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Preparation method of iohexol impurity

A technology of iohexol and propylene glycol, applied in the field of medicinal chemistry

Active Publication Date: 2012-10-24
ZHEJIANG HISYN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, serious adverse reactions still occur from time to time, and the occurrence of adverse reactions is not only related to the pharmacological activity of iohexol itself, but also has a lot to do with the impurities in iohexol

Method used

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  • Preparation method of iohexol impurity
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  • Preparation method of iohexol impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: Synthesis of 3-acetylamino-5-(2,3-diacetoxy-n-propylcarbamoyl)-2,4,6-triiodobenzoic acid

[0048] Weigh the compound of formula (2) 3-amino-5-(2,3-dihydroxy-n-propylcarbamoyl)-2,4,6-triiodobenzoic acid (40.0g, 63.3mmol) into a 500ml reaction flask , add acetic acid (200ml), acetic anhydride (34ml, 362.0mmol), concentrated sulfuric acid (0.5ml), heat up to 65°C, keep stirring for 24h, monitor by TLC until the reaction of raw materials is complete. The solid was filtered out, washed with water until the pH was neutral, and dried to give the compound of formula (3) as a white solid (43.0 g, 89.6%).

Embodiment 2

[0049] Example 2: Synthesis of 3-acetylamino-5-(2,3-diacetoxy n-propylcarbamoyl)-2,4,6-triiodobenzoyl chloride

[0050] Add compound (3) 3-acetamido-5-(2,3-diacetoxy-n-propylcarbamoyl)-2,4,6-triiodobenzoic acid to a 500ml reaction flask equipped with a dry condenser (40.0g, 52.8mmol), chloroform (200ml), pyridine (2ml), stirred and heated to reflux at 70°C. A chloroform solution (200ml) of triphosgene (62.0g, 208.9mmol) was slowly added dropwise, and the addition was completed within 6h. After dripping, keep stirring until the solution is clear and keep warm for 3 hours, and TLC detects that the reaction is complete. Evaporated to dryness under reduced pressure to obtain formula (4) as a light yellow solid compound (38.4 g, 93.7%).

Embodiment 3

[0051] Example 3: 5-Acetamido-N-(2,3-diacetoxy-n-propyl)-N'-(1-hydroxymethyl-2-hydroxyethyl)-2,4,6-triiodo Synthesis of Isophthalamide

[0052] Add the above-mentioned compound of formula (4) (30.0g, 38.6mmol) into a 500ml reaction bottle, add chloroform (150ml), add 2-amino-1,3-propanediol (9.5g, 104.3mmol), stir at room temperature for 24h, TLC detection The chloroform phase was free of starting material and the reaction was terminated. Add water (300ml) and stir until the viscous matter dissolves, let stand to separate layers, separate the water phase and evaporate to dryness to obtain 39.0 g of yellow sticky solid compound of formula (5), HPLC purity 93%, directly proceed to the next step without purification.

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Abstract

The invention relates to a preparation method of an iohexol impurity as shown in formula (1), namely 5-(N-(2, 3-dihydroxy-n-propyl) acetamido)-N-(2, 3-dihydroxy-n-propyl)-N'-(1-hydroxymethyl-2-hydroxyethyl)-2, 4, 6-triiodo-isophthalamide. Through the synthesis of the iohexol impurity, a control article is provided for qualitative and quantitative analysis of the iohexol impurity, and so that the quality standard of iohexol is improved, which provides important guide significance for safe using of the iohexol.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to an impurity component 5-[N-(2,3-dihydroxy n-propyl)acetamido]-N-(2,3- The preparation method of dihydroxy-n-propyl)-N'-(1-hydroxymethyl-2-hydroxyethyl)-2,4,6-triiodoisophthalamide. Background technique [0002] Iohexol belongs to the second generation of non-ionic monomeric contrast agent, and its trade name is "Omnipaque". It was developed and marketed by Nycomed company in Norway in the early 1980s. In 1982, Omnipaque was first launched in Norway and Sweden. In 1985, it was approved by the US FDA to be launched in the United States. With the rapid development of imaging diagnostic equipment in the world, X-CT contrast agents based on iodine contrast agents have achieved unprecedented development. Iohexol has many advantages such as high safety, high contrast, low osmotic pressure and low human toxicity. It has become the best-selling contrast agent in the in...

Claims

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Application Information

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IPC IPC(8): C07C237/46C07C231/12G01N30/02G01N30/06
Inventor 周鸯飞赵岳定王均明王林正马荣生王金凤赵佳怡
Owner ZHEJIANG HISYN PHARMA
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