The invention relates to a method for preparing N, Napos by using solid triphosgene. High-purity preparation method of-carbonyl diimidazole

Abstract

The invention discloses a high-purity preparation method of N, N '-carbonyldiimidazole by using solid triphosgene, and relates to the technical field of organic synthesis.The high-purity preparation method comprises the steps that S1, raw materials are pretreated, and a reaction system is built; s2, optimizing a reaction process; s3, by-product treatment and product separation; s4, performing post-treatment and quality monitoring on the product; and S5, product post-processing and quality monitoring. According to the method, by means of by-product treatment and product separation, residual raw materials can be neutralized, water-soluble impurities can be extracted and separated, the product is subjected to preliminary separation and refining, then elution, crystallization and purification treatment are conducted, different types of impurities are treated in each step, and the content of various impurities in the product is gradually reduced through multi-stage treatment; and finally, the high purity of the product is ensured, the high-purity preparation of N, N '-carbonyldiimidazole is realized, a real-time monitoring and fine tuning mechanism is established, the reaction process is more stable and controllable, and the production efficiency and the consistency of the product quality are improved.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly to a method for preparing high-purity N,N'-carbonyldiimidazole using solid triphosgene. Background Art

[0002] Solid triphosgene, also known as trichloromethyl carbonate, is a relatively stable solid compound with reaction activity similar to that of phosgene and can replace phosgene in many reactions. Using solid triphosgene to replace phosgene for preparing CDI can reduce production risks and improve production safety.

[0003] When preparing N,N'-carbonyldiimidazole using solid triphosgene, various by-products will be generated during the reaction process. The separation of these by-products from N,N'-carbonyldiimidazole is relatively difficult, and conventional separation methods cannot completely remove impurities, affecting the product purity. Summary of the Invention

[0004] The purpose of the present invention is to provide a method for preparing high-purity N,N'-carbonyldiimidazole using solid triphosgene to solve the problem that when preparing N,N'-carbonyldiimidazole using solid triphosgene as mentioned in the above background art, various by-products will be generated during the reaction process, the separation of these by-products from N,N'-carbonyldiimidazole is relatively difficult, and conventional separation methods cannot completely remove impurities, affecting the product purity.

[0005] To achieve the above purpose, the present invention provides the following technical solution: A method for preparing high-purity N,N'-carbonyldiimidazole using solid triphosgene, comprising the following steps:

[0006] S1. Pretreatment of raw materials and construction of reaction system: Select solid triphosgene raw materials, treat the solid triphosgene to obtain high-purity solid triphosgene, dry imidazole in a vacuum oven at a drying temperature of 60°C for 4 hours to complete the pretreatment of the raw materials, and assemble the reaction device to complete the construction of the reaction system;

[0007] S2. Optimization of reaction process: Add the dried imidazole and mixed solvent into the reaction device for low-temperature pre-reaction. After the pre-reaction is completed, adjust the temperature to rise and enter the main reaction stage of temperature rise. During this period, monitor the reaction progress in real time through thin-layer chromatography (TLC);

[0008] S3. Treatment of by-products and separation of products: Through the conversion and removal of by-products, neutralize the residual raw materials, and separate water-soluble impurities by extraction. Then, preliminarily separate and refine the product, successively perform drying to remove water, vacuum distillation for concentration, crystallization and precipitation and washing, and finally perform antisolvent crystallization purification to complete the overall impurity removal;

[0009] S4. Post-treatment and quality monitoring of the product: The product is subjected to fractional crystallization. The crystals after fractional crystallization are collected by suction filtration, dried in a vacuum oven at 50 °C for 5 hours to obtain the N,N'-carbonyldiimidazole product. The purity of the product is detected by high-performance liquid chromatography. If the standard is not met, the fractional crystallization and drying steps are repeated until the product purity is qualified.

[0010] S5. Product verification and packaging: The product purity is verified again. After verification, the N,N'-carbonyldiimidazole product is sealed and packaged for storage.

[0011] Preferably, in S1, when treating the solid triphosgene, recrystallization purification is first carried out. The solid triphosgene is dissolved in an appropriate amount of anhydrous dichloromethane, heated to reflux until completely dissolved, then slowly cooled to 0 °C, white crystals are precipitated, filtered and washed with cold anhydrous dichloromethane, and dried in vacuum to obtain high-purity solid triphosgene.

