Clean production process of 4, 6-dichloropyrimidine

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a clean production process of 4, 6-dichloropyrimidine. According to the clean production process of the 4, 6-dichloropyrimidine, provided by the invention, 4, 6-dihydroxy pyrimidine sodium salt is taken as a raw material, 4, 6-dialkoxy pyrimidine is obtained through etherification reaction, then an amide substance is taken as a catalyst, chlorination reaction is carried out under a specific solvent condition, and the 4, 6-dichloropyrimidine is prepared. The process route is simple, the reaction selectivity and the reaction efficiency are high, the conversion rate of the reaction is effectively improved, the production period is shortened, the prepared 4, 6-dichloropyrimidine product is high in purity, the strict requirements of the fields of high-end medicines, pesticides and the like on the purity of raw materials can be met, and meanwhile, the method is suitable for industrial production. The alkylation reagent and the reaction solvent used in the reaction can be recycled and reused, the yield of wastewater is low, the pressure on the environment is reduced, the development concept of the modern green chemical industry is met, and the method is suitable for industrial popularization and application.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a clean production process of 4,6-dichloropyrimidine. Background Art

[0002] As a key organic intermediate, 4,6-dichloropyrimidine plays an important role in many fields such as medicine, pesticides, dyes and materials science. In addition to being widely used in the synthesis of methoxyacrylate fungicides such as azoxystrobin, it can also be used to produce sulfa-6-methoxypyrimidine and sulfamoxifen for the treatment of hemolytic streptococcal, pneumococcal and meningococcal infections, as well as anticancer drugs such as fluorouracil. With the increasing market demand for azoxystrobin, the synthesis and post-processing technology of 4,6-dichloropyrimidine has received extensive attention in recent years.

[0003] At present, the mainstream process for synthesizing 4,6-dichloropyrimidine in China is: using 4.6-dihydroxypyrimidine as raw material, in a suitable solvent, using phosphorus oxychloride as a chlorination reagent, chlorination is carried out in the presence of a tertiary amine, and then 4,6-dichloropyrimidine is obtained by hydrolysis and separation. This process has a stable yield and a simple process, and the operating conditions are relatively mild. However, a large amount of wastewater containing phosphoric acid and chlorine is produced in the post-treatment, and a large amount of mixed salt is produced in the process of recovering the catalyst tertiary amine, resulting in high total cost and energy consumption. The mainstream process for synthesizing 4,6-dichloropyrimidine abroad is: dispersing 4,6-dihydroxypyrimidine in a special solvent (such as phosphorus oxychloride), treating it with a mixture of phosphorus pentachloride or phosphorus trichloride and chlorine, and distilling to obtain 4,6-dichloropyrimidine and phosphorus oxychloride. This process no longer produces acidic wastewater and has a high degree of continuity. However, the problem is that the raw materials are highly corrosive and a mixed gas of chlorine and HCl is produced as a by-product. Not only is the equipment requirement extremely high, but a large number of separation equipment are also required, and the equipment cost is relatively high. Therefore, it is of great significance to develop a synthesis process for 4,6-dichloropyrimidine that is low-cost, environmentally friendly, suitable for industrial production and has low equipment requirements. Summary of the invention

[0004] In view of the problems of high process energy consumption, complex equipment, large amount of three wastes, high production cost, etc. in the existing process for synthesizing 4,6-dichloropyrimidine, the present invention provides a clean production process for 4,6-dichloropyrimidine. The process mainly uses 4,6-dihydroxypyrimidine sodium salt as a raw material, undergoes etherification with an alkylating agent in an organic solvent, and reacts with a chlorination agent after dissolving the salt and separating the phases to prepare 4,6-dichloropyrimidine. The process effectively improves production efficiency, is simple in post-treatment, generates less three wastes, reduces production costs, and has high prospects for industrial application.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0006] A clean production process for 4,6-dichloropyrimidine comprises the following steps:

[0007] Step a, in a polar organic solvent, 4,6-dihydroxypyrimidine sodium salt and an alkylating agent undergo an etherification reaction to obtain 4,6-dialkoxypyrimidine;

[0008] Step b, in a catalyst and a hydrocarbon solvent, the 4,6-dialkoxypyrimidine is subjected to a chlorination reaction with a chlorination agent to obtain 4,6-dichloropyrimidine; wherein the catalyst is an amide substance, and the hydrocarbon solvent is a halogenated alkane or a benzene solvent. The specific reaction equation is as follows:

[0009]

[0010] Compared with the prior art, the clean production process of 4,6-dichloropyrimidine provided by the present invention uses 4,6-dihydroxypyrimidine sodium salt as a raw material, obtains 4,6-dialkoxypyrimidine through etherification reaction, and then uses amide substances as catalysts to carry out chlorination reaction under specific solvent conditions to prepare 4,6-dichloropyrimidine. The process route is simple, the reaction selectivity and reaction efficiency are high, the reaction conversion rate is effectively improved, the production cycle is shortened, and the prepared 4,6-dichloropyrimidine product has high purity, which can meet the strict requirements of high-end medicine, pesticides and other fields on the purity of raw materials. At the same time, the alkylating agent and reaction solvent used in the reaction can be recycled and reused, the amount of wastewater generated is low, and the pressure on the environment is reduced. It conforms to the development concept of the modern green chemical industry and is suitable for industrial promotion and application.

