Method for high-yield synthesis of iopromide EP impurity F

Abstract

The invention discloses a method for high-yield synthesis of an iopromide EP impurity F. The method comprises the following steps: dissolving iopromide with an organic solvent, and adding hydroxyacetone; after uniformly stirring, adding a catalytic amount of acid, carrying out nitrogen displacement, heating to 75-95 DEG C in an oil bath, and carrying out a reaction; after the reaction is finished, pouring reaction liquid into water, extracting twice with ethyl acetate, and extracting twice with dichloromethane; discarding an organic phase, and carrying out vacuum spin-drying on a water phase; adding a certain amount of water into residues, and then adding activated carbon for decoloration; filtering, and spin-drying filtrate again; and adding the residue into absolute ethyl alcohol, refluxing for 2-4 hours, naturally cooling to room temperature, crystallizing, filtering, adding ethyl alcohol into a filter cake again, repeatedly crystallizing for more than three times, and freeze-drying the obtained filter cake to obtain the iopromide impurity F with the purity of more than 98%. The method for synthesizing the iopromide EP impurity F has the advantages of simple operation, short preparation period, low cost and environmental protection, and the purity is high.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a method for synthesizing iopromide EP impurity F with high yield and high recovery rate. Background Art

[0002] Iopromide, with the trade name Ultravist, was developed by Schering in Germany and first marketed in Germany in 1985. It is clinically used as an X-ray contrast agent, containing the parent structure of 2,4,6-triiodo-5-acetamido-1,3-isophthalamide, and is a neutral, non-ionic compound. Iopromide has the advantages of high water solubility, good contrast enhancement effect, low toxicity, and good tolerance, and is widely used in digital subtraction angiography, urinary tract, renal artery, ventricle, gastrointestinal tract imaging, and CT scans. Iopromide has good safety and ranks among the top in terms of sales in the global contrast agent market, but serious adverse reactions still occur from time to time. Adverse reactions are not only related to the pharmacological activity of iopromide itself, but also closely related to the impurities present in iopromide. Therefore, drug researchers not only need to develop efficient synthesis processes to obtain high-quality active pharmaceutical ingredients, but also need to study the structural sources of impurities in the active pharmaceutical ingredients and control the generation of process impurities. Preparing sufficient impurity reference substances to ensure the conduct of quality inspection work for each batch of active pharmaceutical ingredients (such as impurity HPLC qualitative analysis, quantitative analysis, etc.) is also a necessary and important task.

[0003] Currently, the impurities of iopromide reported in the literature (such as in European Pharmacopoeia EP9.0, pages 2798 - 2801) mainly include impurities A - G. The main method for obtaining impurity F is to enrich and purify impurity F in the iopromide crude product through preparative liquid chromatography. Since the content of impurity F in the iopromide crude product is very low, usually only 0.2 - 0.3%, a large amount of iopromide crude product is required. The amount of organic solvents used in the preparation process is huge, the operation is cumbersome, and a lot of manual time is consumed, making the preparation cost of impurity F very high. Summary of the Invention

[0004] Aiming at the problems existing in the prior art, the present invention provides a method for synthesizing iopromide EP impurity F with high yield and high recovery rate, that is, dehydrating iopromide and hydroxyacetone under acid catalysis to obtain iopromide impurity F.

[0005] The present invention provides a method for synthesizing iopromide EP impurity F with high yield and high recovery rate, comprising the following steps:

[0006] Step S1: Dissolve iopromide in an organic solvent and add hydroxyacetone; by selecting a suitable organic solvent (such as a mixture of toluene and dimethyl sulfoxide), iopromide can be effectively dissolved and uniformly dispersed in the solution;

[0007] Step S2: After stirring evenly, add a catalytic amount of acid, displace with nitrogen, and raise the temperature to 75°C - 95°C in an oil bath for reaction; Stir to make the mixed solution evenly mixed, ensuring sufficient contact between iopromide and hydroxyacetone to create good conditions for the dehydration reaction; Add a catalytic amount of acid to lower the reaction activation energy and accelerate the dehydration reaction; Displace with nitrogen to remove oxygen and moisture in the air and prevent side reactions from occurring; Raise the temperature to 75°C - 95°C in an oil bath to provide suitable temperature conditions for the dehydration reaction; The synergistic effect of stirring and nitrogen displacement can effectively avoid the generation of by-products and improve the purity of impurity F; The addition of an acid catalyst significantly speeds up the dehydration reaction rate and shortens the reaction time; Appropriate temperature control enables the reaction to reach complete conversion in a short time, improving the yield of impurity F and the selectivity of the reaction;

