Iodinated fatty acid esters, processes for their preparation and use

Abstract

This invention relates to the field of organic synthesis technology, specifically to an iodinated fatty acid ester, its preparation method, and its applications. The preparation method involves carrying out an iodination reaction of an unsaturated fatty acid ester in a mixed system of triphenylphosphine and elemental iodine. The preparation method of this invention is efficient, controllable, highly selective, and capable of generating stable iodinated fatty acid esters, thus expanding the application fields of iodinated polyunsaturated fatty acids.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to iodinated fatty acid esters, their preparation methods, and applications. Background Technology

[0002] Polyunsaturated fatty acids are a class of fatty acid compounds containing multiple (two or more) double bonds. They are essential nutrients for the human body and can be mainly divided into two categories: Omega-3 (such as eicosapentaenoic acid, docosahexaenoic acid, etc.) and Omega-6 (such as linoleic acid, gamma-linolenic acid, arachidonic acid, etc.). They play a vital role in the health of the cardiovascular system, brain, eyes, and inflammation regulation.

[0003] Iodination, as an important organic synthesis method, has wide applications in lipid chemistry, currently mainly used for the quantitative analysis of the unsaturation degree of polyunsaturated fatty acids to assess oil quality. However, in polyunsaturated systems, the introduction of iodine is unstable, typically with an iodine content of <40%, leading to inaccurate assessment results. Furthermore, existing methods require multiple protection and deprotection steps, making the process cumbersome.

[0004] Iodination is also used as a protection strategy in organic synthesis, where multiple double bonds are temporarily "protected" by iodine addition to allow for reactions with other functional groups, and then the double bonds are regenerated by reduction elimination. However, existing iodination methods lack selectivity and may react with other groups besides double bonds, generating more byproducts and increasing the difficulty of purification.

[0005] In interventional radiology and medical imaging, iodized fatty acid esters (commonly known as iodized oil) are the gold standard contrast agent and drug carrier, widely used in transcatheter arterial chemoembolization (TACE), lymphangiography, and hysterosalpingography. However, the iodized oil currently used clinically is mainly derived from the iodization of poppy seed oil. Because its raw material comes from natural plants, its composition is actually a complex mixture of various fatty acid ethyl esters, which leads to problems such as large batch-to-batch fluctuations in composition and difficulty in precisely controlling viscosity.

[0006] Furthermore, while the high viscosity of traditional iodized oils is beneficial for deposition, it limits their penetration into the blood supply arteries of small tumors (such as microvessels with a diameter of <50 micrometers) during certain delicate interventional procedures, potentially leading to incomplete embolization or uneven drug distribution. With the development of precision medicine, there is a growing clinical demand for novel iodinated lipid materials with a single composition, well-defined structure, adjustable viscosity, and higher iodine content (to improve imaging clarity). Summary of the Invention

[0007] Based on this, the present invention aims to provide an iodinated fatty acid ester, its preparation method and application, which has the advantages of high efficiency, controllability, high selectivity and ability to generate stable iodinated products, so as to overcome the limitations of the prior art and expand the application of iodinated polyunsaturated fatty acids in new fields, such as developing novel biocompatible materials, diagnostic reagents or high-value chemical synthesis intermediates.

[0008] In one embodiment, the method for preparing the iodinated fatty acid ester of the present invention includes the following steps: S01. Mix unsaturated fatty acid ester, organic base, triphenylphosphine and first organic solvent to prepare first mixture; S02. Under the conditions of -5 to 5℃ and a protective gas atmosphere, elemental iodine is added to the first mixture. After the addition is complete, the mixture is stirred at -5 to 5℃ for 1 to 2 hours to obtain the second mixture. S03. Add a protic reagent to the second mixture to obtain the third mixture; S04. Stir the third mixture at 20-60°C for 15-20 hours, preferably 15-18 hours, to obtain the reaction solution; S05. The reaction solution obtained in step S04 is subjected to quenching and purification treatment to obtain iodinated fatty acid esters.

[0009] While not wishing to be bound by any theoretical analysis, nor to be considered a limitation of the technical solution of this invention, the following describes the reaction mechanism that may be involved in the aforementioned steps. Existing technology has taught that triphenylphosphine (PPh3) can act as a reducing agent and ligand for iodide ions (Wolf-W. du Mont, 1999), and has disclosed the hydroiodination of alkynes using an I2 / PPh3 / H2O system under aqueous conditions to generate iodoalkenyl compounds (Shin-ichi Kawaguchi, 2014). However, due to the significant difference in electrophilic addition activity between alkynes and the alkenyl groups involved in this invention, directly applying this system cannot convert alkenyl groups to iodoalkyl groups (this is also why existing technology can only stop the hydroiodination reaction at the iodoalkenyl compound level). Against this background, the inventors of this invention, through creative labor, surprisingly discovered that by first reacting PPh3 with elemental I2 in a non-aqueous environment, PPh3, acting as a nucleophile, undergoes nucleophilic reaction with I2. Electrophilic interaction produces an iodonium salt intermediate [Ph3PI]. + I - Subsequently, a specific amount of protic solvent was introduced into the system to act as a nucleophile to attack the [Ph3PI] compound. + The intermediate is thus formed in a substantially non-aqueous environment, producing [Ph3POH]. + And releases iodine anions (I₂). - At this point, the conjugate acid [Ph3POH] is present.+ - Hydrated protons H3O + The system further integrates with I - The combination of these elements generates hydroiodic acid (HI) in situ, creating a "HI-equivalent" reaction environment. This provides an effective iodine source for the hydroiodination reaction in a non-aqueous environment, thereby reducing the conversion of HI to carbon. The potential barrier for addition reactions of carbon double bonds (C=C) allows for the introduction of an iodine atom and a hydrogen atom into each double bond. Based on this, the unsaturated fatty acid esters in this invention are preferably unsaturated fatty acids containing double bonds, and more preferably unsaturated fatty acids that include only double bonds as unsaturated bonds.

[0010] This invention does not impose any particular limitation on unsaturated fatty acid esters; any example known in the prior art can be used. In a preferred embodiment, the unsaturated fatty acid ester may have 18 to 25 carbon atoms, preferably 20 to 22 carbon atoms; the unsaturated bond is preferably a carbon-carbon double bond, the number of which is not particularly limited, and may be 1 to 6, preferably 3 to 6; the carbon-carbon double bond in the unsaturated fatty acid ester is preferably located at the ω-3 position and / or ω-6 position. As specific examples of unsaturated fatty acid esters, the sources of the unsaturated fatty acid portion can include soybean oil, linoleic acid, linolenic acid, arachidonic acid, eicosatrienoic acid, palmitoleic acid, octadecanoic acid, walnut oil, corn oil, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), which can be a single unsaturated fatty acid or a combination of two or more fatty acids.

[0011] The unsaturated fatty acid esters used in this invention can be prepared by the following method: under the presence of a base and a catalyst, unsaturated fatty acids and alcohols are subjected to an esterification reaction, wherein the alcohol includes at least one of a monohydric alcohol and a dihydric alcohol, and may have 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms, and more preferably methanol and / or ethanol, thereby generating unsaturated fatty acid methyl esters and / or ethyl esters.

