UA114158C2 - A method for preparing an intermediate of iopromide - Google Patents

Abstract

The present invention relates to a method for preparing an intermediate of iopromide, and more particularly, to a method for preparing an intermediate of iopromide, in which 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride is produced using 1,4-dioxane as a reaction solvent, and then reacted with 3-amino-l, 2-propanediol using a solvent mixture of 1,4-diox-ane or tetrahydrofuran (THF) and isopropanol as a reaction solvent to obtain the intermediate of iopromide with a faster reaction time, a smaller amount of solvent, and a higher yield.

Description

The field of technology

The invention relates to a method for the preparation of an iopromide intermediate, and more specifically, a method for the preparation of an iopromide intermediate, in which a specific reaction solvent is used to improve the efficiency of the reaction and to avoid the need for any additional dimer removal process.

Prerequisites for creating an invention

BBB-methoxyacetylamino-2,4,6-triiodisophthalic acid |(2,3-dihydroxy-M-methyl propyl)-(2,3-dihydroxypropyl)|diamide (hereinafter referred to as "iopromide" in this document) is widely used as a contrast substance for X-ray or CT.

The method of obtaining iopromide is disclosed in US patent Mo 4,364,921, in which methoxyacetic acid interacts with thionyl chloride using dimethylformamide (DMF) as a reaction solvent to obtain methoxyacetyl chloride, and then 5-amino-2,4,6-triiodisophthalic acid dichloride is added and interaction with methoxyacetyl chloride to obtain 5-methoxyacetylamino-2,4,6-triiodisophthalic acid dichloride, which interacts with 2,3-dihydroxypropylamine, i.e. 3-amino-1,2-propanediol, to obtain the intermediate iopromide, 5-methoxyacetylamino-2 ,4,6-triiodisophthalic acid (2,3-dihydroxypropyl)amide chloride, which is used to obtain iopromide.

Korean patent Mo 10-1098553 discloses a method for preparing iopromide in which 5-amino-2,4,6-triiodisophthalic acid dichloride reacts with methoxyacetyl chloride (using dimethylacetamide (DMA) as a reaction solvent) to synthesize 5-methoxyacetylamino-2,4 ,6-triiodisophthalic acid dichloride, which interacts with 2,3-dihydroxypropylamine, i.e., 3-amino-1,2-propanediol, in the solvent of dimethylacetamide in the presence of triethylamine to obtain the intermediate iopromide, 5-methoxyacetylamino-2,A4, 6-triiodisophthalic acid (2,3-dihydroxypropylamide chloride, which is used to obtain iopromide.

However, these generally accepted methods for obtaining iopromide intermediates have disadvantages in terms of long reaction time requirements, the use of a large amount of solvent, and low yield. In addition, an additional process is necessary to remove the dimeric compounds that are obtained as co-products in which the 2,3-dihydroxypropylamine

From the group are inserted into both of the two carbonyl chloride fragments.

Accordingly, there is a need for the development of a new method of obtaining the iopromide intermediate, which will improve the efficiency of the reaction and does not require any additional co-product removal process.

Disclosure) (Technical Problem)

The authors of the invention discovered that 5-amino-2,4,6-triiodisophthalic acid dichloride can interact with methoxyacetyl chloride using 1,4-dioxane as a reaction solvent to obtain 5-methoxyacetylamino-2,4,6-triiododisophthalic acid dichloride, which can react with 3-amino-1,2-propanediol using a solvent mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol as the reaction solvent to give the iopromide intermediate in a shorter reaction time, using less solvent, and with more in high yield, and which also allows isolation of dimers at the crystallization stage, using ethyl acetate (EA) and water without an additional dimer removal process, and isolation of the starting material, thus completing the present invention. (Technical solution)

The invention relates to a method of obtaining the iopromide intermediate, which improves the efficiency of the reaction and does not require any additional dimer removal process.

