A high-purity preparation method of N, N'-carbonyl diimidazole by using solid triphosgene

Abstract

The application discloses a high-purity preparation method of N,N'-carbonyl diimidazole by using solid triphosgene, and relates to the technical field of organic synthesis, comprising the following steps: S1, raw material pretreatment and reaction system building; S2, reaction process optimization; S3, by-product treatment and product separation; S4, product post-treatment and quality monitoring; and S5, product post-treatment and quality monitoring.In the application, the residual raw material can be neutralized, water-soluble impurities can be extracted and separated, the product can be preliminarily separated and refined, and then is subjected to solvus crystallization purification treatment, each step is aimed at treating different types of impurities, the content of various impurities in the product is gradually reduced through multi-stage treatment, the high purity of the product is finally ensured, the high-purity preparation of N,N'-carbonyl diimidazole 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 product quality are improved.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of organic synthesis, in particular to a high-purity preparation method of N,N'-carbonyldiimidazole by using solid triphosgene. BACKGROUND

[0002] Solid triphosgene, also known as trichloromethyl carbonate, is a relatively stable solid compound, and has similar reactivity to phosgene and can replace phosgene in many reactions. The preparation of CDI by using solid triphosgene instead of phosgene can reduce production risk and improve production safety.

[0003] When N,N'-carbonyldiimidazole is prepared by using solid triphosgene, various by-products are generated in the reaction process, and the separation of the by-products from N,N'-carbonyldiimidazole is relatively difficult. The impurities cannot be completely removed by using a conventional separation method, and the product purity is affected. SUMMARY

[0004] The application aims to provide a high-purity preparation method of N,N'-carbonyldiimidazole by using solid triphosgene, so as to solve the problem that, when N,N'-carbonyldiimidazole is prepared by using solid triphosgene, various by-products are generated in the reaction process, the separation of the by-products from N,N'-carbonyldiimidazole is relatively difficult, the impurities cannot be completely removed by using a conventional separation method, and the product purity is affected.

[0005] To achieve the above-mentioned purpose, the application provides the following technical scheme: a high-purity preparation method of N,N'-carbonyldiimidazole by using solid triphosgene, comprising the following steps:

[0006] S1, raw material pretreatment and reaction system building: solid triphosgene raw material is selected, the solid triphosgene is treated to obtain high-purity solid triphosgene, and the imidazole is dried in a vacuum oven at a drying temperature of 60 DEG C for 4 hours, the pretreatment of the raw material is completed, the reaction device is assembled, and the building of the reaction system is completed;

[0007] S2, reaction process optimization: the dried imidazole and mixed solvent are added into the reaction device, and low-temperature pre-reaction is carried out, after the pre-reaction is completed, temperature adjustment is carried out, and the main reaction stage of temperature rise is entered, and the reaction progress is monitored in real time by thin layer chromatography (TLC) during the period;

[0008] S3, by-product treatment and product separation: the by-products are converted and removed, the residual raw material is neutralized, the water-soluble impurities are separated by extraction, then the product is preliminarily separated and refined, drying, water removal, vacuum distillation concentration, crystallization precipitation and washing are sequentially carried out, and finally, the whole impurity removal is completed by solubility crystallization purification.

[0009] S4, product post-processing and quality monitoring: the product is subjected to solvent crystallization, the crystals after solvent crystallization are collected by suction filtration and dried in a vacuum oven at 50°C for 5 hours to obtain the N,N'-carbonyl diimidazole product, the purity of the product is detected by high performance liquid chromatography, if the standard is not reached, the steps of solvent crystallization and drying are repeated until the product purity is qualified;

[0010] S5, product verification and packaging: the purity of the product is verified again, after the verification is correct, the N,N'-carbonyl diimidazole product is sealed and packaged and stored.

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

[0012] Preferably, in S1, the reaction device is equipped with a high-efficiency stirrer, a high-precision thermometer, a constant-pressure dropping funnel, and a fully-closed reflux condenser with inert gas protection. The reaction device is pre-filled with nitrogen to replace air to ensure that the reaction environment is oxygen-free and water-free. The solvent is a mixture of anhydrous-treated tetrahydrofuran and toluene with a volume ratio of 3:2.

