Preparation process of 2, 4-dichloro-5-bromopyrimidine

Abstract

The invention provides a preparation process of 2, 4-dichloro-5-bromopyrimidine, which comprises the following steps: S1, premixing raw materials: mixing 2, 4-dihydroxypyrimidine, a composite solvent and a selective regulator to form a uniform solution; s2, bromination reaction: adding the solution and a brominating agent into a first section of a microchannel reactor, injecting a catalyst at the same time, and carrying out bromination reaction to obtain a 5-bromo-2, 4-dihydroxypyrimidine intermediate; s3, chlorination reaction: introducing the 5-bromo-2, 4-dihydroxypyrimidine intermediate into a second section of the microchannel reactor, synchronously pumping a composite chlorinating agent and composite alkali, and carrying out chlorination reaction; s4, in-situ removal of by-products: arranging a molecular sieve packed bed at an outlet of the chlorination reaction unit, and adsorbing hydrogen chloride and water generated by the reaction through a by-product removal agent to obtain a reaction liquid; and S5, quenching and post-treatment: carrying out quenching treatment on the reaction liquid, separating and recovering the catalyst, and washing and purifying to obtain the 2, 4-dichloro-5-bromopyrimidine. The method can reduce the emission of three wastes and improve the economical efficiency and environmental protection property of the process.

Description

A preparation process for 2,4-dichloro-5-bromopyrimidine Technical Field

[0001] This invention relates to the field of organic synthesis intermediates, specifically to a preparation process for 2,4-dichloro-5-bromopyrimidine. Background Technology

[0002] 2,4-Dichloro-5-bromopyrimidine is an important class of nitrogen-containing heterocyclic compounds, widely used as a key intermediate in the manufacture of pharmaceutical raw materials and formulations. It is particularly indispensable in the synthesis of antitumor drugs such as cyclin-dependent kinase 4 / 6 inhibitors and epidermal growth factor receptor inhibitors. The purity and preparation efficiency of this compound directly affect the quality and economic viability of subsequent raw materials and formulations. Currently, the preparation of this compound mostly uses 2,4-dihydroxypyrimidine as the starting material, achieving the process through a two-step substitution reaction of bromination and chlorination. Traditional processes often employ batch production in a batch reactor, using conventional halogenating agents, solvents, and alkaline reagents to complete the reaction.

[0003] Existing preparation processes still have significant shortcomings in practical applications: On the one hand, traditional reaction systems exhibit poor regioselectivity for pyrimidine cyclohalogenation reactions, easily generating polysubstituted isomers, requiring complex purification steps to meet the purity requirements of pharmaceutical raw materials and formulations, increasing production costs and reducing efficiency; on the other hand, batch reactions have limited mass and heat transfer efficiency, resulting in long reaction times and large emissions of waste, leading to high environmental treatment costs and hindering efficient and green large-scale production. Therefore, developing a 2,4-dichloro-5-bromopyrimidine preparation process that improves reaction selectivity, reduces impurity content, and simultaneously meets the requirements of efficient production and environmental protection has become an urgent technical problem to be solved in the field of pharmaceutical raw material and formulation manufacturing. Summary of the Invention

[0004] To address the problems existing in the prior art, the present invention provides a preparation process for 2,4-dichloro-5-bromopyrimidine.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] This application discloses a process for preparing 2,4-dichloro-5-bromopyrimidine, comprising the following steps:

[0007] S1. Raw material premixing: Mix 2,4-dihydroxypyrimidine, composite solvent and selectivity regulator to form a homogeneous solution;

[0008] S2, Bromination reaction: A homogeneous solution and brominating agent are added to the first section of a microchannel reactor, and a catalyst is injected at the same time. The reaction conditions are controlled to carry out the bromination reaction to obtain 5-bromo-2,4-dihydroxypyrimidine intermediate.

[0009] S3. Chlorination reaction: The 5-bromo-2,4-dihydroxypyrimidine intermediate is introduced into the second stage of the microchannel reactor, and a composite chlorinating agent and a composite base are pumped in simultaneously to control the reaction conditions for chlorination.

[0010] S4. In-situ removal of byproducts: A molecular sieve packed bed is set at the outlet of the chlorination reaction unit, and hydrogen chloride and water generated in the reaction are adsorbed by the byproduct removal agent to obtain the reaction solution;

[0011] S5. Quenching and post-treatment: The reaction solution is quenched, the catalyst is separated and recovered, and after washing and purification, 2,4-dichloro-5-bromopyrimidine is obtained.

[0012] Using the above technical solution, the composite solvent can form a homogeneous solution between 2,4-dihydroxypyrimidine and the selectivity regulator, avoiding side reactions caused by local concentration unevenness; the selectivity regulator can improve the regioselectivity of the bromination reaction and reduce isomer impurities; the catalyst can promote the efficient bromination and chlorination reactions; the microchannel reactor can carry out the bromination and chlorination reactions in stages, which can precisely control the reaction conditions, enhance the mass and heat transfer efficiency, and shorten the reaction time; the synergistic effect of the composite chlorinating agent and the composite base can optimize the chlorination reaction environment and ensure the efficient chlorination of the 2,4-hydroxyl group; the by-product removal agent promotes the forward reaction by adsorbing hydrogen chloride and water in situ, further reducing side reactions; combined with quenching, catalyst recovery and washing purification steps, not only can the catalyst be recycled, but also high-purity 2,4-dichloro-5-bromopyrimidine can be obtained, while reducing the emission of waste gas, wastewater, and solid waste, and improving the economic and environmental benefits of the process.

[0013] Preferably, the raw materials for preparing 2,4-dichloro-5-bromopyrimidine, by weight, include: 95-105 parts of 2,4-dihydroxypyrimidine, 120-150 parts of brominating agent, 240-310 parts of composite chlorinating agent, 600-800 parts of composite solvent, 20-30 parts of composite alkali, 5-8 parts of selectivity regulator, and 15-25 parts of catalyst; 30-50 parts by weight of by-product removal agent 4A molecular sieve are packed in the molecular sieve packed bed at the outlet of the chlorination reaction unit for in-situ removal of by-products.

[0014] Using the above technical solution, 2,4-dihydroxypyrimidine, as the core raw material, provides the pyrimidine ring skeleton and bromination and chlorination reaction sites, laying the foundation for product formation; the brominating agent enables the bromination reaction of the pyrimidine ring, and the selectivity regulator can improve the regioselectivity of the bromination reaction and reduce the generation of isomer impurities; the composite chlorinating agent can complete the chlorination conversion of the hydroxyl group, and the composite base can regulate the reaction system environment to ensure the efficient and orderly progress of the chlorination reaction; the composite solvent can fully dissolve each raw material component to form a homogeneous reaction system and avoid side reactions caused by local uneven concentration; the catalyst can significantly improve the catalytic efficiency of the bromination and chlorination reactions and accelerate the reaction process; the by-product removal agent 4A molecular sieve removes by-products generated by the chlorination reaction in situ, which can eliminate the inhibitory effect of by-products on the reaction equilibrium, promote the forward reaction, and thus improve the product yield and purity. At the same time, the synergistic effect of each component ensures the stability and reliability of the preparation process.

[0015] Preferably, the brominating agent is N-bromosuccinimide; the composite chlorinating agent is prepared by compounding 200-250 parts by weight of phosphorus oxychloride and 40-60 parts by weight of phosphorus pentachloride supported on nano-silica; the composite solvent is a mixture of acetonitrile and 1,3-dichloropropane in a volume ratio of 2:3-2:4.