[0012] Preferably, in S1, the reaction device is equipped with a high-efficiency stirrer, a high-precision thermometer, and a constant-pressure dropping funnel, and is fully enclosed with a reflux condenser tube and protected by inert gas. The reaction device is pre-purged with nitrogen to fully displace the air to ensure an oxygen-free and water-free reaction environment. The solvent is a mixed solvent of tetrahydrofuran and toluene that has been treated for water removal, with a volume ratio of 3:2.

[0013] Preferably, in S2, during the low-temperature pre-reaction, dried imidazole and the mixed solvent are added to the reaction device, stirred to dissolve, cooled to -10 °C to -5 °C, and a tetrahydrofuran solution of solid triphosgene is slowly added dropwise through the constant-pressure dropping funnel. The molar ratio of solid triphosgene to imidazole is controlled at 1:4.5, and the dropping time is 1.5 to 2 hours. During this process, the stirring speed is maintained at 300 to 400 revolutions per minute to initially form a reaction intermediate. During the temperature increase adjustment, the temperature is slowly increased to 20 °C to 25 °C at a rate of 0.5 °C per minute, and the reaction continues for 4 to 5 hours.

[0014] Preferably, in S3, when neutralizing the residual raw materials, triethylamine is added to the reaction system. Triethylamine can react with the residual solid triphosgene and the phosgene generated by its decomposition to form stable salt by-products. During the extraction and separation, deionized water is added and stirred for 15 minutes. The water-soluble by-products such as imidazole hydrochloride generated by the reaction will transfer to the aqueous phase, while N,N'-carbonyldiimidazole remains in the organic phase. Subsequently, the organic phase is separated through a separating funnel.

[0015] Preferably, in S3, the organic phase is dried with anhydrous magnesium sulfate for 2 - 3 hours to remove water. During vacuum distillation, most of the solvent is first distilled off at 40°C and 0.08 MPa to reduce the solvent content and preliminarily concentrate the target product. Then, the temperature is raised to 60°C and 0.09 MPa to further distill off the residual solvent, obtaining crude CDI. When refining the product, anhydrous ether is selected as the good solvent and n - hexane as the anti - solvent. The crude CDI after primary crystallization is added to anhydrous ether, heated to 40°C and stirred until dissolved, filtered through a polytetrafluoroethylene membrane. n - hexane is added dropwise to the ether solution while maintaining a stirring speed of 200 revolutions per minute. After the addition is complete, stirring is continued for 30 minutes, then stirring is stopped, and the mixture is left to stand at 25°C for 1 hour. A Buchner funnel equipped with a filter paper with a pore size of 10 μm is used, and the vacuum is controlled at 0.06 MPa to quickly separate the crystals, and the crystals are washed twice with cold n - hexane to remove the adsorbed ether and trace impurities on the surface.

[0016] Preferably, in S4, when detecting the product purity, the following contents are also included:

[0017] S41. High - performance liquid chromatography purity detection: Turn on the high - performance liquid chromatograph and preheat the instrument to a stable state. Set the detection wavelength to 254 nm, use acetonitrile - water with a volume ratio of 60:40 as the mobile phase, set the flow rate to 1.0 mL / minute, equilibrate the chromatographic column, prepare the sample and inject it for detection, and make a result determination according to the detection results;

[0018] S42. Melting point determination: Preheat the melting point apparatus, place the capillary tube containing the sample into the heating bath of the melting point apparatus and heat it, observe the melting process of the sample, record the initial melting and complete melting temperatures, and compare the measured melting point with the standard melting point range of N,N'-carbonyldiimidazole. If it is within the standard range, it indicates that the purity and structure of the sample meet the requirements; if it deviates from the standard range, it indicates the presence of impurities or abnormal structure;

[0019] S43. Infrared spectrum analysis: Prepare the sample by the tablet - pressing method, place the prepared sample thin slice into the sample cell of the infrared spectrometer, scan the infrared spectrum of the sample, and analyze the results after obtaining the infrared spectrum diagram of the sample to judge whether the structure of the sample is correct.

[0020] Preferably, in S41, when preparing the sample, weigh the prepared N,N'-carbonyldiimidazole sample, dissolve and make up the volume with the mobile phase acetonitrile - water to prepare a sample solution, filter it through a 0.45 - μm membrane to remove insoluble impurities, and take the filtrate as the sample to be measured. When making a result determination, if the purity of N,N'-carbonyldiimidazole in the sample reaches more than 99%, the product is judged to be qualified.