[0008] Step S3: After the reaction is completed, pour the reaction solution into water and extract twice with ethyl acetate and twice with dichloromethane; After the reaction is completed, pour the reaction solution into water, and utilize the property that iopromide impurity F is immiscible with water to separate it from the reaction solution; Extract with ethyl acetate and dichloromethane to further transfer iopromide impurity F from the aqueous phase to the organic phase to achieve its separation from aqueous phase impurities; Through the separation of the aqueous phase and multiple extractions with organic solvents, most of the impurities and unreacted raw materials in the reaction solution can be effectively removed, improving the purity of iopromide impurity F and laying a foundation for subsequent purification steps;

[0009] Step S4: Discard the organic phase and rotary evaporate the aqueous phase to dryness under vacuum; Through rotary evaporation under vacuum, the solvent in the aqueous phase can be completely removed to obtain a dry crude product, reducing the burden of subsequent purification steps and improving the simplicity of operation;

[0010] Step S5: Add a certain amount of water to the residue and then add activated carbon for decolorization; Activated carbon decolorization can effectively remove impurities such as pigments and resins in the crude product, making the color of iopromide impurity F more pure, further improving its purity, and creating good conditions for subsequent crystallization steps;

[0011] Step S6: Filter and rotary evaporate the filtrate to dryness again; Through filtration and rotary evaporation to dryness again, impurities and solvent residues in the crude product can be further removed to obtain a dry and pure crude product, providing high-quality raw materials for subsequent crystallization steps;

[0012] Step S7: Add the residue to anhydrous ethanol, reflux for 2 - 4 h, then naturally cool to room temperature for crystallization. Filter, add ethanol to the filter cake again, repeat the crystallization operation more than three times, and freeze-dry the obtained filter cake to obtain iopromide impurity F with a purity greater than 98%; through multiple crystallizations, the residual impurities in the crude product can be effectively removed, making the purity of iopromide impurity F reach more than 98%, and even up to more than 99%; the freeze-drying operation can ensure the dryness and stability of the final product, meet the requirements of the impurity reference substance, and is applicable to the quality inspection of iopromide raw materials and their preparations.

[0013] Preferably, in step S1, the organic solvent is a mixture of toluene and dimethyl sulfoxide, and the volume ratio of toluene to dimethyl sulfoxide is 1:1 - 3:1; the mixed solvent of toluene and dimethyl sulfoxide can effectively dissolve iopromide to form a uniform solution, providing a good reaction medium for the subsequent dehydration reaction. Toluene has high volatility and low polarity, which is beneficial to the progress of the reaction and the separation of products; dimethyl sulfoxide has high polarity and good solubility, which can further increase the solubility of iopromide and ensure its uniform dispersion in the solution; by optimizing the solvent ratio (1:1 - 3:1), while ensuring the full dissolution of iopromide, the selectivity and yield of the reaction can be improved. A lower ratio of dimethyl sulfoxide (such as 1:1) is beneficial to accelerating the recovery of the solvent and the separation of products, while a higher ratio of dimethyl sulfoxide (such as 3:1) can better dissolve iopromide, ensure its full contact with hydroxyacetone, and thus improve the yield and purity of impurity F.

[0014] Preferably, in step S1, the equivalent of hydroxyacetone is 1 - 1.5.

[0015] Preferably, in step S2, the catalytic amount of acid is selected from one or more of sulfuric acid, acetic acid, p-toluenesulfonic acid, and boron trifluoride, and the equivalent is 0.1 - 0.3;

[0016] By selecting different acids as catalysts, the selectivity and yield of the reaction can be optimized according to specific reaction conditions and requirements. For example, the strong acidity of sulfuric acid and p-toluenesulfonic acid is beneficial to increasing the reaction rate and yield, while the moderate acidity of acetic acid and the Lewis acidity of boron trifluoride help to reduce the generation of by-products and improve the purity of impurity F while maintaining a high yield.

[0017] Preferably, in step S3, the reaction time is 10 - 36 h.

[0018] Preferably, in step 5, the mass of activated carbon is 0.3 - 2 times the mass of iopromide.

