NO134075B - - Google Patents

Description

Process for the preparation of derivatives of 3,5-diamino-2,4,6-triiodobenzoic acid.

Water-soluble inorganic and organic salts of 3,5-diacetamido-2,4,6-triiodobenzoic acid have recently gained great importance as X-ray contrast agents, because they are very water-soluble and relatively non-toxic, at the same time that, due to their high iodine content is very impermeable to X-rays. For this reason, it is important to have at one's disposal safe and simple chemical production methods that allow this compound to be produced in the purest possible form and in good yield.

As early as 1896, Liitgens (Berichte 29, 2835) prepared 3,5-diamino-2,4,6-triiodobenzoic acid (III) by iodizing 3,5-diaminobenzoic acid (II). However, 3,5-diamino-2,4,6-triiodbenzoic acid (III) is a rather unstable compound and has therefore not proven suitable as an X-ray contrast agent. Acetylation of this compound (III) (Am.Chem.Soc. 126th. Meeting, New York, 6 Sept. 1954 — Abstracts p. 11—N; Larsen et al., Am. Soc. 78 (1956); Norwegian patent no. 87 963) however gives 3,5-diacetamido-2,4,6-triiodobenzoic acid (IV) which is stable and, as mentioned above, is very suitable as an X-ray contrast agent.

The hitherto known methods (lOc.cit.) for the production of diacetamido-triiodobenzoic acid (IV) proceed over the following steps:

as 3,5-dinitrobenzoic acid (I) is reduced to

3,5-diaminobenzoic acid (II) which is then iodinated to 3,5-diamino-2,4,6-triiodobenzoic acid (III). This compound (III) is acetylated and gives 3,5-diacetamido-2,4,6-triiodobenzoic acid

(IV).

This process is subject to a number of shortcomings: 1) Reduction of the dinitrobenzoic acid (I) can either a) be carried out by hydrogenation over a noble metal catalyst (platinum) under pressure of an aqueous solution of the sodium salt of the acid (I) after the solution has first been detoxified by boiling with Raney nickel as so f raf Utreres, or b) the reduction can be carried out chemically in the heat with ammonium sulphide (exothermic reaction). In the first case, pressure hydration equipment is required, and in the second case, one has the obvious disadvantages of working with large quantities of foul-smelling ammonium sulphide, and repeated labor and space-consuming rescue operations are necessary to obtain the diamino acid in sufficient purity to be able to subject to iodination to diaminotriiodic acid (III). Other reduction methods could be considered to be used, but they seem to be too expensive or otherwise inappropriate. Thus, e.g. hydrazine is too expensive as a reducing agent, and the solubility conditions seem to limit a practical application of hydration of the free acid. 2) As mentioned, the iodination of the diaminobenzoic acid (II) to the diaminotriiodic acid (III) was already carried out in 1896 by Liitgens (lOc.cit.), who iodinated in an alkaline environment. The unstable diaminotriiodic acid (III) is obtained in very variable, and as a rule poor yields, and the quality (purity) is also poor and this condition increases the instability of the product (III). Iodination in an acidic medium, e.g. rried j odmomoctoride or potassium iodide chloride (Larsens et. al. etc. 10c. eit.) seems to be an improvement, but this process too is capricious and difficult to control, and therefore gives diaminotriiodic acid (III) in varying yields and of varying purity and stability. The resulting product (III) can therefore also be of alternating stability during drying and little, durable during storage. 3) The acetylation of the sensitive diaminotriiodic acid is carried out under relatively drastic conditions by heating with acetyl halide (acetyl chloride) or with acetic anhydride in or without the presence of strong acids as catalysts (perchloric acid or sulfuric acid). In a not-yet-published proposal from the patent holder, a mild acetylation method is described in which the ketene is used at normal temperature. The invention concerns a new process for the preparation of a compound of the general formula (V) where R' and R" are the same or different and are hydrogen or methyl and where Acyl is a lower aliphatic acyl group such as, for example, acetyl or propionyl, and the method is characterized in that a corresponding carboxyl ester of the formula (VI)

where R is a lower aliphatic alkyl group such as methyl or ethyl, and preferably is

methyl, is aminolysed to the corresponding

carboxylic acid by treating with an aliphatic or alicyclic amine such as methylamine, dimethylamine, trimethylamine, cyclohexylamine or ethylenediamine, or a heterocyclic compound containing a strongly basic heteronitrogen, such as e.g. piperidine or morpholine, with or without the presence of a solvent such as e.g. water and/or pyridine. The aminolytic reaction is based on a new discovery, as during the development of the method it has been shown that certain carboxylic acid esters under given conditions when reacted with amines are aminolysed to form corresponding acids and alkylamines, instead of giving the corresponding acid amides as is normal under de-cleaving of the alcohols corresponding to the ester-alkyl group (see also below).

