KR20200077744A - New Methods for Preparing an Intermediate of Contrast Medium and Methods for Preparing Contrast Medium - Google Patents

Abstract

A manufacturing method of the present invention reduces treatment processes when manufacturing a contrast medium or an intermediate thereof, and thus generates less waste solvent, thereby being eco-friendly and capable of significantly reducing a manufacturing cost. Therefore, the manufacturing method of the present invention is economical and suitable for mass production since the production cost of the contrast medium can be greatly reduced.

Description

New method for preparing contrast medium and method for preparing contrast medium using the same {New Methods for Preparing an Intermediate of Contrast Medium and Methods for Preparing Contrast Medium}

The present invention relates to a novel method for preparing a contrast medium and a method for preparing a contrast medium using the same. Specifically, the present invention relates to a manufacturing method capable of manufacturing an in-situ core intermediate for preparing a contrast medium and a method for manufacturing a contrast medium using the same.

Recently, in the contrast medium market, the third generation contrast medium, which is a nonionic low osmotic contrast medium, is widely used. Among these, Iomeprol or Ioversol having the following structure is also used as a contrast agent for X-ray or CT imaging.

[Iomeprole]

[Eoversol]

In order to manufacture the contrast agents according to the conventional manufacturing method, it is necessary to go through several steps, which causes a lot of waste solvent and increases the manufacturing cost.

Accordingly, there is a need to develop a useful manufacturing method that can be applied to mass production by solving these problems.

Korean Patent Publication No. 2018-0073981

An object of the present invention is to provide a method for economically and environmentally friendly production of a core intermediate for the production of iomeprole or ioversol in a simple process.

In addition, another object of the present invention is to provide a method for manufacturing a contrast agent suitable for mass production by lowering the production cost because it is possible to manufacture iomeprole or ioversol with high purity and high efficiency using the intermediate manufacturing method according to the present invention.

However, the problems to be solved by the present application are not limited to the problems described above, and other problems not described will be clearly understood by those skilled in the art from the following description.

According to a first aspect of the present invention, there is provided a method for preparing a compound represented by Formula I comprising the following steps:

(S-1) preparing a compound represented by the following formula (Ib) from the compound represented by the following formula (Ia);

(S-2) preparing a compound represented by the following formula (Ic) by in situ reaction from the reaction solution of step (S-1); And

(S-3) preparing a compound represented by the following formula (I) from the compound represented by the formula (Ic);

[Formula Ia]

[Formula Ib]

[Formula Ic]

[Formula I]

.

.

According to a second aspect of the invention, there is provided a method for the preparation of Iomeprole comprising the following steps:

(A-1) preparing a compound represented by Formula I according to the present invention; And

(A-2) preparing a compound represented by the following formula A from the compound represented by the formula (1);

[Formula I]

[Formula A]

.

.

According to a third aspect of the present invention, there is provided a method of manufacturing an oversole comprising the following steps:

(B-1) preparing a compound represented by Formula I according to the present invention; And

(B-2) preparing a compound represented by the following formula B from the compound represented by the formula (1);

Manufacturing method of this oversole comprising:

[Formula I]

[Formula B]

.

.

The manufacturing method of the present invention shows an effect of reducing the processing process when producing a contrast medium or contrast medium, so that less waste solvent is generated, which is eco-friendly and significantly reduces manufacturing cost. In addition, the manufacturing method of the present invention can produce a high-purity and high-contrast contrast agent without complicated purification and washing processes, so that the production cost of the contrast agent can be significantly reduced, which is economical and suitable for mass production.

Terms used in the present application are only used to describe specific embodiments, and the present application may be implemented in various different forms and is not intended to limit the present invention. Singular expressions include plural expressions unless the context clearly indicates otherwise. In the present application, terms such as “include” or “have” are intended to designate the existence of features, components, and the like described in the specification, and one or more other features or components may not be present or added. It does not mean nothing.

Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person skilled in the art to which the present invention pertains. Terms such as those defined in a commonly used dictionary should be interpreted as having meanings consistent with meanings in the context of related technologies, and should not be interpreted as ideal or excessively formal meanings unless explicitly defined in the present application. Does not.

