A method for preparing 4,6-dichloropyrimidine

Abstract

The present invention provides a method for preparing 4,6-dichloropyrimidine. The preparation method is as follows: An organic phosphine and 4,6-dihydroxypyrimidine are mixed and dissolved in a solvent, and thionyl chloride solution is added dropwise thereto, and 4,6-dichloropyrimidine is obtained by reaction. The present invention uses thionyl chloride instead of phosgene or solid phosgene as a chlorine source, avoiding the use of highly toxic substances, significantly reducing the danger in the reaction process, and the organic phosphine and solvent used can be reused multiple times without generating additional solid waste and liquid waste.

Description

Technical Field

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

[0002] Pyrimidine compounds have an active molecular structure and are intermediates for many pharmaceuticals and pesticides. Among them, 4,6-dichloropyrimidine has attracted much attention from scholars due to its wide applications in the pesticide and pharmaceutical industries, such as the preparation of fungicide azoxystrobin, nucleoside analogs, and bioactive drugs.

[0003] Regarding its preparation methods, there have been many reports in the literature, which can be mainly divided into two routes: one is to prepare 4,6-dichloropyrimidine using amide organic compounds such as formamide and acetamide as raw materials; the other is to prepare 4,6-dichloropyrimidine using 4,6-dihydroxypyrimidine as the raw material. For the method using formamide and acetamide as raw materials, the raw materials react in a system of organic solvents such as chlorobenzene or nitrobenzene under the action of phosgene or solid phosgene at high temperature for about 8 hours to obtain 4,6-dichloropyrimidine. This method has the obvious advantage that the starting materials are cheap and easily available, but the reaction process has high-temperature and high-pressure steps, which take a long time and are accompanied by a large amount of phosgene, posing great danger. Once a leakage accident occurs, it will cause irreparable harm. In addition, this reaction produces a large amount of by-products, which are difficult to separate from the main product. All these disadvantages have led to this synthetic method not being highly regarded. And the method of preparing 4,6-dichloropyrimidine using 4,6-dihydroxypyrimidine as the raw material has become the mainstream preparation method, and there are numerous literature reports.

[0004] US005750694A discloses a process for preparing 4,6-dichloropyrimidine. In this method, 4,6-dihydroxypyrimidine is added to an organic solvent mixed with an organic base, and then phosgene is added thereto, and the reaction is carried out at high temperature. After a reaction time ranging from 1 to 30 hours, the final product is obtained through steps such as cooling, washing with water, and purification. This method takes too long and does not have a time-cost advantage for industrial production. Moreover, it involves the cumbersome processes of recovering and reusing the organic base, as well as additional treatment of the three wastes, and is not a suitable synthetic process.

[0005] CN108341784A discloses a process for preparing 4,6-dichloropyrimidine. In this method, 4,6-dihydroxypyrimidine is mixed with a catalyst, and one or a combination of two of phosgene and triphosgene is added for reaction; after the reaction is completed, the reaction solution is separated and purified to obtain the product 4,6-dichloropyrimidine. No organic base is used in this reaction, avoiding the cumbersome process of organic base recovery and reuse. However, the catalyst used contains cobalt phthalocyanine, making the high cost of the catalyst undeniable. In addition, there is a common problem in existing methods, that is, phosgene or solid phosgene is used in many methods. With the continuous deepening of the concept of environmental protection, the use of highly toxic substances such as phosgene will be more severely restricted, and it will be more urgent to seek alternative methods. Summary of the Invention

[0006] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide a method for preparing 4,6-dichloropyrimidine, which can effectively solve the problem of great potential safety hazards in the reaction process of 4,6-dichloropyrimidine.

[0007] To achieve this purpose, the present invention adopts the following technical solutions:

[0008] On the one hand, the present invention provides a method for preparing 4,6-dichloropyrimidine, and the preparation method is as follows:

[0009] Mix an organic phosphine with 4,6-dihydroxypyrimidine and dissolve them in a solvent, and dropwise add a thionyl chloride solution thereto for reaction to obtain 4,6-dichloropyrimidine;

[0010] The structure of the organic phosphine is as follows:

[0011]

[0012] Wherein R1, R2 and R3 are independently selected from an alkyl group having 1 to 8 carbon atoms (such as C1, C2, C3, C4, C5, C6, C7 or C8), an aryl group having 5 to 12 carbon atoms (such as C5, C6, C7, C8, C9, C10, C11 or C12), an alkoxy group having 1 to 8 carbon atoms (such as C1, C2, C3, C4, C5, C6, C7 or C8) or a halogen, and R1, R2 and R3 are the same or different groups.

