阅读说明：本技术 生产考布曲钙的方法 (Method for producing combretastatin calcium ) 是由 李才龙 李钟洙 姜炳圭 李秉宇 李相晤 尹大明 邦载勋 孙起荣 于 2019-01-11 设计创作，主要内容包括：公开了一种生产用作MRI造影剂的考布曲钙的方法。该方法包括以下步骤：通过使由说明书中化学式1表示的钆布醇与解络剂反应得到由说明书中化学式2表示的布醇；通过使布醇与钙离子反应得到由说明书中化学式3表示的考布曲钙。(A method of producing cobutrol for use as an MRI contrast agent is disclosed. The method comprises the following steps: obtaining a butol represented by chemical formula 2 in the specification by reacting gadobutrol represented by chemical formula 1 in the specification with a decomplexer; combretastatin represented by chemical formula 3 in the specification was obtained by reacting bucinol with calcium ions.)

1. A method of producing cobutrol calcium comprising the steps of:

obtaining butol represented by the following chemical formula 2 by reacting gadobutrol represented by the following chemical formula 1 with a decomplexer; and

reacting calcium ions with the butonol to obtain combretastatin represented by the following chemical formula 3,

[ chemical formula 1]

[ chemical formula 2]

[ chemical formula 3]

2. The method of claim 1, wherein the decomplexing agent is selected from the group consisting of: tartaric acid, succinic acid, citric acid, fumaric acid, and mixtures thereof; the content of the decomplexer is 3.0 to 6.0 equivalents relative to gadobutrol.

3. The method of claim 1 or 2, wherein the butanol is filtered and purified using a nanofilter.

4. The method of claim 1, wherein the calcium ion is selected from the group consisting of: calcium carbonate, calcium hydroxide, calcium chloride, and mixtures thereof; and the content of said calcium ions is from 0.9 to 1.1 equivalents with respect to gadobutrol.

5. The method of claim 1, wherein the cobutrcalcium is crystallized with anhydrous ethanol.

Technical Field

The present invention relates to a method for producing calcobutrol, and more particularly, to a method for producing calcobutrol used in MRI contrast agents.

Background

Gadobutrol (gadobutrol) is sold worldwide under the trade name Gadovist or Gadavist in the field of gadolinium-containing contrast agents.

It has been found to be advantageous for gadolinium-containing contrast agents to apply an excess of complex-forming ligand in the form of a calcium complex. The role of the calcium complex is to prevent the release of free gadolinium from gadobutrol in the formulation after preparation, thus solving the safety problem for renal-derived systemic fibrosis (NSF) caused by the toxicity of the gadolinium cation.

The synthesis of combretastatin is described in detail in the literature (Inorg. chem.1997,36,6086-6093). The method of this document yields a material with a purity of 90-95%, but does not achieve the purity required for the formulation.

In order to further purify 2,2,2- (10-1,3, 4-trihydroxybutan-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid (hereinafter referred to as "butol"), purification by crystallization is not easy due to amphiphilicity of butol (zwitterionic) with an ion exchange resin, and also crystallization is not performed by adjusting pH, and thus purification by crystallization is not possible.

Gadobutrol is a neutral gadolinium complex, which can be obtained in high purity (> 99.6%) by purification and crystallization with an ion exchange column after the reaction, but it has a problem that it is difficult to purify due to the remaining acid functional group. Therefore, the known process for producing cobutrcalcium directly from buconazole is unsuitable in terms of purity.

According to Korean patent No. 10-1057939 to Bayer pharma aktiengesellschaft, a method for manufacturing high-purity combretastatin is known as follows: gadobutrol obtained previously is selected as a starting material and decomplexed, free gadolinium is removed to prepare high purity budesonide, which is then complexed with calcium to prepare calcium cobutrate. However, oxalic acid used for decomplexation in the above method is toxic and has limitations in use. Also, other impurities are removed by adsorption and desorption of the brenol onto the cation exchange resin to produce high purity brenol, which is then reacted with calcium ions to obtain cobutrcalcium. However, these series of processes are not economical and the processes are complicated.

According to korean patent No. 10-1693400 to ST Pharm co., ltd, a method of manufacturing cobutrcalcium is known as follows: the intermediate 3- (1,4,7, 10-tetraazacyclododecane-1-yl) butane 1,2, 4-triol 4 hydrochloride of gadobutrol is taken as a starting material, tert-butyl bromoacetate is introduced, and then deprotection process is carried out; then purifying by resin to obtain high-purity butonol, and reacting with calcium ion to obtain the combretastatin. However, t-butyl bromoacetate used in the above method is harmful to the human body and has a disadvantage of being expensive. Moreover, the deprotection process is uneconomical and the process is complicated.

