DE3001294A1 - X=ray contrast agent intermediate di:cyano-tri:iodo-benzoic acid - prepd. from 3,5-di:amino-2,4,6-tri:iodo-benzoic acid by diazotisation and reaction with cyanide - Google Patents

Abstract

acid (I) is new. Also new is the use of (I) for the prodn. of 2,4,6-triiodo-trimesic acid amide derivs. of formula (III): (where R1 are H or opt. mono or polyhydroxylated alkyl). (I) are useful as intermediates for the non-ionic X-ray contrast agents (III), into which they can be converted by conventional methods (cf. DE3001292). (I) may be prepared by diazotization of 3,5-diamino-2,4,6-triiodo-benzoic acid (II) and reaction of the product with cyanides.

Description

3,5-dicyano-2,4,6-triiodobenzoic acid

The invention relates to 3,5-dicyano-2,4,6-triiodobenzoic acid of the formula I. and a process for its preparation, characterized in that in a manner known per se, 3,5-diamino-2,4,6-triiodobenzoic acid of the formula II diazotized and then reacted with cyanides.

The amino groups in the starting product II are converted by Diazotization and subsequent reaction with cyanides.

The diazotization can be carried out in the usual way by adding nitrites take place.

Advantageously, under weakly acidic conditions, preferably in a pH range from 2 to 4, with cooling, preferably at temperatures between OOC to + 10 C, diazotized. Nitrites suitable for the implementation are, for example Alkaline nitrites such as sodium nitrite and potassium nitrite.

The diazonium salt formed can be separated off or processed further immediately will. The diazonium salt is expediently removed from the solution or suspension not isolated, but immediately implemented further, the approach by adding a Base is brought to pH 4-7.

Suitable bases are, for example, sodium hydroxide, potassium hydroxide, Ammonia -a.a ..

The cyano group is introduced by methods known per se, for example with a Sandmeyer reaction. Here is the diazonium compound in the usual way with a cyanide complex, preferably a copper-cyanide complex salt implemented.

Examples of particularly suitable complex compounds are K2BCu (CN) /, K3BCu (CN) 2, "K2 £ CuNH3 (cN) 47 in aqueous solution.

The cyano group can be introduced at room temperature and elevated temperature temperatures between 20 and 40 ° C. are to be regarded as preferred.

Polar solvents are suitable for the reaction, such as, for example Water, N, N'-dimethylacetamide, N, N'-dimethylformamide and others and mixtures thereof, whereby the aqueous medium is preferred.

The 3,5-dicyano-2,4,6-triiodobenzoic acid (I) according to the invention can easily be converted into 2,4,6-triiodotrimesic acid using methods known per se and is therefore preferred as an intermediate for the production of nonionic X-ray contrast media based on shading Substances with new size structures suitable: where R1 and R2 are identical or different and represent a hydrogen atom or an optionally mono- or polyhydroxylated straight or branched-chain alkyl radical.

The unsubstituted alkyl groups R1 and R2, the straight or branched ones contain 1-6, preferably 1-4 carbon atoms. Called for example especially the methyl, ethyl and propyl radicals. The methyl radical is preferred.

If the alkyl radical is a mono- or polyhydroxyalkyl radical, it can be any long-. and be straight or branched chain. Alkyl radicals are particularly suitable with 2-8, preferably with 2-4 carbon atoms. The hydroxyl groups in the alkyl radical can be present as primary and / or secondary and / or tertiary hydroxyl groups. The alkyl radical can contain 1-5, preferably 1-3, hydroxyl groups. For example Trishydroxymethylmethyl, hydroxyethyl, bishydroxymethylmethyl, in particular, may be mentioned Dihydroxypropyl.

To convert the compound I according to the invention into the ultimately The cyano groups are initially used as shading substances of the formula III saponified in I into the carbamoyl group by methods known per se. Appropriately the starting product is suspended in water and in the presence of excess Alkali at room temperature or elevated temperature, e.g. at 0 - 800C, hydrolyzed. In particular, potassium or sodium hydroxide is used as the alkali, which can be added to the reaction mixture in solid form or as, for example, a 2N alkali metal hydroxide solution can admit. If desired, the aqueous reaction mixture can also be one organic solubilizers, such as, for example, methanol, dioxane, tetrahydrofuran or add similar organic solvents.

