Process for the synthesis and purification of 2,4-diamino-5,6-dichloropyrimidine

Abstract

The present application relates to the field of pharmaceutical chemical technology, and more particularly to a method for synthesizing and purifying 2,4-diamino-5,6-dichloropyrimidine, which comprises reacting 2,4-diamino-6-chloropyrimidine with a dilute hydrochloric acid solution in the presence of a peroxo acid to obtain 2,4-diamino-5,6-dichloropyrimidine. Compared with the traditional method, the method for synthesizing and purifying 2,4-diamino-5,6-dichloropyrimidine has the advantages of easy availability of raw materials, low cost, easy control of reaction, simple post-treatment, high yield, and suitability for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemical technology, and particularly relates to a synthesis and refining method of 2,4-diamino-5,6-dichloropyrimidine. BACKGROUND

[0002] 2,4-diamino-5,6-dichloropyrimidine, chemical formula is C4H4C l2 N4, is a pink crystalline powder. Pyrimidine compounds have active molecular structures, and are intermediates of many medicines and pesticides. Pyrimidine derivatives exist in various forms in human bodies, organisms and nature, and play important roles in physiological activities. Cytosine (C) and thymine (T) in DNA and cytosine (C) and uracil (U) in RNA, and a small amount of modified bases all contain pyrimidine rings. The special structure of pyrimidine compounds determines the unique properties of the compounds, and the compounds have the effects of antibacterial, insecticidal and plant regulating, and are widely used for preparing various medicine products, pesticide products such as insecticides, fungicides and herbicides. Pyrimidine compounds can form metal complexes with metal ions through intermolecular forces, improve pharmacological activity, persistence, prolong the half-life of drugs, effectively reduce toxicity and side effects. When used as a medicine intermediate, the pyrimidine compounds are mainly used for the production of sulfonamides such as sulfadimethoxine, sulfisomidine, sulfamethoxazole, sulfamethoxypyrimidine and the like. Meanwhile, 2,4-diamino-5,6-dichloropyrimidine is also a raw material for synthesizing minoxidil impurities. Therefore, the synthesis of 2,4-diamino-5,6-dichloropyrimidine has important significance.

[0003] At present, there are few reports about the synthesis of 2,4-diamino-5,6-dichloropyrimidine. Although the product can be synthesized through a reaction, either expensive raw materials are used or the post-treatment is complex, which is not suitable for industrial production.

[0004] An overseas patent KR2016002318 uses 2,4-diamino-6-chloropyrimidine as a starting material, and a substitution reaction is performed on the starting material with N-chlorosuccinimide (NCS) in N,N'-dimethylformamide (DMF) as a solvent to obtain 2,4-diamino-5,6-dichloropyrimidine. The method needs to use NCS, and also needs to use the organic solvent DMF as a solvent to make the reaction proceed, and needs to react for 48 hours. The purity and yield of the obtained 2,4-diamino-5,6-dichloropyrimidine need to be improved.

[0005] CN115572265, 2, 4-diamino-6-chloropyrimidine as a starting material, in N, N'-dimethylformamide (DMF) as solvent, and N-chlorosuccinimide (NCS) substitution reaction to get 2, 4-diamino-5, 6-dichloropyrimidine. The method needs to use ethyl acetate (EA) for multiple extractions after the reaction is completed, and the purity and yield of the obtained 2, 4-diamino-5, 6-dichloropyrimidine need to be improved. SUMMARY

[0006] The technical problem to be solved by the present application is: in order to solve the technical problems of less synthesis of 2, 4-diamino-5, 6-dichloropyrimidine in the prior art, and only the synthesis method with low purity and yield. The present application provides a synthesis and purification method of 2, 4-diamino-5, 6-dichloropyrimidine, which has the advantages of easy availability of raw materials, low cost, high efficiency of reaction, high yield and suitability for industrial production. The technical solution adopted by the present application to solve the technical problem is: a synthesis and purification method of 2, 4-diamino-5, 6-dichloropyrimidine, taking 2, 4-diamino-6-chloropyrimidine as raw material, reacting in dilute hydrochloric acid solution in the presence of peroxo acid to obtain 2, 4-diamino-5, 6-dichloropyrimidine.

