A solvent-free electrophilic aromatic iodination method and its application in the preparation of nonionic iodine contrast agents.

Abstract

This invention discloses a solvent-free electrophilic aromatic iodination method and its application in the preparation of nonionic iodine contrast agents. Specifically, the method uses an iodine cation liquid as both the iodination reagent and the reaction medium. The aromatic substrate is directly added to the iodine cation liquid, which is liquid at room temperature, to obtain the iodinated product. This method utilizes the liquid properties of the iodine cation liquid to form a homogeneous reaction system with the substrate, eliminating the mass transfer limitations of solid reagents and achieving efficient iodination of electron-rich aromatic compounds under mild conditions. When applied to the preparation of nonionic iodine contrast agents, the product is free of chlorinated impurities and requires no hydroxyl protection step, offering advantages of a green and efficient process.

Description

Technical Field

[0001] This invention belongs to the fields of organic synthesis and pharmaceutical chemical technology, specifically relating to an iodine positive ion liquid and its preparation method, an iodination method for aromatic compounds based on the liquid, and the application of the iodination method in the preparation of X-ray contrast agent intermediates and active pharmaceutical ingredients. Background Technology

[0002] Aromatic iodides are key intermediates in the pharmaceutical, pesticide, and functional materials fields, playing a central role, particularly in the synthesis of nonionic X-ray contrast agents. Mainstream clinical contrast agents such as iohexol, iodixanol, and iopamidol are all based on the 2,4,6-triiodoisophthalic acid backbone. The key to their synthesis lies in overcoming steric hindrance by iodinizing all 2,4,6-positions of the benzene ring of 5-aminoisophthalic acid or its derivatives. However, due to the strong inductive effect of two electron-withdrawing groups at the 2-position of the substrate and the significant steric hindrance of the iodine atoms on either side, the iodination barrier at this site is extremely high. Current technologies still have significant shortcomings in terms of reactivity, selectivity, and environmental friendliness.

[0003] Currently, the iodination process of iodine chloride in a strongly acidic aqueous solution (ICl / HCl system) is widely used in industry. Although this method is low-cost, the chlorinated reactive species generated after heterolytic cleavage of the polarized I-Cl bond in the ICl reagent compete with the iodide ion for electrophilic substitution. This inevitably leads to the formation of structurally very similar chlorinated byproducts, such as 5-amino-2,4-diiodo-6-chloroisophthalic acid. These impurities are extremely difficult to remove by conventional recrystallization methods, severely affecting the purity and quality of subsequent pharmaceutical raw materials. Furthermore, this process relies on a high-concentration hydrochloric acid medium, which not only causes severe corrosion to the reaction equipment but also generates large amounts of difficult-to-treat acidic and iodine-containing wastewater, posing a significant environmental challenge.

[0004] Another conventional strategy is in-situ iodination using elemental iodine in conjunction with strong oxidizing agents (such as iodic acid and hydrogen peroxide). While this method avoids the introduction of chlorinated impurities, the highly oxidizing reaction environment is extremely unfriendly to sensitive functional groups in the substrate. Especially for contrast agent intermediates with multi-hydroxyl side chains (such as 2,3-dihydroxypropyl), the oxidizing agent readily oxidizes the hydroxyl groups to carbonyl or carboxyl groups. To avoid this side reaction, existing processes typically employ a cumbersome "protection-iodination-deprotection" strategy, i.e., first acetyl-protecting the hydroxyl groups, then iodizing them, and finally hydrolyzing them for deprotection. This significantly increases the number of synthesis steps, prolongs the production cycle, and raises production costs.

[0005] In summary, existing aromatic iodination technologies generally face problems such as difficulty in controlling impurities, harsh reaction conditions, poor tolerance of functional groups, and high environmental impact. These problems are particularly prominent when preparing iodine contrast agent intermediates with complex structures and sensitive functional groups.

[0006] Therefore, there is an urgent need in this field to develop a novel iodination system that combines high electrophilic activity, non-oxidizing properties, chlorine-free characteristics, and suitability for homogeneous reactions. This system would have significant industrial application value in improving the production efficiency and product quality of iodine contrast agents and reducing environmental impact. Summary of the Invention

[0007] The main objective of this invention is to provide a solvent-free aromatic iodination method with high electrophilic activity that does not require oxidation conditions.

[0008] In a first aspect, the present invention provides a solvent-free electrophilic aromatic iodination method, comprising the following steps: reacting an aromatic substrate with an iodine cation liquid to obtain an iodinated product; The iodine cation liquid has the following structure: [I(L)2] + [X] - ; The ligand L is selected from the following group: pyridine, C 1-4 Alkyl-substituted pyridine, C 1-4 Aliphatic nitrile; anion X - It is a non-coordinated or weakly coordinated anion.

[0009] In another preferred embodiment, the iodination product is a triiodination product.

[0010] In another preferred embodiment, the ligand L is selected from the group consisting of pyridine, acetonitrile, and 2,6-dimethylpyridine. The anion X - Selected from the following group: bis(trifluoromethanesulfonyl)imide (Tf2N) - ), hexafluorophosphate (PF6) - ), tetrafluoroborate (BF4) - ).

[0011] In another preferred embodiment, the aromatic substrate is an electron-rich aromatic compound selected from the group consisting of anilines, phenols, anisoles, polyalkylbenzenes, polycyclic aromatic hydrocarbons, thiophenes, or indoles.

[0012] In another preferred embodiment, the aromatic substrate is an aniline or a polyalkylbenzene.

[0013] In another preferred embodiment, the aromatic substrate comprises one or more substituents.

[0014] In another preferred embodiment, the iodine positive ion liquid contains I + The dosage is 1.1 to 2.0 equivalents of the aromatic substrate.

[0015] In another preferred embodiment, the reaction temperature is 25~60°C; and / or the reaction time is 1~5 hours.

[0016] In another preferred embodiment, the iodide positive ion liquid is [I(py)2][Tf2N], and the iodide positive ion liquid contains I... + The molar ratio of the substrate to the reaction medium is 3.0 to 4.0:1, the reaction temperature is 40 to 80°C, and the reaction time is 4 to 6 hours.

[0017] A second aspect of the present invention provides a method for directly preparing triiodinated aromatic compounds, comprising the following steps: reacting an aromatic substrate with an iodine cation liquid to obtain a triiodinated intermediate; The iodine positive ionic liquid is [I(py)2]. + [Tf2N] - .

[0018] A third aspect of the present invention provides a method for preparing a nonionic iodine contrast agent, comprising the following steps: (a) 5-aminoisophthalic acid or its amide derivative is subjected to 2,4,6-triiodination by the method described in the second aspect of the present invention to obtain a triiodination intermediate; (b) The triiodide intermediate is sequentially modified by acylation, amidation and / or alkylation to obtain a nonionic iodine contrast agent.

[0019] In another preferred embodiment, the nonionic iodine contrast agent is selected from the group consisting of: iohexol, iopamidol, iodixanol, and iodofol.

[0020] In a fourth aspect, the present invention provides the use of an iodide positive ionic liquid, said iodide positive ionic liquid (a) as an iodination reagent, and (b) for the preparation of triiodide intermediates for X-ray contrast agents; The iodine positive ionic liquid has [I(L)2] + [X] - The structure, wherein L is a nitrogen-containing heterocyclic ligand or a nitrogen-containing aliphatic ligand, and X - It is a non-coordinated or weakly coordinated anion. In another preferred embodiment, the triiodination intermediate is 5-amino-2,4,6-triiodophthalic acid or 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide.

