Preparation method of melamine-amide hydrochloride

Abstract

The invention discloses a preparation method and a post-treatment optimization method of melamine-amide hydrochloride. Comprising the following steps: adding 5-azacytosine into an acetic acid and hydrogen peroxide system, heating and stirring a reaction mixture, after the reaction is completed and the reaction mixture is cooled, filtering the reaction system, pulping a filter cake with diluted hydrochloric acid, filtering, washing with water, and drying to obtain the high-purity melamine-amide hydrochloride. Reaction materials involved in the method are low in price, the operation process is simple, the reaction yield and the product purity are high, and the method is suitable for industrial production and purification of melamine-amide hydrochloride.

Description

Technical Field

[0001] The invention belongs to the field of organic chemical industry, relates to an organic synthesis and purification method of 5-azacytosine derivatives, and specifically relates to a preparation method of melamine monoamide hydrochloride. The method particularly improves the post-treatment step of melamine monoamide hydrochloride. Background Art

[0002] Melamine monoamide hydrochloride is a colorless needle-shaped crystal, which is commonly used in research fields such as pharmaceutical intermediates, biological preparations, organic catalyst ligand synthesis, supramolecular chemistry, etc., and has high application value. The synthesis of melamine monoamide hydrochloride reported in the literature at this stage usually uses the method of calcining urea under high temperature and high pressure. This method has high energy consumption and may release gas, resulting in greater safety risks, low yield, and greater difficulty in purification, which is not conducive to large-scale industrial production.

[0003] In 2021, patent CN 114181163 A disclosed a method for preparing melamine monoamide hydrochloride, in which 5-azacytosine was oxidized with hydrogen peroxide under acidic conditions to obtain melamine monoamide hydrochloride. However, this method is prone to precipitate unreacted raw materials in the product during the purification process of the product, resulting in reduced product purity. Summary of the invention

[0004] In order to solve the technical problems faced in the synthesis and purification of melamine monoamide hydrochloride, the present invention synthesizes high-purity melamine monoamide hydrochloride through reasonable design. The present invention adopts the following technical scheme: (1) A method for preparing melamine monoamide hydrochloride, comprising the following steps: a) suspending 5-azacytosine in acetic acid to obtain an acetic acid suspension of 5-azacytosine, b) adding a hydrogen peroxide solution to the acetic acid suspension of 5-azacytosine to obtain a reaction mixture, c) heating and stirring the reaction mixture until the reaction is complete and cooling to obtain a crude reaction product, and d) beating the crude reaction product with dilute hydrochloric acid, filtering, washing with water and drying to obtain melamine monoamide hydrochloride.

[0005] (2) The method for preparing melamine monoamide hydrochloride according to (1), wherein in step a), the concentration of the acetic acid suspension of 5-azacytosine is 50 g / L to 100 g / L.

[0006] (3) The method for preparing melamine monoamide hydrochloride according to (1), wherein in step b), the hydrogen peroxide solution is an aqueous solution with a mass fraction of hydrogen peroxide of 30% to 50%, and the volume ratio of the acetic acid suspension of 5-azacytosine to the hydrogen peroxide solution is 1:1 to 1:2.

[0007] (4) The method for preparing melamine monoamide hydrochloride according to (1), wherein in step c), the heating temperature is 50° C. to 80° C., and the reaction time is 24 hours to 36 hours.

[0008] (5) The method for preparing melamine monoamide hydrochloride according to (1), wherein in step d), the concentration of the dilute hydrochloric acid is 1 mol / L to 3 mol / L, and the slurrying is performed using an ultrasonic cleaner or a mechanical stirrer, and the slurrying time is 0.5 hour to 1 hour.

[0009] (6) The method for preparing melamine monoamide hydrochloride according to claim 1, wherein the purity of the melamine monoamide hydrochloride is 96% to 98%, and the yield is 80.0% to 85.8%.

