A method for removing an iodinated contrast agent impurity

Abstract

This invention relates to a method for removing the impurity 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-phenylenediamide (compound of formula 1) from the X-ray contrast agent iodofol, with the structural formula: The method utilizes a strongly basic anion exchange resin to selectively adsorb this impurity, achieving excellent results and contributing to the improvement of the purity and yield of iodofol.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, and specifically relates to a method for removing iodofol impurities. Background Technology

[0002] Ioforol is a nonionic iodine-based contrast agent, developed by Valencia Corporation in 1982 (Ioversol, trade name Optiray). Its chemical name is N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-hydroxyacetamido]-2,4,6-triiodo-1,3-phenylenediamide, and its structural formula is as follows:

[0003] .

[0004] Ioflufenicol has advantages such as high water solubility, low viscosity, low osmotic pressure, and low incidence of adverse reactions. Its formulation, ioflufenicol injection, can be widely used for angiography, arthrography, urography, and head, thoracic, and cervical spine angiography. However, the dosage of ioflufenicol used in angiography is very large (33.9g / 50ml), and as an intravenous injection drug, its purity requirements are very high for safety reasons. Therefore, it is essential to study methods for removing impurities from ioflufenicol.

[0005] There are two main methods for preparing iodofol reported in the literature:

[0006] 1. According to patent US4396598, the preparation route is shown in reaction formula 1:

[0007] .

[0008] 2. According to patent US5648536, the preparation route is shown in reaction formula 2:

[0009] .

[0010] By comparison, the two routes employ different methods for the acylation reaction: reaction 1 uses acetoxyacetyl chloride, while reaction 2 uses chloroacetyl chloride. However, the final step is the same: alkylation of 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-phenylenediamide with chloroethanol to yield iodofol. Therefore, the residual amount of 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-phenylenediamide is directly carried into the crude iodofol and is one of the main impurities in iodofol. The alkylation reaction is carried out under strongly alkaline conditions, and the reaction rate is very slow in the later stages. It is difficult for 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-phenylenediamide to react to a concentration below 1%. If the reaction time is extended, the reaction temperature is increased, or the amount of chloroethanol is increased, it can be further reduced to a concentration below 0.5%, but this will significantly increase other side reactions, such as Smiles rearrangement impurities (US5204005), and other N-alkylation and O-alkylation impurities generated by excess chloroethanol (CN115806500A), which increases the total amount of impurities and is not worth the effort. Ultimately, this makes the purification of iodofol difficult.

[0011] There are many reports on the purification of iodofol, but the main methods with promising industrial applications are solvent recrystallization and macroporous resin column purification (CN114478298). However, the properties of impurities in iodofol are very similar to those of iodofol itself; it is highly water-soluble and insoluble in most organic solvents, making it difficult to obtain pharmaceutically acceptable iodofol using recrystallization alone. Macroporous resin column purification is a commonly used industrial production method for non-ionic contrast agents, and it can yield iodofol with high purity. However, it also requires that the crude product contain as few impurities as possible, especially difficult-to-separate impurities, otherwise the purification yield will be low. 5-Hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-phenylenediamide has a very similar HPLC chromatogram to iodofol, and is an impurity that is difficult to separate from iodofol (HPLC chromatogram attached). Figure 1 ). Summary of the Invention

[0012] This invention provides a method for removing the impurity 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-phenylenediamide from iodofol. Specifically, this method involves treating an aqueous solution of crude iodofol with an anion exchange resin to remove the impurity. After purification using this method, the content of 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-phenylenediamide is less than 0.03%, making subsequent purification of iodofol easier, resulting in higher purification yields and easier control over formulation quality.

[0013] Even more advantageously, once 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-phenylenediamide is no longer a difficult-to-separate impurity, its residual amount can be greatly increased. The process conditions of this alkylation reaction can be optimized, such as shortening the reaction time, lowering the temperature, and reducing the amount of chloroethanol used, in order to reduce impurities generated by other side reactions and greatly alleviate the difficulty of subsequent purification.

[0014] This invention is based on a careful study of the molecular structure of 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-phenylenediamide, suggesting that the hydrogen in the 5-hydroxyacetamido group possesses weak acidic properties and can be removed through exchange adsorption with a strongly basic anion exchange resin. Before conducting the adsorption experiment, any anions or cations that may be present in the solution, such as salts, need to be removed beforehand; otherwise, the experimental results will be affected. The experimental results have verified the correctness of this hypothesis.