[0021] In another preferred embodiment, the iodine positive ion liquid is in a liquid state at 25°C.

[0022] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0023] Through extensive and in-depth research, the inventors have, for the first time, developed the iodine cation liquid ([I(L)2)). + [X] - This invention relates to the application of electrophilic aromatic iodination reactions, where no external organic solvent, strong acid, or oxidizing agent is required. The iodination reaction can directly triiodinate aromatic substrates, showing great potential in the field of nonionic iodine contrast agents. Based on this, the present invention was completed.

[0024] the term Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. As used herein, the terms “comprising,” “including,” and “containing” are used interchangeably and include not only closed definitions but also semi-closed and open definitions. In other words, the terms include “consisting of” and “substantially consisting of”.

[0025] The present invention provides a solvent-free electrophilic aromatic iodination method. This invention provides a solvent-free electrophilic aromatic iodination method using an iodide positive ionic liquid as both the iodination reagent and the reaction medium. The aromatic substrate is directly added to the iodide positive ionic liquid, which is liquid at room temperature. The reaction is carried out with stirring at 0-80°C under conditions of no added organic solvent, strong acid, or oxidizing agent to obtain the iodinated product. The iodide positive ionic liquid is [I(L)2]. + [X] - A room-temperature ionic liquid with a structure in which L is selected from pyridine, C 1-4 Alkyl-substituted pyridine or C 1-4 One of the aliphatic nitrile groups, X - It is a non-coordinated or weakly coordinated anion.

[0026] Specifically, the ligand L is selected from pyridine, acetonitrile, or 2,6-dimethylpyridine; the anion X - Selected from bis(trifluoromethanesulfonyl)imide (Tf2N) - ), hexafluorophosphate (PF6) - ) or tetrafluoroborate (BF4) - One of the following; and the ligand L and the anion X - The specific combination satisfies the condition that the formed iodine positive ion liquid is liquid at 25°C.

[0027] Specifically, the iodine positive ion liquid is selected from one of [I(py)2][Tf2N], [I(CH3CN)2][BF4] or [I(2,6-dimethylpyridine)2][PF6].

[0028] Specifically, the aromatic substrate is an electron-rich aromatic compound selected from anilines, phenols, anisoles, polyalkylbenzenes, polycyclic aromatic hydrocarbons, thiophenes, or indoles.

[0029] In another preferred embodiment, the iodine positive ion liquid contains I + The amount of the substrate used is 1.1 to 2.0 equivalents, the reaction temperature is 25 to 60°C, and the reaction time is 1 to 5 hours.

[0030] In another preferred embodiment, the aromatic substrate is 5-aminoisophthalic acid or an amide derivative thereof, and the iodination is 2,4,6-triiodination including the 2-position of the benzene ring of the substrate.

[0031] In another preferred embodiment, the iodide positive ion liquid is [I(py)2][Tf2N], and the iodide positive ion liquid contains I... + The molar ratio of the substrate to the reaction medium is 3.0 to 4.0:1, the reaction temperature is 40 to 80°C, and the reaction time is 4 to 6 hours.

[0032] In another embodiment, the present invention also provides a method for preparing a nonionic iodine contrast agent, comprising the following steps: (1) Using the aforementioned method, 5-aminoisophthalic acid or its amide derivative is subjected to 2,4,6-triiodination to obtain a triiodination intermediate; (2) The triiodide intermediate is sequentially modified by acylation, amidation and / or alkylation to obtain a nonionic iodine contrast agent.

[0033] In another preferred embodiment, the nonionic iodine contrast agent is selected from one of iohexol, iopamidol, iodixanol, or iodofol.

[0034] In another embodiment, the present invention also provides a [I(L)2] + [X] - Application of iodide-containing positive ionic liquids with a structure in the preparation of iodinated intermediates for X-ray contrast agents, where L is a nitrogen-containing heterocyclic ligand or a nitrogen-containing aliphatic ligand, X - The iodide cation liquid is a non-coordinated or weakly coordinated anion and is in a liquid state at 25°C; the iodination intermediate is 5-amino-2,4,6-triiodophthalic acid or 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide.

[0035] Compared with the prior art, the present invention has the following technical effects: 1. The iodine cation liquid is a highly fluid liquid at room temperature, serving as both an iodination reagent and a reaction medium. After the aromatic substrate dissolves into the liquid system, a homogeneous reaction environment is formed, completely eliminating the lattice energy constraint of the solid reagent and significantly increasing the contact area and mass transfer efficiency between reactant molecules. Comparative Example 2 (solid [I(py)2]BF4, 80℃, 4 hours) showed a conversion rate of less than 15%, while Example 6 of this invention achieved complete 2,4,6-triiodination of the substrate 5-aminoisophthalic acid under the same temperature and time conditions, with a separation yield of 94% and HPLC purity >99.2%.

[0036] 2. The lone pair electrons of the ligands form [NIN] with the iodine atom. + This type of coordination structure effectively disperses the positive charge and inhibits the disproportionation and decomposition of iodide ions, while retaining their high electrophilicity. This cationic iodine species can overcome the extremely high iodination energy barrier formed by the superposition of the electron-withdrawing effect of the dicarboxyl group at the 2-position of 5-aminoisophthalic acid and the steric hindrance effect under mild conditions without the need for external Lewis acid catalysis or strong acid media, achieving complete triiodination. In contrast, [ICl2]-based... - The ionic liquid system of anions (Comparative Example 5) has a high electron cloud density and weak electrophilicity, and the conversion rate is less than 40% under the same conditions, making it almost impossible to obtain triiodinated products.

[0037] 3. The iodination system of this invention completely eliminates the chlorine source from a chemical compositional perspective, fundamentally blocking the reaction pathway in which chloride ions participate in electrophilic attack. No chlorinated byproducts were detected in the product of Example 6, while the conventional ICl / HCl process (Comparative Example 4) detected 0.45% 5-amino-2,4-diiodo-6-chloroisophthalic acid impurity under the same substrate. Because the chlorinated impurity is structurally highly similar to the target product, the conventional process requires an additional purification step to meet the quality standards of the active pharmaceutical ingredient. This invention eliminates this impurity at the source, significantly reducing the difficulty and cost of subsequent purification.

[0038] 4. [NIN] + The iodination mechanism is a pure electrophilic substitution, and the reaction system does not require the addition of strong oxidizing agents such as iodic acid or hydrogen peroxide. Even at 60–80 °C and in the presence of 3.5 equivalents of iodizing reagent, the free hydroxyl groups on the substrate side chain do not undergo oxidation side reactions (Example 8). Under milder conditions (1.2 equivalents of iodizing reagent, 30 °C), no oxidation byproducts were detected in substrates containing four free hydroxyl groups (Example 7). This allows contrast agent intermediates containing multiple hydroxyl side chains (such as 5-amino-N,N'-bis(2,3-dihydroxypropyl)isophthalamide) to be directly iodinated, completely eliminating the cumbersome acetylation and hydrolysis protection steps in traditional processes, shortening the synthetic route by 2–3 steps, and significantly improving the overall yield.