The diazotization of the 3,5-bis-carbamoyl-2,4,6-triiodobenzoic acid thus obtained also takes place in a manner known per se with the reagents customary for this purpose, such as for example nitrosyl chloride, nitrosyl sulfuric acid or sodium or potassium nitrite in the presence of an acid such as hydrochloric acid, sulfuric acid, Acetic acid, etc. The substance to be diazotized is used for practical implementation e.g. in a mixture of water / conc. Hydrochloric acid suspended and slowly with a aqueous sodium nitrite solution added. The reaction takes place at room temperature or expediently at an elevated temperature, preferably at 40-1000C.

The diazotization can equally well be carried out in the same way1 that the CONH2 starting product in an organic solvent such as acetic acid or dimethylformamide with sodium nitrite / conc. Sulfuric acid or with nitrosylsulfuric acid implements.

The 2,4,6-triiodotrimesic acid thus obtained is used to introduce the amide radicals -N.R1R2 first by reaction with thionyl chloride in the usual way in 2,4,6-triiodotrimesic acid trichloride convicted.

The further processing of the 3,5-dicyano-2,4,6-triiodobenzoic acid according to the invention to 2,4,6-triiodotrimesic acid chloride can thus be carried out as follows: 10 g of 3,5-dicyano-2,4,6-triiodobenzoic acid are suspended in 100 ml of water and poured through Addition of 2 g of sodium hydroxide brought into solution. The solution is on for 3 hours + 600C held, then with 100 ml conc. Hydrochloric acid added and heated to 90 ° C warmed up. Under the surface of the solution is kept stirring within A solution of 12 g of sodium nitrite in 60 ml of water is fed in for 5 hours. One lets Stir for a further 2 hours at 90 ° C., then evaporate to dryness in vacuo and stir the residue with 100 ml of diisopropyl ether. The sodium chloride which has separated out is sucked off and the filtrate is concentrated to dryness. 10 g of 2,4,6-triiodobenzene-1,3,5-tricarboxylic acid are obtained as a white powder with a decomposition point above 2800C.

Yield: 93% of theory.

147 g of 2,4,6-triiodotrimesic acid, 588 ml of thionyl chloride and 1.3 ml Dimethylformamide are stirred under reflux on the steam bath for 2 hours, whereby initially violent evolution of HCl occurs. The solution is then in a vacuum at approx. + 500c concentrated and the residue stirred with 1.5 liters of toluene for 2 hours. Little undissolved substance is sucked off and discarded. The filtrate is in vacuo at concentrated to approx. + 50 ° C. and the residue dried in vacuo at + 60 ° C.: yield 151 g (93.9% of theory).

M.p. 258-2600C; Yield 93.3%.

The subsequent amidation reaction to introduce the amide residue -N.R1R2 is also carried out according to methods known per se in a suitable solvent at 0 - 1000C, preferably at 20 - 800C. Suitable solvents include polar ones Solvent. Examples include water, dioxane, tetrahydrofuran, dimethylformamide, Dimethylacetamide, Hexametapol and the like. and their mixtures. Because the amidation reaction If the reaction mixture is exothermic, it may be expedient to light the reaction mixture to cool in order to keep the reaction temperature at about 500C can. Since with the Amidation reaction Hydrogen halide, e.g. hydrogen chloride, free is, you need two equivalents of base per acid-chloride group, conveniently in excess of approx. 10%.

One uses to neutralize the hydrogen chloride formed advantageously tertiary amines, e.g.

