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5-Amino-2,4,6-triiodisophthaloyl acid dichloride derivative and application thereof in synthesis of iopamidol impurities

A technology of triiodoisopeptidyl chloride derivatives and amino groups, which is applied in the field of medicine and can solve problems such as affecting product quality, difficult to control, and residual iopamidol products

Inactive Publication Date: 2019-07-26
江西兄弟医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These kinds of impurities are difficult to control during the synthesis process, and are difficult to completely remove in the subsequent purification process, so they will remain in the iopamidol product and affect the quality of the product

Method used

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  • 5-Amino-2,4,6-triiodisophthaloyl acid dichloride derivative and application thereof in synthesis of iopamidol impurities
  • 5-Amino-2,4,6-triiodisophthaloyl acid dichloride derivative and application thereof in synthesis of iopamidol impurities
  • 5-Amino-2,4,6-triiodisophthaloyl acid dichloride derivative and application thereof in synthesis of iopamidol impurities

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the synthesis of formula 1 compound

[0052] (1) Synthesis of 5-[(2(S)-2-acetoxypropionyl)amino]-2,4,6-triiodo-1,3-phthaloyl chloride (compound of formula 3)

[0053] According to the molar ratio of 5-amino-2,4,6-triiodo-1,3-phthaloyl chloride to 2(S)-2-acetoxypropionyl chloride is 1:2, 30g of 5-amino-2, Put 4,6-triiodo-1,3-phthaloyl chloride in a 250ml reaction flask, add 60mL N,N-dimethylacetamide under nitrogen protection, stir at room temperature until completely dissolved, and cool down to 0-5°C And keep it warm, slowly add 15g of 2(S)-2-acetoxypropionyl chloride dropwise, after the dropwise addition, naturally raise the temperature to 15-20°C and keep it warm for 30-40 hours, add 150mL of dichloromethane, stir for 3-5 minutes, Wash three times with 300 mL of water each time, then wash twice with 200 mL of saturated brine each time, separate the organic phase, concentrate to dryness under reduced pressure, add 90 mL of isopropanol to stir and crystal...

Embodiment 2

[0059] Embodiment 2: the synthesis of iopamidol impurity D

[0060] According to 1-[2-hydroxyacetyl-1-(hydroxyacetylmethyl)ethyl]-3-[benzoyl chloride]-5-[(2(S)-2-acetoxypropionyl)amino]- The molar ratio of 2,4,6-triiodo-benzamide to sodium hydroxide is 1:5, and 15g of 1-[2-hydroxyacetyl-1-(hydroxyacetylmethyl)ethyl]-3-[benzyl Acyl chloride]-5-[(2(S)-2-acetoxypropionyl)amino]-2,4,6-triiodo-benzamide was put into a 250mL reaction bottle, and 60mL of dichloromethane was added to stir at room temperature to dissolve. Then add 60mL of pure water, add 17.7mL of 20% sodium hydroxide dropwise, and react at 20-30°C after the dropwise addition, and follow up and detect the completion of the reaction by HPLC, adjust the pH to 6-7 with 10% hydrochloric acid, and separate the layers to obtain the water layer. After desalting with cation resin and anion resin, the impurity D was obtained with a yield of 70% and a purity of 97.4% by HPLC.

Embodiment 3

[0061] Embodiment 3: the synthesis of iopamidol impurity F

[0062] (1) According to the molar ratio of the compound of formula 1 to triethylamine and dimethylamine 1:1.2:1.6, add 18 g of the compound of formula 1, add 3.3 mL of triethylamine in 20 mL of N,N-dimethylacetamide solution, Cool down in an ice bath, keep warm at 0-10°C, add 3.6g of 40% dimethylamine aqueous solution dropwise, after the drop is complete, heat up to 20-30°C to react, HPLC detects that the reaction is complete, filter, and the filtrate is concentrated under reduced pressure, then add 30mL of isopropanol, and reflux After 2-4 hours, cool down to 20-30°C, slowly add 60mL of acetone dropwise, stir at 20-30°C for 1-2 hours, filter, and dry to obtain 12g of N-[N,N′-dimethyl]-N′-[ 2-Glyoacetyl-1-(hydroxyacetylmethyl)ethyl]-5-[(2(S)-2-acetoxypropionyl)amino]-2,4,6-triiodo-1,3 - Phthalamides.

[0063] (2) According to N-[N,N'-dimethyl]-N'-[2-glycolyl-1-(glycolylmethyl)ethyl]-5-[(2(S)-2- The molar ratio of ...

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Abstract

The invention relates to a production method of iopamidol impurities, in particular to 5-amino-2,4,6-triiodisophthaloyl acid dichloride derivative and application thereof in synthesis of iopamidol impurities, and belongs to the technical field of medicine. The 5-amino-2,4,6-triiodisophthaloyl acid dichloride derivative has a structural formula shown as the formula 1. A key intermediate for the formula 1 compound is synthesized with the starting material, 5-amino-1,3-diphenyl mono-formyl chloride; the intermediate is subjected to aminolysis or hydrolysis with different materials to prepare iopamidol impurities D, F, G and J.

Description

technical field [0001] The invention relates to a production method of iopamidol impurity, in particular to a 5-amino-2,4,6-triiodoisopeptidyl chloride derivative and its application in the synthesis of iopamidol impurity, belonging to the technical field of medicine . Background technique [0002] Iopamidol is currently one of the most widely used non-ionic X-ray contrast agents. Its impurity D, impurity F, impurity G and impurity J are all required to be controlled within 0.1% in the European Pharmacopoeia and the United States Pharmacopoeia. They are as follows: [0003] [0004] During the synthesis of iopamidol, the compound of formula 2 There are two acid chloride groups in the 1-position and 3-position in this structure, therefore, in the subsequent reaction process, the 1-position and 3-position acid chlorides will produce by-products due to the access to different structures, and these by-products will undergo subsequent deacetylation The base forms the corre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/32C07C231/12
CPCC07B2200/07C07C231/02C07C231/12C07C237/32C07C235/16
Inventor 詹国武周中平钱志达
Owner 江西兄弟医药有限公司
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