[0019] Preferably, in step S7, the crystallization solvent is selected from one or more of methanol, ethanol, and isopropanol, the reflux time is 2 - 4 h, and the crystallization operation is carried out 3 - 5 times.

[0020] Adopting the technical solution of the present invention has the following beneficial effects:

[0021] The method for synthesizing iopromide EP impurity F of the present invention has the advantages of simple operation, short preparation period, low cost and environmental friendliness. The prepared iopromide EP impurity F has high purity, no obvious impurity spots, meets the requirements of impurity reference substances, can be used as the iopromide impurity standard substance, and is applied to the qualitative, quantitative research and detection of iopromide impurities, which has certain significance for the quality control of iopromide raw materials and their related preparations; during the synthesis process, the purification is simple, the yield is high, and no highly toxic, explosive and other dangerous substances are used, which conforms to the modern environmental protection and sustainable development concept, and can facilitate the impurity analysis and research of iopromide raw materials and their preparations.

[0022] Improving the yield and purity

[0023] High yield: By optimizing the synthesis steps and conditions, such as selecting appropriate organic solvents, catalyst acids and crystallization solvents, etc., the present application can significantly improve the yield of iopromide impurity F. For example, in step S1, using a mixed solvent of toluene and dimethyl sulfoxide can effectively dissolve iopromide, enabling it to fully contact with hydroxyacetone, thereby increasing the yield of the dehydration reaction; in step S2, a catalytic amount of acid (such as sulfuric acid, p-toluenesulfonic acid, etc.) can accelerate the reaction process, making the reaction more complete and further increasing the yield. In addition, the multiple crystallization operations in step S7 also help to increase the yield of impurity F, enabling it to fully precipitate from the crude product.

[0024] High purity: The synthesis method of the present application can prepare iopromide impurity F with a purity greater than 98%, and even up to more than 99%. In step S3, through multiple extractions with ethyl acetate and dichloromethane, impurities in the aqueous phase can be effectively removed; in step S5, decolorization with activated carbon can remove colored impurities and some organic impurities; the multiple crystallization operations in step S7 further purify impurity F, making its purity meet the requirements of impurity reference substances. High-purity impurity F can provide an accurate and reliable benchmark for the quality detection of iopromide raw materials and their preparations, ensuring the accuracy of detection results.

[0025] Simplifying the operation process

[0026] Clear and simple steps: The synthesis method of the present application has clear steps and simple operations. From dissolving iopromide to finally obtaining high-purity impurity F, the entire process is easy to understand and master. Technicians do not need complex equipment and cumbersome operations, and only need to perform conventional operations such as dissolution, stirring, extraction, decolorization, crystallization, etc. according to the steps to quickly prepare the required impurity reference substance, greatly reducing the technical threshold and operation difficulty.

[0027] Reducing side reactions: By optimizing reaction conditions, such as controlling the equivalent amount of catalyst acid (0.1 - 0.3) and reaction temperature (75°C - 95°C), the occurrence of side reactions can be effectively reduced. An appropriate amount of catalyst acid can promote the dehydration reaction without causing excessive side reactions; appropriate temperature control enables the reaction to reach complete conversion in a short time, avoiding decomposition or other side reactions that may occur at high temperatures, thus simplifying the subsequent purification steps and improving the synthesis efficiency.

[0028] Shortening the preparation cycle

[0029] Short reaction time: Compared with traditional preparation methods, the reaction time of this application is relatively short. For example, in step S2, the dehydration reaction is carried out under an oil bath condition of 75°C - 95°C, and the reaction time is only 10 - 36h, far lower than the longer time that may be required in traditional methods. The rapid reaction process greatly shortens the entire synthesis cycle, enabling a quick response to market demand and promptly producing the required impurity reference substances to meet the quality inspection requirements of iopromide API and its preparations.

[0030] Efficient purification steps: In the purification process, this application adopts efficient extraction, decolorization, and crystallization steps. Multiple extractions with ethyl acetate and dichloromethane can quickly remove impurities in the aqueous phase; the activated carbon decolorization operation is simple and effective; although multiple crystallization operations increase the steps, the time required for each crystallization is short, and the purity can be significantly improved, making the entire purification process efficient and controllable, further shortening the preparation cycle.