[0013] Preferably, in S2, in the low-temperature pre-reaction, dry imidazole and mixed solvents are added to the reaction device, stirred to dissolve them, cooled to -10°C to -5°C, and the solid triphosgene tetrahydrofuran solution is slowly added 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 1.5-2 hours. The stirring speed is maintained at 300-400 revolutions per minute during this process. The intermediate is formed initially, and the temperature is adjusted by slowly increasing the temperature to 20°C-25°C at a rate of 0.5°C per minute. The reaction continues for 4-5 hours.

[0014] Preferably, in S3, when neutralizing the residual raw material, triethylamine is added to the reaction system. Triethylamine can react with residual solid triphosgene and phosgene generated by its decomposition to form stable salt byproducts. When extracting and separating, deionized water is added and stirred for 15 minutes. The water-soluble byproducts such as imidazole hydrochloride generated by the reaction are transferred to the aqueous phase, while N,N'-carbonyl diimidazole remains in the organic phase. Then the organic phase is separated by a separatory funnel.

[0015] Preferably, in S3, the organic phase is dried over anhydrous magnesium sulfate for 2-3 hours to dry and remove water. During the reduced pressure distillation, most of the solvent is first evaporated at 40 ° C and 0.08 MPa to reduce the solvent content and obtain a preliminary concentration of the target product; then the temperature is raised to 60 ° C and 0.09 MPa, and the residual solvent is further evaporated to obtain a crude CDI. When the product is refined, anhydrous ether is selected as a good solvent and n-hexane is selected as an anti-solvent. The crude CDI after the primary crystallization is added to anhydrous ether, heated to 40 ° C and stirred to dissolve, filtered through a polytetrafluoroethylene filter membrane, and n-hexane is added dropwise to the ether solution. The stirring speed is maintained at 200 rpm during the addition. After the addition is complete, stirring is continued for 30 minutes, and then stirring is stopped and allowed to stand at 25 ° C for 1 hour. A Buchner funnel is used with a 10 μm pore size filter paper and the vacuum is controlled to 0.06 MPa to quickly separate the crystals. The crystals are washed twice with cold n-hexane to remove the ether and trace impurities adsorbed on the surface.

[0016] Preferably, in S4, when testing the purity of the product, the following steps are also included:

[0017] S41. HPLC purity test: Turn on the HPLC instrument, preheat the instrument to a stable state, set the detection wavelength to 254 nm, use acetonitrile-water in a volume ratio of 60:40 as the mobile phase, set the flow rate to 1.0 mL / min, equilibrate the chromatographic column, perform sample preparation and injection testing, and make a judgment based on the test results;

[0018] S42. Melting point determination: Preheat the melting point instrument, place the capillary tube containing the sample in the heating tank of the melting point instrument 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 that there are impurities on the surface or the structure is abnormal.

[0019] S43. Infrared spectrum analysis: Prepare the sample by tabletting method, place the prepared sample slice into the sample cell of infrared spectrometer, scan the infrared spectrum of the sample, and analyze the result after obtaining the infrared spectrum of the sample to determine whether the structure of the sample is correct.

[0020] Preferably, in S41, when preparing the sample, the prepared N,N'-carbonyldiimidazole sample is weighed, dissolved and fixed to volume with the mobile phase of acetonitrile-water to prepare a sample solution, filtered through a 0.45 μm filter membrane to remove insoluble impurities, and the filtrate is taken as the sample to be tested; when judging the result, 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 the sample is prepared by tabletting method, the dried N,N'-carbonyl diimidazole sample is mixed with dried potassium bromide powder at 1:100-1:200, ground into fine powder, and the mixture is transferred to a tabletting mold and pressed into a transparent sheet at 8-10 MPa.

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

[0023] Compared with the prior art, the present application has the following advantages:

[0024] 1. In the present application, the residual raw materials are neutralized, the water-soluble impurities are extracted and separated, the product is preliminarily separated and refined, and then subjected to solvent-out crystallization purification treatment, each step is aimed at 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, finally ensuring high purity of the product, and realizing high-purity preparation of N,N'-carbonyl diimidazole.