[0007] The specific synthesis route is as follows:

[0008]

[0009] Further, the synthesis and purification method of 2, 4-diamino-5, 6-dichloropyrimidine comprises the following steps:

[0010]

[0011] Dissolve 2, 4-diamino-6-chloropyrimidine in a predetermined concentration of hydrochloric acid, slowly add peroxo acid at a predetermined temperature, and after the reaction is completed, obtain the intermediate 2, 4-diamino-5, 6-dichloropyrimidine after post-processing.

[0012] Further, the molar ratio of the raw material 2, 4-diamino-6-chloropyrimidine to peroxo acid in the step is 1:1.1-1.3.

[0013] Further, the peroxo acid includes one or more of chlorobenzenesulfonyl peroxide (m-CPBA), peroxoacetic acid (CH3CO3H) and peroxymonocarbonate (HCO3H).

[0014] Further, the concentration of the predetermined hydrochloric acid is in the range of 2.0%-8.0%.

[0015] Further, the mass ratio of 2, 4-diamino-6-chloropyrimidine to total solvent is 1:6-10.

[0016] Further, the preset reaction temperature is 15-30℃, and the reaction time is 4-12h.

[0017] Further, the post-treatment comprises: mixing the crude 2,4-diamino-5,6-dichloropyrimidine and a refining solvent to perform refining, obtaining a refined system, sequentially performing crystallization and suction filtration on the refined system to obtain a filter cake, and finally sequentially performing washing and drying on the filter cake to obtain 2,4-diamino-5,6-dichloropyrimidine.

[0018] Further, the refining solvent comprises one or more of methanol, ethanol and water.

[0019] Further, the refining temperature is 75-85℃, and the crystallization temperature is 0-5℃.

[0020] The present application provides a synthesis and refining method of 2,4-diamino-5,6-dichloropyrimidine, comprising the following steps: mixing 2,4-diamino-6-chloropyrimidine, peroxo acid and dilute hydrochloric acid solution to perform reaction at room temperature to obtain crude 2,4-diamino-5,6-dichloropyrimidine. The present application can improve the purity and yield of 2,4-diamino-5,6-dichloropyrimidine. The results of examples show that the purity of 2,4-diamino-5,6-dichloropyrimidine prepared by the present application is 98.76-99.52%, and the yield is 90.71-96.12%. BRIEF DESCRIPTION OF DRAWINGS

[0021] The present application is further illustrated below in combination with the drawings and examples.

[0022] Figure 1 LC-MS spectrum of 2,4-diamino-5,6-dichloropyrimidine. 1 H-NMR spectrum;

[0023] Figure 2 LC-MS spectrum of 2,4-diamino-5,6-dichloropyrimidine. DETAILED DESCRIPTION

[0024] The present application provides a synthesis and refining method of 2,4-diamino-5,6-dichloropyrimidine, comprising the following steps:

[0025] Mixing 2,4-diamino-6-chloropyrimidine, peroxo acid and dilute hydrochloric acid to perform reaction at room temperature to obtain crude 2,4-diamino-5,6-dichloropyrimidine.

[0026] In the present application, all raw material components are commercially available products well known to those skilled in the art, unless otherwise specified.

[0027] The present application mixes 2,4-diamino-6-chloropyrimidine, peroxy acid and dilute hydrochloric acid, and carries out reaction at room temperature to obtain 2,4-diamino-5,6-dichloropyrimidine crude product. In the present application, the molar ratio of 2,4-diamino-6-chloropyrimidine and peroxy acid is preferably 1:1.1-1.3. In the present application, the concentration of dilute hydrochloric acid is 2.0%-8.0%. In the present application, the peroxy acid includes one or more of m-chloroperbenzoic acid (m-CPBA), peroxy acetic acid (CH3CO3H) and peroxy formic acid (HCO3H).

[0028] In the present application, the mixing of 2,4-diamino-6-chloropyrimidine, peroxy acid and dilute hydrochloric acid preferably includes: dissolving 2,4-diamino-6-chloropyrimidine in part of dilute hydrochloric acid to obtain a 2,4-diamino-6-chloropyrimidine solution, dissolving peroxy acid in the remaining dilute hydrochloric acid to obtain a peroxy acid-dilute hydrochloric acid solution, and adding the peroxy acid-dilute hydrochloric acid solution dropwise to the 2,4-diamino-6-chloropyrimidine solution.