Triethylamine, tributylamine or pyridine. The amidation reaction is detailed explained using the example of the preparation of 214,6-triiodobenzene-1,3,5-tricarboxylic acid (2,3-dihydroxy-N-methyl) triamide (B), 2,4,6-triiodobenzene-1,3,5-tricarboxylic acid-tris- (bis-2-hydroxyethyl) -triamide (C) and 2,4,6-triiodobenzene-1,3,5-tricarboxylic acid-tris- (2,314,5,6-pentahydroxyhexyl-N-methyl) -triamide (D).

B: 127.1 g = 197.6 mmol of triiodo-trimesic acid trichloride is used in 254 ml of DMA (dimethylacetamide) dissolved at 500 C. At 500C it will drop within 15 minutes Stir a solution of 1.883 mol = 145.2 g of N-methylamino-propanediol- (2.3) in 150 ml of DMA added dropwise. Do not let the temperature rise above 600C, possibly with water cool. The reaction mixture is then stirred at about 50 ° C. for 4 hours. After standing overnight, the solution is acidified with 20 ml of concentrated HCl = 250 mmol and concentrated in vacuo.

The residue is dissolved with 1 liter of water and over a column given with approx. 1.5 l of cation exchanger IR 120. It is eluted with water and the eluate is concentrated in vacuo. The moist residue (205 g) is in 1 liter Dissolved water and added through a column with approx. 1.5 1 anion exchanger IRA 410. It is eluted with water. The alkaline eluate (approx. 4.5 l) is used for 30 minutes approx. 200 ml of cation exchanger IR 120 and, after filtration, 30 minutes with 10 g of charcoal touched. The colorless filtrate is concentrated in vacuo and yielded 140 g of residue.

This was dissolved in 1 liter of methanol, filtered and concentrated in vacuo and dried at 800C. Yield: 133.9 g = 157.7 mmol = 79.8% of theory. Fp .: 150-52 ° C.

C: 113 g = 175.7 mmol. Triiodo-trimesic acid trichloride is used in 226 ml of DMA dissolved at 50 ° C. At 50 ° C., with stirring, a Solution of 702.8 mmol = 73.9 g of diethanolamine in 148 ml of DMA were added dropwise. Temperature do not let it rise above 60 ° C, cool if necessary. 702.8 mmol = 167 ml of tributylamine is now entered and then stirred at about 50 ° C. for 4 hours. To The reaction mixture is stirred overnight at room temperature with 30 ml of conc. HC1 = 360 m} Iol acidified and stirred dropwise into 2.8 l of methylene chloride. To 1 hour of stirring was decanted from the sticky-greasy precipitate, again Stirred for 30 minutes with 1 liter of methylene chloride, decanted and at 50 ° C. in vacuo dried. The residue (164 g) is dissolved in 1 liter of water, filtered and analogous Example 1 freed from salts via cation and anion exchangers and in methanol treated with activated charcoal and worked up analogously to Example 1. Yield: 72.3 g = 85.1 mmol = 48.5% of theory. M.p .: 122-350C.

D: 68.3 g = 350 mmol of methyl glucamine is suspended in 175 ml of DMA and heated to 50 ° C. At 50 ° C is then with stirring within 12 minutes Solution of 82.2 g = 50 mmol of triiodotrimesic acid trichloride in 75 ml of DMA was added dropwise. A heat tint occurs up to + 540C and temporary solution. Afterward the reaction mixture is 4 hours at about 50 ° C and then overnight at room temperature touched. The mixture is then concentrated with 6 ml. HC1 = 72 mmol acidified. The precipitate of methylglucamine hydrochloride is filtered off with suction and washed with DMA and then discarded. The filtrate is concentrated in vacuo, the residue in 300 ml Dissolved water (pH approx. 1) and purified analogously to Example 1 using ion exchangers and worked up. Yield: 34.3 g = 30.6 mmol = 61.3% of theory. M.p .: 112-190C.

The new shading substances based on the compounds of general formula III are distinguished by a number of advantages: these new compounds are derived from triiodinated aromatics as the basic body, that is itself are already hydrophilic and relatively non-toxic. The introduction of overly extensive hydrophilic Substituents to reduce chemotoxicity had become dispensable, whereby the compounds according to the invention have a desired high iodine content.