[0021] Preferably, in S43, when preparing the sample by the tabletting method, the dried N,N'-carbonyldiimidazole sample and the dried potassium bromide powder are mixed evenly at a ratio of 1:100 - 1:200, ground into a fine powder, transferred to a tabletting mold, and pressed into a transparent thin sheet at 8 - 10 MPa.

[0022] Preferably, in S43, the infrared spectrum of the sample is scanned, and the scanning range is 4000 - 400 cm -1 , and the number of scanning times is 32 - 64 times.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] 1. In the present invention, through by-product treatment and product separation, residual raw materials can be neutralized, water-soluble impurities can be extracted and separated, the product can be preliminarily separated and refined, and then recrystallization purification treatment is carried out by salting-out. Each step treats different types of impurities, and the content of various impurities in the product is gradually reduced through multi-stage treatment, realizing high-purity, high-efficiency, and safe production of CDI, ultimately ensuring the high purity of the product and achieving the high-purity preparation of N,N'-carbonyldiimidazole;

[0025] 2. In the present invention, through strict pretreatment of solid triphosgene and reaction in a fully enclosed inert gas protection device and other measures, the risk of phosgene leakage is greatly reduced, the safety and health of operators are guaranteed, the potential harm to the environment is reduced, and the reaction conditions including temperature, time, raw material ratio, stirring speed are precisely controlled, and a real-time monitoring and fine-tuning mechanism is established, making the reaction process more stable and controllable, reducing side reactions and product quality instability caused by fluctuations in reaction conditions, and improving production efficiency and product quality consistency. Description of the Drawings

[0026] Figure 1 It is a flowchart of a method for preparing high-purity N,N'-carbonyldiimidazole using solid triphosgene according to the present invention. Detailed Embodiments

[0027] The following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0028] Example 1: Refer to Figure 1Shown: A method for the high-purity preparation of N,N'-carbonyldiimidazole using solid triphosgene. Through by-product treatment and product separation, residual raw materials can be neutralized, water-soluble impurities can be extracted and separated, the product can be preliminarily separated and refined, and then fractional crystallization purification treatment can be carried out to achieve the high-purity preparation of N,N'-carbonyldiimidazole.

[0029] I. Core technical principle

[0030] (I) Raw material pretreatment and reaction environment control - reducing impurity introduction from the source

[0031] Refinement of solid triphosgene

[0032] Remove impurities (such as carbonate derivatives) in the raw materials through recrystallization (dissolve in anhydrous dichloromethane → crystallize at 0 °C → wash with cold solvent) to ensure the purity of solid triphosgene and prevent impurities from participating in the reaction to form by-products.

[0033] Imidazole drying: Vacuum dry at 60 °C for 4 hours to completely remove moisture and prevent water from reacting with solid triphosgene to form phosgene or causing the hydrolysis of CDI.

[0034] Inert gas protection and anhydrous solvent

[0035] The reaction device is pre-purged with nitrogen to replace the air, and the solvent (tetrahydrofuran:toluene = 3:2) is treated anhydrously (reflux distillation with sodium metal) to create an anhydrous and anaerobic environment, inhibit the hydrolysis of solid triphosgene and the oxidation of imidazole, and ensure the specificity of the reaction.

[0036] Equipment precision control: A high-efficiency stirrer ensures uniform mixing of raw materials, and a high-precision thermometer avoids side reactions caused by local overheating.

[0037] (II) Reaction process optimization - controlling the main and side reaction paths in stages

[0038] Low-temperature pre-reaction

[0039] Molar ratio and dropping control: Solid triphosgene:imidazole = 1:4.5 (imidazole in excess), slowly drop by a constant-pressure dropping funnel to evenly disperse solid triphosgene and preferentially generate a monoimidazole carbonyl intermediate to avoid polycarbonylation by-products (such as bisimidazole carbonate).

[0040] Kinetic advantage: Low temperature reduces the reaction activity, inhibits side reactions, and ensures the high-purity generation of the intermediate.

[0041] Heating main reaction

[0042] Gradient heating: Slowly heat at a rate of 0.5 °C / minute, and monitor the reaction progress in real time by TLC (the Rf value of the target product is about 0.6) to promote the complete conversion of the intermediate to CDI and avoid the decomposition of CDI or the generation of impurities due to long-term reaction.

