and easy to control, can meet the requirements of industrial production, has a good industrial application prospect, and is suitable for large-scale production.

Description

Technical Field

[0001] The present application relates to the technical field of organic synthesis, and in particular to a method for preparing 1,3,4-trisubstituted pyrimidine. Background Art

[0002] 1,3,4-trisubstituted pyrimidines are important organic synthesis intermediates and are widely used in the fields of medicine, agricultural chemicals and materials science. In particular, trisubstituted pyrimidine compounds containing specific substituents have good biological activity and antibacterial properties, so their application in medicinal chemistry is becoming increasingly important. Traditional synthesis methods of 1,3,4-trisubstituted pyrimidines mostly rely on complex multi-step reactions or require expensive metal catalysts and oxidants, which makes these methods have certain limitations in practical applications.

[0003] In recent years, some progress has been made in the synthesis of pyrimidines. Among them, dehydrogenation multi-component reactions have become an important way to synthesize pyrimidine compounds due to their high efficiency and simplicity. For example, Kempe et al. reported the synthesis of various pyrimidine compounds through multi-component dehydrogenation coupling reactions of alcohols and amidines. In this reaction, alcohols are oxidized by iridium catalysts to form carbonyl compounds, which are then converted into α,β-unsaturated ketone intermediates by aldehyde condensation, and finally cyclized to form pyrimidine structures. However, this method requires the use of precious metal catalysts, and a large number of by-products may be produced during the reaction, resulting in certain problems in the selectivity and efficiency of the reaction. A palladium-catalyzed oxidative dehydrogenation strategy has also been proposed to synthesize the pyrimidine core structure using enamine intermediates in styrene and DMF. Although this method has improved the synthesis efficiency, it also faces problems such as difficulty in catalyst recovery, high catalyst cost, and harsh reaction conditions. In addition, K2S2O8-mediated multi-component reactions also provide new options for the synthesis of pyrimidine compounds. In this strategy, amidourea and methyl ketones are converted into pyrimidine rings by cyclization, and DMSO is used as the C1 building block. This method simplifies the reaction steps to a certain extent, but it still requires the use of strong oxidants and special solvents, which may cause environmental pollution and product purity problems. A simpler I2-catalyzed dehydrogenation multicomponent reaction has been proposed as a new approach to synthesize polysubstituted pyrimidines through simple aldehydes and amidoureas in the presence of trialkylamines. Although this method has certain advantages, the selectivity of catalysts and reaction conditions is still a challenge, and reaction by-products may affect the final yield.

[0004] Therefore, the prior art needs to be improved. Summary of the invention

[0005] In view of the above-mentioned deficiencies in the prior art, the purpose of the present application is to provide a method for preparing 1,3,4-trisubstituted pyrimidine, aiming to solve the problem that the existing synthesis method of 1,3,4-trisubstituted pyrimidine is overly dependent on precious metal catalysts or strong oxidants.

[0006] The technical solution of this application is as follows:

[0007] In a first aspect of the present application, a method for preparing 1,3,4-trisubstituted pyrimidine is provided, comprising: uniformly mixing an amidine compound, acetylpyridine, polyformaldehyde, potassium carbonate, and a solvent to obtain a mixed solution; heating the mixed solution to react to obtain the 1,3,4-trisubstituted pyrimidine; the amidine compound is selected from benzamidine hydrochloride or formamidine hydrochloride.

[0008] Preferably, the molar ratio of the amidine compound, acetylpyridine, potassium carbonate and paraformaldehyde is 0.6-1.2:0.3:1.2-1.8:1.2-1.8.

[0009] Preferably, the ratio of the volume of the solvent to the sum of the volumes of the amidine compound, acetylpyridine, paraformaldehyde and potassium carbonate is 5-10:1.

[0010] Preferably, the solvent is selected from alcohol compounds;

[0011] Further preferably, the solvent is selected from primary alcohol;

[0012] More preferably, the solvent is selected from at least one of methanol, ethanol and deuterated methanol.