[0013] Preferably, the solvent is any one or a combination of at least two of aromatic solvents or halogenated hydrocarbon solvents.

[0014] Preferably, the aromatic solvents include, but are not limited to, any one or a combination of at least two of toluene, xylene, mesitylene, chlorobenzene, nitrobenzene.

[0015] Preferably, the halogenated hydrocarbon solvent includes, but is not limited to, any one or a combination of at least two of dichloromethane, chloroform, or dichloroethane.

[0016] Preferably, the molar ratio of thionyl chloride to 4,6-dihydroxypyrimidine is 2:1 - 8:1, such as 2:1, 2.5:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, etc.

[0017] Preferably, the thionyl chloride solution is a thionyl chloride solution with a content of 98%.

[0018] Preferably, the molar ratio of 4,6-dihydroxypyrimidine to organophosphine is 10:1 - 1:4, such as 10:1, 9:1, 8:1, 7:1, 5:1, 3:1, 2:1, 1:1, 1:2, 1:3, or 1:4, etc.

[0019] Preferably, the organophosphine includes any one or a combination of at least two of triphenylphosphine oxide, tri-n-octylphosphine oxide, or tributylphosphine oxide.

[0020] Preferably, the temperature of the reaction is 35 - 100 °C, such as 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 70 °C, 80 °C, 90 °C, or 100 °C, preferably 35 - 85 °C, and more preferably 35 - 60 °C.

[0021] Preferably, the reaction time is 3 - 12 h, such as 3 h, 5 h, 8 h, 10 h, or 12 h.

[0022] Preferably, the reaction ends when the mass percentage content of 4,6-dihydroxypyrimidine in the reaction solution is less than 2%; here, 2% refers to the percentage content of 4,6-dihydroxypyrimidine calculated by the area normalization method during the control analysis by liquid chromatography. When the proportion of 4,6-dihydroxypyrimidine is less than 2%, the raw materials have basically reacted completely. Here, the percentage calculation does not include the solvent and organophosphine. When the reaction system contains a solvent and organophosphine, the solvent and organophosphine are not integrated, and the reaction ends when the proportion of 4,6-dihydroxypyrimidine is less than 2%.

[0023] Preferably, after the reaction ends, separation and purification are carried out, and the method of separation and purification is distillation.

[0024] As a preferred technical solution of the present invention, the preparation method of 4,6-dichloropyrimidine specifically includes the following steps:

[0025] Dissolve an organic phosphine and 4,6-dihydroxypyrimidine in a solvent, and dropwise add thionyl chloride solution thereto, wherein the molar ratio of thionyl chloride to 4,6-dihydroxypyrimidine is 2:1 - 8:1, and the molar ratio of 4,6-dihydroxypyrimidine to the organic phosphine is 10:1 - 1:4. React at 35 - 100 °C. At this time, the mass percentage content of 4,6-dihydroxypyrimidine in the reaction solution is lower than 2%. End the reaction to obtain 4,6-dichloropyrimidine;

[0026] The structure of the organic phosphine is as follows:

[0027]

[0028] wherein R1, R2 and R3 are independently selected from alkyl groups with 1 - 8 carbon atoms, aryl groups with 5 - 12 carbon atoms, alkoxy groups with 1 - 8 carbon atoms or halogens, and R1, R2 and R3 are the same or different groups.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1. Using thionyl chloride instead of phosgene or solid phosgene as the chlorine source avoids the use of highly toxic substances, can significantly reduce the danger of the reaction process, the harmfulness of reaction accidents, and the harm to the human body; the cost of phosgene is higher than that of thionyl chloride, the transportation of phosgene is more complex, the procedures are cumbersome, and phosgene is restricted by supply. Using thionyl chloride instead of phosgene will simplify the raw material supply.

[0031] 2. The organic phosphine and solvent used in the present invention can be reused repeatedly without generating additional solid waste and waste liquid. Specific Embodiments

[0032] The technical solutions of the present invention will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments are only for helping to understand the present invention and should not be regarded as specific limitations on the present invention.

