WO2015060657A1 - A method for preparing an intermediate of iopromide - Google Patents
A method for preparing an intermediate of iopromide Download PDFInfo
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- WO2015060657A1 WO2015060657A1 PCT/KR2014/009991 KR2014009991W WO2015060657A1 WO 2015060657 A1 WO2015060657 A1 WO 2015060657A1 KR 2014009991 W KR2014009991 W KR 2014009991W WO 2015060657 A1 WO2015060657 A1 WO 2015060657A1
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- iopromide
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- XMMYZMFHHBOQJF-UHFFFAOYSA-N CC(c1c(C)c(C(C)=O)c(C)c(NC(COC)=O)c1C)=O Chemical compound CC(c1c(C)c(C(C)=O)c(C)c(NC(COC)=O)c1C)=O XMMYZMFHHBOQJF-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B43/00—Formation or introduction of functional groups containing nitrogen
- C07B43/06—Formation or introduction of functional groups containing nitrogen of amide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
- C07C233/15—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
Definitions
- 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 a specific reaction solvent is used to improve reaction efficiency and no additional process of removing dimers is required.
- 5-methoxyacetylamino-2,4,6-triiodo-isophthalic acid-[(2,3-dihydroxy-N-methyl-propyl)-(2,3-dihydroxypropyl)]-diamide (hereinafter, referred to as "iopromide") is widely used as an X-Ray or CT contrast agent.
- a method for preparing iopromide is disclosed in US Patent No. 4,364,921, in which methoxyacetic acid is reacted with thionyl chloride using dimethylformamide (DMF) as a reaction solvent to produce methoxyacetyl chloride, and then 5-amino-2,4,6-triiodoisophthalic acid dichloride is added to and reacted with methoxyacetyl chloride to produce 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride, which is reacted with 2,3-dihydroxypropylamine, that is, 3-amino-1,2-propanediol to produce an intermediate of iopromide, 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride used for preparation of iopromide.
- DMF dimethylformamide
- Korean Patent No. 10-1098553 also discloses a method for preparing iopromide, in which 5-amino-2,4,6-triiodoisophthalic acid dichloride is reacted with methoxyacetyl chloride using dimethylacetamide (DMA) as a reaction solvent to synthesize 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride, which is reacted with 2,3-dihydroxypropylamine, that is, 3-amino-1,2-propanediol, in a dimethylacetamide solvent in the presence of triethylamine to produce an intermediate of iopromide, 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride used for preparation of iopromide.
- DMA dimethylacetamide
- the present inventors found that 5-amino-2,4,6-triiodoisophthalic acid dichloride can be reacted with methoxyacetyl chloride using 1,4-dioxane as a reaction solvent to produce 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride, which can be reacted with 3-amino-1,2-propanediol using a solvent mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol as a reaction solvent to obtain an intermediate of iopromide within a shorter reaction time, using a smaller amount of solvent, and with a higher yield, and also enabling the recovery of dimers through a crystallization step using ethyl acetate (EA) and water without an additional process of removing dimers, and the recovery of the starting material as well, thereby completing the present invention.
- EA ethyl acetate
- An objective of the present invention is to provide a method for preparing an intermediate of iopromide, which improves reaction efficiency and requires no additional process of removing dimers.
- 5-amino-2,4,6-triiodoisophthalic acid dichloride is reacted with methoxyacetyl chloride using 1,4-dioxane as a reaction solvent to produce 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride, which is reacted with 3-amino-1,2-propanediol using a solvent mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol as a reaction solvent to obtain an intermediate of iopromide with a shorter reaction time, a smaller amount of solvent, and a higher yield, and it is possible to recover dimers through a crystallization step using ethyl acetate (EA) and water without an additional process of removing dimers, and it is also possible to recover the starting material.
- EA ethyl acetate
- the present invention provides a method for preparing a compound represented by Chemical Formula 1, as shown in the following Reaction Scheme 1.
- the present invention provides a method for preparing the compound represented by Chemical Formula 1, namely, the first intermediate of iopromide, using 1,4-dioxane as a reaction solvent, as shown in the above Reaction Scheme 1.
- the present invention provides a method for preparing the compound represented by the following Chemical Formula 1, comprising a step (step 1) of reacting a compound represented by the following Chemical Formula 2 with a compound represented by the following Chemical Formula 3 using 1,4-dioxane as a reaction solvent.
- a step (step 1-1) of crystallizing the compound represented by Chemical Formula 1 by adding ethanol may be further comprised after the step 1).
- the step 1) is a step of introducing a methoxyacetyl group to an amino group of 5-amino-2,4,6-triiodoisophthalic acid dichloride using 5-amino-2,4,6-triiodoisophthalic acid dichloride which constitutes a basic skeleton of iopromide, as a starting material.
