Preparation method of iopromide EP impurity E
By optimizing the preparation method of iopromide EP impurity E, using acylation reaction, coupling reaction and alkaline hydrolysis, combined with nanocatalysts and optimization purification technology, the shortcomings of the preparation methods in the existing technology are solved, and high-efficiency and low-cost high-purity impurity preparation is achieved, which is suitable for the research and detection of iopromide impurities.
Patent Information
- Application Number
- CN202510395540.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-31
- Publication Date
- 2025-07-08
AI Technical Summary
The existing preparation method for iodopromide EP impurity E has problems such as cumbersome reaction steps, harsh reaction conditions, low yield and difficult purity to meet the requirements of high purity, which limits the research and quality control of iodoperamine impurities.
3-methoxyacetamide-5-(2,3-dihydroxyn-procarbamoyl)-2,4,6-triiodobenzoyl chloride was used as the raw material, and through acylation reaction, coupling reaction and alkaline hydrolysis, combined with nanocatalysts, bio-based protectors and optimized solvent systems, the reaction conditions were optimized, and the macroporous adsorption resin and anionic resin were used for purification, and finally recrystallized in ethanol.
The preparation of iopromide EP impurity E with high yield and high purity is achieved, with a purity of up to 99.81% and a yield of up to 28.33%. It is suitable for large-scale production, reduces production costs and operation difficulty, and provides high-quality impurity reference materials.
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Figure CN120271464A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a preparation method of iopromide EP impurity E. Background Art
[0002] Iopromide is a non-ionic low-osmolar contrast agent widely used in medical imaging, and it plays an important role in fields such as angiography, brain and abdominal CT scans, and urethrography. However, there are also potential risks of adverse reactions during the use of iopromide, such as systemic damage, respiratory system damage, and cardiovascular system damage. Therefore, quality control and impurity research of iopromide are crucial, especially the preparation method of its impurities, which is of great significance for carrying out research and detection of related impurities of iopromide.
[0003] Currently, there are few reports on the preparation method of iopromide EP impurity E at home and abroad. The existing preparation methods have many deficiencies, such as cumbersome reaction steps, harsh reaction conditions, low yields, and difficulty in achieving the requirements of high-purity impurity reference substances in terms of purity. These deficiencies limit the in-depth research on iopromide impurities and also bring difficulties to the quality control of iopromide.
[0004] In view of this, it is particularly urgent to develop a preparation method that is efficient, has a high yield, and can obtain high-purity iopromide EP impurity E. This not only helps to promote the progress of iopromide impurity research but also provides strong support for the quality control of iopromide, thereby ensuring the safety of patients' medication and promoting the healthy development of the pharmaceutical industry. Summary of the Invention
[0005] In view of the problems existing in the prior art, the present invention provides a preparation method of iopromide EP impurity E.
[0006] To achieve the above object, the present invention provides a preparation method of iopromide EP impurity E, comprising the following steps:
[0007] Step S1: Using 3-methoxyacetamido-5-(2,3-dihydroxypropylcarbamoyl)-2,4,6-triiodobenzoyl chloride as a raw material, after dissolving it in an organic solvent and adding a catalyst, reacting with an acylating reagent to obtain an intermediate product;
[0008] Step S2: Dissolving the intermediate product obtained in Step S1 in Solvent II, adding a base and stirring, then adding iopromide, and reacting to obtain a precursor compound of iopromide EP impurity E;
[0009] Step S3: Subjecting the precursor compound of iopromide EP impurity E obtained in Step S2 to alkaline hydrolysis, extracting with an organic solvent, then adjusting the pH of the aqueous layer to acidic, and precipitating a solid to obtain iopromide EP impurity E.
[0010] Preferably, the acylating agent in step S1 is selected from one or more of acetic anhydride and acetyl chloride,
[0011] Preferably, the catalyst in step S1 is selected from DMAP or a nanocatalyst, and the nanocatalyst is selected from one or more of gold nanoparticles, silver nanoparticles, and metal oxide nanoparticles; the organic solvent is ethyl acetate.
[0012] Preferably, the molar ratio of the intermediate product to iopromide in step S2 is 1:1.5;
[0013] Preferably, the solvent two is selected from one or more of DMF, ACN, DMSO, DCM, and THF; the base is selected from one or more of DIEA, TEA, and K2CO3.
[0014] Preferably, the base used for alkaline hydrolysis in step S3 is NaOH, and the pH of the aqueous layer is adjusted to 2-4.