[0013] Preferably, the amidine compound, acetylpyridine, paraformaldehyde, potassium carbonate and solvent are uniformly mixed to obtain a mixed solution, specifically comprising:

[0014] The amidine compound, acetylpyridine, potassium paraformaldehyde carbonate and solvent are respectively added into a reaction container, and a magnet is added into the reaction container for magnetic stirring to obtain a mixed solution.

[0015] Preferably, the reaction container has a reflux device and a constant temperature heating plate, and the mixed solution is heated to react to obtain the 1,3,4-trisubstituted pyrimidine, specifically comprising:

[0016] The reaction container is heated to a preset temperature using the constant temperature heating plate, and the mixed solution is reacted at the preset temperature for a preset time to obtain the 1,3,4-trisubstituted pyrimidine.

[0017] Preferably, the preset temperature is 75-95 degrees Celsius.

[0018] Preferably, the preset time is 12-24 hours.

[0019] Preferably, the reaction container is heated to a preset temperature using the constant temperature heating plate, and the product of the mixed solution reacting at the preset temperature for a preset time is purified to obtain the 1,3,4-trisubstituted pyrimidine.

[0020] Compared with the prior art, this application has the following advantages:

[0021] The use of a metal-free catalyst reaction system completely relies on oxygen in the air as an oxidant, which simplifies the reaction system, avoids the use of metal catalysts, reduces the risk of metal pollution, and avoids the use of environmentally harmful oxidants. The reaction conditions are mild, the energy consumption is low, the by-products are few, the yield of the target product is high, the safety and operability of the reaction are improved, the reaction cost is greatly reduced, and it meets the requirements of green chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for describing the embodiments are briefly introduced below.

[0023] Figure 1 This is a preparation route for 1,3,4-trisubstituted pyrimidine provided in the examples of the present application. DETAILED DESCRIPTION

[0024] In order to make the purpose, technical solutions and advantages of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below in combination with the drawings and embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments of the present application, all other embodiments obtained by ordinary technicians in this field without making creative work belong to the protection scope of the present application. In the absence of conflict, the following embodiments and features in the embodiments can be combined with each other.

[0025] It should be noted that if there are descriptions involving "first", "second", etc. in the implementation of this application, the descriptions of "first", "second", etc. are only used for descriptive purposes and cannot be understood as indicating or suggesting their relative importance and implicitly indicating the number of technical features indicated. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In addition, the technical solutions between the various embodiments can be combined with each other, but they must be based on the fact that ordinary technicians in the field can implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such combination of technical solutions does not exist and is not within the scope of protection required by this application.

[0026] Combination Figure 1 The present invention provides a method for preparing 1,3,4-trisubstituted pyrimidine, comprising the steps of:

[0027] S1. Evenly mix an amidine compound, acetylpyridine, paraformaldehyde, potassium carbonate and a solvent to obtain a mixed solution; wherein the amidine compound is selected from benzamidine hydrochloride or formamidine hydrochloride.

[0028] Specifically, the amidine compound, acetylpyridine, paraformaldehyde, potassium carbonate and solvent are weighed in proportion, and the above materials are added to a reaction container respectively, and a magnet is added to the reaction container for magnetic stirring to mix the materials evenly to form a mixed solution.

[0029] In some embodiments, the molar ratio of the amidino compound, acetylpyridine, polyformaldehyde, and potassium carbonate is 0.6-1.2:0.3:1.2-1.8:1.2-1.8. For example, the molar ratio of the amidino compound, acetylpyridine, polyformaldehyde, and potassium carbonate is 0.6:0.3:1.2:1.2, 0.8:0.3:1.5:1.5,

[0030] 1:0.3:1.2:1.2, 1.2:0.3:1.8:1.8, 0.9:0.3:1.5:1.5, etc.

[0031] In some embodiments, the ratio of the volume of the solvent to the sum of the volumes of the amidino compound, acetylpyridine, paraformaldehyde, and potassium carbonate is 5-10:1. For example, the ratio of the volume of the solvent to the sum of the volumes of the amidino compound, acetylpyridine, paraformaldehyde, and potassium carbonate is 5:1,

[0032] 6:1, 7:1, 8:1, 9:1 or 10:1, etc.