- the present invention is characterized in that 1,4-dioxane is used as a reaction solvent in step 1).
- dimethylformamide (DMF) was used in US Patent No. 4,364,921 and dimethylacetamide (DMA) was used in Korean Patent No. 10-1098553 as the reaction solvent of step 1) in the preparation of iopromide.
- DMF dimethylformamide
- DMA dimethylacetamide
- the conventional methods have disadvantages of requiring a long reaction time, using large amount of solvent and having low yield. Specifically, when DMF was used, the reaction time was approximately 20 hours, the solvent was needed in an amount of approximately 2.9 L per 1 kg of the starting material, and the yield was 74%. Further, when DMA was used, the reaction time was approximately 17 hours, and the solvent was needed in an amount of approximately 1.26 L per 1 kg of the starting material.
- the reaction time was shortened to approximately 2 to 4 hours, the amount of the solvent used was remarkably reduced by approximately 0.5 L per 1 kg of the starting material, whereas the yield was increased to 92 to 93% by using 1,4-dioxane as the reaction solvent (Examples 1 and 2).
- the compound represented by Chemical Formula 3, namely, methoxyacetyl chloride, which is the starting material of step 1) can be directly prepared by the known method (Example 1), or purchased from commercially available sources (Example 2).
- methoxyacetyl chloride can be prepared by reacting methoxyacetic acid and thionyl chloride.
- the reaction temperature of step 1) may be preferably 80 to 90°C. 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 can be produced, thereby lowing the yield.
- the reaction time of step 1) may be preferably 2 to 4 hours. If the reaction time is shorter than 2 hours, there is a problem that the reaction may not be completed and thus the starting material remains. Typically, the reaction can be completed within 4 hours, and thus a reaction time of over 4 hours may not be needed.
- the step 1-1) is a step of increasing the purity of the compound represented by Chemical Formula 1 by crystallizing the compound represented by Chemical Formula 1 by adding ethanol to a solution with reaction product containing the compound represented by Chemical Formula 1 produced in step 1).
- the amount of ethanol added in step 1-1) may be preferably 1 to 10 volumes, more preferably 3 to 8 volumes, and most preferably 6 volumes, relative to 1 volume of 1,4-dioxane.
- the crystallization temperature of step 1-1) may be 10 to 15°C.
- the compound represented by Chemical Formula 1 which is obtained after crystallization of step 1-1) may be washed with water, and then dried at 40 to 60°C.
- the present invention provides a method for preparing a compound represented by Chemical Formula 4 from the compound represented by Chemical Formula 1 prepared by the above method, as shown in the following Reaction Scheme 2.
- the present invention provides a method for preparing the compound represented by Chemical Formula 4, namely, the second intermediate of iopromide from the compound represented by Chemical Formula 1, namely, the first intermediate of iopromide, by using a solvent mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol as a reaction solvent, as shown in Reaction Scheme 2.
- the present invention provides a method for preparing the compound represented by the following Chemical Formula 4, comprising a step (step 2) of reacting the compound represented by Chemical Formula 1 with a compound represented by the following Chemical Formula 5 using a solvent mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol as a reaction solvent.
- step 2 of reacting the compound represented by Chemical Formula 1 with a compound represented by the following Chemical Formula 5 using a solvent mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol as a reaction solvent.
- a step (step 2-1) of crystallizing the compound represented by Chemical Formula 4 by adding ethyl acetate (EA) and water may be further comprised after the step 2).
- a step (step 3) of recovering the compound represented by Chemical Formula 1 from the ethyl acetate (EA) layer may be further comprised after the step 2-1).
- the step 2) is a step of introducing a 2,3-dihydroxypropylamino group to one of two carbonyl chloride moieties present in the compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 1 and the compound represented by Chemical Formula 5.
- the compound represented by Chemical Formula 1 may be a compound prepared in the same manner as Reaction Scheme 1, or purchased from commercially available sources.
- the mixing ratio of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol may be preferably 0.5-4 : 1 (v/v).
- the step 2) may be performed in the presence of triethylamine (TEA) as a base.
- TAA triethylamine
- a solvent mixture of tetrahydrofuran (THF) and isopropanol is more preferably used as the reaction solvent of the step 2).
- a dimeric compound represented by the following Chemical Formula 6, in which 2,3-dihydroxypropylamino groups are introduced to both of the two carbonyl chloride moieties may be produced as a by-product, together with the compound represented by Chemical Formula 4, in which a 2,3-dihydroxypropylamino group is introduced to one of the two carbonyl chloride groups.
- the present invention is also characterized in that THF is used as the reaction solvent in step 2) to minimize production of dimers.