The related amidolytic reaction was originally discovered as follows:

By subjecting 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester (VII) to alkaline-hydrolytic conditions, a mixture of 3,5-diacetamido-2,4,6-triiodobenzoic acid (IV) and N-methyl-3 ,5-diamethamido-2,4,6-triiodobenzoic acid (VIII).

The invention is based on this new discovery, as it has been shown that certain carboxylic acid esters can react in a previously unknown manner under given conditions. These conditions will be explained in more detail below.

The unmethylated esters (VI, R'=R"=H), which form the starting material for the production according to the invention of both the unmethylated and the methylated carboxylic acids (V), have been described previously (Brit. patent no. 779 500). The can be prepared conveniently and in high yields as follows: 3,5-dinitrobenzoic acid (I) is esterified with an alcohol, e.g. methanol, in the presence of a strong acid (e.g. hydrochloric or perchloric acid) to a 3 ,5-dinitrobenzoic acid ester, e.g. the methyl ester, which is then hydrogenated over a noble metal catalyst (e.g. palladium) or chemically reduced with a metal (e.g. tin) in an acidic medium (e.g. methanolic hydrochloric acid) to 3,5-diamino-benzoic acid ester, e.g. the methyl ester. These two chemical steps can also be carried out in a suite in the same reaction vessel, first esterifying dinitrobenzoic acid by heating with alcoholic acid, after which adds catalyst and hydrates by leading to water under convection (stirring, shaking, vibrating). The ester can then be isolated by cooling, possibly after further addition of acid (hydrochloric acid) or by evaporating the alcoholic solution. The crystallized ester or the evaporated residue is then iodinated in an acidic medium (e.g. with iodine monochloride or potassium iodide chloride) after which the 3,5-diamino-2,4,6-triiodobenzoic acid ester, e.g. the methyl ester is momentarily precipitated. By acetylation according to usual methods (e.g. with acid anhydride or acid halide) of this slate, a 3,5-diacylamido-2,4,6-triiodbenzoic acid ester is obtained, thus e.g. 3,5-diacetamido-2,4,6-troiodobenzoic acid methyl ester (VI, R = CH,,; R' = R" = H; Acyl = Ac) by acetylation.

For the production of the free unmethylated and methylated 3,5-diacylamido-2,4,6-triiodobenzoic acids (V), the 3,5-diacylamido-2,4,6-triiodobenzoic acid methyl esters have proven particularly suitable as the methyl ester -group is significantly more reactive than, for example, the ethyl ester group.

By thus, as previously mentioned, subjecting the methyl ester (VII) to alkaline hydrolytic conditions, a mixture of 3,5-diacetamido-2,4,6-triiodobenzoic acid (IV) and N-methyl-3,5-diacetamido-2,4,6 -triiodobenzoic acid (VIII) as alkali salts, while the alkyl ester under similar conditions either does not react, or is substantially destroyed at a higher temperature.

That (VIII) is N-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid is shown by a) analysis, b) degradation to N-methyl-1,3-diacetamidobenzene identical to the same compound synthesized from N- methyl-n-phenylenediamdn, (c by degradation to N-methyl-3,5-diacetamidobenzoic acid identical to the same compound synthesized from 3-amino-5-nitrobenzoic acid, and d) by synthesis from 3,5-diacetamido-2,4 ,6-triiodobenzoic acid by methylation with dimethyl sulfate.