[0015] The technical solution of this invention is as follows: an aqueous solution of crude iodofol is adsorbed through a strongly alkaline anion exchange resin and then eluted with an eluent to obtain an iodofol solution containing almost no impurities, namely 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-phenylenediamide.

[0016] Furthermore, the strongly basic anion exchange resin contains a quaternary ammonium group -NR3OH (R is a hydrocarbon group), and the selected models are Diaion SA10A, Diaion PA308, Diaion PA408, Purolite A500, Amberjet 4200CL, Amberlite IRA458 CL, Amberlite IRA9000CL, 201*7(717), and Dowex SBR, preferably Diaion PA308 and Amberlite IRA9000CL.

[0017] The adsorption is carried out by a strongly alkaline anion exchange resin, and either static adsorption or dynamic adsorption can be selected, with dynamic adsorption being preferred.

[0018] The eluent is water or an aqueous solution containing a certain amount of solvent, including one or more of methanol, ethanol, isopropanol, n-butanol, or acetonitrile. Preferably, the eluent is a 5% aqueous methanol solution.

[0019] The amount of the strongly basic anion exchange resin is 0.2 to 2 times the weight of the solute iodofol, preferably 0.5 to 1 times.

[0020] The amount of the eluent is 3 to 12 times the weight of iodofol, preferably 6 to 9 times.

[0021] The present invention provides a simple and effective method for removing the impurity 5-hydroxyacetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-phenylenediamide from iodofol. This method achieves a high iodofol recovery rate, significantly reduces the purification difficulty of iodofol, improves the purification yield, and allows for continuous operation, making it suitable for large-scale industrial production. Attached Figure Description

[0022] Figure 1 This is a high-performance liquid chromatogram of crude iodofol. Detailed Implementation

[0023] The present invention will be further explained below with reference to the embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of implementation of the present invention.

[0024] Iodophorol crude product was prepared according to the reference. All anion exchange resins were commercially available. Before use, they were soaked in sodium hydroxide aqueous solution to convert them into hydroxide form.

[0025] Example 1

[0026] 50g of Diaion PA308 anion exchange resin was packed into a glass chromatography column, and an aqueous solution of iodofol (containing 50g of iodofol and 2.5% of Formula 1 impurities) was added while eluting. After elution with 300g of 5% methanol-water solution, the eluent was collected and the content was analyzed by high performance liquid chromatography (HPLC). The Formula 1 impurity was found to be 0.005%, and the recovery rate of iodofol was 99.1%.

[0027] Example 2

[0028] 50g of Amberlite IRA9000CL anion exchange resin was packed into a glass chromatography column, and an aqueous solution of iodofol (containing 70g of iodofol and 2.5% of Formula 1 impurities) was added while eluting. After elution with 450g of water, the eluent was collected and the content was analyzed by high performance liquid chromatography (HPLC). The Formula 1 impurity was found to be 0.02%, and the recovery rate of iodofol was 98.5%.

[0029] Example 3

[0030] 20g of anion exchange resin Amberjet 4200CL was added to an aqueous solution of iodofol (containing 50g of iodofol and 2.5% of Formula 1 impurities). After addition, the solution was stirred for 0.5 hours and then allowed to stand for 2 hours. The solution was then filtered, and the filtrate was collected. The content of the filtrate was analyzed by high performance liquid chromatography (HPLC). The result showed that the Formula 1 impurity was 0.03% and the recovery rate of iodofol was 99.3%.

Claims

1. A method for removing an iodinated contrast agent impurity, characterized by: The anions and cations in the iodinated iodipamide crude aqueous solution are removed in advance, and then the solution is adsorbed by a strong basic anion resin, the type of the strong basic anion resin is Diaion PA308, Amberjet 4200CL, Amberlite IRA9000CL; then eluted by an eluent to obtain an iodinated iodipamide solution containing almost no impurity 5-hydroxyacetylamino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide.

2. The method of claim 1, wherein: The strong basic anion resin is adsorbed by static adsorption or dynamic adsorption.

3. The method of claim 1, wherein: The eluent is water, or an aqueous solution containing one or more of methanol, ethanol, isopropanol, n-butanol or acetonitrile.

4. The method of claim 1, wherein: The amount of the strong basic anion resin is 0.2 to 2 times the weight of iodinated iodipamide.

5. The method of claim 1, wherein: The amount of the eluent is 3 to 12 times the weight of iodinated iodipamide.

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