- dichloromethane may be further added as the reaction solvent in step 2).
- a product namely, the compound represented by Chemical Formula 4 is produced in a solid form without an additional crystallization step (step 2-1), and advantageously separation of the product becomes easier (Example 5).
- the amount of dichloromethane added may be 0.5-2 volumes relative to 1 volume of isopropanol.
- the reaction temperature of step 2) may be preferably 0 to 10°C. 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 production of dimers is increased.
- the reaction time of step 2) may be preferably 1 to 2 hours. If the reaction time is shorter than 1 hour, there is a problem that the reaction may not be completed and thus the starting material can remain. Typically, the reaction can be completed within 2 hours, and thus a reaction time of over 2 hours may not be needed.
- the step 2-1) is a step of increasing the purity of the compound represented by Chemical Formula 4 by crystallizing the compound represented by Chemical Formula 4 by adding ethyl acetate (EA) and water to a solution with reaction product containing the compound represented by Chemical Formula 4, which is produced in the step 2), and also separating the starting material and by-products from the product by dissolving the starting material compound represented by Chemical Formula 1 in an EA layer and a by-product dimer in a water layer and by precipitating the product, the compound represented by Chemical Formula 4, as a crystal.
- EA ethyl acetate
- step 2-1 it is possible to separate dimers using a specific crystallization solvent without an additional process, as in step 2-1). Further, there is an advantage that it is possible to recover the staring material as well as the dimers.
- the mixing ratio of ethyl acetate (EA) and water of step 2-1) may be preferably 0.5-2 : 1 (v/v).
- the step 3) is a step of recovering the compound represented by Chemical Formula 1, which is the starting material being dissolved and remaining in the ethyl acetate (EA) layer after step 2-1).
- the starting material thus recovered can be reused in the reaction of step 2) so as to additionally obtain the compound represented by Chemical Formula 4. Accordingly, the overall yield can be improved.
- the mixture was cooled to 3°C, and aged for 1 hour, and then crystals were filtered and dried under vacuum at 40 to 60°C to obtain the title compound with a yield of 31%.
- the title compound was obtained with a yield of 81% through the first and second reactions.
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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-1,2-propanediol using a solvent mixture of 1,4-dioxane 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 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 a specific reaction solvent is used to improve reaction efficiency and no additional process of removing dimers is required.
5-methoxyacetylamino-2,4,6-triiodo-isophthalic acid-[(2,3-dihydroxy-N-methyl-propyl)-(2,3-dihydroxypropyl)]-diamide (hereinafter, referred to as "iopromide") is widely used as an X-Ray or CT contrast agent.
A method for preparing iopromide is disclosed in US Patent No. 4,364,921, in which methoxyacetic acid is reacted with thionyl chloride using dimethylformamide (DMF) as a reaction solvent to produce methoxyacetyl chloride, and then 5-amino-2,4,6-triiodoisophthalic acid dichloride is added to and reacted with methoxyacetyl chloride to produce 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride, which is reacted with 2,3-dihydroxypropylamine, that is, 3-amino-1,2-propanediol to produce an intermediate of iopromide, 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride used for preparation of iopromide.
Korean Patent No. 10-1098553 also discloses a method for preparing iopromide, in which 5-amino-2,4,6-triiodoisophthalic acid dichloride is reacted with methoxyacetyl chloride using dimethylacetamide (DMA) as a reaction solvent to synthesize 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride, which is reacted with 2,3-dihydroxypropylamine, that is, 3-amino-1,2-propanediol, in a dimethylacetamide solvent in the presence of triethylamine to produce an intermediate of iopromide, 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride used for preparation of iopromide.
However, these conventional methods for preparing the intermediates of iopromide have disadvantages of requiring a long reaction time, using a large amount of solvent and having a low yield. Further, an additional process is required in order to remove dimeric compounds produced as by-products, in which 2,3-dihydroxypropylamino groups are introduced to both of two carbonyl chloride moieties.
Accordingly, there is a demand for the development of a novel method for preparing an intermediate of iopromide, which improves reaction efficiency and requires no additional process of removing by-products.
The present inventors found that 5-amino-2,4,6-triiodoisophthalic acid dichloride can be reacted with methoxyacetyl chloride using 1,4-dioxane as a reaction solvent to produce 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride, which can be reacted with 3-amino-1,2-propanediol using a solvent mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol as a reaction solvent to obtain an intermediate of iopromide within a shorter reaction time, using a smaller amount of solvent, and with a higher yield, and also enabling the recovery of dimers through a crystallization step using ethyl acetate (EA) and water without an additional process of removing dimers, and the recovery of the starting material as well, thereby completing the present invention.