Reaction kinetic studies have shown that the N-methyl acid (VIII) is not formed by an intramolecular rearrangement, as the ratio (IV): (VIII) increases with decreasing concentration of ester (VII), so that a pure hydrolysis of the ester (VII ) to 3,5-diacetamido-2,4,6-triiodobenzoic acid takes place in strong dilution (low ester concentration). However, it has been shown that the ester concentration must be inappropriately low in order to guide the light so that practically only 3,5-diacetamido-2,4,6-triiodobenzoic acid (IV) is formed and that the yields and quality of the product then become poor. With increasing ester concentration, the ratio (IV): (VIII) decreases, approaching approximately 1:1. Furthermore, preliminary investigations in connection with this invention indicate that the dominant reaction mechanism at the medium and higher ester concentrations is characterized by one molecule of 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester (VII) methylating another molecule of ester

(VII) with the formation of one molecule of 3,5-diacetamido-2,4,6-triiodobenzoic acid (IV) and one molecule of N-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester (IX) which then hydrolyzes normal to N-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid (VIII):

The essential thing about this reaction is that a carboxyalkyl group can alkylate an acet-amido group, a previously unknown relationship which is believed to be due to the dimensions and electronegativity of the halogen atoms and the resulting steric hindrances! by the carboxyl group and the relatively high acidity of the acetamido and carboxyl groups.

The method according to the invention utilizes the insight into this new reaction. While alkaline hydrolytic conditions with an amidolytic reaction mechanism lead to a mixture of unmethylated and methylated acid, e.g. according to the invention, unmixed 3,5-diacetamido-2,4,6-ytriiodobenzoic acid (IV) by aminolyzing 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester (VII). Also in this reaction, the methyl esters (VI R=CHS) react more easily than the ethyl esters (III, R = C2H.r)), thus 3,5-diacetamido-2,4,'6-triiodobenzoic acid methyl ester (VII) faster than the corresponding ethyl ester, but the difference is less important in the amidolytic — hydrolytic process described above, where the reaction is practically feasible only in the methyl ethyl ester.

During the aminolysis, it is processed ume-

thylated or methylated ester (VI) with a primary, secondary or tertiary aliphatic or alicyclic amine, or a heterocyclic compound containing a strongly basic heteronitrogen (e.g. methylamine, dimethylamine, trimethylamine, ethylenediamine, cyclohexylamine, piperidine, morpholine, ethanolamine , N,N'-dimethylaminoethanol). The execution usually takes place during heating in a different way, e.g. by dissolving the ester in the amine, or in a mixture of amine, and a solvent (e.g. pyridine or pyridine-water), or in a mixture of amine, water and alkali. In the presence of alkali, which increases the solubility of the ester, it has proved advantageous to keep the alkali concentration as low as possible.

In this way, e.g. the important X-ray contrast agent 3,5-diacetamido-2,4,6-triiodbenzoic acid (IV) is prepared in the highest purity and yield by heating 3,5-diacetamido-2,4,6-triiodbenzoic acid methyl ester (VII) with dimethylamine in aqueous alkaline solution.

The aminolytic reaction is based on the hitherto unknown fact that a carboxyalkyl group can alkylate an amine with the formation of carboxylic acid and alkylamine: while the normal reaction leads to the formation of carboxylic acid amide and alkyl alcohol:

In this reaction too, the newly discovered reactivity of the carboxy-alkyl group is attributed to the influence of the halogen substituents. Just as the normal hydrolytic reaction can take place (at low ester concentration) next to the above-described amidolytic-hydrolytic, amides can occur as by-products in the aminolytic reaction (e.g. at high temperature in pure amine solution).

When choosing aminolytic conditions in the individual case, account is taken of the price of the reagent (amine) and the solubility ratio of the ester. The esters (e.g. 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester (VII) and N-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester

(VI, R = R' = CH„ R" = H, Acyl = AC)

which are soluble in lye are advantageously aminolysed in aqueous alkali. The esters (e.g. N,N'-dimethyl-3,5-dlacetamido-2,4,6-triiodobenzoic acid methyl ester (VI, R = R' = R" = CH3, Acyl = Ac) which are not soluble in such a medium, is preferably aminolysed in a medium to which a suitable solvent, e.g. pyridine, is added.

The methylated esters (VI, R' = CH3; R" = H, CH3) are easily accessible by methylation of the unmethylated esters (VI, R' =

R" = H).