[0010] Compared with the prior art, the present invention has the following advantages and positive effects: 1) The experimental operation is simple; high-temperature calcination of urea and hydrolysis of 2, 4, 6-trisubstituted s-triazine compounds are not required, thus overcoming the safety risks.

[0011] 2) The reagents used are cheap; the traditional synthesis route often uses 2, 4, 6-trisubstituted s-triazine compounds as raw materials, which are relatively expensive. The present invention uses 5-azacytosine and aqueous hydrogen peroxide solution as raw materials, which are much cheaper than the raw materials used in the traditional synthesis method.

[0012] 3) High yield. The highest yield of melamine monoamide hydrochloride synthesized by the prior art is 52.3% to 85.4%, and the method of the present invention can increase the yield to 80.0% to 85.8%. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The figure is a hydrogen nuclear magnetic resonance spectrum of melamine monoamide hydrochloride prepared according to the method of the present invention.

[0014] Figure 2 The figure is a high performance liquid chromatogram of melamine monoamide hydrochloride prepared according to the method of the present invention.

[0015] Figure 3 The figure is a mass spectrum of melamine monoamide hydrochloride prepared according to the method of the present invention. Implementation

[0016] The synthesis method of melamine monoamide hydrochloride according to the present invention is as follows:

[0017] The structural formula (I) is 5-azacytosine, and the structural formula (II) is melamine monoamide hydrochloride.

[0018] Specifically, the method for preparing melamine monoamide hydrochloride according to the present invention comprises the following steps: a) suspending 5-azacytosine in acetic acid to obtain an acetic acid suspension of 5-azacytosine, b) adding a hydrogen peroxide solution to the acetic acid suspension of 5-azacytosine to obtain a reaction mixture, c) heating and stirring the reaction mixture until the reaction is complete and cooling to obtain a crude reaction product, and d) The crude reaction product is slurried with dilute hydrochloric acid, filtered, washed with water and dried to obtain melamine monoamide hydrochloride.

[0019] In one embodiment of the present invention, the concentration of the acetic acid suspension of 5-azacytosine used in step a) is 50 g / L to 100 g / L. When the concentration is less than 50 g / L, the concentration of the raw material is too low, the post-processing pulping and purification is difficult, and the product purity is low; when the concentration is greater than 100 g / L, the concentration of the raw material is too high, resulting in incomplete reaction.

[0020] In one embodiment of the present invention, the hydrogen peroxide solution used in step b) is an aqueous solution with a hydrogen peroxide volume (or mass) concentration of 30% to 50%, and the volume ratio of the acetic acid suspension of 5-azacytosine to the hydrogen peroxide solution is 1:1 to 1:2. When the volume fraction concentration of hydrogen peroxide is lower than 30%, the concentration is too low, resulting in incomplete reaction; when the volume fraction concentration of hydrogen peroxide is higher than 50%, the concentration is high, resulting in possible safety accidents such as explosions in the experiment. When the volume ratio of the acetic acid suspension of 5-azacytosine to the hydrogen peroxide solution is lower than 1:1, the reaction is incomplete; when the volume ratio of the acetic acid suspension of 5-azacytosine to the hydrogen peroxide solution is higher than 1:2, too much hydrogen peroxide solution is added, resulting in a waste of raw materials.

[0021] In one embodiment of the present invention, the heating temperature used in step c) is 50°C to 80°C, and the reaction time is 24 hours to 36 hours.

[0022] In one embodiment of the present invention, the concentration of the dilute hydrochloric acid used in step d) is 1 mol / L to 3 mol / L, and an ultrasonic cleaner or a mechanical stirrer can be used for beating, and the beating time is 0.5 hour to 1 hour. Those skilled in the art know that other mixing instruments known in the art can also be used for beating, as long as the technical effects of the present invention can be achieved. Those skilled in the art can adjust the beating time according to the specific mixing instrument used.

[0023] By using the method for preparing melamine monoamide hydrochloride of the present invention, melamine monoamide hydrochloride with a purity of 96% to 98% can be obtained, and the yield can be 80.0% to 85.8%.