Therefore, there is a need to develop a method for manufacturing high-purity combretastatin that is eco-friendly, economical and simple and less harmful to the human body by excluding resin purification and deprotection processes.

Disclosure of Invention

It is therefore an object of the present invention to provide a process for the production of combretastatin having a higher purity than the process using butol (intermediate of gadobutrol).

It is another object of the present invention to provide a process for the production of combretastatin which is simpler and more economical than the processes for the production of known starting materials of high purity gadobutrol.

To achieve these objects, the present invention provides a method for producing combretastatin, comprising the steps of: obtaining butol represented by the following chemical formula 2 by reacting gadobutrol represented by the following chemical formula 1 with a decomplexer; and reacting the calcium ion with buconazole to obtain combretastatin represented by the following chemical formula 3.

As described above, the process for producing combretastatin according to the invention is simpler and more economical than the conventional process for producing combretastatin using high-purity gadobutrol as a starting material.

Detailed Description

Hereinafter, the present invention will be described in more detail.

To prepare the butol according to the present invention, first, gadolinium complex of 2,2,2- (10-1,3, 4-trihydroxybutan-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) acetic acid (hereinafter referred to as gadobutrol) represented by the following chemical formula 1 as a starting material is reacted with a decomplexer to obtain 2,2,2- (10-1,3, 4-trihydroxybutan-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid (hereinafter referred to as butol) represented by the following chemical formula 2.

[ chemical formula 1]

[ chemical formula 2]

The decomplexer decomplexes gadolinium of gadobutrol to form a poorly water soluble gadolinium salt, such that the budesonide can be separated by a filtration process. The decomplexer comprises tartaric acid, succinic acid, citric acid, fumaric acid, etc., preferably tartaric acid. The content of decomplexer is from 2.0 equivalents to 6.0 equivalents, preferably from 3.0 equivalents to 4.0 equivalents, with respect to 1.0 equivalent of gadobutrol. If the content of the decomplexer is too small, not only reactivity is poor and reaction time is long, but also there are problems in yield and quality due to generation of related substances by heating. If the content of the decomplexer is too high, the cost of removing the decomplexer remaining after the reaction is also increased, resulting in an increase in cost.

The reaction can be carried out in purified water, and the reaction temperature is usually 80 ℃ to 90 ℃. If the reaction temperature is too low, the cost increases due to time delay, and if the temperature is too high, quality problems may occur. The reaction time is 3 to 5 hours. If the reaction time is too short, the yield may be lowered due to the unreacted product, and if it is too long, the increase in working time does not bring economic benefits.

The salt produced by the reaction is filtered and separated, and the filtrate is filtered again, so that the remaining decomplexer and by-products can be removed. The purified filtrate is concentrated to remove gadolinium from gadobutrol to obtain butol.

In particular, nanofiltration is used. The nanofilter system has a spiral-shaped organic membrane and a reverse osmosis apparatus, and is designed to filter or concentrate substances having a molar mass of 200 to 300 daltons or more, so that it can separate and purify water-soluble organic or inorganic materials containing salts and other low molecular weight by the organic membrane to recover only desired substances.

A calcium 2,2,2- (10-1,3, 4-trihydroxybutan-2-yl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetate complex represented by the following chemical formula 3 (hereinafter, referred to as cobutralcium) is obtained by reacting butol represented by the following chemical formula 2 with calcium ions and crystallizing it.

[ chemical formula 3]

The reaction can be carried out in purified water. The calcium ion source includes calcium carbonate, calcium hydroxide, calcium chloride, etc., and calcium carbonate is preferable. The content of the calcium ion source is 0.9 to 1.1 equivalents, preferably 1.0 equivalent, relative to 1.0 equivalent of the bronol. Here, if the content of the calcium source is too small, the formation of the complex is small and the yield is lowered, while if the content of the calcium source is too large, there is a problem that it is difficult to filter the remaining calcium carbonate.

The reaction temperature is usually 85 ℃ to 95 ℃. If the reaction temperature is too low, the yield is lowered due to unreacted materials; whereas if the reaction temperature is too high, related substances may occur and product quality problems may occur. Also, the reaction time of the bronopol and the calcium ion is 2 to 3 hours. If the reaction time is too short, problems of yield reduction and crystallization may be caused due to unreacted materials. If the reaction time is too long, problems may arise in the product quality.

The reaction mass may be filtered on a pad of activated carbon and the filtrate concentrated, dissolved in purified water, crystallized with absolute ethanol and isolated. As the crystallization solvent, an organic solvent such as absolute ethanol, methanol, isopropanol, or acetone can be used, and absolute ethanol is preferred. Specifically, the filtrate may be crystallized under the conditions of purified water-absolute ethanol, generally at 60 ℃ to 80 ℃. Thus, when the crystallized mixture was dried, cobutrol was obtained.