By treating 3,5-diacylamido-2,4,6-triiodobenzoic acid methyl ester (VI, R = CH,,, R' = R" = H) with a methylating agent in an aqueous or aqueous alcoholic medium under alkaline conditions is obtained with a large excess of a strong methylating agent (e.g. dimethyl sulfate or p-toluene sulfonic acid methyl ester) N,N'-dimethyl-3,5-diacylamido-2,4,6-triiodobenzoic acid ester which falls out of the solution as it is formed due to its insolubility in lye. Subsequent aminolysis as described above gives the corresponding acid (V, R' = R" = CH3), thus one can e.g. from 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester (VII) easily prepared N,N'-dimethyl-3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester and the corresponding N,N' -dimethyl-3,5-diacetamido-2,4,6-triiodobenzoic acid in good yields.

In the methylation of 3,5-diacylamino-2,4,6-triiodobenzoic acid methyl ester (VI, R = CH,,; R' = R" = H) with a smaller amount (e.g. one equivalent) of methylating agent (e.g. dimethyl sulfate) N-methyl-3,5-diacylamido-2,4,6-triiodobenzoic acid ester (VI, R = R' = CH3; = H) can be obtained which can then be aminolyzed to N-methyl- 3,5-diacylamido-2,4,-6-triiodbenzoic acid (V, R' = CH 3 ; R" = H).

According to the invention, it is therefore possible to produce both new and previously known X-ray contrast agents. Among those previously known, 3,5-diacetamido-2,4,6-triiodobenzoic acid is particularly important, and the method has a number of advantages over previously described methods, e.g. the following: 1. The yields in all steps from dinitrobenzoic acid are very good and easily repeatable.

2. Pressure equipment is unnecessary.

3. Purification over Raney nickel before hydration is redundant. 4. Use of ammonium sulphide is omitted. 5. Purification of the starting product before iodination is made redundant. 6. The iodinated esters settle to the bottom in a convenient form (filtration, centrifugation) and need little or no drying, especially when traces of alcohol are present during the iodination. 7. All compounds and intermediates are stable and can be conveniently stored. 8. New compounds of potential value as X-ray contrast agents can be produced, possibly as an intermediate step and in combination with the production of 3,5-diacetamido-2,4,6-triiodobenzoic acid (IV).

Of the new compounds that can be produced according to the invention, N-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid has so far been best investigated and has proven to be a particularly promising X-ray contrast agent, as the sodium salt of the acid has a high iodine content, high solubility in water, low toxicity and rapid and high excretion through the kidneys.

Example 1.

3,5-diamino-2,4,6-triiodobenzoic acid ethyl ester.

10.6 g of 3,5-dinitrobenzoic acid are dissolved in 80 ml of abs. ethanol, add 0.25 ml of perchloric acid (70 per cent), and boil at reflux for 5 hours. The ethanolic solution of 3,5-dinitrobenzoic acid ethyl ester (m.p. 91° C) then goes directly to hydrogenation at 50° C and ordinary pressure in the presence of 0.35 g of Pd. After the end of absorption, the palladium is filtered off, and the main amount of ethanol is recovered. The concentrate of 3,5-diaminobenzoic acid ethyl ester is then taken up in 10 ml conc. hydrochloric acid in 350 ml of water and then immediately add iodine. An isolated sample of the diaminoethyl ester melted at 80-82°C, and its dihydrochloride at 223-26°C.

The iodination is carried out with good stirring with 88 ml of 2N KlCl 2 solution, and the stirring continues for 2 hours after the addition is complete, before isolating the separated substance, 3,5-diamino-2,4,6-triiodobenzoic acid ethyl ester. The substance is hard crystallized with a low moisture content, and is easy to dry. A sample recrystallized from ethanol melts at 105° C. Yield from 3,5-dinitrobenzoic acid is 85% cv> 23.7 g.

Example 2.

3, 5- diacetamido- 2, 4, 6-triiodobenzoic acid ethyl ester.

3,5-diamino-2,4,6-triiodobenzoic acid ethyl ester, 23.7 g, prepared as in example 1 is easily dissolved on a steam bath in 100 ml of acetic anhydride. At 50° C, a few drops of concentrated sulfuric acid are added, whereby the temperature increases to close to 70° C, at the same time giving a strong precipitation. The mixture is further heated briefly to 80-90° C, and then stirred continuously while cooling down to approx. 90 percent of the material can be insulated. After washing with acetic anhydride and reprecipitation from hot 5% caustic soda with acetic acid, the substance weighed 22 g dry. This product of 3,5-diacetamido-2,4,6-triiodobenzoic acid ethyl ester melted during destruction at 290-295° C and showed an iodine content of 58.9 per cent against the calculated 59.3 per cent.

