A process for the preparation of 4,6-dichloropyrimidine

Abstract

The application discloses a preparation method of 4,6-dichloropyrimidine, and belongs to the field of organic synthesis. The preparation method is as follows: 4-chloro-6-methoxypyrimidine is mixed with DMF in the presence of an organic solvent or without solvent, a chlorinating reagent is added dropwise under certain temperature conditions, and then incubation reaction is carried out, and then 4,6-dichloropyrimidine is obtained through post-treatment. The preparation method is simple in operation, mild in conditions and simple in post-treatment, and 4,6-dichloropyrimidine can be prepared without using phosphorus-containing reagents and the toxic reagents phosgene or triphosgene.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more specifically, to a method for preparing 4,6-dichloropyrimidine. Background Technology

[0002] 4,6-Dichloropyrimidine is an important pesticide and pharmaceutical intermediate with wide applications. It can be used to synthesize various pesticides and pharmaceutical products such as azoxystrobin, fluopyram, sulfamethoxypyrimidine, or sulfamethoxypyrimidine. 4-Chloro-6-methoxypyrimidine is one of the byproducts in the synthesis of azoxystrobin from 4,6-dichloropyrimidine and needs to be effectively recovered; otherwise, it will lead to resource waste and environmental pollution.

[0003] Numerous methods for preparing 4,6-dichloropyrimidine from 4-chloro-6-methoxypyrimidine have been reported in the literature. For example, German patent document DE19938500A1, filed August 13, 1993, discloses a method for preparing 4,6-dichloropyrimidine from 4-chloro-6-methoxypyrimidine in the presence of triphenylphosphine, thionyl chloride, or sulfur chloride; German patent document DE19935322A1, filed July 28, 1993, discloses a method for preparing 4,6-dichloropyrimidine from 4-chloro-6-methoxypyrimidine using a mixed solvent of 5 times its weight of DMF (N,N-didimethylformamide) and xylene, and phosgene as the acylation agent; and patent document DE1, filed June 26, 1992, discloses a method for preparing 4,6-dichloropyrimidine from 4-chloro-6-methoxypyrimidine. German patent document 9929350A1 discloses a method for preparing 4,6-dichloropyrimidine from 4-chloro-6-methoxypyrimidine by passing hydrogen chloride gas in the presence of a large amount of phosphorus trichloride. International patent application document WO2002000628, filed on June 13, 2002, discloses a method for synthesizing 4,6-dichloropyrimidine from 4-chloro-6-methoxypyrimidine as the main raw material, phosgene as the chlorinating agent, and xylene as the solvent in the presence of a tertiary amine. Chinese patent document CN2013100302632, filed on January 28, 2013, discloses a method for preparing 4,6-dichloropyrimidine from inorganic amines using phosphorus oxychloride as the chlorinating agent.

[0004] Although the aforementioned literature demonstrates the preparation of 4,6-dichloropyrimidine from 4-chloro-6-methoxypyrimidine, the preparation process often involves phosphorus-containing reagents such as phosphorus oxychloride and triphenylphosphine, or the use of highly toxic phosgene as a chlorinating agent. The presence of phosphorus-containing reagents frequently complicates wastewater treatment, leading to excessive phosphorus levels in effluent. Furthermore, the use of highly toxic phosgene poses significant safety risks and can easily cause safety hazards during the preparation process.

[0005] Therefore, there is a need to provide an environmentally friendly and safe process for preparing 4,6-dichloropyrimidine from 4-chloro-6-methoxypyrimidine. Summary of the Invention

[0006] In view of the problems existing in the prior art, the purpose of the present invention is to provide a method for preparing 4,6-dichloropyrimidine, which can be prepared by adding a chlorinating agent to 4-chloro-6-methoxypyrimidine as a raw material in the presence of DMF.

[0007] To solve the above problems, the present invention adopts the following technical solution.

[0008] A method for preparing 4,6-dichloropyrimidine includes reacting 4-chloro-6-methoxypyrimidine with a chlorinating agent in the presence of N,N-dimethylformamide, followed by post-treatment to obtain 4,6-dichloropyrimidine.

[0009] Furthermore, the chlorination reagent does not include phosphorus-containing reagents, phosgene, and triphosgene.

[0010] Further, the molar ratio of N,N-dimethylformamide (DMF) to 4-chloro-6-methoxypyrimidine is 0.01 to 0.6:1. Further, the molar ratio of N,N-dimethylformamide (DMF) to 4-chloro-6-methoxypyrimidine is preferably 0.1 to 0.4:1.

