Preparation method of 2, 4-diamino-6-hydroxy-5-nitroso pyrimidine

Abstract

The invention provides a preparation method of 2, 4-diamino-6-hydroxy-5-nitroso pyrimidine, which comprises the following steps: (a) carrying out cyclization reaction on a sodium methoxide methanol solution, guanidine nitrate and methyl cyanoacetate in a reflux state, and concentrating to recover methanol after the reaction is completed; (b) adding water into the concentrated product for dissolving, and heating to 60-65 DEG C; adding sodium nitrite, stirring and dissolving to obtain cyclization liquid; (c) heating the sulfuric acid solution to 60-65 DEG C, dropwise adding the cyclization liquid and sulfuric acid into the sulfuric acid solution, and controlling the temperature to be 60-70 DEG C during dropwise adding; and filtering, washing and drying after the solid stops separating out. The product with the purity of 99.53% can be obtained, and the method is suitable for industrial production with high purity requirements; in the whole process, the reaction temperature and pressure are controlled mildly, and equipment requirements and safety risks caused by high temperature and high pressure are avoided; and the traditional complex recrystallization and multi-step purification process is simplified.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemical products, and specifically relates to a method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine. Background Art

[0002] 2,4-Diamino-6-hydroxy-5-nitrosopyrimidine is a pyrimidine derivative that shows important application potential in organic synthesis and drug development. In particular, it is considered to be one of the key intermediates in the development of antibiotics and is used to study drug-resistant strains such as Clostridium difficile. This antibacterial effect makes it one of the candidate compounds for the development of new drugs. In addition, its applications in other fields include nucleotide synthesis and the production of derivatives of pyrimidine ring compounds, especially in the synthesis routes of folic acid and guanine.

[0003] Although 2,4-diamino-6-hydroxy-5-nitrosopyrimidine has a wide range of application potential, its nitroso structure may involve certain safety and environmental considerations. During handling and storage, high temperatures and strong oxidizing environments should be avoided to prevent decomposition of the compound and unnecessary side reactions. In the large-scale synthesis process, how to optimize the reaction conditions and safely handle intermediates and by-products remains one of the challenges in the industrial application of this compound. Summary of the invention

[0004] In order to solve the above technical problems, the object of the present invention is to provide a method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine.

[0005] In order to achieve the above technical problem, the present invention provides a method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine, comprising the following steps:

[0006] (a) subjecting a sodium methoxide methanol solution, guanidine nitrate and methyl cyanoacetate to a cyclization reaction under reflux, and concentrating the reaction to recover methanol after the reaction is completed;

[0007] (b) adding water to the concentrated product to dissolve it, raising the temperature to 60-65° C.; then adding sodium nitrite, stirring and dissolving it to obtain a cyclization liquid;

[0008] (c) heating the sulfuric acid solution to 60-65° C., and dripping the cyclization liquid and sulfuric acid thereinto, with the temperature being controlled at 60-70° C.; and filtering, washing, and drying the solid after it stops precipitating.

[0009] Optimally, in step (a), the molar ratio of guanidine nitrate to methyl cyanoacetate is 1 to 1.1:1.

[0010] Furthermore, in step (a), the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 20 to 50%.

[0011] Furthermore, in step (a), the sodium methoxide methanol solution is first added to the reaction container, stirring is started and the temperature is controlled to be ≤40°C, and the guanidine nitrate is added in batches; heating is turned on to reflux state, methyl cyanoacetate is added dropwise, and the reaction is carried out until no obvious impurity points are detected by TLC; the reflux temperature is controlled to be 67-77°C, and the addition time of the methyl cyanoacetate is controlled to be 2-5h.

[0012] In one embodiment of the present invention, in step (a), after the reaction is completed, it is first concentrated under normal pressure to recover the solvent methanol, and then the vacuum degree is controlled to be ≤-0.08MPa to remove the residual methanol until there is no effluent; a small amount of water is added, and the decompression operation is continued until there is no effluent.

[0013] Optimally, in step (b), the molar ratio of the sodium nitrite to the methyl cyanoacetate is 1.1-1.2:1.

[0014] Optimally, in step (c), the sulfuric acid solution is prepared by mixing 50% sulfuric acid and water in an equal mass ratio.

[0015] Optimally, in step (a), methanol is recovered for application; concentration is performed by atmospheric pressure or reduced pressure.

