Synthesis method of 2, 4-dihydroxy-5-cyanopyrimidine

Abstract

The invention relates to the technical field of synthesis of compounds, in particular to a synthesis method of 2, 4-dihydroxy-5-cyanopyrimidine, which specifically comprises the following steps: S1, mixing N-cyano acetyl urethane and N, N-dimethylformamide dimethyl acetal according to a mass ratio of 1: (0.8-1) in a solvent at the temperature of 10-30 DEG C, and adding the mixture into a reaction kettle to obtain a primary mixed solution; s2, stirring the primary mixed solution, heating to 60-70 DEG C, keeping the temperature, and reacting for 2-4 hours until the raw materials are completely converted, so as to obtain a secondary mixed solution; s3, reducing the temperature of the mixed solution obtained in the step S2 to 0-10 DEG C, dropwise adding stronger ammonia water within 1-2 hours, heating to 60-70 DEG C, and keeping the temperature for 1-2 hours; and S4, cooling the solution obtained in the step S3 to 0-10 DEG C again, dropwise adding concentrated hydrochloric acid, adjusting the pH value to 1-2, keeping the temperature for 1-2 hours, filtering, washing and drying to finally obtain the 2, 4-dihydroxy-5-cyanopyrimidine. According to the method, the yield is increased to 92-95%, the purity is stabilized at 99.5% or above, the usage amount of an organic solvent and waste discharge are reduced, and the method conforms to the green chemistry concept.

Description

Technical Field

[0001] The present invention relates to the technical field of compound synthesis, and in particular to a method for synthesizing 2,4-dihydroxy-5-cyanopyrimidine. Background Art

[0002] Anhydrous 2,4-dihydroxy-5-cyanopyrimidine (CAS: 4425-56-3) is an important pharmaceutical intermediate widely used in the synthesis of antiviral and anticancer drugs. The traditional synthesis method uses N-cyanoacetylurea (CAS: 6629-04-5) as the starting material and is prepared through a two-step reaction: first, a condensation reaction is carried out under alkaline conditions to form an intermediate, and then the target product is obtained through acidification and aminolysis. The methods disclosed in the prior art require the separation and purification of the intermediate before the subsequent reaction, resulting in a cumbersome process, high energy consumption, and a long reaction cycle. In addition, the purification process of the intermediate is prone to yield loss, and the yield is usually less than 85%.

[0003] Furthermore, traditional methods require high temperatures, harsh reaction conditions, numerous side reactions, and difficulty maintaining product purity above 99%. These issues significantly increase production costs and limit the efficiency of industrial production. Therefore, there is an urgent need to develop a new synthesis method that simplifies the process, reduces energy consumption, and improves product quality. Summary of the Invention

[0004] In view of the shortcomings of the prior art, the present invention aims to provide a method for synthesizing 2,4-dihydroxy-5-cyanopyrimidine.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] A method for synthesizing 2,4-dihydroxy-5-cyanopyrimidine comprises the following steps:

[0007] S1. N-cyanoacetyl urethane and N, N-dimethylformamide dimethyl acetal are mixed in a solvent at a mass ratio of 1:0.8-1 at a temperature of 10-30°C and added to a reaction vessel to obtain a preliminary mixed solution;

[0008] S2. The preliminary mixture was stirred and heated to 60-70 ° C, and the temperature was maintained for 2-4h until the raw material was completely converted to obtain a secondary step mixture;

[0009] S3. The temperature of the mixture in the second step was lowered to 0-10 ℃, concentrated ammonia was added dropwise, the addition was completed within 1-2h, and then the temperature was raised to 60-70 ℃ and kept warm for 1-2h;

[0010] S4. The solution obtained in step S3 was cooled again to 0-10 ° C, concentrated hydrochloric acid was added dropwise, the pH was adjusted to 1-2, and the mixture was kept warm for 1-2 hours, filtered, washed and dried to obtain 2,4-dihydroxy-5-cyanopyrimidine;

[0011] Among them, the synthesis process of 2,4-dihydroxy-5-cyanopyrimidine can be expressed as:

[0012]

[0013] Preferably, the solvent in step S1 is selected from one of methanol, ethanol or N,N-dimethylformamide.

[0014] Preferably, the stirring speed in step S2 is 350-450 r / min.

[0015] Preferably, in step S3, the mass ratio of concentrated aqueous ammonia to N-cyanoacetylurethane is 1.0-2.0:1.

[0016] Preferably, the mass concentration of the concentrated ammonia water in step S3 is 25-28%.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] 1. The present invention uses N,N-dimethylformamide dimethyl acetal (DMF-DMA) as a key reagent, integrating the traditional two-step reaction into a single reaction system, eliminating the need for intermediate separation and purification, reducing the number of operating steps and equipment investment, and significantly reducing production costs.