Hereinafter, a new method of preparing a contrast medium of the present invention and a method of manufacturing a contrast medium using the same will be described in detail.

Contrast agent intermediate manufacturing method

The present invention is a compound represented by the following formula 1, which is a key intermediate for the preparation of contrast agents, especially iomeprole or ioversol (N,N-bis(2,3-dihydroxypropyl)-5-(2-hydroxyacet) Amido)-2,4,6-triiodoisophthalamide).

[Formula I]

Specifically, the method of preparing the contrast medium of the present invention includes the following steps:

(S-1) preparing a compound represented by the following formula (Ib) from the compound represented by the following formula (Ia);

(S-2) preparing a compound represented by the following formula (Ic) by in situ reaction from the reaction solution of step (S-1); And

(S-3) preparing a compound represented by the following formula (I) from the compound represented by the formula (Ic);

[Formula Ia]

[Formula Ib]

[Formula Ic]

[Formula I]

.

.

According to an embodiment of the present invention, after the completion of the reaction of step (S-1), water, C1-C4 alcohol or a mixture thereof may be further included and stirred. Specifically, the C1-C4 alcohol may be methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, etc., but isopropyl alcohol may be used.

In addition, according to an embodiment of the present invention, the step (S-2) does not separate the compound represented by the formula (Ic) into a solid, and the step (S-3) is the reaction of the step (S-2) It may be to prepare a compound represented by the following formula (I) by in situ reaction from the liquid. Here, the (S-3) step is a step of crystallizing the compound represented by the formula (I) prepared through any one solvent selected from the group consisting of isopropyl alcohol, ethanol, methanol, water, butanol and 2-methoxyethanol It may include. The production method of the present invention according to the above embodiment can be summarized in Scheme 1 below.

[Scheme 1]

Further, according to another embodiment of the present invention, the step (S-2) may include the step of separating the compound represented by the formula (Ic) into a solid. Here, the (S-2) step is a step of crystallizing the compound represented by the formula (I) prepared through any one solvent selected from the group consisting of isopropyl alcohol, ethanol, methanol, water, butanol and 2-methoxyethanol It may include. Further, the step (S-3) is also isopropyl alcohol, ethanol, methanol, water, butanol and a step of crystallizing the compound represented by the formula (I) prepared through any one solvent selected from the group consisting of 2-methoxyethanol It may include. The production method of the present invention according to the above embodiment can be summarized in Scheme 2 below.

[Scheme 2]

Contrast preparation method

The present invention provides a method for preparing a contrast agent, in particular iomeprole or eoversol, using the above-described contrast agent intermediate preparation method.

Method of manufacturing Iomeprole

The present invention provides a method for preparing iomeprole comprising the following steps:

(A-1) preparing a compound represented by Formula I according to the present invention; And

(A-2) preparing a compound represented by the following formula A from the compound represented by the formula (1);

[Formula I]

[Formula A]

.

.

Step (A-1) is as described in the contrast agent intermediate manufacturing method.

Step (A-2) may be performed in the presence of a base. Specifically, the base may be any one or more selected from the group consisting of NaOH, K ₂ CO ₃ , Cs ₂ CO ₃ and CsOH. Specifically, NaOH can be used.

Further, the base may be used in the amount of 1.1 to 1.6 equivalents based on 1 equivalent of the compound represented by Chemical Formula 1. More specifically, the base may use about 1.2 equivalents.

In addition, step (A-2) may be performed under DMAc, DMF or DMSO.

In addition, the (A-2) step is a compound represented by the formula (A) using a C1-C4 alcohol, for example, one or more selected from methanol, ethanol, 2-methoxyethanol, isopropyl alcohol or butanol Crystallization.

Manufacturing method of Eoversole

The present invention provides a method of making an eoversole comprising the following steps:

(B-1) preparing a compound represented by Formula I according to the present invention; And

(B-2) preparing a compound represented by the following formula B from the compound represented by the formula (1);

[Formula I]

[Formula B]

.

.

Step (B-1) is as described in the contrast agent intermediate manufacturing method.