An objective of the present invention is to provide a method for preparing an intermediate of iopromide, which improves reaction efficiency and requires no additional process of removing dimers.
In the present invention, 5-amino-2,4,6-triiodoisophthalic acid dichloride is reacted with methoxyacetyl chloride using 1,4-dioxane as a reaction solvent to produce 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride, which is reacted with 3-amino-1,2-propanediol using a solvent mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol as a reaction solvent to obtain an intermediate of iopromide with a shorter reaction time, a smaller amount of solvent, and a higher yield, and it is possible to recover dimers through a crystallization step using ethyl acetate (EA) and water without an additional process of removing dimers, and it is also possible to recover the starting material.
In order to achieve the above objective, the present invention provides a method for preparing a compound represented by Chemical Formula 1, as shown in the following Reaction Scheme 1.
[Reaction Scheme 1]
In detail, the present invention provides a method for preparing the compound represented by Chemical Formula 1, namely, the first intermediate of iopromide, using 1,4-dioxane as a reaction solvent, as shown in the above Reaction Scheme 1.
That is, the present invention provides a method for preparing the compound represented by the following Chemical Formula 1, comprising a step (step 1) of reacting a compound represented by the following Chemical Formula 2 with a compound represented by the following Chemical Formula 3 using 1,4-dioxane as a reaction solvent.
[Chemical Formula 1]
[Chemical Formula 2]
[Chemical Formula 3]
Preferably, a step (step 1-1) of crystallizing the compound represented by Chemical Formula 1 by adding ethanol may be further comprised after the step 1).
The step 1) is a step of introducing a methoxyacetyl group to an amino group of 5-amino-2,4,6-triiodoisophthalic acid dichloride using 5-amino-2,4,6-triiodoisophthalic acid dichloride which constitutes a basic skeleton of iopromide, as a starting material.
The present invention is characterized in that 1,4-dioxane is used as a reaction solvent in step 1).
Conventionally, dimethylformamide (DMF) was used in US Patent No. 4,364,921 and dimethylacetamide (DMA) was used in Korean Patent No. 10-1098553 as the reaction solvent of step 1) in the preparation of iopromide. However, the conventional methods have disadvantages of requiring a long reaction time, using large amount of solvent and having low yield. Specifically, when DMF was used, the reaction time was approximately 20 hours, the solvent was needed in an amount of approximately 2.9 L per 1 kg of the starting material, and the yield was 74%. Further, when DMA was used, the reaction time was approximately 17 hours, and the solvent was needed in an amount of approximately 1.26 L per 1 kg of the starting material.
In the present invention, however, the reaction time was shortened to approximately 2 to 4 hours, the amount of the solvent used was remarkably reduced by approximately 0.5 L per 1 kg of the starting material, whereas the yield was increased to 92 to 93% by using 1,4-dioxane as the reaction solvent (Examples 1 and 2).
In the present invention, the compound represented by Chemical Formula 3, namely, methoxyacetyl chloride, which is the starting material of step 1), can be directly prepared by the known method (Example 1), or purchased from commercially available sources (Example 2). Specifically, methoxyacetyl chloride can be prepared by reacting methoxyacetic acid and thionyl chloride.
In the present invention, the reaction temperature of step 1) may be preferably 80 to 90℃. If the reaction temperature is lower than 80℃, there is a problem that the reaction rate becomes slow, thereby increasing the reaction time. If the reaction temperature is higher than 90℃, there is a problem that impurities can be produced, thereby lowing the yield.
In the present invention, the reaction time of step 1) may be preferably 2 to 4 hours. If the reaction time is shorter than 2 hours, there is a problem that the reaction may not be completed and thus the starting material remains. Typically, the reaction can be completed within 4 hours, and thus a reaction time of over 4 hours may not be needed.
The step 1-1) is a step of increasing the purity of the compound represented by Chemical Formula 1 by crystallizing the compound represented by Chemical Formula 1 by adding ethanol to a solution with reaction product containing the compound represented by Chemical Formula 1 produced in step 1).
In the present invention, the amount of ethanol added in step 1-1) may be preferably 1 to 10 volumes, more preferably 3 to 8 volumes, and most preferably 6 volumes, relative to 1 volume of 1,4-dioxane.
In the present invention, the crystallization temperature of step 1-1) may be 10 to 15℃.
In the present invention, the compound represented by Chemical Formula 1 which is obtained after crystallization of step 1-1) may be washed with water, and then dried at 40 to 60℃.
Further, the present invention provides a method for preparing a compound represented by Chemical Formula 4 from the compound represented by Chemical Formula 1 prepared by the above method, as shown in the following Reaction Scheme 2.