[0015] Preferably, in step S1, the reaction temperature is 80 °C and the reaction time is 4-6 h.
[0016] Preferably, in step S2, the reaction temperature is room temperature and the reaction time is 2 to 6 h.
[0017] Preferably, in step S3, the reaction time for the alkaline hydrolysis is 4-6 h.
[0018] Preferably, before step S1, there is also a step of pre-treating the raw materials, and the pre-treatment includes modifying the raw materials with a bio-based protecting agent (such as chitosan, cellulose derivatives, or tannic acid) to improve the reaction activity and selectivity.
[0019] Adopting the technical solution of the present invention has the following beneficial effects:
[0020] The present invention provides a method for preparing iopromide-related impurities with high yield and high purity. This method is simple to operate and the raw materials are easily available. The prepared 3-(3-(2,3-dihydroxypropyl)carbamoyl)-2,4,6-triiodo-5-(2-methoxyacetamide)-N-methylbenzamide)-2-hydroxypropyl 3-(2,3-dihydroxypropyl)carbamoyl)-2,4,6-triiodo-5-(2-methoxyacetamide)benzoate is more than 98%, all meeting the requirements as an impurity reference substance, and playing a positive role in the research and inspection of iopromide-related impurities.
[0021] By optimizing the reaction conditions and selecting appropriate catalysts and solvents, the present invention can efficiently synthesize iopromide EP impurity E. The purity of the final product can reach 99.81%, and the highest yield can reach 28.33%, which significantly outperforms the common problems of low purity and low yield in the prior art and can provide high-quality reference substances for the research and detection of iopromide impurities.
[0022] The present invention adopts mild conditions of 80 °C or room temperature in the acylation reaction, avoiding the equipment requirements and safety hazards brought by high temperature and high pressure. The coupling reaction is carried out at 0 °C and then raised to room temperature, effectively controlling the reaction rate and reducing the occurrence of side reactions. These mild reaction conditions not only improve the reaction selectivity and product purity but also reduce the production cost and operation difficulty.
[0023] The preparation method of the present invention has clear operation steps and does not require complex equipment and cumbersome purification processes. For example, purification is carried out through macroporous adsorption resin and anion and cation resins, and finally recrystallization in ethanol can obtain high-purity iopromide EP impurity E. This method is easy to operate, suitable for large-scale production, reduces the production cost, and improves the production efficiency.
[0024] The present invention is not only applicable to the preparation of iopromide EP impurity E but also can be extended to the synthesis of other complex organic compounds. For example, by adjusting the catalyst and solvent system, similar amide compounds can be synthesized, having broad application prospects.
[0025] By optimizing the reaction conditions and increasing the yield, the present invention significantly reduces the production cost. For example, by increasing the dosage of DMAP and using DMSO as the solvent, the reaction efficiency and product yield are further improved, and the production cost per unit product is reduced.
[0026] The reaction conditions adopted by the present invention are mild, avoiding the safety hazards brought by high temperature and high pressure. At the same time, by optimizing the reaction steps, the occurrence of side reactions is reduced, and the operation risk is lowered. For example, using DIEA as the base for the coupling reaction (Example 1) is milder than using K2CO3 (Examples 2 and 3), further improving the reaction safety.
[0027] The preparation method of the present invention has high innovation. By introducing nano-catalysts, biocatalysts, and advanced purification technologies, etc., the reaction selectivity and efficiency are significantly improved, while the purification steps are simplified and the purification cost is reduced. In addition, the preparation method of the present invention is not only applicable to the preparation of iopromide EP impurity E but also can be extended to the synthesis of other complex organic compounds, having broad application prospects.
[0028] The present invention also introduces bio-based protectants (such as chitosan, cellulose derivatives or tannic acid) to modify the raw materials, which improves the activity and selectivity of the reaction and reduces the environmental impact at the same time.
[0029] Through the verification of Specific Examples 1, 2 and 3, the preparation method of the present invention can efficiently synthesize high-purity Iopromide EP Impurity E under different conditions. In Example 1, the product purity reached 99.81% and the yield was 27.15%; in Example 2, the product purity was 99.5% and the yield was 28.33%; in Example 3, the product purity was 99.3% and the yield was 26.67%. These data fully demonstrate the high efficiency and reliability of the method of the present invention. Brief Description of the Drawings
[0030] Figure 1 It is a schematic diagram of the synthesis route of the present invention;
[0031] Figure 2 It is a nuclear magnetic schematic diagram of the present invention;
[0032] Figure 3 It is a mass spectrum schematic diagram of the present invention;
[0033] Figure 4 It is a high performance liquid chromatography schematic diagram of the present invention. Detailed Description of the Invention
[0034] The present invention will be further described below in conjunction with the drawings and specific examples.
