Crystallization purification method for iodixanol

A purification method, iodixanol technology, applied in the separation/purification of carboxylic acid amide, organic chemistry, etc., can solve the problems of long recrystallization time and difficult removal of crystallization solvent, and achieve short time consumption, less solvent residue, and high yield. high rate effect

Active Publication Date: 2018-02-16
CHIA TAI TIANQING PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are many existing crystallization and purification methods for iodixanol, but recrystallization generally takes a long time, and the crystallization solvent needs to be a

Method used

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  • Crystallization purification method for iodixanol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] 50g of crude iodixanol (moisture: 3.0%, HPLC purity: 97.8%) was dissolved in 200mL of methanol, refluxed and stirred to dissolve, 1.5g of activated carbon was added and refluxed for 0.5h, filtered, the filtrate continued to refluxed for 15min, and slowly added 20mL of Water and ethanol, continue to reflux for 15 hours, cool to 35°C, filter, wash the filter cake with a small amount of methanol, blow dry at 80°C for 5-10 hours, then weigh 41g, the yield is 82%, and the HPLC purity is 99.7%. Solvent residue: Methanol was not detected, ethanol 8ppm.

Embodiment 2

[0037] 500g of crude iodixanol (moisture: 2.8%, HPLC purity: 96.8%) was dissolved in 2.5L of methanol, refluxed and stirred to dissolve, added 15g of activated carbon and continued to reflux for 0.5h, filtered, the filtrate continued to reflux for 0.5h, and slowly added 400mL After the addition of absolute ethanol, continue to reflux for 20 hours, cool down to 35°C, filter, wash the filter cake with a small amount of methanol, blow dry at 80°C for 5-10 hours, and then weigh 400g. The yield is 80%, and the HPLC purity is 99.5%. Solvent residue: methanol 2ppm, ethanol 10ppm.

Embodiment 3

[0039] 5Kg of crude iodixanol (moisture: 2.5%, HPLC purity: 97.3%) was dissolved in 25L of methanol, refluxed and stirred to dissolve, added 150g of activated carbon and continued to reflux for 0.5h, filtered, and the filtrate continued to reflux for 0.5h, and slowly added 5L of After adding water and ethanol, add 2g of seed crystals (seed crystals from Example 2), continue to reflux for 20h, cool to 35°C, filter, wash the filter cake with a small amount of methanol, weigh 4.1Kg after drying, and the yield is 82%, HPLC The purity is 99.5%. Solvent residue: methanol 3ppm, ethanol 10ppm.

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Abstract

The invention provides a crystallization purification method for iodixanol. The crystallization purification method uses a simple methanol/ethanol system for recrystallization of a crude iodixanol solid product, does not use an aqueous solution of a crude iodixanol product, and unexpectedly prepares the iodixanol with less solvent residue and high purity. Meanwhile, the crystallization purification method provided by the invention has the advantages of simple operation, less time consumption, high yield, and applicability to industrial mass production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a crystallization and purification method of iodixanol, a non-ionic X-ray contrast agent. Background technique [0002] The chemical name of iodixanol is (1,3-bis(acetylamino)-N,N'-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-tri Iodophenyl]-2-hydroxypropane is a non-ionic dimeric triiodide aromatic compound. Iodixanol injection trade name is Visipaque TM , developed by Nycomed (now GE Healthcare), is an X-ray diagnostic reagent widely used clinically. [0003] At present, the synthesis of iodixanol mainly adopts the first method described in EP108638. The main feature of this method is that the final intermediate 5-acetylamino-N, N'-bis(2,3-dihydroxypropyl )-2,4,6-triiodo-isophthalamide (compound A) reacts with a dimerization reagent such as epichlorohydrin to prepare iodixanol, and the specific route is as follows: [0004] [0005] Utilize above-mentio...

Claims

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Application Information

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IPC IPC(8): C07C231/24C07C237/46
CPCC07C231/24C07C237/46
Inventor 王晶郭猛刘伟明
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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