[Reaction Scheme 2]
In detail, the present invention provides a method for preparing the compound represented by Chemical Formula 4, namely, the second intermediate of iopromide from the compound represented by Chemical Formula 1, namely, the first intermediate of iopromide, by using a solvent mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol as a reaction solvent, as shown in Reaction Scheme 2.
That is, the present invention provides a method for preparing the compound represented by the following Chemical Formula 4, comprising a step (step 2) of reacting the compound represented by Chemical Formula 1 with a compound represented by the following Chemical Formula 5 using a solvent mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol as a reaction solvent.
[Chemical Formula 4]
[Chemical Formula 1]
[Chemical Formula 5]
Preferably, a step (step 2-1) of crystallizing the compound represented by Chemical Formula 4 by adding ethyl acetate (EA) and water may be further comprised after the step 2).
Preferably, a step (step 3) of recovering the compound represented by Chemical Formula 1 from the ethyl acetate (EA) layer may be further comprised after the step 2-1).
The step 2) is a step of introducing a 2,3-dihydroxypropylamino group to one of two carbonyl chloride moieties present in the compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 1 and the compound represented by Chemical Formula 5.
In the present invention, the compound represented by Chemical Formula 1 may be a compound prepared in the same manner as Reaction Scheme 1, or purchased from commercially available sources.
In the present invention, the mixing ratio of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol may be preferably 0.5-4 : 1 (v/v).
In the present invention, the step 2) may be performed in the presence of triethylamine (TEA) as a base.
In the present invention, a solvent mixture of tetrahydrofuran (THF) and isopropanol is more preferably used as the reaction solvent of the step 2).
Generally, when 2,3-dihydroxypropylamino group is introduced to the carbonyl chloride moiety present in the compound represented by Chemical Formula 1, a dimeric compound represented by the following Chemical Formula 6, in which 2,3-dihydroxypropylamino groups are introduced to both of the two carbonyl chloride moieties, may be produced as a by-product, together with the compound represented by Chemical Formula 4, in which a 2,3-dihydroxypropylamino group is introduced to one of the two carbonyl chloride groups.
[Chemical Formula 6]
However, when a solvent mixture of THF and isopropanol is used as the reaction solvent of the step 2), production of dimers can be minimized, and moreover, the reactant 3-amino-1,2-propanediol may also function as a base. Therefore, additional use of a base may not be required (Example 5).
Accordingly, the present invention is also characterized in that THF is used as the reaction solvent in step 2) to minimize production of dimers.
Further, in the present invention, dichloromethane may be further added as the reaction solvent in step 2). When dichloromethane is further added as the reaction solvent, a product, namely, the compound represented by Chemical Formula 4 is produced in a solid form without an additional crystallization step (step 2-1), and advantageously separation of the product becomes easier (Example 5).
In the present invention, the amount of dichloromethane added may be 0.5-2 volumes relative to 1 volume of isopropanol.
In the present invention, the reaction temperature of step 2) may be preferably 0 to 10℃. If the reaction temperature is lower than 0℃, there is a problem that the reaction rate becomes slow, thereby increasing the reaction time. If the reaction temperature is higher than 10℃, there is a problem that production of dimers is increased.
In the present invention, the reaction time of step 2) may be preferably 1 to 2 hours. If the reaction time is shorter than 1 hour, there is a problem that the reaction may not be completed and thus the starting material can remain. Typically, the reaction can be completed within 2 hours, and thus a reaction time of over 2 hours may not be needed.
The step 2-1) is a step of increasing the purity of the compound represented by Chemical Formula 4 by crystallizing the compound represented by Chemical Formula 4 by adding ethyl acetate (EA) and water to a solution with reaction product containing the compound represented by Chemical Formula 4, which is produced in the step 2), and also separating the starting material and by-products from the product by dissolving the starting material compound represented by Chemical Formula 1 in an EA layer and a by-product dimer in a water layer and by precipitating the product, the compound represented by Chemical Formula 4, as a crystal.
In the conventional preparation of iopromide, an additional removal process is required in order to separate and remove the dimeric compound represented by Chemical Formula 6, which is produced as a by-product, from the compound represented by Chemical Formula 4. Specifically, additional acetylation is performed for removal of the dimeric compound in Korean Patent No. 10-1098553.
In the present invention, however, it is possible to separate dimers using a specific crystallization solvent without an additional process, as in step 2-1). Further, there is an advantage that it is possible to recover the staring material as well as the dimers.
In the present invention, the mixing ratio of ethyl acetate (EA) and water of step 2-1) may be preferably 0.5-2 : 1 (v/v).
The step 3) is a step of recovering the compound represented by Chemical Formula 1, which is the starting material being dissolved and remaining in the ethyl acetate (EA) layer after step 2-1). The starting material thus recovered can be reused in the reaction of step 2) so as to additionally obtain the compound represented by Chemical Formula 4. Accordingly, the overall yield can be improved.
