Method for producing calcobutrol

Abstract

Disclosed is a method for producing calcobutrol used as an MRI contrast agent. The method comprises the steps of: obtaining butrol represented by chemical formula 2 in the specification by reacting a gadobutrol represented by chemical formula 1 in the specification and a decomplexing agent; and obtaining a calcobutrol represented by chemical Formula 3 in the specification by reacting butrol with calcium ions.

Claims

1. A method for producing calcobutrol comprising the steps of: obtaining butrol represented by following Chemical Formula 2 by reacting a gadobutrol represented by following Chemical Formula 1 and tartaric acid as a decomplexing agent, wherein the butrol is filtered and purified using a nanofilter system; and reacting calcium ions with the butrol to obtain a calcobutrol represented by following Chemical Formula 3, ##STR00003## wherein the content of the decomplexing agent is 3.0 to 6.0 equivalents with respect to the gadobutrol and the calcium ion is selected from the group consisting of calcium carbonate, calcium hydroxide, calcium chloride and mixtures thereof, and the content of the calcium ion is 0.9 to 1.1 equivalents with respect to the gadobutrol.

2. The method as claimed in claim 1, wherein the calcobutrol is crystallized with ethanol anhydrous.

Description

DETAILED DESCRIPTION OF INVENTION

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

(2) In order to prepare butrol according to the present invention, first, the 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, gadobutrol) represented by the following Chemical Formula 1, a starting material is reacted with a decomplexing agent 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 butrol) represented by the following Chemical Formula 2.

(3) ##STR00001##

(4) The decomplexing agent de-complexes gadolinium of gadobutrol to form a gadolinium salt that is poorly soluble in water, so that butrol can be isolated through a filtration process. The decomplexing agent includes tartaric acid, succinic acid, citric acid, fumaric acid, and so on, preferably tartaric acid is preferred. The content of the decomplexing agent is 2.0 to 6.0 equivalents, preferably is 3.0 to 4.0 equivalents, with respect to 1.0 equivalent of gadobutrol. If the content of the decomplexing agent is too less, not only the reactivity is poor and the reaction time is long, but also it may be a problem in yield and quality due to the generation of a related substance by heat. If the content of the decomplexing agent is too high, the cost of removing the decomplexing agent remaining after the reaction is further incurred, causing a cost increase.

(5) The reaction can be carried out in purified water, and the reaction temperature is generally 80 to 90° C. If the reaction temperature is too low, it causes a rise in cost due to a time delay, and if it is too high, a quality problem may occur. The reaction time is 3 to 5 hours. If the reaction time is too short, the yield due to unreacted products may decrease, and if it is too long, there is no economical benefit from working time increasing.

(6) The salt prepared from the reaction is filtering and separated and the filtrate is again filtered, so that the remaining decomplexing agent and by-products may be removed. Concentrating the purified filtrate removes gadolinium from gadobutrol to obtain a butrol.

(7) Specifically, it is filtered using a nano filter. The nano-filter system has a spiral shape of an organic film and a reverse osmosis device designed to filter or concentrate substances with a molar mass of 200 to 300 Daltons or more, so that water-soluble organic or inorganic materials with salts and other low molecular weights can be separated and purified through the organic film to recover only the desired material.

(8) 2,2,2-(10-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate calcium complex (hereinafter, calcobutrol) represented by the following Chemical Formula 3 is obtained by reacting the butrol represented by the following Chemical Formula 2 with a calcium ions, and crystallizing the same.

(9) ##STR00002##

(10) The reaction can be carried out in purified water. The source of calcium ions includes calcium carbonate, calcium hydroxide, calcium chloride, and so on, and calcium carbonate is preferred. The content of the calcium ion source is 0.9 to 1.1 equivalents, preferably is 1.0 equivalent, with respect to 1.0 equivalent of butrol. Here, if the content of the calcium source is too less, the complex is less formed, yield reduction occurs, and if too large, there is a problem in that the filtering of the remaining calcium carbonate is difficult.

(11) The reaction temperature is generally 85 to 95° C. If the reaction temperature is too low, there is a decrease in yield due to unreacted substances, and if it is too high, related substances can occur and product quality problems can occur. Also, the reaction time of the butrol and calcium ion is 2 to 3 hours. If the reaction time is too short, a problem may occur in yield reduction and crystallization due to unreacted materials. If the reaction time is too long, a problem may occur in the quality of the product.

(12) The reactants can be filtered on an activated carbon pad and the filtrate is concentrated, dissolved in purified water, crystallized and isolated with anhydrous ethanol. As the crystallization solvent an organic solvent such as anhydrous ethanol, methanol, isopropanol, acetone and so on can be used, and anhydrous ethanol is preferred. Specifically, the filtrate can be crystallized under purified water-anhydrous ethanol conditions at generally 60 to 80° C. Therefore, when the crystallized mixture is dried, calcobutrol can be obtained.

EXAMPLES

(13) Hereinafter, the present invention is described in more detail through examples, but the present invention is not limited by the following examples.

[Example 1] Preparation of Butrol Represented by Formula 2

(14) Gadolinium complex of 2,2,2-(10-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (hereinafter, gadobutrol) of 200.0 g, tartaric acid of 241.02 g and purified water of 600 ml were put into a reactor, and heated to 85 to 95° C. to carry out reaction. After the end of reaction, the mixture was cooled to 20 to 30° C., and the produced solid was removed by filtration. The filtrate was subjected to a nano-filter and concentrated under reduced pressure, so that 2,2,2-(10-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid(butrol) of 105.4 g (yield 72.9%, purity 98% (HPLC)) was obtained.

[Example 2] Preparation of Calcobutrol Represented by Formula 3

(15) 2,2,2-(10-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid(butrol) of 50.0 g, calcium carbonate of 15.0 g and purified water of 200 ml were put into the reactor, and then heated to 85 to 95° C. to terminate the reaction, and cooled to 20 to 30° C. The filtrate was subjected to an activated carbon pad and concentrated under reduced pressure. 75 ml of purified water was added, heated to 85 to 95° C., maintained, and crystallized by adding 888.7 g of anhydrous Ethanol. This was refluxed for 1 hour, cooled to 0 to 10° C., and the producing crystals were filtered and washed with 177.7 g of anhydrous ethanol, and then dried, so that calcium complex of 2,2,2-(10-1,3,4-trihydroxybutane-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (hereafter, calcobutrol) of 44.4 g (yield 39.4%, purity 99.5% (HPLC)) was obtained.