[0011] It should be noted that the 4,6-dihydroxypyrimidine sodium salt in the present invention can be prepared by conventional methods in the art, specifically, by reacting formamide, dimethyl malonate and sodium methoxide.

[0012] Furthermore, the polar organic solvent includes at least one of acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-diethylformamide or N,N-dimethylacetamide, preferably N,N-dimethylformamide and N,N-dimethylacetamide.

[0013] Furthermore, the mass ratio of the polar organic solvent to 4,6-dihydroxypyrimidine sodium salt is (3-10):1.

[0014] Preferably, the mass ratio of the polar organic solvent to 4,6-dihydroxypyrimidine sodium salt is (4-8):1.

[0015] The preferred organic solvent can make the 4,6-dihydroxypyrimidine sodium salt and the alkylating agent fully contact, promote the smooth progress of the etherification reaction, and improve the selectivity and conversion rate of the reaction.

[0016] Furthermore, the alkylating agent includes at least one of RX or R2SO4, wherein R is selected from a C1-C3 alkyl group, and X is selected from Cl, Br or I. Preferably, ethyl chloride, methyl chloride, methyl bromide, propyl chloride.

[0017] Furthermore, the molar ratio of the alkylating agent to 4,6-dihydroxypyrimidine sodium salt is (2-6):1.

[0018] Preferably, the molar ratio of the alkylating agent to 4,6-dihydroxypyrimidine sodium salt is (2.5-4):1.

[0019] Furthermore, the temperature of the etherification reaction is 40°C to 100°C, preferably 50°C to 70°C.

[0020] The preferred reaction temperature can promote the full progress of the etherification reaction and reduce the occurrence of side reactions.

[0021] Furthermore, the catalyst is one or both of N,N-dimethylformamide and N,N-dimethylacetamide.

[0022] Furthermore, the added amount of the catalyst is 2% to 30% of the mass of 4,6-dialkoxypyrimidine.

[0023] The preferred catalyst and the amount of catalyst added can increase the reaction rate and selectivity of the chlorination reaction of 4,6-dialkoxypyrimidine, thereby increasing the yield and purity of the 4,6-dichloropyrimidine product.

[0024] Furthermore, the alkyl halide is 1,2-dichloroethane or dichloromethane, and the benzene solvent is toluene or xylene.

[0025] Furthermore, the mass ratio of the hydrocarbon solvent to 4,6-dialkoxypyrimidine is (1-6):1.

[0026] The preferred reaction solvent can provide a homogeneous environment for the reaction, allowing 4,6-dialkoxypyrimidine and the chlorination reagent to fully contact, thereby promoting the smooth progress of the chlorination reaction and improving the selectivity and conversion rate of the reaction.

[0027] Furthermore, the chlorination reagent is at least one of phosgene, diphosgene or triphosgene.

[0028] It should be noted that if phosgene or diphosgene is used as the chlorination reagent, the phosgene can be directly introduced into the reaction system. If triphosgene is used as the chlorination reagent, the triphosgene needs to be dissolved in the reaction solvent and then added to the reaction system so that the triphosgene can be quickly and evenly mixed with 4,6-dialkoxypyrimidine to improve the reaction efficiency.

[0029] Furthermore, the molar ratio of Cl to 4,6-dialkoxypyrimidine in the chlorination reagent is (4-10):1.

[0030] Furthermore, the temperature of the chlorination reaction is 50°C to 110°C.

[0031] As a specific embodiment of the present invention, the clean production process of 4,6-dichloropyrimidine specifically comprises the following steps:

[0032] Adding 4,6-dihydroxypyrimidine sodium salt to a polar solvent, mixing evenly, adding an alkylating agent, heating to carry out an etherification reaction, recovering the alkylating agent and the polar organic solvent after the reaction is completed, then adding water and a hydrocarbon solvent to the system, standing to separate phases, washing the oil phase with water and removing water, adding a catalyst and a chlorination agent, heating to carry out a chlorination reaction, and distilling after the reaction is completed to obtain 4,6-dichloropyrimidine;

[0033] Wherein, the hydrocarbon solvent is a halogenated alkane or a benzene solvent.