[0011] Furthermore, the reaction is carried out in the absence of a solvent or in the presence of an organic solvent; the organic solvent is one or a mixture of two or more of chlorobenzene, dichloromethane, chloroform, tetrachloroethylene, nitrobenzene, dichloroethane, and dimethyl sulfoxide.

[0012] Furthermore, the chlorinating agent is one or a mixture of two or more of sulfonyl chloride, acetyl chloride, hydrogen chloride, thionyl chloride, and oxalyl chloride.

[0013] Furthermore, the chlorinating agent is preferably one of thionyl chloride and oxalyl chloride.

[0014] Furthermore, the reaction is carried out in the presence of a solvent-free environment or an organic solvent; the post-treatment method is as follows: when the reaction is carried out in the presence of an organic solvent, the reaction solution containing the organic solvent is desolventized and then added to water to precipitate the solid, filtered, and dried; when the reaction is carried out in the absence of a solvent, the reaction solution without a solvent is directly mixed with water to precipitate the solid, filtered, and dried.

[0015] Furthermore, the 4-chloro-6-methoxypyrimidine is a pure substance or a mixture containing impurities, the impurity content being 0-20%.

[0016] Furthermore, the molar ratio of the chlorinating agent to 4-chloro-6-methoxypyrimidine is 1 to 5:1.

[0017] Furthermore, the reaction temperature is 50–90°C.

[0018] Specifically, a method for preparing 4,6-dichloropyrimidine includes adding N,N-dimethylformamide (DMF) to 4-chloro-6-methoxypyrimidine in the presence of an organic solvent or in the absence of a solvent, heating the mixture to 50–90°C, then adding a chlorinating agent dropwise, maintaining the reaction temperature, and finally obtaining 4,6-dichloropyrimidine after post-treatment; the equation for this reaction is shown below:

[0019]

[0020] Furthermore, the reaction temperature of the heat preservation reaction is 50-90℃, preferably 70-85℃, and after the temperature is optimized, the reaction time is 5-10h.

[0021] Compared with the prior art, the advantages of this invention are:

[0022] I. This method is simple to operate, operates under mild conditions, and requires simple post-processing. It does not use phosphorus-containing reagents or highly toxic reagents such as phosgene or triphosgene.

[0023] II. In the presence of DMF, 4-chloro-6-methoxypyrimidine can react with other chlorinating reagents other than phosphorus-containing reagents such as phosgene, triphosgene, and phosphorus oxychloride to complete the substitution of the methoxy group in 4-chloro-6-methoxypyrimidine. Moreover, compared with the existing technology, less DMF is used, resulting in lower cost. Detailed Implementation

[0024] Note: DMF, oxaloyl chloride, and thionyl chloride are all commercially available reagents. Unless otherwise specified, the content is calculated as 99%.

[0025] Example 1:

[0026] In a 1000 mL reaction flask, 152.1 g (1.0 mol) of recovered 4-chloro-6-methoxypyrimidine (95% purity) and 14.8 g (0.2 mol) of DMF were added. The mixture was heated to approximately 75 °C, and 180.3 g (1.5 mol) of thionyl chloride was added dropwise. The mixture was kept at this temperature for 5 hours. A sample was taken for analysis. The reaction was considered acceptable when the content of 4-chloro-6-methoxypyrimidine was less than 0.5%. The reaction solution was then added to 400 mL of water under stirring, causing a solid to precipitate. This solid was filtered, dried, and yielded 142.9 g of 4,6-dichloropyrimidine, with a quantitative purity of 98%.

[0027] Example 2:

[0028] In a 1000 mL reaction flask, add 152.1 g (1.0 mol) of recycled 4-chloro-6-methoxypyrimidine with a purity of 95%, 300 mL of dichloroethane, and 22.1 g (0.3 mol) of DMF. Heat up to about 75 °C and dropwise add 180.3 g (1.5 mol) of thionyl chloride. Then heat under reflux for 5 h and take a sample for analysis. When the content of 4-chloro-6-methoxypyrimidine is less than 0.5%, it is qualified. After qualification, remove the solvent under reduced pressure. Add the molten residue to 300 mL of stirred water to precipitate a solid. Filter and dry to obtain 138.5 g of 4,6-dichloropyrimidine with a quantitative content of 98.3%.

[0029] Example 3:

[0030] In a 1000 mL reaction flask, add 152.1 g (1.0 mol) of recycled 4-chloro-6-methoxypyrimidine with a purity of 95%, 300 mL of dichloroethane, and 7.4 g (0.1 mol) of DMF. Heat up to about 60 °C and dropwise add 192.3 g (1.5 mol) of oxalyl chloride. After the addition, heat to reflux for 7 h and take a sample for analysis. When the content of 4-chloro-6-methoxypyrimidine is less than 0.5%, it is qualified. After qualification, remove the solvent under reduced pressure. Add the molten residue to 300 mL of stirred water to precipitate a solid. Filter and dry to obtain 143.3 g of 4,6-dichloropyrimidine with a quantitative content of 98.1%.

