Method for preparing high-purity Gadobutrol

Abstract

The invention provides a method for preparing high-purity Gadobutrol. The method comprises the following steps: taking cycleanine (I) as a starting material, firstly reacting with excess lithium chloride at high temperature to form a high-purity metal lithium complex (II), enabling the high-purity lithium complex (II) to react with 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (III) to generate an intermediate (IV), enabling the intermediate (IV) to react with chloroacetic acid and lithium hydroxide to synthesize an intermediate (V), salifying the intermediate (V) with gadolinium oxide to form a product (VI) namely a Gadobutrol crude product, and recrystallizing the crude product to prepare high-purity Gadobutrol. The method provided by the invention is simple in reaction process and clear in route, does not have redundant operation, ensures that the target compound is relatively high in purity and yield, can be used for greatly reducing the production of three wastes, and is easy to implement industrial application.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of high-purity gadobutrol. Background technique [0002] Gadobutrol is a gadolinium-containing contrast agent for nuclear spin tomography that has been approved in Germany since 2000 as Gadovist for the indication "Contrast enhancement in magnetic resonance tomography (MRT) of the skull and spine" ( EP0448181B1, EP0643705B1, EP0986548B1, EP0596586B1 and CA Patent 1341176). 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-Non-ionic complex composed of triacetic acid (butrol). Gadovist is sold as a 1 molar aqueous solution with the following components in the formulation: gadobutrol, cobutrol calcium sodium salt, tromethamine, hydrochloric acid and water for injections. Its specific preparation method has many kinds, and the main method of preparation at ...

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Problems solved by technology

[0003] In the CN103613557A patent, the boron-based protector of the ring tenning is used to react with 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane, although the selectivity is higher, but the boron The material cost of the compound is expensive, and it is not suitable for industrial mass production

Since all 4 amino groups on the ring can react, the selectivity of the reaction is very unsatisfactory, and the purity of the obtained intermediate is very low, so that the purification and quality control in the later stage are difficult to carry out

[0005] EP0596586 patent adopts free amino protection and deprotection, the selectivity is greatly improved, and the product process control and quality control are relatively easy, but the ring-opening conditions at 120°C and the formyl deprotection reaction conditions are harsh, and impurities are prone to occur , the purification of intermediates and finished products is cumbersome

[0006] In the CN103547573 patent, the conditions for lithium chloride to form complexes are adopted, but lithium chloride is only 0.88 eq of the ring, and about 10% of the ring will form various impurities in the reaction, so that the yield and purity of intermediates and finished products The purity and yield of gadobutrol reported in the literature cannot be reproduced according to the original research process, and the process is relatively cumbersome

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