[0034] The invention uses 4,6-dihydroxypyrimidine sodium salt as a raw material, performs an etherification reaction in a polar organic solvent to prepare 4,6-dialkoxypyrimidine, and after the etherification reaction, the salt impurities in the reaction system can be effectively removed by dissolving salt and separating phases, thereby simplifying subsequent separation and purification steps and reducing production costs and energy consumption; after etherification and desalination treatment, the chlorination reagent is directly reacted to prepare 4,6-dichloropyrimidine, and the continuous reaction step design reduces the processing procedures of intermediate products, shortens the production cycle, improves production efficiency, and also reduces impurities that may be introduced during multiple material transfers and treatments, thereby facilitating improving the purity and quality stability of the product.

[0035] It should be noted that after the etherification reaction is completed, the alkylation reagent in the reaction system is firstly recovered by using a vacuum pump to extract negative pressure, and then the polar organic solvent in the reaction system is recovered by reduced pressure distillation.

[0036] It should be noted that after the etherification reaction is completed, the alkylating agent and the polar organic solvent are recovered, and water and a hydrocarbon solvent are added to the system for phase separation, wherein the hydrocarbon solvent is selected as the reaction solvent for the subsequent chlorination reaction to simplify the reaction process and omit the step of solvent removal and replacement after phase separation. After the subsequent addition of the catalyst and the chlorination agent, if the reaction solvent in the oil phase obtained by phase separation does not meet the range defined in the present invention, a certain amount of hydrocarbon solvent is added.

[0037] Furthermore, the oil phase is dehydrated to a water content of less than 0.5%.

[0038] The production process of 4,6-dichloropyrimidine provided by the present invention uses 4,6-dihydroxypyrimidine sodium salt as a raw material, and prepares high-purity 4,6-dichloropyrimidine through two-step reactions of etherification and chlorination. During the production process, the reaction solvent, alkylating agent, etc. can be recycled and reused, the material cost is significantly reduced, there is no intermediate product separation process during the reaction process, and the product post-treatment is simple, which effectively reduces the equipment investment. In addition, the amount of wastewater generated is small, and the wastewater treatment cost is low. This provides an environmentally friendly and economically efficient new process route for the synthesis of 4,6-dichloropyrimidine, and has extremely high promotion value. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0040] In order to better illustrate the present invention, further examples are given below.

[0041] The raw material 4,6-dihydroxypyrimidine sodium salt used in the following examples and comparative examples was synthesized with reference to Peng Jun (Synthesis Research of 4,6-dichloropyrimidine, Fine Chemical Intermediates, 2009) and Cui Long (Synthesis Process and Kinetics Research of 4,6-dihydroxypyrimidine, Zhengzhou University, 2011). The specific process is as follows:

[0042] To a 1L four-necked flask, add 391g of sodium methoxide-methanol solution (1.991mol of sodium methoxide) with a mass concentration of 27.5% and 62.2g of formamide (content 99%, 1.708mol), stir at 25°C for 0.5h, heat to 50°C, add 75.5g of dimethyl malonate (content 99.5%, 0.569mol) dropwise for 2h, and heat to 65°C for 3h after the addition is completed. After the reaction is completed, distill at 60°C and -0.09MPa until no fraction is extracted, add 300g of water, filter through a nanofiltration membrane, and spray dry the nanofiltrate to obtain 4,6-dihydroxypyrimidine sodium salt with a content of 98.3%, 0.2% sodium formate, and 1.4% water.

[0043] Example 1

[0044] This embodiment provides a clean production process for 4,6-dichloropyrimidine, and the specific steps are as follows:

[0045] Step a, add 600g of N,N-dimethylformamide and 75g (0.473mol) of 4,6-dihydroxypyrimidine sodium salt into the reactor, stir evenly, introduce 116g (1.780mol) of ethyl chloride, seal the reactor, heat to 60°C, keep warm until the system pressure no longer decreases, continue to keep warm for 0.5h, cool to 20-30°C, use a dry vacuum pump to extract excess ethyl chloride in the reactor at negative pressure until the pressure in the reactor drops to below -0.090MPa, and vacuum pump Connect a two-stage -5℃ condensation device to condense and recover ethyl chloride. After ethyl chloride is recovered, increase the vacuum to -0.097MPa, distill at 70℃ until no fraction is produced, and recover 584g of N,N-dimethylformamide in total. Add 200g of water and 370g of toluene to the kettle material after solvent removal, stir at 60℃ for 0.5h, stand and separate, add 50g of water to the oil phase for washing, reflux and dehydrate the washed oil phase to a water content of 0.06%, detect the content of 4,6-diethoxypyrimidine, and the conversion rate is 95.2%;

[0046] Step b, add 3.8 g of N,N-dimethylformamide to the above dehydrated oil phase, raise the temperature to 70°C, slowly introduce 223 g (2.253 mol) of phosgene, and the ventilation time is 5 h. After the ventilation is completed, raise the temperature to 90°C and keep warm for 2 h. During the reaction, the tail gas is condensed to -10°C for recovery, and the condensed and recovered material is separated into ethyl chloride and phosgene by atmospheric distillation. The reaction is controlled by HPLC until the content of the intermediate 4-chloro-6-ethoxypyrimidine is less than 0.5%. The reaction is completed, and the insulation is stopped. The reaction solution is first distilled at 55°C and -0.096 MPa until no fraction is produced, toluene is recovered, and then distilled at 87°C and -0.098 MPa until no fraction is produced, to obtain 65.6 g of 4,6-dichloropyrimidine, with a content of 99.3%. The total yield is 92.4% based on 4,6-dihydroxypyrimidine sodium salt.