[0016] Using the above technical solution, N-bromosuccinimide, as a brominating agent, provides a mild bromide cation active species, enabling selective bromination at specific sites of the pyrimidine ring and avoiding excessive bromination side reactions. In the composite chlorinating agent, phosphorus oxychloride plays a primary role in chlorination and dehydration, promoting the forward chlorination reaction, while nano-silica loaded with phosphorus pentachloride enables the controlled release of chlorine atoms. The combination of the two enhances the selectivity and efficiency of the chlorination reaction. In the composite solvent, acetonitrile improves the solubility of the main raw material 2,4-dihydroxypyrimidine, and 1,3-dichloropropane has good solubility for N-bromosuccinimide, the composite chlorinating agent, and the product. The combination of the two in a volume ratio of 2:3 to 2:4 ensures the homogeneity of the reaction system, eliminates side reactions caused by local concentration gradients, and thus synergistically ensures the orderly and efficient conduct of the bromination and chlorination reactions, improving product purity.

[0017] Preferably, the catalyst is a supported bimetallic ionic liquid catalyst ([Bmim]CuFeCl6 / SAPO-11), and the raw materials for preparing the catalyst include, by weight, 90-110 parts of SAPO-11 molecular sieve, 70-90 parts of 1-butyl-3-methylimidazolium chloride, 40-50 parts of copper chloride dihydrate, and 30-40 parts of ferric chloride hexahydrate.

[0018] Using the above technical solution, SAPO-11 molecular sieve can serve as a support to provide a pore structure, supporting the loading of ionic liquids and metal ions; 1-butyl-3-methylimidazolium chloride can react with copper chloride dihydrate and ferric chloride hexahydrate to form a 1-butyl-3-methylimidazolium copper iron chloride bimetallic ionic liquid, in which the copper ions provided by copper chloride dihydrate and the iron ions provided by ferric chloride hexahydrate can form synergistic catalytic sites, improving the catalytic efficiency of bromination and chlorination reactions; the supported bimetallic ionic liquid catalyst [Bmim]CuFeCl6 / SAPO-11 prepared by the synergistic use of each raw material can regulate the regioselectivity of the reaction through the pore effect of SAPO-11 molecular sieve, while the supported structure gives the catalyst heterogeneous characteristics, laying the foundation for its recovery and reuse.

[0019] Preferably, the catalyst is prepared by the following method:

[0020] (1) Pretreatment: Place SAPO-11 molecular sieve in a muffle furnace and heat it to 540-560℃ at a heating rate of 4-6℃ / min. Keep it heated for 5-7 hours and cool it to room temperature. Then place it in a glove box under nitrogen or argon atmosphere for later use.

[0021] (2) Synthesis of ionic liquid intermediates: Under nitrogen protection, 1-butyl-3-methylimidazolium chloride, copper chloride dihydrate, and ferric chloride hexahydrate were added sequentially to a 500-600 mL three-necked flask. Nitrogen was used for purging throughout the process. Stirring was started and the stirring rate was controlled at 300-400 r / min. The temperature was raised to 75-85℃ and the reaction was stirred continuously for 3-5 h to form a homogeneous [Bmim]CuFeCl6 ionic liquid. The mixture was then cooled to room temperature.

[0022] (3) Loading and activation: The pretreated SAPO-11 molecular sieve was added to [Bmim]CuFeCl6 ionic liquid and impregnated for 5-7 h at 30-40℃ and vacuum degree -0.08~-0.09MPa. Then, the temperature was increased to 110-130℃ at a heating rate of 2-4℃ / min and dried at the above vacuum degree for 9-11 h to obtain the catalyst.

[0023] By employing the above technical solution, the calcination pretreatment of SAPO-11 molecular sieve can remove impurities and moisture from the sieve, ensuring the smooth progress and stability of the subsequent loading process. Synthesizing the ionic liquid intermediate under nitrogen protection ensures sufficient coordination between 1-butyl-3-methylimidazolium chloride and copper chloride dihydrate and ferric chloride hexahydrate, forming a homogeneous [Bmim]CuFeCl6 ionic liquid, laying the foundation for the formation of bimetallic synergistic catalytic active sites. Subsequent vacuum impregnation and drying activation steps promote the uniform entry of the ionic liquid into the SAPO-11 molecular sieve channels and stabilize the loading, ultimately yielding a supported catalyst that combines the pore structure of SAPO-11 molecular sieve with the catalytic activity of bimetallic ions. Simultaneously, the supported structure endows the catalyst with heterogeneous characteristics, providing structural support for its subsequent recovery and reuse.

[0024] Preferably, in step S1, the stirring rate of the raw material premixing is 250-300 r / min, the temperature is 25-30℃, and the time is 8-12 min.

[0025] By adopting the above technical solution, it is possible to ensure that the main raw material 2,4-dihydroxypyrimidine, the composite solvent and the selectivity regulator are fully contacted and dissolved to form a homogeneous and stable mixed system. This homogeneous system can avoid side reactions caused by local material concentration differences in subsequent reaction processes, and at the same time provide a stable material basis for the directional reaction of bromide ions and the 5-position carbon of the pyrimidine ring in the bromination reaction stage, which is conducive to improving the regioselectivity of the reaction and the utilization rate of raw materials.

[0026] Preferably, in step S2, the reaction temperature of the first section of the microchannel reactor is 30-40℃, the pressure is 0.6-0.8MPa (gauge pressure), the residence time is 5-7min, and the catalyst injection rate is 1-4g / min; in step S3, the reaction temperature of the second section of the microchannel reactor is 50-60℃, the pressure is 0.8-1.0MPa (gauge pressure), and the residence time is 8-10min.

[0027] Using the above technical solution, the specific conditions of the first stage of the microchannel reactor are adapted to the reaction characteristics of the bromination reaction, which can promote the release of bromide ions from N-bromosuccinimide and their directional reaction with the 5-carbon of the pyrimidine ring; the specific conditions of the second stage of the microchannel reactor are adapted to the requirements of the chlorination reaction, which can ensure that the chlorination of phosphorus oxychloride and phosphorus pentachloride supported on nano-silica is fully carried out; the synergistic effect of the parameters of the two stages of the reaction not only provides a suitable reaction environment for each step of the reaction, but also reduces side reactions such as excessive halogenation and pyrimidine ring opening, while ensuring sufficient contact of materials and improving the selectivity and conversion rate of the reaction.

[0028] Preferably, in step S3, the chlorination reaction unit is equipped with a static mixing structure, and the fluid linear velocity is controlled to be 0.5-1.5 m / s.

[0029] By adopting the above technical solution, the static mixing structure can enhance the mass transfer effect of the 5-bromo-2,4-dihydroxypyrimidine intermediate, the composite chlorinating agent and the composite base. The fluid linear velocity of 0.5-1.5 m / s can ensure that the materials are fully contacted and mixed evenly, avoiding side reactions such as excessive chlorination caused by excessive local concentration. At the same time, it provides a stable reaction environment for the chlorination reaction of the 2,4-hydroxyl group, promotes the efficient and orderly progress of the chlorination reaction, and is conducive to improving the purity of the product and the reaction conversion rate.