[0029] In the present application, the mass ratio of 2,4-diamino-6-chloropyrimidine and dilute hydrochloric acid is preferably 1:6-10, and more preferably 1:8. In the present application, the concentration of dilute hydrochloric acid is 2.0%-8.0%, and more preferably 5%. In the present application, the dissolving process of 2,4-diamino-6-chloropyrimidine is preferably carried out under stirring, and the temperature of the dissolving process is preferably 10-20°C. The present application preferably maintains the temperature of the 2.4-diamino-6-chloropyrimidine solution at 15-30°C before adding the peroxy acid-dilute hydrochloric acid solution.

[0030] In the present application, the mass ratio of peroxy acid and the remaining acid solvent is preferably 1:3-6, and more preferably 1:4.95. In the present application, the dropping speed of the peroxy acid-dilute hydrochloric acid solution is preferably 0.1 L / min. The present application uses the dropping method to avoid the risk of explosion caused by adding a large amount of peroxy acid at one time, and also to avoid the generation of impurities and improve the purity of the product.

[0031] In the present application, the temperature of the reaction is preferably 15-30°C; the time of the reaction is preferably 4-12h, and more preferably 6-8h. The present application preferably uses TLC to monitor the end point of the reaction.

[0032] In the present application, appropriate post-treatment preferably includes: cooling and stirring the obtained reaction system, overnight crystallization, suction filtration, washing the obtained filter cake with ethanol, and drying to obtain 2,4-diamino-5,6-dichloropyrimidine crude product. In the present application, the temperature of the crystallization is preferably 0-10°C, and more preferably 2-5°C. In the present application, the 2,4-diamino-5,6-dichloropyrimidine crude product is a pink solid.

[0033] In the specific embodiment of the present application, the purity of the crude 2,4-diamino-5,6-dichloropyrimidine is 93.66-97.66%, and the yield is 84.28-98.01%.

[0034] After obtaining the crude 2,4-diamino-5,6-dichloropyrimidine, the crude 2,4-diamino-5,6-dichloropyrimidine is mixed with a refining solvent to refine the crude 2,4-diamino-5,6-dichloropyrimidine to obtain a refined system, the refined system is sequentially subjected to crystallization and suction filtration to obtain a filter cake, and the filter cake is sequentially subjected to washing and drying to obtain 2,4-diamino-5,6-dichloropyrimidine. In the present application, the refining solvent preferably comprises one or more of methanol, ethanol and water, and more preferably a mixture of ethanol and water. In the present application, the water is preferably purified water. In the present application, the mass ratio of ethanol to water in the mixture of methanol and water is preferably 1.2-1.3:1. In the present application, the mass ratio of the refining solvent to the crude 2,4-diamino-5,6-dichloropyrimidine is preferably 7-9:1. In the present application, the refining is preferably carried out under reflux conditions, and the temperature of the refining is preferably 75-85°C; the time of the refining is preferably 1h. In the present application, the temperature of the crystallization is preferably 0-5°C. In the present application, the washing solvent is preferably ethanol.

[0035] In the present application, the 2,4-diamino-5,6-dichloropyrimidine is a pink solid.

[0036] The solvent used in the present application is green, cheap and easy to obtain, and can be reused, reducing production cost and being suitable for industrial production. In the specific embodiment of the present application, the purity of the obtained 2,4-diamino-5,6-dichloropyrimidine is 98.76-99.52%, and the yield is 90.71-96.12%.

[0037] The technical solutions in the present application will be described clearly and completely in combination with the embodiments in the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0038] Example 1

[0039] A. Synthesis of crude 2,4-diamino-5,6-dichloropyrimidine

[0040] Into a reaction kettle, 2 mol of 2,4-diamino-6-chloropyrimidine and 2.3 kg of 5% dilute hydrochloric acid were added, and the system was stirred to dissolve. The system was cooled to 15°C, and a solution of 2.4 mol of meta-chloroperoxybenzoic acid and 2.1 kg of dilute hydrochloric acid was added dropwise into the above reaction kettle at a rate of 0.1 L / min. After the addition was completed, the reaction was carried out at 15°C for 6 hours, and the reaction end point was monitored by TLC. The system was cooled to 5°C and crystallized overnight. The filter cake was washed once with methanol and dried to obtain 0.300 kg of 2,4-diamino-5,6-dichloropyrimidine in the form of a pink solid, with a product purity of 93.66% and a yield of 84.28%.