The step (B-2) may be performed in the presence of a base. Specifically, the base may be any one or more selected from the group consisting of NaOH, K ₂ CO ₃ , Cs ₂ CO ₃ and CsOH. Specifically, NaOH can be used.

In addition, the base may be used in the amount of 2 to 10 equivalents based on 1 equivalent of compound represented by Formula 1. More specifically, the base may use about 8 equivalents.

In addition, the step (B-2) can be performed under a polar solvent. Specifically, it may be performed in water, a C1-C4 alcohol, or a mixed solvent thereof, for example, in a mixed solvent of water and ethanol, water and isopropanol, and water and 2-methoxyethanol.

In addition, the (B-2) step is a compound represented by the formula (B) using a C1-C4 alcohol, for example, one or more selected from methanol, ethanol, 2-methoxyethanol, isopropyl alcohol or butanol Crystallization.

It can be seen that the manufacturing method of the present invention saves the manufacturing cost and significantly reduces the generation of waste solvent by reducing the treatment process after the reaction and limiting the use of the solvent. Therefore, the manufacturing method of the present invention is a manufacturing process suitable for mass production, and the product is significantly lower in the market, and waste solvents and the like are significantly reduced in the manufacturing process.

Example

Hereinafter, preferred embodiments are provided to help understanding of the present invention. However, the following examples are provided only for easier understanding of the present invention, and the contents of the present invention are not limited by the examples.

<Example 1> Synthesis of N,N-bis(2,3-dihydroxypropyl)-5-(2-hydroxyacetamido)-2,4,6-triiodoisophthalamide

Step 1: Synthesis of 2-((3,5-bis(chlorocarbonyl)-2,4,6-triiodophenyl)amino)-2-oxoethyl acetate

100 g (0.168 mol) of 5-amino-2,4,6-triiodoisophthaloyl diacyl chloride and 200 g of N,N-dimethylacetamide were added and dissolved by stirring. Acetoxyacetyl chloride 41.2 g (0.302 mol) was added dropwise to the reaction solution for 30 minutes. After stirring at 20 to 25° C. for 20 hours, reaction completion was confirmed using TLC. 6 g of isopropyl alcohol was added to the reaction solution and stirred for 1 hour.

Step 2: Synthesis of 2-((3,5-bis((2,3-dihydroxypropyl)carbamoyl)-2,4,6-triiodophenyl)amino)-2-oxoethyl acetate

Into the reactor, 36.7 g (0.403 mol) of 3-amino-1,2-propanediol, 67.9 g (0.671 mol) of triethylamine, and 100 g of N,N-dimethylacetamide were added and mixed by stirring. After the reaction solution of step 1 was cooled to 15°C, it was added dropwise to a reactor containing a mixture of 3-amino-1,2-propanediol and stirred at 25 to 30°C for 15 hours to complete the reaction. After the reaction solution was cooled to 10°C or lower, the cooled reaction solution was filtered, and the filtrate was concentrated under reduced pressure at 70°C.

Step 3: Synthesis of N,N-bis(2,3-dihydroxypropyl)-5-(2-hydroxyacetamido)-2,4,6-triiodoisophthalamide

30 g (0.750 mol) of caustic soda and 300 g of purified water were added to the reactor and stirred to dissolve. The dissolved caustic soda solution was added to the concentrated reaction solution of Step 2, and then stirred at 25 to 30°C for 6 hours. After confirming the completion of the reaction using HPLC, the reaction solution was cooled to 10°C or lower and filtered. The filtrate was concentrated under reduced pressure at 65° C., and 300 g of isopropyl alcohol was added to the reactor, followed by stirring for 1 hour. The reaction solution was cooled to 10°C or lower, and the crystals were filtered to obtain the title compound (yield 98.9%, purity 99.15%).