[0031] Reducing costs and good environmental friendliness

[0032] Low raw material cost: The raw materials and reagents used in this application are all common chemical substances, such as iopromide, hydroxyacetone, toluene, dimethyl sulfoxide, sulfuric acid, acetic acid, p-toluenesulfonic acid, boron trifluoride, etc., and the prices are relatively low. At the same time, the dosage is reasonable without waste, reducing the production cost.

[0033] Low equipment cost: Expensive equipment and consumables are not required during the synthesis process, and conventional laboratory equipment can meet the production needs, reducing the equipment investment cost.

[0034] Good environmental friendliness: During the synthesis process, this application does not use dangerous chemicals such as highly toxic and explosive substances, reducing the risk of harm to the environment and operators. The generated waste is less and easy to handle, meeting the modern environmental protection concept, facilitating green production, reducing the negative impact on the ecological environment, and meeting the requirements of sustainable development. Description of the drawings

[0035] Figure 1 This is the chemical reaction formula of the present invention. Detailed implementation manners

[0036] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments.

[0037] Referring to Figure 1 , the present invention provides a method for synthesizing iopromide EP impurity F with high yield and high recovery rate, that is, dehydrating reaction of iopromide and hydroxyacetone under acid catalysis to obtain iopromide impurity F.

[0038] Example 1

[0039] Dissolve 10 g (12.6 mmol) of iopromide in toluene:DMSO = 2:1, and add 1.1 g (15.1 mmol) of hydroxyacetone; after stirring evenly, add 123 mg (1.26 mmol) of concentrated sulfuric acid, replace with nitrogen, heat up to 90 °C in an oil bath and react for 18 h; after monitoring the reaction by LCMS until completion, pour the reaction solution into water, extract twice with ethyl acetate and twice with dichloromethane; discard the organic phase, rotary evaporate the aqueous phase under vacuum; add 80 ml of water to the residue, and then add 5 g of activated carbon to decolorize at 60 °C; filter, and rotary evaporate the filtrate again. Add 50 ml of absolute ethanol to the residue, reflux for 3 h and then naturally cool to room temperature for crystallization, filter, add ethanol to the filter cake again, repeat the crystallization operation more than three times, and lyophilize the obtained filter cake to obtain 6.6 g of iopromide impurity F, with a recovery rate of 62.07% and a purity of 98.5%.

[0040] Example 2

[0041] Dissolve 10 g (12.6 mmol) of iopromide in toluene:DMSO = 2:1, and add 1.1 g (15.1 mmol) of hydroxyacetone; after stirring evenly, add 216.7 mg (1.26 mmol) of p-toluenesulfonic acid, replace with nitrogen, heat up to 90 °C in an oil bath and react for 20 h; after monitoring the reaction by LCMS until completion, pour the reaction solution into water, extract twice with ethyl acetate and twice with dichloromethane; discard the organic phase, rotary evaporate the aqueous phase under vacuum; add 80 ml of water to the residue, and then add 8 g of activated carbon to decolorize at 60 °C; filter, and rotary evaporate the filtrate again. Add 60 ml of absolute ethanol to the residue, reflux for 3 h and then naturally cool to room temperature for crystallization, filter, add ethanol to the filter cake again, repeat the crystallization operation more than three times, and lyophilize the obtained filter cake to obtain 8.2 g of iopromide impurity F, with a recovery rate of 77.1% and a purity of 99.8%.

[0042] Example 3

[0043] Dissolve 10 g (12.6 mmol) of iopromide in toluene:DMSO = 1:1, and add 1.4 g (18.9 mmol) of hydroxyacetone; after stirring evenly, add 438.5 mg (2.52 mmol) of p-toluenesulfonic acid, displace with nitrogen, heat up to 90 °C in an oil bath and react for 24 h; after monitoring the reaction by LCMS and completion, pour the reaction solution into water, extract twice with ethyl acetate and twice with dichloromethane; discard the organic phase, rotary evaporate the aqueous phase to dryness under vacuum; add 80 ml of water to the residue, and then add 10 g of activated carbon for decolorization at 60 °C; filter, and rotary evaporate the filtrate again. Add 60 ml of absolute ethanol to the residue, reflux for 3 h and then naturally cool to room temperature for crystallization, filter, add ethanol to the filter cake again, repeat the crystallization operation more than three times, freeze-dry the obtained filter cake to obtain 7.6 g of iopromide impurity F, with a yield of 70.1% and a purity of 99.1%.