[0033] The contents involved below are all mass contents.

[0034] Example 1

[0035] In this example, 4,6-dichloropyrimidine is prepared by the following method, which specifically includes the following steps:

[0036] Set up a four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer, and a reflux condenser. Weigh 30.00 g (content 98%) of 4,6-dihydroxypyrimidine and 7.37 g (content 99%) of triphenylphosphine oxide, dissolve them in 150 mL of nitrobenzene, mix evenly, heat up to 80 °C, and dropwise add 127.40 g (content 98%) of thionyl chloride solution. The dropping time is 1 h.

[0037] After the addition of thionyl chloride solution was completed, the reaction was carried out for 12 h and then sampled for analysis. The HPLC analysis showed that the content of 4,6-dihydroxypyrimidine was 1.99% and the content of 4,6-dichloropyrimidine was 92.75% (the HPLC data here is the calculation result after removing the solvent and organic phosphine peaks). The reaction was ended, and the reaction mixture was subjected to vacuum distillation (oil bath temperature 105 °C, vacuum degree -0.095 Mpa), and the fraction at 90 - 100 °C was collected to obtain 35.34 g of 4,6-dichloropyrimidine (HPLC external standard content 98.46%), with a yield of 89.04%. The residue in the kettle was 189.73 g (4,6-dichloropyrimidine HPLC external standard content 0.26%), and the residual 4,6-dichloropyrimidine was 0.49 g, and the total conversion rate was 90.30% (calculated based on 4,6-dihydroxypyrimidine).

[0038] Example 2

[0039] In this example, 4,6-dichloropyrimidine was prepared by the following method, which specifically included the following steps:

[0040] 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. 30.00 g (content 98%) of 4,6-dihydroxypyrimidine and 14.74 g (content 99%) of triphenylphosphine oxide were weighed and dissolved in 150 mL of nitrobenzene. After mixing evenly, the temperature was raised to 85 °C, and 127.40 g (content 98%) of thionyl chloride solution was added dropwise over 1 h.

[0041] After the addition of thionyl chloride solution was completed, the reaction was carried out for 7 h and then sampled for analysis. The HPLC analysis showed that the content of 4,6-dihydroxypyrimidine was 1.94% and the content of 4,6-dichloropyrimidine was 93.78% (the HPLC data here is the calculation result after removing the solvent and organic phosphine peaks). The reaction was ended, and the reaction mixture was subjected to vacuum distillation (oil bath temperature 125 °C, vacuum degree -0.095 Mpa), and the fraction at 90 - 100 °C was collected to obtain 35.75 g of 4,6-dichloropyrimidine (HPLC external standard content 98.55%), with a yield of 90.15%. The residue in the kettle was 199.87 g (4,6-dichloropyrimidine HPLC external standard content 0.23%), and the residual 4,6-dichloropyrimidine was 0.46 g, and the total conversion rate was 91.33% (calculated based on 4,6-dihydroxypyrimidine).

[0042] Example 3

[0043] In this example, 4,6-dichloropyrimidine was prepared by the following method, which specifically included the following steps:

[0044] Set up a four-necked flask reaction device equipped with a constant-pressure dropping funnel, a stirring paddle, a thermometer, and a reflux condenser. Weigh 30.00 g (content 98%) of 4,6-dihydroxypyrimidine and 36.86 g (content 99%) of triphenylphosphine oxide, dissolve them in 150 mL of nitrobenzene, mix well, heat up to 80 °C, and dropwise add 127.40 g (content 98%) of thionyl chloride solution over 1 hour.

[0045] After the addition of thionyl chloride solution is completed, react for 3 hours and then take a sample for analysis. By HPLC analysis, the content of 4,6-dihydroxypyrimidine is 1.86% and the content of 4,6-dichloropyrimidine is 95.43% (here the HPLC data is the calculation result after removing the solvent and organic phosphine peaks). The reaction ends. Distill the reaction mixture under reduced pressure (oil bath temperature 105 °C, vacuum degree -0.095 Mpa), collect the fraction at 90 - 100 °C, and obtain 36.55 g of 4,6-dichloropyrimidine (HPLC external standard content 98.15%), with a yield of 91.80%. The residue in the kettle is 221.63 g (HPLC external standard content of 4,6-dichloropyrimidine 0.29%), and the residual 4,6-dichloropyrimidine is 0.64 g. The total conversion rate is 93.44% (calculated based on 4,6-dihydroxypyrimidine).

