RU2795091C2 - Method for obtaining yomeprol,the contrast agent - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method for producing iomeprol, the radiopaque agent, and more specifically, to a method for producing iomeprol by adding an inorganic base, an inorganic chloride, a solvent, etc. The invention relates to a method for producing iomeprol, the radiopaque agent. The method consists in N-methylation of 5-(2-hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide by adding an N-methylating reagent, an inorganic base, an inorganic chloride, and a solvent that dissolves the inorganic chloride. The inorganic base is any compound from the group consisting of the following: lithium hydroxide, calcium hydroxide, magnesium hydroxide, beryllium hydroxide, or combinations thereof.

EFFECT: method makes it possible to easily separate and remove inorganic salts formed during the reaction without treatment with an ion exchange resin, reducing the time to obtain the product and minimizing the formation of impurities during the reaction.

9 cl, 2 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to a novel process for the preparation of the radiopaque agent iomeprol.

More specifically, the present invention relates to a new method for producing the radiopaque agent iomeprol, which can easily separate and remove inorganic salts formed during the reaction without treatment with an ion exchange resin while reducing the available production time using a one-step synthesis method by carrying out an N-methylation reaction by adding an inorganic base, an inorganic chloride and a solvent to 5-(2-hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.

With the present invention, yomeprol, a contrast compound, can be economically obtained in a high yield of 99% or more by a one-step synthesis and recrystallization method as described above.

BACKGROUND OF THE INVENTION

Iomeprol is a third generation nonionic contrast agent which is N,N'-bis(2,3-dihydroxypropyl)-5-(2-hydroxy-N-methylacetamido)-2,4,6-triiodoisophthalamide having the following formula 1a. It is obtained by methylation of the compound of the following formula 1b. It is a radiopaque and CT contrast agent triiodisophthalamide developed by Bracco Imaging S.p.A, Italy and is used in various cases in angiography and is first described in European Patent No. EP 0026281.

In addition, routes for the preparation of 5-(hydroxyacyl)amino derivatives based on the Smiles rearrangement reaction are described in International Publication Nos. WO 88/09328 and WO 00/32651.

The advantage of the synthesis method described in International Publication No. WO 00/32561 is mainly that some reagents and solvents such as thionyl chloride, acetic anhydride, methyl iodide, methylene chloride and chloroform are not used, or the reaction with hydrogen using catalysts and etc.

The synthesis method indicated above is as follows (Scheme 1).

Scheme 1

In the synthesis method given in International Publication No. WO 00/32561, harmful substances are not used under industrial production conditions. However, the synthesis step is lengthy, and when going from the compound of formula (III) to the compound of the last step, the terminal group contains an hydroxy group, indicating water solubility. Thus, there is a difficult task of removing the inorganic material used in steps 4 and 7.

Since iomeprol is soluble in water, it is very difficult to separate and remove if inorganic salts are formed during preparation.

To solve this problem and obtain the target product of high purity, not only yomeprol, but also other iodine-based contrast agents are purified by using an ion exchange resin in the final stage of removing inorganic substances.

From the point of view of the industrial production environment, the ion exchange resin device has the economic disadvantages that its cost is not low, it requires space to install, and the resin needs to be replaced after a while.

The synthesis process described in International Publication No. WO 88/09328 requires a shorter preparation time than that described in International Publication No. WO 00/32561. However, since inorganic salts are also used in the final step of the synthesis process described in International Publication No. WO 88/09328, an ion exchange resin device must be used to separate the resulting iomeprol from the inorganic substances.

A production method without treatment with an ion exchange resin, which was used to suppress the formation of inorganic substances, which was a difficulty in the above patents, is registered by the authors of the present invention as Korean Patent 101833334.

In the above patent, each hydroxy group of the starting material is acetylated to form a protecting group so that it is highly soluble in an organic solvent.

Thereafter, a method for the synthesis of iomeprol was proposed in which inorganic substances were removed by a deprotection reaction after a methylation reaction of the synthesized new substance. N,N'-bis(2,3-diacetylate propyl)-5-(2-acetoxy-N-methylacetamido)-2,4,6-triiodoisophthalamide (Scheme 2).

Scheme 2

Although the above production method has the advantage that inorganic substances are removed in the extraction process using a new oil-soluble intermediate, it has the disadvantage that the preparation is time consuming since the production method consists of 4 steps, which increases the actual production cost.

Therefore, in order to compensate for the disadvantages of the above production methods, it is necessary to develop a production method in which inorganic salts are removed without using an ion exchange resin, and a production technology capable of guaranteeing economic efficiency while reducing production time and minimizing the formation of impurities during the reaction.

