Refining method of gadadotec acid meglumine

A technology of gadoteric acid meglumine and meglumine is applied in the field of preparation and purification of gadoteric acid meglumine, and can solve problems such as affecting the nervous system.

Active Publication Date: 2021-12-17
ANHUI POLY PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The synthetic route of gadoterate meglumine is as follows Image 6 As shown; the purification method of gadoterate meglumine in the prior art can be generalized as anion-cation resin and crystallization method, which requires frequent operations and alternate use of cleaning ion-exchange resins, and the Gd contrast agent increases in circulation ti

Method used

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  • Refining method of gadadotec acid meglumine
  • Refining method of gadadotec acid meglumine
  • Refining method of gadadotec acid meglumine

Examples

Experimental program
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Effect test

Embodiment 2

[0030] Add 3.75g of purified DOTA to the reaction bottle, add pure water, stir and dissolve at room temperature, add gadolinium oxide (2.15g) and microporous calcium silicate particles 15g, then add 2.2-3g of meglumine until the solution pH=7 -9, ultrasonically oscillate for 1 hour, filter, heat the filtrate to 40-50°C and stir at a speed of 80r / min, react for 2-4 hours, filter the precipitate, and dry it in vacuum.

[0031] The microporous calcium silicate particles have an average pore diameter of 20-50nm, ultrasonic frequency of 20-50KHZ, and power of 150W.

[0032] The purity of the gadoterate meglumine prepared by the invention is more than or equal to 99.6%, the content of simple impurities is less than 0.02%, and the content of free gadolinium is less than 0.001%.

Embodiment 3

[0034] Add 3.75g of purified DOTA to the reaction bottle, add pure water, stir and dissolve at room temperature, add gadolinium oxide (2.15g) and microporous calcium silicate particles 15g, then add 2.2-3g of meglumine until the solution PH=8 -9, ultrasonically oscillate for 1 hour, filter, heat the filtrate to 40-50°C and stir at a speed of 80r / min, react for 2-4 hours, filter the precipitate, and dry it in vacuum.

[0035] The microporous calcium silicate particles have an average pore diameter of 20-50nm, ultrasonic frequency of 20-50KHZ, and power of 150W.

[0036] The purity of the gadoterate meglumine prepared by the invention is more than or equal to 99.6%, the content of simple impurities is less than 0.02%, and the content of free gadolinium is less than 0.001%.

[0037] Dissolve 2 g of the above-mentioned gadoterate meglumine in 100 ml of methanol, heat to dissolve under stirring, add 50 ml of water under stirring, stop stirring, cool down naturally, slowly precipita...

Embodiment 4

[0039] The gadoteric acid meglumine 2g that comparative example 1 obtains is dissolved in the methanol of 100ml, is heated to dissolving under stirring, adds 50ml water under stirring, stops stirring, naturally cools down, slowly separates out fine crystal, cools to 5 after 3 hours. Add 30ml of water under stirring at -10°C, stop stirring after adding, place to crystallize, filter the precipitated white crystals with suction, wash with a small amount of methanol, and dry in vacuum at 60°C to obtain a crystalline powder with a purity of 99.6% by HPLC analysis.

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Abstract

The invention provides a preparation process and a purification process of gadadotec acid meglumine. The preparation process comprises the steps of adding purified DOTA into pure water, stirring and dissolving at room temperature, adding gadolinium oxide and microporous calcium silicate particles, adding meglumine until the pH value of the solution is 7-9, carrying out ultrasonic oscillation, filtering, heating the filtrate to the temperature of 40-50 DEG C, stirring, reacting for 2-4 hours, filtering the precipitate, and performing vacuum drying to obtain the product. The purification method provided by the invention comprises the steps of dissolving a crude product gadadotec acid meglumine in 100ml of methanol, heating while stirring until the gadadotec acid meglumine is dissolved, adding 50ml of water while stirring, stopping stirring, naturally cooling, slowly separating out fine crystals, cooling to the temperature of 5-10 DEG C after 3 hours, adding 30ml of water while stirring, stopping stirring after adding, standing for crystallization, and carrying out suction filtration on the separated white crystals, washing with a small amount of methanol, and carrying out vacuum drying at the temperature of 60 DEG C to obtain crystalline powder.

Description

technical field [0001] The invention belongs to the field of contrast agent preparation methods, in particular to the preparation and purification of gadoterate meglumine. Background technique [0002] Gadoterate meglumine, chemical name 1,4,7,10-tetraazadodecane-1,4,7,10-tetraacetate gadolinium meglumine, was developed and marketed by Guerbet, used for nuclear magnetic resonance Imaging contrast agent. [0003] Gadoterate meglumine is an ion ring gadolinium preparation, which can be used for central, systemic and angiography. At present, the preparation method of gadoterate meglumine disclosed in the technology usually first synthesizes the ligand rotenine tetraacetic acid (DOTA), and then complexes Combining gadolinium ions, and then forming a salt with meglumine, the scores are as follows: [0004] Using rhodotendine and tert-butyl bromoacetate as raw materials, under the conditions of potassium carbonate as alkali and chloroform as solvent, N-alkylation reaction occurs...

Claims

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Application Information

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IPC IPC(8): C07D257/02C07C213/10C07C215/10C07C213/08
CPCC07D257/02C07C213/10C07C213/08C07C215/10
Inventor 朱逸凡范敏华周胜军吴族悌施海峰陆翠军聂良邓
Owner ANHUI POLY PHARM CO LTD
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