[0035] Example 1:
[0036] Referring to Figures 1 to 4 , the present invention provides a preparation method of Iopromide EP Impurity E, comprising the following steps:
[0037] Step S1: Acylation reaction
[0038] Dissolve 3 g of Iopromide intermediate 3-methoxyacetamido-5-(2,3-dihydroxypropylcarbamoyl)-2,4,6-triiodobenzoyl chloride in ethyl acetate, add 2 equivalents of DMAP (1.01 g), stir for 10 min, then dropwise add 3 equivalents of acetic anhydride (1.27 g), raise the temperature to 80 °C and react for 5 h, then quench with absolute ethanol. After cooling, a white solid precipitates, which can be directly used for the next step of the reaction;
[0039] Step S2: Coupling reaction
[0040] Dissolve the white solid obtained in the above steps in DMF, add DIEA and stir for 30 min. Then, slowly add iopromide (1.5 g equivalent) at 0 °C. After the addition is complete, raise the temperature to room temperature and continue the reaction. Monitor the reaction progress by HPLC until the product no longer increases. Filter and concentrate the reaction solution, add ether and stir to precipitate a solid, and purify to obtain the precursor compound of iopromide EP impurity E;
[0041] Step S3: Alkaline hydrolysis
[0042] Place the precursor compound of iopromide EP impurity E in a 250 mL three-necked flask, add 50 mL of water, stir and dissolve at room temperature, then add 15 mL of 2 mol / L NaOH and continue to stir at room temperature for 5 h. After sampling and detecting by HPLC, filter the reaction solution to remove insoluble impurities. Dilute the filtrate with water and adjust the pH to 6.0 - 7.0 with concentrated HCl. Purify the reaction solution through macroporous adsorption resin and anion and cation resins to obtain the crude product of iopromide EP impurity E. Finally, recrystallize in ethanol solvent to obtain 1.65 g of iopromide EP impurity E (yield 27.15%), with a purity of 99.81%. Refer to Figures 2 to 4 , and confirm iopromide EP impurity E by NMR, mass spectrometry and high performance liquid chromatography:
[0043] MS (M / Z): 1477.6 (M + H)+, 1499.6 (M + Na)+
[0044] 1 1H NMR (400 MHz, DMSO-d6) δ 10.12 - 10.01 (m, 2H), 8.59 (d, J = 12 Hz, 2H), 5.23 (d, J = 7.5 Hz, 1H), 4.69 (d, J = 4.1 Hz, 2H), 4.66 (d, J = 3.9 Hz, 2H), 4.51 - 4.47 (m, 2H), 4.01 (s, 5H), 3.47 (s, 3H), 3.32 - 3.27 (m, 16H), 3.07 (d, J = 4 Hz 1H).
[0045] Example 2
[0046] Step S1: Acylation reaction
[0047] Dissolve iopromide intermediate 3-methoxyacetamido-5-(2,3-dihydroxypropylcarbamoyl)-2,4,6-triiodobenzoyl chloride (3 g) in ethyl acetate, add 3 equivalents of DMAP (1.51 g) and stir for 10 min. Then, dropwise add 4 equivalents of acetic anhydride (1.69 g), raise the temperature to 80 °C and react for 5 h. Quench with anhydrous ethanol, and a white solid will precipitate after cooling, which can be directly used for the next step;
[0048] Step S2: Coupling Reaction
[0049] Dissolve the white solid obtained in the above step in DMSO, add K2CO3, stir for 30 min, then slowly add iopromide (1.5 equivalents) at 0 °C. After the addition is complete, raise the temperature to room temperature and react. Monitor the reaction by HPLC. Stop the reaction when the product no longer increases. Filter and concentrate the reaction solution. Add ether and stir to precipitate a solid. Purify to obtain the precursor compound of iopromide EP impurity E.
[0050] Step S3: Alkaline Hydrolysis
[0051] Place the precursor compound of iopromide EP impurity E in a 250 mL three-necked flask, add 50 mL of water, stir to dissolve at room temperature, then add 15 mL of 2 mol / L NaOH solution and stir at room temperature for 5 hours.