Positive effects

In the invention, 5-amino-2,4,6-triiodisophthalic acid dichloride interacts with Kk! methoxyacetyl chloride using 1,4-dioxane as a reaction solvent to obtain

B-methoxyacetylamino-2,4,6-triiodisophthalic acid dichloride, which reacts with 3-amino-1,2-propanediol using a solvent mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol as a reaction solvent, obtaining an intermediate of iopromide for a shorter reaction time, using a smaller amount of solvent, and with a higher yield, and it is possible to isolate the dimers at the crystallization stage using ethyl acetate (EA) and water without an additional dimer removal process, and it is also possible to isolate the starting material.

And the best way)

In order to achieve the above, the invention relates to a method for preparing a compound of chemical formula 1, as shown in the following reaction scheme 1.

Reaction scheme 11

Oh ns Oz And about 1.4-di

AND-. and | 4-dioxan o Z t y ppenitanosntneotkotnnia ; ! - Me0 - !

N "Aa cha stage 1 MeO.. day 2 | N

Io Z Io 2 1

In detail, the invention relates to a method of obtaining the compound of chemical formula 1, namely, the first intermediate iopromide, using 1,4-dioxane as a reaction solvent, as shown in the above reaction scheme 1.

That is, the invention relates to the method of obtaining the compound of the following chemical formula 1, which includes the stage (stage 1) of the interaction of the compound of the following chemical formula 2 with the compound of the following chemical formula 3, using 1,4-dioxane as a reaction solvent.

Chemical formula 11)

Oh S

AND

6) meo.. Yes and oh,

Its chemical formula is 21 0. p

What are you doing?

NhM: and Fr

The chemical formula of ZI

Preferably, the step (step 1-1) of crystallization of the compound of chemical formula 1 by adding ethanol can be additionally included after step 1).

Stage 1) is the stage of introducing a methoxyacetyl group into the amino group of 5-amino-2,4,6-triiodisophthalic acid dichloride, using 5-amino-2,4,6-triiodisophthalic acid dichloride, which makes up the main skeleton of iopromide, as a starting material.

The invention is characterized by the fact that 1,4-dioxane is used as a reaction solvent in stage 1).

Generally, dimethylformamide (DMF) was used in US patent Mo 4,364,921, and dimethylacetamide (DMA) was used in Korean patent Mo 10-1098553 as the reaction solvent of stage 1) in the preparation of iopromide. However, conventional methods suffer from the disadvantages of requiring a long reaction time, using a large amount of solvent, and obtaining a low yield. For example, when DMF was used, the reaction time was about 20 hours, the solvent was needed in an amount of about 2.9 L per 1 kg of starting material, and the yield was 74 95. In addition, when DMA was used, the reaction time was about 17 hours, and the solvent was required in an amount of approximately 1.26 liters per 1 kg of starting material.

In the invention, however, the reaction time was reduced to about 2-4 hours, the amount of solvent used was significantly reduced to about 0.5 L per 1 kg of starting material, while the yield was increased to 92-93 95 by using 1,4-dioxane as the reaction solvent (Examples 1 and 2).

In the invention, the compound of chemical formula 3, namely, methoxyacetyl chloride, which is the starting material of stage 1), can be directly obtained by a known method (Example 1) or purchased from commercially available sources (Example 2). In particular, methoxyacetyl chloride can be obtained by the interaction of methoxyacetic acid and thionyl chloride.

In the invention, the reaction temperature at stage 1) can be preferably 80-907C. If the reaction temperature is lower than 80°C, there is a problem that the reaction rate becomes slow, thereby increasing the reaction time. If the reaction temperature is higher than 90°C, there is a problem that impurities may be formed, thereby reducing the yield.

In the invention, the reaction time of stage 1) can be preferably 2-4 hours. If the reaction time is less than 2 hours, there is a problem that the reaction may not be completed and thus the starting material remains. Generally, the reaction can be completed within 4 hours, and thus a reaction time of more than 4 hours may not be necessary.

Stage 1-1) is a stage of increasing the purity of the compound of chemical formula 1 by crystallization of the compound of chemical formula 1 by adding ethanol to the solution with the reaction product containing the compound of chemical formula 1 obtained in stage 1).

