Preparation method of 4, 5, 6-trichloropyrimidine

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 4, 5, 6-trichloropyrimidine, which comprises the following steps: reacting 4, 6-dihydroxypyrimidine with a chlorination reagent in the presence of a catalyst and a solvent to obtain 4, 6-dihydroxy-5-chloropyrimidine; the preparation method comprises the following steps: reacting 4, 6-dihydroxy-5-chloropyrimidine with phosphorus oxychloride to obtain 4, 5, 6-trichloropyrimidine; wherein the catalyst is Lewis acid; the solvent is one or more of carbon tetrachloride, carbon disulfide and phosphorus oxychloride; the chlorination reagent is chlorine or phosphorus pentachloride. The chlorination reagent is low in price, the preparation method is easy to operate, the cost is low, the atom utilization rate is high, the product yield and purity are high, reaction tail gas is single hydrogen chloride gas and is convenient to recycle, organic alkali and organic reagents are not used in the technological process, and the method is environmentally friendly and has good industrialization prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing 4,5,6-trichloropyrimidine. Background Art

[0002] Pyrimidine compounds are a class of nitrogen-containing heterocyclic compounds. Due to their special structure, pyrimidine compounds have certain antifungal and plant growth regulating effects and are widely used in the preparation of pesticides such as insecticides, fungicides and herbicides. At the same time, as a very important class of endogenous biological substances, pyrimidine compounds are widely used in the synthesis of anti-tumor drugs, anti-cancer drugs, anti-AIDS drugs and antifungal drugs in the medical field.

[0003] As an important intermediate of pyrimidine compounds, 4,5,6-trichloropyrimidine has attracted extensive attention from researchers in the fields of medicine and pesticides.

[0004] The existing literature (Journal of the Chemical Society, 1955, p.3478, 3481) reports a method for preparing 4,5,6-trichloropyrimidine, which uses 4,6-dihydroxypyrimidine as a raw material and iodine chloride as a chlorination reagent to first prepare 4,6-dihydroxy-5-chloropyrimidine, and then reacts under the conditions of phosphorus oxychloride and an organic base to obtain 4,5,6-trichloropyrimidine. This method uses iodine chloride as a chlorination reagent, and the yield is low, and the total yield of the two steps is only 40%.

[0005] CN101646657A discloses a method for preparing 4,5,6-trichloropyrimidine, which uses 4,6-dihydroxypyrimidine as a raw material, sulfonyl chloride and phosphorus oxychloride as chlorination reagents, and chlorobenzene as a solvent to prepare 4,5,6-trichloropyrimidine in the presence of an organic base. However, in the method, sulfur dioxide and hydrogen chloride generated after chlorination of sulfonyl chloride are difficult to separate, and the recovery of organic bases and solvents in the post-treatment process is relatively troublesome, making it difficult to achieve industrial production.

[0006] CN102250016A discloses a method for preparing 4,5,6-trichloropyrimidine, which uses 4,6-dihydroxypyrimidine as a raw material, first brominates to generate 4,6-dihydroxy-5-bromopyrimidine, and then further reacts with phosphorus oxychloride and a phase transfer catalyst to generate 4,5,6-trichloropyrimidine. In this method, the raw material is first brominated and then chlorinated, the atomic utilization rate is low, and a large amount of acidic wastewater is generated in the post-treatment process, which is difficult to realize resource recovery.

[0007] CN111440123A discloses a method for synthesizing 4,5,6-trichloropyrimidine, which uses diethyl malonate as a raw material, first chlorinates with chlorosuccinimide to generate diethyl 2-chloromalonate, then reacts with formamidine hydrochloride and sodium methoxide to prepare 4,6-dihydroxy-5-chloropyrimidine, and finally prepares 4,5,6-trichloropyrimidine under the action of phosphorus oxychloride and an organic base. The method has a long operation process, the chlorination reagent chlorosuccinimide used is expensive, and the economic value of the entire method is low. Summary of the invention

[0008] Problem that the invention aims to solve

[0009] In view of the problems existing in the above-mentioned prior art, the purpose of the present invention is to provide a method for preparing 4,5,6-trichloropyrimidine with simple operation, low cost, high yield and purity. At the same time, the post-treatment process of the preparation method does not involve the treatment of organic bases and organic solvents and the discharge of wastewater, which is truly green, economical and environmentally friendly, and has strong market competitiveness.

