A preparation method of 4,6-dihydroxypyrimidine

Abstract

The present invention provides a preparation method of 4,6-dihydroxypyrimidine, and the preparation method comprises the following steps: adding a mixed solution of malonate and formamide to an alkali metal alcoholate / solvent containing a catalyst, and then keeping the mixture warm for reaction after the addition is completed. After the reaction is completed, the solvent is evaporated to dryness, and after being dissolved in water, the mixture is acidified to a pH of 2-3, filtered, washed with water, and dried to obtain 4,6-dihydroxypyrimidine. The present invention utilizes a catalyst to catalyze the reaction, thereby improving the reaction yield, having a high atomic economy, and reducing the amount of raw materials used, reducing the generation of saline wastewater, and alleviating environmental pressure.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and specifically relates to a preparation method of 4,6-dihydroxypyrimidine. Background Art

[0002] 4,6-Dihydroxypyrimidine is an important fine chemical raw material or organic synthesis intermediate. It has a wide range of uses in medicine, pesticides and fungicides. For example, it is used as an intermediate in the production of sulfonamide drugs sulfamoxifen, vitamin B4, anti-tumor drugs and auxiliary drugs in the pharmaceutical industry; it is used as an intermediate in the preparation of methoxyacrylate fungicide azoxystrobin in pesticides, etc.

[0003] There are two main approaches to prepare 4,6-dihydroxypyrimidine in the prior art: (1) using malonamide and esters (such as ethyl formate or triethyl orthoformate, etc.) as raw materials to prepare 4,6-dihydroxypyrimidine; (2) using malonate esters (such as dimethyl malonate, diethyl malonate, etc.) and formamide or formamidine hydrochloride as raw materials to prepare 4,6-dihydroxypyrimidine. The first approach has been gradually replaced by the second approach due to the problems of malonamide not being able to achieve industrial supply and high material consumption. The second approach has been widely studied and applied due to the advantages of easy commercialization of raw materials in large quantities, fast reaction, and safe and controllable process. Many literatures have reported on related research.

[0004] US6096892 reports a method for preparing 4,6-dihydroxypyrimidine using dimethyl malonate and formamide as raw materials. In this method, sodium methoxide and formamide are mixed, the mixed solution is heated to 50°C, and then dimethyl malonate is slowly added thereto. After the reaction is completed, the final product is obtained with a yield of only about 70-76.4% through the steps of dissolution, concentration, acidification, filtration, water washing and drying. Moreover, since 3.5 molar equivalents of strong base sodium methoxide relative to malonate are used in this method, when this method is applied to the continuous industrial production of 4,6-dihydroxypyrimidine, a large amount of wastewater with high salt content and high content of organic byproducts or impurities is bound to be generated. Such wastewater treatment is difficult and costly, and it is difficult to meet the current environmental protection requirements.

[0005] CN103319420A reports a method for preparing 4,6-dihydroxypyrimidine using formamidine hydrochloride, malonate and base as raw materials, wherein formamidine hydrochloride, malonate and base are added to a solvent, stirred at reflux temperature for 2-10 hours, and then neutralized with acid, desolventized, filtered, recrystallized and other steps to obtain the final product. Although the yield is as high as 90% or more as described in paragraph

[008] on page 3 of the CN103319420A specification, according to the amount of 4,6-dihydroxypyrimidine product obtained in Examples 1-4, the highest yield of 4,6-dihydroxypyrimidine is calculated based on the amount of malonate used, which is 89.2%. When this method is applied to the continuous industrial production of 4,6-dihydroxypyrimidine, the content of organic byproducts or impurities in the wastewater generated is still high, and wastewater treatment is still difficult. In the face of the increasingly high environmental protection requirements and expectations for greener chemistry in today's society and industry, such a synthesis method still has shortcomings.

