Preparation and purification of iodixanol

A technology for iodixanol and iohexol is applied in the preparation of organic compounds, preparation of carboxylic acid amides, separation/purification of carboxylic acid amides, etc., and can solve the problems of difficult production, lack of preparation efficiency and economy, and the like

Active Publication Date: 2011-06-01
ZHEJIANG HISYN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method needs to be refined more than five times, and the yield is only below 30%, which does not have the high efficiency and economy of preparation, and is difficult to apply to production

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 an aqueous solution (water 1232.6kg) containing KOH (140.0kg, 2.25kmol) at 20°C, when all solids were dissolved, the temperature dropped below 20°C, and boric acid was added evenly in portions (64.9kg, 1.05kmol), then added dropwise hydrochloric acid (30.4kg, 0.30kmol), and then added dropwise epichlorohydrin (83.3kg, 0.90kmol). The pH during the reaction was 10-11. When the HPLC monitors that the compound A≤5, the reaction is completed, water (1232.6 kg) is added, the pH value is adjusted to 5-6 with 18% hydrochloric acid, and the activated carbon is decolorized.

[0089] According to HPLC analysis, the filtrate contained 86.3% iodixanol, 7.5% iohexol, 2.9% compound A, 2.7% alkoxy compounds and other minor impurities.

Embodiment 2

[0091] Compound A (1120.5kg, 1.50kmol) was dissolved in an aqueous solution (1232.6kg) containing NaOH (78.0kg, 1.95kmol) at 20°C. After all the solids were dissolved, the temperature dropped below 20°C, and boric acid ( 51.0kg, 0.83kmol), then 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. When HPLC monitors compound A≤5, the reaction ends, add water (1232.6kg), adjust the pH value to 5-6 with 18% hydrochloric acid, remove inorganic ions with anion and cation exchange resins, decolorize with activated carbon, evaporate to dryness, and obtain iodine Kexanol crude product 1163.0kg.

[0092] According to HPLC analysis, it contained 85.0% iodixanol, 7.1% iohexol, 3.0% compound A, 2.9% alkoxy compounds and other minor impurities.

Embodiment 3

[0094] Compound A (11.2kg, 15.0mol) was dissolved in 2-methoxyethanol solution (12.3kg) containing NaOH (0.96kg, 24.0mol) at 20°C, when all solids were dissolved, the temperature dropped below 20°C, Boric acid (0.65kg, 10.5mol) was uniformly added in portions, then 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. When the HPLC monitors that the compound A≤5, the reaction is completed, water (12.3 kg) is added, the pH value is adjusted to 5-6 with 18% hydrochloric acid, and the activated carbon is decolorized.

[0095] According to HPLC analysis, the filtrate contained 84.2% iodixanol, 5.1% iohexol, 4.8% compound A, 2.5% alkoxy compounds and other minor impurities.

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Abstract

The invention provides an improved synthesis method of iodixanol and macroporous adsorbent resin chromatography column purification and solvent recrystallization purification processes which are easy to be used for industrialization. In the synthesis method, iodixanol is synthesized by dimerisation of 5-acetamido-N, N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide ('Compound A'), wherein hydroxyacid containing boron or borate and the like are used to form a buffer solution for controlling the pH value of a reaction process, thus side reactions such as excessive alkylation and the like are effectively inhibited and the transformation ratio for transforming into the iodixanol is improved, the crude product containing 85-90% of iodixanol is obtained and then is purified by a macroporous adsorbent resin chromatography column, the total recovery of the iodixanol is 90-95%, the purity of the iodixanol is more than 97%; and the iodixanol is subjected to recrystallization in a solvent containing 2-methoxy ethanol, the recovery of the iodixanol is 90-95%, and the purity of the iodixanol is more 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-triiodophenyl]-2-hydroxypropane) preparation and purification method. Background technique [0002] Iodixanol (trade name ) is a non-ionic X-ray contrast agent developed by Nycomed Company of Norway, which was launched in 1993 and is being mass-produced. [0003] The production of this non-ionic X-ray contrast agent includes the production of chemical raw materials (i.e. primary production) and the production of pharmaceutical preparations (i.e. secondary production); the primary production of iodixanol includes multi-step chemical synthesis and thorough Purification process. [0004] Iodixanol injection is directly injected into human blood vessels, and the dosage specification is high, which undoubtedly determines the high requirements for the quality of its raw materials, even higher tha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/46C07C231/12C07C231/24
Inventor 胡志奇张火英
Owner ZHEJIANG HISYN PHARMA
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