[0010] Solutions for solving problems

[0011] In order to solve the above problems, the present invention provides a method for preparing 4,5,6-trichloropyrimidine, which comprises the following steps:

[0012]

[0013] Step (1): in the presence of a catalyst and a solvent, 4,6-dihydroxypyrimidine reacts with a chlorination agent to obtain 4,6-dihydroxy-5-chloropyrimidine;

[0014] Step (2): reacting the 4,6-dihydroxy-5-chloropyrimidine obtained in step (1) with phosphorus oxychloride to obtain 4,5,6-trichloropyrimidine;

[0015] Wherein, the catalyst is Lewis acid; the solvent is one or more of carbon tetrachloride, carbon disulfide and phosphorus oxychloride; and the chlorination agent is chlorine or phosphorus pentachloride.

[0016] Preferably, no organic base is used in the reaction in step (2).

[0017] Preferably, the Lewis acid is a metal halide; more preferably, the Lewis acid is one or more of the halides of Fe, Al, Sn, Zn and Mg, preferably one or more of FeCl3, AlCl3, SnCl4, ZnCl2 and MgCl2, further preferably one or more of FeCl3, AlCl3 and SnCl4, most preferably SnCl4.

[0018] Preferably, the solvent is one or more of carbon tetrachloride and phosphorus oxychloride, preferably phosphorus oxychloride.

[0019] Preferably, the reaction temperature in step (1) is 20-100°C, preferably 30-70°C, more preferably 40-60°C.

[0020] Preferably, the reaction temperature in step (2) is 60-100°C, preferably 70-100°C, more preferably 80-90°C.

[0021] Preferably, the mass of the catalyst in step (1) is 0.01%-5%, preferably 0.05%-2%, of the mass of the 4,6-dihydroxypyrimidine.

[0022] Preferably, the molar ratio of the chlorination reagent to the 4,6-dihydroxypyrimidine in step (1) is (0.8-3):1, preferably (1-3):1, more preferably (1-1.5):1.

[0023] Preferably, in step (1), the mass ratio of the solvent to the 4,6-dihydroxypyrimidine is (5-20):1, preferably (5-15):1.

[0024] Preferably, when the solvent in step (1) is phosphorus oxychloride, after the reaction in step (1) is completed, no post-treatment is required and step (2) can be directly performed; or

[0025] When the solvent in step (1) is one or more of carbon tetrachloride and carbon disulfide, phosphorus oxychloride is added after the reaction in step (1) to carry out step (2), wherein the molar ratio of the phosphorus oxychloride to the 4,6-dihydroxypyrimidine is not less than 2:1, preferably not less than 5:1; or

[0026] When the solvent in step (1) is one or more of carbon tetrachloride and carbon disulfide, the solvent is removed after the reaction in step (1) is completed, and phosphorus oxychloride is added to carry out step (2), wherein the mass ratio of the phosphorus oxychloride to the 4,6-dihydroxypyrimidine is (5-20):1, preferably (5-15):1; more preferably, the method for removing the solvent is distillation, preferably reduced pressure distillation.

[0027] Preferably, after the reaction in step (2) is completed, the phosphorus oxychloride is recovered by vacuum distillation, and the remaining residual liquid is distilled to obtain the 4,5,6-trichloropyrimidine.