[0012] The first organic solvent used in this invention is only required to effectively dissolve unsaturated fatty acid esters and not affect the iodonium salt intermediate [Ph3PI]. + I -The generation and subsequent transformation of the first organic solvent are not particularly limited. The first organic solvent can be immiscible with water, or miscible or partially miscible with water. Specific examples of water-immiscible first organic solvents include aromatic hydrocarbons such as toluene, xylene, ethylbenzene, and cumene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, and dichlorobenzene; specific examples of water-miscible or partially miscible first organic solvents include ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and methyl tert-butyl ether; and ketones such as acetone, butanone, and methyl isobutyl ketone. The aforementioned examples of first organic solvents can be used alone or in combination of two or more. In a preferred embodiment, the first organic solvent is selected from one or a combination of two or more of toluene, dichloromethane, and tetrahydrofuran.

[0013] The protonating agent of this invention is compatible with [Ph3PI]. + I - A protonating agent that generates hydroiodic acid (HI) in situ. Specific examples of protonating agents include water, methanol, and ethanol; these protonating agents can be used alone or in combination of two or more. In a preferred embodiment, water (H2O) is used as the protonating agent, specifically one or a combination of two or more of the following: distilled water, double-distilled water, sub-boiling distilled water, deionized water, ultrapure water, reverse osmosis purified water, electrodialysis purified water, and ultrafiltration purified water.

[0014] To improve the efficiency of hydroiodization, this invention further introduces an organic base into the aforementioned reaction system. Again, without being bound by any theoretical analysis or considered a limitation of this invention, the reaction mechanism of the organic base in the reaction system may be as follows: the organic base plays a dual role: as a base, it acts as an acid-binding agent, capturing excess hydroiodic acid (HI) generated during the reaction and driving the reaction towards I₂→I₂. - The reaction proceeds in the direction of [Ph3PI], maintaining a suitable reaction environment; simultaneously, as a nucleophilic ligand, it interacts with excess I2, effectively regulating [Ph3PI]. +By controlling the generation and concentration of active iodides, the electrophilicity of the reaction can be precisely adjusted, thereby suppressing side reactions such as multi-site overiodination. Ultimately, PPh3 is directionally oxidized to Ph3P=O, and byproducts are easily removed. There are no particular limitations on specific examples of organic bases; any known organic base that can achieve the above effects and is compatible with the reaction environment can be used. Examples include: imidazole derivatives, such as imidazole, N-methylimidazolium, 2-methylimidazolium, 4-methylimidazolium, 2-ethylimidazolium, benzimidazole, 2-phenylimidazolium, etc.; and pyridine derivatives, such as pyridine, 2-methylpyridine (α-picolin), 3-methylpyridine (β-picolin), 4-methylpyridine (γ-picolin), 2,4-dimethylpyridine, 2,6-dimethylpyridine, 3,5- Dimethylpyridine, 4-dimethylaminopyridine (DMAP), 2-chloropyridine, 4-chloropyridine, quinoline, isoquinoline, acridine, etc.; aliphatic amines, such as triethylamine, tripropylamine, diisopropylethylamine (DIPEA), tributylamine, N,N-dimethylbenzylamine, dimethylmethylamine, piperidine, piperazine, morpholine, N-methylmorpholine, pyrrolidine, etc.; aromatic amines, such as aniline, N,N-dimethylaniline, diphenylamine, triphenylamine, o-phenylenediamine, p-phenylenediamine, etc.; heterocyclic amines, such as pyrrole, pyrazine, pyrimidine, pyridazine, indole, isoindole, carbazole, etc. These organic bases can be used alone or in combination of two or more. In a preferred embodiment, imidazole derivatives are specifically used, preferably alkyl-substituted or unsubstituted imidazoles. In another preferred embodiment, pyridine derivatives are specifically used, preferably alkyl-substituted or unsubstituted pyridines. In a further preferred embodiment, imidazole and / or pyridine are specifically used. In another preferred embodiment, the molar ratio of triphenylphosphine to the organic base is 1:(1.1-1.5). Excessive use of the organic base will result in excessive salt precipitation during the post-treatment quenching stage, increasing the difficulty of washing and purification. Furthermore, excess base may promote the elimination reaction (dehydroiodide removal) of iodine substitution, reducing the iodine content of the product. Insufficient use will fail to effectively neutralize any trace acidic byproducts that may be generated during the reaction, easily inducing oxidation or polymerization side reactions of fatty acid chains, leading to a darker product color. In another preferred embodiment, when elemental iodine is added in solution form, the concentration of the iodine solution should be 1-5 mol / L.

[0015] In one embodiment, the molar ratio of triphenylphosphine to iodine is 1:(1-1.2), preferably 1:(1.02-1.08). Excessive use of iodine will prevent effective conversion of iodine, affecting iodization efficiency. Residual free iodine in the system will trigger side reactions and significantly increase the pressure on subsequent decolorization. Insufficient use of iodine will result in excess triphenylphosphine reagent reacting with solvents or impurities, increasing the amount of the byproduct triphenylphosphine oxide (POPh3). Since POPh3 has similar polarity to iodinated fatty acid esters, it greatly increases the burden on subsequent chromatographic purification, reducing product purity.

[0016] In another embodiment, the molar ratio of triphenylphosphine to the unsaturated bonds contained in the unsaturated fatty acid ester is 1:(1~1.4), preferably 1:(1.05~1.15). If the amount of triphenylphosphine is too small, the double bond addition will be incomplete, and the iodine content of the product will be lower than the theoretical value; if the amount is too large, although it can slightly improve the conversion rate, it will lead to excessive viscosity of the reaction system, which is not conducive to process scale-up.

[0017] In a preferred embodiment, between steps S03 and S04, the following step is further included: S031. Stir the third mixture at -5 to 5°C for 5 to 15 minutes.

[0018] By stirring briefly at -5 to 5°C, the in-situ generated active iodide and protic reagent are fully homogenized, consuming the most reactive free radicals in the system. This avoids localized boiling or product carbonization caused by intense local exothermic reactions, ensuring the addition reaction proceeds under controlled and mild conditions. Similarly, without being bound by any theoretical analysis or considered a limitation of this invention, it is important to note that in unsaturated fatty acid ester systems, elemental iodine is highly sensitive to its instantaneous effective concentration in the reaction system. Compared to simply adjusting the total amount of iodine fed, pre-dissolving elemental iodine and adding it to the reaction system at a controlled feed rate can effectively reduce local iodine concentration peaks, thereby suppressing side reactions and improving the effective utilization rate of iodine. Therefore, while ensuring the total amount of iodine meets the stoichiometric requirements of the reaction, the concentration of the iodine solution and the feed rate together constitute the key to controlling the hydroiodization reaction pathway.