[0033] In some embodiments, the solvent is selected from alcohol compounds. Preferably, the solvent is selected from primary alcohols. More preferably, the solvent is selected from at least one of methanol, ethanol, and deuterated methanol.

[0034] Most existing synthesis methods rely on precious metal catalysts (such as iridium, palladium, etc.) or transition metal catalysts, which not only increase the reaction cost, but also may cause the influence of metal residues on the final product, and even increase the complexity of separating and recovering the catalyst. The preparation method of 1,3,4-trisubstituted pyrimidine in the present application adopts a metal catalyst-free reaction system, completely relying on oxygen in the air as an oxidant, avoiding the use of metal catalysts, reducing the risk of metal pollution, and greatly reducing the cost of the reaction, which meets the requirements of green chemistry.

[0035] Meanwhile, existing synthesis methods often involve multiple steps or complex multi-component reactions, and require expensive catalysts or complex reaction conditions. The preparation method of 1,3,4-trisubstituted pyrimidine in the present application is a single-step reaction, using amidine compounds, acetylpyridine and polyformaldehyde as main raw materials, with a simple and efficient reaction process, convenient operation, fewer reaction steps, reduced complexity in the production process, and high process operability.

[0036] In addition, by avoiding the use of precious metal catalysts and complex oxidants, and realizing the dehydrogenation process through air oxidation, the production cost is greatly reduced, and the environmental protection requirements of green chemistry are met. Compared with traditional methods, this application provides a more economical and environmentally friendly synthesis route with high market competitiveness.

[0037] S2, heating the mixed solution to react, to obtain the 1,3,4-trisubstituted pyrimidine.

[0038] Specifically, the reaction container of S1 has a reflux device and a constant temperature heating plate. The reaction container is placed on the constant temperature heating plate and heated to a preset temperature, so that the mixed solution reacts at the preset temperature for a preset time to obtain 1,3,4-trisubstituted pyrimidine.

[0039] In some embodiments, the preset temperature is 75-95 degrees Celsius. For example, the preset temperature is 75 degrees Celsius, 76 degrees Celsius, 77 degrees Celsius, 78 degrees Celsius, 79 degrees Celsius, 80 degrees Celsius, 81 degrees Celsius, 82 degrees Celsius, 83 degrees Celsius, 84 degrees Celsius, 85 degrees Celsius, 86 degrees Celsius, 87 degrees Celsius, 88 degrees Celsius, 89 degrees Celsius, 90 degrees Celsius, 91 degrees Celsius, 92 degrees Celsius, 93 degrees Celsius, 94 degrees Celsius or 95 degrees Celsius, etc.

[0040] Most of the synthetic routes in the prior art need to be carried out at higher temperatures (such as above 100°C) or under high pressure conditions, and some methods use harsh solvents and reaction environments, which not only increases energy consumption, but also makes the operation more complicated and dangerous. Compared with these methods, the preparation method of 1,3,4-trisubstituted pyrimidine in the present application only needs to be heated under mild conditions (temperature range), which greatly simplifies the operation process, reduces energy consumption, and improves the safety and operability of the reaction.

[0041] In addition, the method for preparing 1,3,4-trisubstituted pyrimidine of the present application has good reaction selectivity and less by-products. Therefore, the yield of the target product is high and the purity is good. The problems of many by-products and poor selectivity that may occur in the existing method are solved, and the high quality of the final product is ensured.

[0042] In some embodiments, the preset time is 12-24 hours. For example, the preset time is 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours.

[0043] In some embodiments, the reaction container is heated to a preset temperature using a thermostatic heating plate, and the mixed solution is reacted at the preset temperature for a preset time to purify the product, thereby finally obtaining 1,3,4-trisubstituted pyrimidine. The purification method is selected from one or more of recrystallization and silica gel column chromatography.

[0044] The present application also provides a 1,3,4-trisubstituted pyrimidine prepared by the method for preparing 1,3,4-trisubstituted pyrimidine as described above.

[0045] The following is further described by means of specific examples.

[0046] First, the reagents and equipment used in the examples are described.