PUBLICATION OF THE PRIOR ART

PATENT PUBLICATION

Patent Publication 1: WO 0032561 A

Patent Publication 2: WO 8809328 A

Patent Publication 3: Korean Patent No. 101833334 A

CONTENT OF THE INVENTION

SOLVED PROBLEM

The object of the present invention is to provide a process for the preparation of the radiopaque agent iomeprol, in which the formation of impurities during the reaction can be minimized and inorganic salts can be easily removed with a significant reduction in preparation time compared to that available by carrying out the N-methylation reaction by adding an inorganic base, an inorganic chloride and a solvent , which dissolves the inorganic chloride to give commercially available 5-(2-hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.

TECHNICAL MEANS

To solve this technical problem, in the first object of the present invention, a new method for obtaining the contrast agent iomeprol, described by formula 1a, is proposed, including the stage of fast and stable carrying out the N-methylation reaction by adding an N-methylating reagent, an inorganic base, an inorganic chloride and a solvent that dissolves the inorganic chloride such as methanol, DMSO, DMAc and DMF to 5-(2-hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide of formula 1b.

THE EFFECT OF THE INVENTION

The process for producing iomeprol according to the present invention can shorten the production time, minimize the formation of impurities in the reaction, and obtain iomeprol of high purity of 99% or more by allowing the inorganic chloride to be dissolved in the reaction solvent and the crystallization solvent at effectively separating and removing the inorganic salt without using a separate ion exchange resin by carrying out the N-methylation reaction at a special temperature by adding an N-methylating reagent, an inorganic base, an inorganic chloride, and a solvent that dissolves the inorganic chloride to form 5-(2-hydroxyacetamido)-N ,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (formula 1b).

SPECIFIC WAY FOR CARRYING OUT THE INVENTION

The present invention is described in more detail below.

The process for producing iomeprol according to the present invention includes the step of carrying out an N-methylation reaction by adding an N-methylating agent, an inorganic base, an inorganic chloride and a solvent to 5-(2-hydroxyacetamido)-N,N'-bis(2,3- dihydroxypropyl)-2,4,6-triiodoisophthalamide (formula 1b).

The method of production proposed in the present invention, in particular, is the method shown below in scheme 3.

Scheme 3

In the method of preparation proposed in the present invention, the contrast agent iomeprol (formula 1a) is obtained by adding an N-methylating reagent, an inorganic base, an inorganic chloride and a solvent that dissolves the inorganic chloride, to 5-(2-hydroxyacetamido)-N,N' -bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (formula 1b).

5-(2-Hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide of formula 1b contains five hydroxyl groups but does not have good solubility in water or alcohol.

To carry out the N-methylation reaction, the compound of formula 1b must first be dissolved. To do this, an inorganic chloride, i.e. calcium chloride, is added to form an ionic bond with the hydroxy group to create conditions for dissolution in water or methanol.

The inorganic base acts as a Bronsted base to remove hydrogen from the amide group for the N-methylation reaction.

Specifically, as shown in Scheme 3, after adding 5-(2-hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (Formula 1b) and inorganic chloride to the solvent, such as dimethyl sulfoxide (DMSO) or methanol, and stirring to dissolve, a Bronsted base, i.e., sodium hydroxide, is added, and the N-methylating reagent, dimethyl sulfate, is dissolved in a solvent to carry out the reaction.

The N-methylation reagent used in the production process of the present invention is selected from the group consisting of: dimethyl sulfate, methyl iodide, and a combination thereof, and is preferably dimethyl sulfate.

In the method of obtaining proposed in the present invention, use 1 or more equivalents, preferably from 3 to 4 eq. N-methylating reagent in terms of 1 eq. 5-(2-hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.

If the content of the N-methylating reagent is less than the above numerical range, the reaction may not proceed sufficiently and the reaction time may increase. If the content of the N-methylating reagent is greater than the above numerical range, the amount of impurities may increase.

The inorganic base used in the production method of the present invention is selected from the group consisting of lithium hydroxide, calcium hydroxide, magnesium hydroxide, beryllium hydroxide, and a combination thereof, and is preferably calcium hydroxide.

Inorganic bases such as calcium hydroxide form inorganic salts such as calcium chloride after completion of the reaction, and water, and calcium chloride is highly soluble in methanol as a reaction solvent and then in a crystallization solvent, so that the inorganic salts can be effectively removed without the use of an ion exchange resin. As a result, high purity yomeprol can be obtained (formula 1a).