Example 3.

3, 5-diamino- 2, 4, 6-triiodobenzoic acid methyl ester.

Dissolve 10.6 g of 3,5-dinitrobenzoic acid hot in 70 ml of methanol, add 0.25 ml of HC104,

and refluxed for 6 hours. An isolated sample of the formed 3,5-dinitrobenzoic acid methyl ester melted from 108-110° C. The mixture then goes directly to hydration at 50° C in the presence of 0.35 g of Pd. After absorption of 6 mol of hydrogen gas, the catalyst is filtered off and most of the methanol is recovered in vacuum.

The concentrate of 3,5-diaminobenzoic acid methyl ester (cm.p. 121-122° C) is now taken up in 9 ml conc. HC1 in 350 ml of cold water. and immediately iodinated while stirring with 88 ml of 2N KICl2 solution. The stirring continues for 2 hours after the addition has ended, before the well-developed, separated crystals of 3,5-diamino-2,4,6-triiodobenzoic acid methyl ester are isolated. The compound appears very stable, and with its low moisture content needs minimal drying in order to be acetylated.

Yield: 23 g cv> 85 percent from dinitrobenzoic acid. A sample recrystallized from methanol melts at 142-3°C.

Example 4.

3, 5-diamino- 2, 4, 6-triiodobenzoic acid methyl ester. Dissolve 10 g of 3,5-dinitrobenzoic acid methyl ester cold in 80 ml of glacial acetic acid, add 2 ml of PdCl2 solution of strength 2.67 g Pd/100 ml, and hydrate at normal pressure and room temperature. After 6-8 hours, everything has been absorbed, the catalyst is filtered off and the acetic acid solution of 3,5-diaminobenzoic acid methyl ester is ready for iodination, as described above (Example 3).

Example 5.

3, 5-diamino- 2, 4, 6-triiodobenzoic acid methyl ester. 20 g of 3,5-dinitrobezoic acid methyl ester are dissolved in 200 ml of methanol and hydrated at 40° C. at ordinary pressure and in the presence of 0.7 g of Pd. After end of absorption, approx. 8 hours, the catalyst is filtered off, the methanol is recovered and the 3,5-diaminobenzoic acid methyl ester is taken up in hydrochloric acid and water. It is now ready for iodination with 2N KICl, solution as described in Example 3. An isolated sample of the diaminomethyl ester's dihydrochloride melted at 234-6°C.

Example 6.

3, 5-diamino- 2, 4, 6-triiodobenzoic acid methyl ester.

Dissolve 9 g of 3,5-dinitrobenzoic acid methyl ester in 90 ml of hot methanol (keep at the boiling point). 15 g tin is poured over with 300 ml HC1 conc. and put in a steam bath. The hot methanolic solution is added in portions. A vigorous reaction occurs and the solution darkens in colour. However, this dissipates rather quickly and more nitro-ester solution can be added. After everything has been added, the reaction mixture is kept on a steam bath until the dark color has disappeared and the solution is yellow-green in color and all the tin has been consumed. A slightly faster reaction towards the end can be achieved by adding slightly more hydrochloric acid.

The reaction mixture is evaporated in vacuo. The residue, a tough amorphous mass, is dissolved in water and the tin is removed by adding alkali (NH4OH conc.) while stirring to pH 4. This can probably be carried out hot, as the amino ester is then more soluble.

Precipitated stannous hydroxide is filtered off, the filtrate is made hydrochloric acid and is ready for iodination as described in example 3.

The 3,5-diaminobenzoic acid methyl ester is isolated by adding further ammonia to the filtrate. The ester then precipitates out, m.p. 121 -122° C.

Example 7.

3, 5- diacetamido- 2, 4, 6-triiodobenzoic acid methyl ester.

3,5-diamino-2,4,6-triiodobenzoic acid methyl ester (22 g) prepared as in example 3, is easily dissolved on a steam bath in 66 ml of acetic anhydride.