[0019] 2. By optimizing the reagent combination, the reaction temperature was reduced to 60-70°C, reducing side reactions and energy consumption while improving reaction safety.

[0020] 3. The present invention increases the yield to 92-95%, stabilizes the purity at above 99.5%, shortens the total reaction time to 6-8 hours, increases production efficiency by more than 30%, reduces the intermediate purification steps, reduces the use of organic solvents and waste emissions, and conforms to the concept of green chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The present invention is a flow chart of the synthesis process of 2,4-dihydroxy-5-cyanopyrimidine. DETAILED DESCRIPTION

[0022] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0023] See also Figure 1 , the present invention provides a technical solution:

[0024] Example 1

[0025] A method for synthesizing 2,4-dihydroxy-5-cyanopyrimidine:

[0026] S1. 2 kg N-cyanoacetyl urethane and 1.6 kg N, N-dimethylformamide dimethyl acetal were mixed in 10 kg methanol at a temperature of 10 ° C and added to the reaction vessel to obtain a preliminary mixed solution;

[0027] S2. The preliminary mixture was stirred and heated to reflux at a stirring speed of 350 r / min, and the reaction temperature was maintained at reflux for 2 h until the raw material was completely converted to obtain a secondary step mixture;

[0028] S3. The temperature of the mixture in the second step was lowered to 0 ℃, 2.0kg of concentrated ammonia with a concentration of 25% was added dropwise within 1h, and then the temperature was raised to 60 ℃ and kept warm for 1h;

[0029] S4. The solution obtained in step S3 was cooled to 0°C again, concentrated hydrochloric acid with a mass concentration of 30% was added dropwise, the pH was adjusted to 1, and the mixture was kept warm for 1 hour, filtered, washed and dried to finally obtain 2,4-dihydroxy-5-cyanopyrimidine with a purity of 99.6% and a yield of 95%.

[0030] Example 2

[0031] A method for synthesizing 2,4-dihydroxy-5-cyanopyrimidine:

[0032] S1. 2kgN-cyanoacetyl urethane and 1.8kgN, N-dimethylformamide dimethyl acetal were mixed in 10kg ethanol at a temperature of 30°C and added to the reaction vessel to obtain a preliminary mixed solution;

[0033] S2. The preliminary mixture was stirred and heated to 70 ° C, the stirring speed was 450r / min, and the temperature was maintained for 4h until the raw material was completely converted to obtain a secondary step mixture;

[0034] S3. The temperature of the mixture in the second step was lowered to 10 ℃, 3kg of concentrated ammonia with a concentration of 28% was added dropwise within 2h, and then the temperature was raised to 70 ℃ and kept warm for 2h;

[0035] S4. The solution obtained in step S3 was cooled to 10°C again, concentrated hydrochloric acid with a mass concentration of 30% was added dropwise, the pH was adjusted to 2, and the mixture was kept warm for 2 hours, filtered, washed and dried to finally obtain 2,4-dihydroxy-5-cyanopyrimidine with a purity of 99.5% and a yield of 95%.

[0036] Example 3

[0037] A method for synthesizing 2,4-dihydroxy-5-cyanopyrimidine:

[0038] S1. At a temperature of 20 ℃, 2kgN-cyanoacetyl urethane and 2.0kgN, N-dimethylformamide dimethyl acetal were mixed in 10kgN, N-dimethylformamide and added to the reaction vessel to obtain a preliminary mixture;

[0039] S2. The preliminary mixture was stirred and heated to 65 ° C, the stirring speed was 400 r / min, and the temperature was maintained for 3h until the raw material was completely converted to obtain a secondary step mixture;

[0040] S3. The temperature of the mixture in the second step was lowered to 4 ° C, 4.0kg of concentrated ammonia with a concentration of 28% was added dropwise, the addition was completed within 1.5h, and then the temperature was raised to 65 ° C and kept warm for 1.5h;

[0041] S4. The solution obtained in step S3 was cooled to 4°C again, concentrated hydrochloric acid with a mass concentration of 30% was added dropwise, the pH was adjusted to 1.5, and the mixture was kept warm for 1.5 hours, filtered, washed and dried to finally obtain 2,4-dihydroxy-5-cyanopyrimidine with a purity of 99.7% and a yield of 92%.

