CN115611761B - Preparation method of iohexol or iodixanol and intermediate thereof - Google Patents

Preparation method of iohexol or iodixanol and intermediate thereof Download PDF

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CN115611761B
CN115611761B CN202211251227.4A CN202211251227A CN115611761B CN 115611761 B CN115611761 B CN 115611761B CN 202211251227 A CN202211251227 A CN 202211251227A CN 115611761 B CN115611761 B CN 115611761B
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iodixanol
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iohexol
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陈新龙
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Hangzhou Xinxi Technology Co ltd
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    • C07C231/00—Preparation of carboxylic acid amides
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
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Abstract

The application relates to a preparation method of an iohexol or iodixanol intermediate, which comprises the following steps: adding mixed solution of 5-nitroisophthalic acid dimethyl ester, 3-amino-1, 2-propylene glycol, sodium methoxide, methanol and isopropanol into a reaction kettle, and heating for reaction for 30-120min; obtaining a nitro intermediate solution; adjusting the pH value of the solution of the nitro intermediate to 4-6 by using dilute sulfuric acid, adding a graphene palladium-carbon catalyst, heating to 60-70 ℃, and carrying out hydrogenation reaction at 4-7bar until no hydrogen is consumed, and continuing the reaction for 2-5h to obtain an amino intermediate; adding iodine and potassium iodate into a reaction kettle, heating to 50-60 ℃, stirring for 2-5h, controlling the temperature to 50-60 ℃, dropwise adding a reduction filtrate, carrying out heat preservation reaction for 10-20h, controlling Wen Di, adding 20% sodium hydroxide solution to adjust the pH to 5-6, recovering distilled iodine-containing water under reduced pressure until effluent is colorless, cooling to 0-10 ℃, carrying out heat preservation for 1-3h, carrying out three-in-one leaching, and carrying out reduced pressure drying on a filter cake at 70-80 ℃ for 10-20h to obtain the iohexol intermediate. Compared with the prior art, the preparation method reduces the process steps, and ensures the yield and purity.

Description

Preparation method of iohexol or iodixanol and intermediate thereof
Technical Field
The application relates to a preparation method of iohexol or iodixanol and an intermediate thereof.
Background
Iohexol is an isotonic iodine contrast agent for the 3 rd generation nonionic dimer and is widely used in clinical interventional radiology procedures. Common adverse reactions are mild paresthesias such as heat sensation or temporary metallic taste sensation. Abdominal discomfort or pain is rare (incidence < 1:1000), as is gastrointestinal reactions such as nausea and vomiting (incidence <1:100, but > 1:1000). Allergic reactions are less common and are often manifested as mild respiratory and skin reactions such as dyspnea, rash, erythema, urticaria, itching and angioedema, which can occur immediately after injection or after several days. Serious reactions such as laryngeal oedema, bronchospasm or pulmonary oedema are very rare.
Iodixanol is also a most commonly used reagent in the process of diagnosing X-rays, is suitable for intracavitary radiography, cardiovascular and cerebrovascular angiography and intravenous urography, and has the action principle that the iodine is combined to absorb X-rays in blood vessels or tissues to cause image display. The synthesis routes of iohexol and iodixanol are similar and can be obtained based on the same drug intermediate. In the prior art, the synthesis process for improving the yield and purity of iohexol and iodixanol is not ideal enough, so that the synthesis cost is too high and the product quality is low.
Disclosure of Invention
The application aims to solve the defects in the prior art, and provides a synthesis process of an iohexol intermediate, which comprises the following steps:
adding mixed solution of 5-nitroisophthalic acid dimethyl ester, 3-amino-1, 2-propylene glycol, sodium methoxide, methanol and isopropanol into a reaction kettle, and heating for reaction for 30-120min; obtaining a nitro intermediate solution;
adjusting the pH value of the solution of the nitro intermediate to 4-6 by using dilute sulfuric acid, adding a graphene palladium-carbon catalyst, heating to 60-70 ℃, and carrying out hydrogenation reaction at 4-7bar until no hydrogen is consumed, and continuing the reaction for 2-5h to obtain an amino intermediate;
adding iodine and potassium iodate into a reaction kettle, heating to 50-60 ℃, stirring for 2-5h, controlling the temperature to 50-60 ℃, dropwise adding a reduction filtrate, carrying out heat preservation reaction for 10-20h, controlling Wen Di, adding 20% sodium hydroxide solution to adjust the pH to 5-6, recovering distilled iodine-containing water under reduced pressure until effluent is colorless, cooling to 0-10 ℃, carrying out heat preservation for 1-3h, carrying out three-in-one leaching, and carrying out reduced pressure drying on a filter cake at 70-80 ℃ for 10-20h to obtain the iohexol intermediate.