[0046] Example 4

[0047] In this example, 4,6-dichloropyrimidine is prepared by the following method, which specifically includes the following steps:

[0048] Set up a four-necked flask reaction device equipped with a constant-pressure dropping funnel, a stirring paddle, a thermometer, and a reflux condenser. Weigh 30.00 g (content 98%) of 4,6-dihydroxypyrimidine and 73.73 g (content 99%) of triphenylphosphine oxide, dissolve them in 150 mL of nitrobenzene, mix well, heat up to 80 °C, and dropwise add 127.40 g (content 98%) of thionyl chloride solution over 1 hour.

[0049] After the addition of thionyl chloride solution is completed, react for 3 hours and then take a sample for analysis. By HPLC analysis, the content of 4,6-dihydroxypyrimidine is 1.75% and the content of 4,6-dichloropyrimidine is 94.78% (here the HPLC data is the calculation result after removing the solvent and organic phosphine peaks). The reaction ends. Distill the reaction mixture under reduced pressure (oil bath temperature 105 °C, vacuum degree -0.095 Mpa), collect the fraction at 90 - 100 °C, and obtain 36.14 g of 4,6-dichloropyrimidine (HPLC external standard content 98.24%), with a yield of 90.85%. The residue in the kettle is 263.58 g (HPLC external standard content of 4,6-dichloropyrimidine 0.26%), and the residual 4,6-dichloropyrimidine is 0.69 g. The total conversion rate is 92.60% (calculated based on 4,6-dihydroxypyrimidine).

[0050] Example 5

[0051] In this embodiment, 4,6-dichloropyrimidine is prepared by the following method, which specifically includes the following steps:

[0052] Set up a four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer, and a reflux condenser. Weigh 30.00 g (content 98%) of 4,6-dihydroxypyrimidine and 36.86 g (content 99%) of triphenylphosphine oxide, dissolve them in 150 mL of nitrobenzene, mix evenly, heat up to 85 °C, and dropwise add 95.55 g (content 98%) of thionyl chloride solution over 1 hour.

[0053] After the addition of the thionyl chloride solution is completed, sample and analyze after reacting for 3 hours. By HPLC analysis, the content of 4,6-dihydroxypyrimidine is 1.86% and the content of 4,6-dichloropyrimidine is 94.98% (the HPLC data here is the calculation result after removing the solvent and organic phosphine peaks). The reaction ends, and the reaction mixture is subjected to vacuum distillation (oil bath temperature 105 °C, vacuum degree -0.095 Mpa), and the fraction at 90 - 100 °C is collected to obtain 36.36 g of 4,6-dichloropyrimidine (HPLC external standard content 98.34%), with a yield of 91.50%. The residue in the kettle is 219.64 g (HPLC external standard content of 4,6-dichloropyrimidine 0.24%), and the residual 4,6-dichloropyrimidine is 0.53 g. The total conversion rate is 92.84% (calculated based on 4,6-dihydroxypyrimidine).

[0054] Example 6

[0055] In this embodiment, 4,6-dichloropyrimidine is prepared by the following method, which specifically includes the following steps:

[0056] Set up a four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer, and a reflux condenser. Weigh 30.00 g (content 98%) of 4,6-dihydroxypyrimidine and 73.73 g (content 99%) of triphenylphosphine oxide, dissolve them in 150 mL of nitrobenzene, mix evenly, heat up to 85 °C, and dropwise add 82.81 g (content 98%) of thionyl chloride solution over 1 hour.

[0057] After the addition of the thionyl chloride solution is completed, sample and analyze after reacting for 3 hours. By HPLC analysis, the content of 4,6-dihydroxypyrimidine is 1.98% and the content of 4,6-dichloropyrimidine is 94.65% (the HPLC data here is the calculation result after removing the solvent and organic phosphine peaks). The reaction ends, and the reaction mixture is subjected to vacuum distillation (oil bath temperature 125 °C, vacuum degree -0.095 Mpa), and the fraction at 90 - 100 °C is collected to obtain 36.13 g of 4,6-dichloropyrimidine (HPLC external standard content 98.00%), with a yield of 90.60%. The residue in the kettle is 258.37 g (HPLC external standard content of 4,6-dichloropyrimidine 0.28%), and the residual 4,6-dichloropyrimidine is 0.72 g. The total conversion rate is 92.45% (calculated based on 4,6-dihydroxypyrimidine).