[0039] 5. This invention uses iodine cation liquid itself as the reaction medium, completely avoiding the use of volatile organic solvents (VOCs) and eliminating solvent recovery and waste liquid treatment. For the preparation of contrast agent triiodide intermediates (Examples 6 and 8), post-processing only requires pouring the reaction solution into ice water, adding a small amount of sodium bisulfite aqueous solution to reduce trace amounts of residual free iodine, and then filtering and washing with water to obtain a high-purity product, without the need for acid-base neutralization or column chromatography separation. For highly reactive monoiodide small molecule products (Examples 12 and 13, etc.), the product can be directly precipitated after pouring the reaction solution into ice water, and high-purity product can be obtained by filtration; for other monoiodide substrates (Example 2, etc.), separation can also be completed by simple water-organic solvent extraction. For selective iodination intermediates (such as the diiodide product of Example 7), further purification by column chromatography can be performed as needed. Compared with the traditional ICl / DCM process (Comparative Example 1, which requires low-temperature reaction, multi-step washing and column chromatography, with a yield of 78%), the post-processing operation of this invention is significantly simplified, reducing the emission of waste gas, wastewater, and solid waste from the source, and has outstanding advantages in green chemical industry.

[0040] 6. The iodide cation liquid described above exhibits good reactivity with a variety of electron-rich aromatic substrates, including anilines, phenols, anisoles, polyalkylbenzenes, fused-ring aromatics, thiophenes, and indoles, with separation yields of 79%–96% (Examples 2, 4, 12, 14–22). The regioselectivity of the products is greater than 95%, requiring no external directing or protecting groups. The iodination position selectivity can be further controlled by adjusting the type of ligand (e.g., introducing sterically hindered 2,6-dimethylpyridine). The system is highly flexible and suitable for the synthesis of diverse pharmaceutical intermediates.

[0041] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed according to the conditions described in the conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0043] In this invention, unless otherwise stated, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0044] In this invention, unless otherwise stated, the term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0045] In this invention, unless otherwise specified, the experimental methods used in the embodiments of this invention are conventional methods, and the materials and reagents used are commercially available unless otherwise specified.

[0046] The following examples are for illustrative purposes only and are not intended to limit the scope of the invention. Unless otherwise specified, all examples were conducted under nitrogen protection at atmospheric pressure.

[0047] Example 1: Preparation of iodine positive ionic liquid In a dry 50 mL round-bottom flask, elemental iodine (I₂, 254 mg, 1.0 mmol) and silver bis(trifluoromethanesulfonyl)imide (AgTf₂N, 388 mg, 1.0 mmol) were added. 5 mL of anhydrous acetonitrile (dried via a 4 Å molecular sieve) was injected using a syringe, and the mixture was magnetically stirred at room temperature in the dark for 2 hours. The reaction mixture gradually changed from dark brown to light yellow. The silver iodide precipitate was removed by filtration through a short-core funnel filled with diatomaceous earth, and the clear filtrate was collected in another dry flask. Pyridine (160 mg, 2.0 mmol) was slowly added dropwise to this filtrate, and the mixture was stirred at room temperature for another 1 hour. The reaction mixture was then transferred to a rotary evaporator, and all volatile components were completely removed under reduced pressure in a 40 °C water bath, yielding a pale yellow, viscous, oily liquid, which was the target product [I(py)₂][Tf₂N], weighing approximately 510 mg (yield approximately 90%).

[0048] The product structure characterization data are as follows: 1 HNMR(400MHz,CD3CN)δ:8.80(d,J=5.6Hz,2H),8.20(tt,J=7.8,1.6Hz,1H),7.70(t,(J=7.0)Hz,2H)ppm.

[0049] 19 FNMR(376MHz,CD3CN)δ:-79.5(s,6F)ppm.

[0050] ESI-MS (m / z): [M] + calcdforC 10 H 10 IN2284.99, found285.00.

[0051] Example 2 In a 10 mL reaction tube equipped with a magnetic stir bar, accurately weigh approximately 244 mg of the iodide positive ion liquid [I(py)2][Tf2N] synthesized in Example 1 (containing I... +0.432 mmol). Add 2-methylaniline (53.6 mg, 0.5 mmol). Seal the reaction tube and place it in an oil bath preheated to 25°C with stirring for 2.5 hours. Monitor the reaction completion by TLC. After the reaction, dilute the reaction solution with 15 mL of deionized water and extract with ethyl acetate (3 × 5 mL). Combine the organic phases and process according to standard procedures to obtain the product 4-iodo-2-methylaniline. Yield: 79%. Example 3 Following the method in Example 1, the iodide positive ion liquid [I(acetonitrile)2][BF4] was synthesized.

[0052] In a dry 50 mL round-bottom flask, elemental iodine (I₂, 254 mg, 1.0 mmol) and silver tetrafluoroborate (AgBF₄, 194 mg, 1.0 mmol) were added. 5 mL of anhydrous acetonitrile (dried via a 4 Å molecular sieve) was injected using a syringe, and the mixture was magnetically stirred at room temperature in the dark for 2 hours. The reaction mixture gradually changed from dark brown to light yellow. The silver iodide precipitate was removed by filtration through a short-core funnel filled with diatomaceous earth, and the clear filtrate was collected in another dry flask. The reaction mixture was then transferred to a rotary evaporator, and all volatile components were completely removed under reduced pressure in a 40 °C water bath, yielding a pale yellow, viscous, oily liquid, which was the target product [I(acetonitrile)₂][BF₄].

[0053] Take the liquid (containing I) + 0.6 mmol) was mixed with anisole (54.1 mg, 0.5 mmol) and stirred at 0 °C (ice-water bath) and 60 °C, respectively. The reaction progress was monitored by TLC. result: The reaction was carried out at 0℃ for 6 hours, with a conversion rate of >95%, and 4-iodoanisole was isolated with a yield of 90%.

[0054] Reacting at 60℃ for 1 hour, the conversion rate is >99% and the separation yield is 87%.

[0055] The reaction temperature can be flexibly adjusted within a wide range. Low temperatures are beneficial for temperature-sensitive substrates, while high temperatures can accelerate the reaction.

[0056] The kinetic studies conducted in this embodiment at different reaction temperatures (0°C and 60°C) reveal the significant regulatory effect of temperature on the reaction rate. Experimental data show that when the reaction system temperature is increased from ice bath conditions (0°C) to 60°C, the time required to reach the endpoint is significantly reduced from 6 hours to 1 hour while maintaining stable yield and high conversion. This indicates that the ionic liquid-mediated electrophilic substitution reaction exhibits typical thermal activation characteristics. By flexibly adjusting the reaction temperature, the effective collision frequency of molecules in the reaction system and their ability to overcome activation barriers can be effectively controlled. This allows the system to broadly adapt to the iodination requirements of different active substrates, achieving highly selective conversion at low temperatures or efficient and rapid reactions at high temperatures.

[0057] Example 4 In a dry 50 mL round-bottom flask, elemental iodine (I₂, 254 mg, 1.0 mmol) and silver bis(trifluoromethanesulfonyl)imide (AgTf₂N, 388 mg, 1.0 mmol) were added. 5 mL of anhydrous acetonitrile (dried via a 4 Å molecular sieve) was injected using a syringe, and the mixture was magnetically stirred at room temperature in the dark for 2 hours. The reaction mixture gradually changed from dark brown to light yellow. The silver iodide precipitate was removed by filtration through a short-core funnel filled with diatomaceous earth, and the clear filtrate was collected in another dry flask. 2,6-Dimethylpyridine (approximately 236 mg, 2.2 mmol) was slowly added dropwise to this filtrate, and the mixture was stirred at room temperature for another 1 hour. The reaction mixture was then transferred to a rotary evaporator, and all volatile components were completely removed under reduced pressure in a 40 °C water bath to obtain a pale yellow, viscous, oily liquid.