[0016] The method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine of the present invention comprises the following steps: performing a cyclization reaction on guanidine nitrate and methyl cyanoacetate in a sodium methoxide methanol solution under reflux, and reacting the intermediate obtained by reacting with sodium nitrite and sulfuric acid, so as to obtain a product with a purity of 99.53%, and the product is suitable for industrial production with high purity requirements; the reaction temperature and pressure are controlled relatively mildly in the whole process, thus avoiding the equipment requirements and safety risks brought by high temperature and high pressure, and the process operation is simple and suitable for large-scale production; and the conventional complex recrystallization and multi-step purification process is simplified by reasonably controlling the solvent recovery and concentration operations in each step, thus greatly improving the production efficiency and reducing the cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 The chemical reaction formula for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine of the present invention is as follows;

[0018] Figure 2 The process flow chart of preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine of the present invention;

[0019] Figure 3 The present invention provides a liquid phase spectrum for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine. DETAILED DESCRIPTION

[0020] The preparation method of 2,4-diamino-6-hydroxy-5-nitrosopyrimidine comprises the following steps: (a) subjecting a sodium methoxide methanol solution, guanidine nitrate and methyl cyanoacetate to a cyclization reaction under reflux, and concentrating the solution after the reaction is completed to recover methanol; (b) adding water to the concentrated product to dissolve the solution, and heating the solution to 60-65°C; then adding sodium nitrite, stirring and dissolving the solution to obtain a cyclization liquid; (c) heating a sulfuric acid solution to 60-65°C, and dripping the cyclization liquid and sulfuric acid therein, wherein the temperature is controlled to be 60-70°C during the dripping; and filtering, washing and drying the solution after solids stop precipitating. By allowing guanidine nitrate and methyl cyanoacetate to undergo a cyclization reaction under reflux in a sodium methoxide methanol solution, and reacting the intermediate obtained by reaction with sodium nitrite and sulfuric acid, a product with a purity of 99.53% can be obtained, which is suitable for industrial production with high purity requirements; the reaction temperature and pressure are controlled relatively mildly in the entire process, avoiding the equipment requirements and safety risks brought about by high temperature and high pressure, and the process operation is simple and suitable for large-scale production; by reasonably controlling the solvent recovery and concentration operations in each step, the traditional complex recrystallization and multi-step purification process is simplified, the production efficiency is greatly improved and the cost is reduced.

[0021] In step (a), the molar ratio of guanidine nitrate to methyl cyanoacetate is 1-1.1:1; the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 20-50%, preferably 30%. In step (a), the sodium methoxide methanol solution is first added to the reaction vessel, stirring is started and the temperature is controlled to be ≤40°C, and the guanidine nitrate is added in batches; heating is turned on to reflux state, methyl cyanoacetate is added dropwise, and the reaction is carried out until there is no obvious impurity point by TLC detection; the reflux temperature is controlled to be 67-77°C, and the dropping time of methyl cyanoacetate is controlled to be 2-5h. In step (a), after the reaction is completed, it is first concentrated under normal pressure to recover the solvent methanol, and then the vacuum degree is controlled to be ≤-0.08MPa (the display value of the vacuum distillation instrument) to remove the residual methanol until there is no effluent; a small amount of water is added, and the decompression operation is continued until there is no effluent.

[0022] In step (b), the molar ratio of the sodium nitrite to the methyl cyanoacetate is 1.1-1.2:1. In step (c), the sulfuric acid solution is prepared by mixing 50% sulfuric acid and water in an equal mass ratio. In step (a), methanol is recovered for reuse; and the concentration operation is performed under normal pressure or reduced pressure.

[0023] The present invention will be further described below in conjunction with the embodiments shown in the accompanying drawings.

[0024] Example 1

[0025] This embodiment provides a method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine. Figure 1 and Figure 2 As shown, the following steps are included:

[0026] (a) In a 500 ml three-necked flask, 95 g of sodium methoxide methanol solution was added (methanol was first added to the three-necked flask, and then sodium methoxide was added to dissolve to obtain sodium methoxide methanol solution, so that the mass ratio of sodium methoxide in the sodium methoxide methanol solution was 30%; that is, sodium methoxide was 28.5 g and methanol was 66.5 g), stirring was started and the temperature was controlled to be ≤40°C; within 30 minutes, 32.5 g (122 g / mol, 0.266 mol) of guanidine nitrate was added in two batches (with equal mass); after the addition of the materials was completed, heating was turned on to reflux state; under reflux state, the reflux temperature was controlled at 72°C±5°C, and 25.3 g (99 g / mol, 0.256 mol; the dropping time was 3.5 hours) of methyl cyanoacetate was slowly added dropwise, and the reaction was completed when no obvious impurity spots were detected by TLC.

[0027] (b) After the reaction is completed, first concentrate at room temperature and pressure to recover the solvent methanol; then, use a commercially available vacuum distillation apparatus to remove residual methanol by vacuum concentration, and control the vacuum degree at ≤-0.08MPa until there is basically no effluent. At this time, add 40g of water, continue to carry out the vacuum entrainment operation until there is almost no effluent; add 200g of water, and stir to completely dissolve the solid, heat the reaction system to 60-65°C, then add 20g of sodium nitrite (69g, 0.29mol), stir to dissolve, and set aside (i.e., the cyclization liquid).