At 50° C, a few drops of concentrated sulfuric acid are added with stirring, and the whole is heated briefly to 80-90° C, before cooling and isolation of the separated substance. After washing with acetic anhydride, and effectively washing the same with acetone, the substance weighed 21 g dry. The diacetylated methyl ester (18 g) is obtained by reprecipitation from hot 5% caustic soda to acetic acid reaction. The compound is destroyed from 263-265° C and shows an iodine content of 60.15 per cent, calculated 60.65 per cent.

Example 8.

3,5-dipropioamido-2,4,6-triiodobenzoic acid methyl ester.

2.72 g of 3,5-diamino-2,4,6-triiodobenzoic acid methyl ester, prepared as in example 3, is dissolved under careful heating in 8.2 ml of propionic anhydride and a drop of conc. sulfuric acid. After some time

stand is cooled, filtered and washed on the filter with alcohol and with ether. After air-drying, 2.2 g of 3,5-dipropioamido-2,4,6-triiodobenzoic acid methyl ester is obtained as a light purple-gray colored substance, insoluble in boiling methanol, soluble on heating in pyridine and in strong potassium hydroxide.

Example 9.

3, 5-diacetamido-2, 4, 6-triiodobenzoic acid.

0.5 g, 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester prepared as in example 7 is added to 1 ml of 70% ethylenediamine, mixed well and heated to boiling until everything has dissolved in the course of a few minutes. 2 ml of water are added and then acidified with glacial acetic acid, decolorized hot with charcoal and filtered. After cooling, hydrochloric acid (1:2) is added to the filtrate to pH 1-0.5 and stirred for a few hours. The precipitated 3,5-diacetamido-2,4,6-triiodobenzoic acid amounts to 0.3 g after filtration, washing and drying.

Example 10.

3, 5- diacetamido- 2, 4, 6- triiodobenzoic acid.

0.5 g of 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester prepared as in example 7 is dissolved hot in morpholine and boiled under reflux for 6 hours. The morpholine is then distilled off in a vacuum, and the residue is dissolved in a little lye, acidified with glacial acetic acid and filtered. The filtrate is decolorized hot with activated charcoal and combined with hydrochloric acid which is added to pH 1-0.5. The precipitated 3,5-diacetamido-2,4,6-triiodobenzoic acid is washed and dried.

Example 11.

3, 5- diacetamido- 2, 4, 6- triiodobenzoic acid.

As Example 10, using piperidine instead of morpholine.

Example 12.

3, 5- diacetamido- 2, 4, 6- triiodobenzoic acid.

1.00 g of 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester prepared as in example 7 is mixed with stirring with 1 ml of ethanolamine, after which the mixture is heated and the temperature is maintained at 120-130° C. for 10 minutes. The mixture is then cooled and conc. hydrochloric acid is added to pH 1-0.5,

and the mixture is stirred for 24 hours. After filtration, washing with a little water and drying, 0.62 g of 3,5-diacetamido-2,4,6-triiodobenzoic acid is obtained.

Example 13.

3, 5- diacetamido- 2, 4, 6- triiodobenzoic acid.

1.00 g of 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester prepared as in example 7 is heated for three hours with stirring with a mixture of 3.5 ml of ethanolamine, 1 ml of 5N KOH and 4 ml of water. After cooling, acidify with glacial acetic acid. After a short period of time, it is filtered and the filtrate is added conc. hydrochloric acid to pH 1-0.5. After stirring for 24 hours, filter and wash with a little water. After drying, 0.520 g of 3,5-diacetamido-2,4,6-triiodobenzoic acid is obtained.

Example 14.

3, 5- diacetamido- 2, 4, 6- triiodobenzoic acid.

1.00 g of 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester prepared as in example 7 is mixed with 1 ml of 5N potassium hydroxide, 2 ml of water and 0.6 ml of 33% trimethylamine and kept for 20 hours at 55° C in a closed flask. Then cool and add glacial acetic acid to pH approx. 3-4. After a short period of time, the solution is filtered from unreacted ester (.0.46 g), hydrochloric acid is added to the filtrate to pH 1-0.5. After stirring overnight, the precipitate is collected on a filter, washed with a little water and dried, whereby 0.50 g of 3,5-diacetamido-2,4,6-triiodobenzoic acid is obtained.

Example 15.

3, 5- diacetamido- 2, 4, 6- triiodobenzoic acid.