[0052] After the reaction is completed, take a sample and detect it by HPLC. Filter the reaction solution to remove insoluble impurities. Dilute the filtrate with water and adjust the pH to 6.0 - 7.0 with concentrated HCl. Purify the reaction solution with macroporous adsorption resin and anion and cation resins to obtain the crude product of iopromide EP impurity E. Finally, recrystallize in ethanol solvent to obtain 1.70 g of iopromide EP impurity, with a product purity of 99.5% and a yield of 28.33%.
[0053] Example 3
[0054] Step S1: Acylation Reaction
[0055] Dissolve iopromide intermediate 3-methoxyacetamido-5-(2,3-dihydroxypropylcarbamoyl)-2,4,6-triiodobenzoyl chloride (3 g) in ethyl acetate, add 3 equivalents of TEA (1.51 g), stir for 10 min, then dropwise add 3 equivalents of acetyl chloride (1.25 g). React at room temperature for 5 h, then quench with anhydrous ethanol. A white solid precipitates after cooling.
[0056] Step S2: Coupling Reaction
[0057] Dissolve the white solid obtained in the above step in ACN, add K2CO3, stir for 30 min, then slowly add iopromide (1.5 equivalents) at 0 °C. After the addition is complete, raise the temperature to room temperature and react. Monitor the reaction by HPLC. Stop the reaction when the product no longer increases. Filter and concentrate the reaction solution. Add ether and stir to precipitate a solid. Purify to obtain the precursor compound of iopromide EP impurity E.
[0058] Step S3: The iopromide EP impurity E precursor compound is placed in a 250mL three-necked flask, 50mL of water is added, and after stirring and dissolving at room temperature, 15mL of 2mol / L NaOH solution is added, and stirred at room temperature for 5 hours. After the reaction is completed, sampling is detected by HPLC, the reaction solution is filtered to remove insoluble impurities, and the filtrate is diluted with water, and the pH is adjusted to 6.0-7.0 with concentrated HCl. The reaction solution is purified by macroporous adsorption resin and anionic and cationic resin to obtain iopromide EP impurity E crude product, and finally recrystallized in ethanol solvent to obtain iopromide EP impurity E1.60g, the product purity is 99.3%, and the yield is 26.67%.
[0059] As can be seen from the above embodiments, the present invention provides a method for preparing iopromide-related impurities with high yield and high purity. The method is simple to operate and the raw materials are convenient and easy to obtain. More than 98% of 3-(3-(2,3-dihydroxypropyl)carbamoyl)-2,4,6-triiodo-5-(2-methoxyacetamide)-N-methylbenzamide)-2-hydroxypropyl 3-(2,3-dihydroxypropyl)carbamoyl)-2,4,6-triiodo-5-(2-methoxyacetamide)benzoate is obtained, which meets the requirements of being used as an impurity reference substance and plays a positive role in the research and inspection of iopromide-related impurities.
[0060] The present invention can efficiently synthesize iopromide EP impurity E by optimizing reaction conditions and selecting suitable catalysts and solvents. The purity of the final product can reach 99.81%, and the yield can reach up to 28.33%, which is significantly better than the common low purity and low yield problems in the prior art, and can provide a high-quality reference substance for the research and detection of iopromide impurities.
[0061] The present invention adopts mild conditions of 80°C or room temperature in the acylation reaction, avoiding the equipment requirements and safety hazards caused by high temperature and high pressure. The coupling reaction is carried out at 0°C and then raised to room temperature, which effectively controls the reaction rate and reduces the occurrence of side reactions. These mild reaction conditions not only improve the selectivity of the reaction and the purity of the product, but also reduce the production cost and operation difficulty.
[0062] The preparation method of the present invention has clear operation steps and does not require complicated equipment and cumbersome purification process. For example, purification is performed by macroporous adsorption resin and anion and cation resin, and finally recrystallization is performed in ethanol to obtain high-purity iopromide EP impurity E. This method is easy to operate, suitable for large-scale production, reduces production costs, and improves production efficiency.
[0063] The present invention is not only applicable to the preparation of iopromide EP impurity E, but can also be extended to the synthesis of other complex organic compounds. For example, by adjusting the catalyst and solvent system, similar amide compounds can be synthesized, which has broad application prospects.