[0030] Preferably, quenching and post-treatment include:

[0031] Quenching: Slowly add the reaction solution to 150-200 parts by weight of an ice-water mixture at 0-5℃, stir at 150-200 r / min until the system is homogeneous, and control the system temperature to not exceed 20℃. After complete quenching, the quenching solution is obtained.

[0032] Catalyst recovery: The quenching solution is passed through a ceramic membrane filter with a pore size of 0.18-0.22μm to separate and recover the catalyst. After washing with ethanol 2-3 times, the filter cake is dried at 95-105℃ for 3-5h and then recovered and reused.

[0033] Washing: Transfer the filtrate into a separatory funnel and wash with 100-150 parts by weight of saturated saline for 8-12 minutes. After standing and separating the layers, discard the aqueous phase. Wash the organic phase with 80-100 parts by weight of deionized water 2-3 times until the pH of the aqueous phase is 7.0-7.5.

[0034] Purification: After drying the organic phase with anhydrous sodium sulfate, the composite solvent was recovered by atmospheric distillation (the fraction at 75-90℃ was collected first to recover acetonitrile). The remaining crude product was distilled under reduced pressure (gauge pressure -0.09~-0.095MPa, temperature 125-135℃) to collect the fraction and recover 1,3-dichloropropane, yielding 2,4-dichloro-5-bromopyrimidine as the final product.

[0035] Using the above technical solution, the unreacted chlorinating agent can be effectively terminated through a low-temperature ice-water system and temperature control, avoiding subsequent side reactions. Catalyst recovery utilizes ceramic membrane filtration to separate the bimetallic ionic liquid catalyst ([Bmim]CuFeCl6 / SAPO-11), which can be reused after washing and drying, reducing production costs. The washing step removes impurities such as salts and residual acids from the system through stepwise washing with saturated brine and deionized water, adjusting the organic phase to neutrality and laying the foundation for subsequent purification. The purification process achieves the recovery and reuse of the composite solvent (acetonitrile-1,3-dichloropropane) through stepwise distillation, while obtaining a high-purity 2,4-dichloro-5-bromopyrimidine product. The overall post-processing ensures product purity and yield, combining green environmental protection with economic efficiency.

[0036] Preferably, the composite alkali is a mixture of triethylamine and 4-dimethylaminopyridine in a weight ratio of 4:1 to 5:1; the selectivity modifier is thiourea dioxide.

[0037] Using the above technical solution, the composite base composed of triethylamine and 4-dimethylaminopyridine can neutralize hydrogen chloride, a byproduct generated in the chlorination reaction. At the same time, 4-dimethylaminopyridine can form an active complex with phosphorus oxychloride in the composite chlorinating agent, reducing the activation energy of the chlorination reaction. The two work together to ensure the efficient conduct of the chlorination reaction. Thiourea dioxide, as a selectivity regulator, can form a transient charge transfer complex with bromide ions, preferentially activating the electrophilic substitution activity of the 5-carbon atom of the pyrimidine ring, inhibiting the 2,6-position parabromination reaction, reducing the formation of isomer impurities, and thus improving the regioselectivity and purity of the product.

[0038] The beneficial effects of this invention are as follows:

[0039] The composite solvent enables 2,4-dihydroxypyrimidine to form a homogeneous solution with the selectivity regulator, avoiding side reactions caused by localized concentration unevenness; the selectivity regulator can improve the regioselectivity of the bromination reaction and reduce isomer impurities; the catalyst can promote the efficient bromination and chlorination reactions; the microchannel reactor can carry out the bromination and chlorination reactions in stages, which can precisely control the reaction conditions, enhance the mass and heat transfer efficiency, and shorten the reaction time; the synergistic effect of the composite chlorinating agent and the composite base can optimize the chlorination reaction environment and ensure the efficient chlorination of the 2,4-hydroxyl group; the by-product removal agent promotes the forward reaction by adsorbing hydrogen chloride and water in situ, further reducing side reactions; combined with quenching, catalyst recovery and washing purification steps, not only can the catalyst be recycled, but also high-purity 2,4-dichloro-5-bromopyrimidine can be obtained, while reducing the emission of waste gas, wastewater, and solid waste, and improving the economic and environmental benefits of the process.

[0040] SAPO-11 molecular sieves can serve as a support, providing a pore structure that supports the loading of ionic liquids and metal ions. 1-Butyl-3-methylimidazolium chloride can react with copper chloride dihydrate and ferric chloride hexahydrate to form a 1-butyl-3-methylimidazolium copper-iron-chloride bimetallic ionic liquid. The copper ions provided by copper chloride dihydrate and the iron ions provided by ferric chloride hexahydrate can form synergistic catalytic sites, improving the catalytic efficiency of bromination and chlorination reactions. The supported bimetallic ionic liquid catalyst [Bmim]CuFeCl6 / SAPO-11, prepared by the synergistic use of various raw materials, can regulate the regioselectivity of the reaction through the pore effect of SAPO-11 molecular sieves. At the same time, the supported structure gives the catalyst heterogeneous characteristics, laying the foundation for its recycling and reuse. Attached Figure Description

[0041] Figure 1 shows the reaction equation for the preparation of 2,4-dichloro-5-bromopyrimidine in this invention. Detailed Implementation

[0042] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0043] Specific information on the raw materials used in the embodiments of this invention is shown in Table 1:

[0044] Table 1. Raw material names and sources

[0045] Component Specifications: Manufacturer 2,4-Dihydroxypyrimidine purity ≥99% Shanghai Fusheng Industrial Co., Ltd., CAS No.: 66-22-8; N-bromosuccinimide purity ≥99.0% Huangshi Jingsheng Biotechnology Co., Ltd., CAS No.: 128-08-5; Phosphorus oxychloride AR (Shanghai Test), ≥99.0%; Sinopharm Chemical Reagent Co., Ltd., Sinopharm No.: 80103061; Nano silica-supported phosphorus pentachloride, phosphorus pentachloride loading 35-40%, particle size 50-80nm Nanjing Xianfeng Nanomaterials Technology Co., Ltd., model XFN-PCl5-SiO2-02; Acetonitrile purity ≥99.9% Shanghai Ke'e Chemical Technology Co., Ltd., CAS No.: 75-05-81,3-dihydroxypyrimidine purity ≥99.9%; Chloropropane purity 98% Jiangsu Runfeng Synthetic Technology Co., Ltd., CAS No.: 142-28-9; Triethylamine purity ≥99.0% Shanghai Anpu Experimental Technology Co., Ltd., Research Reagent / CFEQ-4-520434-00054; Dimethylaminopyridine purity ≥99.8% Maclean Biochemical Technology Co., Ltd., CAS No.: 1122-58-3; Thiourea dioxide, industrial grade, content ≥98%; Jiaen Chemical (Shandong) Co., Ltd.; 4A molecular sieve particle size 0.3-0.8mm, water content ≤0.2%; Shanghai Hengye Molecular Sieve Co., Ltd.; Supported bimetallic ion liquid catalyst, loading 28-32wt%, acidic site density 1.0-1.4mmol / g, preparation method is described below. surface

[0046] Example 1:

[0047] This embodiment discloses a preparation process for 2,4-dichloro-5-bromopyrimidine. The raw materials for preparing 2,4-dichloro-5-bromopyrimidine include: 95g of 2,4-dihydroxypyrimidine, 120g of N-bromosuccinimide, 200g of phosphorus oxychloride, 40g of phosphorus pentachloride supported on nano-silica, 600g of composite solvent, 20g of composite base, 5g of thiourea dioxide, and 15g of catalyst.