[0028] Effects of the Invention

[0029] The present invention has the following excellent technical effects:

[0030] (1) The present invention selects cheap chlorine or phosphorus pentachloride as the chlorination reagent, and the preparation method is simple to operate and low in cost;

[0031] (2) The method for preparing 4,5,6-trichloropyrimidine of the present invention has high atomic utilization rate, high product yield and purity. The total yield of 4,5,6-trichloropyrimidine can reach more than 80%, or more than 90%, and the purity can reach more than 99%;

[0032] (3) The tail gas of the preparation method of the present invention is a single hydrogen chloride gas, which is easy to recycle. The process does not use organic bases and organic solvents. There is no need to consider the recovery of organic bases, the treatment of organic solvents and the discharge of wastewater. It is in line with the development concept of green environmental protection and has good industrial prospects. DETAILED DESCRIPTION

[0033] Various exemplary embodiments, features and aspects of the present invention will be described in detail below. The word "exemplary" used here means "used as an example, embodiment or illustrative". Any embodiment described here as "exemplary" is not necessarily interpreted as being superior or better than other embodiments.

[0034] In addition, in order to better illustrate the present invention, numerous specific details are provided in the following specific embodiments. It should be understood by those skilled in the art that the present invention can be implemented without certain specific details. In other examples, methods, means, equipment and steps well known to those skilled in the art are not described in detail in order to highlight the subject matter of the present invention.

[0035] Unless otherwise stated, the units used in this specification are all international standard units, and the numerical values ​​and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0036] In this specification, the word "may" means both performing a certain process and not performing a certain process.

[0037] In this specification, the references to "some specific / preferred embodiments", "other specific / preferred embodiments", "embodiments", etc., mean that the specific elements (e.g., features, structures, properties and / or characteristics) described in connection with the embodiments are included in at least one embodiment described herein, and may or may not exist in other embodiments. In addition, it should be understood that the elements may be combined in various embodiments in any suitable manner.

[0038] In this specification, the numerical range expressed using "numerical value A - numerical value B" means a range including the endpoint numerical values ​​A and B.

[0039] In the present specification, "yield" refers to the yield of 4,5,6-trichloropyrimidine product, that is, the total yield of 4,5,6-trichloropyrimidine obtained by reacting 4,6-dihydroxypyrimidine.

[0040] In this specification, "purity" refers to the purity of the 4,5,6-trichloropyrimidine product; in a specific embodiment, the HPLC content of the 4,5,6-trichloropyrimidine product is the purity of the 4,5,6-trichloropyrimidine product.

[0041] In the prior art, the currently widely used 4,5,6-trichloropyrimidine preparation schemes all use 4,6-dihydroxypyrimidine as a raw material, iodine chloride or sulfonyl chloride as a chlorination reagent, or adopt a method of first bromination and then chlorination, or adopt an organic base catalytic reaction, or use an organic solvent. The chlorination reagents used in these schemes are expensive, and irrelevant elements such as iodine, bromine or sulfur are introduced into the system. The atomic utilization rate of the reaction is low, the total yield is low, and the post-treatment of the organic base and the organic solvent is cumbersome and costly, making it difficult to achieve industrial application.

[0042] In order to solve the above problems, the present invention provides an improved method for preparing 4,5,6-trichloropyrimidine, which comprises the following steps:

[0043]

[0044] Step (1): in the presence of a catalyst and a solvent, 4,6-dihydroxypyrimidine reacts with a chlorination agent to obtain 4,6-dihydroxy-5-chloropyrimidine;

[0045] Step (2): reacting the 4,6-dihydroxy-5-chloropyrimidine obtained in step (1) with phosphorus oxychloride to obtain 4,5,6-trichloropyrimidine;

[0046] Wherein, the catalyst is Lewis acid; the solvent is one or more of carbon tetrachloride, carbon disulfide and phosphorus oxychloride; and the chlorination agent is chlorine or phosphorus pentachloride.

[0047] In the present invention, the reaction in step (2) does not require the addition of an organic base.

