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A kind of preparation method of iomeprol impurity

A compound, methylamino technology, used in the preparation of organic compounds, the preparation of carboxylic acid amides, chemical instruments and methods, etc., can solve problems such as adverse reactions, and achieve the effects of stable quality, mild reaction conditions and high purity

Active Publication Date: 2018-01-19
CHONGQING CHANGJIE MEDICINE CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, iomeprol and its similar contrast agents are used as high-concentration large infusion solutions, and trace impurities will be aggregated and amplified into a relatively large amount, which may cause serious adverse reactions

Method used

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  • A kind of preparation method of iomeprol impurity
  • A kind of preparation method of iomeprol impurity
  • A kind of preparation method of iomeprol impurity

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0029] Example 1: Compound 3-N-(2,3-diacetoxypropylcarbamoyl)-5-[(acetoxyacetyl)methylamino]-2,4,6- Synthesis of Triiodobenzoyl Chloride

[0030]The compound of formula (2) 5-[(acetoxyacetyl)methylamino]-2,4,6-triiodo-1,3-phthaloyl chloride (10g) was dissolved in N,N-dimethyl In acetamide (20ml), dropwise into 3-amino-1,2-propanediol (1.3g, dissolved in 6ml N,N-dimethylacetamide and 2.3ml triethylamine), control the reaction temperature during the dropwise addition The temperature is 0-5°C, and the reaction is kept for 1 hour after dropping. After the reaction is completed, add 4-dimethylaminopyridine (0.1g), dropwise add acetic anhydride (3.4ml), control the temperature and react at less than 30°C, and react at 25-30°C for 2h after dropping. After the reaction is complete, add water (20ml), stir for 10min, then add dichloromethane (45ml), stir for 30min, then separate layers, extract the aqueous layer once with dichloromethane (45ml), combine the organic layers, add water (...

Embodiment 2

[0031] Example 2: Formula (4) compound N-(1,3-diacetoxypropyl)-N ’ -Synthesis of (2,3-diacetoxypropyl)-5-[(acetoxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide

[0032] The formula (3) compound 3-N-(2,3-diacetoxypropylcarbamoyl)-5-[(acetoxyacetyl)methylamino]-2,4,6-triiodobenzene Refined formyl chloride (6.5g) was dissolved in N,N-dimethylacetamide (13ml), dropped into 2-amino-1,3-propanediol (dissolved in 7ml N,N-dimethylacetamide and 1.5 ml triethylamine), after dropping, keep the reaction at 20-25°C for 1.5h. After the reaction is complete, add 4-dimethylaminopyridine (0.07g), dropwise add acetic anhydride (2.2ml), control the temperature below 30°C, and react at 25-30°C for 2h after dropping. After the reaction is complete, add water (13ml), stir for 10min, then add dichloromethane (25ml), stir for 30min, then separate layers, extract the aqueous layer once with dichloromethane (25ml), combine the organic layers, add water (13ml) and stir, Adjust the pH to ...

Embodiment 3

[0033] Embodiment 3: Formula (1) compound N-(1,3-dihydroxypropyl)-N ’ -Synthesis of (2,3-dihydroxypropyl)-5-[(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide

[0034] The formula (4) compound N-(1,3-diacetoxypropyl)-N ’ -(2,3-diacetoxypropyl)-5-[(acetoxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide (5.7g) Dissolve in methanol (45ml), add 30% sodium methoxide methanol solution dropwise to make the pH 8-9, and react at 25°C for 1h until the reaction is complete. Add cationic resin to make the pH to 7, filter with suction, and evaporate methanol to dryness under reduced pressure to obtain the crude compound of formula (1) (4.3 g, HPLC purity 96%). Dissolve the crude compound of formula (1) in water (20ml), add anionic resin, stir for 0.5h, filter with suction, and evaporate to dryness under reduced pressure to obtain the refined compound of formula (1) (3.7g, HPLC purity greater than 99%). 1 H-NMR (800MHz, DMSO- d 6 ) δ (ppm): 8.45-8.59 (m, 2H...

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Abstract

The invention relates to a preparation method of an iomeprol impurity N-(1,3-dihydroxy propyl)-N'-(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)methylamino)-2,4,6-triiodo-1,3-phthaldiamide represented by the formula (1). The iomeprol impurity has the following structural formula described in the specification. Through synthesis of the iomeprol impurity, a reference substance is provided for qualitative and quantitative analysis of the iomeprol impurity, so that the quality standard of iomeprol is improved, and important guidance is provided for medication safety of iomeprol.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to an impurity N-(1,3-dihydroxypropyl)-N produced during the preparation of iomeprol ’ -(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide. Background technique [0002] Iomeprol is a non-ionic X-ray contrast agent developed by Bracco, Italy. It can be widely used in intravascular, subarachnoid and intracorporeal angiography. It was launched in Italy in May 1993 and December 1992 respectively. It was approved for marketing in the UK, approved for import in 2006, and has been widely used clinically. Compared with the same type of non-ionic contrast agents (such as iohexol, iopamidol and ioversol) on the market today, iomeprol has the lowest osmotic pressure and lower viscosity at the same concentration, and can be produced A high-concentration preparation of up to 400mg(I) / ml has a better contrast effect. Therefore, iomepro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/46C07C231/12
Inventor 柳加兵
Owner CHONGQING CHANGJIE MEDICINE CHEM
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