Process for the preparation of an iomeprol intermediate

Abstract

The present application relates to a kind of preparation method of iodine meglumine intermediate 5-methylamino-2,4,6-triiodoisophthalic acid (compound of formula 1), structural formula, the compound of this method is prepared 5-methylamino-2,4,6-triiodoisophthalic acid in mixed acid reaction, avoid the use of large amount of sulfuric acid, reduce the generation of dimethylated impurities, process is simpler, solvent can be recycled, the yield of prepared 5-methylamino-2,4,6-triiodoisophthalic acid is high, purity is good, suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, more particularly relates to a preparation method of 5-methylamino-2,4,6-triiodoisophthalic acid, an intermediate of iomeprol. BACKGROUND

[0002] Iomeprol is a non-ionic X-ray contrast agent developed by Bracco Company in Italy, which can be widely used in intravascular, subarachnoid and body cavity imaging. It was approved for marketing in Italy in May 1993 and in the United Kingdom in December 1992. Compared with the same type of non-ionic contrast agent on the market (such as iohexol, iopamidol and ioversol, etc.), iomeprol has the lowest osmotic pressure and lower viscosity at the same concentration, and can be prepared into a high-concentration preparation of up to 400 mg (I) / ml, and has more excellent imaging effect. Therefore, iomeprol has a broad potential application market.

[0003] 5-methylamino-2,4,6-triiodoisophthalic acid is an important intermediate for preparing iomeprol. The prior art scheme (see patent WO200947319) uses concentrated sulfuric acid as a solvent, the amount of concentrated sulfuric acid is 7.36 times the weight of 5-amino-2,4,6-triiodoisophthalic acid, and then reacts with a methylating agent 38% formaldehyde aqueous solution. After the reaction is completed, a large amount of water is added to precipitate the product. The use of a large amount of concentrated sulfuric acid generates a large amount of dilute sulfuric acid wastewater, which is difficult to treat.

[0004] Chinese patent CN104356023 improves the above technical scheme, uses polyformaldehyde as a methylating agent, and reacts in a mixed solvent of methanol and concentrated sulfuric acid. After the reaction is completed, a large amount of water is also added to precipitate crystals, and then methanol water is used for refining. This method reduces the amount of concentrated sulfuric acid, but the amount of concentrated sulfuric acid still reaches 1.3-1.8 times the weight of 5-amino-2,4,6-triiodoisophthalic acid. After adding water to precipitate crystals, a large amount of dilute sulfuric acid wastewater is still generated. In addition, 5-amino-2,4,6-triiodoisophthalic acid and methanol will inevitably produce 5-amino-2,4,6-triiodoisophthalic acid methyl ester impurities under the catalysis of sulfuric acid, which affects the yield and purity of the product. The highest yield reported in this patent is 87%.

[0005] In summary, the existing technical methods for preparing 5-methylamino-2,4,6-triiodoisophthalic acid cannot avoid the use of concentrated sulfuric acid, and a large amount of dilute sulfuric acid wastewater is generated. The yield and purity are also not satisfactory. SUMMARY

[0006] In view of the deficiencies of the prior art, the present application provides a preparation method of iomeprol intermediate 5-methylamino-2, 4, 6-triiodoisophthalic acid. The present inventors found that the amino group in 5-amino-2, 4, 6-triiodoisophthalic acid can be easily methylated by using the classical formic acid / formaldehyde reaction system, but there are many dimethylated by-products. When the existing process technology is repeated and optimized, it is also found that a large amount of concentrated sulfuric acid is important for the reaction, and reducing the amount or concentration of concentrated sulfuric acid will also increase the dimethylated by-products, which may be another reason for the low yield of patent CN104356023.

[0007] The present inventors found through a large number of theoretical and experimental comparative studies that after the amino group in 5-amino-2, 4, 6-triiodoisophthalic acid is monomethylated, the nucleophilicity of the nitrogen atom is stronger, and it is easier to be methylated to obtain dimethylated product. However, in a large amount of strong acid environment, the monomethylated amino group is passivated by accepting the proton of the acid, and it is difficult to be methylated to obtain dimethylated product. On this basis, the present inventors add other acids to the formic acid solution, and find that only strong acid can passivate the methylated amino group to prevent the generation of dimethylated product, and the stronger the acidity and the smaller the steric hindrance of the acid, the smaller the amount of strong acid required. The inventors surprisingly found that the amount of strong acid required is only slightly greater than the equimolar amount of 5-amino-2, 4, 6-triiodoisophthalic acid, which can prevent the generation of dimethylated product, and the generated 5-methylamino-2, 4, 6-triiodoisophthalic acid can be cooled and precipitated from the formic acid system, and the product can be obtained by filtration, greatly simplifying the post-treatment process. The formic acid can also be recovered by distillation and reused, greatly reducing the amount of wastewater discharge and the difficulty of treatment.

[0008] Therefore, the present application actually provides an improved method for preparing 5-methylamino-2, 4, 6-triiodoisophthalic acid, which is realized by the following scheme: dissolving 5-amino-2, 4, 6-triiodoisophthalic acid in a mixed acid composed of formic acid and another strong acid, then adding a methylation reagent, cooling and crystallizing after the reaction is completed, and filtering to obtain 5-methylamino-2, 4, 6-triiodoisophthalic acid. The chemical equation of the present application is:

[0009] .

