CS200079B1 - Method for the purification of n,n'-adipoyl-bis/2,4,6-triiod-3-aminobenzoic acid - Google Patents

Description

The present invention relates to a process for the purification of M, N-adipoylbie (2,4,6-triiodo-3-aminobeazonaate), an important contrast agent (H). Proewe et al. 87, 651 (1954); U.S. Patent No. 2,572J3; British patent £. 748786), manufactured under various trade names, applied in a 50% aqueous solution of the N-methylglucamine salt injectable in gall bladder and bile cos * X-ray diffraction, therefore, extremely stringent requirements are placed on the quality of the starting substance.

In the synthesis of N, N-adipoyl-bis (2,4,6-triiodo-3-aminobenzoic acid), it is usually started from a reactive adipic acid halide (chloride) which in a hydrophobic medium such as aromatics such as benzene, toluene or chlorobenzene , reacts slowly with 2,4,6-triiodaminobenzoic acid. A constant problem with the contrast agent is the stability of the injectable solution and its color, which vary with the conditions of preparation.

Complications in this sense may arise both in the synthesis of the substance and in the preparation of the injection solution.

Condensation, which takes place slowly over a period of up to 24 hours, gives rise to a wide variety of by-products, the origin of which can be found, on the one hand, in the impurities introduced with the basic components of the reaction, and on the other. The starting 2,4,6-triiodo-3-aminobenzoic acid is of variable quality. During its production, the acids below produce iodinated, probably mono and diiodo derivatives, as well as strongly colored substances whose origin is due to changes in the amino group of the starting 3-aminobehzoic acid.

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This acid, like most substances and the free aromatic amino group, is very sensitive to environmental influences / redox systems, light, etc. A Also used is adipic acid chloride, prepared using various chlorinating agents such as phosphorus trichloride, thionyl chloride or phosgene / Etaix, A .Ch. (7), 9, 369} W. Borsch, Ber. 45, 3715, 1912} 44, 3185, 1911} Triebs, er. 85, 611 (1952)} Chem. Abstr. 51, 5831 (1957), is a carrier of color changes which originate from residues of chlorinating agents which may be involved in side reactions. The reaction of 2,4,6-triiodo-3-aminobenzoic acid with adipic acid chloride results in a number of substances which yield 10 to 16 atopes in thin layer chromatography, depending on the sensitivity of the chromatographic plates used. Some of them have been isolated and identified as mono- or poly-substituted amino-benzoic acids, possibly diaminoderivatives, and more iodine atoms. Different concentrations of these compounds cause color changes in the produced epecielity, unless the impurities have been sufficiently edited in advance. edaou, due to undesirable color changes in injectable solutions, are unidentified derivatives of the aalae group, either free, or amidically bound to the remainder of the adipic acid. The thistle of US Pharmacopoeia No. 15 is ordered to test the so-called free amines, whose interaction with atmospheric oxygen and iodine from the aromatic portion of the molecule begins to decompose, resulting in the color of the injection solution. However, even those substances which do not contain free amlacoscubs in such a sufficient quantity that they can be the initiator of breakdown shifts change color in the Injection Solution. Probably this involves altering the amlnockupine in the 2,4,6-triiedo-3-aminobensoic acid starting material and the interaction of the afflicted substances with the adipic acid chloride.

To date, the purification of X, h-adipoyl-bis- (2,4, β-triiodo-3-ebenaeic acid) by dissolving eubstence in the form of the sodium salt in about 50% aqueous methanol, filtering the solution through the active material and recovering it acid from the filtrate at a temperature of 50 to 60 ° C by acidification with a mineral acid, usually hydrochloric acid. This operation was repeated until the injected rostok, prepared from a substance considered satisfactory, met the analytical standard. In this way, it was possible to remove lower molecular weight impurities from the crude substance, but impurities based on color compounds resulting from amidoda-hydrogen interactions having approximately the same molecular weight as the substances themselves were minimally affected by the operation described. The quality of the injectable solutions prepared from the substance thus purified did not meet the requirements of therapeutic application, in particular in terms of coloring, after a relatively short storage period.