[0044] Example 4

[0045] Dissolve 10 g (12.6 mmol) of iopromide in toluene:DMSO = 2:1, and add 1.4 g (18.9 mmol) of hydroxyacetone; after stirring evenly, add 161 mg (2.52 mmol) of glacial acetic acid, displace with nitrogen, heat up to 90 °C in an oil bath and react for 36 h; after monitoring the reaction by LCMS and completion, pour the reaction solution into water, extract twice with ethyl acetate and twice with dichloromethane; discard the organic phase, rotary evaporate the aqueous phase to dryness under vacuum; add 80 ml of water to the residue, and then add 10 g of activated carbon for decolorization at 60 °C; filter, and rotary evaporate the filtrate again. Add 60 ml of methanol to the residue, reflux for 2 h and then naturally cool to room temperature for crystallization, filter, add ethanol to the filter cake again, repeat the crystallization operation more than three times, freeze-dry the obtained filter cake to obtain 7.9 g of iopromide impurity F with a purity greater than 98%, with a yield of 73.8% and a purity of 98.9%.

[0046] As can be seen from the above examples, the method for synthesizing iopromide EP impurity F of the present invention has the advantages of simple operation, short preparation period, low cost and environmental protection. The prepared iopromide EP impurity F has high purity, no obvious impurity spots, meets the requirements of impurity reference standards, can be used as an iopromide impurity standard, and is applied to the qualitative, quantitative research and detection of iopromide impurities, which has certain significance for the quality control of iopromide raw materials and their related preparations; during the synthesis process, purification is simple, the yield is high, and no highly toxic and explosive dangerous goods are used, which meets the modern environmental protection and sustainable development concepts, and can facilitate the impurity analysis and research of iopromide raw materials and their preparations.

[0047] Improve the yield and purity

[0048] High yield: By optimizing the synthesis steps and conditions, such as selecting appropriate organic solvents, catalyst acids, and crystallization solvents, etc., this application can significantly increase the yield of iopromide impurity F. For example, in step S1, using a mixed solvent of toluene and dimethyl sulfoxide can effectively dissolve iopromide, enabling it to come into full contact with hydroxyacetone, thereby increasing the yield of the dehydration reaction; in step S2, a catalytic amount of acid (such as sulfuric acid, p-toluenesulfonic acid, etc.) can accelerate the reaction process, making the reaction more complete and further increasing the yield. In addition, the multiple crystallization operations in step S7 also contribute to increasing the yield of impurity F, enabling it to fully precipitate from the crude product.

[0049] High purity: The synthesis method of this application can prepare iopromide impurity F with a purity greater than 98%, and even up to more than 99%. In step S3, through multiple extractions with ethyl acetate and dichloromethane, impurities in the aqueous phase can be effectively removed; in step S5, decolorization with activated carbon can remove colored impurities and some organic impurities; the multiple crystallization operations in step S7 further purify impurity F, making its purity meet the requirements of the impurity reference substance. High-purity impurity F can provide an accurate and reliable benchmark for the quality detection of iopromide bulk drug and its preparations, ensuring the accuracy of the detection results.

[0050] Simplify the operation process

[0051] Clear and simple steps: The synthesis method of this application has clear steps and is easy to operate. From dissolving iopromide to finally obtaining high-purity impurity F, the entire process is easy to understand and master. Technicians do not need complex equipment and cumbersome operations. They only need to perform conventional operations such as dissolution, stirring, extraction, decolorization, and crystallization according to the steps, and they can quickly prepare the required impurity reference substance, greatly reducing the technical threshold and operation difficulty.

[0052] Reduce side reactions: By optimizing the reaction conditions, such as controlling the equivalent amount of catalyst acid (0.1 - 0.3) and reaction temperature (75°C - 95°C), the occurrence of side reactions can be effectively reduced. An appropriate amount of catalyst acid can promote the dehydration reaction but will not cause excessive side reactions; appropriate temperature control enables the reaction to reach complete conversion in a short time, avoiding decomposition or other side reactions that may occur at high temperatures, thereby simplifying the subsequent purification steps and improving the synthesis efficiency.

[0053] Shorten the preparation cycle

[0054] Short reaction time: Compared with traditional preparation methods, the reaction time of this application is relatively short. For example, in step S2, the dehydration reaction is carried out under an oil bath condition of 75°C to 95°C, and the reaction time is only 10 to 36 hours, which is much lower than the longer time that may be required in traditional methods. The rapid reaction process greatly shortens the entire synthesis cycle, enabling a quick response to market demands, promptly producing the required impurity reference substances, and meeting the quality inspection requirements of iopromide bulk drugs and their preparations.