[0006] Based on the existing technology, the industry is still looking forward to the development of a more efficient process for preparing 4,6-dihydroxypyrimidine, an important organic intermediate with a wide range of applications, which has small organic by-products or impurities, lower amounts of three wastes, and lower costs, and is of great significance. Summary of the invention

[0007] In view of the deficiencies in the prior art, the object of the present invention is to provide a method for preparing 4,6-dihydroxypyrimidine. The method of the present invention can prepare 4,6-dihydroxypyrimidine more efficiently, with smaller organic by-products or impurities generated, lower three wastes, and lower costs.

[0008] To achieve this object, the present invention adopts the following technical solutions:

[0009] The present invention provides a method for preparing 4,6-dihydroxypyrimidine, wherein the method comprises: reacting malonate with formamide in the presence of an alkali metal strong base using a quaternary ammonium base as a catalyst, and obtaining 4,6-dihydroxypyrimidine after the reaction is complete and post-processing. The chemical reaction formula for the preparation is as follows:

[0010]

[0011] The invention provides a method for preparing 4,6-dihydroxypyrimidine, wherein the quaternary ammonium base is any one of tetramethylammonium hydroxide, trimethylethylammonium hydroxide and trimethylbenzylammonium hydroxide or their hydrates, aqueous solutions and alcohol solutions, or a combination of any two or more thereof.

[0012] Preferably, the quaternary ammonium base is any one of tetramethylammonium hydroxide pentahydrate, trimethylethylammonium hydroxide and trimethylbenzylammonium hydroxide, or a combination of any two or more thereof.

[0013] The present invention provides a method for preparing 4,6-dihydroxypyrimidine, wherein the alkali metal strong base is an alkali metal hydroxide, an alkali metal alkoxide or an alcohol solution of an alkali metal alkoxide.

[0014] Preferably, the alkali metal strong base is an alkali metal alkoxide or an alcohol solution of an alkali metal alkoxide.

[0015] Preferably, the alkali metal strong base is sodium methoxide, sodium ethoxide, sodium methoxide alcohol solution or sodium ethoxide alcohol solution.

[0016] Preferably, the alkali metal strong base is a methanol solution of sodium methoxide or an ethanol solution of sodium ethoxide.

[0017] Preferably, the alkali metal strong base is a 20%-40% sodium methoxide / methanol solution or a 20% sodium ethoxide / ethanol solution.

[0018] The present invention provides a method for preparing 4,6-dihydroxypyrimidine, wherein the malonate is an alkyl ester.

[0019] Preferably, the malonate is dimethyl malonate or diethyl malonate.

[0020] The present invention provides a method for preparing 4,6-dihydroxypyrimidine, wherein the molar ratio of the malonate to the quaternary ammonium base catalyst is 1:0.005-0.02, such as 1:0.005, 1:0.008, 1:0.012, 1:0.015 or 1:0.020.

[0021] The present invention provides a method for preparing 4,6-dihydroxypyrimidine, wherein the molar ratio of the malonate to the formamide is

[0022] 1:2.2-1:4, for example, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.5 or 1:4, etc.

[0023] Preferably, the molar ratio of the malonate to formamide is 1:2.2-1:3.0.

[0024] The present invention provides a method for preparing 4,6-dihydroxypyrimidine, wherein the molar ratio of the malonate to the alkali metal alcoholate is 1:1.5-1:2.5;

[0025] Preferably, the molar ratio of the malonate to the alkali metal alcoholate is 1:2.0-1:2.5.

[0026] The invention provides a method for preparing 4,6-dihydroxypyrimidine. The malonate and formamide are uniformly mixed and then added into a reaction system within 45 minutes to 1 hour. During the addition process, the temperature of the reaction system is controlled at 60-70° C. and the reaction is kept warm for 1-3 hours.

[0027] The present invention provides a method for preparing 4,6-dihydroxypyrimidine, wherein the post-treatment process comprises: evaporating the solvent after the reaction is completed, adding water to dissolve the residue, acidifying to a pH of 2-3, filtering, washing with water, and drying the filter cake to obtain 4,6-dihydroxypyrimidine.