¹ H-NMR 400 MHz (DMSO): δ 3.15-3.18 (m, 2H); 3.47-3.51 (m, 4H); 3.67-3.71 (m, 4H); 4.02-4.03 (d, 2H); 4.45-4.50 (m, 2H); 4.79 (s, 1 H); 5.62-5.65 (s, 2H); 8.45-8.53 (m, 2H); 9.79 (s, 1H)

<Example 2> Synthesis of N,N-bis(2,3-dihydroxypropyl)-5-(2-hydroxyacetamido)-2,4,6-triiodoisophthalamide

The title compound was obtained in the same manner as in Example 1, except that 2 g of purified water was added instead of 6 g of isopropyl alcohol in Step 1 of Example 1 (yield 98.0%, purity 99.28%).

¹ H-NMR 400 MHz (DMSO): δ 3.15-3.18 (m, 2H); 3.47-3.51 (m, 4H); 3.67-3.71 (m, 4H); 4.02-4.03 (d, 2H); 4.45-4.50 (m, 2H); 4.79 (s, 1 H); 5.62-5.65 (s, 2H); 8.45-8.53 (m, 2H); 9.79 (s, 1H)

<Example 3> Synthesis of N,N-bis(2,3-dihydroxypropyl)-5-(2-hydroxyacetamido)-2,4,6-triiodoisophthalamide

Step 1: Synthesis of 2-((3,5-bis(chlorocarbonyl)-2,4,6-triiodophenyl)amino)-2-oxoethyl acetate

The procedure was the same as in Step 1 of Example 1.

Step 2: Synthesis of 2-((3,5-bis((2,3-dihydroxypropyl)carbamoyl)-2,4,6-triiodophenyl)amino)-2-oxoethyl acetate

Into the reactor, 36.7 g (0.403 mol) of 3-amino-1,2-propanediol, 67.9 g (0.671 mol) of triethylamine, and 100 g of N,N-dimethylacetamide were added and stirred to mix. The reaction solution from Step 1 was cooled to 15°C and added dropwise to a reactor containing a mixture of 3-amino-1,2-propanediol. After stirring at 25 to 30°C for 15 hours, after confirming the completion of the reaction using HPLC, the reaction solution was cooled to 10°C or less. The cooled reaction solution was filtered and the filtrate was concentrated under reduced pressure at 70°C. While maintaining the concentrated residue at 60°C, 300 g of isopropyl alcohol was added, cooled to 10°C or less, and stirred for 1 hour. The resulting solid was filtered to obtain a wet body, and the wet body was dried under reduced pressure in an oven at 60° C. for 12 hours to obtain the title compound (yield 98.8%, purity 94.9%).

Step 3: Synthesis of N,N-bis(2,3-dihydroxypropyl)-5-(2-hydroxyacetamido)-2,4,6-triiodoisophthalamide

30 g of caustic soda (0.750 mol) and 300 g of purified water were added and stirred to dissolve. The dried 2-((3,5-bis((2,3-dihydroxypropyl)carbamoyl)-2,4,6-triiodophenyl)amino)-2-oxoethyl acetate crystal is introduced into the reactor. And stirred at 25 to 30 ℃ for 8 hours and confirmed the completion of the reaction using HPLC. After the reaction solution was concentrated under reduced pressure at 65° C., 300 g of isopropyl alcohol was added to the reactor and stirred for 1 hour. The reaction solution was cooled to 10°C or lower, and the crystals were filtered to obtain the title compound (yield 99.2%, purity 99.54%).

¹ H-NMR 400 MHz (DMSO): δ 3.15-3.18 (m, 2H); 3.47-3.51 (m, 4H); 3.67-3.71 (m, 4H); 4.02-4.03 (d, 2H); 4.45-4.50 (m, 2H); 4.79 (s, 1 H); 5.62-5.65 (s, 2H); 8.45-8.53 (m, 2H); 9.79 (s, 1H)

<Example 4> Synthesis of N,N-bis(2,3-dihydroxypropyl)-5-(2-hydroxyacetamido)-2,4,6-triiodoisophthalamide

Step 1: Synthesis of 2-((3,5-bis(chlorocarbonyl)-2,4,6-triiodophenyl)amino)-2-oxoethyl acetate

The procedure was the same as in Step 1 of Example 2.