[0048] In some embodiments, the Lewis acid is a metal halide, such as a metal chloride, a metal bromide, and the like.

[0049] In some specific embodiments, the Lewis acid is one or more of the halides (preferably chlorides) of Fe, Al, Sn, Zn and Mg. In some preferred embodiments, the Lewis acid is one or more of FeCl3, AlCl3, SnCl4, ZnCl2 and MgCl2, more preferably one or more of FeCl3, AlCl3 and SnCl4, further preferably SnCl4.

[0050] Different from the use of organic bases or phase transfer catalysts in the prior art, the present invention uses Lewis acid as a catalyst. Experimental verification shows that the Lewis acid of the present invention can efficiently catalyze the chlorination reaction of 4,6-dihydroxypyrimidine.

[0051] Chlorine (or phosphorus pentachloride) reacts with 4,6-dihydroxypyrimidine in the presence of a Lewis acid catalyst to generate 4,6-dihydroxy-5-chloropyrimidine and hydrogen chloride (chlorination of phosphorus pentachloride produces one molecule of phosphorus trichloride); 4,6-dihydroxy-5-chloropyrimidine and phosphorus oxychloride generate a dichlorophosphate intermediate, and the chloride ion attacks the pyrimidine ring to generate 4-hydroxy-5,6-dichloropyrimidine. 4-hydroxy-5,6-dichloropyrimidine and phosphorus oxychloride repeat the above process to finally generate the chlorinated product 4,5,6-trichloropyrimidine.

[0052] The reaction in the preparation method of the present invention uses a one-pot process, the Lewis acid added in the first step reaction continues to participate in the second step reaction without separation, and the same Lewis acid is used in both the first step and the second step. The catalyst in the second step is mainly used to increase the concentration of chloride ions in the system, thereby improving the ability of chloride ions to attack the pyrimidine ring. This step can be achieved without adding a catalyst (i.e., hydrogen chloride provides chloride ions), and adding a catalyst can improve the reaction efficiency (i.e., both metal chloride and hydrogen chloride can provide chloride ions).

[0053] In some embodiments, the solvent is one or more of carbon tetrachloride and phosphorus oxychloride, preferably phosphorus oxychloride.

[0054] In some embodiments, the reaction temperature in step (1) is 20-100°C, preferably 30-70°C, more preferably 40-60°C, for example 25°C, 35°C, 45°C, 50°C, 55°C, 65°C, 75°C, etc.

[0055] In some embodiments, the reaction temperature in step (2) is 60-100°C, preferably 70-100°C, more preferably 80-90°C, such as 65°C, 75°C, 85°C, 95°C, etc.

[0056] In some embodiments, the mass of the catalyst in step (1) is 0.01%-5%, preferably 0.05%-2%, such as 0.08%, 1%, 1.1%, 1.2%, 1.5%, 3%, etc., of the mass of the 4,6-dihydroxypyrimidine.

[0057] In some embodiments, the molar ratio of the chlorination reagent and the 4,6-dihydroxypyrimidine in step (1) is (0.8-3):1, preferably (1-3):1, more preferably (1-1.5):1, for example 0.9:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, etc.

[0058] In some embodiments, the mass ratio of the solvent to the 4,6-dihydroxypyrimidine in step (1) is (5-20):1, preferably (5-15):1, for example 6:1, 8:1, 10:1, 12:1, 14:1, 16:1, 18:1, etc.

[0059] In some embodiments, if the solvent in step (1) is phosphorus oxychloride, the reaction in step (1) can be directly carried out to step (2) without post-treatment, that is, the phosphorus oxychloride in step (1) can be used as the chlorination agent and solvent in step (2).