[0019] In step S01, the addition of elemental iodine can be achieved by directly adding solid elemental iodine, introducing gaseous elemental iodine, or adding iodine after preparing it into a solution. When directly adding solid elemental iodine, it is preferable to add the solid elemental iodine in batches. In a preferred embodiment, the operation of adding elemental iodine in step S01 includes the following steps: S021. Iodine is dissolved in a second organic solvent to obtain an iodine solution, wherein the molar concentration of iodine in the iodine solution is 1–5 mol / L. S022. The iodine solution is mixed with the first mixture at a first rate.

[0020] Examples of the second solvent can be the same materials as the aforementioned first solvent. Specifically, the second solvent can be a single material or a mixture of two or more materials; the second solvent can be the same as or different from the material used in the aforementioned first solvent. In a preferred embodiment, the second organic solvent is selected from one or a combination of two or more of toluene, dichloromethane, and tetrahydrofuran.

[0021] The aforementioned first rate is not particularly limited, as long as it can maintain a stable and efficient conversion of elemental iodine to iodonium salts. In a preferred embodiment, the first rate can be 1–10 mL / min. The iodine solution can be fed continuously or in portions. In a further preferred embodiment, in step S022, the iodine solution is provided in 4–6 portions with stirring, and the interval between two feedings is 20–40 min. Again, it is not intended to be bound by any theoretical analysis or considered as any limitation on the invention. When elemental iodine is added in solution form, its solution concentration and feeding rate together determine the instantaneous effective iodine concentration in the reaction system. To avoid side reactions caused by excessively high local iodine concentrations, an appropriate feeding rate needs to be controlled within the concentration range. This invention achieves stable and controllable reaction processes by limiting the synergistic range of iodine solution concentration and feeding rate.

[0022] Since the reaction solution obtained in step S04 contains a large amount of reactive substances, which hinders the subsequent purification of the target product, iodinated fatty acid ethyl ester, it is necessary to quench it first. In one embodiment, the quenching treatment in step S05 includes the following steps: S051. Add the quencher while stirring and continue stirring for 20-40 minutes to obtain the quenched mixture.

[0023] There are no particular limitations on the type of quencher, as long as it can inhibit or even eliminate the activity of iodonium salts. Specific examples include: thiosulfates, such as sodium thiosulfate, potassium thiosulfate, and ammonium thiosulfate; sulfites, such as sodium sulfite, potassium sulfite, sodium dithionite (sodium hydrosulfite), ammonium sulfite, and sodium metabisulfite; and bisulfites, such as sodium bisulfite and potassium bisulfite. These quenchers can be used alone or in combination of two or more. In a preferred embodiment, the quencher is prepared as a 5-10 wt.% aqueous solution before feeding. In a further preferred embodiment, a 6-9 wt.% thiosulfate quencher is used.

[0024] In one embodiment, the purification process in step S05 includes the following steps: S052. Separate the quenched mixture from step S051 and collect the organic phase. S053. The organic phase obtained in step S051 is washed with water until the pH value of the aqueous phase is 6.8-7.2. The organic phase is collected to obtain crude liquid. S054. The crude liquid obtained above shall be purified, specifically by means of purification.

[0025] In step S053, deionized water is preferably used for the washing operation, and the washing is preferably performed 3 times or more.

[0026] Following step S053, a further drying and concentration step is preferably included, specifically: S0531. Add water-absorbing inorganic salt to the crude liquid obtained in step S053 and dry it to obtain dried crude liquid. S0532. The dried crude liquid obtained in step S0531 is subjected to vacuum distillation to remove most of the organic solvent, resulting in a concentrated crude liquid.

[0027] In step S0531, the hygroscopic inorganic salt is not particularly limited. Specific examples include: sulfates, such as anhydrous sodium sulfate, anhydrous magnesium sulfate, and calcium sulfate (calcined gypsum); carbonates, such as anhydrous potassium carbonate and anhydrous sodium carbonate; and chlorides, such as anhydrous calcium chloride and anhydrous magnesium chloride. In step S0532, the specific process conditions for vacuum distillation are not particularly limited and can be determined based on the type and properties of the organic solvent in the system. Preferably, the distillation is carried out under conditions not exceeding 50°C and not exceeding 0.5 atm.

[0028] In step S054, the concentration can be purified by at least one of column chromatography, molecular distillation and extraction washing; preferably, molecular distillation is used, and more preferably, molecular distillation is carried out under a vacuum of 0.5 to 0.8 Pa and a temperature of 130 to 150 °C, with a feed rate of 1.0 to 2.0 mL / min.

[0029] The present invention also provides an iodinated fatty acid ester prepared by the preparation method described above.

[0030] The present invention also provides the application of the iodinated fatty acid esters described above in the preparation of pharmaceutical intermediates, iodine supplements, iodized health products, iodized foods, or imaging materials.

[0031] Beneficial effects: The preparation method of the present invention can selectively iodize the double bonds in unsaturated fatty acids, effectively reducing the proportion of by-products and the difficulty of purification. It can also controllably iodize unsaturated bonds, expanding its applications in the preparation of pharmaceutical intermediates, iodine supplements, iodized health products, iodized foods, or imaging materials. Moreover, it can achieve complete iodization, thereby improving the accuracy of unsaturation degree determination results.

[0032] Compared with the traditional iodination method, the preparation method of the present invention has milder reaction conditions, simpler operation, no toxic solvent residue, is suitable for large-scale industrial production, and can avoid the destruction of double bonds during iodination, thus improving the reaction yield and product purity. Detailed Implementation

[0033] The present invention will be further described below with reference to embodiments and examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the protection scope of the appended claims.

[0034] 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. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0035] In some embodiments, the iodinated fatty acid esters of this invention are used not only as pharmaceutical intermediates, iodine supplements, or nutritional fortifiers, but also as novel contrast agents or integrated diagnostic-therapeutic materials. Not limited by theory, when the iodinated fatty acid esters are injected via catheter into targeted blood vessels, cavities, or tissues, their high iodine content and excellent biocompatibility enable them to achieve good distribution and localization in vivo, and exhibit clear contrast under imaging examinations (such as X-rays, CT scans, etc.).

[0036] In this process, the iodinated fatty acid esters can be formulated with carrier materials or other pharmaceutical excipients to form stable emulsions, nanodispersions, or microsphere formulations. When injected into vascular lesions (such as tumor-feeding arteries, arteriovenous malformations, chronic inflammatory cavities, etc.), their lipid-soluble structure and affinity for tissues enable sustained retention in the target area. Simultaneously, the high atomic number of iodine endows this product with excellent radiopaque properties, allowing for high-resolution imaging and tracking both intraoperatively and postoperatively.

[0037] In some embodiments, the iodinated fatty acid esters may be chemically inert or biodegradable in vivo, and their metabolites can be effectively cleared by the body, avoiding the safety hazards caused by long-term accumulation. Furthermore, thanks to the highly selective iodination of unsaturated double bonds by the method of the present invention, the product structure is uniform and the impurity content is low, thereby reducing the risk of immunogenic reactions and allergies.

