A method for deiodination of X-CT iodine series contrast agents and intermediates thereof

Abstract

The application discloses a method suitable for X-CT iodine series contrast agent and intermediates benzene ring deiodination, under alkaline conditions, with iron oxide powder as a catalyst, X-CT iodine series contrast agent and intermediates benzene ring iodine is hydrolyzed into free iodine ion. The application uses iron oxide powder as a catalyst to promote the alkaline hydrolysis of halogenated benzene, has the advantages of high deiodination efficiency of organic iodine (i.e. iodine atoms on the organic matter which has not been treated into free iodine ions), fast speed, low cost, small environmental pollution, safe and controllable process, etc. And because the iron oxide is relatively stable in the system, it can be continuously recycled and reused.

Description

Technical Field

[0001] This invention relates to a deiodination method, specifically a method applicable to the deiodination of benzene rings in X-CT iodine-based contrast agents and their intermediates. Background Technology

[0002] The wastewater and solid waste generated during the production of X-CT contrast agents and their intermediates contain significant amounts of aromatic iodinated compounds. Furthermore, the global annual consumption of iodine-based contrast agents exceeds tens of thousands of tons, meaning the amount of iodine used is also close to tens of thousands of tons. In addition, because iodine-based contrast agents are used at high concentrations in actual medical imaging and are largely not degraded after injection, they are almost directly excreted in urine. Therefore, the deiodination of aromatic iodinated compounds is not only suitable for iodine-based contrast agent manufacturers to recover iodine and save costs, but also for the recovery of iodine from the metabolites of contrast patients, such as urine containing high concentrations of contrast agents, indicating significant market value and potential.

[0003] Most common methods for deiodinizing iodinated aromatic compounds employ reduction methods, where the iodine on the benzene ring is reduced with a reducing agent to obtain iodide ions, which are then further oxidized to elemental iodine. However, this process has several drawbacks:

[0004] 1. Safety of reducing agents: In common processes, sodium hydrosulfite, hydrazine hydrate, zinc powder and other common strong reducing substances are used to reduce iodine in iodinated aromatic compounds. However, such reducing agents have some safety issues.

[0005] 2. The cost of reducing agents: Solving the deiodization process through reduction reactions requires a large amount of reducing agents, resulting in significant cost losses and potentially leading to losses during iodine recovery.

[0006] Another part of the deiodization process uses a more primitive strong acid or strong base hydrolysis method. This route involves forced hydrolysis to remove iodine in a high-temperature acid or base environment. The disadvantages of this process are that the reaction conditions are relatively extreme, the equipment requirements are high in the high-temperature environment of strong acid and strong base, the deiodization effect is not ideal, the deiodization rate (free iodide ions / benzene ring iodine × 100%) is low, there is no suitable catalyst that can be applied, and the cost is high. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a method for deiodination of benzene rings in X-CT iodine-based contrast agents and their intermediates, which is simple and thorough.

[0008] This invention discloses a method for deiodizing the benzene ring of X-CT iodine-based contrast agents and their intermediates. Under alkaline conditions, using iron oxide powder as a catalyst, the iodine on the benzene ring of the X-CT iodine-based contrast agents and their intermediates is hydrolyzed into free iodide ions. The structural formulas of the X-CT iodine-based contrast agents and their intermediates are shown in formula (Ⅰ), and the reaction formulas are shown in formula (1).

[0009]

[0010] When R, R1, R2, and R3 are different substituents, they correspond to different X-CT iodine-based contrast agents or their intermediates. For example, when R and R1 are -H and R2 and R3 are both -COOH, formula (Ⅰ) is 5-amino-2,4,6-triiodoisopeptide.

[0011] Furthermore, after hydrolysis to obtain free iodide ions, they are oxidized to elemental iodine by hydrogen peroxide and precipitated. After further processing, they are easy to collect.

[0012] Furthermore, the alkaline conditions for hydrolysis are pH ≥ 11.

[0013] Furthermore, the hydrolysis temperature is 60-100℃.

[0014] Furthermore, the hydrolysis temperature is 80-100℃.

