CS222729B1 - Process for the preparation of adipo-bis (2,4,6-triiodo-1-carboxy-3-anilide) - Google Patents

Abstract

The invention relates to a method for producing adipio- -bis(2,4,6-triiodo-1-carboxy-3-anilide), an important, clinically used X-ray contrast agent, by reacting crude adipic acid dichloride, contained in the reaction mixture after the reaction of adipic acid with a phosphorus or sulfur halide, with 2,4,6- -triiodo-3-aminobenzoic acid, in an ethyl or butyl acetate environment, at the boiling temperature of the reaction mixture.

Description

The present invention relates to a process for the preparation of adipio-bis (2,4,6-triiodo-1-carboxy-3-anilide), an important clinically used X-ray contrast agent, by reacting the crude adipic acid dichloride contained in the reaction mixture after the adipic acid reaction. with phosphorus or sulfur halide, with 2,4,6-triiodo-3-amino-benzoic acid, in ethyl acetate or butyl acetate, at the boiling point of the reaction mixture.

The present invention relates to a process for the preparation of adipo-bls (2,4,6-triiodo-1-carboxy-3-anilde), an X-ray contrast agent manufactured by piod of many trade names and applied in clinical practice as an injectable solution intravenously (H. Priewe sp. Ber., 87, 651 (1954); U.S. Patent No. 2,657,233; GB Patent No. 748,746).

The synthesis of this contrast agent is usually based on adipic acid dichlorides, which are reacted with 2,4,6-triiodo-3-aminobenzoic acid in organic solvents boiling above 100 ° C. Typically, the starting adipic acid dichloride is prepared by reacting adipic acid with phosphorus or sulfur halides, for example, phiosfortryl chloride or thionyl chloride, usually without solvents, using an excess of chilling. reagents.

The disadvantage of this process was the very unpleasant and very lossy isolation and purification of adipic acid dichlorides. In a detailed study aimed at simplifying and economizing the entire synthesis, new conditions for the preparation of adipo-bis (2,4,6-triiodo-1-carboxy-3-anilide) by reacting adipic acid dichloride with 2,4,6- in the environment of an inert organic solvent according to the invention. of the starting adipic acid dichloride utilizes the crude product contained. reacting adipic acid with phosphorus or sulfur chloride, for example phosphorus trichloride or thiOnyl chloride in an equivalent amount, in an aromatic or halogenated hydrocarbon medium, preferably benzene or trichlorethylene, after diluting the reaction mixture with a 2- to 6-fold volume of acid ester acetic acid having ¹ to 5 carbon atoms, preferably ethyl acetate or butyl acetate, the crude dichloride contained therein is reacted with 2,4,6-iodo-3-amino-benzoic acid at a temperature of from 50 ° C to the boiling point of the reaction mixture.

In addition to the solvents mentioned, i.e. benzene or trichlorethylene, other solvents, for example suitable gasoline fractions, carbon tetrachloride, dichloromethane, chloroform, dioxane, tetrahydrofuran or ethyl acetate, may be used in the preparation of adipic acid dichlorides. The dichloride prepared as described is not isolated but, after dilution with a large excess of ethyl acetate or butyl acetate, is directly used for the acylation of 2,4,6-triiodo-3-aminobenzoic acid equivalent, which proceeds smoothly to give practically the theoretical amount of adlpo-bis (2,4 6-tri-iodo-1-carboxy-3-anilide) of high purity.

The process according to the invention contributes both to the improvement of the working conditions and to the economical production of the important X-ray contrast agent.

Further details of the method according to the invention can be found in the following example, which is illustrative but not limiting.

mole (146.1 g of adipoic acid is suspended in 500 ml of benzene (or trichlorethylene)), 1.3 to 2 moles of phosphoric acid (or 2 moles of thionyl chloride) are added, the mixture is heated at 50 ° C for 1 h and boiling for 2 h. Then, the reaction mixture is diluted with 6 liters of ethyl acetate (or butyl), 1.6 mol of 2,4,6-triiodo-3-amino-benzoic acid are added and heated to boiling for 30 h. After cooling, the precipitated product is filtered off with suction, washed with The yield of adipo-bis (2,4,6-triiodo-1-carboxy-3-anilide) is 100% of theory, the product is sufficiently pure for further pharmaceutical purposes (treatment by further purification procedures).

Claims (1)

A process for the preparation of adlpo-bis (2,4,6-triiodo-1-carboxy-3-anilide) by reacting adipic acid dichlorides with 2,4,6-triiodo-3-aminobenzoic acid in an inert organic solvent, that it uses as the starting adipic acid dichloride the crude product contained in the reaction mixture after the reaction of the adipic acid with a phosphorus or sulfur chloride, e.g. The reaction mixture is reacted with 2,4,6-triiodo-3-aminobenzoic acid by reacting the reaction mixture with 2- to 6-fold by volume of an acetic acid ester with a C1-C5 alkanol, preferably ethyl or butyl acetate. at a temperature of from 50 ° C to the boiling point of the reaction mixture.