[0038] In some implementations, the iodinated fatty acid esters can be used synergistically with various interventional therapeutic materials (such as microspheres, drug-loaded polymers, liquid embolic agents, etc.) to achieve integrated diagnosis and treatment. For example, they can be compounded with medical cyanoacrylate adhesives to prepare an embolic agent with radiopaque properties. During application, the iodinated fatty acid esters not only provide real-time visual localization but also participate in the polymerization reaction to distribute uniformly within the final polymer network, preventing the embolic agent from being washed away by the bloodstream.

[0039] In some implementations, the iodinated fatty acid esters within the polymer matrix can sustainably impart significant image contrast to the embolization, enabling physicians to non-invasively track the morphology, location, and stability of the embolization using CT or X-rays 1 day, 3 days, or even longer after the procedure, without the need for repeated injections of conventional contrast agents. This simplifies the procedure and improves patient safety and comfort.

[0040] In some implementation schemes, the high-purity iodinated fatty acid esters described in this invention enable the related preparations to exhibit excellent chemical and thermo-photometric stability during long-term storage and clinical application, and they are not prone to degradation or discoloration, thus ensuring product quality consistency and safety.

[0041] In some embodiments, during the preparation of the iodinated fatty acid esters of the present invention, the degree of iodization is precisely controlled by adjusting the molar ratio of triphenylphosphine to iodine and the dropping rate. This ensures efficient iodization of all unsaturated double bonds while effectively suppressing overiodization and side reactions, thereby obtaining a target product with high purity and controllable structure.

[0042] In some embodiments, the unsaturated fatty acid ester raw materials can be derived from natural vegetable oils, marine fish oils, or microbial fermentation products, and can be pre-purified by methods such as molecular distillation and column chromatography to ensure the smooth progress of subsequent reactions. Using the method of this invention, unsaturated fatty acid esters from different sources can be adapted, demonstrating good raw material compatibility and process versatility.

[0043] In some implementation schemes, to further improve product purity and safety, a multi-stage post-processing is employed after the reaction, including quenching, separation, washing, drying, and impurity adsorption steps, to effectively remove free iodine, triphenylphosphine oxide, and other byproducts. Finally, high-purity iodinated fatty acid esters are obtained through molecular distillation or extraction washing.

[0044] In some implementation schemes, the process of this invention exhibits good scalability and industrialization prospects. Related experimental data show that, at scales ranging from hundreds of grams to kilograms, the product yield and purity are essentially consistent with those under small-scale conditions, and byproducts are easily separated, waste liquid treatment is simple, making it suitable for continuous or automated production lines, thus providing a reliable production foundation for subsequent clinical and market promotion.

[0045] In some implementation schemes, the obtained iodinated fatty acid esters can not only be used as a single component, but also further used as an active carrier to be compounded with various drugs, fat-soluble vitamins, anti-tumor factors, etc., for the development of targeted delivery, controlled-release formulations or functional foods, thus expanding the downstream application areas of the products.

[0046] In some implementation schemes, the product of the present invention can also be used as a food additive to fortify edible oils, dairy products, functional beverages, etc., which can not only supplement the iodine element required by the human body, but also provide the nutritional value of polyunsaturated fatty acids, meeting the health needs of special groups (such as pregnant women, children, and the elderly).

[0047] In some embodiments, the iodofatty acid esters and their compositions described in this invention can be used as novel radiopaque liquid embolizing agents for direct application in interventional radiotherapy, particularly suitable for middle meningeal artery (MMA) embolization (MMAE) of chronic subdural hematoma (cSDH). After injection, the composition rapidly reacts with anions in blood or tissue fluid to form a dense polymer network, achieving permanent occlusion of the feeding artery or pathological vessel, reducing the recurrence rate of cSDH, and improving long-term patient prognosis.

[0048] In some implementation schemes, iodoform fatty acid esters, when combined with cyanoacrylate monomers or other medical polymers, combine high radiopaque linearity, rapid coagulation, and excellent vascular visualization. Clinically, physicians can monitor the distribution of the embolic agent in real time during the procedure using CT or X-rays to determine the occlusion effect, eliminating the need for additional contrast agents and reducing procedural complexity and patient risk.

[0049] In some embodiments, the compositions of the present invention can serve as upgraded alternatives to mainstream liquid embolization agents such as n-BCA (n-butyl cyanoacrylate) and EVOH (ethylene vinyl alcohol copolymer), and are suitable for embolization treatment of benign prostatic hyperplasia (BPH), hepatic artery chemoembolization (TACE), arteriovenous malformation (AVM), and other solid tumor-feeding arteries in MMAE and PAE treatment.

[0050] In some implementations, the iodinated fatty acid ester can be used alone as a liquid embolizing agent or mixed with NBCA, EVOH, etc., providing both rapid occlusion and long-term imaging follow-up capabilities. Compared with traditional PVA particles or coils, liquid embolizing agents perform better in complex vascular anatomy and occlusion of small branches, improving the success rate and safety of interventional treatments such as MMAE.

[0051] In some embodiments, the iodinated fatty acid ester composite liquid embolizing agent of the present invention has broad application prospects in many interventional radiology fields, such as the prevention and treatment of recurrent chronic subdural hematoma, vascular malformations, and tumor embolization. Animal and preclinical experiments have shown that after injection, this type of embolizing agent can form a high-density occlusion in the blood vessel, induce local fibrosis, promote the organization of diseased blood vessels, and reduce the risk of recurrence.

[0052] In some implementations, the iodinated fatty acid ester embolizing agent has excellent biocompatibility and degradability, and will not cause significant inflammation or foreign body reaction when retained in the body for a long time. Its metabolites can be safely cleared by the body over time, making it suitable for high-risk groups such as elderly patients and patients undergoing anticoagulation or antiplatelet therapy.

[0053] In some implementation schemes, the high iodine content of iodinated fatty acid esters endows them with excellent radiopaque properties, enabling them to provide clear image contrasts during intraoperative and postoperative follow-up phases (such as 24 hours, 72 hours and longer), facilitating physicians to dynamically monitor the closure status of hematoma cavities and guide subsequent treatment decisions.

[0054] In some implementations, the present invention can also be extended to other interventional treatment areas such as prostate artery embolization (PAE) for the treatment of diseases such as benign prostatic hyperplasia (BPH), demonstrating good vascular occlusion capability, imaging visualization and long-term safety.

[0055] The iodinated fatty acid ester liquid embolizing agent of this invention is applicable to multiple disciplines such as neurosurgery, interventional radiology, urology, and oncology. It can be widely used for: interventional embolization of lesions such as chronic subdural hematoma (cSDH), middle meningeal artery embolization (MMAE), arteriovenous malformations, aneurysms, and tumor feeding arteries; prostate artery embolization (PAE) for the treatment of benign prostatic hyperplasia (BPH); interventional treatment of solid tumors such as transarterial chemoembolization (TACE); and other diseases requiring permanent vascular occlusion and imaging follow-up. The following are some specific examples.

[0056] For experimental parameters not specified in the following specific embodiments, please refer to the guidelines given in this invention document first, or refer to experimental manuals or other experimental methods known in the art, or refer to the experimental conditions recommended by the manufacturer.

[0057] The raw materials and reagents whose sources are not explicitly stated in the following specific embodiments can all be purchased.