[0048] The composite solvent is a mixture of acetonitrile and 1,3-dichloropropane in a volume ratio of 2:3. The composite base is a mixture of triethylamine and 4-dimethylaminopyridine in a weight ratio of 4:1.

[0049] The catalyst is [Bmim]CuFeCl6 / SAPO-11, and the raw materials for preparing the catalyst include: 90g of SAPO-11 molecular sieve, 70g of 1-butyl-3-methylimidazolium chloride, 40g of copper chloride dihydrate, and 30g of ferric chloride hexahydrate.

[0050] The catalyst is prepared as follows:

[0051] (1) Pretreatment: Place SAPO-11 molecular sieve in a muffle furnace, heat it to 540℃ at a heating rate of 4℃ / min, keep it at the temperature for 5h, cool it to room temperature and then place it in a glove box under nitrogen or argon atmosphere for later use.

[0052] (2) Synthesis of ionic liquid intermediates: Under nitrogen protection, 1-butyl-3-methylimidazolium chloride, copper chloride dihydrate and ferric chloride hexahydrate were added sequentially to a 500 mL three-necked flask. Stirring was started and the stirring rate was controlled at 300 r / min. The temperature was raised to 75 °C and the reaction was stirred continuously for 3 h to form a homogeneous [Bmim]CuFeCl6 ionic liquid. The mixture was then cooled to room temperature.

[0053] (3) Loading and activation: The pretreated SAPO-11 molecular sieve was added to [Bmim]CuFeCl6 ionic liquid and impregnated for 5 h at 30 °C and vacuum degree -0.08 MPa. Then, the temperature was increased to 110 °C at a heating rate of 2 °C / min and dried at the above vacuum degree for 9 h to obtain the catalyst.

[0054] The preparation process of 2,4-dichloro-5-bromopyrimidine includes the following steps:

[0055] S1. Raw material premixing: Mix 2,4-dihydroxypyrimidine, composite solvent, and thiourea dioxide, and control the stirring rate at 250 r / min, the temperature at 25℃, and the time at 8 min to form a homogeneous solution;

[0056] S2, Bromination reaction: A homogeneous solution and N-bromosuccinimide were added to the first section of a microchannel reactor, while a catalyst was injected at a rate of 1 g / min. The reaction temperature was controlled at 30 °C, the pressure at 0.6 MPa (gauge pressure), and the residence time at 5 min to carry out the bromination reaction and obtain 5-bromo-2,4-dihydroxypyrimidine intermediate.

[0057] S3. Chlorination reaction: 5-bromo-2,4-dihydroxypyrimidine intermediate is introduced into the second section of the microchannel reactor, and phosphorus oxychloride, nano-silica-supported phosphorus pentachloride and composite base are pumped in simultaneously. The reaction temperature is controlled at 50℃, the pressure is 0.8MPa (gauge pressure) and the residence time is 8min to carry out the chlorination reaction.

[0058] The chlorination reaction unit is equipped with a static mixing structure to control the fluid linear velocity at 0.5 m / s.

[0059] S4. In-situ removal of byproducts: A molecular sieve packed bed is set at the outlet of the chlorination reaction unit. The molecular sieve packed bed is filled with 30g of 4A molecular sieve (byproduct removal agent). The hydrogen chloride and water generated by the reaction are adsorbed by the 4A molecular sieve to obtain the reaction solution.

[0060] S5. Quenching and Post-processing:

[0061] Quenching: Slowly add the reaction solution to 150g of ice-water mixture at 0℃, stir at 150r / min until the system is homogeneous, control the system temperature to not exceed 20℃, and obtain the quenching solution after complete quenching;

[0062] Catalyst recovery: The quenching solution was passed through a ceramic membrane filter with a pore size of 0.18 μm to separate and recover the catalyst. After washing twice with ethanol, the filter cake was dried at 95 °C for 3 h and then recovered and reused.

[0063] Washing: Transfer the filtrate to a separatory funnel, wash with 100g saturated saline for 8 minutes, let stand for separation and discard the aqueous phase. Wash the organic phase twice with 80g deionized water until the pH of the aqueous phase is 7.0-7.5.

[0064] Purification: After drying the organic phase with anhydrous sodium sulfate, the complex solvent was recovered by atmospheric distillation (the fraction at 75℃ was collected first to recover acetonitrile). The remaining crude product was distilled under reduced pressure (vacuum degree -0.09MPa, temperature 125℃) to collect the fraction and recover 1,3-dichloropropane, yielding 182.3g of 2,4-dichloro-5-bromopyrimidine product, with a yield of 94.2%.

[0065] Example 2:

[0066] This embodiment discloses a preparation process for 2,4-dichloro-5-bromopyrimidine. The raw materials for preparing 2,4-dichloro-5-bromopyrimidine include: 105g of 2,4-dihydroxypyrimidine, 150g of N-bromosuccinimide, 250g of phosphorus oxychloride, 60g of phosphorus pentachloride supported on nano-silica, 800g of composite solvent, 30g of composite base, 8g of thiourea dioxide, and 25g of catalyst.

[0067] The composite solvent is a mixture of acetonitrile and 1,3-dichloropropane in a volume ratio of 2:4. The composite base is a mixture of triethylamine and 4-dimethylaminopyridine in a weight ratio of 5:1.

[0068] The catalyst is [Bmim]CuFeCl6 / SAPO-11, and the raw materials for preparing the catalyst include: 110g of SAPO-11 molecular sieve, 90g of 1-butyl-3-methylimidazolium chloride, 50g of copper chloride dihydrate, and 40g of ferric chloride hexahydrate.

[0069] The catalyst is prepared as follows:

[0070] (1) Pretreatment: Place SAPO-11 molecular sieve in a muffle furnace, heat it to 560°C at a heating rate of 6°C / min, keep it heated for 7 hours, cool it to room temperature and then place it in a glove box under nitrogen or argon atmosphere for later use.

[0071] (2) Synthesis of ionic liquid intermediates: Under nitrogen protection, 1-butyl-3-methylimidazolium chloride, copper chloride dihydrate and ferric chloride hexahydrate were added sequentially to a 600 mL three-necked flask. Stirring was started and the stirring rate was controlled at 400 r / min. The temperature was raised to 85 °C and the reaction was stirred continuously for 5 h to form a homogeneous [Bmim]CuFeCl6 ionic liquid. The mixture was then cooled to room temperature.

[0072] (3) Loading and activation: The pretreated SAPO-11 molecular sieve was added to [Bmim]CuFeCl6 ionic liquid and impregnated for 7 h at 40 °C and vacuum degree -0.09 MPa. Then, the temperature was increased to 130 °C at a heating rate of 4 °C / min and dried at the above vacuum degree for 11 h to obtain the catalyst.

[0073] The preparation process of 2,4-dichloro-5-bromopyrimidine includes the following steps:

[0074] S1. Raw material premixing: Mix 2,4-dihydroxypyrimidine, composite solvent, and thiourea dioxide, and control the stirring rate at 300 r / min, the temperature at 30℃, and the time at 12 min to form a homogeneous solution;

[0075] S2, Bromination reaction: A homogeneous solution and N-bromosuccinimide were added to the first section of a microchannel reactor, while a catalyst was injected at a rate of 4 g / min. The reaction temperature was controlled at 40 °C, the pressure at 0.8 MPa (gauge pressure), and the residence time at 7 min to carry out the bromination reaction and obtain 5-bromo-2,4-dihydroxypyrimidine intermediate.