Hereinafter, the present invention will be described in detail with reference to the following Examples. However, these Examples are for illustrative purposes only, and the invention is not intended to be limited by these Examples.
Example 1
Preparation of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride (Chemical Formula 1) I
0.8 kg of methoxyacetic acid and 1.0 L of 1,4-dioxane were added to a first reactor, and then cooled to 10℃. 1.0 kg of thionyl chloride was slowly added dropwise at 0 to 10℃, and then stirred for 1 hour while maintaining the temperature, thereby synthesizing methoxyacetyl chloride. 2.0 kg of 5-amino-2,4,6-triiodoisophthalic acid dichloride was added to the first reactor at room temperature (20 to 25℃), and then stirred at 80 to 90℃ for 2 to 4 hours to complete the reaction. After completion of the reaction, the reaction solution was cooled to 10 to 15℃, and then 6 L of ethanol was added thereto. 11.4 L of water was added to a second reactor and the reaction solution was added dropwise and stirred for 30 minutes, followed by filtration. After filtration, the resultant was dried under vacuum at 40 to 60℃ to obtain the title compound (compound of Chemical Formula 1) with a yield of 92%.
1H NMR(DMSO-D6, 500MHz) : 10.18 (s, 1H), 4.03 (s, 2H), 3.47 (s, 3H)
Example 2
Preparation of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride (Chemical Formula 1) II
2.0 kg of 5-amino-2,4,6-triiodoisophthalic acid dichloride and 1.0 L of 1,4-dioxane were added to the first reactor at room temperature (20 to 25℃), and then 0.95 kg of methoxyacetyl chloride was added thereto. The mixture was stirred at 80 to 90℃ for 2 to 4 hours to complete the reaction. After completion of the reaction, the reaction solution was cooled to 10 to 15℃, and then 6 L of ethanol was added thereto. 11.4 L of water was added to the second reactor and the reaction solution was added dropwise and stirred for 30 minutes, followed by filtration. After filtration, the resultant was dried under vacuum at 40 to 60℃ to obtain the title compound (compound of Chemical Formula 1) in the yield of 93%.
1H NMR(DMSO-D6, 500MHz) : 10.18 (s, 1H), 4.03 (s, 2H), 3.47 (s, 3H)
Example 3
Preparation of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride (Chemical Formula 4, R=H) I
Step 1
2.02 kg of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride was added to a reactor and dissolved in 4.04 L of 1,4-dioxane and 2.02 L of isopropanol added, and then the mixture was cooled to 0 to 10℃. 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 to 2 hours while maintaining the same temperature. After completion of the reaction, the resultant was concentrated below 40℃. After concentration, 20.2 L of ethyl acetate and 20.2 L of water were added and stirred. The mixture was cooled to 3℃, and aged for 1 hour, and then crystals were filtered and dried under vacuum at 40 to 60℃ to obtain the title compound with a yield of 50%. Further, an organic layer (ethyl acetate layer) was recovered from the filtrate, and treated with magnesium sulfate, and then filtered and concentrated to recover 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride.
Step 2
2.02 L of 1,4-dioxane and 1.01 L of isopropanol were added to 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride which was recovered in step 1. The mixture was dissolved and cooled to 0 to 10℃. 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 to 2 hours while maintaining the same temperature. After completion of the reaction, the resultant was concentrated below 40℃. After concentration, 10.1 L of ethyl acetate and 10.1 L of water were added and stirred. The mixture was cooled to 3℃, and aged for 1 hour, and then crystals were filtered and dried under vacuum at 40 to 60℃ to obtain the title compound with a yield of 31%. The title compound was obtained with a yield of 81% through the first and second reactions.
1H NMR(DMSO-D6, 500MHz) : 10.15 (d, NH), 8.72 (t, NH), 4.03 (s, 2H), 3.70 (d, 2H), 3.49 (d, 4H), 3.20~3.14 (m, 2H)
Example 4
Preparation of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride (Chemical Formula 4, R=H) II
2.02 kg of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride was added to a 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 to 10℃. 0.37 kg of triethylamine was added, and 0.33 kg of 3-amino-1,2-propanediol dissolved in 2.02 L of isopropanol was added dropwise. The mixture was stirred for 1 to 2 hours while maintaining the same temperature. After completion of the reaction, the resultant was concentrated below 40℃. After concentration, 20.2 L of ethyl acetate and 20.2 L of water were added and stirred. The mixture was cooled to 3℃, and aged for 1 hour, and then crystals were filtered and dried under vacuum at 40 to 60℃ to obtain the title compound with a yield of 78%.