[0058] Example 1 1. Raw materials, reagents and materials Main raw materials: EPA (purity 98.5%, acid value ≤0.3mgKOH / g, Sigma-Aldrich); esterification reagent: anhydrous methanol (chromatographic grade, moisture <0.01%, Merck); esterification catalyst: molecular sieve, 3A (2-3mm, Maclean); iodination reagents: triphenylphosphine (99%, Alfa), elemental iodine (99.9%, Aladdin), imidazole (99%, TCI); solvent: dichloromethane (chromatographic grade, moisture <0.005%, Sinopharm); purification material: silica gel (200-300 mesh, Qingdao Ocean Chemical).

[0059] 2. Preparation of EPA methyl ester 50.0 g (0.114 mol) of EPA, 160 mL (3.97 mol, molar ratio 1:35) of anhydrous methanol, and 4.0 g (8% by mass) of esterification catalyst were added to a 500 mL four-necked flask. The mixture was heated to 55 °C under nitrogen protection and mechanical stirring (300 rpm) for 4 h. The reaction was terminated when the acid value was <0.08 mg KOH / g. The catalyst was recovered by filtration, and the filtrate was distilled under reduced pressure (40 °C / 1.5 kPa) to remove excess methanol, yielding 49.5 g of a pale yellow transparent liquid. HPLC conditions: C18 column, methanol:water / 98:2, flow rate 1.0 mL / min, tR = 7.8 min, HPLC purity 98.7%, product yield calculated based on EPA feed amount 96.8%. 1H NMR characterization results: 1 HNMR (CDCl3, 400MHz): δ5.32-5.40 (m, 10H), δ3.67 (s, 3H), δ2.80 (m, 8H), δ2.34 (t, 2H), δ0.96 (t, 3H).

[0060] 3. Iodination reaction of EPA methyl ester In a 250 mL four-necked flask, 13.9 g of EPA methyl ester (0.044 mol, total double bond amount 0.22 mol), 100 mL of dichloromethane (solid-liquid ratio 1:5), 69.5 g of triphenylphosphine (0.265 mol, 1.2 times the double bond equivalent), and 18.4 g of imidazole (0.270 mol) were added sequentially. After mixing, the mixture was purged with nitrogen three times and cooled to 0 °C in an ice bath. Under magnetic stirring (500 rpm), a dichloromethane solution (60 mL) containing 67.2 g of iodine (0.265 mol) was slowly added dropwise at a rate of 1.5 mL / min. After the addition was complete, the reaction was maintained at 0 °C for 1.5 h. At 0 °C, 3.96 mL of deionized water (0.22 mol, equimolar based on total double bond amount) was pre-emulsified with 10 mL of dichloromethane and added to the reaction system in five portions (10 min apart). After each addition, the mixture was stirred at 0 °C for 10 min. The temperature was then raised to 20°C and the reaction was carried out for 16 hours. HPLC monitoring showed that the starting material peak (tR=7.8 min) completely disappeared, and the target product peak (tR=13.2 min) had a purity of >95%, at which point the reaction was terminated.

[0061] 4. Post-processing and purification Post-processing: Add 70 mL of 8% sodium thiosulfate solution to the reaction solution and stir for 40 min until the brown color fades. Separate the liquid. Wash the organic phase three times with deionized water (60 mL each time). The pH of the aqueous phase was measured to be 6.8–7.2. After washing, collect the organic phase and dry it with anhydrous sodium sulfate for 3 h. The solvent was removed from the dried organic phase under reduced pressure at 35 °C and 1 kPa to obtain 14 g of brownish-yellow oily crude product (purity 89.2%). The brownish-yellow oily crude product was further purified by molecular distillation under the following conditions: feed rate: 1.5 mL / min, vacuum: 0.6 Pa, distillation temperature: 145 °C. Collect the main fraction to obtain 12.1 g of pale yellow viscous liquid.

[0062] 5. Key parameters and characterization of the product Yield: 86.7%; Iodine content: 47.6%; HPLC purity: 99.3% (HPLC conditions: C18 column, methanol:water = 98:2, flow rate 1.0 mL / min, tR = 13.2 min); Iodine content: 47.6% (theoretical value 47.8%, oxygen flask combustion-ion chromatography). 1 HNMR (CDCl3, 400MHz): δ3.68 (s, 3H, -OCH3), δ3.10-3.25 (m, 10H, -CHI-), δ2.35 (t, 2H, -CH2COO-), δ1.20-1.80 (m), δ0.97 (t, 3H); Solvent residue: dichloromethane <8ppm (headspace GC, DB-624 column, detection limit 0.1ppm); Heavy metals: Pb <0.05ppm, As <0.01ppm (ICP-MS).

[0063] Example 2 1. Raw materials, reagents and materials Main raw materials: DHA (purity 97.9%, ≤0.8mgKOH / g, Acros Organics); esterification reagent: anhydrous ethanol (chromatographic grade); esterification catalyst: Amberlyst-15 strong acid cation exchange resin (Sigma-Aldrich, catalog number 243822); iodination reagents: triphenylphosphine (99%, Alfa), elemental iodine (99.9%, Aladdin), pyridine (99%, Sinopharm); solvent: tetrahydrofuran (THF, anhydrous, moisture <0.005%); purification material: silica gel (200-300 mesh, Qingdao Ocean Chemical).

[0064] 2. Preparation of DHA ethyl ester 40.0 g (0.081 mol) of DHA, 120 mL (2.13 mol) of anhydrous ethanol, and 3.6 g (9% w / w) of Amberlyst-15 resin were added to a 250 mL flask. The mixture was heated to 50 °C and stirred for 3.5 h under nitrogen protection and mechanical stirring (300 rpm). The acid value was measured to be ≤0.5 mg KOH / g. The resin was recovered by filtration, and the filtrate was distilled under reduced pressure (45 °C and 1 kPa) to remove excess ethanol, yielding 39.3 g of a brown oily product with an HPLC purity of 98.4% and a yield of 95.7% based on the DHA feed amount. Hydrogen spectroscopy characterization results: 1 HNMR (CDCl3, 400MHz): δ5.30-5.38 (m, 12H), δ4.12 (q, 2H), δ1.25 (t, 3H).

[0065] 3. Iodination reaction of DHA ethyl ester In a 250 mL four-necked flask, 10.3 g (0.029 mol, total double bond amount 0.174 mol), 90 mL (1:6 w / v) of anhydrous THF, 55.3 g (0.211 mol, 1.21 eq) of triphenylphosphine, and 16.8 g (0.212 mol) of pyridine were added sequentially. After dissolving by stirring at 25 °C, 53.5 g (0.211 mol) of elemental iodine was added in 5 equal portions at 30 min intervals. At 0 °C, 3.96 mL (0.22 mol, equimolar of total double bond amount) of deionized water and 10 mL of dichloromethane were pre-emulsified and added to the reaction system in 5 portions at 10 min intervals. After each addition, stirring was continued at 0 °C for 10 min. After the addition was complete, the reaction was carried out at 25-30 °C for 16.5 h.