1 g of 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester, prepared as in example 7, is mixed with 0.5 ml of 33% methylamine, 1 ml of 5N potassium hydroxide and 2 ml of water and heated to 55°C for 20 hours in a closed container. Worked up as described in example 14. 0.62 g of unreacted ester and 0.28 g of 3,5-diacetamido-2,4,6-triiodobenzoic acid were obtained.

Example 16.

3, 5- diacetamido- 2, 4, 6- triiodobenzoic acid.

A mixture consisting of 100.0 g of 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester prepared as in Example 7, 90 ml of 5N potassium chloride (f = 1.005), 50 ml of 33% dimethylamine and 400 ml water is stirred at room temperature until everything has dissolved, and then heated in a closed container to 55° C for 19-20 hours. The burgundy solution is cooled and a sample gives no precipitate when acidified with glacial acetic acid. 5N hydrochloric acid (200-210 ml) is added with mechanical stirring to pH 1-0.5. Stirring continues overnight, after which it is filtered and washed with a little water.

The crude product (94 g dry), which is almost colourless, is stirred with 500 ml of water and dissolved by adding 2N soda solution. The pH is adjusted to 5-6, and the solution is treated with activated carbon at 45-50° C and filtered. After cooling, 5N hydrochloric acid is added with mechanical stirring to pH 1-0.5. Stirring continues overnight, after which the precipitate is filtered off, washed with a little distilled water and dried to constant weight. 92 g of chromatographically pure, colorless 3,5-diacetamiido-2,4,6-triiodobenzoic acid is obtained, m.p. 290—295° C (de-comp.), I = 61.7 percent (ber. 62.1); N = 4.57 percent (ref. 4.56). Eq. weight = 630 (ber. 614).

Further cleaning can be carried out if necessary, e.g. by one of the following methods or a combination of them: a) by boiling the moist product with equal parts of methanol, whereby the substance is again separated in a pure state after temporary dissolution,

b) Extraction with ethanol,

c) Precipitation over ammonium salt.

One achieves a dividend in these ways

of approx. 60 percent pure 3,5-diacetamido-2,4,6-triiodbenzoic acid, calculated on the amount of dinitrobenzoic acid used.

Example 17.

3, 5- diacetamido- 2, 4, 6- triiodobenzoic acid.

1.00 g of 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester, prepared as in example 7 and recrystallized from glacial acetic acid, is mixed with 1 ml of 5N potassium hydroxide, 0.45 ml of 33% dimethylamine and 2 ml water in a glass ampoule which is melted again and shaken until everything has dissolved. After 10 days at room temperature (approx. 20° C), the reaction is complete. The clear solution with a faint pink tint is added while stirring with hydrochloric acid to pH 1-0.5. After stirring for a few hours, the precipitate is separated by filtration, washed with a little distilled water and dried. The chromatographically pure, colorless 3,5-diacetamido-2,4,6-triiodbenzoic acid weighs 0.970 g (99.4 percent)

Example 18.

3, 5- diacetamido- 2, 4, 6- triiodobenzoic acid. 1 g of 3,5-diacetamido-2,4,6-triiodobenzoic acid ethyl ester from example 2 is added to 1 ml of 5N potassium hydroxide, 0.7 ml of 33% dimethylamine and 2 ml of water and heated to 60-65°C in a closed ampoule for 20 hours. After cooling, glacial acetic acid is added to pH 4-5 and 0.6 g of unreacted ester is filtered off. Hydrochloric acid is added to the filtrate to pH 1-0.5 while stirring. After a period of time, the precipitate is filtered, washed and dried, whereby 0.3 g of 3,5-diacetamido-2,4,6-triiodobenzoic acid is obtained.

Example 19.

N,N'-dimethyl-3,5-diacetamido-2,4,6-tribenzoic acid methyl ester.

50 g of 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester, prepared as in example 7, is dissolved in a mixture of 50 ml of 5N potassium hydroxide (f = 1.00) and 200 ml of water by gentle heating under mechanical stirring. At 48-50° C, add 21.5 ml of dimethylsulphate, 12-16 drops per minute. After the solution has become neutral, heat for 5 minutes to 55-65° C. The product is filtered off, extracted for a few minutes in the heat with 2 N potassium hydroxide, cooled, filtered, washed and dried, whereby 50.0 g (94 per cent) pure N,N'-dimethyl-3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester

be isolated.