[0025] 2. In the present application, through strict pretreatment of solid triphosgene, reaction in a fully closed inert gas protection device and other measures, the risk of phosgene leakage is greatly reduced, the safety and health of the operators are ensured, the potential harm to the environment is reduced, the reaction conditions including temperature, time, raw material ratio, stirring speed are accurately controlled, a real-time monitoring and fine-tuning mechanism is established, the reaction process is more stable and controllable, the side reactions and unstable product quality caused by fluctuation of reaction conditions are reduced, and the consistency of production efficiency and product quality is improved. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 The flow chart of the present application for high-purity preparation of N,N'-carbonyl diimidazole using solid triphosgene. DETAILED DESCRIPTION

[0027] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0028] Example 1: Refer to Figure 1The application discloses a high-purity preparation method of N, N'-carbonyl diimidazole by using solid triphosgene.

[0029] I. Core technical principle

[0030] (1) Raw material pretreatment and reaction environment control - reduce impurity introduction from the source

[0031] Solid triphosgene refining

[0032] Impurities (such as carbonate derivatives) in the raw material are removed by recrystallization method (anhydrous dichloromethane dissolution -> 0 DEG C low-temperature crystallization -> cold solvent washing) to ensure the purity of solid triphosgene and avoid impurities participating in the reaction to generate byproducts.

[0033] Imidazole drying: 60 DEG C vacuum drying for 4 hours, completely remove water, prevent water from reacting with solid triphosgene to generate phosgene or cause CDI hydrolysis.

[0034] Inert gas protection and anhydrous solvent

[0035] The reaction device is replaced with nitrogen in advance, and the solvent (tetrahydrofuran:toluene = 3:2) is treated with anhydrous sodium (metal sodium reflux distillation) to create an anhydrous and oxygen-free environment, inhibit the hydrolysis of solid triphosgene and the oxidation of imidazole, and ensure the reaction specificity.

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

[0037] (2) Reaction process optimization - stage control of main and side reaction paths

[0038] Low-temperature pre-reaction

[0039] Molar ratio and drop control: solid triphosgene:imidazole = 1:4.5 (excess imidazole), slowly drop through a constant-pressure dropping funnel to make the solid triphosgene uniformly dispersed, preferentially generate a single imidazole carbonyl intermediate, and avoid multi-carbonylation byproducts (such as bisimidazole carbonate).

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

[0041] Temperature rising main reaction

[0042] Gradient temperature rising: slowly rise the temperature at a rate of 0.5 DEG C / minute, monitor the reaction progress in real time through TLC (the Rf value of the target product is about 0.6), promote the intermediate to be completely converted into CDI, and avoid long-time reaction to cause CDI decomposition or impurity generation.

[0043] Dynamic adjustment: fine-tune temperature and stirring speed according to TLC spot changes to ensure uniform reaction progress and improve conversion rate.

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

[0045] By-product conversion and preliminary separation

[0046] Triethylamine neutralization: After the reaction, add an equal molar amount of triethylamine to react with residual solid triphosgene and phosgene to form stable salts (such as triethylamine hydrochloride), eliminating the risk of toxicity and preventing the generation of new impurities in subsequent reactions.

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

[0048] Vacuum distillation and solvent crystallization - deep purification

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

[0050] Innovative solvent crystallization:

[0051] Solvent system: good solvent (anhydrous ether) dissolves the crude product, dropwise addition of anti-solvent (n-hexane, volume ratio 1:3) to rapidly reduce the solubility of CDI, prompting the precipitation of crystals (solubility from 15g / L to 2g / L).

[0052] Controlled crystallization: dropwise rate 1mL / min, stirring speed 200rpm, control the uniform growth of crystal nucleus, reduce impurity wrapping; 25℃ standing for 1 hour to promote crystal agglomeration and improve purity.

[0053] (IV) Product post-treatment and quality control - purity guarantee throughout the process

[0054] Vacuum drying to remove solvent

[0055] Vacuum drying at 50℃ for 5 hours to remove residual ether and n-hexane on the surface and micropores of the crystals, meeting the pharmaceutical grade solvent residue standards.