They are distinguished by high chemical stability, in particular also with regard to undesired elimination of ron iodide.

Solutions of the compounds of the formula I according to the invention can thus usually also by heating to 1200C at physiological pg-ert sterilized. The solutions have been compared even at high iodine concentrations with the ionic X-ray contrast media currently in use a low one osmotic pressure, which is a prerequisite for good local tolerance in particular is.

The substances according to the invention showed in animal experiments very good general and excellent local for different animal species Tolerance, very good cardiovascular tolerance and only low neurotoxicity. In addition, the substances according to the invention only showed one in the in vitro test extremely low interaction with proteins and only very little membrane-damaging Effect.

Finally, the new compounds show only minor epileptogenic effects Effect after subarachnoid administration, especially because of its non-ionic Character and the low electron density in the nucleus.

The table below shows the advantageous properties the nonionic X-ray contrast media based on the compounds of the formula III using the example of the shading substances B = 2,416-triiodobenzene-1,3,5-tricarboxylic acid (2,3-dihydroxy-N-methyl) triamide, C = 2,4,6-triiodobenzene-1,315-tricarboxylic acid-tris- (bis-2 hydroxyethyl) -triamide D = 2,4,6-triiodobenzene-1,3,5-tricarboxylic acid-tris- (2,3,4,5,6-pentahydroxyhexyl-N-methyl) -triamide compared to the known A = metrizamide.

Table stable with heat distribution co-erythrocyte substance sterilization efficient ten-Schadi-Butanol / Puf- gung fer pK 7.6 A no 0.259 10 B yes 0.064 2.1 C yes 0.131 1.8 D yes c 0.001 s0.3 The partition coefficient was in the usual way certainly. The erythrocyte damage was also determined in the usual way, the formation of echinocytes on dog erythrocytes was measured. The toxic one Effect of metrizamide was placed 1 10, the smaller numerical values mean one correspondingly better tolerance.

Example: 7 g of sodium nitrite are dissolved in 84 ml of a + 5 ° C tempered conc. Sulfuric acid entered. You then hold on to that at + 700C until solution has occurred is and then cools to + 50C away. After 42 ml of glacial acetic acid have been added dropwise with good cooling, the mixture is carried in portions 21 g of 3,5-diamino-2,4,6-triiodobenzoic acid (purified via the dioxane adduct) under Stir in so that the internal temperature is between OOC and + 50C. One lets stir the batch for a further 2 hours and pour on the green-colored suspension 400 g of ice. 500 ml of conc. Ammonia with 320 ml of water and dissolves in it 35.6 g copper-I cyanide and 67 g potassium cyanide. The diazotization batch is added to this solution, heavy foaming occurs. The mixture is left to stir for a further 2 hours and then added the approach after standing overnight first with 500 ml of ethyl acetate, then with excess conc.

Hydrochloric acid. After suctioning off the excreted copper salts with Ethyl acetate are washed out, the aqueous phase is separated off in the filtrate and it re-extracted several times with ethyl acetate. The vinegar ester extracts are: combined, backwashed with water and then dried over sodium sulfate and concentrated. The dark-colored residue is treated hot with 100 ml of acetone, the acetone Solution filtered from undissolved components and then concentrated to half. After several hours of stirring, the crystals are filtered off with suction with ice-cold acetone washed and dried at 50 ° C. 8.5 g (= 38% of theory) of 3,5-dicyano-2,4,6-triiodobenzoic acid are obtained as a white powder with a decomposition point above 2800C.

Claims (3)

Claims: 3,5-dicyano-2,4,6-triiodobenzoic acid. 2. Process for the preparation of 3,5-dicyano-2,4,6-triiodobenzoic acid, characterized in that 3,5-diamino-2,4,6-triiodobenzene is diazotized and then with cyanides. 3. Use of 3,5-dicyano-2,4,6-triiodobenzoic acid for the preparation of compounds of the general formula III in which R1 and R2 are identical or different and denote a hydrogen atom or an optionally mono- or polyhydroxylated straight or branched-chain alkyl radical.