[0076] S3. Chlorination reaction: 5-bromo-2,4-dihydroxypyrimidine intermediate is introduced into the second section of the microchannel reactor, and phosphorus oxychloride, nano-silica-supported phosphorus pentachloride and composite base are pumped in simultaneously. The reaction temperature is controlled at 60℃, the pressure is 1.0MPa (gauge pressure) and the residence time is 10min to carry out the chlorination reaction.

[0077] The chlorination reaction unit is equipped with a static mixing structure to control the fluid linear velocity at 1.5 m / s.

[0078] S4. In-situ removal of byproducts: A molecular sieve packed bed is set at the outlet of the chlorination reaction unit. The molecular sieve packed bed is filled with 50g of 4A molecular sieve (byproduct removal agent). The hydrogen chloride and water generated by the reaction are adsorbed by the 4A molecular sieve to obtain the reaction solution.

[0079] S5. Quenching and Post-processing:

[0080] Quenching: Slowly add the reaction solution to 200g of ice-water mixture at 5℃, stir at 200r / min until the system is homogeneous, control the system temperature not to exceed 20℃, and obtain the quenching solution after complete quenching;

[0081] Catalyst recovery: The quenching solution was passed through a ceramic membrane filter with a pore size of 0.22 μm to separate and recover the catalyst. After washing with ethanol three times, the filter cake was dried at 105 °C for 5 h and then recovered and reused.

[0082] Washing: Transfer the filtrate to a separatory funnel, wash with 150g saturated saline for 12min, let stand for separation and discard the aqueous phase, wash the organic phase with 100g deionized water 3 times until the pH of the aqueous phase is 7.0-7.5.

[0083] Purification: After drying the organic phase with anhydrous sodium sulfate, the complex solvent was recovered by atmospheric distillation (the fraction at 90℃ was collected first to recover acetonitrile). The remaining crude product was distilled under reduced pressure (vacuum degree -0.095MPa, temperature 135℃) to collect the fraction and recover 1,3-dichloropropane, yielding 204.3g of 2,4-dichloro-5-bromopyrimidine product, with a yield of 95.5%.

[0084] Example 3:

[0085] This embodiment discloses a preparation process for 2,4-dichloro-5-bromopyrimidine. The raw materials for preparing 2,4-dichloro-5-bromopyrimidine include: 100g of 2,4-dihydroxypyrimidine, 135g of N-bromosuccinimide, 225g of phosphorus oxychloride, 50g of phosphorus pentachloride supported on nano-silica, 700g of composite solvent, 25g of composite base, 7g of thiourea dioxide, and 20g of catalyst.

[0086] The composite solvent is a mixture of acetonitrile and 1,3-dichloropropane in a volume ratio of 2:3. The composite base is a mixture of triethylamine and 4-dimethylaminopyridine in a weight ratio of 5:1.

[0087] The catalyst is [Bmim]CuFeCl6 / SAPO-11, and the raw materials for preparing the catalyst include: 100g of SAPO-11 molecular sieve, 80g of 1-butyl-3-methylimidazolium chloride, 45g of copper chloride dihydrate, and 35g of ferric chloride hexahydrate.

[0088] The catalyst is prepared as follows:

[0089] (1) Pretreatment: Place SAPO-11 molecular sieve in a muffle furnace, heat it to 550°C at a heating rate of 5°C / min, keep it heated for 6 hours, cool it to room temperature and then place it in a glove box under nitrogen or argon atmosphere for later use.

[0090] (2) Synthesis of ionic liquid intermediate: Under nitrogen protection, 1-butyl-3-methylimidazolium chloride, copper chloride dihydrate and ferric chloride hexahydrate were added sequentially to a 550 mL three-necked flask. Stirring was started and the stirring rate was controlled at 350 r / min. The temperature was raised to 80 °C and the reaction was stirred continuously for 4 h to form a homogeneous [Bmim]CuFeCl6 ionic liquid. The mixture was then cooled to room temperature.

[0091] (3) Loading and activation: The pretreated SAPO-11 molecular sieve was added to [Bmim]CuFeCl6 ionic liquid and impregnated for 6 h at 35 °C and vacuum degree -0.085 MPa. Then, the temperature was increased to 120 °C at a heating rate of 3 °C / min and dried at the above vacuum degree for 10 h to obtain the catalyst.

[0092] The preparation process of 2,4-dichloro-5-bromopyrimidine includes the following steps:

[0093] S1. Raw material premixing: Mix 2,4-dihydroxypyrimidine, composite solvent, and thiourea dioxide, and control the stirring rate at 275 r / min, the temperature at 28℃, and the time at 10 min to form a homogeneous solution;

[0094] S2, Bromination reaction: A homogeneous solution and N-bromosuccinimide were added to the first section of a microchannel reactor, while a catalyst was injected at a rate of 2 g / min. The reaction temperature was controlled at 35 °C, the pressure at 0.7 MPa (gauge pressure), and the residence time at 6 min to carry out the bromination reaction and obtain 5-bromo-2,4-dihydroxypyrimidine intermediate.

[0095] S3. Chlorination reaction: 5-bromo-2,4-dihydroxypyrimidine intermediate is introduced into the second section of the microchannel reactor, and phosphorus oxychloride, nano-silica-supported phosphorus pentachloride and composite base are pumped in simultaneously. The reaction temperature is controlled at 55℃, the pressure is 0.9MPa (gauge pressure) and the residence time is 9min to carry out the chlorination reaction.

[0096] The chlorination reaction unit is equipped with a static mixing structure to control the fluid linear velocity at 1.0 m / s.

[0097] S4. In-situ removal of byproducts: A molecular sieve packed bed is set at the outlet of the chlorination reaction unit. The molecular sieve packed bed is filled with 40g of 4A molecular sieve (byproduct removal agent). The hydrogen chloride and water generated by the reaction are adsorbed by the 4A molecular sieve to obtain the reaction solution.

[0098] S5. Quenching and Post-processing:

[0099] Quenching: Slowly add the reaction solution to 175g of ice-water mixture at 2℃, stir at 175r / min until the system is homogeneous, control the system temperature not to exceed 20℃, and obtain the quenching solution after complete quenching;

[0100] Catalyst recovery: The quenching solution was passed through a ceramic membrane filter with a pore size of 0.20 μm to separate and recover the catalyst. After washing with ethanol three times, the filter cake was dried at 100℃ for 4 h and then recovered and reused.

[0101] Washing: Transfer the filtrate to a separatory funnel, wash with 125g saturated saline for 10min, let stand for separation and discard the aqueous phase. Wash the organic phase 3 times with 90g deionized water until the pH of the aqueous phase is 7.0-7.5.

[0102] Purification: After drying the organic phase with anhydrous sodium sulfate, the complex solvent was recovered by atmospheric distillation (the fraction at 80℃ was collected first to recover acetonitrile). The remaining crude product was distilled under reduced pressure (vacuum degree -0.095MPa, temperature 130℃) to collect the fraction and recover 1,3-dichloropropane, yielding 195.7g of 2,4-dichloro-5-bromopyrimidine product, with a yield of 96.3%.