A process for preparing iodixanol, the process comprising the steps of:
the iohexol intermediate is prepared according to the mode;
adding iohexol intermediate, p-toluenesulfonic acid and acetic anhydride into a reaction kettle, stirring to dissolve, heating for reaction for 30-120min, and stopping heating to obtain a completely formylated intermediate solution;
and (3) dropwise adding a sodium hydroxide solution into the completely formylated intermediate solution, carrying out hydrolysis reaction for 12-36 hours, adding epichlorohydrin, and stirring and reacting for 24-48 hours to obtain the iodixanol solution.
The dosage of the acetic anhydride is 80-200% of the mass of the iohexol intermediate.
The dosage of the epichlorohydrin is 30-60% of the mass of the fully formylated intermediate solution.
The preparation method further comprises the purification step of:
dropwise adding concentrated hydrochloric acid into iodixanol solution to adjust the pH value of the solution to 7, adding strong acid ion exchange resin, stirring for 15min, filtering, washing, adding strong alkali ion into mother liquor, stirring for 15min, filtering, washing, and concentrating the mother liquor under reduced pressure to obtain crude iodixanol;
and dissolving the crude iodixanol with a mixed solvent of ethanol, dimethyl ether and acetone, heating to 80 ℃, quickly cooling to below 10 ℃, and filtering to obtain white solid iodixanol.
The application adopts the mixed solution of methanol and isopropanol, improves the boiling point and the reaction temperature, and shortens the reaction time. The application adopts the graphene palladium-carbon catalyst, and improves the hydrogenation efficiency. Compared with the prior art, the preparation method reduces the process steps, and ensures the yield and purity.
The above as well as additional features, aspects, and advantages of the present application will become more readily apparent with reference to the following detailed description.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present application more clear, the technical solutions of the embodiments of the present application will be clearly and completely described below in conjunction with the embodiments of the present application. It will be apparent that the described examples are some, but not all, embodiments of the application. All other embodiments, which can be made by a person skilled in the art without creative efforts, based on the described embodiments of the present application fall within the protection scope of the present application.
Unless defined otherwise, technical or scientific terms used herein should be given the ordinary meaning as understood by one of ordinary skill in the art to which this application belongs. The terms "first," "second," and the like in the description and in the claims, are not used for any order, quantity, or importance, but are used for distinguishing between different elements. Likewise, the terms "a" or "an" and the like do not denote a limitation of quantity, but rather denote the presence of at least one.
Preparation of graphene palladium-carbon catalyst
Preparing active carbon slurry, and modifying active carbon by using nitric acid solution to obtain modified active carbon material;
and adding graphene into the modified activated carbon material to obtain graphene activated carbon slurry.
Dissolving palladium chloride in 1L absolute ethyl alcohol, and uniformly stirring to form palladium alcohol solution;
placing graphene activated carbon slurry into an ammonia reaction kettle, and standing to obtain modified graphene activated carbon;
adding modified graphene active carbon into palladium alcohol solution for ultrasonic treatment (ammonia reaction kettle contains 10% by volume of water vapor with the pressure of 0.1MPa; the ammonia reaction kettle is taken out and dried to obtain ammonia modified graphene palladium carbon;
and (3) standing the ammonia modified graphene palladium carbon in a reaction kettle for standing reaction for 20min, taking out and drying, and performing reduction reaction (hydrogen, and the reduction temperature is 90 ℃) to obtain the graphene palladium carbon catalyst.
Examples of iohexol synthesis are as follows:
300g of dimethyl 5-nitroisophthalate, 240g of 3-amino-1, 2-propanediol, 100g of sodium methoxide and 1000g of mixed solution of methanol and isopropanol (the mass ratio of methanol to isopropanol is 1:3) are added into a reaction kettle, and the reaction is carried out for 50min at the temperature of 50 ℃; a nitro intermediate solution is obtained.
In the synthesis step, the mixed solution of methanol and isopropanol is adopted, so that the boiling point and the reaction temperature are improved, and the reaction time is shortened.
