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Preparation method of iohexol impurity

A technology of iohexol and impurities, applied in the field of medicinal chemistry, can solve the problems of no sales and no public information report (formula 1) compound synthesis method, etc., and achieve the effect of short time consumption, suitable for large-scale production, and low price

Active Publication Date: 2015-03-11
SHANGHAI STARRY PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] 17 impurities are listed in the European Pharmacopoeia's quality standards for iohexol, and the impurity H (compound of formula 1) is not sold on the market, and there is no public information to report the synthetic method of the compound of (formula 1)

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Add 30 g of iohexol into the reaction flask, add water at room temperature and stir to dissolve and clarify. Add 500ml of 0.8% sodium borohydride solution dropwise at 15-35°C, react at 15-35°C until HPLC detection shows that the raw material iohexol is less than 0.1%, then stop the reaction, adjust the pH to 5-7 with hydrochloric acid, water bath Concentrate to dryness under pressure. Add water (120ml) to dissolve, pour the reaction solution into an LX-18 separation resin column with a volume of more than 20 times, absorb for 0.5-2.0 hours, and then elute with purified water. The eluate is detected by HPLC, and the cut-off content is greater than 99.5 % fractions were distilled under reduced pressure to obtain the target product formula (1) as a white solid compound (15.0 g, yield 59.06%, HPLC purity 99.4%). 1 H-NMR (400MHz,D 2 O) δ (ppm) 7.50 (m, 1H), 3.99–3.81 (m, 3H), 3.78–3.21 (m, 12H), 1.78 (s, 3H). 13 C-NMR (100MHz,D 2 O)δ174.4, 174.1, 172.5, 150.2,...

Embodiment 2

[0033] Example 2: Add 30 g of iohexol into the reaction flask, add water at room temperature and stir to dissolve and clarify. Add 300ml of 0.8% potassium borohydride solution dropwise at 15-35°C, and react at 15-35°C until HPLC detection shows that the raw material iohexol is less than 0.1%. Concentrate to dryness under pressure. Add water (60ml) to dissolve it, pour the reaction solution into a separation resin column with a volume of more than 20 times, absorb for 0.5-2.0 hours, and then elute with purified water. The eluate is detected by HPLC, and the fraction with a content greater than 99.5% parts, and distilled under reduced pressure to obtain the target product formula (1) as a white solid compound (12.6 g, yield 49.61%, HPLC purity 99.5%). 1 H-NMR (400MHz,D 2 O) δ (ppm) 7.50 (m, 1H), 3.99–3.81 (m, 3H), 3.78–3.21 (m, 12H), 1.78 (s, 3H). 13 C-NMR (100MHz,D 2 O)δ174.4, 174.1, 172.5, 150.2, 146.5, 144.6, 128.8, 100.6, 90.4, 70.0, 69.7, 68.0, 63.6, 63.4, 51.9, 50.1, 4...

Embodiment 3

[0034] Example 3: Add 30 g of iohexol into the reaction flask, add water at room temperature and stir to dissolve and clarify. Add 100ml of 0.8% potassium borohydride solution dropwise at 15°C, react at 15-35°C until HPLC detection shows that the raw material iohexol is less than 0.1%, then stop the reaction, adjust the pH to 5 with hydrochloric acid, and concentrate to dryness in a water bath under reduced pressure . Add water to dissolve it, pour the reaction solution into a separation resin column with a volume of more than 20 times, absorb for 0.5 hours, and then elute with purified water. The eluate is detected by HPLC, and the fraction with a content greater than 99.5% is intercepted and distilled under reduced pressure. , to obtain the target product formula (1) white solid compound.

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Abstract

The invention relates to a preparation method of an iohexol impurity component, namely, 5-(N-(2,3-dihydroxypropyl)acetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4-diiodo-1,3-benzenedicarboxamide, represented by formula (1). A reference substance is provided for qualitative and quantitative analysis of an iohexol impurity through preparation of the iohexol impurity, so that the quality standard of iohexol is improved, and the important guiding significance is provided for safe medication of the iohexol. The formula (1) is shown in the specification.

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-dihydroxypropyl)acetamido]-N,N'-bis( A preparation method of 2,3-dihydroxypropyl)-2,4-diiodo-1,3-benzenedicarboxamide. Background technique [0002] Iohexol (Iohexol) belongs to the second generation of non-ionic monomeric contrast agent, and its trade name is "Omnipaque". It was developed and listed by the Norwegian company Nycomed 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 international market...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/42C07C231/12
Inventor 方钦虎李奇彪沈伟艺王恺沈鑫龙王金凤吴金韦
Owner SHANGHAI STARRY PHARMA CO LTD
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