Step 2: Synthesis of 2-((3,5-bis((2,3-dihydroxypropyl)carbamoyl)-2,4,6-triiodophenyl)amino)-2-oxoethyl acetate

The same procedure as in Step 2 of Example 3 was obtained to obtain the title compound (yield 98.2%, purity 95.3%).

Step 3: Synthesis of N,N-bis(2,3-dihydroxypropyl)-5-(2-hydroxyacetamido)-2,4,6-triiodoisophthalamide

The same procedure as in Step 3 of Example 3 was obtained to obtain the title compound (yield 98.9%, purity 99.51%).

¹ H-NMR 400 MHz (DMSO): δ 3.15-3.18 (m, 2H); 3.47-3.51 (m, 4H); 3.67-3.71 (m, 4H); 4.02-4.03 (d, 2H); 4.45-4.50 (m, 2H); 4.79 (s, 1 H); 5.62-5.65 (s, 2H); 8.45-8.53 (m, 2H); 9.79 (s, 1H)

<Example 5> Synthesis of N,N-bis(2,3-dihydroxypropyl)-5-(2-hydroxyacetamido)-2,4,6-triiodoisophthalamide

2-((3,5-bis((2,3-dihydroxypropyl)carbamoyl)-2,4,6-triiodophenyl)amino)-2-oxo prepared in Step 2 of Example 3 100 g (0.21 mol) of ethyl acetate was dissolved in 130 g of purified water at room temperature. Ca(OH) ₂ 9.25 g (0.25 mol) was added, stirred for 30 minutes, and then filtered. The filtrate was concentrated under reduced pressure at 45 to 65°C. After adding 300 g of N,N-dimethylacetamide to the concentrated reaction solution, it was dissolved at 65°C. After filtering while maintaining at 65°C, the filtrate was concentrated under reduced pressure at 45 to 65°C. Crystallized by adding 300 g of isopropyl alcohol to the concentrated reaction and stirring. After cooling to 10° C. or less, the mixture was stirred for 1 hour and then filtered to obtain a wet body. Drying in an oven at 60° C. for 12 hours gave the title compound (yield 95.1%, purity 99.08%).

¹ H-NMR 400 MHz (DMSO): 3.15-3.18 (m, 2H); 3.47-3.51 (m, 4H); 3.67-3.71 (m, 4H); 4.02-4.03 (d, 2H); 4.45-4.50 (m, 2H); 4.79 (s, 1 H); 5.62-5.65 (s, 2H); 8.45-8.53 (m, 2H); 9.79 (s, 1H)

<Example 6> Synthesis of Iomeprole

20 g (0.026 mol) of N,N-bis(2,3-dihydroxypropyl)-5-(2-hydroxyacetamido)-2,4,6-triiodoisophthalamide prepared as a reactor And 60 g of N,N-dimethylacetamide was added, followed by heating and stirring at 60°C to dissolve. Caustic soda 1.3 g (0.033 mol) was added to the reactor and stirred to dissolve. The reactor was cooled to 10° C. or lower, and 4.5 g (0.032 mol) of iodomethane was introduced into the reactor, and stirred at 25° C. for 14 to 16 hours. Upon completion of the reaction, acetic acid was added to neutralize the reaction solution. The solvent was removed by concentrating under reduced pressure at 60 to 65° C., and 60 g of ethanol was added to crystallize. Filtration to obtain a wet body and drying under reduced pressure in an oven at 60° C. for 12 hours yielded iomeprole (yield 95%, purity 99.8%).

¹ H-NMR 500 MHz (DMSO): δ 2.96 (s, 3H); 3.00-3.20 (m, 4H); 3.28 (s, 2 H); 3.34-3.52 (m, 6H); 3.66-3.75 (m, 3H); 4.66-4.85 (m, 2H); 8.43-8.57 (m, 2H)

<Example 7> Synthesis of Eoversol

20 g (0.026 mol) of N,N-bis(2,3-dihydroxypropyl)-5-(2-hydroxyacetamido)-2,4,6-triiodoisophthalamide prepared as a reactor After adding 100 g of purified water, 8.4 g (0.210 mol) of caustic soda was added to the reactor and stirred to dissolve. 4.2 g (0.052 mol) of 2-chloroethanol was added to the reaction solution and stirred at 25° C. for 14 to 16 hours. Upon completion of the reaction, acetic acid was added to neutralize the reaction solution. The solvent was removed at 60 to 65° C. through concentration under reduced pressure, and 60 g of isopropyl alcohol was added to crystallize. Filtration was obtained to obtain a wet body and dried under reduced pressure in an oven at 60° C. for 12 hours to obtain Eoversol (93% yield, 99.8% purity).