[0047] Raw materials: amidine compounds (benzamidine hydrochloride and formamidine hydrochloride), purity 99%, purchased conventionally. Paraformaldehyde, purchased conventionally. Acetylpyridine, purchased conventionally. Methanol (CHOH), analytical grade. Potassium carbonate, purchased conventionally.

[0048] Experimental equipment: Reaction flask: used for mixing and heating the reaction solution. Constant temperature heating plate: used for precise control of the reaction temperature. Magnetic stirrer: to maintain the uniformity of the reaction system. Purification column: used for separation of the reaction product. Evaporator: used for solvent removal and product concentration.

[0049] Other reagents: Air: provides oxygen as an oxidant.

[0050] Example 1

[0051] (1) Add benzamidine hydrochloride (140 mg, 0.9 mmol), paraformaldehyde (45 mg, 1.5 mmol), acetylpyridine (36.3 mg, 0.3 mmol), and potassium carbonate (207 mg, 1.5 mmol) to 5 mL of methanol, stir evenly with a magnetic stirrer to ensure that the reactants are completely dissolved to obtain a mixed solution. Transfer the mixed solution to a reaction flask, install a reflux device, and place the reaction flask on a constant temperature heating plate. By setting the temperature of the constant temperature heating plate, the temperature of the mixed solution in the reaction flask is raised to 80 degrees Celsius, and the temperature is maintained, and the reaction is continued for 12 hours. During the reaction, air naturally enters the reaction system to ensure that the oxygen supply is sufficient to provide oxygen for the dehydrogenation reaction.

[0052] (2) Reaction monitoring: During the reaction, the progress of the reaction can be monitored by thin layer chromatography (TLC). As the reaction proceeds, benzamidine hydrochloride, acetylpyridine and paraformaldehyde are gradually converted into 1,3,4-trisubstituted pyrimidine. When the acetylpyridine raw material is no longer detected in the reaction solution, it means that the reaction is close to completion.

[0053] (3) Post-reaction treatment: After the reaction is completed, turn off the heating source and allow the reaction mixture to cool to room temperature. Remove the reaction solution by rotary evaporation to obtain a crude product.

[0054] (4) Product purification: The crude product was dissolved in an appropriate amount of ethyl acetate and purified by silica gel column chromatography to obtain pure 1,3,4-trisubstituted pyrimidine, which was confirmed by nuclear magnetic resonance and mass spectrometry analysis.

[0055] Example 2

[0056] (1) Add benzamidine hydrochloride (140 mg, 0.9 mmol), paraformaldehyde (45 mg, 1.5 mmol), acetylpyridine (36.3 mg, 0.3 mmol), and potassium carbonate (207 mg, 1.5 mmol) to 5 mL of ethanol, stir evenly with a magnetic stirrer to ensure that the reactants are completely dissolved to obtain a mixed solution. Transfer the mixed solution to a reaction flask, install a reflux device, and place the reaction flask on a constant temperature heating plate. By setting the temperature of the constant temperature heating plate, the temperature of the mixed solution in the reaction flask is raised to 90 degrees Celsius, and the temperature is maintained, and the reaction is continued for 24 hours. During the reaction, air naturally enters the reaction system to ensure sufficient oxygen supply to provide oxygen for the dehydrogenation reaction.

[0057] (2) Reaction monitoring: During the reaction, the progress of the reaction can be monitored by thin layer chromatography (TLC). As the reaction proceeds, benzamidine hydrochloride, acetylpyridine and paraformaldehyde are gradually converted into 1,3,4-trisubstituted pyrimidine. When the acetylpyridine raw material is no longer detected in the reaction solution, it means that the reaction is close to completion.

[0058] (3) Post-reaction treatment: After the reaction is completed, turn off the heating source and allow the reaction mixture to cool to room temperature. Remove the reaction solution by rotary evaporation to obtain a crude product.

[0059] (4) Product purification: The crude product was dissolved in an appropriate amount of ethyl acetate and purified by silica gel column chromatography to obtain pure 1,3,4-trisubstituted pyrimidine, which was confirmed by nuclear magnetic resonance and mass spectrometry analysis.