[0055] Efficient purification steps: In the purification process, this application adopts efficient extraction, decolorization, and crystallization steps. Multiple extractions with ethyl acetate and dichloromethane can quickly remove impurities in the aqueous phase; the activated carbon decolorization operation is simple and has a significant effect; although multiple crystallization operations increase the steps, the time required for each crystallization is short, and it can significantly improve the purity, making the entire purification process efficient and controllable, and further shortening the preparation cycle.

[0056] Cost reduction and good environmental friendliness

[0057] Low raw material cost: The raw materials and reagents used in this application are all common chemical substances, such as iopromide, hydroxyacetone, toluene, dimethyl sulfoxide, sulfuric acid, acetic acid, p-toluenesulfonic acid, boron trifluoride, etc., and the prices are relatively low. At the same time, the dosage is reasonable without waste, reducing the production cost.

[0058] Low equipment cost: Expensive equipment and consumables are not required during the synthesis process, and conventional laboratory equipment can meet the production needs, reducing the equipment investment cost.

[0059] Good environmental friendliness: During the synthesis process, this application does not use dangerous chemicals such as highly toxic and explosive substances, reducing the risk of harm to the environment and operators. The generated waste is less and easy to handle, meeting the modern environmental protection concept, facilitating green production, reducing the negative impact on the ecological environment, and meeting the requirements of sustainable development.

[0060] The above are only the preferred embodiments of the present invention, and do not limit the patent scope of the present invention. Any equivalent structural transformation made under the inventive concept of the present invention by using the content of the specification and drawings of the present invention, or any direct / indirect application in other related technical fields, is included in the patent protection scope of the present invention.

Claims

1. A method for synthesizing iopromide EP impurity F with high yield and high recovery rate, characterized in that, It includes the following steps: Step S1: Dissolve iopromide in an organic solvent, and add hydroxyacetone; Step S2: After stirring evenly, add a catalytic amount of acid, displace with nitrogen, and raise the temperature to 75°C - 95°C in an oil bath for reaction; Step S3: After the reaction is completed, pour the reaction solution into water, extract twice with ethyl acetate and twice with dichloromethane; Step S4: Discard the organic phase, and rotary evaporate the aqueous phase to dryness under vacuum; Step S5: Add a certain amount of water to the residue, and then add activated carbon for decolorization; Step S6: Filter, and rotary evaporate the filtrate again; Step S7: Add anhydrous ethanol to the residue, reflux for 2 - 4 h, then naturally cool to room temperature for crystallization, filter, add ethanol to the filter cake again, repeat the crystallization operation more than three times, and freeze-dry the obtained filter cake to obtain iopromide impurity F with a purity greater than 98%; 2. The method for synthesizing iopromide EP impurity F with high yield and high recovery rate according to claim 1, characterized in that, In Step S1, the organic solvent is a mixture of toluene and dimethyl sulfoxide, and the volume ratio of toluene to dimethyl sulfoxide is 1:1 - 3:

1.

3. The method for synthesizing iopromide EP impurity F with high yield and high recovery rate according to claim 1, characterized in that, In Step S1, the equivalent of hydroxyacetone is 1 - 1.

5.

4. The method for synthesizing iopromide EP impurity F with high yield and high recovery rate according to claim 1, characterized in that, In Step S2, the catalytic amount of acid is selected from one or more of sulfuric acid, acetic acid, p-toluenesulfonic acid, and boron trifluoride, and the equivalent is 0.1 - 0.

3.

5. The method for synthesizing iopromide EP impurity F with high yield and high recovery rate according to claim 1, characterized in that, In Step S3, the reaction time is 10 - 36 h.

6. The method for synthesizing iopromide EP impurity F with high yield and high recovery rate according to claim 1, characterized in that, In Step 5, the mass of the activated carbon is 0.3 - 2 times the mass of iopromide.

7. The method for synthesizing iopromide EP impurity F with high yield and high recovery rate according to claim 1, characterized in that, In Step S7, the crystallization solvent is selected from one or more of methanol, ethanol, and isopropanol, the reflux time is 2 - 4 h, and the crystallization operation is 3 - 5 times.

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