[0043] Dynamic adjustment: fine-tune the temperature and stirring speed according to the changes in TLC spots to ensure the reaction proceeds at a uniform speed and improve the conversion rate.

[0044] (III) Byproduct treatment and multi-stage purification - systematic removal of impurities

[0045] By-product conversion and initial separation

[0046] Neutralization with triethylamine: After the reaction is completed, an equal mole of triethylamine is added to react with the residual solid triphosgene and phosgene to form stable salts (such as triethylamine hydrochloride), eliminating the toxicity risk and preventing the generation of new impurities in subsequent reactions.

[0047] Liquid-liquid extraction: Add water to dissolve polar by-products (such as imidazole hydrochloride), and use the weak polarity of CDI (LogP = 1.2) to retain them in the organic phase. After separation, most water-soluble impurities are removed.

[0048] Vacuum distillation and dissolution crystallization - deep purification

[0049] Gradient vacuum distillation: 40°C / 0.08 MPa to remove low-boiling point solvents (tetrahydrofuran, toluene), 60°C / 0.09 MPa to further concentrate the crude CDI to avoid high-temperature decomposition.

[0050] Innovation of dissolution crystallization:

[0051] Solvent system: The crude product was dissolved in a good solvent (anhydrous ether), and an anti-solvent (n-hexane, volume ratio 1:3) was added dropwise to rapidly reduce the solubility of CDI and promote crystal precipitation (the solubility dropped sharply from 15 g / L to 2 g / L).

[0052] Controlled crystallization rate: Addition rate 1mL / min, stirring speed 200 rpm, control uniform growth of crystal nuclei and reduce impurity inclusion; stand at 25℃ for 1 hour to promote crystal agglomeration and improve purity.

[0053] (IV) Product post-processing and quality control – purity assurance throughout the entire process

[0054] Vacuum drying to remove solvent

[0055] Vacuum drying at 50°C for 5 hours removed the ether and n-hexane remaining on the crystal surface and in the micropores, meeting the pharmaceutical-grade solvent residue standards.

[0056] Multi-dimensional quality inspection

[0057] HPLC quantification: wavelength 254nm, mobile phase acetonitrile-water (60:40), purity was determined to be qualified, and impurity content was accurately quantified.

[0058] Melting point and infrared spectrum: melting point 120℃ to verify purity, infrared spectrum (carbonyl 1750cm -1Characteristic peaks are used to confirm the molecular structure and exclude isomerization or decomposition products.

[0059] In this example, the reaction path is precisely controlled. Through low-temperature pre-reaction + gradient temperature increase for staged regulation, combined with real-time monitoring by TLC, side reactions are reduced, the conversion rate of the target product is increased, and a multi-stage purification process is adopted. Anti-solvent crystallization replaces traditional cooling crystallization: using an anti-solvent (n-hexane) to rapidly reduce solubility, improve the yield, and maintain high purity at the same time, solving the problems of low yield and long time consumption in traditional methods.

[0060] Triethylamine neutralization + liquid-liquid extraction: highly efficient removal of polar impurities and residual poisons, significantly improved safety, reduction of phosgene residues, fully enclosed safety system, inert gas protection, solvent anhydrous treatment, exhaust gas absorption device, construction of an anhydrous and oxygen-free reaction environment, reduction of phosgene leakage risk, meeting industrial safety standards.

[0061] Example 2: Refer to Figure 1 As shown: A method for preparing high-purity N,N'-carbonyldiimidazole using solid triphosgene includes the following steps:

[0062] Step 1. Raw material pretreatment and reaction system setup: High-purity solid triphosgene is selected. After purchase, it is first recrystallized and purified. The solid triphosgene is dissolved in an appropriate amount of anhydrous dichloromethane, heated to reflux until completely dissolved, and then slowly cooled to 0 °C to precipitate white crystals. The crystals are filtered, washed with cold anhydrous dichloromethane, and dried under vacuum to obtain high-purity solid triphosgene. Imidazole of analytical grade is used and dried in a vacuum oven at 60 °C for 4 hours before use to remove moisture.

[0063] The reaction is carried out in a fully enclosed, inert gas-protected reaction device equipped with a high-efficiency stirrer, a high-precision thermometer, a constant-pressure dropping funnel, and a reflux condenser. The reaction device is pre-purged with nitrogen to fully displace the air to ensure an oxygen-free and water-free reaction environment. The solvent is a mixed solvent of tetrahydrofuran and toluene (volume ratio 3:2) that has been treated anhydrously.