[0047] Example 2

[0048] This embodiment provides a clean production process for 4,6-dichloropyrimidine, and the specific steps are as follows:

[0049] Step a, add 300g of N,N-dimethylformamide and 75g (0.473mol) of 4,6-dihydroxypyrimidine sodium salt into the reactor, stir evenly, introduce 60g (1.189mol) of methyl chloride, seal the reactor, heat to 70°C, keep warm until the system pressure no longer decreases, keep warm for 0.5h, cool to 20-30°C, extract excess methyl chloride in the reactor with negative pressure of dry vacuum pump until the pressure in the reactor drops to below -0.090MPa, and connect the vacuum pump to 0°C N ,N-dimethylformamide was frozen to recover chloromethane. After the chloromethane was recovered, the vacuum was increased to -0.097MPa, and distilled at 70°C until no fraction was produced. A total of 295g of N,N-dimethylformamide was recovered. 200g of water and 150g of 1,2-dichloroethane were added to the kettle material after the solvent was removed. The mixture was stirred at 60°C for 0.5h, and the mixture was allowed to stand for separation. 50g of water was added to the oil phase for washing. The washed oil phase was refluxed and dehydrated to a water content of 0.07%. The content of 4,6-dimethoxypyrimidine was detected, and the conversion rate was 94.5%;

[0050] Step b, add 4 g of N,N-dimethylformamide to the dehydrated oil phase, raise the temperature to 70°C, slowly dropwise add 168.5 g of triphosgene (0.568 mol) and 253 g of The solution of 1,2-dichloroethane was added dropwise for 5 hours. After the addition was completed, the temperature was raised to 83°C and kept warm for 2 hours. During the reaction, the tail gas was condensed to -5°C and phosgene was recovered. The non-condensable chloromethane was absorbed by N,N-dimethylformamide. The reaction was controlled by HPLC until the content of the intermediate 4-chloro-6-methoxypyrimidine was less than 0.5%. The reaction was completed and the insulation was stopped. The reaction solution was first distilled at 50°C and -0.090MPa until no fraction was produced, 1,2-dichloroethane was recovered, and then distilled at 87°C and -0.098MPa until no fraction was produced. 4,6-dichloropyrimidine 66.2g was obtained with a content of 99.1%. The total yield was 93.08% based on 4,6-dihydroxypyrimidine sodium salt.

[0051] Example 3

[0052] This embodiment provides a clean production process for 4,6-dichloropyrimidine, and the specific steps are as follows:

[0053] Step a, add 450g of N,N-dimethylacetamide and 75g (0.473mol) of 4,6-dihydroxypyrimidine sodium salt into the reactor, stir evenly, introduce 75g (1.486mol) of methyl chloride, seal the reactor, heat to 50°C, keep warm until the system pressure no longer decreases, keep warm for 0.5h, cool to 20-30°C, extract excess methyl chloride in the reactor with negative pressure of dry vacuum pump until the pressure in the reactor drops to below -0.090MPa, and connect the vacuum pump to 0°C N,N -dimethylacetamide was used to absorb and recover chloromethane. After the chloromethane was recovered, the vacuum was increased to -0.097MPa, and distilled at 80°C until no fraction was produced. A total of 435g of N,N-dimethylacetamide was recovered. 200g of water and 200g of 1,2-dichloroethane were added to the kettle material after the solvent was removed. The mixture was stirred at 60°C for 0.5h, and the mixture was allowed to stand for separation. 50g of water was added to the oil phase for washing. The washed oil phase was refluxed and dehydrated to a water content of 0.05%. The 4,6-dimethoxypyrimidine content was detected, and the conversion rate was 95.3%;

[0054] Step b, add 3.5 g of N,N-dimethylacetamide to the dehydrated oil phase, raise the temperature to 70°C, slowly dropwise add 103.0 g of triphosgene (0.347 mol) and 180 g of The solution of 1,2-dichloroethane was added dropwise for 6 hours. After the addition was completed, the temperature was raised to 83°C and kept warm for 2 hours. During the reaction, the tail gas was condensed to -5°C and phosgene was recovered. The non-condensable chloromethane was absorbed by N,N-dimethylacetamide. The reaction was controlled by HPLC until the content of the intermediate 4-chloro-6-methoxypyrimidine was less than 0.5%. The reaction was completed and the insulation was stopped. The reaction solution was first distilled at 55°C and -0.09MPa until no fraction was produced, 1,2-dichloroethane was recovered, and then distilled at 87°C and -0.098MPa until no fraction was produced, to obtain 63.1 g of 4,6-dichloropyrimidine with a content of 98.5%. The total yield was 88.19% based on 4,6-dihydroxypyrimidine sodium salt.

