CS200825B1 - Method of crystallization of the 2,4,6-triiodine-3-aminobenzoin acid - Google Patents

Description

The invention relates to a process for the crystallization of 2,4,6-triiodo-3-aminobenzoic acid of the formula

an intermediate intermediate for the production of important radio-diagnostic agents, in particular its 3-acetylamino derivative or the bis-N-methylglucamine salt of bis (2,4,6-triiodo-3-carboxyanilide) adipic acid.

In particular, this substance is of particular importance in X-ray diagnostics, since it allows relatively safe and easy imaging not only of the gallbladder but also of the bile ducts, which essentially reduced the need for surgical cholangiography. It is given exclusively as an intravenous injection of a 50 to 70% solution. High concentrations of the active substance in injection solutions impose proportionally high purity requirements on the substance used. It is logical that in order to improve the quality of the contrast agents, it is necessary to use the purest intermediates for their synthesis.

0 0 8 2 N

The preparation of 2,4,6-triiodo-3-aminobenzoic acid as a basic intermediate of said preparations is well described in the literature; in each case iodination of 3-aminobenzoic acid with chlorine iodine in an inorganic acid medium, at different temperatures and at different dilutions, optionally under irradiation with UV light. The most preferred process that has proven operationally and is in use is the Wallingford sp. /J.Am.Chem.Soc. 74, 4365 (1952)]. In all cases, however, in addition to the desired acid, the corresponding monoiodo and diiodo derivative and the unidentified color impurities that are formed are formed by changes in the amino group. The methods of purifying 2,4,6-triiodo-3-aminobenzoic acid described in the literature are mostly based on converting it into an alkali metal salt, preferably sodium salt, which is isolated and crystallized from water. Because of the different solubility of the sodium salts, the more soluble diiodo derivative can be separated. However, it is not possible to remove the other colored impurities which, upon release or precipitation of 2,4,6-triiodo-3-aminobenzoic acid from solutions of its alkali metal salts, are entrained, polluted and stained into the final product. These impurities cannot be removed by crystallization; it is known from operational experience that even repeated crystallization from ethanol does not lead to completely pure and colorless 2,4,6-triiodo-3-aminobenzoic acid

According to the invention, the method of crystallizing 2,4,6-triiodo-3-aminobenzoic acid according to the invention is characterized in that the alkali metal salt of 2,4,6-triiodo-3-aminobenzoic acid, in particular sodium salt, is decomposed into aqueous solution containing hydrochloric acid, methanol and acetic acid at 60 to 75 ° C and the liberated 2,4,6-triiodo-3-aminobenzoic acid is crystallized from this solution at 0 to 20 ° C.

In a preferred embodiment, a mixture of 0.20 to 0.50 parts by volume of concentrated hydrochloric acid, 5.00 to 5.50 parts by volume of methanol, 0.75 to 1.0 parts by volume of acetic acid, and 3.20 to 4.00 parts by volume of water, based on 1 part by weight of the alkali metal salt of 2,4,6-triiodo-3-aminobenzoic acid, in particular sodium salt.

The yields of the described operation are very good, ranging from 80 to 90% of theory, and the obtained substance is chromatographically completely pure and suitable for further work. The crystallization process according to the invention is technologically undemanding, easy to reproduce and represents a valuable improvement in the quality of the X-ray diagnostics which are produced from 2,4,6-triiodo-3-aminobenzoic acid, since all the color constituents formed are removed from the mixture. for example, by oxidative changes at the amino group and other low-iodine undesired products.

Example

Water-crystallized 4250 g of dry 2,4,6-triiodo-3-aminobenzoic acid, sodium salt, is dissolved in a glass 801-liter kettle in 17.2 liters of methanol and heated to 50 ° C under reflux, then added. 425 g of activated carbon suspended in 3 liters of methanol. After stirring for half an hour, the mixture was filtered and the filter was washed with 1 L

200 82!

of methanol. The filtrate is placed in a clean 80 liter kettle, 14 liters of deionized water are added and the solution is heated to 65-68 ° C under reflux with stirring. A mixture of 3.5 liters of 99% pure acetic acid and 1000 ml of concentrated pure hydrochloric acid is then added with stirring and stirring is stopped. 2,4,6-triiodo-3-aminobenzoic acid begins to crystallize gradually. Its solution is cooled first with water and then with brine to 5-10 ° C and left to crystallize overnight. The next day, the precipitated acid is filtered off with suction, washed first with 400 ml of methanol and then with water until the acid reaction is lost and again sucked off and dried in an oven at 50 ° C. The yield of the chromatographically uniform product is 3435-3800 g, i

80.5 to 88% of theory.

Claims (2)

Process for crystallizing 2,4,6-triiodo-3-aminobenzoic acid, characterized in that the alkali metal salt of 2,4,6-triiodo-3-aminobenzoic acid, in particular sodium salt, is decomposed in an aqueous solution containing hydrochloric acid, methanol and acetic acid at 60-75 ° C and the liberated 2,4,6-triiodo-3-aminobenzoic acid crystallized from this solution at 0-10 ° C. 2. The process according to claim 1, wherein a mixture of 0.20 to 0.50 parts by volume of concentrated hydrochloric acid, 5.00 to 5.50 parts by volume of methanol, 0.75 to 0.50 parts by volume of hydrogen chloride is used for decomposition and crystallization. 1.0 part by volume of acetic acid and 3.20 to 4.00 parts by weight of water, based on 1 part by weight of the alkali metal salt of 2,4,6-triiodo-3-aminobenzoic acid, in particular sodium salt.