[0056] Multi-dimensional quality detection

[0057] HPLC quantification: wavelength 254nm, mobile phase acetonitrile-water (60:40), purity determination qualified, accurate quantification of impurity content.

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

[0059] In this example, the reaction path is precisely controlled through low-temperature pre-reaction + gradient temperature control in stages, combined with real-time monitoring by TLC, to reduce side reactions and improve the conversion rate of the target product. The multi-stage purification process replaces traditional cooling crystallization with solvent-analytical crystallization, which uses anti-solvent (n-hexane) to rapidly reduce solubility and improve yield while maintaining high purity. This solves the problems of low yield and long time consumption in traditional methods.

[0060] Triethylamine neutralization + liquid-liquid extraction: efficient removal of polar impurities and residual toxic substances, significantly improving safety and reducing phosgene residue. The fully closed safety system includes inert gas protection, solvent anhydrous treatment, and waste gas absorption device, creating an anhydrous and anaerobic reaction environment to reduce the risk of phosgene leakage and meet industrial safety standards.

[0061] Example 2: Reference Figure 1 The preparation method of N,N'-carbonyl diimidazole with high purity 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. Dissolve the solid triphosgene in an appropriate amount of anhydrous dichloromethane, heat to reflux to completely dissolve it, then slowly cool to 0°C, precipitate white crystals, filter and wash with cold anhydrous dichloromethane, and vacuum dry to obtain high-purity solid triphosgene. Imidazole is selected as analytical grade and dried in a vacuum oven at 60°C for 4 hours before use to remove water.

[0063] The reaction is carried out in a fully closed, inert gas protected reaction device equipped with a high-efficiency stirrer, high-precision thermometer, constant-pressure dropping funnel, and reflux condenser. The reaction device is pre-filled with nitrogen to replace air to ensure an oxygen-free and water-free reaction environment. The solvent is a mixture of anhydrous treated tetrahydrofuran and toluene (volume ratio 3:2).

[0064] Step 2: Reaction process optimization: Add dry imidazole and mixed solvent to the reaction device, stir to dissolve, cool to -10°C, and slowly add solid triphosgene tetrahydrofuran solution (molar ratio of solid triphosgene to imidazole controlled at 1:4.5) through a constant-pressure dropping funnel. The drop time is controlled within 2 hours. Maintain the stirring speed at 400 rpm during this process to carry out low-temperature pre-reaction and initially form reaction intermediates to reduce side reactions.

[0065] After pre-reaction, slowly raise the temperature to 25°C at a rate of 0.5°C / min and continue to react for 5 hours. During this period, monitor the reaction progress in real time by thin layer chromatography (TLC) and adjust the reaction temperature and stirring speed according to the reaction conditions.

[0066] Step three, by-product treatment and product separation: through by-product conversion and removal, neutralization of residual raw materials, and separation of water-soluble impurities by extraction, the product is then preliminarily separated and refined, followed by drying, vacuum distillation, crystallization and washing, and finally, solvus crystallization purification, completing the overall impurity removal;

[0067] When neutralizing the residual raw materials, triethylamine (in equimolar amount with the unreacted solid trimethylol propane) is added to the reaction system. The triethylamine can react with the residual solid trimethylol propane and the phosgene generated by its decomposition to form stable salt by-products, which can convert the toxic and potentially affecting subsequent separation raw materials into relatively stable and easy-to-handle substances, reducing the safety risk while avoiding their continued participation in the reaction to generate more impurities in subsequent operations. A GC-MS detection step is added after neutralization to monitor the residual amount of solid trimethylol propane;

[0068] During the extraction separation, deionized water is added and stirred for 15 minutes. The water-soluble by-products such as imidazole hydrochloride generated by the reaction are transferred to the aqueous phase, while the organic substances such as N,N'-carbonyl diimidazole remain in the organic phase. Subsequently, the organic phase is separated by a separatory funnel, achieving preliminary separation of most water-soluble impurities and target products;

[0069] The organic phase is dried with anhydrous magnesium sulfate for 3 hours to remove water. The water-sulfuric acid has strong water absorption, which can absorb the residual water in the organic phase, avoiding the influence of water on the subsequent distillation and crystallization process. After drying, the magnesium sulfate solid is removed by filtration. During vacuum distillation, most of the solvent is evaporated at 40°C and 0.08 MPa, reducing the solvent content and preliminarily concentrating the target product. Then, the temperature is raised to 60°C and 0.09 MPa to further evaporate the residual solvent, obtaining the crude CDI. Vacuum distillation can reduce the boiling point of the solvent, avoiding the decomposition of the target product or other side reactions at high temperatures, and also more efficiently removing the solvent.