[0058] After synthesis, anion exchange was performed: the obtained liquid was dissolved in 5 mL of water, and an aqueous solution of potassium hexafluorophosphate (KPF6, about 184 mg, 1.0 mmol) (dissolved in 5 mL of water) was added. After stirring for 30 minutes, the mixture was extracted with dichloromethane (3 × 5 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to obtain the iodide positive ion liquid [I(2,6-lutidine)2][PF6].

[0059] Take the above liquid (containing I) + 0.6 mmol of phenol (47.1 mg, 0.5 mmol) was added to a reaction tube, and the mixture was stirred in an oil bath at 35°C for 2 hours. The post-treatment method was the same as in Example 2, yielding 4-iodophenol. The calculated separation yield was 89%. A comprehensive review of the synthesis results in Examples 1, 3, and 4 shows that regardless of whether common nitrogen- or cyano-containing ligands such as pyridine or acetonitrile are used, or sterically hindered 2,6-dimethylpyridine is introduced, a stable iodide cation liquid can be constructed with a separation yield exceeding 90% via a one-pot reaction. This is mainly attributed to the strong coordination bond formed between the lone pair electrons in the ligand molecule and the central iodine atom. This "NIN" or "NI-Solvent" type coordination structure not only effectively disperses the positive charge center of the iodine atom, reducing the energy of the system and thus suppressing the common disproportionation decomposition side reaction of iodide cations, but also retains its reactivity as a strong electrophilic reagent. This precise control of reactivity and storage stability at the molecular level successfully overcomes the inherent defects of traditional iodination reagents (such as ICl, NIS, etc.), such as poor stability, need for on-site preparation, or low atom economy, laying the material foundation for the large-scale preparation and industrial application of this type of reagent.

[0060] Example 5 In a dry 10 mL reaction tube, accurately weigh approximately 1017 mg of the iodide positive ion liquid [I(py)2][Tf2N] synthesized in Example 1 (containing I...). + 1.8 mmol). Tris(methylbenzene) (60.1 mg, 0.5 mmol) was added. The reaction tube was sealed and placed in an oil bath preheated to 40 °C with stirring for 4 hours. TLC monitoring (developing solvent: petroleum ether) showed complete conversion of the starting material, with the appearance of a single spot of the main product (Rf value approximately 0.5). After the reaction was complete, the reaction solution was diluted with 10 mL of ice water, and a white solid precipitated. The solid was filtered, washed with a small amount of cold water, and dried under vacuum to obtain a white solid. 1 HNMR analysis identified it as 1,3,5-triiodo-2,4,6-trimethylbenzene (CAS: 28188-31-0). Separation yield: 85% (based on mesitylene), HPLC purity >98%. Example 6 In a dry reaction vessel, add the liquid iodine positive ion liquid [I(py)2][Tf2N] (containing active iodine I) prepared in Example 1. + 192.5 mmol (approximately 3.5 equivalents) was then added directly to the above liquid. Stirring was started and the temperature was slowly increased to 80 °C. It was observed that the solid substrate dissolved rapidly with increasing temperature, and the reaction system transformed into a homogeneous, deep red, transparent liquid. The reaction was maintained at 80 °C with stirring for 4 hours.

[0061] After the reaction was complete, the reaction mixture was slowly poured into 200 mL of ice water and stirred vigorously. A saturated sodium bisulfite (NaHSO3) aqueous solution was added dropwise to the system until the deep red color completely disappeared (quenching trace amounts of free iodine), at which point a large amount of white precipitate formed. After standing for a short time, the mixture was filtered, and the filter cake was washed with cold water (3 × 50 mL). Finally, it was dried under vacuum at 60 °C to constant weight. 29.0 g of a white powdery solid was obtained, which was the target product, 5-amino-2,4,6-triiodophthalic acid. The calculated yield was 94%. HPLC analysis showed a purity >99.2%.

[0062] The 2-position of 5-aminoisophthalic acid is simultaneously affected by the strong electron-withdrawing effect and steric hindrance of two carboxyl groups, making it difficult to iodinate in conventional processes or requiring strong acid catalysis. This invention utilizes the cation [NIN]. + Its strong electrophilicity allows this high-barrier reaction to be completed under mild conditions (acid-free, 80°C). Compared with the traditional ICl / HCl process (which requires high-temperature reflux, strong acid corrosion, and the generation of chlorinated impurities), this method has a shorter reaction time, and because no chlorinating reagent is used, the product is completely free of chlorinated impurities (such as 5-amino-2,4-diiodo-6-chloroisophthalic acid), significantly reducing the difficulty of subsequent purification. Example 7 Add [I(py)2][Tf2N] (containing I) to the reaction tube + 1.2 mmol) and 5-amino-N,N'-bis(2,3-dihydroxypropyl)isophthalamide (163.70 mg, 0.5 mmol) were reacted at 30 °C with stirring for 5 hours. After the reaction was complete, 10 mL of water was added for dilution, and the mixture was extracted with ethyl acetate (3 × 8 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient elution) to give a white foamy solid, which was a highly regioselective diiodoform product (4-iodo-5-amino-N,N-bis(2,3-dihydroxypropyl)isophthalamide), with a separation yield of 82% and a selectivity >97%. Example 8 verifies that the method of the present invention can perform full iodination without hydroxyl protection. In a dry reaction vessel, the liquid iodine positive ion liquid [I(py)2][Tf2N] (containing active iodine I) prepared in Example 1 was placed... +The solution (3.5 equivalents) was heated to 60°C. 10 mmol of the substrate 5-amino-N,N'-bis(2,3-dihydroxypropyl)isophthalamide was added directly to the heated ionic liquid. The reaction was stirred at a constant temperature for 6 hours. After the reaction was complete, the mixture was poured into ice water, quenched with sodium bisulfite, and post-treated to obtain the product. The calculated yield was 92%, and HPLC showed a conversion >98%. This substrate contains four free hydroxyl groups, making it extremely sensitive to oxidants. Traditional industrial processes (ICl / HIO3) readily oxidize these hydroxyl groups, requiring complex protecting group strategies. This example demonstrates the non-oxidizing environment of the ionic liquid system, enabling direct full iodination without protecting the hydroxyl groups, showcasing significant process advantages.

[0063] The experimental results of Example 8 further confirm the chemoselectivity and functional group tolerance of this ionic liquid system. Even under harsh conditions of 60°C and the presence of excess iodide, the reaction still proceeded with electrophilic substitution on the aromatic ring, while the oxidation-sensitive aliphatic side-chain hydroxyl groups did not undergo any oxidative degradation. This is mainly attributed to the unique non-oxidizing reaction mechanism of this cationic iodine system, which is fundamentally different from traditional strongly oxidizing iodination systems such as I₂ / HIO₃, thus avoiding side reactions such as the oxidation of alcohol hydroxyl groups to aldehydes, ketones, or acids. This characteristic eliminates the need for cumbersome protecting / deprotecting synthetic strategies when synthesizing complex iodides with multiple hydroxyl side chains, significantly shortening the synthetic route and increasing the overall yield.

[0064] Example 9: Preparation of the contrast agent triiodide intermediate (iohexol) The 5-amino-2,4,6-triiodophthalic acid prepared in Example 6 above was used as a key intermediate in the preparation of iohexol.