[0060] Example 3

[0061] (1) Add benzamidine hydrochloride (140 mg, 0.9 mmol), paraformaldehyde (45 mg, 1.5 mmol), 1-tetralone (43.8 mg, 0.3 mmol), and potassium carbonate (207 mg, 1.5 mmol) to 5 mL of methanol, stir evenly with a magnetic stirrer to ensure that the reactants are completely dissolved to obtain a mixed solution. Transfer the mixed solution to a reaction flask, install a reflux device, and place the reaction flask on a constant temperature heating plate. By setting the temperature of the constant temperature heating plate, the temperature of the mixed solution in the reaction flask is raised to 78 degrees Celsius, and the temperature is maintained, and the reaction is continued for 24 hours. During the reaction, air naturally enters the reaction system to ensure sufficient oxygen supply and provide oxygen for the dehydrogenation reaction.

[0062] (2) Reaction monitoring: During the reaction, the progress of the reaction can be monitored by thin layer chromatography (TLC) and other methods. As the reaction proceeds, benzamidine hydrochloride, acetylpyridine and paraformaldehyde are gradually converted into 1,3,4-trisubstituted pyrimidine. When the 1-tetralone raw material is no longer detected in the reaction solution, it means that the reaction is close to completion.

[0063] (3) Post-reaction treatment: After the reaction is completed, turn off the heating source and allow the reaction mixture to cool to room temperature. Remove the reaction solution by rotary evaporation to obtain a crude product.

[0064] (4) Product purification: The crude product was dissolved in an appropriate amount of ethyl acetate and purified by silica gel column chromatography to obtain pure 1,3,4-trisubstituted pyrimidine, which was confirmed by nuclear magnetic resonance and mass spectrometry analysis.

[0065] Example 4

[0066] (1) Add benzamidine hydrochloride (140 mg, 0.9 mmol), paraformaldehyde (45 mg, 1.5 mmol), acetylpyridine (36.3 mg, 0.3 mmol), and potassium carbonate (207 mg, 1.5 mmol) to 5 mL of deuterated methanol, stir evenly with a magnetic stirrer to ensure that the reactants are completely dissolved to obtain a mixed solution. Transfer the mixed solution to a reaction flask, install a reflux device, and place the reaction flask on a constant temperature heating plate. By setting the temperature of the constant temperature heating plate, the temperature of the mixed solution in the reaction flask is raised to 82 degrees Celsius, and the temperature is maintained, and the reaction is continued for 24 hours. During the reaction, air naturally enters the reaction system to ensure sufficient oxygen supply and provide oxygen for dehydrogenation reaction.

[0067] (2) Reaction monitoring: During the reaction, the progress of the reaction can be monitored by thin layer chromatography (TLC). As the reaction proceeds, amidine, acetylpyridine and paraformaldehyde are gradually converted into 1,3,4-trisubstituted pyrimidine. When the acetylpyridine raw material is no longer detected in the reaction solution, it means that the reaction is close to completion.

[0068] (3) Post-reaction treatment: After the reaction is completed, turn off the heating source and allow the reaction mixture to cool to room temperature. Remove the reaction solution by rotary evaporation to obtain a crude product.

[0069] (4) Product purification: The crude product was dissolved in an appropriate amount of ethyl acetate and purified by silica gel column chromatography to obtain pure 1,3,4-trisubstituted pyrimidine, which was confirmed by nuclear magnetic resonance and mass spectrometry analysis.

[0070] Example 5

[0071] (1) Add formamidine hydrochloride (84.6 mg, 0.9 mmol), paraformaldehyde (45 mg, 1.5 mmol), acetylpyridine (36.3 mg, 0.3 mmol), and potassium carbonate (207 mg, 1.5 mmol) to 5 mL of methanol, stir evenly with a magnetic stirrer to ensure that the reactants are completely dissolved to obtain a mixed solution. Transfer the mixed solution to a reaction flask, install a reflux device, and place the reaction flask on a constant temperature heating plate. By setting the temperature of the constant temperature heating plate, the temperature of the mixed solution in the reaction flask is raised to 85 degrees Celsius, and the temperature is maintained, and the reaction is continued for 24 hours. During the reaction, air naturally enters the reaction system to ensure sufficient oxygen supply to provide oxygen for the dehydrogenation reaction.