[0066] 4. Post-processing and purification Same as in Example 1, 8.56g of a pale yellow viscous liquid was obtained.

[0067] 5. Key parameters and characterization of the product Yield after purification: 83.2%; HPLC purity: 99.2% (tR=14.5min); Iodine content: 45.4% (theoretical value 45.6%). 1 ¹H NMR: The double bond proton peak completely disappeared, and a characteristic peak appeared at δ 3.08-3.22 (m, 12H, -CHI-). As the reaction proceeded, the unsaturated double bond proton signal at δ 5.32 gradually weakened, while a new -CH-I iodine-carbon proton signal appeared in the δ 4.10-4.35 region. Solvent residues: THF < 5 ppm, ethanol undetectable; Heavy metals: Pb < 0.05 ppm, As < 0.01 ppm (ICP-MS).

[0068] Example 3 The steps in this embodiment are the same as in Example 1, except that EPA ethyl ester is prepared using EPA (purity 98.5%, acid value ≤0.3 mg KOH / g, Sigma-Aldrich) and anhydrous ethanol (chromatographic grade, water <0.01%, Merck) as the esterification reagent, and then further subjected to an iodination reaction to obtain iodo-EPA ethyl ester. After the reaction, the yield after purification is 85.1%, the HPLC purity is 99.1%, and the iodine content is 45.3%.

[0069] Example 4 The steps in this embodiment are the same as in Example 1, except that ethyl linoleate is prepared using linoleic acid (99.0% purity, Maclean, L812256-25g) and anhydrous ethanol (chromatographic grade, water content <0.01%, Merck) as the esterification reagent, and then further subjected to an iodination reaction to obtain iodo-iodolinoleic acid ethyl ester. The yield after the reaction was 91.2%, the HPLC purity was 99.4%, and the iodine content was 36.1%.

[0070] Comparative Example 1 Following Example 1, after preparing and obtaining EPA methyl ester, according to the one-pot reaction mode disclosed in the prior art (kawaguchi, 2014), 13.9 g of EPA methyl ester (0.044 mol, total double bond amount 0.22 mol), 100 mL of dichloromethane (solid-liquid ratio 1:5), 69.5 g of triphenylphosphine (0.265 mol, 1.2 times the double bond equivalent), 18.4 g of imidazole (0.270 mol), 67.2 g of iodine (0.265 mol) in dichloromethane solution (60 mL), and 3.96 mL of deionized water (0.22 mol) were added in a 250 mL four-necked flask in a one-pot reaction. After mixing, the mixture was purged with nitrogen three times and reacted at 20 °C for 16 h.

[0071] Although the double bond of EPA methyl ester was transformed, the reaction system was difficult to effectively control the hydroiodization process, resulting in a significant increase in side reactions and low iodine utilization. After post-treatment and purification, the yield of the target iodinated fatty acid ester was only 30%, the HPLC purity was only 52.5%, and the iodine content was 20%.

[0072] This demonstrates that the existing one-pot reaction strategy is difficult to apply to unsaturated fatty acid ester systems and cannot stably and efficiently prepare high-purity, high-thermal-stability iodinated fatty acid esters.

[0073] Example 5 The target compound prepared in this embodiment is the same as that in Example 1, except that: instead of using a dichloromethane solution of elemental iodine, 67.2 g (0.265 mol) of solid elemental iodine was added in four portions, with an interval of 30 min between each addition, and each addition amounted to 25% of the total amount.

[0074] Post-processing and purification yielded 11.6 g of a pale yellow viscous liquid. Key parameters and characterization of the product are as follows: The yield after purification was 83.5%; HPLC purity: 98.0% (under the same conditions, tR = 13.2 min); iodine content: 47.5% (theoretical value 47.8%). 1 HNMR (CDCl3, 400MHz): δ3.68 (s, 3H, -OCH3), δ3.12-3.24 (m, 10H, -CHI-), δ2.35 (t, 2H, -CH2COO-), δ1.22-1.78 (m), δ0.97 (t, 3H); Solvent residue: dichloromethane <10ppm; Heavy metals: Pb <0.05ppm, As <0.01ppm.

[0075] Example 6 The steps in this embodiment are the same as in Example 1, except that: 67.2 g (0.265 mol) of iodine in dichloromethane solution (15 mL, iodine molar concentration of 4.5 mol / L) is added dropwise at a rate of 15 mL / min. That is, the concentration of the iodine solution added is 10 times that in Example 1, and the iodine solution is added at a faster rate.

[0076] After post-processing and purification, 8.4 g of a pale yellow viscous liquid was obtained. Key parameters and characterization of the product are as follows: The yield after purification was 60%; HPLC purity: 82.6% (under the same conditions, tR = 13.2 min); iodine content: 39.3% (theoretical value 39.8%). 1HNMR (CDCl3, 400MHz): δ3.68 (s, 3H, -OCH3), δ3.11-3.25 (m, 10H, -CHI-), δ2.35 (t, 2H, -CH2COO-), δ1.21-1.79 (m), δ0.97 (t, 3H); Solvent residue: dichloromethane <12ppm; Heavy metals: Pb <0.05ppm, As <0.01ppm.

[0077] Comparative Example 2 The steps in this embodiment are the same as in Example 1, except that: 60.5 g (0.239 mol) of elemental iodine in a dichloromethane solution (60 mL) is used, and the molar ratio of triphenylphosphine to elemental iodine is 1:0.9. After purification, the yield is 72.4%, the HPLC purity is 91.5%, and the iodine content is 45.8%.

[0078] According to this comparative example, when the molar ratio of triphenylphosphine to iodine exceeds the endpoint value of 1:1 (i.e., the amount of iodine added is insufficient, or triphenylphosphine is in excess relative to iodine), the iodine content of iodo-EPA methyl ester is lower than that in Example 1, and the yield of crude EPA methyl ester after purification is much lower than that in Example 1.

[0079] Comparative Example 3 The steps in this embodiment are the same as in Example 1, except that: 94.0 g (0.331 mol) of elemental iodine in a dichloromethane solution (60 mL) is used, and the molar ratio of triphenylphosphine to elemental iodine is 1:1.25. After the reaction, the yield after purification is 78.2%, the HPLC purity is 95.8%, and the iodine content is 41.5%.

[0080] According to this comparative example, when the molar ratio of triphenylphosphine to iodine exceeds the endpoint value of 1:1.2 (i.e., the amount of triphenylphosphine is insufficient relative to iodine), the iodine content of iodo-EPA methyl ester is lower than that in Example 1, and the yield of crude EPA methyl ester after purification is much lower than that in Example 1.