[0055] Example 4

[0056] This embodiment provides a clean production process for 4,6-dichloropyrimidine, and the specific steps are as follows:

[0057] Step a, add 450g of N,N-dimethylformamide and 75g (0.473mol) of 4,6-dihydroxypyrimidine sodium salt into the reactor, stir evenly, introduce 110g (1.158mol) of methyl bromide, seal the reactor, heat to 60°C, keep warm until the system pressure no longer decreases, keep warm for 0.5h, cool to 20-30°C, extract excess methyl bromide in the reactor with a dry vacuum pump under negative pressure until the pressure in the reactor drops to below -0.090MPa, and connect the vacuum pump to -10°C. The condensation device condenses and recovers methyl bromide, and after liquefaction, it is refrigerated and stored at -5°C. After the methyl bromide is recovered, the vacuum is increased to -0.097MPa, and distilled at 70°C until no fraction is produced. A total of 442g of N,N-dimethylformamide is recovered. 200g of water and 300g of xylene are added to the kettle material after the solvent is removed, and stirred at 60°C for 0.5h. The mixture is allowed to stand for separation, and 50g of water is added to the oil phase for washing. The washed oil phase is refluxed and dehydrated to a water content of 0.07%. The content of 4,6-dimethoxypyrimidine is detected, and the conversion rate is 96.2%;

[0058] Step b, add 4g of N,N-dimethylformamide to the above dehydrated oil phase, raise the temperature to 70°C, slowly introduce 140.5g (1.419mol) of phosgene, and the ventilation time is 6h. After the ventilation is completed, raise the temperature to 110°C and keep warm for 2h. During the reaction, the tail gas is condensed to -5°C to recover the phosgene, and the non-condensable chloromethane is absorbed by N,N-dimethylformamide. The reaction is controlled by HPLC until the content of the intermediate 4-chloro-6-methoxypyrimidine is less than 0.5%. The reaction is completed, and the insulation is stopped. The reaction solution is first distilled at 83°C and -0.09MPa until no fraction is produced, xylene is recovered, and then distilled at 87°C and -0.098MPa until no fraction is produced, to obtain 67.1g of 4,6-dichloropyrimidine, with a content of 98.3%. The total yield is 93.59% based on 4,6-dihydroxypyrimidine sodium salt.

[0059] Example 5

[0060] This embodiment provides a clean production process for 4,6-dichloropyrimidine, and the specific steps are as follows:

[0061] Step a, add 450g of N,N-dimethylformamide and 75g (0.473mol) of sodium salt of 4,6-dihydroxypyrimidine into the reactor, stir evenly, introduce 80g (1.019mol) of chloropropane, seal the reactor, heat to 70°C, keep warm until the system pressure no longer decreases, keep warm for 0.5h, cool to 20-30°C, extract excess chloropropane in the reactor with negative pressure of a dry vacuum pump until the pressure in the reactor drops to below -0.090MPa, vacuum The pump was connected to a 0°C condensation device to condense and recover chloropropane. After the chloropropane was recovered, the vacuum was increased to -0.097MPa, and distilled at 70°C until no fraction was produced. A total of 440g of N,N-dimethylformamide was recovered. 200g of water and 200g of toluene were added to the kettle material after the solvent was removed. The mixture was stirred at 60°C for 0.5h, and the mixture was allowed to stand for separation. 60g of water was added to the oil phase for washing. The washed oil phase was refluxed and dehydrated to a water content of 0.06%. The content of 4,6-di-n-propoxypyrimidine was detected, and the conversion rate was 93.1%;

[0062] Step b, add 4g of N,N-dimethylformamide to the above dehydrated oil phase, raise the temperature to 70°C, slowly dropwise add a solution of 100g of triphosgene (0.337mol) and 200g of toluene, the dropwise addition time is 7h, after the dropwise addition is completed, raise the temperature to 100°C and keep warm for 2h, and during the reaction, the tail gas is graded and condensed and recovered, firstly recovering chloropropane with a 20°C condenser, and further recovering phosgene with a -5°C condenser for non-condensable gas, and controlling the reaction by HPLC until the content of the intermediate 4-chloro-6-n-propoxypyrimidine is less than 0.5%, and the reaction is completed, and the insulation is stopped, and the reaction solution is first distilled at 55°C and -0.096MPa until no fraction is produced, toluene is recovered, and then distilled at 87°C and -0.098MPa until no fraction is produced, to obtain 64.4g of 4,6-dichloropyrimidine, with a content of 99.3%, and the total yield is 90.7% based on 4,6-dihydroxypyrimidine sodium salt.