[0024] The present invention is further described below in conjunction with specific examples. Unless otherwise specified, the methods used in the examples are conventional methods and known tools. Example

[0025] Suspend 50 g of 5-azacytosine in 500 mL of acetic acid to obtain an acetic acid suspension of 5-azacytosine. Add 500 mL of an aqueous solution with a mass fraction of 30% hydrogen peroxide to the above suspension, stir at 50 °C for 24 hours, and cool to room temperature to obtain a crude reaction product. At this time, there is a large amount of white precipitate in the reaction system. Filter the crude reaction product, place the filter cake in a beaker, add 500 mL of 3 mol / L dilute hydrochloric acid, and ultrasonically beat in an ultrasonic cleaner for 1 hour. Then filter, rinse the filter cake three times with 500 mL of deionized water, and dry to obtain 48.2 g of melamine monoamide hydrochloride with a yield of 84.4% and a purity of 96%.

[0026] The nuclear magnetic resonance hydrogen spectrum of melamine monoamide hydrochloride obtained by the above preparation method is as follows Figure 1 As shown, 1 H NMR (DMSO-d6, 400MHz, δ): 11.83 ppm, 8.93 ppm, 6.70 ppm.

[0027] The HPLC chromatogram of melamine monoamide hydrochloride obtained by the above preparation method is as follows: Figure 2 As shown, the peak at the retention time of 0.407 min is the target product melamine monoamide hydrochloride.

[0028] The mass spectrum of melamine monoamide hydrochloride obtained by the above preparation method is as follows Figure 3 As shown, 257.0 is the peak [2M+H] after melamine monoamide hydrochloride removes hydrogen chloride and dimerizes when melamine monoamide hydrochloride is ionized (M is the molecular weight of melamine monoamide hydrochloride that removes hydrogen chloride when ionized).

[0029] According to the above results, melamine monoamide hydrochloride is prepared by the method of the present invention, and its purity can be as high as 96%, and the yield is as high as 84.4%. Example

[0030] Suspend 50 g of 5-azacytosine in 500 mL of acetic acid to obtain an acetic acid suspension of 5-azacytosine. Add 500 mL of an aqueous solution of 50% by mass of hydrogen peroxide to the above suspension, stir at 50 °C for 24 hours, and cool to room temperature to obtain a crude reaction product. At this time, there is a large amount of white precipitate in the reaction system. Filter the crude reaction product, place the filter cake in a beaker, add 500 mL of 1 mol / L dilute hydrochloric acid, and ultrasonically beat in an ultrasonic cleaner for 1 hour. Then filter, rinse the filter cake three times with 500 mL of deionized water, and dry to obtain 45.5 g of melamine monoamide hydrochloride with a yield of 80.0% and a purity of 98%. Example

[0031] Suspend 50 g of 5-azacytosine in 500 mL of acetic acid to obtain an acetic acid suspension of 5-azacytosine. Add 500 mL of an aqueous solution of 50% by mass of hydrogen peroxide to the above suspension, stir at 60 ° C for 24 hours, and cool to room temperature to obtain a crude reaction product. At this time, there is a large amount of white precipitate in the reaction system. Filter the crude reaction product, place the filter cake in a beaker, add 500 mL of 1 mol / L dilute hydrochloric acid, and ultrasonically beat in an ultrasonic cleaner for 0.5 hours. Then filter, rinse the filter cake three times with 500 mL of deionized water, and dry to obtain 47.3 g of melamine monoamide hydrochloride with a yield of 83.2% and a purity of 96%. Example

[0032] Suspend 50 g of 5-azacytosine in 500 mL of acetic acid to obtain an acetic acid suspension of 5-azacytosine. Add 1000 mL of an aqueous solution of 50% by mass of hydrogen peroxide to the above suspension, stir at 50 °C for 24 hours, and cool to room temperature to obtain a crude reaction product. At this time, there is a large amount of white precipitate in the reaction system. Filter the crude reaction product, place the filter cake in a beaker, add 500 mL of 1 mol / L dilute hydrochloric acid, and ultrasonically beat in an ultrasonic cleaner for 1 hour. Then filter, rinse the filter cake three times with 500 mL of deionized water, and dry to obtain 46.4 g of melamine monoamide hydrochloride with a yield of 81.5% and a purity of 96%.