[0070] Anhydrous diethyl ether is selected as the good solvent, and n-hexane is selected as the anti-solvent. The crude CDI after the first crystallization is added to anhydrous diethyl ether at a ratio of 1:10 (g / mL), heated to 40°C and stirred to dissolve, forming a transparent solution. The solution is filtered through a 0.45 μm polytetrafluoroethylene filter membrane to remove insoluble mechanical impurities,

[0071] At 25°C, n-hexane (anti-solvent) is added to the diethyl ether solution at a rate of 1 mL / min (the volume ratio of anti-solvent to good solvent is finally controlled at 3:1, i.e. 100 mL of diethyl ether solution plus 300 mL of n-hexane). The stirring speed is maintained at 200 rpm during the addition process to ensure uniform dispersion of the anti-solvent. When the volume ratio reaches 1:1 (diethyl ether:n-hexane = 1:1), if no turbidity is observed, a small amount of CDI seed can be added to induce crystallization, avoiding the supersaturation state;

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

[0073] Step four, product post-treatment and quality monitoring: dissolve the washed crystals again in anhydrous ethanol, heat to reflux to completely dissolve, then slowly cool to room temperature, and then put into the refrigerator (4°C) for 12 hours to perform solvent-out crystallization. The crystals after solvent-out crystallization are collected by suction filtration and dried in a vacuum oven at 50°C for 5 hours to obtain high-purity N,N'-carbonyl diimidazole product.

[0074] When detecting the purity of the product, the following contents are also included:

[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 with a volume ratio of 60:40 as the mobile phase, set the flow rate to 1.0 mL / min, equilibrate the chromatographic column, prepare the sample and inject for detection, and determine the results according to the detection results;

[0076] When preparing the sample, weigh the prepared N,N'-carbonyl diimidazole sample, dissolve and dilute it with the mobile phase (acetonitrile-water) 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 tested. When determining the results, if the purity of N,N'-carbonyl diimidazole in the sample is 99% or higher, the product is determined to be qualified.

[0077] 42. Melting point determination: preheat the melting point determination instrument, place the capillary tube containing the sample into the heating tank of the melting point determination instrument, 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'-carbonyl diimidazole, 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 that there are impurities or abnormal structures.

[0078] 43. Infrared spectrum analysis: prepare the sample by tabletting method, place the prepared sample tablet into the sample cell of the infrared spectrometer, scan the infrared spectrum of the sample, and the scanning range is 2000 cm -1After the infrared spectrum of the sample is obtained by scanning 50 times, the result is analyzed to determine whether the structure of the sample is correct.

[0079] When the tabletting method is used to prepare the sample, the dried N,N'-carbonyl diimidazole sample is mixed with dried potassium bromide powder at a ratio of 1:150, ground into fine powder, and then transferred to a tabletting mold to be pressed into a transparent thin sheet under a pressure of 10 MPa.

[0080] Step five, product verification and packaging: the purity of the product is verified again, and after the verification is correct, the N,N'-carbonyl diimidazole product is sealed and packaged for storage.