[0042] Example 4

[0043] A method for synthesizing 2,4-dihydroxy-5-cyanopyrimidine:

[0044] S1. 2 kg N-cyanoacetyl urethane and 2.0 kg N, N-dimethylformamide dimethyl acetal were mixed in 10 kg ethanol at a temperature of 25 ° C and added to the reaction vessel to obtain a preliminary mixture;

[0045] S2. The preliminary mixture was stirred and heated to 67 ° C, the stirring speed was 420r / min, and the temperature was maintained for 3.5h until the raw material was completely converted to obtain a secondary step mixture;

[0046] S3. The temperature of the mixture in the second step was lowered to 8 ℃, 4.0kg of concentrated ammonia with a concentration of 25% was added dropwise, the addition was completed within 1.5h, and then the temperature was raised to 68 ℃ and kept warm for 1.5h;

[0047] S4. The solution obtained in step S3 was cooled to 8°C again, concentrated hydrochloric acid with a mass concentration of 30% was added dropwise, the pH was adjusted to 1.5, and the mixture was kept warm for 1.5 hours, filtered, washed and dried to finally obtain 2,4-dihydroxy-5-cyanopyrimidine with a purity of 99.5% and a yield of 94%.

[0048] Comparative Example

[0049] 2,4-dihydroxy-5-cyanopyrimidine was synthesized using a traditional two-step method with N-cyanoacetylurea (cas: 6629-04-5) as the raw material. The total reaction time was 12 h, and the amount of solvent used was 2.5 times that of the example.

[0050] Performance testing:

[0051] High-performance liquid chromatography (HPLC, Agilent 1260 Infinity II) was used for detection. The chromatographic conditions were: a C18 column (4.6×250 mm, 5 μm), a mobile phase of acetonitrile-water (70:30), a flow rate of 1.0 mL / min, and a detection wavelength of 254 nm. Yield (%) = (actual product mass / feed amount) × 100%, where the feed amount was calculated based on the amount of N-cyanoacetylurea (molar conversion assumed to be 100%). The results are shown in Table 1 below:

[0052] Table 1

[0053] Feeding amount (kg) Product mass (kg) Yield (%) purity(%) Example 1 2.0 1.92 95 99.6 Example 2 2.0 1.90 95 99.5 Example 3 2.0 1.84 92 99.7 Example 4 2.0 1.88 94 99.5 Comparative Example 2.0 1.62 81 97.8

[0054] As shown in Table 1, the two-step reaction is completed by one-pot reaction of the present invention, which not only reduces production operation, but also reduces the reaction temperature of the reaction, accelerates the reaction speed, and the purity and yield of the product are also greatly improved compared with the prior art, with yields all being more than 95% and purity all being more than 99.5%. Simultaneously, by-product types and contents in the reaction solution are detected by LC-MS (liquid chromatography-mass spectrometry), and no significant by-products (content < 0.3%) are detected for the 2,4-dihydroxy-5-cyanopyrimidine obtained in Examples 1-4, which are mainly trace hydrolysis products (such as cyanoacetic acid). The comparative example by-product content is as high as 2.5-3.8% (such as dimers, oxidation products). The side reaction of the present invention is very few, further demonstrating the superiority of low-temperature reaction and one-pot process.

[0055] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing 2,4-dihydroxy-5-cyanopyrimidine, characterized in that: The following steps are involved: S1. N-cyanoacetyl urethane and N, N-dimethylformamide dimethyl acetal are mixed in a solvent at a mass ratio of 1:0.8-1 at a temperature of 10-30°C and added to a reaction vessel to obtain a preliminary mixed solution; S2. The preliminary mixture was stirred and heated to 60-70 ° C, and the temperature was maintained for 2-4h until the raw material was completely converted to obtain a secondary step mixture; S3. The temperature of the mixture in the second step was lowered to 0-10 ℃, concentrated ammonia was added dropwise, the addition was completed within 1-2h, and then the temperature was raised to 60-70 ℃ and kept warm for 1-2h; S4. The solution obtained in step S3 is cooled again to 0-10°C, concentrated hydrochloric acid is added dropwise to adjust the pH to 1-2, and the mixture is kept warm for 1-2 hours, filtered, washed and dried to finally obtain 2,4-dihydroxy-5-cyanopyrimidine.

2. The method for synthesizing 2,4-dihydroxy-5-cyanopyrimidine according to claim 1, wherein: In step S1, the solvent is selected from one of methanol, ethanol or N,N-dimethylformamide.

3. The method for synthesizing 2,4-dihydroxy-5-cyanopyrimidine according to claim 1, wherein: The stirring speed in step S2 is 350-450 r / min.

4. The method for synthesizing 2,4-dihydroxy-5-cyanopyrimidine according to claim 1, wherein: In step S3, the mass ratio of concentrated aqueous ammonia to N-cyanoacetylurethane is 1.0-2.0:

1.

5. The method for synthesizing 2,4-dihydroxy-5-cyanopyrimidine according to claim 1, wherein: The mass concentration of the concentrated ammonia water in step S3 is 25-28%.

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