[0065] Step A (N-acetylation): 100 g of 5-amino-2,4,6-triiodophthalic acid was suspended in acetic anhydride (300 mL), and a catalytic amount of concentrated sulfuric acid was added. The mixture was heated to 50-60 °C and stirred to react. After the reaction was complete, the reaction solution was slowly poured into ice water to precipitate a solid. The solid was filtered, and the filter cake was thoroughly washed with cold water and dried to obtain 5-acetamido-2,4,6-triiodophthalic acid (compound A).

[0066] Step B (amidation): Compound A was suspended in an appropriate amount of thionyl chloride (SOCl2), and a catalytic amount of N,N-dimethylformamide (DMF) was added. The mixture was heated under reflux for 2-3 hours until the solid was completely dissolved and no more HCl gas was emitted from the tail gas. Excess SOCl2 was removed by vacuum distillation to obtain 5-acetamido-2,4,6-triiodophthaloyl chloride. The obtained acyl chloride was dissolved in anhydrous tetrahydrofuran and slowly added dropwise to an aqueous solution of 1-amino-2,3-propanediol (adjusted to pH 9-10 with NaOH) at 0-5°C. After the addition was complete, the mixture was stirred at room temperature for 2 hours to obtain compound B.

[0067] Step C (N-alkylation): Compound B was dissolved in 2-methoxyethanol, and the pH was adjusted to alkaline by adding an aqueous sodium hydroxide solution. 3-chloro-1,2-propanediol was added dropwise at 50°C to induce N-alkylation of the 5-acetamino nitrogen, and the reaction was monitored until the starting material disappeared.

[0068] Step D (Refining): The reaction solution is desalted and decolorized through a macroporous adsorption resin, and the effluent is collected and concentrated. The residue is recrystallized in a n-butanol / water system to obtain a white crystalline powder, which is the finished product, Iohexol.

[0069] Following the above steps, the overall yield of iohexol, based on 5-amino-2,4,6-triiodophthalic acid, was 58%, with an HPLC purity ≥99.0%. The triiodide intermediate prepared by the method of this invention has extremely high purity and no oxidation byproducts, significantly improving the overall yield and final product quality of subsequent iohexol synthesis.

[0070] Example 10: Preparation of the contrast agent triiodide intermediate (iophanate-methyl) The 5-amino-2,4,6-triiodophthalic acid prepared in Example 6 was used as the starting material.

[0071] Step A (Aminoacylation): The above iodinated intermediate was dissolved in dimethylacetamide (DMAC), and (S)-(-)-2-acetoxypropionyl chloride was slowly added dropwise under cooling conditions of 0-5°C. After the addition was complete, the mixture was heated to room temperature and stirred until the amino group of the starting material was completely converted to give 5-[(S)-2-acetoxypropionylamino]-2,4,6-triiodoisophthalic acid. This step introduces a protected lactic acid side chain at the 5-amino group.

[0072] Step B (amidation): The product from step A is acylated (refer to Example 9) and then reacted with 1-amino-2,3-propanediol (i.e., 2,3-dihydroxypropylamine) to obtain the corresponding diamide derivative.

[0073] Step C (hydrolysis protection): Add sodium hydroxide aqueous solution to the reaction solution to adjust the pH to 10-11, heat to 40-50℃ to carry out the hydrolysis reaction, and remove the acetyl protecting group on the lactic acid side chain.

[0074] Step D (Refining): The reaction solution is desalted using a cation / anion exchange resin column, and the effluent is collected. After decolorization with activated carbon, it is concentrated under reduced pressure and recrystallized in ethanol to obtain a white crystalline powder, which is the finished product, iopamidol.

[0075] Following the above steps, the overall yield of iopamidol, based on 5-amino-2,4,6-triiodophthalic acid, was 57%, with an HPLC purity ≥99.0%. Because the nucleophilicity of aromatic amino groups is significantly higher than that of carboxyl groups, and because the acyl chloride is added stoichiometrically, (S)-(-)-2-acetoxypropionyl chloride preferentially undergoes amidation with the 5-position amino group under low-temperature (0~5℃) conditions. Even if trace amounts of mixed anhydrides may form between the carboxyl group and the acyl chloride, these are completely hydrolyzed into free carboxylic acid in the subsequent alkaline hydrolysis step (step C), without affecting the purity of the final product. Furthermore, because the preceding iodination step uses the non-acidic iodine cation liquid system of this invention, the hydrolysis of the amide bonds in the substrate and intermediates by the acidic medium is effectively avoided, resulting in a 5~8 percentage point increase in the overall yield of the final iopamidol product compared to the traditional ICl / HCl process.

[0076] Example 11 Preparation of contrast agent triiodide intermediate (iodixanol) Step A (N-acetylation): 5-acetamido-2,4,6-triiodophthalic acid (compound A) was prepared from 5-amino-2,4,6-triiodophthalic acid using the same method as in Step A of Example 9.

[0077] Step B (amidation): Compound A is acylated (refer to Example 9) and then reacted with 1-amino-2,3-propanediol to give 5-acetamido-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide (compound B). Because the iodination product of this invention has extremely high purity, it can be directly used in subsequent reactions without recrystallization.

[0078] Step C (dimerization reaction): Compound B is dissolved in a water / 2-methoxyethanol mixed solvent, and sodium hydroxide is added. At 50°C, epichlorohydrin, a dimerizing agent, is slowly added dropwise, and the pH value of the reaction is controlled to carry out the dimerization cross-linking reaction.

[0079] Step D (Purification): After the reaction, monomers and small molecule impurities are removed by nanofiltration, followed by desalting with ion exchange resin. The concentrate is recrystallized in a methanol / isopropanol system to obtain iodixanol.

[0080] Following the above steps, the total yield of iodixanol, based on 5-amino-2,4,6-triiodophthalic acid, was 43%, with an HPLC purity ≥99.0%. The monomer prepared by this invention is free of oxidative byproducts, significantly reducing the formation of oxidized dimer impurities such as O, which are extremely difficult to remove during the dimerization reaction, and greatly reducing the subsequent purification load.

[0081] Example 12 Take approximately 339 mg of the iodide positive ion liquid [I(py)2][Tf2N] synthesized in Example 1 (containing I... + 0.6 mmol of N-acetanilide (67.6 mg, 0.5 mmol) was added directly to a reaction tube. The mixture was stirred in an oil bath at 35 °C for 2.5 hours. After the reaction was complete, the reaction solution was poured directly into 10 mL of water and simply extracted with ethyl acetate (3 x 5 mL). The organic phases were combined, dried, and concentrated to obtain the high-purity product. The calculated separation yield was 90%, and the HPLC purity was >99%.

[0082] The total operation time is about 4 hours. Compared with traditional methods, this invention completely avoids the addition of volatile organic solvents (VOCs), eliminates stoichiometric inorganic salts or acid byproducts from the source, greatly simplifies the operation steps (no need for strong acid neutralization or column chromatography purification), makes the reaction conditions milder, and significantly improves the yield and selectivity, fully demonstrating the characteristics of being green, efficient and simplified. Example 13 In a 50 mL round-bottom flask, add the [I(py)2][Tf2N] (containing I) synthesized in Example 1. + 6.0 mmol (approximately 3.39 g) and N-acetanilide (675 mg, 5.0 mmol) were reacted in an oil bath at 35 °C with stirring for 3 hours. After the reaction was complete, the reaction solution was slowly poured into 50 mL of ice water while stirring, and a large amount of solid precipitated immediately. Stirring was continued for 15 minutes, and the mixture was filtered. The filter cake was washed with a small amount of cold water and dried under vacuum to directly obtain the off-white solid product 4-iodo-N-acetanilide. The product weight was 1.17 g, the separation yield was 90%, and the HPLC purity was >99%.