[0081] The working principle of the present application is as follows: first, the raw materials are pretreated by treating solid triphosgene and imidazole respectively, then the reaction device is assembled, the reaction system is built, and the reaction is carried out in a fully closed, 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 risk of phosgene leakage is greatly reduced through strict pretreatment of solid triphosgene, reaction in a fully closed inert gas protected device and timely treatment of by-products, the safety and health of the operators are ensured, the potential harm to the environment is reduced, the reaction is divided into stages through low-temperature pre-reaction and temperature rising main reaction, the reaction process is optimized, the reaction progress is monitored in real time, the by-products generated in the reaction are converted and removed, the product is preliminarily separated and refined, the generation of by-products is reduced, the innovative reaction process optimization and the fine multi-stage crystallization, washing and drying post-treatment process effectively remove various impurities generated in the reaction process, the purity of the product can be stabilized to more than 99%, the purity of the product is ensured, through product post-treatment and quality monitoring, the purity of the product can be further controlled, in the quality monitoring, the product structure is qualitatively confirmed through high-performance liquid chromatography purity detection, melting point determination and infrared spectrum analysis, unqualified products are detected in time, and the unqualified products are subjected to dissolution crystallization and drying treatment, so that the purity of the product is ensured, the accurate reaction condition control (including temperature, time, raw material ratio, stirring speed, etc.) and real-time monitoring and fine-tuning mechanism make the reaction process more stable and controllable, reduce the side reactions and unstable product quality problems caused by fluctuation of reaction conditions, and improve the consistency of production efficiency and product quality.

[0082] Through the whole process control of "raw material refining-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 solid triphosgene method are systematically solved. The core principle is to break through the traditional purification bottleneck by using dissolution crystallization technology, combined with accurate reaction condition control and multi-dimensional quality monitoring, to realize the safe production of CDI with high purity and high efficiency, and to provide a standardized and replicable technical solution for the preparation of organic synthesis intermediates, which has significant economic value and social significance.

[0083] Although the present application has been described in detail with reference to the foregoing embodiments, the technical solutions recorded in the foregoing embodiments can be modified, or some of the technical features can be replaced by equivalent features, by those skilled in the art, any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing high-purity N,N'-carbonyldiimidazole using solid triphosgene, characterized by: The following steps are involved: S1. Raw material pretreatment and reaction system construction: solid triphosgene raw material is selected, solid triphosgene is treated to obtain high-purity solid triphosgene, imidazole is dried in a vacuum oven at a drying temperature of 60°C and a drying time of 4 hours to complete the pretreatment of the raw materials, the reaction device is assembled, and the reaction system is completed. When treating the fixed triphosgene, recrystallization purification is first performed, the solid triphosgene is dissolved in an appropriate amount of anhydrous dichloromethane, heated to reflux to completely dissolve it, and then slowly cooled to 0°C to precipitate white crystals, which are filtered and washed with cold anhydrous dichloromethane, and vacuum dried to obtain high-purity solid triphosgene. The reaction device is equipped with a high-efficiency stirrer, a high-precision thermometer, a constant pressure dropping funnel, a fully enclosed reflux condenser, and inert gas protection. The air in the reaction device is fully replaced with nitrogen in advance to ensure that the reaction environment is oxygen-free and anhydrous. The solvent is a mixed solvent of anhydrous tetrahydrofuran and toluene with a volume ratio of 3:2; S2, reaction process optimization: add dried imidazole and mixed solvent to the reaction apparatus, carry out low-temperature pre-reaction, after the pre-reaction is completed, carry out temperature regulation, enter the temperature raising main reaction stage, during which the reaction progress is monitored in real time by thin layer chromatography TLC, during the low-temperature pre-reaction, add dried imidazole and mixed solvent to the reaction apparatus, stir to dissolve, cool to -10°C ~ -5°C, slowly add solid triphosgene tetrahydrofuran solution dropwise through a constant pressure dropping funnel, the molar ratio of solid triphosgene to imidazole is controlled at 1:4.5, the addition time is 1.5 ~ 2 hours, during this process, the stirring speed is maintained at 300 ~ 400 rpm, a reaction intermediate is initially formed, and when temperature regulation, the temperature is slowly increased to 20 ° C ~ 25 ° C at a rate of 0.5 ° C per minute, and the reaction is continued for 4 ~ 5 hours; S3. By-product treatment and product separation: by converting and removing by-products, neutralizing residual raw materials, and separating water-soluble impurities by extraction, then preliminarily separating and refining the product, followed by drying and dehydration, vacuum distillation concentration, crystallization and washing, and finally purification by dissolution and crystallization to complete the overall removal of impurities. When neutralizing the residual raw materials, triethylamine is added to the reaction system. Triethylamine can react with the residual solid triphosgene and the phosgene produced by its decomposition to produce a stable salt by-product. During extraction and separation, deionized water is added and stirred for 15 minutes. The water-soluble by-product imidazole hydrochloride produced by the reaction will transfer to the aqueous phase, while N,N'-carbonyldiimidazole will remain in the organic phase. The organic phase is then separated by a separatory funnel and dried over anhydrous magnesium sulfate for 2-3 hours to dry and remove water. During vacuum distillation, the mixture is first heated at 40°C and 0. Most of the solvent was evaporated under 0.08MPa conditions to reduce the solvent content and obtain a preliminary concentration of the target product; then the temperature was raised to 60°C and 0.09MPa, and the residual solvent was further evaporated to obtain crude CDI. When the product was refined, anhydrous ether was selected as a good solvent and n-hexane was selected as an anti-solvent. The crude CDI after primary crystallization was added to anhydrous ether, heated to 40°C and stirred to dissolve, filtered through a polytetrafluoroethylene filter membrane, and n-hexane was added dropwise to the ether solution. The stirring speed was maintained at 200 rpm during the dropwise addition. After the dropwise addition was completed, stirring was continued for 30 minutes, and then stirring was stopped. The product was allowed to stand at 25°C for 1 hour. A Buchner funnel was used with a 10μm pore size filter paper and the vacuum degree was controlled at 0.06MPa to quickly separate the crystals. The crystals were washed twice with cold n-hexane to remove the ether and trace impurities adsorbed on the surface; S4. Product post-processing and quality control: The product is subjected to dissolution and crystallization. The crystals after dissolution and crystallization are collected by suction filtration and dried in a vacuum oven at 50°C for 5 hours to obtain N,N'-carbonyldiimidazole product. The product purity is tested by high performance liquid chromatography. If it does not meet the standard, the dissolution, crystallization and drying steps are repeated until the product purity meets the standard; S5. Product post-processing and quality control: Verify the product purity again. Once verified, seal and package the N,N'-carbonyldiimidazole product and store it.