[0064] By optimizing the reaction conditions and increasing the yield, the present invention significantly reduces the production cost. For example, by increasing the amount of DMAP used and using DMSO as the solvent, the reaction efficiency and the product yield are further improved, and the production cost per unit product is reduced.
[0065] The reaction conditions adopted in the present invention are mild, avoiding the safety hazards brought by high temperature and high pressure. At the same time, by optimizing the reaction steps, the occurrence of side reactions is reduced, and the operation risk is lowered. For example, using DIEA as the base for the coupling reaction (Example 1) is milder than using K2CO3 (Examples 2 and 3), further improving the safety of the reaction.
[0066] The preparation method of the present invention has high innovation. By introducing nano-catalysts, biocatalysts, and advanced purification technologies, etc., the selectivity and efficiency of the reaction are significantly improved. At the same time, the purification steps are simplified and the purification cost is reduced. In addition, the preparation method of the present invention is not only applicable to the preparation of iopromide EP impurity E, but also can be extended to the synthesis of other complex organic compounds, having a wide application prospect.
[0067] The present invention also introduces bio-based protecting agents (such as chitosan, cellulose derivatives, or tannic acid) to modify the raw materials, improving the reactivity and selectivity of the reaction, and at the same time reducing the impact on the environment.
[0068] Through the verification of Specific Examples 1, 2, and 3, the preparation method of the present invention can efficiently synthesize high-purity iopromide EP impurity E under different conditions. In Example 1, the product purity reaches 99.81%, and the yield is 27.15%; in Example 2, the product purity is 99.5%, and the yield is 28.33%; in Example 3, the product purity is 99.3%, and the yield is 26.67%. These data fully prove the high efficiency and reliability of the method of the present invention.
[0069] The above are only the preferred embodiments of the present invention, and do not limit the patent scope of the present invention accordingly. 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 directly / indirectly applied in other related technical fields, is included in the patent protection scope of the present invention.
Claims
1. A method for preparing iopromide EP impurity E, characterized in that, Comprising the following steps: Step S1: Using 3-methoxyacetamido-5-(2,3-dihydroxypropylcarbamoyl)-2,4,6-triiodobenzoyl chloride as a raw material, dissolving it in an organic solvent, adding a catalyst, and reacting with an acylating agent to obtain an intermediate product; Step S2: Dissolving the intermediate product obtained in Step S1 in Solvent 2, adding a base and stirring, then adding iopromide, and reacting to obtain a precursor compound of iopromide EP impurity E; Step S3: Subjecting the precursor compound of iopromide EP impurity E obtained in Step S2 to alkaline hydrolysis, extracting with an organic solvent, adjusting the pH of the aqueous layer to acidic, and precipitating a solid to obtain iopromide EP impurity E.
2. The preparation method of iopromide EP impurity E according to claim 1, characterized in that, The acylating agent in Step S1 is selected from one or more of acetic anhydride and acetyl chloride.
3. The preparation method of iopromide EP impurity E according to claim 1, characterized in that, The catalyst in Step S1 is selected from DMAP or a nanocatalyst, and the nanocatalyst is selected from one or more of gold nanoparticles, silver nanoparticles, and metal oxide nanoparticles; the organic solvent is ethyl acetate.
4. The preparation method of iopromide EP impurity E according to claim 1, characterized in that, The molar ratio of the intermediate product to iopromide in Step S2 is 1:1.
5.
5. The method for preparing iopromide EP impurity E according to claim 1, wherein Solvent 2 is selected from one or more of DMF, ACN, DMSO, DCM, and THF, and the base is selected from one or more of DIEA, TEA, and K2CO3.
6. The preparation method of iopromide EP impurity E according to claim 1, characterized in that, The base used for alkaline hydrolysis in Step S3 is NaOH, and the pH of the aqueous layer is adjusted to 2-4.
7. The preparation method of iopromide EP impurity E according to claim 1, characterized in that, In Step S1, the reaction temperature is 80°C and the reaction time is 4-6 h.
8. The preparation method of iopromide EP impurity E according to claim 1, characterized in that, In Step S2, the reaction temperature is room temperature and the reaction time is 2 to 6 h.
9. The preparation method of iopromide EP impurity E according to claim 1, characterized in that, In Step S3, the reaction time for alkaline hydrolysis is 4-6 h.
10. The preparation method according to claim 1, characterized in that, Before Step S1, there is also a step of pre-treating the raw material, and the pre-treatment includes modifying the raw material with a bio-based protecting agent to improve the reaction activity and selectivity.