Adjusting the pH value of the solution to 5 by using dilute sulfuric acid, adding 5wt% of graphene palladium-carbon catalyst, controlling the temperature to 70 ℃, carrying out hydrogenation reaction until no hydrogen is consumed, and continuing the reaction for 2 hours; an amino intermediate is obtained.
Adding 1080g of iodine and 170g of potassium iodate into a reaction kettle, heating to 60 ℃ and stirring for 3 hours, controlling the temperature to 50-60 ℃ and dropwise adding the reduction filtrate, carrying out heat preservation reaction for 16 hours, controlling Wen Di to add 20% sodium hydroxide solution to adjust the pH to 5-6, and recovering distilled water containing iodine under reduced pressure until effluent liquid is colorless. Cooling to 0-10 deg.c, maintaining for 1-3 hr, and leaching in three steps. The filter cake is dried for 10 to 20 hours under reduced pressure at the temperature of 70 to 80 ℃ to obtain the iohexol intermediate, and the reaction formula is as follows:
in a three-neck flask equipped with a stirrer and a reflux condenser, 900g of iohexol intermediate and 2500ml of acetic anhydride are added, the temperature is raised to 50 ℃, 15ml of concentrated sulfuric acid is slowly added, the temperature is raised to 65 ℃, stirring is continued for 1.5 hours, the solvent is distilled off under reduced pressure, the residue is dissolved in 2000ml of methanol, 2000ml of ammonia water is slowly added, stirring at room temperature is carried out overnight, solid is separated out, filtration and washing with water are carried out for a plurality of times, and the white solid product 5-acetamido-N, N' -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodiisophthalamide is obtained after drying.
400g of 5-acetamido-N, N' -bis (2, 3-dihydroxypropyl) 2,4, 6-triiodoisophthalamide was suspended in 1100ml of 1, 2-propanediol, 70g of a 50% sodium methoxide solution was added with stirring and gradually warmed to 50℃and, after all the starting materials had been dissolved, methanol was removed under reduced pressure, cooled to room temperature, 75g of 3-chloro-1, 2-propanediol was added, stirred at room temperature for 40-70 hours, checked for starting materials by thin layer chromatography on silica gel GF254, the spots disappeared, the reaction solution was distilled off under reduced pressure to remove the solvent, the residue was dissolved in 1200ml of methanol, after filtration to remove insoluble materials, 3000ml of water was added, the cations and anions of the solution were removed with 732 cation exchange resin and 717 anion exchange resin, the pH of the solution was adjusted to about 4.9 with dilute hydrochloric acid, and the solvent was removed under vacuum, thus obtaining an oily residue. The residue was triturated in n-butanol to give a white solid. Dissolving the solid in water, and evaporating the solvent under reduced pressure to obtain a solid. Recrystallizing the solid with n-butanol, dissolving in water, centrifuging, spray drying to remove solvent, repeating the above steps, dissolving in water, centrifuging, spray drying to remove solvent, and collecting iohexol. (purity of liquid phase 95.1%, yield 86.45%)
Example 1
300g of dimethyl 5-nitroisophthalate, 240g of 3-amino-1, 2-propanediol, 100g of sodium methoxide and 1000g of mixed solution of methanol and isopropanol (the mass ratio of methanol to isopropanol is 1:3) are added into a reaction kettle, and the reaction is carried out for 50min at the temperature of 50 ℃; a nitro intermediate solution is obtained. The reaction formula is as follows:
in the synthesis step, the mixed solution of methanol and isopropanol is adopted, so that the boiling point and the reaction temperature are improved, and the reaction time is shortened.