In the method of obtaining proposed in the present invention, you can use from 0.5 to 2 eq., preferably from 0.6 to 1.2 eq., more preferably from 0.6 to 0.7 eq. inorganic base in terms of 1 eq. 5-(2-hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (formula 1b).

If the content of the inorganic base is less than the specified in the above numerical range, the reaction rate may decrease. If the content is greater than the above numerical range, the amount of impurities may increase.

As the inorganic chloride used in the production method of the present invention, calcium chloride, lithium chloride, beryllium chloride, magnesium chloride, etc. can be used, which can be dissolved in methanol as a reaction solvent.

In the case of obtaining iomeprol without the addition of inorganic chloride, the reagent 5-(2-hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (formula 1b) does not dissolve in methanol, which is solvent for the reaction. The reaction does not proceed easily, and even if the reaction partially proceeds, the reaction may not be completed and a reagent may remain.

Since the remaining reagent, the compound of formula 1b, has a structure similar to that of iomeprol, it is very difficult to remove it after the reaction is completed.

In the method of obtaining proposed in the present invention, you can use from 2 to 10 eq., preferably from 2 to 4 eq., more preferably 3 eq. inorganic chloride in terms of 1 eq. 5-(2-hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (formula 1b).

If the content of inorganic chloride is too high, the concentration of the reaction mixture solution is high, so that dissolution or stirring may be difficult. If its content is too low or absent, the reaction may not be completed because the compound of formula 1b does not dissolve.

The solvent used in the production process of the present invention can be selected from the group consisting of: methanol, dimethylformamide (DMF), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), and a combination thereof. Preferably, methanol can be used.

In the production process of the present invention, the ratio of the mass of solvent to the mass of 5-(2-hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (formula 1b) can be from 4 to 10, preferably 5 to 7.

If the solvent content is less than the above numerical range, dissolution may be difficult. If the content is greater than the above-mentioned numerical range, the output of the crystallization step may not be ensured.

The production method of the present invention further includes the step of crystallizing the product by adding a crystallization solvent to the product obtained from the N-methylation reaction.

The crystallization solvent may be any one selected from the group consisting of: methanol, ethanol, isopropanol, normal butanol, 2-butanol, or a combination thereof, preferably methanol.

The crystallization solvent is used to effectively remove the inorganic salt and increase the yield.

In the crystallization step after completion of the N-methylation reaction, an acid (HCl, etc.) is added to acidify, and then a crystallization solvent is added to boil and stir at room temperature to 80°C, preferably 70 to 80°C , for 2 to 24 hours, preferably 3 hours.

Then, the crystals are filtered off, washed sufficiently with a crystallization solvent, and dried under reduced pressure at a temperature of 50 to 90°C.

The present invention is described in more detail using the following examples and comparative examples. However, they do not limit the scope of the present invention in any way.

EXAMPLES

Example 1

Getting iomeprol

5 g (1 eq.) 5-(2-Hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (Formula 1b) and 3.6 g (5 eq.) calcium chloride was added together to 25 g of methanol and then dissolved by heating at room temperature or 70° C. for 60 minutes.

After lowering the temperature of the solution by 10-15°C, 0.3 g (0.62 equiv.) of calcium hydroxide was added, then stirred at the same temperature for 1 hour.

2.48 g (3 eq.) of dimethyl sulfate was added to the reaction mixture solution and stirred at the same temperature for 3 h until the reaction was complete.

After completion of the reaction, 1 ml of HCl (35%) was added to acidify, and 25 mg of 2-butanol was added and stirred at a temperature of 70 to 80°C for 2 hours. yomeprol.

After adding the above crude iomeprol to a mixture of 25 ml of methanol and 10 ml of water, the temperature was raised to 50°C to dissolve them, then 20 ml of 2-butanol was added and refluxed at 90°C for 3 hours. Then the mixture was cooled to room temperature and filtered the resulting crystals.

After washing with 2-butanol, they were dried under reduced pressure at 90° C. for 12 hours to obtain 4.17 g of iomeprol (HPLC: 99.3%).

Example 2

Getting Yomeprol

5 g (1 eq.) 5-(2-Hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (Formula 1b) and 3.6 g (5 eq.) calcium chloride was added together to 25 g of methanol, and then dissolved by heating at room temperature or 70° C. for 30 minutes.

After lowering the temperature of the solution by 0-5°C, 0.3 g (0.62 equiv.) of calcium hydroxide was added, then stirred at the same temperature for 1 hour.

2.48 g (3 eq.) of dimethyl sulfate was added to the reaction mixture solution and stirred at the same temperature for 7 hours until the reaction was complete.

After completion of the reaction, 1 ml of HCl (35%) was added to acidify, and 25 mg of 2-butanol was added and stirred at a temperature of 70 to 80°C for 2 hours. yomeprol.