[0083] Furthermore, we selected different iodine cation liquids and carried out iodination reactions on various aromatic substrates under optimized conditions. The results are shown in the table below: Abbreviations: py = pyridine, AN = acetonitrile, 2,6-lut = 2,6-dimethylpyridine.

[0084] Extensive substrate studies based on Examples 2, 4, 12 and Examples 14 to 22 demonstrate that this iodine cation liquid system exhibits excellent reactivity in the monoiodination modification of electron-rich aromatic compounds. For aniline, phenol, anisole, and heterocyclic compounds such as thiophene and indole, the system exhibits extremely high electrophilic substitution activity and regioselectivity, with results showing selectivity greater than 95% at the para-position or specific active sites.

[0085] This result strongly confirms that the dissociated cationic iodine species in the reaction system possess extremely strong electrophilicity, enabling them to rapidly and specifically attack the sites with the highest electron cloud density on the substrate under mild conditions without the need for external Lewis acid catalysis. This high selectivity not only significantly improves the utilization rate of raw materials but also significantly reduces the formation of isomer byproducts, simplifying the purification process from the source.

[0086] Example 23 Preparation of contrast agent triiodide intermediate (iodophorol) The 5-amino-2,4,6-triiodophthalic acid prepared in Example 6 was used as a starting material for the preparation of iodofol.

[0087] Step A (N-acetylation): 5-Amino-2,4,6-triiodophthalic acid was suspended in acetic anhydride, and a catalytic amount of concentrated sulfuric acid was added. The mixture was heated to 50-60°C and stirred to react. After the reaction was completed, the mixture was cooled to crystallize, filtered, and dried to obtain 5-acetamido-2,4,6-triiodophthalic acid (compound A).

[0088] Step B (amidation): Compound A was acylated (see Example 9) and then reacted with 1-amino-2,3-propanediol to give 5-acetamido-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide (compound B).

[0089] Step C (N-alkylation): Compound B was dissolved in 2-methoxyethanol, and the pH was adjusted to alkaline by adding an aqueous sodium hydroxide solution. 2-chloroethanol was added dropwise at 50°C to N-alkylate the acetamino nitrogen at the 5-position, introducing a 2-hydroxyethyl group to yield 5-[acetyl(2-hydroxyethyl)amino]-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide. The reaction was monitored until the starting material disappeared.

[0090] Step D (Purification): The reaction solution is desalted using ion exchange resin and decolorized with activated carbon. After concentration under reduced pressure, it is recrystallized in an ethanol / isopropanol system to obtain a white crystalline powder, which is the Ioversol product. The yield of this purification step (based on crude product) is approximately 85-90%. The overall yield (based on 5-amino-2,4,6-triiodophthalic acid) is approximately 57%, and the HPLC purity is ≥99.0%.

[0091] The high-purity triiodide intermediate prepared using the method of this invention was applied to the synthesis of contrast agent active pharmaceutical ingredients (APIs) such as iohexol, iopamidol, and iodixanol (Examples 9-11, 23, etc.). The results showed a significant improvement in both the overall yield and quality of the final product. This is mainly because, in the preceding iodination step, the high selectivity of this system effectively eliminated the formation of oxidized dimer impurities and structurally similar chlorinated / brominated impurities. These impurities are often difficult to remove using conventional recrystallization methods in traditional processes and significantly interfere with subsequent alkylation or dimerization reactions. Therefore, obtaining a high-quality intermediate greatly reduces the purification load of the final API and lowers production costs, demonstrating the significant technical advantages and application value of this method in the entire industrial process of non-ionic iodine contrast agents.

[0092] Those skilled in the art will understand that the solvent-free liquid iodization system ([I(py)2][Tf2N], etc.) provided by this invention is not only applicable to the specific embodiments described above, but can also be widely used in the preparation of various X-ray contrast agent intermediates containing a 5-aminoisophthalic acid backbone. The obtained high-purity triiodide intermediates can be converted into various nonionic iodine contrast agents, including but not limited to iohexol, iopamidol, iodixanol, iopromide, and ioflufenicol, through conventional acylation (such as acetic anhydride, hydroxypropionyl chloride, etc.) and / or alkylation (such as epichlorohydrin, chloropropanediol, etc.).

[0093] Comparative Example 1 In a dry 25 mL round-bottom flask, N-acetanilide (67.6 mg, 0.5 mmol) and 5 mL of anhydrous dichloromethane (CH₂Cl₂) were added as solvent, and the mixture was cooled to 0 °C in an ice-water bath. While stirring, 1 mL of dichloromethane solution containing iodine chloride (ICl, 81.5 mg, 0.5 mmol) was slowly added using a syringe. The ice bath was removed, and the mixture was allowed to rise to room temperature with stirring for 3 hours. After the reaction was complete as monitored by TLC, the reaction mixture was poured into 10 mL of ice water, and excess ICl was quenched with saturated sodium sulfite (Na₂S₂O₃) solution. The mixture was separated, and the aqueous phase was back-extracted with dichloromethane (2 × 5 mL). The combined organic phases were washed successively with saturated sodium bicarbonate (NaHCO₃) solution and brine to remove the hydrochloric acid produced in the reaction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate).

[0094] 4-Iodo-N-acetanilide was isolated in 78% yield. The total time was approximately 6-8 hours (including complex post-processing and column chromatography). Defect analysis: 1) Extremely low atom economy: chlorine atoms in ICl become useless byproducts HCl; 2) Dependence on external toxic solvents; 3) Complex and dangerous operation: requires low temperature, quenching, neutralization and multiple washings; 4) Generates acidic waste liquid.

[0095] Comparing the process flow and experimental results of Example 12 of this invention with Comparative Example 1, the significant advantages of the method of this invention in terms of green chemistry and atom economy can be clearly seen. This method utilizes the significant physical difference in solubility between ionic liquid products and inorganic salt byproducts, requiring only simple water precipitation and filtration to obtain the target product with a separation yield of up to 90% and a purity greater than 99%. In contrast, the traditional ICl / DCM process not only has a lower separation yield (78%), but also requires energy-intensive and polluting steps such as quenching residual oxidants, acid-base neutralization, organic solvent extraction, and cumbersome column chromatography separation. This technological innovation stems from the unique design concept of this system, which functions as both a reagent and a medium, completely eliminating the use of volatile organic solvents (VOCs) and the discharge of acidic waste liquid, greatly simplifying the operating unit and reducing the cost of waste treatment.

[0096] Comparative Example 2 [I(py)2]BF4 was prepared according to the method reported in the classic literature OrganicSyntheses (2010, 87, 288-298): Iodine, silver tetrafluoroborate and excess pyridine were reacted in dry dichloromethane. After filtering to remove the silver iodide precipitate, the powder was recrystallized and dried under vacuum to obtain a white crystalline powder with a melting point >140℃. It was solid at the set temperature (80℃) for subsequent reactions.