[0063] Example 6

[0064] This embodiment provides a clean production process for 4,6-dichloropyrimidine, and the specific steps are as follows:

[0065] Step a, add 550g of N,N-dimethylformamide and 75g (0.473mol) of 4,6-dihydroxypyrimidine sodium salt into the reactor, stir evenly, introduce 95.55g (1.892mol) of methyl chloride, seal the reactor, heat to 70°C, keep warm until the system pressure no longer decreases, keep warm for 0.5h, cool to 20-30°C, extract excess methyl chloride in the reactor with negative pressure of dry vacuum pump until the pressure in the reactor drops to below -0.090MPa, and connect the vacuum pump to 0°C. After the recovery of chloroformamide, the vacuum was increased to -0.097MPa, and distilled at 70°C until no fraction was produced. A total of 535g of N,N-dimethylformamide was recovered. 200g of water and 240g of 1,2-dichloroethane were added to the kettle material after the solvent was removed, and stirred at 60°C for 0.5h. The mixture was allowed to stand for separation, and 50g of water was added to the oil phase for washing. The washed oil phase was refluxed and dehydrated to a water content of 0.07%. The content of 4,6-dimethoxypyrimidine was detected, and the conversion rate was 96.7%;

[0066] Step b, add 5 g of N,N-dimethylacetamide to the dehydrated oil phase, raise the temperature to 60°C, slowly dropwise add 110 g of triphosgene (0.370 mol) and 200 g of The solution of 1,2-dichloroethane was ventilated for 6 hours. After the venting was completed, the temperature was raised to 83°C and kept warm for 3 hours. During the reaction, the tail gas was condensed to -5°C to recover the phosgene. The non-condensable chloromethane was absorbed by N,N-dimethylformamide. The reaction was controlled by HPLC until the content of the intermediate 4-chloro-6-methoxypyrimidine was less than 0.5%. The reaction was terminated and the insulation was stopped. The reaction solution was first distilled at 50°C and -0.090MPa until no fraction was produced, 1,2-dichloroethane was recovered, and then distilled at 87°C and -0.098MPa until no fraction was produced, to obtain 67.6 g of 4,6-dichloropyrimidine with a content of 99.1%. The total yield was 95.1% based on 4,6-dihydroxypyrimidine sodium salt.

[0067] Example 7

[0068] This embodiment provides a clean production process for 4,6-dichloropyrimidine, and the specific steps are as follows:

[0069] Step a, add 646g of N,N-dimethylformamide solution containing 96g (1.901mol) of recovered chloromethane and 75g (0.473mol) of 4,6-dihydroxypyrimidine sodium salt into the reactor, stir evenly, seal the reactor, heat to 70°C, keep warm until the system pressure no longer decreases, keep warm for 0.5h, cool to 20-30°C, extract excess chloromethane in the reactor with negative pressure of dry vacuum pump until the pressure in the reactor drops to below -0.090MPa, and connect the vacuum pump to 0°C. The N,N-dimethylformamide was frozen to recover chloromethane. After the chloromethane was recovered, the vacuum was increased to -0.097MPa, and distilled at 70°C until no fraction was produced. A total of 533g of N,N-dimethylformamide was recovered. 200g of water and 440g of 1,2-dichloroethane were added to the kettle material after the solvent was removed. The mixture was stirred at 60°C for 0.5h, and the mixture was allowed to stand for separation. 50g of water was added to the oil phase for washing. The washed oil phase was refluxed and dehydrated to a water content of 0.07%. The content of 4,6-dimethoxypyrimidine was detected, and the conversion rate was 96.5%.

[0070] Step b, add 5g of N,N-dimethylacetamide to the above dehydrated oil phase, raise the temperature to 60°C, slowly introduce 109g (1.101mol) of recovered phosgene, and the ventilation time is 7h. After the ventilation is completed, raise the temperature to 83°C and keep warm for 3h. During the reaction, the tail gas is condensed to -5°C to recover the phosgene, and the non-condensable chloromethane is absorbed and recovered by N,N-dimethylformamide. The reaction is controlled by HPLC until the content of the intermediate 4-chloro-6-methoxypyrimidine is less than 0.5%. The reaction is completed, and the insulation is stopped. The reaction solution is first distilled at 50°C and -0.09MPa until no fraction is produced, 1,2-dichloroethane is recovered, and then distilled at 87°C and -0.098MPa until no fraction is produced, to obtain 67.3g of 4,6-dichloropyrimidine, with a content of 99.2%. The total yield is 94.73% based on 4,6-dihydroxypyrimidine sodium salt.