[0060] In other embodiments, if the solvent in step (1) is one or more of carbon tetrachloride and carbon disulfide, after the reaction in step (1) is completed, the solvent may not be removed and phosphorus oxychloride may be directly added to carry out the reaction in step (2); or the solvent may be removed and phosphorus oxychloride may be added to carry out the reaction in step (2). In some specific embodiments, when the solvent is not removed, the molar ratio of the amount of phosphorus oxychloride added to the 4,6-dihydroxypyrimidine is not less than 2:1, preferably not less than 5:1, such as 5:1, 6:1, 8:1, 10:1, 20:1, etc. In some specific embodiments, when the solvent is removed, the mass ratio of the amount of phosphorus oxychloride added to the 4,6-dihydroxypyrimidine is (5-20):1, preferably (5-15):1, such as 6:1, 8:1, 10:1, 12:1, 14:1, 16:1, 18:1, etc. In some more specific embodiments, the method for removing the solvent may be distillation, such as reduced pressure distillation.

[0061] In some embodiments, after the reaction in step (2) is completed, the phosphorus oxychloride is recovered by vacuum distillation, and the remaining residual liquid is distilled to obtain the product 4,5,6-trichloropyrimidine. In some specific embodiments, when the remaining residual liquid is distilled, the distillation pressure is -0.05MPa to -0.2MPa, preferably -0.08MPa to -0.15MPa, such as -0.09MPa, -0.1MPa, -0.12MPa, etc.; the distillation temperature is 100-140°C, preferably 110-130°C, such as 105°C, 115°C, 125°C, 135°C, etc.

[0062] In the present invention, the reaction tail gas is relatively simple, which is hydrogen chloride gas. In some embodiments, the reaction tail gas needs to be washed with water, which can remove a small amount of residual phosphorus oxychloride vapor. After the reaction tail gas is treated, it can be used to prepare industrial hydrochloric acid, further improving the economic efficiency of the preparation method of the present invention.

[0063] Example

[0064] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0065] Example 1

[0066] Add 22.4g 4,6-dihydroxypyrimidine (0.2mol) and 200g carbon tetrachloride to the reaction flask, add 0.22g anhydrous ferric chloride, stir evenly, heat to 50℃, slowly introduce 14.2g (0.2mol) of chlorine gas, the introduction time is about 2h, and the reaction is stopped when the HPLC detection of 4,6-dihydroxypyrimidine content is less than 1%. Reduced pressure distillation, recover carbon tetrachloride. Add 200g phosphorus oxychloride to the residual liquid, heat to 90℃ and stir to dissolve, keep warm and stir for 0.5h after dissolving, and the reaction is completed. Reduced pressure distillation, recover phosphorus oxychloride, and reduce pressure distillation of the residual liquid (vacuum degree is -0.092MPa, temperature is 110-130℃) to obtain 29.3g of 4,5,6-trichloropyrimidine product, HPLC detection content is 99.2%, and the yield is 80.1%. The reaction tail gas is washed with water to remove a small amount of phosphorus oxychloride vapor to obtain a single hydrogen chloride product.

[0067] Example 2

[0068] Add 22.4g 4,6-dihydroxypyrimidine (0.2mol) and 200g phosphorus oxychloride to the reaction bottle, add 0.22g anhydrous aluminum chloride, stir evenly, heat to 50℃, slowly introduce 14.2g (0.2mol) of chlorine gas, the introduction time is about 2h, and the reaction is stopped when the HPLC detection of 4,6-dihydroxypyrimidine content is less than 1%. Heat to 90℃ and stir to dissolve clearly, keep warm and stir for 0.5h after dissolving clearly, and the reaction is completed. Vacuum distillation, recover phosphorus oxychloride, and vacuum distillation of the residual liquid (vacuum degree is -0.092MPa, temperature is 110-130℃) to obtain 30.1g of 4,5,6-trichloropyrimidine product, HPLC detection content is 99.0%, and the yield is 81.9%. The reaction tail gas is washed with water to remove a small amount of phosphorus oxychloride vapor to obtain a single hydrogen chloride product.