In the invention, the amount of ethanol added at stage 1-1) can be preferably 1-10 volumes, more preferably 3-8 volumes, and most preferably 6 volumes, relative to 1 volume of 1,4- dioxane

In the invention, the crystallization temperature for stage 1-1) can be 10-1576.

In the invention, the compound of chemical formula 1, which is obtained after crystallization at stage 1-1), can be washed with water, and then dried at 440-600.

In addition, the invention relates to a method of obtaining a compound of chemical formula 4 from a compound of chemical formula 1 obtained by the above-mentioned method, as shown in the following reaction scheme 2.

Reaction scheme 21

O.S. -c and OH /z,4-Dioxane (or TGFUTS | I o. grade - N. A. Durtya o t zm OH

Me. is OT Stage 2 Meb--k ze No ON

But in! But 1 4

In detail, the invention relates to a method of obtaining the compound of chemical formula 4, namely, the second intermediate of iopromide, from the compound of chemical formula 1, namely, the first intermediate of iopromide, using a solvent mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol as of the reaction solvent, as shown in reaction scheme 2.

That is, the invention relates to the method of obtaining the compound of the following chemical formula 4, which includes the stage (stage 2) of the interaction of the compound of the chemical formula 1 with the compound of the following chemical formula 5 using a solvent mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol as a reaction solvent

Its chemical formula is 41

OH OS

HOW

N month S.A.J.M. J.O.O

N E she;

Chemical formula 11)

Oh c

AND

From

Me. M residential complex

NN | o)

Chemical formula 5) tm. Zholon

Preferably, the step (step 2-1) of crystallization of the compound of chemical formula 4 by adding ethyl acetate (EA) and water can be additionally included after step 2).

Preferably, the step (step 3) of isolating the compound of chemical formula 1 from the ethyl acetate (EA) layer can be additionally included after step 2-1).

Stage 2) is the stage of introducing a 2,3-dihydroxypropylamino group into one of the two carbonyl chloride fragments present in the compound of chemical formula 1, by the interaction of the compound of chemical formula 1 and the compound of chemical formula 5.

In the invention, the compound of chemical formula 1 can be a compound obtained by the same method as in reaction scheme 1 or purchased from commercially available sources.

In the invention, the ratio in the mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol can be preferably 0.5-4: 1 (vol./o6.).

In the invention, stage 2) can be carried out in the presence of triethylamine (TEA) as a base.

In the invention, a solvent mixture of tetrahydrofuran (THF) and isopropanol is used more preferably as a reaction solvent of stage 2).

Typically, upon introduction of a 2,3-dihydroxypropylamino group into the carbonyl chloride moiety present in a compound of chemical formula 1, a dimeric compound of the following chemical formula 6, in which 2,3-dihydroxypropylamino groups are introduced into both of the two carbonyl chloride moieties, can be obtained as a co-product, together with the compound of chemical formula 4, in which the 2,3-dihydroxypropylamino group is introduced into one of the two carbonyl chloride groups.

Its chemical formula 6)

Finn

N o-IM. M lon

I. "shchi! | N me". J MAM OM M oon n o,

However, when a solvent mixture of THF and isopropanol is used as the reaction solvent in step 2), the formation of dimers can be minimized, and moreover, the reagent 3-amino-1,2-propanediol can also function as a base. Therefore, additional application of the base may not be necessary (Example 5).

Accordingly, the invention is also characterized by the fact that THF is used as a reaction solvent in stage 2) to minimize the formation of dimers.

In addition, in the invention, dichloromethane can be additionally added as a reaction solvent in stage 2). When dichloromethane is additionally added as a reaction solvent, the product, namely, the compound of chemical formula 4 is obtained in solid form without an additional crystallization step (steps 2-1), and preferably the separation of the product becomes easier (Example 5).

In the invention, the amount of added dichloromethane can be 0.5-2 volumes in relation to 1 volume of isopropanol.

In the invention, the reaction temperature at stage 2) can be preferably 0-107C. If the reaction temperature is lower than 0"C, there is a problem that the reaction rate becomes slow, thereby increasing the reaction time. If the reaction temperature is higher than 10"C, there is a problem that the formation of dimers increases.