[0097] 5-Aminophthalic acid powder was added to 3.5 equivalents of solid [I(py)2]BF4 and placed in a reactor equipped with a mechanical stirrer and a condenser. The system was a solid-solid heterogeneous physical mixture, lacking a liquid medium; stirring only caused the powder to tumble and could not achieve effective molecular-level contact. After stirring at 80°C for 4 hours, blackish-brown spots of overheating decomposition due to uneven local thermal conduction were observed, and a large amount of white solid remained unconsumed. Dimethyl sulfoxide (DMSO) was added to the reaction mixture to dissolve the solid residue, and then a saturated sodium bisulfite aqueous solution was added to quench the residual oxidizing species. HPLC analysis showed that the substrate conversion rate was <15%, with the vast majority being unreacted raw materials, the target triiodinated product being only trace amounts, and multiple decomposition impurity peaks were detected.

[0098] The above results indicate that, under solvent-free conditions, the contact between the solid iodide cation reagent and the solid substrate is limited to the outer surface of the particles. The mass transfer of iodide ions to substrate molecules is severely restricted by the solid-solid interface, and an effective iodination reaction cannot be achieved even under conditions of heating and long-term stirring.

[0099] Comparative Example 3 10 g (55 mmol) of 5-aminoisophthalic acid was suspended in 150 mL of anhydrous dichloromethane (DCM), and 3.5 equivalents of solid [I(py)2]BF4 were added. The mixture was heated under reflux with stirring in an oil bath at 40 °C. The reaction system remained in a turbid suspension throughout, indicating poor solubility of the substrate in the solvent. The reaction was continued for 24 hours to ensure sufficient reaction time. After the reaction was completed, the mixture was cooled to room temperature, and the reaction was quenched by adding an appropriate amount of saturated sodium bisulfite aqueous solution. The mixture was separated into liquid and liquid phases. The aqueous phase was back-extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product.

[0100] Despite extending the reaction time to six times that of the method of this invention (4 hours), HPLC analysis showed that the conversion rate of the raw materials was only about 60%. The main components were monoiodinated and diiodinated intermediates, and the content of the target triiodinated product (5-amino-2,4,6-triiodophthalic acid) was less than 5%, failing to achieve complete iodization.

[0101] The reasons may include: 1) The low boiling point of dichloromethane (~40°C) limits the reaction temperature and cannot provide enough energy to overcome the sterically hindered energy barrier of the 2-position iodination reaction (this step usually requires a higher temperature to drive); 2) The introduction of solvents significantly dilutes the reactant concentration, resulting in a decrease in the effective collision frequency.

[0102] Comparative Example 4 In a 250 mL three-necked flask equipped with a reflux condenser, 10 g (55 mmol) of 5-aminoisophthalic acid and 100 mL of dilute hydrochloric acid (1 M) were added, and the mixture was stirred and heated to 80 °C to partially dissolve or disperse the precipitate. Iodine chloride (ICl, 31.2 g, 192.5 mmol, 3.5 equivalents) was dissolved in 20 mL of concentrated hydrochloric acid to prepare a deep red solution. The ICl solution was slowly added dropwise through a dropping funnel over approximately 1 hour with stirring at 80 °C. After the addition was complete, the reaction was continued at this temperature for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, and excess sodium bisulfite aqueous solution was added to quench any remaining ICl, causing a precipitate to form. The precipitate was filtered, washed with copious amounts of water until neutral, and dried under vacuum. The crude product was obtained, with a yield of 88% calculated by weight.

[0103] HPLC analysis showed the main peak to be the target triiodinated product, but an impurity peak at 0.45% was detected, identified by MS as 5-amino-2,4-diiodo-6-chloroisophthalic acid. The formation of this chlorinated impurity is attributed to the competition between iodination and chlorination, two electrophilic substitution reactions, in the ICl / HCl system. Under strongly acidic conditions, the system inevitably contains electrophilic chlorinated species (such as in-situ generated Cl2), leading to the substitution of a small number of aromatic ring sites by chlorine atoms rather than iodine atoms. Because this impurity is structurally highly similar to the target product, conventional recrystallization is insufficient for its effective removal. Furthermore, the reaction is carried out in a strongly acidic (HCl) medium, placing extremely high demands on the equipment materials and generating a large amount of acidic iodine-containing wastewater, resulting in high treatment costs.

[0104] Comparative Example 5 1-Butyl-3-methylimidazolium dichloroiodate ([Bmim][ICl2]) was prepared as the reaction medium according to the method described in the literature (10.1039 / C5RA14702F). In a dry reaction vessel, 10 g (55 mmol) of 5-aminoisophthalic acid and [Bmim][ICl2] (equivalent to 3.5 equivalents of active iodine) were added. The reaction system was heated to 80 °C and reacted for 4 hours under magnetic stirring. After the reaction was completed, the mixture was quenched with an aqueous solution of sodium thiosulfate, extracted with ethyl acetate, and subjected to routine post-treatment.

[0105] HPLC analysis of the sample revealed a raw material conversion rate of less than 40%, with the products primarily being monoiodinated derivatives and almost no triiodinated derivatives detected. This is mainly because the iodine in this system exists in anionic form ([ICl2]). - [NIN] exists, and its electron cloud density is high, while its electrophilicity is much weaker than that of [NIN] in the cationic system of this invention. + The structure makes it impossible to overcome substrate steric hindrance for deep triiodination.

[0106] Compared to Comparative Example 2 (solid-state [I(py)2]BF4 solvent-free system, conversion <15%), Example 6 (liquid [I(py)2][Tf2N] solvent-free system, yield 94%) showed a yield increase of over 6 times. Both examples used [I(py)2] as the iodination active species. + Cations are chemically identical, and BF4 - and Tf2N - Both are weakly coordinating anions, which have minimal impact on the electrophilic activity of iodocations. Therefore, this huge difference cannot be attributed to the electronic effect of the anions, but rather to the phase transition of the reaction system from a solid heterogeneous phase to a liquid homogeneous phase. The liquid iodocation is completely miscible with the substrate, eliminating the mass transfer limitation of solid particles. At the same time, the concentration of iodocation is maintained at the highest level under solvent-free conditions, effectively overcoming the steric hindrance of iodination at the 2-position of the benzene ring and achieving regioselectivity of >99%.

[0107] Compared with Comparative Example 3 (solvent dilution system, conversion rate of about 60%), the solvent-free system of the present invention avoids the reduction of the effective concentration of iodide ions due to solvent dilution, and is not limited by the upper limit of the reaction temperature by low-boiling-point solvents.

[0108] Compared with Comparative Example 5 (based on [ICl2]) - Compared to anionic systems (with a conversion rate of <40%), this invention is based on [NIN]. + The cationic iodine in this structure has a lower electron cloud density and stronger electrophilic activity. Furthermore, in stark contrast to the 0.45% chlorinated impurity detected in the ICl process in this comparative example, no chlorinated byproducts were detected in the product of Example 6. This is because the chemical composition of this system completely eliminates the chlorine source, fundamentally blocking the occurrence of chlorination side reactions.

[0109] The above comparison demonstrates that the physical state of iodide cations (liquid vs. solid) has a far greater impact on reaction efficiency than the chemical influence of the anion species itself. The use of liquid iodide cations as both reagents and reaction media brings not only operational convenience but also a qualitative leap in reactivity and selectivity—a discovery that was difficult for those skilled in the art to anticipate.

[0110] Comparative Example 6 Following the method of Example 1, a trial was conducted to prepare the iodine positive ion liquid [I(Et3N)2][Tf2N] by replacing pyridine with triethylamine as the ligand.