1H NMR(DMSO-D6, 500MHz) : 10.15 (d, NH), 8.72 (t, NH), 4.03 (s, 2H), 3.70 (d, 2H), 3.49 (d, 4H), 3.20~3.14 (m, 2H)
Example 5
Preparation of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride (Chemical Formula 5, R=H) III
2.02 kg of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride was added to a reactor, and then 6.06 L of tetrahydrofuran and 2.02 L of isopropanol were added. The mixture was dissolved and cooled to 0 to 10℃. 0.47 kg of 3-amino-1,2-propanediol dissolved in 1.35 L of isopropanol was added dropwise while maintaining the temperature at 0 to 10℃. 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 completion of the reaction, 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 to 50℃, and cooled to 10 to 15℃. 8.08 L of ethyl acetate and 14.14 L of water were added to the second reactor, followed by stirring. The mixture was aged at the same temperature for 30 minutes to 1 hour, and then crystals were filtered and dried under vacuum at 40 to 60℃ to obtain the title compound with a yield of 80%.
1H NMR(DMSO-D6, 500MHz) : 10.15 (d, NH), 8.72 (t, NH), 4.03 (s, 2H), 3.70 (d, 2H), 3.49 (d, 4H), 3.20~3.14 (m, 2H)
Claims (16)
- A method for preparing a compound represented by the following Chemical Formula 1, comprising a step (step 1) of reacting a compound represented by the following Chemical Formula 2 with a compound represented by the following Chemical Formula 3 using 1,4-dioxane as a reaction solvent:[Chemical Formula 1]
[Chemical Formula 2]
[Chemical Formula 3].
- The method according to claim 1, further comprising a step (step 1-1) of crystallizing the compound represented by Chemical Formula 1 by adding ethanol after the step 1).
- The method according to claim 1, wherein the reaction of step 1) is carried out at a temperature of 80 to 90℃.
- The method according to claim 1, wherein the reaction of step 1) is carried out for 2 to 4 hours.
- A method for preparing a compound represented by the following Chemical Formula 4, comprising a step (step 2) of reacting a compound represented by the following Chemical Formula 1 with a compound represented by the following Chemical Formula 5 using a solvent mixture of 1,4-dioxane or tetrahydrofuran (THF) and isopropanol as a reaction solvent:[Chemical Formula 4]
[Chemical Formula 1]
[Chemical Formula 5].
- The method according to claim 5, further comprising a step (step 2-1) of crystallizing the compound represented by Chemical Formula 4 by adding ethyl acetate (EA) and water after the step 2).
- The method according to claim 6, further comprising a step (step 3) of recovering the compound represented by Chemical Formula 1 from the ethyl acetate (EA) layer after the step 2-1).
- The method according to claim 5, wherein the compound represented by Chemical Formula 1 is prepared by the method of claim 1 or 2.
- The method according to claim 5, wherein 1,4-dioxane or tetrahydrofuran (THF) and isopropanol in the solvent mixture are mixed at a ratio of 0.5-4 : 1 (v/v).
- The method according to claim 5, wherein the step 2) is performed in the presence of triethylamine (TEA) or 3-amino-1,2-propanediol as a base.
- The method according to claim 5, wherein a solvent mixture of tetrahydrofuran (THF) and isopropanol is used as the reaction solvent.
- The method according to claim 5, wherein dichloromethane is further added as the reaction solvent.
- The method according to claim 12, wherein the amount of dichloromethane added is 0.5-2 volumes relative to 1 volume of isopropanol.
- The method according to claim 5, wherein the reaction of step 2) is carried out at a temperature of 0 to 10℃.
- The method according to claim 5, wherein the reaction of step 2) is carried out for 1 to 2 hours.
- The method according to claim 6, wherein ethyl acetate (EA) and water in the step 2-1) are used at a ratio of 0.5-2 : 1 (v/v).