After adding the above crude iomeprol to a mixture of 25 ml of methanol and 10 ml of water, the temperature was raised to 50°C to dissolve them, then 20 ml of 2-butanol was added and refluxed at 90°C for 3 hours. Then the mixture was cooled to room temperature and filtered the resulting crystals.

After washing with 2-butanol, they were dried under reduced pressure at 90° C. for 12 hours to obtain 4.21 g of iomeprol (HPLC: 99.1%).

Comparative Example 1 (no addition of inorganic chloride)

5-(2-Hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (Formula 1b) was added to 25 g of methanol and then refluxed for 30 minutes.

After lowering the temperature of the cloudy solution by 10-15°C, 0.3 g (0.62 equiv.) of calcium hydroxide was added, then stirred at the same temperature for 1 hour.

2.48 g (3 equiv.) of dimethyl sulfate was added to the reaction mixture solution and stirred at the same temperature for 5 hours.

According to HPLC reactivity study, iomeprol synthesis proceeded at 5% and it was found that the reactivity was very low, since more than 90% of 5-(2-hydroxyacetamido)-N,N'-bis(2,3 -dihydroxypropyl)-2,4,6-triiodoisophthalamide (formula 1b).

Comparative Example 2 (without addition of inorganic base)

5-(2-Hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (Formula 1b) and 3.6 g (5 eq.) calcium chloride were added together to 25 g methanol and then refluxed for 30 minutes.

After lowering the temperature of the solution by 10-15°C, 2.48 g (3 equiv.) of dimethyl sulfate was added to the reaction mixture solution and stirred at the same temperature for 5 hours.

HPLC reactivity showed that 5% synthesis of iomeprol proceeded and found that the reactivity was very low as more than 99% of 5-(2-hydroxyacetamido)-N,N'-bis(2,3 -dihydroxypropyl)-2,4,6-triiodoisophthalamide (formula 1b).

As shown above, since in the present invention the compound of formula 1a is obtained by methylation of the compound of formula 1b without additional intermediate steps by using inorganic bases, inorganic chlorides and a solvent that dissolves inorganic chlorides, the present invention can lead to a reduction in the available production method and time for obtaining high purity iomeprol without the need for cleaning with a separate ion exchange resin device.

The detailed description of the present invention is merely illustrative of the present invention and is used only to describe the present invention without limiting the spirit or scope of the present invention as defined by the claims.

Therefore, those of ordinary skill in the art will appreciate that various modifications and other equivalent embodiments are possible.

Therefore, the true technical scope of protection for the present invention should be determined by the scope of the appended claims.

Claims (11)

1. A method for producing iomeprol, comprising the step of carrying out an N-methylation reaction by adding an N-methylating reagent, an inorganic base, an inorganic chloride, and a solvent that dissolves the inorganic chloride, to 5-(2-hydroxyacetamido)-N,N'-bis(2 ,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, where the inorganic base is any one selected from the group consisting of: lithium hydroxide, calcium hydroxide, magnesium hydroxide, beryllium hydroxide, or combinations thereof. 2. The method for producing iomeprol according to claim 1, wherein the N-methylating reagent is any one selected from the group consisting of: dimethyl sulfate, methyl iodide, or a combination thereof. 3. The method of obtaining iomeprol according to claim 1, which uses from 1 to 10 eq. N-methylating reagent in terms of 1 eq. 5-(2-hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. 4. The method of obtaining iomeprol according to claim 1, which uses from 1 to 10 eq. inorganic base in terms of 1 eq. 5-(2-hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. 5. The method for producing iomeprol according to claim 1, wherein the inorganic chloride is any one selected from: calcium chloride, lithium chloride, beryllium chloride, and magnesium chloride. 6. The method of obtaining iomeprol according to claim 1, which uses from 2 to 10 eq. inorganic chloride in terms of 1 eq. 5-(2-hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. 7. A process for preparing iomeprol according to claim 1, wherein the solvent is any one selected from the group consisting of: dimethylformamide (DMF), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), methanol, or a combination thereof. 8. The method for producing iomeprol according to claim 1, in which the ratio of the mass of the solvent to the mass of 5-(2-hydroxyacetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is from 4 to 10. 9. The method for producing iomeprol according to claim 1, further comprising the step of crystallizing the product by adding a crystallization solvent to the product obtained by the N-methylation reaction. 10. The process for producing iomeprol according to claim 9, wherein the crystallization solvent is any one selected from the group consisting of: methanol, ethanol, isopropanol, normal butanol, 2-butanol, or a combination thereof.