[0064] Step 2. Reaction process optimization: Add the dried imidazole and the mixed solvent to the reaction device, stir to dissolve it, cool to -10 °C, and slowly drip a tetrahydrofuran solution of solid triphosgene (the molar ratio of solid triphosgene to imidazole is controlled at 1:4.5) through the constant-pressure dropping funnel. The dropping time is controlled within 2 hours. During this process, the stirring speed is maintained at 400 revolutions per minute for low-temperature pre-reaction to initially form reaction intermediates and reduce the occurrence of side reactions.

[0065] After the pre-reaction ends, slowly raise the temperature to 25 °C at a rate of 0.5 °C per minute and continue the reaction for 5 hours. During this period, the reaction progress is monitored in real time by thin-layer chromatography (TLC), and the reaction temperature and stirring speed are adjusted slightly according to the reaction situation.

[0066] Step 3. By-Product Treatment and Product Separation: Through by-product conversion and removal, neutralize the residual raw materials, and separate water-soluble impurities by extraction. Then, preliminarily separate and purify the product, successively perform drying to remove water, vacuum distillation for concentration, and crystallization and washing, and finally perform antisolvent crystallization purification to complete the overall impurity removal;

[0067] When neutralizing the residual raw materials, add triethylamine (equimolar to the unreacted solid triphosgene) to the reaction system. Triethylamine can react with the residual solid triphosgene and the phosgene generated by its decomposition to form stable salt by-products, which can convert the toxic raw materials that may affect subsequent separation into relatively stable and easily treatable substances, reducing safety risks and avoiding their continued participation in the reaction to generate more impurities in subsequent operations. After neutralization, add a GC-MS detection step to monitor the residual amount of solid triphosgene;

[0068] During extraction separation, add deionized water and stir for 15 minutes. Water-soluble by-products such as imidazole hydrochloride generated by the reaction will transfer to the aqueous phase, while organic substances such as N,N'-carbonyldiimidazole remain in the organic phase. Subsequently, separate the organic phase through a separatory funnel to achieve the preliminary separation of most water-soluble impurities and the target product;

[0069] Dry the organic phase with anhydrous magnesium sulfate for 3 hours to remove water. Anhydrous magnesium sulfate has strong water absorption and can absorb the residual water in the organic phase, avoiding the influence of water on subsequent distillation and crystallization processes. After drying, filter off the magnesium sulfate solid. During vacuum distillation, first evaporate most of the solvent at 40 °C and 0.08 MPa to reduce the solvent content and preliminarily concentrate the target product; then raise the temperature to 60 °C and 0.09 MPa to further evaporate the residual solvent to obtain crude CDI. Vacuum distillation can reduce the boiling point of the solvent, avoid the decomposition of the target product or the generation of other side reactions at high temperatures, and can also remove the solvent more efficiently.

[0070] Select anhydrous ether as the good solvent and n-hexane as the antisolvent. Add the crude CDI after the first crystallization to anhydrous ether at a ratio of 1:10 (g / mL), heat to 40 °C and stir to dissolve to form a transparent solution, and remove insoluble mechanical impurities through a 0.45 μm polytetrafluoroethylene filter membrane,

[0071] At 25 °C, slowly add n-hexane to the ether solution at a rate of 1 mL / min (the volume ratio of the antisolvent to the good solvent is finally controlled at 3:1, that is, add 300 mL of n-hexane to 100 mL of ether solution). During the addition process, keep the stirring speed at 200 revolutions per minute to ensure the uniform dispersion of the antisolvent. When the volume ratio reaches 1:1 (ether:n-hexane = 1:1), if no turbidity is observed, a small amount of CDI seed crystals can be added to induce crystallization to avoid the supersaturated state;

[0072] After the dropping is completed, continue stirring for 30 minutes to allow the crystals to grow initially; then stop stirring and let it stand at 25 °C for 1 hour to promote crystal agglomeration and enlargement (reduce the entrainment of fine crystals with impurities). If further purity improvement is required, the system can be cooled to 5 °C and left standing for 2 hours to further precipitate the residual CDI using the temperature difference. Use a Buchner funnel with a 10 μm pore size filter paper, control the vacuum degree at 0.06 MPa, quickly separate the crystals, recycle the mother liquor (ether / n - hexane can be recycled by distillation), wash the crystals twice with cold n - hexane (5 °C) (the amount used each time is twice the mass of the crystals) to remove the adsorbed ether and trace impurities on the surface, and then dry in a vacuum oven at 50 °C for 5 hours to obtain high - purity N,N'-carbonyldiimidazole product.