Adjusting the pH value of the solution to 5 by using dilute sulfuric acid, adding 5wt% of graphene palladium-carbon catalyst, controlling the temperature to 70 ℃, carrying out hydrogenation reaction until no hydrogen is consumed, and continuing the reaction for 2 hours; an amino intermediate is obtained. The reaction formula is as follows:
adding 1080g of iodine and 170g of potassium iodate into a reaction kettle, heating to 60 ℃ and stirring for 3 hours, controlling the temperature to 50-60 ℃ and dropwise adding the reduction filtrate, carrying out heat preservation reaction for 16 hours, controlling Wen Di to add 20% sodium hydroxide solution to adjust the pH to 5-6, and recovering distilled water containing iodine under reduced pressure until effluent liquid is colorless. Cooling to 0-10 deg.c, maintaining for 1-3 hr, and leaching in three steps. The filter cake is dried for 10 to 20 hours under reduced pressure at the temperature of 70 to 80 ℃ to obtain the iohexol intermediate, and the reaction formula is as follows:
adding 100 parts by weight of iohexol intermediate, 10 parts by weight of p-toluenesulfonic acid and 100 parts by weight of acetic anhydride into a reaction kettle, stirring to dissolve, heating for 1h, and stopping heating to obtain a fully formylated amino intermediate solution. The reaction formula is as follows:
100 parts by weight of the completely formylated amino intermediate solution and 100 parts by weight (20 wt%) of sodium hydroxide solution were added dropwise, and after 24 hours of reaction, 50 parts by weight of epichlorohydrin was further added, and after 48 hours of reaction with stirring, iodixanol solution was obtained. The reaction formula is as follows:
and (3) purification:
dropwise adding concentrated hydrochloric acid into iodixanol solution to adjust the pH value of the solution to 7, adding strong acid ion exchange resin, stirring for 15min, filtering, washing, adding strong alkali ion into mother liquor, stirring for 15min, filtering, washing, and concentrating the mother liquor under reduced pressure to obtain crude iodixanol;
and (3) dissolving the crude iodixanol by using a mixed solvent of ethanol, dimethyl ether and acetone (1:1:2), heating to 80 ℃, and rapidly cooling to below 5 ℃ within 10-60 seconds to obtain white solid iodixanol.
Example 2 (compared to example 1, the mass ratio of methanol to isopropanol is 1:2, the others being unchanged)
300g of dimethyl 5-nitroisophthalate, 240g of 3-amino-1, 2-propanediol, 100g of sodium methoxide and 1000g of mixed solution of methanol and isopropanol (the mass ratio of methanol to isopropanol is 1:2) are added into a reaction kettle, and the reaction is carried out for 50min at the temperature of 50 ℃; a nitro intermediate solution is obtained.
Adjusting the pH value of the solution to 5 by using dilute sulfuric acid, adding a 5% graphene palladium-carbon catalyst, controlling the temperature to 70 ℃, carrying out hydrogenation reaction until no hydrogen is consumed, and continuing the reaction for 2 hours; an amino intermediate is obtained.
Adding 1080g of iodine and 170g of potassium iodate into a reaction kettle, heating to 60 ℃ and stirring for 3 hours, controlling the temperature to 50-60 ℃ and dropwise adding the reduction filtrate, carrying out heat preservation reaction for 16 hours, controlling Wen Di to add 20% sodium hydroxide solution to adjust the pH to 5-6, and recovering distilled water containing iodine under reduced pressure until effluent liquid is colorless. Cooling to 0-10 deg.c, maintaining for 1-3 hr, and leaching in three steps. And (3) drying the filter cake at 70-80 ℃ under reduced pressure for 10-20h to obtain the iohexol intermediate.
Adding 100 parts by weight of iohexol intermediate, 10 parts by weight of p-toluenesulfonic acid and 100 parts by weight of acetic anhydride into a reaction kettle, stirring to dissolve, heating for 1h, and stopping heating to obtain a fully formylated amino intermediate solution.
100 parts by weight of the completely formylated amino intermediate solution and 100 parts by weight (20 wt%) of sodium hydroxide solution were added dropwise, and after 24 hours of reaction, 50 parts by weight of epichlorohydrin was further added, and after 48 hours of reaction with stirring, an iohexol solution was obtained.
Dropwise adding concentrated hydrochloric acid into iodixanol solution to adjust the pH value of the solution to 7, adding strong acid ion exchange resin, stirring for 15min, filtering, washing, adding strong alkali ion into mother liquor, stirring for 15min, filtering, washing, and concentrating the mother liquor under reduced pressure to obtain crude iodixanol;
and (3) dissolving the crude iodixanol by using a mixed solvent of ethanol, dimethyl ether and acetone (1:1:2), heating to 80 ℃, and rapidly cooling to below 5 ℃ within 10-60 seconds to obtain white solid iodixanol.
Example 3 (compared to example 2, ethanol+dimethyl ether+acetone mixed solvent (1:2:1), the others are unchanged)
300g of dimethyl 5-nitroisophthalate, 240g of 3-amino-1, 2-propanediol, 100g of sodium methoxide and 1000g of mixed solution of methanol and isopropanol (the mass ratio of methanol to isopropanol is 1:2) are added into a reaction kettle, and the reaction is carried out for 50min at the temperature of 50 ℃; a nitro intermediate solution is obtained.