In the invention, the reaction time at stage 2) can be preferably 1-2 hours. If the reaction time is less than 1 hour, there is a problem that the reaction may not be completed and thus the starting material may remain. As a rule, the reaction can be completed within 2 hours, and thus a reaction time of more than 2 hours. may not be necessary.

Stage 2-1) is the stage of increasing the purity of the compound of chemical formula 4 by crystallization of the compound of chemical formula 4 by adding ethyl acetate (EA) and water to the solution with the reaction product containing the compound of chemical formula 4 obtained in stage 2), and also separating the starting material and co-products from the product by dissolving the starting substance of the compound of chemical formula 1 in the EA layer and the dimer of the co-product in the aqueous layer and precipitation of the product, the compound of chemical formula 4 in the form of a crystal.

In the conventional preparation of iopromide, an additional removal method is necessary to separate and remove the dimeric compound of chemical formula 6, which is obtained as

It is a co-product from the compound of chemical formula 4. In particular, additional acetylation is performed to remove the dimeric compound in Korean patent Mo 10-1098553.

In the invention, however, it is possible to separate the dimers using a specific crystallization solvent without an additional process as in step 2-1). In addition, there is an advantage in that it is possible to isolate the starting substance as well as dimers.

In the invention, the ratio of the mixture of ethyl acetate (EA) and water in stage 2-1) can be preferably 0.5-2: 1 (v/v).

Stage 3) is a stage for isolating the compound of chemical formula 1, which is the starting material, and which is soluble and remains in the ethyl acetate (EA) layer after stage 2-1). The starting material thus isolated can be repeatedly used in the reaction in step 2) to further obtain the compound of chemical formula 4. Accordingly, the overall yield can be improved.

(method according to the invention)

In the document, the invention will be described in detail with reference to the following examples. However, these examples are provided for illustration purposes only, and the invention is not intended to be limited by these examples.

Example 1

Preparation of 5-methoxyacetylamino-2,4,b-triiodisophthalic acid dichloride (Chemical formula 1) And 0.8 kg of methoxyacetic acid and 1.0 L of 1,4-dioxane were added to the first reactor, and then cooled to 100. 1.0 kg of thionyl chloride was slowly added dropwise at 0-102С, and then stirred for 1 hour, at the same time maintaining the temperature, thereby synthesizing methoxyacetyl chloride. 2.0 kg of 5-amino-2,4,6-triiodisophthalic acid dichloride was added to the first reactor at room temperature (20-257C), and then stirred at 80-90" for 2-4 hours until the completion of the reaction. After completion reaction, the reaction solution was cooled to 10-157C, and then 6 L of ethanol was added to it. 11.4 L of water was added to the second reactor, and the reaction solution was added dropwise and stirred for 30 min, followed by filtration. After filtration, obtained in as a result, the product was dried in a vacuum at 40-607"C, obtaining the desired compound (compound of chemical formula 1) with a yield of 92 95. "H NMR (DMSO-O6, 500 MHz): 10.18 (s, 1H), 4.03 ( s, 2H), 3.47 (s, ЗН)

Example 2

Preparation of 5-methoxyacetylamino-2,4,b-triiodisophthalic acid dichloride (Chemical formula 1) II 2.0 kg of 5-amino-2,4,6-triiodisophthalic acid dichloride and 1.0 l of 1,4-dioxane were added to the first reactor at room temperature (20-257"C), and then 0.95 kg of methoxyacetyl chloride was added to it. The mixture was stirred at 80-90" for 2-4 hours. completion of the reaction.

After completion of the reaction, the reaction solution was cooled to 10-157C, and then ethanol was added to it. 11.4 l of water was added to the second reactor, and the reaction solution was added dropwise and stirred for 30 min, followed by filtration. After filtration, the resulting product was dried in a vacuum at 40-60"C, obtaining the desired compound (compound of chemical formula 1) with a yield of 93 95. 1H NMR (DMSO-O6, 500 MHz): 10.18 (s, 1H) , 4.03 (c, 2H), 3.47 (c, ZN).