[0072] (2) Reaction monitoring: During the reaction, the progress of the reaction can be monitored by thin layer chromatography (TLC). As the reaction proceeds, amidine, acetylpyridine and paraformaldehyde are gradually converted into 1,3,4-trisubstituted pyrimidine. When the acetylpyridine raw material is no longer detected in the reaction solution, it means that the reaction is close to completion.

[0073] (3) Post-reaction treatment: After the reaction is completed, turn off the heating source and allow the reaction mixture to cool to room temperature. Remove the reaction solution by rotary evaporation to obtain a crude product.

[0074] (4) Product purification: The crude product was dissolved in an appropriate amount of ethyl acetate and purified by silica gel column chromatography to obtain pure 1,3,4-trisubstituted pyrimidine, which was confirmed by nuclear magnetic resonance and mass spectrometry analysis.

[0075] In summary, the preparation method of 1,3,4-trisubstituted pyrimidine in the present application can effectively reduce production costs because it does not require a metal catalyst, has a low reaction temperature and a wide range of raw material sources. The reaction conditions are mild and easy to control, can meet the requirements of industrial production, has good industrial application prospects, and is suitable for large-scale production.

[0076] It should be understood that the application of the present application is not limited to the above examples. For ordinary technicians in this field, improvements or changes can be made based on the above description. All these improvements and changes should fall within the scope of protection of the claims attached to this application.

Claims

1. A method for preparing 1,3,4-trisubstituted pyrimidine, characterized in that: Includes steps: The amidine compound, acetylpyridine, paraformaldehyde, potassium carbonate and solvent are uniformly mixed to obtain a mixed solution; heating the mixed solution and reacting it to obtain the 1,3,4-trisubstituted pyrimidine; The amidine compound is selected from benzamidine hydrochloride or formamidine hydrochloride.

2. The method for preparing 1,3,4-trisubstituted pyrimidine according to claim 1, characterized in that: The molar ratio of the amidine compound, acetylpyridine, polyformaldehyde and potassium carbonate is 0.6-1.2:0.3:1.2-1.8:1.2-1.

8.

3. The method for preparing 1,3,4-trisubstituted pyrimidine according to claim 1, characterized in that: The ratio of the volume of the solvent to the sum of the volumes of the amidine compound, acetylpyridine, paraformaldehyde and potassium carbonate is 5-10:

1.

4. The method for preparing 1,3,4-trisubstituted pyrimidine according to claim 1, characterized in that: The solvent is selected from alcohol compounds; Preferably, the solvent is selected from primary alcohols; Preferably, the solvent is selected from at least one of methanol, ethanol and deuterated methanol.

5. The method for preparing 1,3,4-trisubstituted pyrimidine according to claim 1, characterized in that: The amidine compound, acetylpyridine, paraformaldehyde, potassium carbonate and a solvent are uniformly mixed to obtain a mixed solution, which specifically comprises: The amidine compound, acetylpyridine, paraformaldehyde, potassium carbonate and solvent are respectively added into a reaction container, and a magnet is added into the reaction container for magnetic stirring to obtain a mixed solution.

6. The method for preparing 1,3,4-trisubstituted pyrimidine according to claim 5, characterized in that: The reaction container has a reflux device and a constant temperature heating plate, and the mixed solution is heated to react to obtain the 1,3,4-trisubstituted pyrimidine, which specifically includes: The reaction container is heated to a preset temperature using the constant temperature heating plate, and the mixed solution is reacted at the preset temperature for a preset time to obtain the 1,3,4-trisubstituted pyrimidine.

7. The method for preparing 1,3,4-trisubstituted pyrimidine according to claim 6, characterized in that: The preset temperature is 75-95 degrees Celsius.

8. The method for preparing 1,3,4-trisubstituted pyrimidine according to claim 6, characterized in that: The preset time is 12-24 hours.

9. The method for preparing 1,3,4-trisubstituted pyrimidine according to claim 6, characterized in that: The reaction container is heated to a preset temperature using the constant temperature heating plate, and the mixed solution is reacted at the preset temperature for a preset time, and the product is purified to obtain the 1,3,4-trisubstituted pyrimidine.

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