[0081] Example 7 The steps in this embodiment are the same as in Example 1, except that an equal amount of methyl tert-butyl ether (chromatographic grade, water content <0.005%, Sinopharm) is used instead of dichloromethane to prepare an iodine solution; the temperature is raised to 20℃ and the reaction is carried out for 16 hours. HPLC monitoring shows that the starting material peak (tR=7.8 min) completely disappears, and the target product peak (tR=13.0 min) has a purity >96%, at which point the reaction is terminated. After post-processing and purification, 12.4 g of a pale yellow viscous liquid is obtained. The yield and iodine content of the product are basically the same as in Example 1. The key parameters and characterization of the product are as follows: The yield after purification was 88.6%; HPLC purity: 99.5% (under the same conditions, tR = 13.0 min); iodine content: 47.7% (theoretical value 47.8%). 1 HNMR (CDCl3, 400MHz): δ3.68 (s, 3H, -OCH3), δ3.10-3.24 (m, 10H, -CHI-), δ2.35 (t, 2H, -CH2COO-), δ1.20-1.80 (m), δ0.97 (t, 3H); Solvent residue: methyl tert-butyl ether <5ppm; Heavy metals: Pb <0.05ppm, As <0.01ppm.

[0082] Comparative Example 4 The steps in this embodiment are the same as in Example 1, except that imidazole is not added. After 16 hours of reaction, sampling and monitoring revealed that the reaction failed. This proves that an organic base is a necessary condition for the successful conduct of the iodination reaction.

[0083] Comparative Example 5 The steps in this embodiment are the same as in Example 1, except that: 3.96 mL of deionized water (0.22 mol, equimolar based on the total double bond amount) and 10 mL of dichloromethane were pre-emulsified and added to the reaction system in 5 portions (10 min apart each time). After the addition was complete, the temperature was directly raised to 20 °C and the reaction was carried out for 16 h. After the reaction was completed, the yield after purification was 76.5%, the purity of HPLC was 95.1%, and the iodine content was 42.6%.

[0084] This comparative example shows that after adding the protic reagent, stirring at -5℃ to 5℃ for 5 to 15 minutes is necessary; omitting this step and directly raising the temperature will lead to a decrease in the yield of iodofatty acid esters.

[0085] Comparative Example 6 The steps in this embodiment are the same as in Example 1, except that 29.5 g of imidazole (0.432 mol, which is 1.6 times the molar amount of triphenylphosphine) was added. After the reaction was completed, the yield after purification was 81.5%, the purity of HPLC was 97.4%, and the iodine content was 44.2%.

[0086] According to this comparison, an excess of organic base will produce too much salt precipitation during the post-treatment quenching stage, increasing the difficulty of washing and purification. Furthermore, excess base may promote the elimination reaction of iodine substitution (dehydroiodide), reducing the iodine content of the product.

[0087] Comparative Example 7 The steps in this embodiment are the same as in Example 1, except that: imidazole 15.7g (0.230mol, which is 0.85 times the molar amount of triphenylphosphine). After the reaction, the yield after purification was 45.2%, the purity by HPLC was 88.6%, and the iodine content was 32.5%.

[0088] According to this comparative example, insufficient use of organic base leads to a significant decrease in product yield, which cannot effectively neutralize the trace acidic byproducts that may be generated during the reaction. This can easily induce side reactions such as oxidation or polymerization of fatty acid chains, resulting in a darker product color.

[0089] Comparative Example 8 The steps in this embodiment are the same as in Example 1, except that the amount of EPA methyl ester added is increased to 15.2 g (0.048 mol, total double bond content 0.24 mol), at which point the molar ratio of triphenylphosphine to double bond is 1:0.9. After the reaction, the yield after purification is 70.8%, the HPLC purity is 94.2%, and the iodine content is 35.8%.

[0090] According to this comparative example, when the molar ratio of triphenylphosphine to double bond exceeds the endpoint value of 1:1 (i.e., the amount of triphenylphosphine used is too much relative to the double bond), the yield of the reaction is observed to be lower than that of Example 1. This is because the double bond addition is incomplete and the iodine content of the product is lower than the theoretical value.

[0091] Comparative Example 9 The steps in this embodiment are the same as in Example 1, except that the amount of EPA methyl ester added is reduced to 11.1 g (0.035 mol, total double bond content 0.175 mol), at which point the triphenylphosphine:double bond ratio is 1:1.5 on a molar basis. After the reaction, the yield after purification is 87.5%, the purity by HPLC is 98.2%, and the iodine content is 47.7%.

[0092] According to this comparative example, when the molar ratio of triphenylphosphine to double bond exceeds the endpoint value of 1:1.4 (i.e., the amount of triphenylphosphine used is reduced relative to the double bond), the reaction yield is observed to be slightly higher than that of Example 1. Although it can slightly improve the conversion rate, it will lead to excessive viscosity of the reaction system and reduced heat transfer efficiency of the reactants, which is not conducive to large-scale industrial production. In the application of contrast agents, the contrast effect achieved by the reaction product of this comparative example is not as good as that of Example 1.

[0093] Example 8 The steps in this embodiment are the same as in Example 1, except that the post-processing and purification methods are different. After the reaction is complete, the organic solvent is removed by vacuum distillation. The resulting brownish-yellow oily crude product is not purified by molecular distillation, but by repeated liquid-liquid extraction. Specifically, the brownish-yellow oily crude product is washed three times with deionized water (60 mL each time) until the pH of the aqueous phase is 6.8–7.2. After separation, the organic phase is collected and dried with anhydrous sodium sulfate. After drying, the solvent is removed by vacuum distillation at 35°C and 1 kPa, yielding 9.8 g of a deep yellow oily substance with a yield of 70%, a purity of 92%, and an iodine content of 39.9%.

[0094] Example 9 The steps in this embodiment are the same as those in Embodiment 1, except that the post-processing and purification methods are different.

[0095] After the reaction was completed, the organic solvent was removed by vacuum distillation. The resulting brownish-yellow oily crude product was not purified by molecular distillation or repeated extraction, but by silica gel column chromatography. The column chromatography operation was performed according to the conventional method disclosed in the prior art (Kawaguchi, 2014), using silica gel as the stationary phase. The target fraction was collected and concentrated, finally yielding 10.5 g of a pale yellow oily product, with a yield of 75.7%, a purity of 98%, and an iodine content of 47.7%.

[0096] Examples 1, 8, and 9 demonstrate that the target product obtained from the reaction system of this invention exhibits good separation stability and can be effectively separated using conventional column chromatography. However, column chromatography, as a routine laboratory separation method, has significant limitations in terms of operational complexity, solvent consumption, and feasibility for industrial scale-up. In contrast, the molecular distillation method used in Example 1 offers advantages in terms of continuous operation, industrial applicability, and overall performance.

[0097] Comparative Example 10 The steps in this embodiment are the same as in Embodiment 1, except that the terminal purification step is omitted in the post-processing.

[0098] After the reaction was completed, the organic solvent was removed by vacuum distillation. The resulting brownish-yellow oily crude product was then used directly as the final product without any further purification treatment such as molecular distillation, liquid-liquid extraction or column chromatography. 13g of brownish-yellow oily substance was obtained, with a yield of 92%, a purity of 76%, and an iodine content of 35%.

[0099] Test Example 1: Thermogravimetric Analysis (TGA) Experiment The thermal stability of the obtained iodinated fatty acid esters was investigated using thermogravimetric analysis (TGA). Approximately 10 mg of sample was placed in an alumina crucible and heated from 30°C to 600°C at a heating rate of 10°C / min under nitrogen gas flow (50 mL / min). The mass change of the sample as a function of temperature was continuously recorded, and its thermal decomposition onset temperature (T0) was calculated. d ) and 5% mass loss temperature (T) 5% ).