[0028] (c) Add 15 g of 50% sulfuric acid and 15 g of water to the reaction flask and heat to 60°C; slowly add the cyclization liquid (in step (b)) dropwise, and at the same time add 35 g of sulfuric acid dropwise, and control the temperature at 60-70°C during the addition. Solids gradually precipitate, and 70 g of wet product is obtained by filtration. After drying the wet product, 39 g of solid product is obtained. Liquid phase detection purity: 99.637% (see Figure 3 ), yield 87%.

[0029] Example 2

[0030] This embodiment provides a method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine, which is basically the same as that in Example 1, except that: in step (a), 23.9 g of methyl cyanoacetate (99 g / mol, 0.24 mol; the dropping time is 3.5 hours) is slowly added dropwise; 36.9 g of solid product is obtained. Liquid phase detection purity: 99.65%, yield 83.8%.

[0031] Example 3

[0032] This embodiment provides a method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine, which is basically the same as that in Example 1, except that: in step (a), 26.3 g of methyl cyanoacetate (99 g / mol, 0.266 mol; the addition time is 3.5 hours) is slowly added dropwise; 40.5 g of solid product is obtained. Liquid phase detection purity: 99.670%, yield 90.07%

[0033] Comparative Example 1

[0034] This example provides a method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine, which is basically the same as that in Example 1, except that in step (b), 200 g of water is directly added instead of adding 40 g of water to continue the vacuum entrainment operation; 35 g of solid product is obtained. Liquid phase detection purity: 97.000%, yield 75.74%.

[0035] Comparative Example 2

[0036] This example provides a method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine, which is basically the same as that in Example 1, except that in step (c), the temperature is controlled at 85-90°C during the dropwise addition, and 36 g of solid product is obtained. The liquid phase detection purity is 98.200%, and the yield is 78.87%.

[0037] Comparative Example 3

[0038] This example provides a method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine, which is basically the same as that in Example 1, except that in step (c), the temperature is controlled at 40-50°C during the dropwise addition, and 30 g of solid product is obtained. The liquid phase detection purity is 97.800%, and the yield is 66.93%.

[0039] Comparative Example 4

[0040] This example provides a method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine, which is basically the same as that in Example 1, except that in step (c), 35 g of sulfuric acid is not added dropwise; 25 g of solid product is obtained. Liquid phase detection purity: 97.500%, yield 55.78%.

[0041] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine, characterized in that: The following steps are involved: (a) subjecting a sodium methoxide methanol solution, guanidine nitrate and methyl cyanoacetate to a cyclization reaction under reflux, and concentrating the reaction after completion to recover methanol; (b) adding water to the concentrated product to dissolve it, raising the temperature to 60-65° C.; then adding sodium nitrite, stirring and dissolving to obtain a cyclization liquid; (c) heating the sulfuric acid solution to 60-65°C, and dripping the cyclization liquid and sulfuric acid thereinto, with the temperature being controlled at 60-70°C; and filtering, washing and drying the solution after the solid stops precipitating.

2. The method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine according to claim 1, characterized in that: In step (a), the molar ratio of guanidine nitrate to methyl cyanoacetate is 1-1.1:

1.

3. The method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine according to claim 1 or 2, characterized in that: In step (a), the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 20-50%.

4. The method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine according to claim 3, characterized in that: In step (a), the sodium methoxide methanol solution is first added to the reaction container, stirring is started and the temperature is controlled to be ≤40° C., and the guanidine nitrate is added in batches; heating is turned on to reflux state, methyl cyanoacetate is added dropwise, and the reaction is carried out until no obvious impurity points are detected by TLC; the reflux temperature is controlled to be 67-77° C., and the addition time of the methyl cyanoacetate is controlled to be 2-5 hours.

5. The method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine according to claim 4, characterized in that: In step (a), after the reaction is completed, the reaction mixture is first concentrated under normal pressure to recover the solvent methanol, and then the vacuum degree is controlled to be ≤-0.08 MPa to remove the residual methanol until no effluent is left; a small amount of water is added, and the decompression operation is continued until no effluent is left.

6. The method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine according to claim 1, characterized in that: In step (b), the molar ratio of the sodium nitrite to the methyl cyanoacetate is 1.1-1.2:

1.

7. The method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine according to claim 1, characterized in that: In step (c), the sulfuric acid solution is prepared by mixing 50% sulfuric acid and water in an equal mass ratio.

8. The method for preparing 2,4-diamino-6-hydroxy-5-nitrosopyrimidine according to claim 1, characterized in that: In step (a), methanol is recovered for reuse; and concentration is performed under normal pressure or reduced pressure.

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