Adjusting the pH value of the solution to 5 by using dilute sulfuric acid, adding a 5% graphene palladium-carbon catalyst, controlling the temperature to 70 ℃, carrying out hydrogenation reaction until no hydrogen is consumed, and continuing the reaction for 2 hours; an amino intermediate is obtained.
Adding 1080g of iodine and 170g of potassium iodate into a reaction kettle, heating to 60 ℃ and stirring for 3 hours, controlling the temperature to 50-60 ℃ and dropwise adding the reduction filtrate, carrying out heat preservation reaction for 16 hours, controlling Wen Di to add 20% sodium hydroxide solution to adjust the pH to 5-6, and recovering distilled water containing iodine under reduced pressure until effluent liquid is colorless. Cooling to 0-10 deg.c, maintaining for 1-3 hr, and leaching in three steps. And (3) drying the filter cake at 70-80 ℃ under reduced pressure for 10-20h to obtain the iohexol intermediate.
Adding 100 parts by weight of iohexol intermediate, 10 parts by weight of p-toluenesulfonic acid and 100 parts by weight of acetic anhydride into a reaction kettle, stirring to dissolve, heating for 1h, and stopping heating to obtain a fully formylated amino intermediate solution.
100 parts by weight of the completely formylated amino intermediate solution and 100 parts by weight (20 wt%) of sodium hydroxide solution were added dropwise, and after 24 hours of reaction, 50 parts by weight of epichlorohydrin was further added, and after 48 hours of reaction with stirring, an iohexol solution was obtained.
Dropwise adding concentrated hydrochloric acid into iodixanol solution to adjust the pH value of the solution to 7, adding strong acid ion exchange resin, stirring for 15min, filtering, washing, adding strong alkali ion into mother liquor, stirring for 15min, filtering, washing, and concentrating the mother liquor under reduced pressure to obtain crude iodixanol;
and (3) dissolving the crude iodixanol by using a mixed solvent of ethanol, dimethyl ether and acetone (1:2:1), heating to 80 ℃, and rapidly cooling to below 5 ℃ within 10-60 seconds to obtain white solid iodixanol.
Comparative example 1 (methanol alone compared to example 1)
300g of 5-nitroisophthalic acid dimethyl ester, 240g of 3-amino-1, 2-propanediol, 100g of sodium methoxide and 1000g of methanol are added into a reaction kettle and reacted for 50min at the temperature of 50 ℃; a nitro intermediate solution is obtained.
Adjusting the pH value of the solution to 5 by using dilute sulfuric acid, adding a 5% graphene palladium-carbon catalyst, controlling the temperature to 70 ℃, carrying out hydrogenation reaction until no hydrogen is consumed, and continuing the reaction for 2 hours; an amino intermediate is obtained.
Adding 1080g of iodine and 170g of potassium iodate into a reaction kettle, heating to 60 ℃ and stirring for 3 hours, controlling the temperature to 50-60 ℃ and dropwise adding the reduction filtrate, carrying out heat preservation reaction for 16 hours, controlling Wen Di to add 20% sodium hydroxide solution to adjust the pH to 5-6, and recovering distilled water containing iodine under reduced pressure until effluent liquid is colorless. Cooling to 0-10 deg.c, maintaining for 1-3 hr, and leaching in three steps. And (3) drying the filter cake at 70-80 ℃ under reduced pressure for 10-20h to obtain the iohexol intermediate.
Comparative example 2 (compared to example 1, methanol alone and palladium on carbon catalyst)
300g of 5-nitroisophthalic acid dimethyl ester, 240g of 3-amino-1, 2-propanediol, 100g of sodium methoxide and 1000g of methanol are added into a reaction kettle and reacted for 50min at the temperature of 50 ℃; a nitro intermediate solution is obtained.
Adjusting the pH value of the solution to 5 by using dilute sulfuric acid, adding a 5% palladium-carbon catalyst, controlling the temperature to 70 ℃, carrying out hydrogenation reaction until no hydrogen is consumed, and continuing the reaction for 2 hours; an amino intermediate is obtained.
Adding 1080g of iodine and 170g of potassium iodate into a reaction kettle, heating to 60 ℃ and stirring for 3 hours, controlling the temperature to 50-60 ℃ and dropwise adding the reduction filtrate, carrying out heat preservation reaction for 16 hours, controlling Wen Di to add 20% sodium hydroxide solution to adjust the pH to 5-6, and recovering distilled water containing iodine under reduced pressure until effluent liquid is colorless. Cooling to 0-10 deg.c, maintaining for 1-3 hr, and leaching in three steps. And (3) drying the filter cake at 70-80 ℃ under reduced pressure for 10-20h to obtain the iohexol intermediate.