[0069] Example 3

[0070] Add 22.4g 4,6-dihydroxypyrimidine (0.2mol) and 200g phosphorus oxychloride to the reaction bottle, add 0.22g anhydrous SnCl4, stir evenly, heat to 50℃, slowly introduce 14.2g chlorine (0.2mol), the introduction time is about 2h, and the reaction is stopped when the HPLC detection of 4,6-dihydroxypyrimidine content is less than 1%. Heat to 90℃ and stir evenly, keep warm and stir for 0.5h after dissolving, and the reaction is complete. Vacuum distillation, recover phosphorus oxychloride, and vacuum distill the residual liquid (vacuum degree is -0.092MPa, temperature is 110-130℃) to obtain 32.9g of 4,5,6-trichloropyrimidine product, HPLC detection content is 99.2%, and the yield is 89.7%. The reaction tail gas is washed with water to remove a small amount of phosphorus oxychloride vapor to obtain a single hydrogen chloride product.

[0071] Example 4

[0072] Add 22.4g 4,6-dihydroxypyrimidine (0.2mol) and 200g phosphorus oxychloride to the reaction flask, add 0.22g anhydrous SnCl4, stir evenly, heat to 50℃, add 45.8g phosphorus pentachloride (0.22mol) in batches, keep warm and stir for 0.5h, HPLC detects that the content of 4,6-dihydroxypyrimidine is less than 1%, and stop the reaction. Heat to 90℃ and stir evenly, keep warm and stir for 0.5h after dissolving, and the reaction is complete. Vacuum distillation, recover phosphorus oxychloride, and vacuum distill the residual liquid (vacuum degree is -0.092MPa, temperature is 110-130℃) to obtain 31.2g of 4,5,6-trichloropyrimidine product, HPLC detects the content of 99.3%, and the yield is 85.1%. The reaction tail gas is washed with water to remove a small amount of phosphorus oxychloride vapor to obtain a single hydrogen chloride product.

[0073] Example 5

[0074] Add 22.4g 4,6-dihydroxypyrimidine (0.2mol), 30.2g phosphorus trichloride (0.22mol) and 200g phosphorus oxychloride to the reaction bottle, add 0.22g anhydrous SnCl4, stir evenly, heat to 50℃, slowly introduce 15.6g (0.22mol) of chlorine gas, the introduction time is about 2h, keep warm and stir for 0.5h, HPLC detects that the content of 4,6-dihydroxypyrimidine is less than 1%, and stop the reaction. Heat to 90℃ and stir evenly, keep warm and stir for 0.5h after dissolving, and the reaction is complete. Reduce pressure distillation, recover phosphorus oxychloride, and reduce pressure distillation of the residual liquid (vacuum degree is -0.092MPa, temperature is 110-130℃) to obtain 33.4g of 4,5,6-trichloropyrimidine product, HPLC detects the content of 99.3%, and the yield is 90.9%. The reaction tail gas is washed with water to remove a small amount of phosphorus oxychloride vapor to obtain a single hydrogen chloride product.

[0075] Comparative Example 1

[0076] Add 22.4g 4,6-dihydroxypyrimidine (0.2mol) and 200g phosphorus oxychloride to the reaction bottle, stir evenly, heat to 50℃, add 45.8g phosphorus pentachloride (0.22mol) in batches, and keep warm and stir for 0.5h. Heat to 90℃ and stir evenly. After dissolving, keep warm and stir for 0.5h. The reaction is complete. Vacuum distillation, recover phosphorus oxychloride, and vacuum distill the residual liquid (vacuum degree is -0.092MPa, temperature is 110-130℃) to obtain 17.2g of 4,5,6-trichloropyrimidine product, HPLC detection content is 99.3%, and the yield is 47.1%.