[0071] Comparative Example 1

[0072] This comparative example provides a production process of 4,6-dichloropyrimidine, which is different from Example 2 only in that the solvent of the etherification reaction in step a is replaced with water. The specific steps are as follows:

[0073] Add 300 g of water and 75 g (0.473 mol) of 4,6-dihydroxypyrimidine sodium salt into the reactor, stir to dissolve, raise the temperature to 70°C, introduce chloroform intermittently to 0.4 MPa, and keep the temperature to react until the system pressure no longer decreases. Continue to keep the temperature for 0.5 h, cool to 20-30°C, and HPLC detection shows that only 5.3% of 4-hydroxy-6-methoxypyrimidine is generated in the reaction solution.

[0074] Comparative Example 2

[0075] This comparative example provides a production process of 4,6-dichloropyrimidine, which is different from Example 2 only in that the catalyst for the chlorination reaction in step b is replaced with triethylamine. The specific steps are as follows:

[0076] Step a is exactly the same as in Example 2;

[0077] Step b, add 4g of triethylamine to the dehydrated oil phase, raise the temperature to 70°C, slowly dropwise add a solution of 168.5g of triphosgene (0.568mol) and 253g of 1,2-dichloroethane, the dropwise addition time is 5h, after the dropwise addition is completed, raise the temperature to 83°C and keep warm for 2h, condense the tail gas to -5°C to recover the phosgene during the reaction, absorb the non-condensable chloromethane with N,N-dimethylformamide, absorb the non-condensable N,N-dimethylformamide to increase the weight by 41.3g, detect the content of 4-chloro-6-methoxypyrimidine in the reaction solution to be 14.9%, the total area content of 4,6-dichloropyrimidine to be 84.5%, the content of external standard 4,6-dichloropyrimidine, and the conversion rate is 83.2%.

[0078] Comparative Example 3

[0079] This comparative example provides a production process of 4,6-dichloropyrimidine, which is different from Example 2 only in that the catalyst for the chlorination reaction in step b is replaced with triethylamine. The specific steps are as follows:

[0080] Step a is exactly the same as in Example 2;

[0081] Step b, add 8g of triethylamine to the dehydrated oil phase, raise the temperature to 70°C, slowly dropwise add a solution of 168.5g of triphosgene (0.568mol) and 253g of 1,2-dichloroethane, the dropwise addition time is 5h, after the dropwise addition is completed, raise the temperature to 83°C and keep warm for 2h, condense the tail gas to -5°C to recover the phosgene during the reaction, absorb the non-condensable chloromethane with N,N-dimethylformamide, absorb the non-condensable N,N-dimethylformamide to increase the weight by 42.3g, detect the content of 4-chloro-6-methoxypyrimidine in the reaction solution to be 10.4%, the total area content of 4,6-dichloropyrimidine to be 88.7%, the content of external standard 4,6-dichloropyrimidine, and the conversion rate is 87.3%.

[0082] Comparative Example 4

[0083] This comparative example provides a production process of 4,6-dichloropyrimidine, which is different from Example 2 only in that the catalyst for the chlorination reaction in step b is replaced with potassium carbonate. The specific steps are as follows:

[0084] Step a is exactly the same as in Example 2;

[0085] Step b, add 4g of potassium carbonate to the dehydrated oil phase, raise the temperature to 70°C, slowly dropwise add a solution of 168.5g of triphosgene (0.568mol) and 253g of 1,2-dichloroethane, the dropwise addition time is 5h, after the dropwise addition is completed, raise the temperature to 83°C and keep warm for 2h, condense the tail gas to -5°C to recover the phosgene during the reaction, absorb the non-condensable chloromethane with N,N-dimethylformamide, absorb the non-condensable N,N-dimethylformamide to increase the weight by 2.1g, detect the content of 4-chloro-6-methoxypyrimidine in the reaction solution to be 9.3%, the total area content of 4,6-dimethoxypyrimidine to be 90.2%, and substantially no 4,6-dichloropyrimidine is generated.

[0086] Comparative Example 5

[0087] This comparative example provides a production process of 4,6-dichloropyrimidine, which is different from Example 2 only in that the solvent of the chlorination reaction in step b is replaced with N,N-dimethylformamide. The specific steps are as follows:

[0088] Step a, add 300g N,N-dimethylformamide and 75g (0.473mol) of 4,6-dihydroxypyrimidine sodium salt into the reactor, stir evenly, introduce 60g (1.189mol) of methyl chloride, seal the reactor, heat to 70°C, keep warm until the system pressure no longer decreases, keep warm for 0.5h, cool to 20-30°C, extract excess methyl chloride in the reactor with negative pressure of dry vacuum pump until the pressure in the reactor drops to -0. The temperature was below 090MPa, and the vacuum pump was connected to 0℃ N,N-dimethylformamide to freeze and recover chloromethane. After the chloromethane was recovered, the vacuum was increased to -0.097MPa, and distilled at 70℃ until no fraction was produced. A total of 293g of N,N-dimethylformamide was recovered. 200g of water and 150g of 1,2-dichloroethane were added to the kettle material after the solvent was removed. The mixture was stirred at 60℃ for 0.5h, and the mixture was allowed to stand for separation. 50g of water was added to the oil phase for washing. The washed oil phase was distilled to 50℃.