[0058] Example 7

[0059] In this example, 4,6-dichloropyrimidine was prepared by the following method, which specifically included the following steps:

[0060] Set up a four-necked flask reaction device equipped with a constant-pressure dropping funnel, a stirring paddle, a thermometer, and a reflux condenser. Weigh 30.00 g (content 98%) of 4,6-dihydroxypyrimidine and 51.22 g (content 99%) of tri-n-octylphosphine oxide, dissolve them in 150 mL of nitrobenzene, mix evenly, heat up to 80 °C, and dropwise add 127.40 g (content 98%) of thionyl chloride solution. The dropping time is 1 h.

[0061] After the addition of the thionyl chloride solution is completed, sample and analyze after reacting for 3 h. The HPLC analysis shows that the content of 4,6-dihydroxypyrimidine is 1.65% and the content of 4,6-dichloropyrimidine is 95.31% (here the HPLC data is the calculation result after removing the solvent and organic phosphine peaks). The reaction ends, and the reaction mixture is subjected to vacuum distillation (oil bath temperature 110 °C, vacuum degree -0.095 Mpa), and the fraction at 90 - 100 °C is collected to obtain 36.32 g of 4,6-dichloropyrimidine (HPLC external standard content 98.55%), with a yield of 91.59%. The residue in the kettle is 236.75 g (HPLC external standard content of 4,6-dichloropyrimidine is 0.28%), and the residual 4,6-dichloropyrimidine is 0.66 g. The total conversion rate is 93.29% (calculated based on 4,6-dihydroxypyrimidine).

[0062] Example 8

[0063] In this example, 4,6-dichloropyrimidine was prepared by the following method, which specifically included the following steps:

[0064] Set up a four-necked flask reaction device equipped with a constant-pressure dropping funnel, a stirring paddle, a thermometer, and a reflux condenser. Weigh 30.00 g (content 98%) of 4,6-dihydroxypyrimidine and 51.22 g (content 99%) of tri-n-octylphosphine oxide, dissolve them in 150 mL of nitrobenzene, mix evenly, heat up to 80 °C, and dropwise add 95.55 g (content 98%) of thionyl chloride solution. The dropping time is 1 h.

[0065] After the addition of thionyl chloride solution was completed, the reaction was carried out for 3 h and then sampled for analysis. By HPLC analysis, the content of 4,6-dihydroxypyrimidine was 1.89% and the content of 4,6-dichloropyrimidine was 95.11% (here the HPLC data is the calculation result after removing the solvent and organic phosphine peaks). The reaction was ended, and the reaction mixture was subjected to vacuum distillation (oil bath temperature 110 °C, vacuum degree -0.095 Mpa), and the fraction at 90 - 100 °C was collected to obtain 36.22 g of 4,6-dichloropyrimidine (HPLC external standard content 98.76%), with a yield of 91.53%. The residue in the kettle was 234.38 g (HPLC external standard content of 4,6-dichloropyrimidine 0.22%), and the residual 4,6-dichloropyrimidine was 0.52 g. The total conversion rate was 92.85% (calculated based on 4,6-dihydroxypyrimidine).

[0066] Example 9

[0067] In this example, 4,6-dichloropyrimidine was prepared by the following method, which specifically included the following steps:

[0068] 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. 30.00 g (content 98%) of 4,6-dihydroxypyrimidine and 73.73 g (content 99%) of triphenylphosphine oxide were weighed and dissolved in 150 mL of toluene. After mixing evenly, the temperature was raised to 100 °C, and 82.81 g (content 98%) of thionyl chloride solution was added dropwise over 1 h.

[0069] After the addition of thionyl chloride solution was completed, the reaction was carried out for 3 h and then sampled for analysis. By HPLC analysis, the content of 4,6-dihydroxypyrimidine was 1.93% and the content of 4,6-dichloropyrimidine was 93.17% (here the HPLC data is the calculation result after removing the solvent and organic phosphine peaks). The reaction was ended, and the reaction mixture was subjected to vacuum distillation (oil bath temperature 110 °C, vacuum degree -0.095 Mpa), and the fraction at 90 - 100 °C was collected to obtain 33.74 g of 4,6-dichloropyrimidine (HPLC external standard content 97.53%), with a yield of 84.20%. The residue in the kettle was 88.71 g (HPLC external standard content of 4,6-dichloropyrimidine 2.71%), and the residual 4,6-dichloropyrimidine was 2.40 g. The total conversion rate was 90.35% (calculated based on 4,6-dihydroxypyrimidine).