[0028] The invention provides a preparation method of 4,6-dihydroxypyrimidine. The preparation method comprises the following steps: in the presence of 20%-40% sodium methoxide / methanol solution or 20% sodium ethoxide / ethanol solution, any one of tetramethylammonium hydroxide pentahydrate, trimethylethylammonium hydroxide and trimethylbenzylammonium hydroxide or any combination of two or more thereof is used as a catalyst, malonic acid ester and formamide are uniformly mixed and then added into a reaction system within 45min-1h, the temperature of the reaction system is controlled to be 60-70°C during the addition process, the reaction is kept warm for 1-3h after the addition is completed, the solvent is evaporated after the reaction is completed, the residue is dissolved in water, acidified to a pH of 2-3, filtered, washed with water, and the filter cake is dried to obtain 4,6-dihydroxypyrimidine.

[0029] The catalyst is any one of tetramethylammonium hydroxide pentahydrate, trimethylethylammonium hydroxide and trimethylbenzylammonium hydroxide or a combination of any two or more thereof.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] 1. Using quaternary ammonium hydroxide tetramethylammonium hydroxide, trimethylethylammonium hydroxide or trimethylbenzylammonium hydroxide as a catalytic reaction improves the reaction yield, improves the utilization rate of raw materials, improves the atom economy, reduces organic by-products and impurities, and reduces the amount, difficulty and cost of organic waste treatment;

[0032] 2. The amount of alkali metal alcoholate used is reduced, and the amount of acid used for neutralization is reduced, thereby reducing the generation of saline wastewater, alleviating environmental pressure, and reducing subsequent treatment costs and the production cost of 4,6-dihydroxypyrimidine;

[0033] 3. The recovered solvent is of high purity and can be sold as a by-product or used in the production of other products that require the recovered solvent. Not only does it not generate additional waste liquid, but it can also be utilized as a resource to achieve economic benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1It is a chemical reaction formula in which malonic acid ester reacts with formamide in the presence of an alkali metal strong base and a catalyst to obtain 4,6-dihydroxypyrimidine. DETAILED DESCRIPTION

[0035] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0036] The contents mentioned below are all by mass.

[0037] Example 1

[0038] In this embodiment, 4,6-dihydroxypyrimidine is prepared by the following method, which specifically includes the following steps:

[0039] A four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer and a reflux condenser was set up, 81.03g (0.450mol) (content 30%) sodium methoxide / methanol solution and 0.43g (0.0023mol) (content 97%) tetramethylammonium hydroxide pentahydrate were weighed, stirred evenly, heated to 60°C, and a mixed solution of 30.03g (0.225mol) (content 99%) dimethyl malonate and 25.57g (0.562mol) (content 99%) formamide was added dropwise for 45min. After the addition was completed, the mixture was kept at 60°C for 3h. Then, the methanol was recovered by distillation to dryness, and the residual solid was dissolved in water, acidified with 30% hydrochloric acid at 25°C to a pH of 2.53, filtered, washed with water, and dried to obtain 24.06 g of 4,6-dihydroxypyrimidine with a content of 98.16% and a yield of 93.64% (based on dimethyl malonate). The recovered methanol was detected by gas chromatography to have a content of 98.57%.

[0040] Example 2

[0041] In this embodiment, 4,6-dihydroxypyrimidine is prepared by the following method, which specifically includes the following steps:

[0042] A four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer and a reflux condenser was set up, 81.03g (0.450mol) (content 30%) sodium methoxide / methanol solution and 0.24g (0.0013mol) (content 97%) tetramethylammonium hydroxide pentahydrate were weighed, stirred evenly, heated to 65°C, and a mixed solution of 30.03g (0.225mol) (content 99%) dimethyl malonate and 25.57g (0.562mol) (content 99%) formamide was added dropwise for 1 hour. After the addition was completed, the mixture was kept at 65°C for 2 hours. Then, the methanol was recovered by distillation to dryness, and the residual solid was dissolved in water, acidified with 30% hydrochloric acid at 23°C to a pH of 2.75, filtered, washed with water, and dried to obtain 23.88 g of 4,6-dihydroxypyrimidine with a content of 98.31% and a yield of 93.09% (calculated as dimethyl malonate). The recovered methanol was detected by gas chromatography to have a content of 98.23%.