¹ H-NMR 500 MHz (DMSO): δ 2.99-3.07 (m, 1H); 3.14-3.18 (m, 1H); 3.24-3.30 (m, 2H); 3.38-3.51 (m, 5H); 4.48-4.55 (m, 2H); 4.68-4.76 (m, 3H); 8.32-8.57 (m, 2H)

Claims (19)

(S-1) preparing a compound represented by the following formula (Ib) from the compound represented by the following formula (Ia);
(S-2) preparing a compound represented by the following formula (Ic) by in situ reaction from the reaction solution of step (S-1); And
(S-3) preparing a compound represented by the following formula (I) from the compound represented by the formula (Ic);
Method for preparing a compound represented by the formula (I) comprising:
[Formula Ia]

[Formula Ib]

[Formula Ic]

[Formula I]

.
According to claim 1,
After the reaction of the step (S-1), further comprising the step of adding water, C1-C4 alcohol or a mixture thereof and stirring, the manufacturing method.
According to claim 2,
The C1-C4 alcohol is isopropyl alcohol, the production method.
According to claim 1,
The (S-2) step does not separate the compound represented by the formula (Ic) into a solid,
The (S-3) step is to prepare a compound represented by the following formula (I) in an in situ reaction from the reaction solution of the (S-2) step.
The method of claim 4,
The step (S-3) includes the step of crystallizing the compound represented by the formula (I) prepared through any one solvent selected from the group consisting of isopropyl alcohol, ethanol, methanol, water, butanol and 2-methoxyethanol. That is, the manufacturing method.
According to claim 1,
The (S-2) step comprises the step of separating the compound represented by the formula (Ic) into a solid.
The method of claim 6,
The (S-2) step includes the step of crystallizing the compound represented by Formula I prepared through any one solvent selected from the group consisting of isopropyl alcohol, ethanol, methanol, water, butanol, and 2-methoxyethanol. That is, the manufacturing method.
(A-1) preparing a compound represented by the following formula (I) according to any one of items 1 to 7; And
(A-2) preparing a compound represented by Formula A below from a compound represented by Formula 1;
Method of manufacturing Iomeprole comprising:
[Formula I]

[Formula A]

.
The method of claim 8,
The (A-2) step is carried out in the presence of a base, the production method.
The method of claim 9,
The base is any one or more selected from the group consisting of NaOH, K ₂ CO ₃ , Cs ₂ CO ₃ and CsOH, the production method.
The method of claim 8,
The (A-2) step is to prepare a compound represented by the formula (A) to crystallize with C1-C4 alcohol.
The method of claim 11,
The C1-C4 alcohol is ethanol, production method.
(B-1) preparing a compound represented by the following formula (I) according to any one of items 1 to 7; And
(B-2) preparing a compound represented by the following formula B from the compound represented by the formula (1);
Manufacturing method of this oversole comprising:
[Formula I]

[Formula B]

.
The method of claim 13,
The (B-2) step is to be carried out in the presence of a base, the production method.
The method of claim 14,
The base is any one or more selected from the group consisting of NaOH, K ₂ CO ₃ , Cs ₂ CO ₃ and CsOH, the production method.
The method of claim 13,
The (B-2) step is to prepare a compound represented by the formula (B) to crystallize with C1-C4 alcohol.
The method of claim 16,
The C1-C4 alcohol is isopropyl alcohol, the production method.
The method of claim 13,
The (B-2) step is carried out in water, C1-C4 alcohol or a mixed solvent thereof, the production method.
The method of claim 18,
The mixed solvent is water and ethanol, water and isopropanol, or water and 2-methoxyethanol.