Synthetic methods of an impurity A and an impurity B of iopamidol

A synthesis method and a technology of iopamidol, applied in the field of medicine, can solve the problems of difficult control of the reaction process, poor ester solubility, difficult removal and the like, and achieve the effects of simple solvent category and simple separation and purification

Inactive Publication Date: 2016-04-06
ZHEJIANG HAIZHOU PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Both impurity A and impurity B have poor ester solubility and have similar chemical properties to iopamidol. It is difficult to completely remove them when they are separated and purified from iopamidol products, and they are difficult to control during the reaction process. Eventually, iopamidol will remain. Influencing product qual

Method used

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  • Synthetic methods of an impurity A and an impurity B of iopamidol
  • Synthetic methods of an impurity A and an impurity B of iopamidol
  • Synthetic methods of an impurity A and an impurity B of iopamidol

Examples

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Effect test

Embodiment 1

[0037] Embodiment 1: the synthesis of iopamidol impurity A

[0038] According to the mass volume ratio of 5-amino-1,3-phthaloyl chloride and N,N-dimethylacetamide is 1g:2mL, put 59.6g of 5-amino-1,3-phthaloyl chloride in the reaction bottle Add 119mL of N,N-dimethylacetamide, stir at room temperature to dissolve completely, add 32mL of triethylamine, cool to 0-5°C in an ice bath, dissolve 21g of serinol in 168mL of N,N-dimethylacetamide , slowly drop into the solution, keep the solution temperature less than 10°C, after the drop is completed, heat up to 20-30°C for reaction, TLC tracking detection (tetrahydrofuran: dichloromethane = 1:1), react for 27 hours, concentrate under reduced pressure, Cool down to room temperature, add 298 mL of absolute ethanol to the residue, heat and reflux for 2 hours, lower to room temperature and stir for 30 minutes, filter, and rinse the solid with absolute ethanol 3 times, 15 mL each time, to obtain 60.6 g of light yellow solid iodine Alcohol...

Embodiment 2

[0039] Embodiment 2: the synthesis of iopamidol impurity A

[0040] According to the mass volume ratio of 5-amino-1,3-dibenzoyl chloride and N,N-dimethylacetamide is 1g:2mL, put 90g of 5-amino-1,3-dibenzoyl chloride in 1000mL three-port reaction In the bottle, add 180mL N,N-dimethylacetamide, stir at room temperature to dissolve completely, add 48.3mL triethylamine, cool to 0-5°C in an ice bath, dissolve 31.5g serinol in 252mL N , in N-dimethylacetamide, slowly dropwise, keeping the solution temperature below 5°C, after the drop, raise the temperature to 20-30°C to react, TLC tracking detection (developing agent is tetrahydrofuran: dichloromethane = 1:1) , reacted for 26 hours, concentrated under reduced pressure, lowered to room temperature, added 450 mL of isopropanol to the residue, heated to reflux for 3 hours, lowered to room temperature and stirred for 30 minutes, filtered, and the solid was rinsed with absolute ethanol 3 times, 40 mL each time , to obtain 85.2g light y...

Embodiment 3

[0041] Embodiment 3: the synthesis of iopamidol impurity A

[0042] In the step of synthesizing impurity A in this example, triethylamine was replaced by diisopropylethylamine, and other steps were the same as in Example 1 to obtain 58.5 g of impurity A, which was higher than 95% as determined by HPLC.

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Abstract

The invention relates to synthetic methods of an impurity A and an impurity B of iopamidol that is a nonionic X-radiographic contrast medium. 5-amino-1,3-phthaloyl dichloride is adopted as an initial raw material. The impurity A and the impurity B of the iopamidol can provide qualified contrasts for quality control of the iopamidol.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a method for synthesizing impurity A and impurity B in iopamidol. Background technique [0002] Iopamidol is one of the non-ionic X-ray contrast agents widely used at present, and its impurity A and impurity B are all required to be controlled within 0.1% in the European Pharmacopoeia and the United States Pharmacopoeia, and their respective structures are as follows: [0003] [0004] Both impurity A and impurity B have poor ester solubility and have similar chemical properties to iopamidol. It is difficult to completely remove them when they are separated and purified from iopamidol products, and they are difficult to control during the reaction process. Eventually, iopamidol will remain. Palyl products affect product quality. The synthetic method of relevant iopamidol impurity A and impurity B has no bibliographical information, therefore, a kind of synthetic method of ...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C237/46
CPCC07C231/02C07C231/12C07C237/46C07C237/42
Inventor 宋卫怀哲明何启航徐大国袁继雷胡寓言
Owner ZHEJIANG HAIZHOU PHARMA CO LTD
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