[0070] Example 10

[0071] In this example, 4,6-dichloropyrimidine was prepared by the following method, which specifically included the following steps:

[0072] Set up a four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer, and a reflux condenser. Weigh 30.00 g (content 98%) of 4,6-dihydroxypyrimidine and 73.73 g (content 99%) of triphenylphosphine oxide, dissolve them in 150 mL of chloroform, mix well, heat up to 40 °C, and dropwise add 82.81 g (content 98%) of thionyl chloride solution over 1 h.

[0073] After the addition of thionyl chloride solution is completed, sample and analyze after reacting for 9 h. By HPLC analysis, the content of 4,6-dihydroxypyrimidine is 1.98% and the content of 4,6-dichloropyrimidine is 91.89% (here the HPLC data is the calculation result after removing the solvent and organic phosphine peaks). The reaction ends. Distill the reaction mixture under reduced pressure (oil bath temperature 110 °C, vacuum degree -0.095 Mpa), collect the fraction at 90 - 100 °C, and obtain 32.68 g of 4,6-dichloropyrimidine (HPLC external standard content 97.96%), with a yield of 81.92%. The residue in the kettle is 88.58 g (HPLC external standard content of 4,6-dichloropyrimidine is 3.24%), and the remaining 4,6-dichloropyrimidine is 2.87 g. The total conversion rate is 89.26% (calculated based on 4,6-dihydroxypyrimidine).

[0074] Comparative Example 1

[0075] In this comparative example, 4,6-dichloropyrimidine was prepared by the following method, which specifically includes the following steps:

[0076] Set up a four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer, and a reflux condenser. Weigh 30.00 g (content 98%) of 4,6-dihydroxypyrimidine, dissolve it in 150 mL of nitrobenzene, mix well, heat up to 80 °C, and dropwise add 127.40 g (content 98%) of thionyl chloride solution over 1 h.

[0077] After the addition of thionyl chloride solution is completed, sample and analyze after reacting for 3 h. By HPLC analysis, the content of 4,6-dihydroxypyrimidine is 99.12% and the content of 4,6-dichloropyrimidine is less than 1.0% (here the HPLC data is the calculation result after removing the solvent and organic phosphine peaks). The reaction cannot proceed.

[0078] Comparative Example 2

[0079] In this comparative example, 4,6-dichloropyrimidine was prepared by the following method, which specifically includes the following steps:

[0080] Set up a four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer, and a reflux condenser. Weigh 30.00 g (content 98%) of 4,6-dihydroxypyrimidine, dissolve it in 150 mL of nitrobenzene, mix well, heat up to 80 °C, and dropwise add 82.81 g (content 98%) of thionyl chloride solution over 1 h.

[0081] After the addition of thionyl chloride solution was completed, the reaction was carried out for 3 h and then sampled for analysis. The HPLC analysis showed that the content of 4,6-dihydroxypyrimidine was 98.87% and the content of 4,6-dichloropyrimidine was less than 1.0% (the HPLC data here is the calculation result after removing the solvent and organic phosphine peaks), and the reaction could not proceed.

[0082] Comparative Example 3

[0083] In this comparative example, 4,6-dichloropyrimidine was prepared by the following method, which specifically included the following steps:

[0084] 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. 30.00 g (content 98%) of 4,6-dihydroxypyrimidine was weighed and dissolved in 150 mL of nitrobenzene. After mixing evenly, the temperature was raised to 80 °C, and 191.10 g (content 98%) of thionyl chloride solution was added dropwise over 1 h.

[0085] After the addition of thionyl chloride solution was completed, the reaction was carried out for 3 h and then sampled for analysis. The HPLC analysis showed that the content of 4,6-dihydroxypyrimidine was 98.99% and the content of 4,6-dichloropyrimidine was less than 1.0% (the HPLC data here is the calculation result after removing the solvent and organic phosphine peaks), and the reaction could not proceed.