[0073] Step 4. Product post - treatment and quality monitoring: Dissolve the washed crystals in absolute ethanol again, heat to reflux until completely dissolved, then slowly cool to room temperature, and place in the refrigerator freezer (4 °C) and let it stand for 12 hours for fractional crystallization. The crystals after fractional crystallization are collected by suction filtration and dried in a vacuum oven at 50 °C for 5 hours to obtain high - purity N,N'-carbonyldiimidazole product;

[0074] When detecting the product purity, it also includes the following content:

[0075] 41. High - performance liquid chromatography purity detection: Turn on the high - performance liquid chromatograph, preheat the instrument to a stable state, set the detection wavelength to 254 nm, use acetonitrile - water volume ratio 60:40 as the mobile phase, set the flow rate to 1.0 mL / minute, equilibrate the chromatographic column, carry out sample preparation and injection for detection, and make a result judgment according to the detection results;

[0076] When preparing the sample, weigh the prepared N,N'-carbonyldiimidazole sample, dissolve and make up the volume with the mobile phase (acetonitrile - water) to prepare a sample solution, filter through a 0.45 μm filter membrane to remove insoluble impurities, and take the filtrate as the sample to be detected; when making a result judgment, if the purity of N,N'-carbonyldiimidazole in the sample reaches more than 99%, the product is judged to be qualified;

[0077] 42. Melting point determination: Preheat the melting point apparatus, place the capillary tube containing the sample in the heating bath of the melting point apparatus and heat, observe the melting process of the sample, record the initial melting and complete melting temperatures, compare the measured melting point with the standard melting point range of N,N'-carbonyldiimidazole. If it is within the standard range, it indicates that the purity and structure of the sample meet the requirements; if it deviates from the standard range, it indicates the presence of impurities or abnormal structure;

[0078] 43. Infrared spectrum analysis: Prepare the sample by the tablet - pressing method, place the prepared sample thin slice into the sample cell of the infrared spectrometer, scan the infrared spectrum of the sample, and the scanning range is 2000 cm -1, the scanning was performed 50 times. After obtaining the infrared spectrum of the sample, the results were analyzed to determine whether the structure of the sample was correct;

[0079] When preparing the sample by the tablet pressing method, the dried N,N'-carbonyldiimidazole sample and the dried potassium bromide powder were mixed evenly at a ratio of 1:150, ground into fine powder, and the mixture was transferred to a tablet pressing mold and pressed into a transparent thin film at 10 MPa;

[0080] Step Five: Product verification and packaging: Re-verify the product purity. After verification, the N,N'-carbonyldiimidazole product was sealed and packaged for storage.

[0081] The working principle of the present invention: First, the solid triphosgene and imidazole were respectively treated to complete the pretreatment of the raw materials, and then the reaction device was assembled to complete the construction of the reaction system, so that the reaction was carried out in a fully enclosed, inert gas-protected reaction device equipped with a high-efficiency stirrer, a high-precision thermometer, a constant-pressure dropping funnel and a reflux condenser. By strictly pre-treating the solid triphosgene, reacting in a fully enclosed inert gas protection device and timely treating the by-products and other measures, the risk of phosgene leakage was greatly reduced, the safety and health of the operators were guaranteed, and the potential harm to the environment was reduced. The reaction was divided into stages by low-temperature pre-reaction and heating main reaction, the reaction process was optimized, the reaction progress was monitored in real time, the by-products generated by the reaction were converted and removed, the product was initially separated and refined, the generation of by-products could be reduced, the innovative reaction process optimization and the fine post-treatment processes such as multi-stage crystallization, washing and drying effectively removed various impurities generated during the reaction process, and the product purity could be stably reached above 99%, ensuring the product purity. Through product post-treatment and quality monitoring, the product purity could be further controlled. During quality monitoring, through high-performance liquid chromatography purity detection, melting point determination and infrared spectrum analysis, the product structure was qualitatively confirmed, unqualified products were detected in time, and the unqualified products were subjected to fractional crystallization and drying treatment to ensure the product purity. Precise reaction condition control (including temperature, time, raw material ratio, stirring speed, etc.) and real-time monitoring and fine-tuning mechanism made the reaction process more stable and controllable, reduced the side reactions and product quality instability problems caused by reaction condition fluctuations, and improved the production efficiency and product quality consistency;