[0103] Comparative Example 1:

[0104] A preparation process for 2,4-dichloro-5-bromopyrimidine, which differs from Example 3 only in that a supported bimetallic ionic liquid catalyst is not added, while the other components and processes remain unchanged.

[0105] Comparative Example 2:

[0106] A preparation process for 2,4-dichloro-5-bromopyrimidine, which differs from Example 3 only in that the supported bimetallic ionic liquid catalyst is replaced with a monometallic ionic liquid catalyst ([Bmim]CuCl3 / SAPO-11), while the other components and processes remain unchanged.

[0107] Comparative Example 3:

[0108] A preparation process for 2,4-dichloro-5-bromopyrimidine, which differs from Example 3 only in that thiourea dioxide is not added, while the other components and processes remain unchanged.

[0109] Comparative Example 4:

[0110] A preparation process for 2,4-dichloro-5-bromopyrimidine, which differs from Example 3 only in that the composite chlorinating agent (phosphorus oxychloride and nano-silica-supported phosphorus pentachloride) is replaced with single phosphorus oxychloride (275g, the same as the total weight of the composite chlorinating agent in Example 3), and the rest remains unchanged.

[0111] Comparative Example 5:

[0112] A preparation process for 2,4-dichloro-5-bromopyrimidine, which differs from Example 3 only in that the complex base (a mixture of triethylamine and 4-dimethylaminopyridine in a weight ratio of 5:1) is replaced with 25g of triethylamine alone, while the other components and processes remain unchanged.

[0113] Comparative Example 6:

[0114] A preparation process for 2,4-dichloro-5-bromopyrimidine differs from Example 3 only in that the composite solvent (a mixed solvent of acetonitrile and 1,3-dichloropropane in a volume ratio of 2:3) is replaced with 700g of acetonitrile alone, while the other components and processes remain unchanged.

[0115] Comparative Example 7:

[0116] A preparation process for 2,4-dichloro-5-bromopyrimidine, which differs from Example 3 only in that 4A molecular sieve is not added to the molecular sieve packed bed at the outlet of the chlorination reaction unit, while the other components and processes remain unchanged.

[0117] Comparative Example 8:

[0118] A preparation process for 2,4-dichloro-5-bromopyrimidine, which differs from Example 3 only in that the catalyst is replaced with an unsupported 1-butyl-3-methylimidazolium copper iron chloride ionic liquid ([Bmim]CuFeCl6), while the other components and processes remain unchanged.

[0119] The preparation processes of Examples 1-3 and Comparative Examples 1-8 were tested for product purity, isomer impurity content, 5-bromine substitution selectivity, catalyst activity retention rate, waste acid generation, total reaction time, product melting point, solvent recovery rate, and batch-to-batch relative standard deviation. The testing methods and standards are as follows:

[0120] (a) Product purity testing

[0121] The purity of the product was determined by high performance liquid chromatography (HPLC) in accordance with the "General Rules for High Performance Liquid Chromatography of Chemical Reagents" (GB / T 9721-2006).

[0122] 1. Sample pretreatment: Accurately weigh 0.1 g of 2,4-dichloro-5-bromopyrimidine product (accurate to 0.0001 g), place it in a 100 mL volumetric flask, add acetonitrile, sonicate to dissolve and dilute to the mark, shake well and filter through a 0.22 μm organic phase filter membrane, and take the filtrate as the test solution;

[0123] 2. Detection instrument: Agilent 1260 Infinity II high-performance liquid chromatograph;

[0124] 3. Chromatographic conditions: Column: Waters XBridge C18 (4.6 mm × 250 mm, 5 μm); Mobile phase: Acetonitrile: 0.02 mol / L potassium dihydrogen phosphate buffer (pH = 3.5) = 70:30 (volume ratio); Flow rate: 1.0 mL / min; Detection wavelength: 254 nm; Column temperature: 30 °C; Injection volume: 20 μL.

[0125] 4. Determination and calculation: Inject the test solution into the high performance liquid chromatograph, record the chromatogram, and calculate the purity using the area normalization method. Purity (%) = (target product main peak area / total peak area) × 100%.

[0126] (ii) Detection of isomer impurity content

[0127] The content of isomer impurities was determined by gas chromatography-mass spectrometry (GC-MS) according to the standard GB / T 32263-2015, "Determination of Trace Impurities in Organic Chemical Products by Gas Chromatography-Mass Spectrometry". The instrument used was a Thermo ISQ 7000 GC-MS system with an HP-5MS column (30m × 0.25mm × 0.25μm). The programmed temperature conditions were: initial temperature of 60℃ for 2 min, then ramping to 200℃ at a rate of 10℃ / min and holding for 5 min; the ion source temperature was 230℃. Quantification was performed using the internal standard method (o-xylene as the internal standard). The isomer impurity content (%) was calculated as: (isomer peak area × internal standard mass × correction factor) / (internal standard peak area × sample mass) × 100%.

[0128] (III) Selective Detection of 5-Bromo Substitution

[0129] 5-Bromo substitution selectivity was determined by proton nuclear magnetic resonance spectroscopy (NMR). 1 Detection was performed by nuclear magnetic resonance (NMR) according to the "General Rules for Determination of the Structure of Organic Compounds by Nuclear Magnetic Resonance Spectroscopy" (GB / T 2366-2008). The instrument used was a Bruker AVANCE III 400MHz NMR spectrometer, and the solvent was deuterated chloroform (CDCl3). The chemical shift of the characteristic peak of the 5-position hydrogen atom of the pyrimidine ring was δ=8.0-8.2ppm. This peak disappeared after bromine substitution. Selectivity (%) = (1 - integral area of ​​residual peak / integral area of ​​standard peak) × 100%.

[0130] (iv) Detection of catalyst activity retention rate

[0131] The catalyst activity retention rate was determined by a recycling experiment. The recovered catalyst was washed with ethanol three times and dried at 100°C for 4 hours. The same preparation reaction was repeated eight times. The product yields of the first and eighth reactions were recorded. The calculation formula was: Activity retention rate (%) = (yield of the eighth reaction / yield of the first reaction) × 100%.

[0132] (v) Detection of waste acid generation

[0133] The amount of waste acid generated was determined by neutralization titration, referring to "Preparation of Standard Solutions for Titration Analysis (Volume Analysis) of Chemical Reagents" (GB / T 601-2016). 10 mL of the quenched aqueous phase was taken, phenolphthalein indicator was added, and titrated to the endpoint with 0.5 mol / L sodium hydroxide standard solution. The volume of sodium hydroxide standard solution consumed was recorded. The hydrogen ion concentration (H+) in the aqueous phase was calculated based on the consumed volume. + The molar amount is converted into the amount of waste acid generated per kilogram of product (calculated as hydrogen chloride). The calculation formula is: Waste acid generation (kg / kg product) = (volume of sodium hydroxide consumed × 0.5 × 36.46) / (sample mass × 1000).

[0134] (vi) Record of total reaction time

[0135] The total reaction time is the cumulative time from the start of raw material premixing to the end of the chlorination reaction, recorded using a timer with an accuracy of 0.1 min, excluding post-processing time.

[0136] (vii) Product melting point testing

[0137] The melting point of the product was determined by the capillary method, referring to the Pharmacopoeia of the People's Republic of China (General Chapter 0612, 2020 edition). The testing instrument was a Buchi M-565 melting point apparatus with a capillary inner diameter of 1.0-1.2 mm and a heating rate of 1℃ / min. The temperature range from the start of melting to complete melting of the sample was recorded.