[0041] B. Purification of 2,4-diamino-5,6-dichloropyrimidine

[0042] Into a reaction kettle, 2 mol of 2,4-diamino-6-chloropyrimidine and 2.3 kg of 5% dilute hydrochloric acid were added, and the system was stirred to dissolve. The system was cooled to 15°C, and a solution of 2.4 mol of meta-chloroperoxybenzoic acid and 2.1 kg of dilute hydrochloric acid was added dropwise into the above reaction kettle at a rate of 0.1 L / min. After the addition was completed, the reaction was carried out at 15°C for 6 hours, and the reaction end point was monitored by TLC. The system was cooled to 5°C and crystallized overnight. The filter cake was washed once with methanol and dried to obtain 0.300 kg of 2,4-diamino-5,6-dichloropyrimidine in the form of a pink solid, with a product purity of 93.66% and a yield of 84.28%.

[0043] The chemical reaction formula for preparing 2,4-diamino-5,6-dichloropyrimidine in this example is as follows:

[0044]

[0045] Example 2

[0046] A. Synthesis of 2,4-diamino-5,6-dichloropyrimidine crude product

[0047] Into a reaction kettle, 2 mol of 2,4-diamino-6-chloropyrimidine and 2.3 kg of 5% dilute hydrochloric acid were added, and the system was stirred to dissolve. The system was cooled to 15°C, and a solution of 2.4 mol of meta-chloroperoxybenzoic acid and 2.1 kg of dilute hydrochloric acid was added dropwise into the above reaction kettle at a rate of 0.1 L / min. After the addition was completed, the reaction was carried out at 15°C for 6 hours, and the reaction end point was monitored by TLC. The system was cooled to 5°C and crystallized overnight. The filter cake was washed once with methanol and dried to obtain 0.300 kg of 2,4-diamino-5,6-dichloropyrimidine in the form of a pink solid, with a product purity of 93.66% and a yield of 84.28%.

[0048] B. Purification of 2,4-diamino-5,6-dichloropyrimidine

[0049] Into a reaction kettle, 0.349 kg of 2,4-diamino-5,6-dichloropyrimidine crude product, 1.6 kg of ethanol and 1.2 kg of purified water were added, and the system was stirred to dissolve at 80°C. The reaction was carried out for 1 hour, and the system was allowed to dissolve. The system was stirred to cool to 5°C, and the product was allowed to crystallize overnight. The product was filtered, washed with ethanol once, and dried to obtain 0.342 kg of 2,4-diamino-5,6-dichloropyrimidine in the form of a pink solid. The purity of the product was 99.52%, and the yield was 98.07%.

[0050] The chemical reaction formula for preparing 2,4-diamino-5,6-dichloropyrimidine in this example is as follows:

[0051]

[0052] Example 3

[0053] A. Synthesis of 2,4-diamino-5,6-dichloropyrimidine crude product

[0054] Into a reaction kettle, 2 mol of 2,4-diamino-5,6-dichloropyrimidine and 2.3 kg of 5% hydrochloric acid were added, and the system was stirred to dissolve. The system was stirred to cool to 15°C. A solution of 2.4 mol of meta-chloroperbenzoic acid and 0.737 kg of hydrochloric acid was prepared, and the solution was added dropwise to the above reaction kettle at a rate of 0.1 L / min. After the dropwise addition was completed, the system was allowed to react at 15°C for 6 hours. The reaction was monitored by TLC. The system was stirred to cool to 5°C, and the product was allowed to crystallize overnight. The product was filtered, washed with methanol once, and dried to obtain 0.331 kg of 2,4-diamino-5,6-dichloropyrimidine in the form of a pink solid. The purity of the product was 95.66%, and the yield was 93.01%.

[0055] B. Purification of 2,4-diamino-5,6-dichloropyrimidine

[0056] Into a reaction kettle, 0.331 kg of 2,4-diamino-5,6-dichloropyrimidine crude product, 1.5 kg of ethanol and 1.1 kg of purified water were added, and the system was stirred to dissolve at 80°C. The reaction was carried out for 1 hour, and the system was allowed to dissolve. The system was stirred to cool to 5°C, and the product was allowed to crystallize overnight. The product was filtered, washed with ethanol once, and dried to obtain 0.314 kg of 2,4-diamino-5,6-dichloropyrimidine in the form of a pink solid. The purity of the product was 98.54%, and the yield was 94.86%.

[0057] The chemical reaction formula for preparing 2,4-diamino-5,6-dichloropyrimidine in this example is as follows:

[0058]

[0059] Comparative Example 1

[0060] Using the example in overseas patent KR2016002318 as a comparative example, it was found that the reaction time was too long, which was not conducive to the monitoring of the reaction, and there were many side reactions.