2. The method for preparing high-purity N,N'-carbonyldiimidazole using solid triphosgene according to claim 1, characterized in that: In S4, when testing the purity of the product, the following are also included: S41. HPLC purity test: Turn on the HPLC instrument, preheat the instrument to a stable state, set the detection wavelength to 254 nm, use acetonitrile-water in a volume ratio of 60:40 as the mobile phase, set the flow rate to 1.0 mL / min, equilibrate the chromatographic column, perform sample preparation and injection testing, and make a judgment based on the test results; S42. Melting point determination: Preheat the melting point instrument, place the capillary tube containing the sample in the heating tank of the melting point instrument 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 that there are impurities on the surface or the structure is abnormal. S43. Infrared spectrum analysis: Prepare the sample by tabletting method, place the prepared sample slice into the sample cell of infrared spectrometer, scan the infrared spectrum of the sample, and analyze the result after obtaining the infrared spectrum of the sample to determine whether the structure of the sample is correct.

3. The method for preparing high-purity N,N'-carbonyldiimidazole using solid triphosgene according to claim 2, wherein: In S41, during sample preparation, the prepared N,N'-carbonyldiimidazole sample is weighed, dissolved and fixed to volume with the mobile phase of acetonitrile-water to prepare a sample solution, filtered through a 0.45 μm filter membrane to remove insoluble impurities, and the filtrate is taken as the sample to be tested; when judging the results, if the purity of N,N'-carbonyldiimidazole in the sample reaches more than 99%, the product is judged to be qualified.

4. The method for preparing high-purity N,N'-carbonyldiimidazole using solid triphosgene according to claim 2, wherein: In S43, when the sample is prepared by the tableting method, the dried N,N'-carbonyldiimidazole sample is mixed with dry potassium bromide powder at a ratio of 1:100-1:200, ground into a fine powder, and the mixture is transferred to a tableting mold and pressed into a transparent sheet at 8-10 MPa.

5. The method for preparing high-purity N,N'-carbonyldiimidazole using solid triphosgene according to claim 2, wherein: In S43, scan the infrared spectrum of the sample in the range of 4000-400 cm -1 , the number of scans is 32-64 times.

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