[0031] Example 4:

[0032] In a 1000 mL reaction flask, add 152.1 g (1.0 mol) of 4-chloro-6-methoxypyrimidine with a purity of 95% and 44.3 g (0.6 mol) of DMF. Heat up to about 60 °C and dropwise add 180.3 g (1.5 mol) of thionyl chloride. After the addition, heat to about 70 °C and hold for 5 h and take a sample for analysis. When the content of 4-chloro-6-methoxypyrimidine is less than 0.5%, it is qualified. Add 600 mL of water under stirring to precipitate a solid. Filter and dry to obtain 134 g of 4,6-dichloropyrimidine with a quantitative content of 97.7%.

[0033] Example 5:

[0034] In a 1000 mL reaction flask, add 152.1 g (1.0 mol) of 4-chloro-6-methoxypyrimidine with a purity of 95% and 0.74 g (0.01 mol) of DMF. Heat up to about 70 °C and dropwise add 180.3 g (1.5 mol) of thionyl chloride. After the addition, heat to about 78 °C and hold for 10 h and take a sample for analysis. When the content of 4-chloro-6-methoxypyrimidine is less than 1.5%, it is qualified. Add it to 300 mL of stirred water to precipitate a solid. Filter and dry to obtain 133 g of 4,6-dichloropyrimidine with a quantitative content of 95.5%.

[0035] Example 6:

[0036] In a 1000 mL reaction flask, 152.1 g (1.0 mol) of 4-chloro-6-methoxypyrimidine with a purity of 95% and 74.1 g (1.0 mol) of DMF were added. The temperature was raised to about 60 °C, and 180.3 g (1.5 mol) of thionyl chloride was added dropwise. After the addition, the temperature was raised to about 70 °C and kept warm for 5 h. Sampling and analysis were carried out. When the content of 4-chloro-6-methoxypyrimidine was less than 0.5%, it was qualified. 600 mL of water was added under stirring, and a solid was precipitated. After filtration and drying, 126 g of 4,6-dichloropyrimidine was obtained, and the quantitative content was 95.8%.

[0037] Comparative Example 1:

[0038] In a 1000 mL reaction flask, 152.1 g (1.0 mol) of 4-chloro-6-methoxypyrimidine with a content of 95% was added. The temperature was raised to 60 °C, and 180.3 g (1.5 mol) of thionyl chloride was added dropwise. After the addition, the temperature was raised to 75 °C and kept warm for 5 h. Sampling and analysis were carried out, and 4,6-dichloropyrimidine was not detected.

[0039] It can be seen from Examples 1 - 6 and Comparative Example 1 that the phosphorus-free chlorinating reagent used in the present invention can react with 4-chloro-6-methoxypyrimidine under the participation of DMF (N,N-dimethylformamide) to generate 4,6-dichloropyrimidine. Moreover, the 4,6-dichloropyrimidine obtained by this method not only has a relatively high purity but also a considerable yield.

Claims

1. A method for preparing 4,6-dichloropyrimidine, characterized in that: In the presence of N,N-dimethylformamide, 4-chloro-6-methoxypyrimidine reacts with a chlorinating agent, followed by post-treatment to obtain 4,6-dichloropyrimidine; the chlorinating agent is one of thionyl chloride and oxalyl chloride; the molar ratio of N,N-dimethylformamide to 4-chloro-6-methoxypyrimidine is 0.1~0.4:1; the molar ratio of the chlorinating agent to 4-chloro-6-methoxypyrimidine is 1~5:1; the reaction temperature is 50~90℃; the reaction can occur in the presence of either no solvent or an organic solvent; the post-treatment method is as follows: when reacting in the presence of an organic solvent, the reaction solution containing the organic solvent is desolventized, then added to water to precipitate the solid, filtered, and dried; when reacting in the absence of a solvent, the solvent-free reaction solution is directly mixed with water to precipitate the solid, filtered, and dried.

2. The method for preparing 4,6-dichloropyrimidine according to claim 1, characterized in that: The reaction is carried out in the absence of a solvent or in the presence of an organic solvent; the organic solvent is one or a mixture of two or more of chlorobenzene, dichloromethane, chloroform, tetrachloroethylene, nitrobenzene, dichloroethane and dimethyl sulfoxide.

3. The method for preparing 4,6-dichloropyrimidine according to claim 1, characterized in that: The 4-chloro-6-methoxypyrimidine is a pure substance or a mixture containing impurities, wherein the impurity content is 0-20%.

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