[0086] Comparative Example 4

[0087] In this comparative example, 4,6-dichloropyrimidine was prepared by the following method, which specifically included the following steps:

[0088] 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. 30.00 g (content 98%) of 4,6-dihydroxypyrimidine and 69.50 g (content 99%) of triphenylphosphine were weighed and dissolved in 150 mL of nitrobenzene. After mixing evenly, the temperature was raised to 80 °C, and 95.55 g (content 98%) of thionyl chloride solution was added dropwise over 1 h.

[0089] After the addition of thionyl chloride solution was completed, the reaction was carried out for 3 h and then sampled for analysis. The HPLC analysis showed that the content of 4,6-dihydroxypyrimidine was 98.86% and the content of 4,6-dichloropyrimidine was less than 1.0% (the HPLC data here is the calculation result after removing the solvent and organic phosphine peaks), and the reaction could not proceed.

[0090] Comparative Example 5

[0091] In this comparative example, 4,6-dichloropyrimidine was prepared by the following method, which specifically included the following steps:

[0092] Set up a four-necked flask reaction device equipped with a constant pressure dropping funnel, a stirring paddle, a thermometer, and a reflux condenser. Weigh 30.00 g (content 98%) of 4,6-dihydroxypyrimidine and 61.00 g (content 99%) of diphenyl ethoxyphosphine, dissolve them in 150 mL of nitrobenzene, mix well, heat up to 85 °C, and dropwise add 95.55 g (content 98%) of thionyl chloride solution over 1 hour.

[0093] After the addition of the thionyl chloride solution is complete, sample and analyze after reacting for 3 hours. The HPLC analysis shows that the content of 4,6-dihydroxypyrimidine is 99.01% and the content of 4,6-dichloropyrimidine is less than 1.0% (here the HPLC data is the calculation result after removing the solvent and organic phosphine peaks), and the reaction cannot proceed.

[0094] The applicant declares that the present invention illustrates the preparation method of 4,6-dichloropyrimidine of the present invention through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvement to the present invention, the equivalent substitution of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the protection scope and the disclosure scope of the present invention.

Claims

1. A preparation method of 4,6-dichloropyrimidine, characterized in that, The preparation method is as follows: Mix an organic phosphine and 4,6-dihydroxypyrimidine and dissolve them in a solvent, then dropwise add a thionyl chloride solution thereto and react to obtain 4,6-dichloropyrimidine; The temperature of the reaction is 35-85°C; The solvent is any one or a combination of at least two of aromatic solvents or halogenated hydrocarbon solvents; The aromatic solvents are selected from any one or a combination of at least two of toluene, xylene, mesitylene, chlorobenzene, and nitrobenzene; The halogenated hydrocarbon solvents are selected from any one or a combination of at least two of dichloromethane, chloroform, or dichloroethane; The organic phosphine is selected from any one or a combination of at least two of triphenylphosphine oxide, tri-n-octylphosphine oxide, or tributylphosphine oxide; 2. The preparation method of 4,6-dichloropyrimidine according to claim 1, characterized in that, The molar ratio of thionyl chloride to 4,6-dihydroxypyrimidine is 2:1-8:1; 3. The preparation method of 4,6-dichloropyrimidine according to claim 1, characterized in that, The thionyl chloride solution is a thionyl chloride solution with a content of 98%; 4. The preparation method of 4,6-dichloropyrimidine according to claim 1, wherein, The molar ratio of 4,6-dihydroxypyrimidine to the organic phosphine is 10:1-1:4; 5. The preparation method of 4,6-dichloropyrimidine according to claim 1, characterized in that, The temperature of the reaction is 35-60°C; 6. The preparation method of 4,6-dichloropyrimidine according to claim 1, characterized in that, The reaction time is 3-12 h; 7. The preparation method of 4,6-dichloropyrimidine according to claim 1, characterized in that, The preparation method specifically includes the following steps: Mix an organic phosphine and 4,6-dihydroxypyrimidine and dissolve them in a solvent, then dropwise add a thionyl chloride solution thereto, wherein the molar ratio of thionyl chloride to 4,6-dihydroxypyrimidine is 2:1-8:1, the molar ratio of 4,6-dihydroxypyrimidine to the organic phosphine is 10:1-1:4, react at 35-85°C. At this time, the mass percentage content of 4,6-dihydroxypyrimidine in the reaction solution is lower than 2%, end the reaction, and obtain 4,6-dichloropyrimidine.

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