[0043] Example 3

[0044] In this embodiment, 4,6-dihydroxypyrimidine is prepared by the following method, which specifically includes the following steps:

[0045] A four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer and a reflux condenser was set up, 60.77g (0.450mol) (content 40%) sodium methoxide / methanol solution and 0.64g (0.0034mol) (content 97%) tetramethylammonium hydroxide pentahydrate were weighed, stirred evenly, heated to 65°C, and a mixed solution of 30.03g (0.225mol) (content 99%) dimethyl malonate and 28.66g (0.630mol) (content 99%) formamide was added dropwise for 1 hour. After the addition was completed, the mixture was kept at 65°C for 2 hours. Then, the methanol was recovered by distillation to dryness, and the residual solid was dissolved in water, acidified with 30% hydrochloric acid at 25°C to a pH of 2.46, filtered, washed with water, and dried to obtain 24.16 g of 4,6-dihydroxypyrimidine with a content of 98.20% and a yield of 94.07% (based on dimethyl malonate). The recovered methanol was detected by gas chromatography to have a content of 98.61%.

[0046] Example 4

[0047] A four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer and a reflux condenser was set up, 153.11g (0.450mol) (content 20%) sodium ethoxide / ethanol solution, 0.43g (0.0023mol) (content 97%) tetramethylammonium hydroxide pentahydrate were weighed, stirred evenly, heated to 65°C, and a mixed solution of 36.40g (0.225mol) (content 99%) diethyl malonate and 25.57g (0.562mol) (content 99%) formamide was added dropwise for 1 hour. After the addition was completed, the mixture was kept at 65°C for 2 hours. Then, the mixture was distilled to dryness to recover ethanol, and the residual solid was dissolved in water, acidified with 30% hydrochloric acid at 26°C to a pH of 2.59, filtered, washed with water, and dried to obtain 23.43 g of 4,6-dihydroxypyrimidine with a content of 98.24% and a yield of 91.27% (based on diethyl malonate). The recovered ethanol content was 97.85% as determined by gas chromatography.

[0048] Example 5

[0049] In this embodiment, 4,6-dihydroxypyrimidine is prepared by the following method, which specifically includes the following steps:

[0050] A four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer and a reflux condenser was set up, 60.77g (0.450mol) (content 40%) sodium methoxide / methanol solution and 0.13g (0.0012mol) (content 97%) trimethylethylammonium hydroxide were weighed, stirred evenly, heated to 65°C, and a mixed solution of 30.03g (0.225mol) (content 99%) dimethyl malonate and 28.66g (0.630mol) (content 99%) formamide was added dropwise for 1 hour. After the addition was completed, the mixture was kept at 70°C for 1 hour. Then, the methanol was recovered by distillation to dryness, and the residual solid was dissolved in water, acidified with 30% hydrochloric acid at 25°C to a pH of 2.57, filtered, washed with water, and dried to obtain 23.88 g of 4,6-dihydroxypyrimidine with a content of 98.06% and a yield of 92.85% (based on dimethyl malonate). The recovered methanol was detected by gas chromatography to have a content of 98.34%.