[0077] Comparative Example 2

[0078] Add 22.4g 4,6-dihydroxypyrimidine (0.2mol) and 200g phosphorus oxychloride to the reaction bottle, stir evenly, heat to 50℃, slowly introduce chlorine (chlorine needs to be excessive), and stop the reaction when the 4,6-dihydroxypyrimidine content is less than 1% by HPLC. Heat to 90℃ and stir evenly, keep warm for 0.5h after dissolving, and the reaction is complete. Rectify under reduced pressure, recover phosphorus oxychloride, and distill the residual liquid (vacuum degree is -0.092MPa, temperature is 110-130℃) to obtain 12.1g of 4,5,6-trichloropyrimidine product, HPLC detection content is 99.1%, and the yield is 33.2%.

[0079] It should be noted that, although the technical solution of the present invention is introduced with specific examples, those skilled in the art will appreciate that the present invention should not be limited thereto.

[0080] The embodiments of the present invention have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The selection of terms used herein is intended to best explain the principles of the embodiments, practical applications, or technical improvements in the market, or to enable other persons of ordinary skill in the art to understand the embodiments disclosed herein.

Claims

1. A method for preparing 4,5,6-trichloropyrimidine, comprising the following steps: Step (1): in the presence of a catalyst and a solvent, 4,6-dihydroxypyrimidine reacts with a chlorination agent to obtain 4,6-dihydroxy-5-chloropyrimidine; Step (2): reacting the 4,6-dihydroxy-5-chloropyrimidine obtained in step (1) with phosphorus oxychloride to obtain 4,5,6-trichloropyrimidine; Wherein, the catalyst is Lewis acid; the solvent is one or more of carbon tetrachloride, carbon disulfide and phosphorus oxychloride; and the chlorination agent is chlorine or phosphorus pentachloride.

2. The preparation method according to claim 1, characterized in that: No organic base is used in the step (2).

3. The preparation method according to claim 1 or 2, characterized in that: The Lewis acid is a metal halide; preferably, the Lewis acid is one or more halides of Fe, Al, Sn, Zn and Mg, preferably one or more of FeCl3, AlCl3, SnCl4, ZnCl2 and MgCl2, more preferably one or more of FeCl3, AlCl3 and SnCl4, further preferably SnCl4.

4. The preparation method according to any one of claims 1 to 3, characterized in that The solvent is one or more of carbon tetrachloride and phosphorus oxychloride, preferably phosphorus oxychloride.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The reaction temperature in step (1) is 20-100°C, preferably 30-70°C, more preferably 40-60°C.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The reaction temperature in step (2) is 60-100°C, preferably 70-100°C, more preferably 80-90°C.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The mass of the catalyst in step (1) is 0.01%-5%, preferably 0.05%-2% of the mass of the 4,6-dihydroxypyrimidine.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The molar ratio of the chlorination reagent to the 4,6-dihydroxypyrimidine in step (1) is (0.8-3):1, preferably (1-3):1, and more preferably (1-1.5):

1.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The mass ratio of the solvent to the 4,6-dihydroxypyrimidine in step (1) is (5-20):1, preferably (5-15):

1.

10. The preparation method according to any one of claims 1 to 9, characterized in that: When the solvent in step (1) is phosphorus oxychloride, after the reaction in step (1) is completed, no post-treatment is required and step (2) can be directly performed; or When the solvent in step (1) is one or more of carbon tetrachloride and carbon disulfide, phosphorus oxychloride is added after the reaction in step (1) to carry out step (2), wherein the molar ratio of the phosphorus oxychloride to the 4,6-dihydroxypyrimidine is not less than 2:1, preferably not less than 5:1; or When the solvent in step (1) is one or more of carbon tetrachloride and carbon disulfide, the solvent is removed after the reaction in step (1) is completed, and phosphorus oxychloride is added to carry out step (2), wherein the mass ratio of the phosphorus oxychloride to the 4,6-dihydroxypyrimidine is (5-20):1, preferably (5-15):1; preferably, the method for removing the solvent is distillation, preferably reduced pressure distillation.

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