[0015] Furthermore, the hydrolysis temperature is 80-90℃.

[0016] Furthermore, the weight of the iron oxide powder is 1-5% of the weight of the material to be treated. The iron oxide powder can be repeatedly recycled and reused in multiple batches.

[0017] Furthermore, the X-CT contrast agent is any one of iodofol, iopamidol, iohexol, iodixanol, iodiprin, iomethol, diatrizoate, iopromide, or iopamidol.

[0018] Further, the X-CT contrast agent intermediate is any one of 5-amino-2,4,6-triiodoisopeptidic acid, 5-amino-2,4,6-triiodoisopeptidyl chloride, N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopeptidamide, N,N'-bis(2,3-dihydroxypropyl)-5-acetylhydroxy-2,4,6-triiodoisopeptidamide, or N,N'-bis(2,3-dihydroxypropyl)-5-acetyl-2,4,6-triiodoisopeptidamide.

[0019] This invention uses iron oxide powder as a catalyst to promote the alkaline hydrolysis of halobenzenes. It offers advantages such as high efficiency and speed in removing iodine from organic iodine (i.e., iodine atoms on organic matter that have not yet been converted into free iodide ions), low cost, minimal environmental pollution, and safe and controllable process. Furthermore, because iron oxide is relatively stable in the system, it can be continuously recycled and reused. Detailed Implementation

[0020] The present invention will be further explained below with reference to the embodiments. The following embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0021] Example 1: Iodine recovery from iodipyline ((S)-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxypropyl)amino]-2,4,6-triiodo-1,3-phenylenediamide)

[0022] The hydrolysis reaction formula is shown in formula (2):

[0023]

[0024] 77.7 g (0.1 mol) of iopamidol was added to a 500 mL reaction flask, along with 310 g of water and 0.7 g of iron oxide powder. After stirring and heating to 80-85 °C, 30% sodium hydroxide solution was added dropwise to bring the pH of the reaction solution to 11-12. The reaction was stirred for 6 h, maintaining the pH of the reaction system at 11-12. After cooling to room temperature, the mixture was filtered, and the filter cake was set aside. The pH of the filtrate was adjusted to 2-3, and the temperature was raised to 65-70 °C. 10% hydrogen peroxide was added dropwise to the filtrate. At this point, the reaction flask turned reddish-brown. A small amount of nitrogen gas was introduced to blow off the iodine vapor and distill it into a condenser. The iodine vapor condensed into solid flakes of iodine, and 34 g of elemental iodine was collected, with an iodine yield of 89.24%.

[0025] Example 2: Iodine recovery from iodofol (N,N′ bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)(2-hydroxyethyl)amino]-2,4,6-triiodo-1,3-phenylenediamide)

[0026] The hydrolysis reaction is shown in equation (3):

[0027]

[0028] 80.7 g (0.1 mol) of iodophorol was added to a 500 mL reaction flask, along with 400 g of water and 0.8 g of iron oxide powder. The mixture was stirred and heated to 80-85 °C. Then, 30% sodium hydroxide solution was added dropwise to bring the pH of the reaction solution to 11-12. The mixture was kept at this temperature and stirred for 6 hours, maintaining the pH of the system at 11-12 throughout the reaction. After cooling to room temperature, the mixture was filtered. Hydrochloric acid was added dropwise to adjust the pH of the filtrate to 2-3. The temperature was then raised to 65-70 °C, and 10% hydrogen peroxide was added dropwise to the filtrate. At this point, the mixture in the reaction flask turned reddish-brown. A small amount of nitrogen gas was introduced to expel the iodine vapor into a condenser. The iodine vapor condensed into solid flakes of iodine. 35 g of elemental iodine was collected, resulting in an iodine yield of 91.36%.