[0033] Comparative Example 1: Suspend 50 g of 5-azacytosine in 500 mL of acetic acid to obtain an acetic acid suspension of 5-azacytosine. Add 500 mL of an aqueous solution of 50% by mass of hydrogen peroxide to the above suspension, stir at 50 °C for 24 hours, and cool to room temperature to obtain a crude reaction product. At this time, there is a large amount of white precipitate in the reaction system. Filter the crude reaction product, place the filter cake in a beaker, add 500 mL of deionized water, and ultrasonically beat in an ultrasonic cleaner for 1 hour. Then filter, rinse the filter cake three times with 500 mL of deionized water, and dry to obtain 48.8 g of melamine monoamide hydrochloride with a yield of 85.8% and a purity of 81%.

[0034] Comparative Example 2: 50 g of 5-azacytosine was suspended in 500 mL of acetic acid to obtain an acetic acid suspension of 5-azacytosine. 500 mL of an aqueous solution of 50% by mass of hydrogen peroxide was added to the above suspension, stirred at 50 °C for 24 hours, and then cooled to room temperature to obtain a crude reaction product. At this time, there was a large amount of white precipitate in the reaction system. The crude reaction product was filtered, the filter cake was placed in a beaker, 500 mL of anhydrous ethanol was added, and ultrasonic beating was performed in an ultrasonic cleaner for 1 hour. Then it was filtered, the filter cake was rinsed three times with 500 mL of deionized water, and 47.2 g of melamine monoamide hydrochloride was obtained after drying, with a yield of 83.0% and a purity of 79%.

[0035] It can be seen from the results of Comparative Examples 1-2 that when deionized water or other solutions (such as anhydrous ethanol) are used for the pulping step, melamine monoamide hydrochloride can also be obtained, but the purity of melamine monoamide hydrochloride is relatively low, only about 80%, which is much lower than the 96% to 98% purity of melamine monoamide hydrochloride obtained by the method of the present invention.

Claims

1. A method for preparing melamine monoamide hydrochloride, The following steps are involved: a) suspending 5-azacytosine in acetic acid to obtain an acetic acid suspension of 5-azacytosine, b) adding a hydrogen peroxide solution to the acetic acid suspension of 5-azacytosine to obtain a reaction mixture, c) heating and stirring the reaction mixture until the reaction is complete and cooling to obtain a crude reaction product, and d) beating the crude reaction product with dilute hydrochloric acid, filtering, washing with water and drying to obtain melamine monoamide hydrochloride.

2. The method for preparing melamine monoamide hydrochloride according to claim 1, wherein in step a), the concentration of the acetic acid suspension of 5-azacytosine is 50 g / L to 100 g / L.

3. The method for preparing melamine monoamide hydrochloride according to claim 1, wherein in step b), the hydrogen peroxide solution is an aqueous solution with a mass fraction of hydrogen peroxide of 30% to 50%, and the volume ratio of the acetic acid suspension of 5-azacytosine to the hydrogen peroxide solution is 1:1 to 1:

2.

4. The method for preparing melamine monoamide hydrochloride according to claim 1, wherein in step c), the heating temperature is 50°C to 80°C, and the reaction time is 24 hours to 36 hours.

5. The method for preparing melamine monoamide hydrochloride according to claim 1, wherein in step d), the concentration of the dilute hydrochloric acid is 1 mol / L to 3 mol / L, and an ultrasonic cleaner or a mechanical stirrer is used for the slurrying, and the slurrying time is 0.5 hour to 1 hour.

6. The method for preparing melamine monoamide hydrochloride according to claim 1, wherein the purity of the melamine monoamide hydrochloride is 96% to 98%, and the yield is 80.0% to 85.8%.

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