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Preparation method for ioversol

A technology of ioversol and alkylation reaction, which is applied in the field of ioversol preparation and can solve problems such as difficulty in removing and increasing the number of refining times of ioversol

Active Publication Date: 2017-05-31
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this case, N,N'-bis(2,3-dihydroxypropyl)-2,3,5,6-tetrahydro-9-iodo-3-oxo Subo-[1,4]oxazine(4,3,2-d)4-benzoxazine-8,10-dicarboxamide (impurity I), which is difficult to remove even in the subsequent purification process, needs to be added Refining Times of Ioversol

Method used

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  • Preparation method for ioversol
  • Preparation method for ioversol
  • Preparation method for ioversol

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Embodiment 1: the synthesis of ioversol (water used is purified water, iron content is 0.05ppm or lower)

[0041] In a three-necked flask equipped with a stirrer and a reflux condenser, add 50g (0.06mol) of 5-chloroacetamido-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6- Triiodo-1,3-phthalamide, sodium hydroxide (4.8g, purified water 100ml, pH=12.5), tetrahydrofuran 30ml, stir to dissolve, add 14.5g (0.18mol) chloroethanol, heat up to 50°C, stir Reaction 11.5h. Use 5mol / L hydrochloric acid solution to adjust the pH of the reaction solution to 6.0, add 26g (0.317mol) of anhydrous sodium acetate, add concentrated hydrochloric acid or sodium hydroxide solution dropwise under stirring to adjust the pH to 6.5, and heat to reflux for 13h. The purity of HPLC was 93.12%, and the impurity I was 2.95% (direct sampling for detection).

[0042]Concentrate under reduced pressure, add methanol to the residue, filter, concentrate the filtrate to remove methanol, add 100ml of water, add 2g of...

Embodiment 2

[0043] Embodiment 2: the synthesis of ioversol (water used is industrial water, iron content is 500ppm)

[0044] In a three-necked flask equipped with a stirrer and a reflux condenser, add 20g (0.024mol) of 5-chloroacetamido-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6- Triiodo-1,3-phthalamide, sodium hydroxide (1.92g, industrial water 40ml, pH=12.5), tetrahydrofuran 30ml, stir to dissolve, add 5.8g (0.072mol) chloroethanol, heat up to 50°C, stir Reaction 11h. Use 5 mol / L hydrochloric acid solution to adjust the pH of the reaction solution to 6.0, add 10.4 g of anhydrous sodium acetate, add concentrated hydrochloric acid or sodium hydroxide solution dropwise under stirring to adjust the pH to 6.5, and heat to reflux for 12 hours. The purity detected by HPLC was 87.21%, and the impurity I was 9.72% (directly sampled for detection).

[0045] Concentrate under reduced pressure, add methanol to the residue, filter, concentrate the filtrate to remove methanol, add 40ml of water, add 0.8g...

Embodiment 3

[0046] Embodiment 3: the synthesis of ioversol (water used is purified water, adds 0.4g iron trichloride)

[0047] In a three-necked flask equipped with a stirrer and a reflux condenser, add 20g (0.024mol) of 5-chloroacetamido-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6- Triiodo-1,3-phthalamide, sodium hydroxide (1.92g, purified water 40ml, pH=12.5), tetrahydrofuran 30ml, stir to dissolve, add 5.8g (0.072mol) chloroethanol, heat up to 50°C, stir Reaction 11h. Use 5mol / L hydrochloric acid solution to adjust the pH of the reaction solution to 6.0, add 10.4g of anhydrous sodium acetate and 0.4g of ferric chloride, add concentrated hydrochloric acid or sodium hydroxide solution dropwise under stirring to adjust the pH to 6.5, and heat to reflux for 12h. The purity detected by HPLC was 83.21%, and the impurity I was 12.67% (directly sampled for detection).

[0048] Exploration of process conditions - screening reaction conditions

[0049] With reference to the method for preparing iove...

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Abstract

The invention provides a preparation method for ioversol. Specifically speaking, the method comprises the following steps: (1) performing an alkylation reaction on 5-chloracetyl amino-N,N'-bi-(2,3- dyhydroxyl propyl)-2,4,6-triiodo-1,3-phthalic diamide and chlorethyl alcohol under an alkaline condition; (2) hydrolyzing through sodium acetate to obtain the ioversol. A container of which the inner wall is coated with a corrosion-resistant coating is used in the reactions of the former two steps, and the water with the iron content of below 0.05 ppm is used. The method can effectively avoid the production of impurities which are difficult to remove, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of ioversol. Background technique [0002] Ioversol, chemical name N,N'-bis(2,3 dihydroxypropyl)-5-[N-(2-hydroxyethyl)-glycolamide]-2,4,6-triiodo- 1,3-phthalamide, the structural formula is as follows: [0003] [0004] Because ioversol has the advantages of large water solubility, low viscosity, low osmotic pressure, and low incidence of adverse reactions, it is one of the contrast agents widely used clinically. Specifically, it can be used as angiography, venous digital silhouette angiography, Arthrography, urography, chest and cervical spine imaging and gastrointestinal examination, etc. [0005] Regarding the synthesis of ioversol, many synthetic routes have been disclosed in the prior art. Triiodo-1,3-benzenedicarboxamide is used as a raw material, and acetoxyacetyl chloride is used as an acylating reagent, first acylated, then hydrolyzed, and then reacted with chloroethanol to prepare ioversol. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C237/46
CPCC07C231/12C07C237/46
Inventor 侯宪山王俊琰王庆乐徐燕
Owner JIANGSU HENGRUI MEDICINE CO LTD
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