[0029] Example 3: Iodine recovery from 5-amino-2,4,6-triiodoisopeptide

[0030] The hydrolysis reaction formula is shown in formula (4):

[0031]

[0032] 55.9 g (0.1 mol) of 5-amino-2,4,6-triiodoisopeptide was added to a 500 mL reaction flask, along with 350 g of water and 0.5 g of iron oxide powder. The mixture was stirred and heated to 80-85 °C. Then, 30% sodium hydroxide solution was added dropwise to bring the pH of the reaction solution to 11-12. The mixture was kept at this temperature and stirred for 4 hours, maintaining the pH of the system at 11-12 during the reaction. After cooling to room temperature, the mixture was filtered. Hydrochloric acid was added dropwise to adjust the pH of the filtrate to 2-3. The temperature was then raised to 70-75 °C, and 10% hydrogen peroxide was added dropwise to the filtrate. A small amount of nitrogen gas was introduced to blow the iodine vapor into a condenser. The iodine vapor condensed into solid flakes of iodine, and 36 g of elemental iodine was collected, resulting in an iodine yield of 94.44%.

[0033] Example 4: Iodine recovery from N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopeptide

[0034] The hydrolysis reaction formula is shown in formula (5):

[0035]

[0036] 70.5 g (0.1 mol) of N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopeptidamide was added to a 500 mL reaction flask, along with 420 g of water and 0.7 g of iron oxide powder. The mixture was stirred and heated to 90-95 °C. Then, 30% sodium hydroxide solution was added dropwise to bring the pH of the reaction solution to 11-12. The mixture was kept at this temperature and stirred for 3 hours, maintaining the pH of the system at 11-12 throughout the reaction. After cooling to room temperature, the mixture was filtered. Hydrochloric acid was added dropwise to adjust the pH of the filtrate to 2-3. The temperature was then raised to 60-70 °C, and 10% hydrogen peroxide was added dropwise to the filtrate. At this point, the reaction flask was filled with a purplish-red gas. A small amount of nitrogen was introduced to blow the iodine vapor into a condenser, where the iodine vapor condensed into solid flakes of iodine. 35.5 g of elemental iodine was collected, yielding an iodine yield of 93.18%.

[0037] In the above embodiments, the filtered filter cake was washed with water and reused. Repeating the operation resulted in a relatively constant iodine yield, indicating that the iron oxide powder could be reused for multiple batches. When used for 10 batches, the deiodination efficiency was not significantly affected.

Claims

1. A method for deiodinizing the benzene ring of iodine-based contrast agents and their intermediates in X-CT, characterized in that: Under alkaline conditions with pH ≥ 11, using iron oxide powder as a catalyst, the iodine on the benzene ring of X-CT iodine-based contrast agents and their intermediates is hydrolyzed into free iodide ions at a temperature of 60-100℃.

2. The method for deiodination of the benzene ring in X-CT iodine-based contrast agents and their intermediates according to claim 1, characterized in that: After hydrolysis to obtain free iodide ions, they are then oxidized with hydrogen peroxide to precipitate iodine.

3. The method for deiodination of the benzene ring in X-CT iodine-based contrast agents and their intermediates according to claim 1, characterized in that: The hydrolysis temperature is 80-100℃.

4. The method for deiodination of the benzene ring in X-CT iodine-based contrast agents and their intermediates according to claim 3, characterized in that: The hydrolysis temperature is 80-90℃.

5. The method for deiodination of the benzene ring in X-CT iodine-based contrast agents and their intermediates according to claim 1, characterized in that: The weight of the iron oxide powder is 1-5% of the weight of the material to be treated.

6. The method for deiodination of the benzene ring in X-CT iodine-based contrast agents and their intermediates according to claim 1, characterized in that: The X-CT iodine series contrast agents are any one of iodofol, iopamidol, iohexol, iodixanol, iodiprin, iomethol, diatrizoate, and iopromide.

7. The method for deiodination of the benzene ring in X-CT iodine-based contrast agents and their intermediates according to claim 1, characterized in that: The X-CT iodine-based contrast agent intermediate is any one of 5-amino-2,4,6-triiodoisopeptidic acid, 5-amino-2,4,6-triiodoisopeptidyl chloride, N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopeptidamide, N,N'-bis(2,3-dihydroxypropyl)-5-acetylhydroxy-2,4,6-triiodoisopeptidamide, or N,N'-bis(2,3-dihydroxypropyl)-5-acetyl-2,4,6-triiodoisopeptidamide.

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