Preparation method of ioversol

A technology of ioversol and intermediate, applied in the field of preparation of ioversol, can solve problems such as affecting the quality and yield of the final product

Active Publication Date: 2017-01-04
JIANGSU HENGRUI MEDICINE CO LTD +1
View PDF4 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] However, this method produces the impurity N,N'-bis(2,3-dihydroxypropyl)-5-[(2-(2-hydroxyethoxy)-N-(2-hydroxy

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of ioversol
  • Preparation method of ioversol
  • Preparation method of ioversol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1: the synthesis of ioversol

[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-sodium borate buffer solution (sodium hydroxide 4.8g, water 100g, add sodium borate dodecahydrate to adjust the pH to 12.5), tetrahydrofuran 30ml, stir to dissolve, add 14.5 g (0.18mol) chloroethanol, warmed up to 50°C, and stirred for 11.5h. Use 5 mol / L hydrochloric acid solution to adjust the pH of the reaction solution to 6.0, add 26 g (0.317 mol) of anhydrous sodium acetate, and add concentrated hydrochloric acid dropwise under stirring to adjust the pH to 6.5. Heat to reflux for 13 hours, during which time 5mol / L hydrochloric acid is added to adjust the pH and maintain it at 5.5-6.5. The HPLC detection purity was 96.4%, wherein the impurity B was 1.32%, and the impurity D was 0.12% (direct sampling for detection).

[0042] Afte...

Embodiment 16

[0052] Embodiment 16: the synthesis of ioversol

[0053] 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-sodium borate buffer (sodium hydroxide 4.8g, water 100g, add sodium borate 12 water to adjust the pH to 11.5), ethylene glycol 20ml, stir to dissolve, add 15.4g (0.19mol) of chloroethanol was heated up to 50°C and stirred for 15h. Use 5 mol / L hydrochloric acid solution to adjust the pH of the reaction solution to 6.0, add 26 g (0.317 mol) of anhydrous sodium acetate, and add concentrated hydrochloric acid dropwise under stirring to adjust the pH to 6.5. Heat to reflux for 15 hours, during which 5mol / L hydrochloric acid is added to adjust the pH and maintain it at 5.5-6.5.

[0054] The reaction was completed, and the refining method was referred to Example 1 to obtain 36.7 g of a white solid with a yield of 75.9%. The HPLC detectio...

Embodiment 17

[0055] Embodiment 17: the synthesis of ioversol

[0056] 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-sodium borate buffer solution (sodium hydroxide 4.8g, water 100g, add sodium borate 12 water to adjust the pH to 13), tetrahydrofuran 50ml, stir to dissolve, add 14.5g (0.18mol) chloroethanol, the temperature was raised to 50°C, and the reaction was stirred for 10h. Use 5 mol / L hydrochloric acid solution to adjust the pH of the reaction solution to 6.0, add 26 g (0.317 mol) of anhydrous sodium acetate, and add concentrated hydrochloric acid dropwise under stirring to adjust the pH to 6.5. Heat to reflux for 11 hours, during which time 5 mol / L hydrochloric acid is added to adjust the pH and maintain it at 5.5-6.5. The purity detected by HPLC was 96.4%, the impurity B was 1.32%, and the impurity D was 0.02%.

[0057] The reaction wa...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention provides a preparation method of ioversol. Particularly, the method provided by the invention comprises the following steps: carrying out alkylation reaction on 5-chloracetylamino-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-phenyldiformamide and chloroethanol by using sodium hydroxide/sodium borate or sodium hydroxide/lithium chloride; and meanwhile, directly hydrolyzing the product by a one-pot multistep process, and carrying out desalting and purification to prepare the ioversol. The method simplifies the production technique process, effectively controls the generation of irremovable impurities, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of ioversol, which is widely used as a non-ionic X-ray contrast agent. 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,...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07C231/12C07C237/46
CPCC07C231/12C07C237/46
Inventor 侯宪山王俊琰王治安仲新光
Owner JIANGSU HENGRUI MEDICINE CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products