[0100] Table 1 Thermal stability of iodinated fatty acid esters During the iodination of unsaturated fatty acid esters, the localized, instantaneous, and intense exothermic reaction in the reaction system can lead to uncontrollable side reactions in the fatty acid chains, generating impurities with extremely poor thermal stability. These impurities undergo deiodination at relatively low temperatures, seriously threatening the safety of clinical use. Therefore, specific purification process conditions are required to remove these impurities.

[0101] As shown in Table 1, Example 1, which strictly follows the preferred embodiment of the present invention, exhibits excellent thermal stability after purification. Replacing the crucial molecular distillation step, the purified samples of Examples 8 and 9, which are considered less optimal, demonstrate good thermal stability. However, Comparative Example 10 did not employ the purification method specified in this invention, resulting in a significant amount of unremoved byproducts and impurities in the product. Consequently, the product purity and stability were significantly insufficient, and the thermal stability of the sample was poor, making it difficult to meet the application requirements for high-purity iodinated fatty acid esters.

[0102] Test Example 2: Imaging Sharpness (CT Value Test) Experiment (1) Experimental equipment: The scanning instrument used was a multi-slice spiral CT scanner (GE Revolution, scanning parameters: tube voltage 120kVp (routine clinical parameters), tube current 200mA, slice thickness 0.625mm, field of view 25cm).

[0103] (2) Sample preparation: The sample to be tested was diluted with anhydrous n-hexane in a serial dilution. The choice of this solvent was to ensure the chemical structural integrity of the iodinated product during the dilution process and to avoid trace deiodination caused by protons. A series of solutions with iodine concentrations of 5, 10, 20, 50, and 100 mgI / mL were prepared. At the same time, pure solvent was used as a blank background control, and commercially available traditional iodized oil (Lipiodol) was used as a parallel control. The solutions of each concentration were placed into sterile centrifuge tubes of the same size, sealed in 1.5 mL non-color polypropylene (PP) tubes, and vertically fixed in a cylindrical PMMA air mold with a diameter of 15 cm. The sample tubes were arranged in a ring symmetrical distribution with a center distance of 5 cm.

[0104] (3) Test steps Place the mold in the center of the CT scanning bed and perform axial scanning. ROI measurement: On the obtained CT image, select the central region of the lumen as the region of interest (ROI, area approximately 20-50 mm²), and automatically measure its average CT value (HU).

[0105] Table 2 CT value test of iodinated fatty acid esters As can be seen from the table, at the same iodine concentration (e.g., 100 mgI / mL), the CT value of Example 1 (2560 HU) is significantly higher than that of Comparative Example 1 (2150 HU) and conventional iodized oil (2420 HU). This demonstrates that the product of the present invention, due to the uniform distribution of iodine atoms on the carbon chain, greatly reduces the interference of impurities (such as unreacted double bonds or oxidation byproducts) on X-rays, thereby improving the X-ray blocking efficiency per unit mass.

[0106] Example 10 This embodiment provides an industrial-scale production method, employing essentially the same preparation method as in Example 1, except that the main raw material is EPA fatty acid, with a feed rate increased to 100g to verify the scale-up process. The yield of iodinated fatty acid ethyl esters was 210g, with an iodine content of 47.1% and a yield of 90%. This demonstrates that the process of this invention has good scalability and promising industrial application prospects.

[0107] The embodiments described above merely illustrate several implementations of the present invention and should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Furthermore, it should be understood that after reading the above teachings, those skilled in the art can make various alterations or modifications to the present invention, and the equivalent forms obtained also fall within the protection scope of the present invention. It should also be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided by the present invention through logical analysis, reasoning, or limited experimentation are all within the protection scope of the appended claims. Therefore, the protection scope of this invention patent should be determined by the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A method for preparing iodinated fatty acid esters, characterized in that, The preparation method includes the following steps: S01. Mix unsaturated fatty acid ester, organic base, triphenylphosphine and first organic solvent to prepare first mixture; S02. Under the conditions of -5 to 5℃ and a protective gas atmosphere, elemental iodine is added to the first mixture. After the addition is complete, the mixture is stirred at -5 to 5℃ for 1 to 2 hours to obtain the second mixture. S03. Add a protic reagent to the second mixture to obtain the third mixture; S04. Stir the third mixture at 20-60°C for 15-20 hours to obtain a reaction solution; S05. The reaction solution is subjected to quenching and purification treatment to obtain the iodinated fatty acid ester.

2. The preparation method according to claim 1, characterized in that, The unsaturated fatty acid ester has 18 to 25 carbon atoms and 1 to 6 carbon-carbon double bonds.

3. The preparation method according to claim 1 or 2, characterized in that, The unsaturated fatty acid ester is obtained by esterification of unsaturated fatty acids and alcohols in the presence of a base and a catalyst. The alcohols include monohydric alcohols and / or dihydric alcohols and have 1 to 5 carbon atoms.

4. The preparation method according to any one of claims 1 to 3, characterized in that, The molar ratio of the triphenylphosphine to the iodine is 1:(1 to 1.2); and / or, the molar ratio of the triphenylphosphine to the unsaturated bonds contained in the unsaturated fatty acid ester is 1:(1 to 1.4).

5. The preparation method according to any one of claims 1 to 4, characterized in that, The preparation method satisfies one or more of the following conditions: - The first organic solvent is selected from aromatic hydrocarbons, halogenated hydrocarbons, ethers, and ketones. - The protonating agent is compatible with [Ph3PI]. + I - A reagent that produces hydroiodic acid (HI) in situ; - The organic base is selected from imidazole and its derivatives, pyridine and its derivatives, non-pyridine heterocyclic amines and their derivatives, and combinations thereof.

6. The preparation method according to any one of claims 1 to 5, characterized in that, Between steps S03 and S04, the following steps are also included: S031. Stir the third mixture at -5 to 5°C for 5 to 15 minutes.

7. The preparation method according to any one of claims 1 to 6, characterized in that, The operation of adding elemental iodine in step S02 includes the following steps: S021. Dissolve elemental iodine in a second organic solvent to obtain an elemental iodine solution; S022. Mix the iodine solution with the first mixture at a feed rate of 1-10 mL / min; The second organic solvent is selected from aromatic hydrocarbons, halogenated hydrocarbons, ethers, and ketones.

8. The preparation method according to claim 7, characterized in that, In step S022, the iodine solution is provided in 4 to 6 portions with stirring, and the interval between the two feedings is 20 to 40 minutes.

9. The preparation method according to any one of claims 1 to 8, characterized in that, In step S05, the purification process includes at least one purification method selected from column chromatography, molecular distillation, and extraction washing.

10. Iodinated fatty acid esters obtained by the preparation method according to any one of claims 1-9.

11. The use of the iodinated fatty acid ester according to claim 10 in the preparation of pharmaceutical intermediates, iodine supplements, iodized health products, iodized foods, or imaging materials.

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