TABLE 1 iodixanol
While the fundamental and principal features of the application and advantages of the application have been shown and described, it will be apparent to those skilled in the art that the application is not limited to the details of the foregoing exemplary embodiments, but may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the application being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.

Claims (8)

1. A preparation method of iohexol or iodixanol intermediate is characterized in that,
the preparation method comprises the following steps:
adding mixed solution of 5-nitroisophthalic acid dimethyl ester, 3-amino-1, 2-propylene glycol, sodium methoxide, methanol and isopropanol into a reaction kettle, and heating for reaction for 30-120min; obtaining a nitro intermediate solution;
adjusting the pH value of the solution of the nitro intermediate to 4-6 by using dilute sulfuric acid, adding a graphene palladium-carbon catalyst, heating to 60-70 ℃, and carrying out hydrogenation reaction at 4-7bar until no hydrogen is consumed, and continuing the reaction for 2-5h to obtain an amino intermediate;
adding iodine and potassium iodate into a reaction kettle, heating to 50-60 ℃ and stirring for 2-5 hours, controlling the temperature to 50-60 ℃, dropwise adding a reduction filtrate, carrying out heat preservation and reaction for 10-20 hours, controlling Wen Di to add 20% sodium hydroxide solution to adjust the pH to 5-6, recovering distilled iodine-containing water under reduced pressure until effluent is colorless, cooling to 0-10 ℃, carrying out heat preservation for 1-3 hours, carrying out three-in-one leaching, and carrying out reduced pressure drying on a filter cake at 70-80 ℃ for 10-20 hours to obtain an intermediate of iohexol or iodixanol; wherein:
the structural formula of the nitro intermediate is；
The structural formula of the amino intermediate is；
The structural formula of the intermediate of iohexol or iodixanol is ；
In the mixed solution of methanol and isopropanol, the mass ratio of the methanol to the isopropanol is 1:2-4;
the dosage of the graphene palladium carbon catalyst is 3-8% of the mass of the nitrointermediate solution.
2. The process for preparing iohexol or iodixanol intermediates according to claim 1, characterized in that in the step of preparing the nitro intermediate solution, the reaction temperature is 50-70 ℃ and the reaction time is 40-60min.
3. A method for preparing iodixanol, comprising the steps of:
an intermediate of iohexol or iodixanol prepared according to the process of claim 1 or 2;
adding the iohexol or iodixanol intermediate, p-toluenesulfonic acid and acetic anhydride into a reaction kettle, stirring to dissolve, heating for reaction for 30-120min, and stopping heating to obtain a fully formylated intermediate solution;
dropwise adding a sodium hydroxide solution into the completely formylated intermediate solution, carrying out hydrolysis reaction for 12-36 hours, adding epichlorohydrin, and stirring and reacting for 24-48 hours to obtain iodixanol solution; wherein:
the structural formula of the fully formylated intermediate is。
4. A process for the preparation of iodixanol according to claim 3 characterized in that the amount of acetic anhydride is 80-200% of the mass of iohexol intermediate.
5. A process for the preparation of iodixanol according to claim 3 characterized in that the epichlorohydrin is used in an amount of 30-60% by mass of the fully formylated intermediate solution.
6. A process for the preparation of iodixanol according to claim 3 characterized in that it further comprises a purification step:
dropwise adding concentrated hydrochloric acid into iodixanol solution to adjust the pH value of the solution to 7, adding strong acid ion exchange resin, stirring for 15min, filtering, washing, adding strong alkali ion into mother liquor, stirring for 15min, filtering, washing, and concentrating the mother liquor under reduced pressure to obtain crude iodixanol;
and dissolving the crude iodixanol with a mixed solvent of ethanol, dimethyl ether and acetone, heating to 80 ℃, quickly cooling to below 10 ℃, and filtering to obtain white solid iodixanol.
7. The preparation method of iodixanol according to claim 6, which is characterized in that the mass ratio of the ethanol dimethyl ether acetone in the ethanol dimethyl ether acetone mixed solvent is 1 (1-2): (0.5-3).
8. The method for preparing iodixanol according to claim 6, characterized in that the rapid cooling is performed by rapidly cooling to below 10 ℃ within 10-60 seconds.
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