[0082] Through the whole-process control of "raw material refinement - reaction impurity control - multi-stage purification - strict quality inspection", the problems of difficult separation of by-products, low purity and poor safety in the preparation of CDI by the solid triphosgene method were systematically solved. The core principle was to break through the traditional purification bottleneck by using fractional crystallization technology, combined with precise reaction condition control and multi-dimensional quality monitoring, realizing the high-purity, high-efficiency and safe production of CDI, providing a standardized and replicable technical solution for the preparation of organic synthesis intermediates, and having significant economic value and social significance.

[0083] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing high-purity N,N'-carbonyldiimidazole using solid triphosgene, characterized in that: It includes the following steps: S1. Pretreatment of raw materials and setup of reaction system: Select solid triphosgene as the raw material, treat the solid triphosgene to obtain high-purity solid triphosgene. Dry imidazole in a vacuum oven at a drying temperature of 60 °C for 4 hours to complete the pretreatment of the raw materials. Assemble the reaction device to complete the setup of the reaction system; S2. Optimization of reaction process: Add the dried imidazole and mixed solvent into the reaction device for low-temperature pre-reaction. After the pre-reaction ends, adjust the temperature upward to enter the main reaction stage of temperature rise. During this period, monitor the reaction progress in real time through thin-layer chromatography (TLC); S3. Treatment of by-products and separation of products: Through the conversion and removal of by-products, neutralize the residual raw materials, and separate water-soluble impurities by extraction. Then, conduct preliminary separation and purification of the product, successively carry out drying to remove water, concentration by vacuum distillation, crystallization precipitation and washing, and finally carry out antisolvent crystallization purification to complete the overall impurity removal; S4. Post-treatment of product and quality monitoring: Conduct antisolvent crystallization on the product. The crystals after antisolvent crystallization are collected by suction filtration and dried in a vacuum oven at 50 °C for 5 hours to obtain the N,N'-carbonyldiimidazole product. Use high-performance liquid chromatography to detect the purity of the product. If the standard is not met, repeat the steps of antisolvent crystallization and drying until the product purity is qualified; S5. Post-treatment of product and quality monitoring: Re-check the product purity. After verification, seal and package the N,N'-carbonyldiimidazole product for storage.

2. The high-purity preparation method of N,N'-carbonyldiimidazole using solid triphosgene according to claim 1, characterized in that: In S1, when treating the fixed triphosgene, first conduct recrystallization purification. Dissolve the solid triphosgene in an appropriate amount of anhydrous dichloromethane, heat to reflux until it is completely dissolved, then slowly cool to 0 °C to precipitate white crystals. Filter and wash with cold anhydrous dichloromethane, and dry in vacuum to obtain high-purity solid triphosgene.

3. The high-purity preparation method of N,N'-carbonyldiimidazole using solid triphosgene according to claim 1, characterized in that: In S1, the reaction device is equipped with a high-efficiency stirrer, a high-precision thermometer, a constant-pressure dropping funnel, and is fully enclosed with a reflux condenser and protected by inert gas. The reaction device is pre-filled with nitrogen to fully displace the air to ensure an oxygen-free and water-free reaction environment. The solvent is a mixed solvent of tetrahydrofuran and toluene that has been treated for water removal, with a volume ratio of 3:

2.

4. The high-purity preparation method of N,N'-carbonyldiimidazole using solid triphosgene according to claim 1, characterized in that: In S2, during the low-temperature pre-reaction, add the dried imidazole and mixed solvent into the reaction device, stir to dissolve it, cool to -10 °C to -5 °C, and slowly drip the tetrahydrofuran solution of solid triphosgene through the constant-pressure dropping funnel. The molar ratio of solid triphosgene to imidazole is controlled at 1:4.5, and the dropping time is 1.5 to 2 hours. During this process, maintain the stirring speed at 300 to 400 revolutions per minute to initially form a reaction intermediate. During the temperature rise adjustment, slowly raise the temperature to 20 °C to 25 °C at a rate of 0.5 °C per minute and continue the reaction for 4 to 5 hours.