Example C

Preparation of 5-methoxyacetylamino-2,4,6-triiodisophthalic acid (2,3-dihydroxypropyl)amide chloride (Chemical formula 4)

Stage 1 2.02 kg of 5-methoxyacetylamino-2,4,6-triiodisophthalic acid dichloride was added to the reactor and dissolved in 4.04 L of 1,4-dioxane and 2.02 L of isopropanol was added, and then the mixture was cooled to 0-107 "C. 0.18 kg of triethylamine was added, and 0.17 kg of 3-amino-1,2-propanediol, dissolved in 2.02 l of isopropanol, was added dropwise. The mixture was stirred for 1-2 hours, while maintaining the same temperature. After completion of the reaction, the resulting product was concentrated at a temperature below 40"C. After concentration, 20.2 L of ethyl acetate and 20.2 L of water were added and mixed. The mixture was cooled to 33°C and kept for 1 hour, and then the crystals were filtered and dried in a vacuum at 40-60, obtaining the desired compound with a yield of 50 95. In addition, the organic layer (ethyl acetate layer) was separated from the filtrate and processed magnesium sulfate, and then filtered and concentrated to give 5-methoxyacetylamino-2,4,6-triiododisophthalic acid dichloride.

Stage 2 2.02 l of 1,4-dioxane and 1.01 l of isopropanol were added to 5-methoxyacetylamino-2,4,6-triiodisophthalic acid dichloride, which was isolated in stage 1. The mixture was dissolved and cooled to 0-10"C. 0.155 kg of triethylamine was added, and 0.142 kg of 3-amino-1,2-propanediol dissolved in 1.01 L of isopropanol was added dropwise. The mixture was stirred for 1-2 h while maintaining the same temperature. After the reaction was complete , the resulting product was concentrated at a temperature below 40"C. After concentration, 10.1 L of ethyl acetate and 10.01 L of water were added and mixed. The mixture was cooled to 33°C and kept for 1 hour, and then the crystals were filtered and dried in a vacuum at 40-6070, obtaining the desired compound with a yield of 31 95. The desired compound was obtained with a yield of 81 95 for the first and second reactions. 1TH NMR (DMSO-O6, 500 MHz): 10.15 (d, MH), 8.72 (t, MH), 4.03 (s, 2H), 3.70 (d, 2H), 3.49 (d ,

AN), 3.20-3.14 (m, 2H).

Example 4

Preparation of 5-methoxyacetylamino-2,4,6-triiododisophthalic acid (2,3-dihydroxypropyl)amide chloride (Chemical formula 4) II 2.02 kg of 5-methoxyacetylamino-2,4,6-triiododisophthalic acid dichloride was added to the reactor, and then 4.04 L of 1,4-dioxane and 2.02 L of isopropanol were added. The mixture was dissolved and cooled to 0-107"C. 0.37 kg of triethylamine was added, and 0.33 kg of 3-bo amino-1,2-propanediol, dissolved in 2.02 l of isopropanol, was added dropwise. The mixture was stirred for 1- 2 h., while maintaining the same temperature. After the completion of the reaction, the resulting product was concentrated below 40"C. After concentration, 20.2 L of ethyl acetate and 20.2 L of water were added and mixed. The mixture was cooled to 3"C and kept for 1 hour, and then the crystals were filtered and dried in vacuum at 40-607"C, obtaining the desired compound with a yield of 78 95. 1TN NMR (DMSO-O6, 500 MHz): 10, 15 (d, MH), 8.72 (t, MH), 4.03 (s, 2H), 3.70 (d, 2H), 3.49 (d,

AN), 3.20--3.14 (m, 2H).