[0111] In a dry 50 mL round-bottom flask, elemental iodine (I₂, 254 mg, 1.0 mmol) and silver bis(trifluoromethanesulfonyl)imide (AgTf₂N, 388 mg, 1.0 mmol) were added. 5 mL of anhydrous acetonitrile (dried via a 4 Å molecular sieve) was injected using a syringe, and the mixture was magnetically stirred at room temperature in the dark for 2 hours. The mixture was filtered through a short-core funnel containing diatomaceous earth to remove the silver iodide precipitate, and the clear filtrate was collected. Triethylamine (202 mg, 2.0 mmol) was slowly added dropwise to the filtrate, and the mixture was stirred at room temperature for another 1 hour. Subsequently, all volatile components were completely removed under reduced pressure in a 40 °C water bath to obtain a pale yellow to brownish-yellow waxy solid.

[0112] 10.0 g (55 mmol) of 5-aminoisophthalic acid was added to 3.5 equivalents of the above solid [I(Et3N)2][Tf2N], and the reaction was carried out in a mechanically stirred reactor at 80 °C for 4 hours. Similar to Comparative Example 2, the system remained in a solid-solid heterogeneous state throughout, and stirring only caused the powder to tumble. After the reaction was completed, DMSO was added to dissolve the residual solid, and the reaction was quenched with a saturated sodium bisulfite aqueous solution. HPLC analysis showed that the substrate conversion was less than 25%, the product was mainly the monoiodinated product, and the target triiodinated product was only present in trace amounts.

[0113] This may be because although the three ethyl groups of triethylamine endow the ligands with a strong electron-donating ability, its molecular conformation is relatively symmetrical and the flexibility of the alkyl chain is limited, resulting in [I(Et3N)2]. + The cations have high geometric regularity, similar to Tf2N. - Anions can still form an ordered ionic stack, and the lattice energy is not fully destroyed, thus failing to achieve room-temperature liquefaction. In contrast, the planar aromatic structure of pyridine is similar to Tf₂N. - Significant geometric mismatch exists between the flexible asymmetric conformations, which effectively suppresses the ordered arrangement of ions, greatly reducing the lattice energy, thus making it liquid at room temperature.

[0114] Based on the content of Example 6 and Comparative Example 2, even when using Tf2N, which is recognized in the art for reducing the melting point of ionic liquids, - When anions are replaced with different ligands, the resulting products are not necessarily liquid, and the iodination performance decreases significantly. The room-temperature liquid properties of iodocation liquids are not solely determined by the anion, but rather depend on the specific matching relationship between the cation structure and the anion.

[0115] Comparative Example 7 In a dry 50 mL round-bottom flask, elemental iodine (I₂, 254 mg, 1.0 mmol) and silver hexafluorophosphate (AgPF₆, 253 mg, 1.0 mmol) were added. 5 mL of anhydrous acetonitrile (dried via a 4 Å molecular sieve) was injected using a syringe, and the mixture was magnetically stirred for 2 hours at room temperature in the dark. The mixture was filtered through a short-core funnel containing diatomaceous earth to remove the silver iodide precipitate, and the clear filtrate was collected. Pyridine (160 mg, 2.0 mmol) was slowly added dropwise to the filtrate, and stirring was continued for 1 hour at room temperature. All volatile components were removed under reduced pressure in a 40 °C water bath to obtain a pale yellow semi-solid paste. DSC analysis showed that the melt onset temperature of this substance was 58 °C, and it was non-flowable at 25 °C.

[0116] 10.0 g (55 mmol) of 5-aminoisophthalic acid was added to 3.5 equivalents of the above [I(py)2][PF6], and the reaction was stirred at 80 °C for 4 hours. Since [I(py)2][PF6] exceeds its melting point at 80 °C, the system was in a partially molten, semi-homogeneous state, with mass transfer efficiency between Comparative Example 2 (completely solid) and Example 6 (completely liquid). After the reaction was complete, DMSO was added to dissolve the residue, and the reaction was quenched with a saturated sodium bisulfite aqueous solution. HPLC analysis showed a substrate conversion of approximately 55%, with the products mainly consisting of monoiodinated and diiodinated intermediates, and the target triiodinated product comprising approximately 18%.

[0117] The result of this comparative example is in Comparative Example 2 (Solid BF4) - (conversion rate <15%) and Example 6 (liquid Tf2N)- The yield was between 94% and the homogeneity of the physical state, showing a clear positive correlation. Although [I(py)2][PF6] melted at the reaction temperature (80°C), its system viscosity remained high, and the substrate dispersion was insufficient, failing to form a completely homogeneous environment like the iodide cation liquid (liquid at room temperature) in Example 6. This intermediate result in a semi-molten and semi-homogeneous state strongly confirms the intrinsic correlation between reaction efficiency and the degree of liquefaction of iodide cation species.

[0118] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A solvent-free electrophilic aromatic iodination method, characterized in that, Includes the following steps: Aromatic substrates react with iodide cation liquids to yield iodide products; The iodine cation liquid has the following structure: [I(L)2] + [X] - ; The ligand L is selected from the following group: pyridine, C 1-4 Alkyl-substituted pyridine, C 1-4 Aliphatic nitrile; anion X - It is a non-coordinated or weakly coordinated anion.

2. The method as described in claim 1, characterized in that, The iodide product is a triiodide product.

3. The method as described in claim 1, characterized in that, The ligand L is selected from the group consisting of: pyridine, acetonitrile, and 2,6-dimethylpyridine. The anion X - Selected from the following group: bis(trifluoromethanesulfonyl)imide (Tf2N) - ), hexafluorophosphate (PF6) - ), tetrafluoroborate (BF4) - ).

4. The method as described in claim 1, characterized in that, The aromatic substrate is an electron-rich aromatic compound selected from the group consisting of anilines, phenols, anisoles, polyalkylbenzenes, polycyclic aromatic hydrocarbons, thiophenes, or indoles.

5. The method as described in claim 1, characterized in that, I in iodine positive ion liquid + The dosage is 1.1 to 2.0 equivalents of the aromatic substrate.

6. The method as described in claim 1, characterized in that, The reaction temperature is 25~60℃; and / or the reaction time is 1~5 hours.

7. A method for directly preparing triiodinated aromatic compounds, characterized in that, Includes the following steps: The aromatic substrate reacts with an iodide cation liquid to yield a triiodide intermediate. The iodine positive ionic liquid is [I(py)2]. + [Tf2N] - .

8. A method for preparing a nonionic iodine contrast agent, characterized in that, Includes the following steps: (a) 5-aminoisophthalic acid or its amide derivative is subjected to 2,4,6-triiodination by the method of claim 7 to obtain a triiodination intermediate; (b) The triiodide intermediate is sequentially modified by acylation, amidation and / or alkylation to obtain a nonionic iodine contrast agent.

9. The preparation method according to claim 8, characterized in that, The nonionic iodine contrast agent is selected from the following group: iohexol, iopamidol, iodixanol, and iodofol.

10. The use of an iodine positive ionic liquid, characterized in that, The iodide positive ion liquid (a) is used as an iodination reagent, and (b) is used to prepare triiodide intermediates for X-ray contrast agents; The iodine positive ionic liquid has [I(L)2] + [X] - The structure, wherein L is a nitrogen-containing heterocyclic ligand or a nitrogen-containing aliphatic ligand, and X - It is a non-coordinated or weakly coordinated anion.

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