These drawbacks are eliminated by a method of purifying N, N-adipic-bis (2,4,6-triiodo-3-aminobenzoic acid) acidic acid in the form of its sodium salt, prepared from acidic acid and aqueous sodium hydroxide solution, pre-purified by precipitation to a standard chromatographic image of the substance. SUMMARY OF THE INVENTION characterized in that crystalline sodium salt substance is separated from the ^2W to 30% sodium salt solution by addition of solid sodium bicarbonate at a temperature of 60 to 100 ° C, which is isolated and which is repeated once more, whereupon the substance obtained dissolves in a volume of 8 to 12 times 25 to 30% by weight of aqueous methanol, based on the weight of the starting substance sodium salt, the solution is filtered over activated carbon and the filtrate is liberated by acidification with acetic acid at 60 to 75 ° C

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Ν, Ν'-adipoyl-bis (2,4,6-triiodo-3-eminobenzoic acid), which is isolated after crystallization.

In the process according to the invention, in the first stage of the purification, the beneficial effect is obtained by salting out the substance of the sodium salt from its solutions by the action of solid sodium bicarbonate. In the second phase, the purification consists in dissolving the reaction by-products in aqueous methanol, in which the lower molecular weight substances are partially soluble, but not the sodium salt. Next, the charcoal properties of the charcoal are used to remove the color and potentially color components as demonstrated by thin layer chromatography. The method according to the invention has been successfully applied to substances obtained from unsatisfactory injectable solutions, which have not been cleaned in the usual way, i.e. those color sources which are concentrated on the acylated amino-acid and which have so far resisted the standard cleaning process have been eliminated. When applied to the substances prepared by synthesis, they can be obtained so pure that the prepared solution for injection satisfies all requirements.

More detailed requirements can be seen from the example:

100 g of N, N * -edipoylbia acid (2,4,6-triiodo-3-aminobenzoic acid) are mixed with 300 ml of water and a solution of its sodium salt is added by stirring at room temperature with the addition of 50% aqueous sodium hydroxide solution. The solution is slowly heated and 40 g of sodium bicarbonate are added at 60 ° C. The temperature was further raised to 83-95 ° C and maintained for 15 minutes. During this time, the sodium salt crystallizes. The crystal suspension is cooled to room temperature, the sodium salt is filtered off with suction, washed with ethanol and dried at not more than 50 ° C.

Dissolve 100 g of dry anodic salt in 300 ml of water and repeat the above crystallization procedure. The sodium salt is dried at not more than 50 ° C. Yield: 85-96% of the theoretical amount of the salt formed from the starting acid, depending on its degree of purity.

Dissolve 100 g of the obtained sodium salt in 1100 ml of a mixture of methanol and water (3> 8) and filter the resulting solution through a layer of 10 g of activated carbon. The colorless, clear and clear filtrate is heated to 70 ° C and acidified with 5500 ml of acetic acid with stirring. By cooling the solution, N, N-adipoyl-bis (2,4,6-triiodo-3-aminobenzoic acid) crystallizes. After cooling to -5 ° C t

the substance is filtered off with suction and washed with distilled water. Dry at not more than 50 ° C. Yield =

78 to 85% of theory, based on the starting acid, according to its degree of purity.

The obtained substance is of high quality, its stereographic image has almost uniform trace.

Claims (1)

SUBJECT OF THE INVENTION A process for the purification of N, Na-adipoyl-bis (2,4,6-triiodo-3-amlnobenzoic acid) in the form of its sodium salt, prepared from an acid and an aqueous solution of sodium hydroxide, pretreated by precipitation into a standard ohromatographic image of a substance. from a 20 to 30% solution of sodium salt by addition of solid sodium bicarbonate at 60 to 100 ° C the crystalline substance of the sodium salt is isolated and isolated with which the operation is repeated at least once more, after which the substance obtained dissolves in a volume of 8 to 12 times up to 30% aqueous methanol based on the weight of the sodium salt starting material, The 200 078 solution is filtered through activated carbon and the filtrate is subsequently freed from the filtrate at 60 DEG-75 DEG C. by acidification with acetic acid to give the starting material, N, N-adipoyl-bis (2,4,6-triiodo-3-eminobenzoic acid). .