[0138] (viii) Solvent recovery rate test

[0139] Solvent recovery rate is calculated by the mass of solvent recovered by distillation. The calculation formula is: Solvent recovery rate (%) = (mass of recovered solvent / mass of input solvent) × 100%. The mass of recovered solvent is weighed using an analytical balance with an accuracy of 0.1 mg.

[0140] (ix) Batch-to-batch relative standard deviation (RSD) testing

[0141] Three batches of preparation experiments were conducted consecutively, and the product yield, purity and isomer impurity content of each batch were determined. The relative standard deviation of each index was calculated using the formula: RSD (%) = (standard deviation / average value) × 100%.

[0142] The results are shown in Table 2.

[0143] Table 2. Test results of the core performance of 2,4-dichloro-5-bromopyrimidine obtained in Examples 1-3 and Comparative Examples 1-8

[0144] Group | Product Yield (%) | Product Purity (%) | Isomer Impurity Content (%) | 5-Bromo Substitution Selectivity (%) | Melting Point (°C) | Example 1 | 94.2 | 99.5 | 0.2 | 8 | 99.7 | 29.8 | -30.1 | Example 2 | 95.5 | 99.7 | 0.2 | 1 | 99.8 | 29.8 | -30.3 | Example 3 | 96.3 | 99.8 | 0.1 | 7 | 99.9 | 29.9 | -30.4 | Comparative Example 1 | 89.6 | 98.6 | 0.5 | 2 | 99.2 | 29.3 | -30.6 | Comparative Example 2 | 92.4 | 99.2 | 0.3 | 8 | 99.4 | 29 0.5-30.5 Comparative Example 391.899.00.4599.329.4-30.7 Comparative Example 494.099.50.2499.729.8-30.4 Comparative Example 594.399.60.2299.829.8-30.5 Comparative Example 693.199.30.3399.529.6-30.6 Comparative Example 795.299.70.2099.829.9-30.4 Comparative Example 890.198.70.4899.229.3-30.7 surface

[0145] Table 3. Results of process performance and catalyst stability tests of 2,4-dichloro-5-bromopyrimidine obtained in Examples 1-3 and Comparative Examples 1-8

[0146] Group | Total Reaction Time (min) | Waste Acid Generation (kg / kg Product) | Catalyst Activity Retention (%) | Solvent Recovery (%) | Batch-to-Batch RSD (%) | Example 1 | 19.8 | 0.06 | 85.3 | 90.2 | 1.4 | Example 2 | 17.5 | 0.05 | 87.6 | 92.5 | 1.2 | Example 3 | 15.2 | 0.04 | 89.5 | 94.3 | 1.1 | Comparative Example 1 | 23.7 | 0.10 | -90.0 | 1.6 | Comparative Example 2 | 20.30 0.0784.291.81.4 Comparative Example 3 19.90.0989.192.61.5 Comparative Example 4 17.60.0689.793.51.2 Comparative Example 5 17.30.0589.593.91.2 Comparative Example 6 21.20.0888.991.11.5 Comparative Example 7 18.50.0689.894.11.2 Comparative Example 8 23.10.0977.391.61.7 surface

[0147] Using Example 3 as the control group, the performance differences and causes of Comparative Examples 1-8 are analyzed as follows:

[0148] (a) Catalyst-related comparative examples (Comparative Examples 1, 2, and 8)

[0149] Comparative Example 1 (without catalyst): The product yield decreased from 96.3% in Example 3 to 89.6%, a decrease of 6.9%; the isomer impurity content increased from 0.17% to 0.52%, an increase of 206%; and the reaction time increased from 15.2 min to 23.7 min, an increase of 55.9%. This is because the lack of active sites provided by the supported bimetallic ionic liquid catalyst slightly reduced the bromide cation release efficiency of N-bromosuccinimide and the chlorination activity of phosphorus oxychloride. Furthermore, the absence of nano-confinement effects to regulate substrate conformation led to a slight increase in side reactions, a slight decrease in product yield and selectivity, and a slower reaction rate.

[0150] Comparative Example 2 (single metal catalyst): Product yield was 92.4%, a decrease of 4.1% compared to Example 3; isomer impurity content was 0.38%, an increase of 124% compared to Example 3. The reason is that copper ions alone can only promote the bromination reaction and cannot synergistically enhance the chlorination reaction activity with iron ions. The lack of bimetallic synergistic catalysis resulted in a slightly lower reaction rate and selectivity than in Example 3.

[0151] Comparative Example 8 (without catalyst): Product yield was 90.1%, a decrease of 6.4% compared to Example 3; catalyst activity retention was only 77.3%, a decrease of 13.6% compared to Example 3; waste acid generation was 0.09 kg / kg product, an increase of 125% compared to Example 3. The reasons are: the lack of the nano-confinement effect of SAPO-11 molecular sieves prevented the substrate conformation from oriented, resulting in decreased regioselectivity; furthermore, the ionic liquid lacked support, leading to severe loss of active components during recovery and rapid decay of catalytic activity; simultaneously, the homogeneous catalyst could not effectively disperse acidic species in the reaction system, resulting in increased waste acid generation.

[0152] (II) Comparative examples of selectivity regulators and reaction media (Comparative examples 3, 4, 5, and 6)

[0153] Comparative Example 3 (without thiourea dioxide): The content of isomer impurities was 0.45%, which was 165% higher than that of Example 3; the yield was 91.8%, which was 4.7% lower than that of Example 3. The reason is that the lack of the charge transfer complex formed by thiourea dioxide and bromide ions prevented the effective inhibition of the 2,6-position parabromination reaction of the pyrimidine ring, resulting in an increase in isomers and a slight decrease in the utilization rate of raw materials.

[0154] Comparative Example 4 (single chlorinating agent): yield 94.0%, a decrease of 2.4% compared to Example 3; solvent recovery rate 93.5%, a decrease of 0.8% compared to Example 3. The reason is the lack of controlled chlorination function of phosphorus pentachloride supported on nano-silica, the excessively high reactivity of phosphorus oxychloride, and the excessively high local concentration leading to a small amount of over-chlorination byproducts, resulting in a slight decrease in product yield.

[0155] Comparative Example 5 (Single Compound Alkali): Yield 94.3%, a decrease of 2.1% compared to Example 3; Waste acid production was 0.05 kg / kg of product, the same as in Example 3. The reason is the lack of complexation activation between 4-dimethylaminopyridine and phosphorus oxychloride, resulting in a higher activation energy for the chlorination reaction and a slightly lower reaction rate. However, triethylamine alone can still meet the requirements for neutralizing hydrogen chloride, so the waste acid production did not change significantly.

[0156] Comparative Example 6 (single solvent): yield 93.1%, a decrease of 3.3% compared to Example 3; isomer impurity content 0.33%, an increase of 94% compared to Example 3. The reason is that acetonitrile alone has poor solubility in phosphorus oxychloride, resulting in an inhomogeneous chlorination reaction system. Local concentration gradients triggered a small number of side reactions, leading to a slight decrease in product yield and selectivity.

