High-purity calcobutrol preparing method

A high-purity technology of calcobutrol, applied in the field of medicine, can solve the problems of difficulty in obtaining high-purity ligands, failure to obtain ligand crystals, large industrial wastes, etc., and achieves easy industrial application, reduction of three-waste generation, and clear routes. Effect

Active Publication Date: 2016-12-07
HARVEST PHARMA HUNAN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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. New impurities are generated 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 filtrat

Method used

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  • High-purity calcobutrol preparing method

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Effect test

Embodiment 1

[0039] At room temperature, add 10 g of gadobutrol (purity ≥99%) into 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 calcium carbonate to the filtrate for reflux reaction for 5 h, cool to room temperature and filter, add 1500 mL of ethanol to the filtrate to reflux for crystallization for 3 h, cool to room temperature, filter out the crystals, rinse with an appropriate amount of ethanol, and place the filter cake at 50°C for 5 h in a vacuum. Calcium cobutrol was obtained 6.2 g, the yield was 78%, and the purity by HPLC was 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, heat up to 90 °C and stir for 6 h to remove gadolinium. Cool to room temperature, filter, add 82.6 g of calcium carbonate to the filtrate to reflux for 5 h, cool to room temperature and filter, add 7500 mL of ethanol to the filtrate to reflux and crystallize for 3 h, cool to room temperature, filter out the crystals, rinse with an appropriate amount of ethanol, and place the filter cake in After vacuum-drying at 50°C for 5 h, 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 50 g of gadobutrol (purity ≥ 99%) into the reactor, add 500 ml of purified water and stir to dissolve, add 150 g of oxalic acid, heat up to 100°C and stir for 6 h to remove gadolinium, cool to room temperature, filter, and the filtrate Add 82.6 g of calcium carbonate for reflux reaction for 5 h, cool to room temperature and filter, add 7500 mL of ethanol to the filtrate for reflux crystallization for 3 h, cool to room temperature, filter out the crystals, rinse with an appropriate amount of ethanol, and dry the filter cake in vacuum at 50 °C for 5 h , to obtain 32.1 g, the yield was 79.5%, and the purity by HPLC was 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 formulation (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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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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