[0061] Comparative Example 2

[0062] Using Reference Example 3 in Chinese Patent CN115572265 as a comparative example, it was found that the product was difficult to extract from water.

[0063] like Figure 1 As shown, this image is of 2,4-diamino-5,6-dichloropyrimidine. 1 The H-NMR spectrum shows four sets of peaks. The peak at δ = 2.5 represents the solvent DMSO, the peak at δ = 3.33 represents water, the peak at δ = 6.49 represents a singlet from the two hydrogens at the 2-position amino group, and the peak at δ = 6.97 represents a broad singlet from the two hydrogens at the 4-position amino group. Therefore, the NMR data are... 1 ¹H NMR (400MHz, DMSO-d6): δ 6.97 (brs, 2H), 6.49 (s, 2H), confirming that the prepared substance is 2,4-diamino-5,6-dichloropyrimidine;

[0064] like Figure 2 As shown, this image is the LG-MS spectrum of a mixture of 2,4-diamino-5,6-dichloropyrimidine and 2,4-diamino-6-chloropyrimidine. Two sets of peaks are visible in the image. The peak at Time = 1.27 represents 2,4-diamino-6-chloropyrimidine in the liquid phase, while [M+H] is detected in the mass spectrometer. + =145.1 is consistent with the actual value; Time = 2.39 is the peak of 2,4-diamino-5,6-dichloropyrimidine in the liquid phase, and [M+H] was detected in the mass spectrometer. + =179.0, which is consistent with the actual value; therefore, the mass spectrometry data for 2,4-diamino-5,6-dichloropyrimidine is HRMS(ESI) m / z: [M+H] + Calculation for, C4H5Cl2N4, 179.0, found 179.0, further confirming that the synthesized compound is 2,4-diamino-5,6-dichloropyrimidine.

[0065] In summary, the method for synthesizing and purifying 2,4-diamino-5,6-dichloropyrimidine of the present invention can improve the purity and yield of 2,4-diamino-5,6-dichloropyrimidine, and has the advantages of readily available raw materials, low cost, high reaction efficiency, high yield, and suitability for industrial production.

[0066] With the above ideal embodiments according to the present application as the inspiration, through the above description, relevant staff can make various changes and modifications without deviating from the technical idea of the present application. The technical scope of the present application is not limited to the content of the specification, and must be determined by the scope of the claims.

Claims

1. A process for the synthesis of 2,4-diamino-5,6-dichloropyrimidine, characterized in that: Specifically, the steps are as follows: 2,4-diamino-6-chloropyrimidine is dissolved in hydrochloric acid with a preset concentration, and peroxo acid is slowly added dropwise at a preset temperature, and after the reaction is completed, the intermediate 2,4-diamino-5,6-dichloropyrimidine is obtained after post-treatment; The peroxo acid is one or more of m-chloroperbenzoic acid, peroxyacetic acid and peroxyformic acid; The preset reaction temperature is 15-30°C, and the reaction time is 4-12h.

2. The process for the synthesis of 2,4-diamino-5,6-dichloropyrimidine according to claim 1, characterized in that: The molar ratio of 2,4-diamino-6-chloropyrimidine to peroxo acid in the step is 1:1.1-1.

3.

3. The method for synthesizing 2,4-diamino-5,6-dichloropyrimidine as described in claim 1, characterized in that: The concentration of the preset hydrochloric acid is in the range of 2.0%-8.0%.

4. The method for synthesizing 2,4-diamino-5,6-dichloropyrimidine as described in claim 1, characterized in that: The mass ratio of 2,4-diamino-6-chloropyrimidine to total solvent is 1:6-10.

5. The method for synthesizing 2,4-diamino-5,6-dichloropyrimidine as described in claim 1, characterized in that: The post-treatment is as follows: 2,4-diamino-5,6-dichloropyrimidine crude product obtained by reaction is mixed with refining solvent to refine to obtain a refined system, and the refined system is sequentially subjected to crystallization and suction filtration to obtain a filter cake, and finally the filter cake is sequentially subjected to washing and drying to obtain 2,4-diamino-5,6-dichloropyrimidine.

6. The method of claim 5, wherein: The refining solvent is one or more of methanol, ethanol and water.

7. The method for synthesizing 2,4-diamino-5,6-dichloropyrimidine as described in claim 5, characterized in that: The refining temperature is 75-85°C, and the crystallization temperature is 0-5°C.

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