Preparation and purification of iodixanol

一种碘克沙醇、碘海醇的技术，应用在有机化合物的纯化/分离/稳定化、羧酸酰胺分离/纯化、有机化学等方向，能够解决限制纯化效率和产品质量等问题

Active Publication Date: 2012-10-10
IMAX DIAGNOSTIC IMAGING HLDG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The chemical synthesis process certainly limits any improvement in purification efficiency and product quality

Method used

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  • Preparation and purification of iodixanol
  • Preparation and purification of iodixanol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Compound A (1120.5kg, 1.50kmol) was dissolved in KOH (140.0kg, 2.25kmol) in water (1232.6kg), the temperature was controlled below 20°C, and boric acid (64.9kg, 1.05 kmol), hydrochloric acid (30.4kg, 0.30kmol) was added dropwise, and then epichlorohydrin (83.3kg, 0.90kmol) was added dropwise. The pH during the reaction was 10-11. The reaction was monitored and samples were analyzed by HPLC. When the compound A content was lower than 5%, the reaction was quenched by adding water (1232.6 kg) and adjusting the pH in the range of 5-6 with 18% hydrochloric acid.

[0089] The reaction mixture was then desalted with active charcoal and filtered. By HPLC analysis, the filtrate contained 86.3% iodixanol, 7.5% iohexol, 2.9% compound A and 2.7% O-alkylated by-products and other impurities.

Embodiment 2

[0091] Compound A (1120.5kg, 1.50kmol) was dissolved in NaOH (78.0kg, 1.95kmol) in water (1232.6kg), the temperature was controlled below 20°C, and boric acid (51.0kg, 0.83 kmol), hydrochloric acid (23.3kg, 0.23kmol) was added dropwise, and then epichlorohydrin (83.3kg, 0.90kmol) was added dropwise. The pH during the reaction was 10-11. The reaction was monitored and samples were analyzed by HPLC. When the compound A content was lower than 5%, the reaction was quenched by adding water (1232.6 kg) and adjusting the pH in the range of 5-6 with 18% hydrochloric acid.

[0092] Inorganic ions were removed by passing through a column containing anion and cation exchange resins, followed by decolorization with activated carbon; the filtrate was concentrated by evaporation to dryness to obtain crude iodixanol (1163.0 kg)

[0093] Contents by HPLC (analysis) were 85.0% iodixanol, 7.1% iohexol, 3.0% compound A, 2.9% O-alkylated by-products and small amounts of other impurities.

Embodiment 3

[0095] Compound A (11.2kg, 15.0mol) was dissolved in NaOH (0.96kg, 24.0mol) in 2-methoxyethanol solution, the temperature was controlled below 20°C, and boric acid (0.65kg, 10.5 mol), hydrochloric acid (0.55kg, 5.4mol) was added dropwise, and then epichlorohydrin (0.75kg, 8.1mol) was added dropwise. The pH during the reaction was 10-11. The reaction was monitored and samples were analyzed by HPLC. When the compound A content was lower than 5%, the reaction was quenched by adding water (12.3 kg) and adjusting the pH in the range of 5-6 with 18% hydrochloric acid.

[0096] The reaction mixture was then decolorized with activated charcoal. By HPLC analysis, the filtrate contained 84.2% iodixanol, 5.1% iohexol, 4.8% compound A and 2.5% O-alkylated by-products and other impurities.

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Abstract

An improved synthesis method for preparation of iodixanol, and a purification process through macroporous adsorption resin chromatographic column and recrystallization are provided. The synthesis method relates to dimerization of 5-acetamido-N, N'-bis(2,3-dihydroxypropyl)-2,4,6- triiodo-isophthalamide (compound A) to prepare iodixanol, wherein excessive side reactions such as alkylation are effectively inhibited by controlling the pH of the reaction mixture with a boron-containing acidic substance or salts thereof such as boric acid. In this way, the conversion rate of compound A to iodixanol is 85-90%. The iodixanol crude product is purified by a macroporous adsorption resin chromatographic column, obtaining iodixanol product with recovery of 90-95% and purity of 96-98%. The iodixanol crude product is recrystallized in mixed solvent containing 2-methoxyethanol, obtaining iodixanol product with recovery of 90-95% and purity of greater than 99%.

Description

technical field [0001] The invention belongs to the field of chemical medicine and relates to iodixanol (1,3-bis(acetylamino)-N,N'-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2 , 4,6-triiodo-phenyl]-2-hydroxypropane) preparation and purification method. Background technique [0002] Iodixanol, brand name Developed by Nycomed as a non-ionic X-ray contrast agent. Iodixanol was introduced in 1993 and is produced in large quantities. [0003] The production of this non-ionic X-ray contrast agent includes chemical manufacturing (primary production (primary production)) and pharmaceutical preparation manufacturing (secondary production (secondary production)); iodixanol The primary production of methionin involves multi-step chemical synthesis and is completed by a purification process. [0004] Iodixanol for injection is injected directly into human blood vessels in very high doses, which means that the iodixanol used as raw material in secondary production needs to be of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B63/00C07C231/24C07C237/46B01D15/08
CPCC07C231/24C07B63/00C07C237/46B01D15/22B01D2015/3838
Inventor 胡志奇张火英
Owner IMAX DIAGNOSTIC IMAGING HLDG
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