5. The high-purity preparation method of N,N'-carbonyldiimidazole using solid triphosgene according to claim 1, characterized in that: In S3, when neutralizing the residual raw materials, add triethylamine to the reaction system. Triethylamine can react with the residual solid triphosgene and the phosgene generated by its decomposition to form stable salt by-products. During the extraction separation, add deionized water and stir for 15 minutes. The water-soluble by-products such as imidazole hydrochloride generated by the reaction will transfer to the aqueous phase, while N,N'-carbonyldiimidazole remains in the organic phase. Subsequently, separate the organic phase through a separating funnel.

6. The method for preparing high-purity N,N'-carbonyldiimidazole using solid triphosgene according to claim 1, wherein: In S3, the organic phase is dried with anhydrous magnesium sulfate for 2 - 3 hours to remove water. During vacuum distillation, most of the solvent is first distilled off at 40°C and 0.08 MPa to reduce the solvent content and preliminarily concentrate the target product. Then, the temperature is raised to 60°C and 0.09 MPa to further distill off the residual solvent, obtaining crude CDI. When refining the product, anhydrous ether is selected as the good solvent and n - hexane as the anti - solvent. The crude CDI after the first crystallization is added to anhydrous ether, heated to 40°C and stirred until dissolved, filtered through a polytetrafluoroethylene filter membrane. n - hexane is added dropwise to the ether solution while maintaining a stirring speed of 200 revolutions per minute. After the addition is complete, stirring is continued for 30 minutes, then stirring is stopped, and the mixture is left to stand at 25°C for 1 hour. A Buchner funnel equipped with a 10 - μm pore - size filter paper is used, and the vacuum is controlled at 0.06 MPa to quickly separate the crystals, and the crystals are washed twice with cold n - hexane to remove the adsorbed ether and trace impurities on the surface.

7. The high-purity preparation method of N,N'-carbonyldiimidazole using solid triphosgene according to claim 1, characterized in that: In S4, when detecting the product purity, the following contents are also included: S41. High - performance liquid chromatography purity detection: Turn on the high - performance liquid chromatograph, preheat the instrument to a stable state, set the detection wavelength to 254 nm, use acetonitrile - water with a volume ratio of 60:40 as the mobile phase, set the flow rate to 1.0 mL / minute, equilibrate the chromatographic column, perform sample preparation and injection for detection, and make a result determination based on the detection results; S42. Melting point determination: Preheat the melting point apparatus, place the capillary tube containing the sample into the heating bath of the melting point apparatus for heating, observe the melting process of the sample, record the initial melting and complete melting temperatures, and compare the measured melting point with the standard melting point range of N,N'-carbonyldiimidazole. If it is within the standard range, it indicates that the purity and structure of the sample meet the requirements; if it deviates from the standard range, it indicates the presence of impurities or abnormal structure; S43. Infrared spectrum analysis: Prepare the sample by the tablet - pressing method. Place the prepared sample thin slice into the sample cell of the infrared spectrometer, scan the infrared spectrum of the sample, and perform result analysis after obtaining the infrared spectrum diagram of the sample to determine whether the structure of the sample is correct.

8. The high-purity preparation method of N,N'-carbonyldiimidazole using solid triphosgene according to claim 1, characterized in that: In S41, when preparing the sample, weigh the prepared N,N'-carbonyldiimidazole sample, dissolve it with the mobile phase acetonitrile - water and make up the volume to prepare a sample solution, filter it through a 0.45 - μm filter membrane to remove insoluble impurities, and take the filtrate as the sample to be detected. When making a result determination, if the purity of N,N'-carbonyldiimidazole in the sample reaches more than 99%, the product is judged to be qualified.

9. The high-purity preparation method of N,N'-carbonyldiimidazole using solid triphosgene according to claim 1, characterized in that: In S43, when preparing the sample by the tablet - pressing method, take the dried N,N'-carbonyldiimidazole sample and mix it evenly with the dried potassium bromide powder in a ratio of 1:100 - 1:200, grind it into a fine powder, transfer the mixture to a tablet - pressing mold, and press it into a transparent thin slice at 8 - 10 MPa.

10. The method for preparing high-purity N,N'-carbonyldiimidazole using solid triphosgene according to claim 1, wherein: In S43, the infrared spectrum of the sample is scanned, and the scanning range is 4000 - 400 cm -1 , and the number of scans is 32 - 64 times.

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