[0157] (III) Comparative Examples Related to Processes and Equipment (Comparative Example 7)

[0158] Comparative Example 7 (without molecular sieve): Yield 95.2%, 1.1% lower than Example 3; reaction time 18.5 min; waste acid production 0.06 kg / kg product, 50% higher than Example 3. The reason is that the hydrogen chloride and water generated in the reaction could not be removed in time, slightly inhibiting the forward halogenation reaction, slowing down the reaction rate, and the hydrogen chloride made the system slightly more acidic, resulting in a slight increase in waste acid production.

[0159] In summary, the supported bimetallic ionic liquid catalyst significantly improves reaction selectivity and catalytic efficiency through nano-confinment effect and bimetallic synergistic catalysis, keeping the content of isomer impurities below 0.3% and allowing the catalyst to be recycled more than 8 times. The composite chlorinating agent and composite base synergistically optimize the chlorination reaction environment, reducing the amount of chlorinating agent used and the generation of waste acid; the composite solvent ensures reaction homogeneity, and the microchannel process enhances mass transfer, significantly shortening the reaction time. Thiourea dioxide and the catalyst form dual selectivity control, and the in-situ removal of byproducts by 4A molecular sieves promotes the forward reaction.

[0160] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A process for preparing 2,4-dichloro-5-bromopyrimidine, characterized in that, The process includes the following steps: S1, Raw material premixing: 2,4-dihydroxypyrimidine, a composite solvent, and a selectivity regulator are mixed to form a homogeneous solution; S2, Bromination reaction: The homogeneous solution and the brominating agent are added to the first section of a microchannel reactor, and a catalyst is injected simultaneously. The reaction conditions are controlled to carry out the bromination reaction, yielding a 5-bromo-2,4-dihydroxypyrimidine intermediate; S3, Chlorination reaction: The 5-bromo-2,4-dihydroxypyrimidine intermediate is introduced into the second section of the microchannel reactor, and a composite chlorinating agent and a composite base are pumped in simultaneously. The reaction conditions are controlled to carry out the chlorination reaction; S4, In-situ removal of byproducts: A molecular sieve packed bed is set at the outlet of the chlorination reaction unit. Hydrogen chloride and water generated in the reaction are adsorbed by a byproduct removal agent to obtain a reaction solution; S5, Quenching and post-treatment: The reaction solution is quenched, the catalyst is separated and recovered, and after washing and purification, the 2,4-dichloro-5-bromopyrimidine product is obtained.

2. The preparation process of 2,4-dichloro-5-bromopyrimidine according to claim 1, characterized in that, The raw materials for preparing 2,4-dichloro-5-bromopyrimidine, by weight, include: 95-105 parts of 2,4-dihydroxypyrimidine, 120-150 parts of brominating agent, 240-310 parts of composite chlorinating agent, 600-800 parts of composite solvent, 20-30 parts of composite alkali, 5-8 parts of selectivity regulator, and 15-25 parts of catalyst; 30-50 parts by weight of by-product removal agent are packed into the molecular sieve packed bed at the outlet of the chlorination reaction unit for in-situ removal of by-products.

3. The preparation process of 2,4-dichloro-5-bromopyrimidine according to claim 2, characterized in that, The brominating agent is N-bromosuccinimide; the composite chlorinating agent is composed of 200-250 parts by weight of phosphorus oxychloride and 40-60 parts by weight of phosphorus pentachloride supported on nano-silica; the composite solvent is a mixture of acetonitrile and 1,3-dichloropropane in a volume ratio of 2:3-2:

4.

4. The preparation process of 2,4-dichloro-5-bromopyrimidine according to claim 2, characterized in that, The catalyst is a supported bimetallic ionic liquid catalyst. By weight, the raw materials for preparing the catalyst include: 90-110 parts of SAPO-11 molecular sieve, 70-90 parts of 1-butyl-3-methylimidazolium chloride, 40-50 parts of copper chloride dihydrate, and 30-40 parts of ferric chloride hexahydrate.

5. The preparation process of 2,4-dichloro-5-bromopyrimidine according to claim 4, characterized in that, The catalyst is prepared as follows: (1) Pretreatment: SAPO-11 molecular sieve is placed in a muffle furnace and heated to 540-560℃ at a heating rate of 4-6℃ / min, and calcined for 5-7h; (2) Synthesis of ionic liquid intermediate: Under nitrogen protection, 1-butyl-3-methylimidazolium chloride, copper chloride dihydrate, and ferric chloride hexahydrate are added sequentially to a 500-600mL three-necked flask, stirring is started, the stirring rate is controlled at 300-400r / min, and the temperature is raised to 75-80℃. 5℃, continuously stir the reaction for 3-5h to form a homogeneous [Bmim]CuFeCl6 ionic liquid, and cool to room temperature; (3) Loading and activation: add the pretreated SAPO-11 molecular sieve into the [Bmim]CuFeCl6 ionic liquid, impregnate it for 5-7h at 30-40℃ and vacuum degree -0.08~-0.09MPa, then raise the temperature to 110-130℃ at a heating rate of 2-4℃ / min, and dry it at the above vacuum degree for 9-11h to obtain the catalyst.

6. The preparation process of 2,4-dichloro-5-bromopyrimidine according to claim 1, characterized in that, In step S1, the stirring rate for premixing the raw materials is 250-300 r / min, the temperature is 25-30℃, and the time is 8-12 min.

7. The preparation process of 2,4-dichloro-5-bromopyrimidine according to claim 1, characterized in that, In step S2, the reaction temperature of the first section of the microchannel reactor is 30-40℃, the pressure is 0.6-0.8MPa, the residence time is 5-7min, and the catalyst injection rate is 1-4g / min; in step S3, the reaction temperature of the second section of the microchannel reactor is 50-60℃, the pressure is 0.8-1.0MPa, and the residence time is 8-10min.

8. The preparation process of 2,4-dichloro-5-bromopyrimidine according to claim 1, characterized in that, In step S3, the chlorination reaction unit is set with a static mixing structure, and the fluid linear velocity is controlled to be 0.5-1.5 m / s.

9. The preparation process of 2,4-dichloro-5-bromopyrimidine according to claim 1, characterized in that, Quenching and post-treatment include: Quenching: Slowly add the reaction solution to 150-200 parts by weight of an ice-water mixture at 0-5℃, stir at 150-200 r / min until the system is homogeneous, and control the system temperature to not exceed 20℃ to obtain the quenching solution; Catalyst recovery: Pass the quenching solution through a ceramic membrane filter with a pore size of 0.18-0.22 μm to separate and recover the catalyst, wash it 2-3 times with ethanol, and dry the filter cake at 95-105℃ for 3-5 h for recycling; Washing Washing: Transfer the filtrate into a separatory funnel and wash with 100-150 parts by weight of saturated saline for 8-12 minutes. After standing and separating the layers, discard the aqueous phase. Wash the organic phase with 80-100 parts by weight of deionized water 2-3 times until the pH of the aqueous phase is 7.0-7.

5. Purification: After drying the organic phase with anhydrous sodium sulfate, recover the acetonitrile in the composite solvent by atmospheric distillation. The remaining crude product is recovered from the 1,3-dichloropropane in the composite solvent by vacuum distillation to obtain the 2,4-dichloro-5-bromopyrimidine product.

10. The preparation process of 2,4-dichloro-5-bromopyrimidine according to claim 1, characterized in that, The composite alkali is a mixture of triethylamine and 4-dimethylaminopyridine in a weight ratio of 4:1 to 5:1; the selectivity modifier is thiourea dioxide.

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