[0010] According to the above scheme, the strong acid is trifluoromethanesulfonic acid, perchloric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid or nitric acid, preferably hydrochloric acid, and the molar ratio of the strong acid to 5-amino-2, 4, 6-triiodoisophthalic acid is 1-3:1, preferably 1.5-2:1.

[0011] According to the above scheme, the methylation reagent is 35-38% formaldehyde aqueous solution or paraformaldehyde, and the molar ratio of 35-38% formaldehyde aqueous solution or paraformaldehyde to 5-amino-2, 4, 6-triiodoisophthalic acid is 5-15:1, preferably 8-12:1.

[0012] According to the above scheme, the reaction temperature is 50-120°C, preferably 50-80°C; the reaction time is 6-15h, preferably 8-12h; and the cooling temperature is 0-30°C, preferably 0-10°C.

[0013] The present application has the following beneficial effects:

[0014] 1. The use of a large amount of concentrated sulfuric acid is completely avoided, the safety hazard of using concentrated sulfuric acid is eliminated, and a large amount of dilute sulfuric acid wastewater does not need to be treated again;

[0015] 2. The mixed acid composed of formic acid and strong acid is creatively used as the reaction medium, the amount of strong acid is at most 0.5 times the weight of 5-amino-2, 4, 6-triiodoisophthalic acid, formic acid can be recycled and used, and a large amount of water does not need to be added for dilution, the acid waste liquid is greatly reduced compared to the current process, and the difficulty and cost of waste liquid treatment are greatly reduced;

[0016] 3. The process is simple and easy to implement, the product yield is high (more than 90%) after cooling and crystallization after reaction, the purity is good (HPLC purity is more than 99%), and further solvent refining is not needed. DETAILED DESCRIPTION

[0017] The present application will be further explained below in combination with examples, and the examples of the present application are only used to illustrate the technical solutions of the present application, and are not intended to limit the implementation range of the present application.

[0018] Example 1:

[0019] In a 1000ml three-necked flask, add formic acid 400ml and 35% hydrochloric acid 14g, stir and heat to 50°C, add 5-amino-2, 4, 6-triiodoisophthalic acid 50g, then slowly add 37% formaldehyde aqueous solution 72.4g, heat to 60°C after adding, and react for 8h. After the reaction is completed, cool the reaction liquid to about 5°C, stir for 1h, then filter, wash the filter cake with a small amount of water, and dry at 60°C under reduced pressure for 8h to obtain grayish white 5-methylamino-2, 4, 6-triiodoisophthalic acid solid 48.2g, with a yield of 94.0% and a purity of 99.5%.

[0020] Example 2:

[0021] In 1000ml three-necked flask, add formic acid 400ml and 35% hydrochloric acid 18.7g, stirring to warm to 50℃, add 5-amino-2,4,6-triiodoisophthalic acid 50g, then slowly add paraformaldehyde 32.1g, after adding, warm to 80℃ and react for 9h. After the reaction is completed, cool the reaction liquid to about 5℃, stir for 1h, then filter, wash the filter cake with a small amount of water, and dry at 60℃ under reduced pressure for 8h to obtain off-white 5-methylamino-2,4,6-triiodoisophthalic acid solid 47.9g, with a yield of 93.5% and a purity of 99.4%.

[0022] Example 3:

[0023] In 1000ml three-necked flask, add formic acid 400ml and 35% hydrochloric acid 18.7g, stirring to warm to 50℃, add 5-amino-2,4,6-triiodoisophthalic acid 50g, then slowly add paraformaldehyde 32.1g, after adding, warm to 80℃ and react for 9h. After the reaction is completed, cool the reaction liquid to about 5℃, stir for 1h, then filter, wash the filter cake with a small amount of water, and dry at 60℃ under reduced pressure for 8h to obtain off-white 5-methylamino-2,4,6-triiodoisophthalic acid solid 47.9g, with a yield of 93.5% and a purity of 99.4%.

Claims

1. A method for preparing 5-methylamino-2,4,6-triiodoisophthalic acid, an iodine meprolic intermediate, is characterized in that: 5-amino-2,4,6-triiodoisophthalic acid is dissolved in a mixed acid consisting of formic acid and a strong acid, and then a 35-38% formaldehyde aqueous solution or paraformaldehyde is added. After the heating reaction is completed, the mixture is cooled for crystallization and filtered to obtain 5-methylamino-2,4,6-triiodoisophthalic acid, wherein the strong acid is hydrochloric acid or perchloric acid.

2. The method according to claim 1, wherein: The molar ratio of the strong acid to 5-amino-2,4,6-triiodoisophthalic acid is 1-3:

1.

3. The method according to claim 1, wherein: The molar ratio of the 35-38% formaldehyde aqueous solution or paraformaldehyde to 5-amino-2,4,6-triiodoisophthalic acid is 5-15:

1.

4. The method according to claim 1, wherein: The reaction temperature is 50-120° C.; the reaction time is 6-15 hours; and the cooling temperature is 0-30° C.

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