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A kind of iodixanol, the preparation method of iohexol impurity

A technology of iodixanol and iohexol is applied in the preparation of organic compounds, the preparation of carboxylic acid esters, the preparation of carboxylic acid amides, etc., and can solve the problems of no preparation method, affecting product quality, difficult to remove, etc. By-product formation and high conversion rate

Active Publication Date: 2022-05-17
ZHEJIANG HAIZHOU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During the reaction, with the continuous hydrolysis of 5-acetylamino-2,4,6-triiodo-N,N-bis-(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide, This impurity will be generated, and the polarity of this impurity is very close to that of iodixanol. It is difficult to remove from the beginning of the reaction to the final product, which seriously affects the quality of the product. Therefore, research on this impurity is essential, but at present There is no related preparation method of this impurity in the prior art

Method used

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  • A kind of iodixanol, the preparation method of iohexol impurity
  • A kind of iodixanol, the preparation method of iohexol impurity
  • A kind of iodixanol, the preparation method of iohexol impurity

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preparation example Construction

[0027] A kind of iodixanol, the preparation method of iohexol impurity, comprises the steps:

[0028] Step 1. Using epichlorohydrin and acetic acid as raw materials, under the action of catalyst anhydrous ferric chloride, react at low temperature first, and then react at high temperature; after the reaction is completed, evaporate, dilute, filter, wash, dry, concentrate or precipitate , evaporated, diluted, filtered, washed, dried, and concentrated to obtain 2-hydroxy-3-chloropropyl acetate;

[0029] Step 2. Mix 5-acetamido-2,4,6-triiodo-N,N-bis-(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide with solvent, including water , N-methylpyrrolidone (NMP), ethylene glycol monomethyl ether, dimethylacetamide (DMA) or methanol, preferably ethylene glycol monomethyl ether or DMA, more preferably DMA; use triethylamine, sodium hydroxide , lithium hydroxide or sodium methylate, preferably sodium hydroxide or sodium methylate, more preferably sodium methylate, adjust the pH to 10-13, pref...

Embodiment 1

[0033] Put 150g 1.62mol epichlorohydrin into the reaction bottle, lower the temperature to 10°C with a freezing tank, and set aside; weigh 106.8g 1.78mol acetic acid, add 5g 0.03mol anhydrous ferric trichloride, and stir evenly; The acetic acid of ferric chloride is slowly dripped into epichlorohydrin twice, each time is about 2h, and the temperature is required to be controlled at 10°C-15°C; after the dropwise addition, stir at this temperature for 5h ( Keep this temperature, reduce the reaction rate, and reduce the generation of by-products; about 1 / 3 of the total amount can be reacted in 5 hours, and the remaining temperature must be raised to continue the reaction); after the stirring is completed, the temperature is raised to 50°C-55°C, and the heat preservation reaction is carried out for 28 hours; after the reaction is completed , add 2.53g 0.03mol sodium acetate, stir evenly (you can directly carry out subsequent rotary evaporation without adding sodium acetate), remove...

Embodiment 2

[0038] Put 150g 1.62mol epichlorohydrin into the reaction bottle, lower the temperature to 10°C with a freezing tank, and set aside; weigh 106.8g 1.78mol acetic acid, add 5g 0.03mol anhydrous ferric trichloride, and stir evenly; The acetic acid of ferric chloride is slowly dripped into epichlorohydrin twice, each time is about 2h, and the temperature is required to be controlled at 10°C-15°C; after the dropwise addition, stir at this temperature for 5h ( Keep this temperature, reduce the reaction rate, and reduce the generation of by-products; about 1 / 3 of the total amount can be reacted in 5 hours, and the remaining temperature must be raised to continue the reaction); after the stirring is completed, the temperature is raised to 50°C-55°C, and the heat preservation reaction is carried out for 28 hours; after the reaction is completed , add 2.53g 0.03mol sodium acetate, stir evenly (you can directly carry out subsequent rotary evaporation without adding sodium acetate), remove...

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Abstract

The invention discloses a preparation method of iodixanol and iohexol impurities, comprising the following steps: step 1, preparing 2-hydroxy-3-chloropropyl acetate; step 2, using 5-acetamido-2, 4,6-triiodo-N,N-bis-(2,3-dihydroxypropyl)-1,3-phthalamide and 2-hydroxy-3-chloropropyl acetate as raw materials, in solvent After the reaction is completed, the impurity 5-[N-(2-hydroxypropyl acetate) acetamido]-2,4,6-triiodo-N,N'-bis(2,3 ‑dihydroxypropyl)‑1,3‑phthalamide. The impurity of the present invention is easily produced in the preparation process of iodixanol and iohexol, which is difficult to separate and has a great impact on the purity. At present, there is no related preparation method for this impurity in the prior art. The present invention will fill in the preparation of this impurity Gaps in the method.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a method for preparing iodixanol and iohexol impurities. Background technique [0002] 5-Acetamido-2,4,6-triiodo-N,N-bis-(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide is a contrast agent iodixanol, iohexol key intermediates. During the reaction, with the continuous hydrolysis of 5-acetylamino-2,4,6-triiodo-N,N-bis-(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide, This impurity will be generated. The polarity of this impurity is very close to that of iodixanol. It is difficult to remove from the beginning of the reaction to the final product, which seriously affects the quality of the product. Therefore, research on this impurity is essential, but at present There is no related preparation method of this impurity in the prior art. [0003] The specific information of the impurity is as follows: [0004] Name: 5-[N-(2-hydroxypropylacetate)acetamido]-2,4,6-triiodo-N,N'...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/12C07C237/32C07C231/24
CPCC07C67/26C07C231/12C07C231/24C07C69/16C07C237/32
Inventor 段香江陈曦虞选旺林照棋曾永东
Owner ZHEJIANG HAIZHOU PHARMA CO LTD