Example 20.

N,N'-dimethyl-3,5-diacetamido-2,4,6-triodobenzoic acid. 60 g of N,N'-dimethyl-3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester (prepared as in example 19) is heated in a closed reaction vessel with 60 ml of pyridine and 42 ml of 33% dimethylamine to 100 ° C for 2V2— 3 hours.

After cooling to room temperature, the contents are washed into a beaker with a little water and 4-5 N hydrochloric acid, acidified with hydrochloric acid to pH 5 and decolorized with activated charcoal at 50-55° C. A further 4-5 N hydrochloric acid is added to the filtrate with mechanical stirring to pH 1—0.5. After one hour, filter and wash with water, dry and weigh. There, 55 g (093.7 percent) of N,N'-dimethyl-3,5-diacetamido-2,4,6-triodebenzoic acid are isolated.

Example 21.

3, 5-dipropioamido-2, 4, 6-triiodobenzoic acid.

250 mg of 3,5-dipropioamido-2,4,6-triiodobenzoic acid methyl ester from Example 8 is heated in a mixture of 0.5 ml of pyridine and 0.3 ml of 33% dimethylamine for 2 hours at 100° C. clear solution is diluted with 5 ml of water and combined with 5 N hydrochloric acid to pH 1-0.5. The precipitated acid is filtered, washed and dried and chromatographed comparatively with 3,5-dipropioamido-2,4,6-triodobenzoic acid, with which it is found to be identical.

Example 22.

N- methyl- 3, 5- diacetamido- 2, 4, 6-tribenzoic acid methyl ester.

5.0 g of methyl-3,5-diacetamido-2,4,6-triiodobenzoate was dissolved in 3.8 ml of 5-n KOH and diluted with 15 ml of water. 0.8 ml (1.1 eq.) of dimethyl sulphate dissolved in 1 ml of acetone was added with stirring (temp. 10-12° C). After stirring for 42 hours, 0.3 g of alkali-insoluble methyl N,N'-dimethyl-3,5-diacetamido-2,4,6-triiodobenzoate was filtered off. The filtrate was acidified with HCl conc. (2 ml), precipitated ester filtered and washed with water. The ester was dissolved in approx. 30 ml of 0.5-1 N KOH and 0.4 g of insoluble N,N'-dimethyl ester filtered off. By acidifying the filtrate with HCl conc., filtering, washing with water and drying, 3.8 g of methyl N-methyl-3,5-diacetamido-2,4,6-triiodbenzoate were isolated.

Example 23.

N-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid.

2.57 g of methyl N-methyl-3,5-diacetamido-2,4,6-triiodbenzoate was dissolved in 2.8 ml of 5-n KOH (3.5 equiv.), diluted with 13 ml of water and added 2 .18 ml (4 eq.) of 33% aqueous dimethylamine. The solution was kept at 58°C for 22 hours in a closed ampoule. 20 mg of undissolved substance was filtered off and the filtrate

acidified with HC1 1:1 to pH approx. 0.5. After 2 hours of stirring, 2.27 g (90%) of N-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid were isolated.

Claims (3)

1. Method for the production of a carboxylic acid of the formula: where R' and R" are the same or different and are hydrogen or methyl and where Acyl is a lower aliphatic acyl group such as, for example, acetyl or propionyl, characterized in that a corresponding carboxyl ester of the formula: where R is a lower aliphatic alkyl group such as methyl or ethyl, and is preferably methyl, is aminolysed to the corresponding carbonic acid ■ by treatment with an aliphatic or alicyclic amine, such as e.g. methylamine, dimethylamine, trimethylamine, cyclohexylamine or ethylenediamine, or a heterocyclic compound containing a strongly basic heteronitrogen, such as e.g. piperidine or morpholine, with or without the presence of a solvent such as e.g. water and/or pyridine. 2. Process according to claim 1, characterized in that 3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester or N-methyl-3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester is amino-lysed in aqueous alkaline solution with dimethylamine to the corresponding carboxylic acids. 3. Process according to claim 1, characterized in that N,N-dimethyl-3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester is aminolysed with dimethylamine in aqueous pyridine to the corresponding carboxylic acid.