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Preparation method of high-purity kobutrol calcium

A high-purity technology of calbutril calcium, applied in the field of medicine, can solve problems such as difficulty in obtaining high-purity ligands, failure to obtain ligand crystals, large industrial wastes, etc., to achieve easy industrial application, reduce the generation of wastes, and clear routes Effect

Active Publication Date: 2018-10-19
HARVEST PHARMA HUNAN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In US5595714, Gadobutrol and oxalic acid were mixed, adjusted to pH = 0.8 by hydrochloric acid, stirred at 20°C for 6 hours, the precipitated gadolinium oxalate was filtered off, and the filtrate was adjusted to pH for crystallization, but ligand crystals could not be obtained, and because the method was New impurities are produced under strong acid, making it difficult to obtain high-purity ligands
[0004] In WO2011054827, gadobutrol and oxalic acid are mixed, gadolinium is removed by precipitation, the filtrate is eluted with an acidic ion resin, concentrated to dryness, and after continuing to dissolve, the specific pH is adjusted to 3.72 by quantitatively adding an acidic ion resin, and then filtered, and the filtrate is lyophilized to obtain butrol Ligand, butrol ligand reacts with calcium carbonate to obtain a sample of kabutrol calcium. This method can obtain pure kabutrol calcium, but the process is complicated and requires multiple resin purifications, and a large amount of industrial waste

Method used

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  • Preparation method of high-purity kobutrol calcium
  • Preparation method of high-purity kobutrol calcium

Examples

Experimental program
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Effect test

Embodiment 1

[0039] At room temperature, take 10 g of gadobutrol (purity ≥ 99%) and add it to the reactor, add 100 ml of purified water and stir to dissolve, add 14.9 g of oxalic acid, heat up to 95 ° C and stir for 6 h to remove gadolinium, cool to room temperature, filter, add 16.5 g of the filtrate g calcium carbonate was refluxed for 5 hours, cooled to room temperature and filtered, the filtrate was added with 1500mL of ethanol to reflux and crystallized for 3 hours, cooled to room temperature, filtered out the crystals, rinsed with an appropriate amount of ethanol, and the filter cake was vacuum-dried at 50°C for 5 hours to obtain Cobutrol Calcium 6.2g, yield 78%, HPLC detection purity 99.8%.

Embodiment 2

[0041] At room temperature, add 50 g of gadobutrol (purity ≥ 99%) into the reactor, add 500 ml of purified water and stir to dissolve, add 74.5 g of oxalic acid, raise the temperature to 90° C. and stir to remove gadolinium for 6 hours. Cool to room temperature, filter, add 82.6g of calcium carbonate to the filtrate to reflux for 5 hours, cool to room temperature and filter, add 7500mL ethanol to the filtrate to reflux and crystallize for 3 hours, cool to room temperature, filter out the crystals, rinse with an appropriate amount of ethanol, and place the filter cake at 50°C After vacuum drying for 5 hours, 33.5 g of Calcium Cobutrol was obtained with a yield of 82.9% and a purity of 99.5% by HPLC.

Embodiment 3

[0043] At room temperature, take 50g of gadobutrol (purity ≥ 99%) into the reactor, add 500ml of purified water and stir to dissolve, add 150g of oxalic acid, heat up to 100°C and stir for 6 hours to remove gadolinium, cool to room temperature, filter, add 82.6g of filtrate Calcium carbonate was refluxed for 5 hours, cooled to room temperature and filtered, and 7500 mL of ethanol was added to the filtrate to reflux for crystallization for 3 hours, cooled to room temperature, the crystals were filtered out, rinsed with an appropriate amount of ethanol, and the filter cake was vacuum-dried at 50°C for 5 hours to obtain 32.1 g, yield 79.5%, the HPLC detection purity is 99%.

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Abstract

The invention provides a high-purity calcobutrol preparing method. Gadolinium ions are extracted from gadobutrol which serves as a starting material under the action of acid, and filtration is conducted; a calcium preparation is added to filtrate, then refluxing reaction is conducted to generate calcobutrol, and excessive calcium carbonate and the byproduct calcium oxalate are filtered out; a nucleation agent is added to obtained calcobutrol solution, and heating, refluxing, crystallization and then filtration are conducted, so that high-purity calcobutrol is obtained. By the adoption of the method, the obtained product is highly pure, the method is simple, purification is easy, and industrial pollution rate is low.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to 10-(2,3-dihydroxy-1-(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecane-1,4,7 -The preparation method of the calcium complex of triacetic acid, also known as Calcium Cobutrol. Background technique [0002] Cobutrol calcium is one of the excipients of gadobutrol, which solves the problem of the release of free gadolinium in the gadobutrol preparation (solution). Gadobutrol is composed of gadolinium(III) and the macrocyclic ligand 10-(2,3-dihydroxy-1-(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecane -1,4,7-Nonionic complex composed of triacetic acid. Gadobutrol preparations are used in the diagnosis of contrast-enhanced magnetic resonance imaging (MRI) of the brain and spinal cord, contrast-enhanced magnetic resonance angiography (CE-MRA). The main ingredient of Gadobutrol Injection is Gadobutrol, and the excipients used are Cobutrol Calcium Sodium, Clomethamine, Hydrochloric Acid ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D257/02
CPCC07D257/02
Inventor 袁金桥竺来发曹宇刘虎
Owner HARVEST PHARMA HUNAN CO LTD
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