[0051] Example 6

[0052] In this embodiment, 4,6-dihydroxypyrimidine is prepared by the following method, which specifically includes the following steps:

[0053] A four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer and a reflux condenser was set up, 60.77g (0.450mol) (content 40%) sodium methoxide / methanol solution and 0.76g (0.0045mol) (content 99%) trimethylbenzylammonium hydroxide were weighed, stirred evenly, heated to 65°C, and a mixed solution of 30.03g (0.225mol) (content 99%) dimethyl malonate and 28.66g (0.630mol) (content 99%) formamide was added dropwise for 1 hour. After the addition was completed, the mixture was kept at 65°C for 2 hours. Then, the methanol was recovered by distillation to dryness, and the residual solid was dissolved in water, acidified with 30% hydrochloric acid at 25°C to a pH of 2.60, filtered, washed with water, and dried to obtain 24.40 g of 4,6-dihydroxypyrimidine with a content of 98.38% and a yield of 95.18% (based on dimethyl malonate). The recovered methanol was detected by gas chromatography to have a content of 97.78%.

[0054] The methanol content recovered in the above Examples 1-3 and 5-6 is relatively high, and can be directly sold as a by-product or used in the production of other products of the applicant that require the use of methanol. The ethanol content recovered in the above Example 4 is relatively high, and can be directly sold as a by-product or used in the production of other products of the applicant that require the use of ethanol.

[0055] Comparative Example 1

[0056] In this comparative example, 4,6-dihydroxypyrimidine was prepared by the following method, which specifically includes the following steps:

[0057] A four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer and a reflux condenser was built, 101.20g (0.562mol) (content 30%) sodium methoxide / methanol solution was weighed, the temperature was raised to 60°C, and a mixture of 30.03g (0.225mol) (content 99%) dimethyl malonate and 40.90g (0.899mol) (content 99%) formamide was added dropwise, and the addition time was 50min. After the addition was completed, the mixture was kept at 60°C for 3h. Methanol was then distilled to dryness to recover the methanol, and the residual solid was dissolved in water, acidified with 30% hydrochloric acid at 23°C to a pH of 2.62, filtered, washed with water, and dried to obtain 18.87g of 4,6-dihydroxypyrimidine, with a content of 98.05% and a yield of 73.36% (in terms of dimethyl malonate). The methanol content was recovered to 98.31%.

[0058] This example shows that when no quaternary ammonium base is used, even if the amount of formamide is increased, the yield can only be increased slightly, and a satisfactory yield cannot be achieved.

[0059] Comparative Example 2

[0060] In this comparative example, 4,6-dihydroxypyrimidine was prepared by the following method, which specifically includes the following steps:

[0061] A four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer and a reflux condenser was set up, 145.85g (0.810mol) (content 30%) sodium methoxide / methanol solution was weighed, the temperature was raised to 65°C, and a mixture of 30.03g (0.225mol) (content 99%) dimethyl malonate and 40.90g (0.899mol) (content 99%) formamide was added dropwise, and the addition time was 1h. After the addition was completed, the mixture was kept at 65°C for 2h. Methanol was then distilled to dryness to recover the methanol, and the residual solid was dissolved in water, acidified with 30% hydrochloric acid to a pH of 2.58 at 24°C, filtered, washed with water, and dried to obtain 21.13g of 4,6-dihydroxypyrimidine, with a content of 98.19% and a yield of 82.27% (in terms of dimethyl malonate). The methanol content was recovered to 98.49%.

[0062] This embodiment shows that in the absence of quaternary ammonium base, even if the dosage of formamide and sodium methoxide is increased at the same time, the yield can only be improved slightly, and more waste salt will be produced, and the overall economic benefit is poor.

[0063] The applicant declares that the present invention illustrates the preparation method of 4,6-dihydroxypyrimidine of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing 4,6-dihydroxypyrimidine, characterized in that: In the presence of an alkali metal strong base, using a quaternary ammonium base as a catalyst, malonate and formamide are reacted, and after the reaction is completed and post-processed, 4,6-dihydroxypyrimidine is obtained; The alkali metal strong base is an alkali metal hydroxide, an alkali metal alkoxide or an alcohol solution of an alkali metal alkoxide; the quaternary ammonium base is any one of tetramethylammonium hydroxide, trimethylethylammonium hydroxide and trimethylbenzylammonium hydroxide or their hydrates, aqueous solutions and alcohol solutions or a combination of any two or more thereof.