Example 5

Preparation of 5-methoxyacetylamino-2,4,6-triiodisophthalic acid (2,3-dihydroxypropyl)amide chloride (Chemical formula 4) 2.02 kg of 5-methoxyacetylamino-2,4,6-triiodisophthalic acid dichloride was added to the reactor, and then 6.06 L of tetrahydrofuran and 2.02 L of isopropanol were added. The mixture was dissolved and cooled to 0-107C. 0.47 kg of 3-amino-1,2-propanediol, dissolved in 1.35 l of isopropanol, was added dropwise, at the same time maintaining the temperature at 0-107"C. After completion of the first dropwise addition, 2.02 l of dichloromethane was added and stirred for 1 hour. The second dropwise addition of 0.09 kg of 3-amino-1,2-propanediol dissolved in 0.2 l of isopropanol was carried out at the same temperature, and the third dropwise addition of 0.02 kg of 3-amino -1,2-propanediol dissolved in 0.06 L of isopropanol was carried out at the same temperature. After the reaction was completed, 0.1 kg of concentrated hydrochloric acid was added, and the reaction solution and crystals were transferred to the second reactor. The reaction solution was concentrated at 40- 507 C, and cooled to 10-157 C. 8.08 L of ethyl acetate and 14.14 L of water were added to the second reactor, and then stirred. The mixture was kept at the same temperature for 30 minutes to 1 hour, and then the crystals were filtered and dried in vacuum at 40-60"C, obtaining the desired compound in a yield of 80 95. 1 NMR (DMSO-O6, 500 MHz): 10.15 (d, MH), 8.72 (t, MH), 4.03 (s, 2H), 3.70 (d, 2H), 3.49 (d,

AN), 3.20--3.14 (m, 2H).

Claims (16)

FORMULA OF THE INVENTION Zo 1. The method of obtaining the compound of the chemical formula 1, which includes a stage (stage 1), in which the compound of the chemical formula 2 is subjected to interaction with the compound of the chemical formula 3, using 1,4-dioxane as a reaction solvent: (c) SI ( in) mo. D SI M N ! O Chemical formula 1) (c) SI o nm I Tv) g. ; Chemical formula 21 (c) mo. DU ЗB SI, YChemical formula C) 2. The method according to claim 1, which additionally includes the stage (stage 1-1) of crystallization of the compound of chemical formula 1 by adding ethanol after stage 1. 3. The method according to claim 1, in which the reaction of stage 1 is carried out at a temperature of 80-90 "С. 4. The method according to claim 1, in which the reaction of stage 1 is carried out within 2-4 hours. 40 5. The method of obtaining the compound of chemical formula 4, which includes a stage (stage 2), in which the compound of chemical formula 1, which is obtained according to the method according to claim 1, is subjected to interaction with the compound of chemical formula 5, using a mixture of solvents with 1.4 -dioxane or tetrahydrofuran (THF) and isopropanol as a reaction solvent: (c) SI (c) on H me. ДЖ КОЖ он МН ! o "Chemical formula 4) (c) SI (c) mo. si M N I Ge) 6. ; (Chemical formula 11) on. ZhK oon. Chemical formula 5) b. The method according to claim 5, which additionally includes the stage (stage 2-1) of crystallization of the compound of chemical formula 4 by adding ethyl acetate (EA) and water after stage 2. 7. The method according to claim 6, which additionally includes the stage (stage 3) of isolating the compound of chemical formula 1 from the ethyl acetate (EA) layer after stage 2-1. 8. The method according to claim 5, in which the compound of chemical formula 1 is obtained by the method according to claim 1 or 2. 9. The method according to claim 5, in which 1,4-dioxane or tetrahydrofuran (THF) and isopropanol are mixed in a mixture of solvents in a ratio of 0.5-4:1 (vol./06.). 10. The method according to claim 5, in which stage 2 is carried out in the presence of triethylamine (TEA) or 3-amino-1,2-propanediol as a base. 11. The method according to claim 5, in which a solvent mixture of tetrahydrofuran (THF) and isopropanol is used as a reaction solvent. 12. The method according to claim 5, in which dichloromethane was additionally added as a reaction solvent. 13. The method according to claim 12, in which the amount of dichloromethane added is 0.5-2 volumes relative to 1 volume of isopropanol. 14. The method according to claim 5, in which the reaction of stage 2 is carried out at a temperature of 0-10 "С. 15. The method according to claim 5, in which the reaction of stage 2 is carried out within 1-2 hours. 16. The method according to claim 6, in which ethyl acetate (EA) and water in stage 2-1 are used in a ratio of 0.5-2:1 (vol./06.).