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EA201690757A EA031801B1 (en) | 2013-10-25 | 2014-10-23 | Method for preparing an intermediate of iopromide |
| CN201480056144.7A CN105636933B (en) | 2013-10-25 | 2014-10-23 | The method for preparing the intermediate of Iopromide |
| UAA201603924A UA114158C2 (en) | 2013-10-25 | 2014-10-23 | A method for preparing an intermediate of iopromide |
| SA516370977A SA516370977B1 (en) | 2013-10-25 | 2016-04-20 | A method for preparing an intermediate of iopromide |
| PH12016500749A PH12016500749A1 (en) | 2013-10-25 | 2016-04-21 | A method for preparing an intermediate of iopromide |
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| KR10-2013-0128154 | 2013-10-25 | ||
| KR1020130128154A KR101520187B1 (en) | 2013-10-25 | 2013-10-25 | A method for preparation of an intermediate of iopromide |
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| PCT/KR2014/009991 WO2015060657A1 (en) | 2013-10-25 | 2014-10-23 | A method for preparing an intermediate of iopromide |
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| Country | Link |
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| KR (1) | KR101520187B1 (en) |
| CN (1) | CN105636933B (en) |
| EA (1) | EA031801B1 (en) |
| PH (1) | PH12016500749A1 (en) |
| SA (1) | SA516370977B1 (en) |
| UA (1) | UA114158C2 (en) |
| WO (1) | WO2015060657A1 (en) |
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| CN110078636B (en) * | 2019-05-23 | 2022-05-17 | 浙江海洲制药有限公司 | Method for preparing iopromide intermediate |
| CN114436880B (en) * | 2020-11-03 | 2023-04-28 | 成都倍特药业股份有限公司 | Preparation method of iopromide intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4364921A (en) * | 1979-03-08 | 1982-12-21 | Schering, Aktiengesellschaft | Novel triiodinated isophthalic acid diamides as nonionic X-ray contrast media |
| WO1998024757A1 (en) * | 1996-12-04 | 1998-06-11 | Dibra S.P.A. | A process for the preparation of 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid derivatives |
| WO1998054124A1 (en) * | 1997-05-30 | 1998-12-03 | Bracco S.P.A. | A process for the preparation of 5-[acetyl (2,3-dihydroxypropyl)amino]-n,n'-bis (2,3-dihydroxypropyl)-2,4,6- triiodo-1,3-benzenedicarboxamide |
| KR20000061780A (en) * | 1999-03-31 | 2000-10-25 | 강재헌 | Process for preparing iopromide |
| KR20090114729A (en) * | 2008-04-30 | 2009-11-04 | 주식회사 엘지생명과학 | Novel Process for Preparation of Iopromide |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3429949A1 (en) * | 1984-08-10 | 1986-02-20 | Schering AG, 1000 Berlin und 4709 Bergkamen | Novel non-ionic 2,4,6-triiodoisophthalic acid bisamides, process for the preparation thereof and the use thereof as X-ray contrast media |
| WO1994005337A1 (en) * | 1992-09-02 | 1994-03-17 | Mallinckrodt Medical, Inc. | Nonionic x-ray contrast agents, compositions and methods |
| JP2011506286A (en) * | 2007-12-05 | 2011-03-03 | ジーイー・ヘルスケア・アクスイェ・セルスカプ | Contrast agent |
-
2013
- 2013-10-25 KR KR1020130128154A patent/KR101520187B1/en active IP Right Grant
-
2014
- 2014-10-23 WO PCT/KR2014/009991 patent/WO2015060657A1/en active Application Filing
- 2014-10-23 EA EA201690757A patent/EA031801B1/en not_active IP Right Cessation
- 2014-10-23 UA UAA201603924A patent/UA114158C2/en unknown
- 2014-10-23 CN CN201480056144.7A patent/CN105636933B/en not_active Expired - Fee Related
-
2016
- 2016-04-20 SA SA516370977A patent/SA516370977B1/en unknown
- 2016-04-21 PH PH12016500749A patent/PH12016500749A1/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4364921A (en) * | 1979-03-08 | 1982-12-21 | Schering, Aktiengesellschaft | Novel triiodinated isophthalic acid diamides as nonionic X-ray contrast media |
| WO1998024757A1 (en) * | 1996-12-04 | 1998-06-11 | Dibra S.P.A. | A process for the preparation of 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid derivatives |
| WO1998054124A1 (en) * | 1997-05-30 | 1998-12-03 | Bracco S.P.A. | A process for the preparation of 5-[acetyl (2,3-dihydroxypropyl)amino]-n,n'-bis (2,3-dihydroxypropyl)-2,4,6- triiodo-1,3-benzenedicarboxamide |
| KR20000061780A (en) * | 1999-03-31 | 2000-10-25 | 강재헌 | Process for preparing iopromide |
| KR20090114729A (en) * | 2008-04-30 | 2009-11-04 | 주식회사 엘지생명과학 | Novel Process for Preparation of Iopromide |
Also Published As
| Publication number | Publication date |
|---|---|
| EA031801B1 (en) | 2019-02-28 |
| KR20150047997A (en) | 2015-05-06 |
| CN105636933A (en) | 2016-06-01 |
| EA201690757A1 (en) | 2016-10-31 |
| CN105636933B (en) | 2017-12-15 |
| KR101520187B1 (en) | 2015-05-13 |
| UA114158C2 (en) | 2017-04-25 |
| PH12016500749B1 (en) | 2016-06-13 |
| SA516370977B1 (en) | 2017-08-21 |
| PH12016500749A1 (en) | 2016-06-13 |
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