2. The method for preparing 4,6-dihydroxypyrimidine according to claim 1, characterized in that: The quaternary ammonium base is any one of tetramethylammonium hydroxide pentahydrate, trimethylethylammonium hydroxide and trimethylbenzylammonium hydroxide, or a combination of any two or more thereof.

3. The method for preparing 4,6-dihydroxypyrimidine according to claim 1, characterized in that: The alkali metal strong base is an alkali metal alkoxide or an alcohol solution of an alkali metal alkoxide.

4. The method for preparing 4,6-dihydroxypyrimidine according to claim 1, characterized in that: The alkali metal strong base is sodium methoxide, sodium ethoxide, sodium methoxide alcohol solution or sodium ethoxide alcohol solution.

5. The method for preparing 4,6-dihydroxypyrimidine according to claim 1, characterized in that: The alkali metal strong base is a methanol solution of sodium methoxide or an ethanol solution of sodium ethoxide.

6. The method for preparing 4,6-dihydroxypyrimidine according to claim 1, characterized in that: The alkali metal strong base is a 20%-40% sodium methoxide / methanol solution or a 20% sodium ethoxide / ethanol solution.

7. A method for preparing 4,6-dihydroxypyrimidine according to any one of claims 1 to 6, characterized in that: The malonate ester is an alkyl ester.

8. The method for preparing 4,6-dihydroxypyrimidine according to claim 7, characterized in that: The malonate is dimethyl malonate or diethyl malonate.

9. A method for preparing 4,6-dihydroxypyrimidine according to any one of claims 1 to 6, characterized in that: The molar ratio of the malonate to the quaternary ammonium base catalyst is 1:0.005-0.

02.

10. A method for preparing 4,6-dihydroxypyrimidine according to any one of claims 1 to 6, characterized in that: The molar ratio of the malonate to formamide is 1:2.2-1:

4.

11. The method for preparing 4,6-dihydroxypyrimidine according to claim 10, characterized in that: The molar ratio of the malonate to formamide is 1:2.2-1:3.

0.

12. A method for preparing 4,6-dihydroxypyrimidine according to any one of claims 1 to 6, characterized in that: The molar ratio of the malonate to the alkali metal alcoholate is 1:1.5-1:2.

5.

13. The method for preparing 4,6-dihydroxypyrimidine according to claim 12, characterized in that: The molar ratio of the malonate to the alkali metal alcoholate is 1:2.0-1:2.

5.

14. A method for preparing 4,6-dihydroxypyrimidine according to any one of claims 1 to 6, characterized in that: The malonate and formamide are mixed evenly and then added to the reaction system within 45 minutes to 1 hour. During the addition process, the temperature of the reaction system is controlled at 60-70° C. After the addition, the reaction is kept warm for 1-3 hours.

15. A method for preparing 4,6-dihydroxypyrimidine according to any one of claims 1 to 6, characterized in that: The post-treatment process is as follows: after the reaction is completed, the solvent is evaporated to dryness, the residue is dissolved in water, acidified to a pH of 2-3, filtered, washed with water, and the filter cake is dried to obtain 4,6-dihydroxypyrimidine.

16. A method for preparing 4,6-dihydroxypyrimidine according to any one of claims 1 to 6, characterized in that: In the presence of 20%-40% sodium methoxide / methanol solution or 20% sodium ethoxide / ethanol solution, any one of tetramethylammonium hydroxide pentahydrate, trimethylethylammonium hydroxide and trimethylbenzylammonium hydroxide or any combination of two or more thereof is used as a catalyst, malonate and formamide are uniformly mixed and then added to the reaction system within 45min-1h, the temperature of the reaction system is controlled at 60-70°C during the addition process, and the reaction is kept warm for 1-3h. After the reaction is completed, the solvent is evaporated, the residue is dissolved in water, acidified to a pH of 2-3, filtered, washed with water, and the filter cake is dried to obtain 4,6-dihydroxypyrimidine.

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