[0089] -0.090MPa no fraction was produced, 150g of N,N-dimethylformamide was added, and the content of 4,6-dimethoxypyrimidine was detected, and the conversion rate was 92.7%;

[0090] Step b, the oil phase is heated to 70 ° C, and 168.5 g of triphosgene (0.568 mol) and 253 g of N, N-dimethylformamide solution are slowly added dropwise for 5 hours. After the addition is completed, the temperature is raised to 83 ° C and kept warm for 2 hours. During the reaction, the tail gas is condensed to -5 ° C to recover the phosgene, and the non-condensable chloromethane is absorbed by N, N-dimethylformamide. The non-condensable N, N-dimethylformamide is absorbed to increase the weight by 38.7 g. The content of 4-chloro-6-methoxypyrimidine in the reaction solution is detected to be 2.6%, the total area content of 4,6-dichloropyrimidine is 73.8%, and the content of unknown impurities is 23.4%.

[0091] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A clean production process for 4,6-dichloropyrimidine, characterized in that: The steps include: Step a, in a polar organic solvent, 4,6-dihydroxypyrimidine sodium salt and an alkylating agent undergo an etherification reaction to obtain 4,6-dialkoxypyrimidine; Step b, in the presence of a catalyst and a hydrocarbon solvent, the 4,6-dialkoxypyrimidine is subjected to a chlorination reaction with a chlorination agent to obtain 4,6-dichloropyrimidine; wherein the catalyst is an amide substance, and the hydrocarbon solvent is a halogenated alkane or a benzene solvent.

2. The clean production process of 4,6-dichloropyrimidine according to claim 1, characterized in that: The polar organic solvent comprises at least one of acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-diethylformamide or N,N-dimethylacetamide; and / or The alkylating agent comprises at least one of RX or R2SO4, wherein R is selected from a C1-C3 alkyl group, and X is selected from Cl, Br or I.

3. The clean production process of 4,6-dichloropyrimidine according to claim 1, characterized in that: The mass ratio of the polar organic solvent to 4,6-dihydroxypyrimidine sodium salt is (3-10):

1.

4. The clean production process of 4,6-dichloropyrimidine according to claim 1, characterized in that: The molar ratio of the alkylating agent to the sodium salt of 4,6-dihydroxypyrimidine is (2-6):

1.

5. The clean production process of 4,6-dichloropyrimidine according to claim 1, characterized in that: The temperature of the etherification reaction is 40°C to 100°C.

6. The clean production process of 4,6-dichloropyrimidine according to claim 1, characterized in that: The catalyst is one or both of N,N-dimethylformamide and N,N-dimethylacetamide; and / or The alkyl halide is 1,2-dichloroethane or dichloromethane, and the benzene solvent is toluene or xylene; and / or The chlorination agent is at least one of phosgene, diphosgene or triphosgene.

7. The clean production process of 4,6-dichloropyrimidine according to claim 1, characterized in that: The amount of the catalyst added is 2% to 30% of the mass of 4,6-dialkoxypyrimidine; and / or The mass ratio of the hydrocarbon solvent to 4,6-dialkoxypyrimidine is (1-6):1; and / or The molar ratio of Cl to 4,6-dialkoxypyrimidine in the chlorination reagent is (4-10):

1.

8. The clean production process of 4,6-dichloropyrimidine according to claim 1, characterized in that: The temperature of the chlorination reaction is 50°C to 110°C.

9. The clean production process of 4,6-dichloropyrimidine according to any one of claims 1 to 8, characterized in that: The specific steps include: Adding 4,6-dihydroxypyrimidine sodium salt to a polar solvent, mixing evenly, adding an alkylating agent, heating to carry out an etherification reaction, recovering the alkylating agent and the polar organic solvent after the reaction is completed, then adding water and a hydrocarbon solvent to the system, standing to separate phases, washing the oil phase with water and removing water, adding a catalyst and a chlorination agent, heating to carry out a chlorination reaction, and distilling after the reaction is completed to obtain 4,6-dichloropyrimidine; Wherein, the hydrocarbon solvent is a halogenated alkane or a benzene solvent.

10. The clean production process of 4,6-dichloropyrimidine according to claim 9, characterized in that: The oil phase is dehydrated to a water content of less than 0.5%.

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