DE1137019B - Process for the preparation of four or five times iodinated benzoic acid esters or amides - Google Patents

Description

Process for the preparation of four or five times iodinated benzoic acid esters or amides The invention relates to a process for the production of four or five times iodinated benzoic acid esters or amides.

Surprisingly, the new benzoic acid chlorides of the formula in which X denotes a hydrogen atom, an iodine atom, an amino group, a low molecular weight acylamino group or a thionylamino group, compounds are found which react smoothly with active hydrogen atoms bonded to oxygen or nitrogen atoms or the corresponding metal derivatives of organic compounds and therefore the production of the 0- or N-3-amino-2,4,5,6-tetraiodo, 3-acylamino-2,4,5,6-tetraiodo, 2,4,5,6-tetraiodo or

Pentajodobenzoyl compounds in a simple manner and in good yield enable.

This reaction which can be carried out according to the invention is sometimes carried out promoted the presence of acid-binding agents.

In the reaction of the new pentaiodobenzoyl chloride, the new 3-acylamino-2,4,5,6-tetraiodobenzoyl chloride and the new 2,4,5,6-tetraiodobenzoyl chloride with organic compounds, the contain active hydrogen atoms bound to oxygen or nitrogen atoms, one arrives directly to 0- or N-pentaiodo-, 3-acylamino-2,4,5,6-tetraiodo- or 2,4,5,6-tetraiodobenzoic acid esters or amides. Using 3-Amino-2,4,5,6-tetraiodo- or 3-thionylamino-2,4,5,6-tetraiodobenzoyl chloride as Starting material for the corresponding 3-amino-2,4,5,6-tetraiodobenzoic acid esters or amides, in the case of using the tetraj od-thionylamino-benzoyl chloride the thionylamino group subsequently to the reaction by the action of basic or acidic agents, usually in the cold, must be converted into the amino group, if not already during the reaction of the iodinated benzoic acid chloride with the an organic compound containing an active hydrogen atom, this conversion has already taken place.

The new four or five times iodinated benzoic acid chlorides have properties which are unusual in themselves for acid chlorides. They are very persistent and melt (with the exception of 3-thionylamino-2,4,5,6-tetraiodobenzoyl chloride) at one temperature between 100 and 300 "C without decomposing. They are also in aqueous solution largely stable in the presence of alkalis.

Despite this surprising resistance in aqueous, even alkali containing solution, these acid chlorides react in organic solvents or even with the exclusion of solvents very quickly and smoothly, sometimes under considerable heat generation, with alcohols, phenols, amines or hydrazino compounds to the corresponding esters, amides or hydrazines. This reaction is special Surprising, since the astonishing inertia in an aqueous mixture is essential should also suggest such in organic solvents, at least but certainly not a quick, almost stormy reaction to be expected.

For the implementation with the new four or five times iodinated benzoic acid chlorides of the above general formula are useful as oxygen-containing compounds all organic compounds with free acylatable hydroxyl groups are suitable. Under these are mainly primary, secondary and tertiary aliphatic, araliphatic and cycloaliphatic mono- and polyalcohols and their substitution products, such as oxyacids or halogen alcohols, phenols, which can be substituted in any way in the core can as well as heterocyclic oxy compounds and their substitution products to name. Primary and secondary compounds are particularly suitable as nitrogen-containing compounds aliphatic, cycloaliphatic, araliphatic and aromatic mono- or polyamines and their substitution products, such as amino acids or amino alcohols, since the Amino group is acylated before the oxy group. But they also react on the nitrogen atom acylatable nitrogen-containing heterocycles, such as pyrrolidine, thiazolidine, piperidine, Piperazine and morpholine, their substitution products, such as tetrahydronicotinic acid, and also heterocyclic amino compounds such as aminothiazole, 2,3-dimethyl-4-aminoisoxazole and aminopyrimidines smoothly with those to be used according to the invention as starting material Acid chlorides of the general formula above.

Finally, compounds that carry a hydrazino group are also and acid amides, especially sulfonic acid amides, are suitable as reactants.

The new four or five times iodinated benzoic acid chlorides of the above general formula can easily be implemented by implementing the likewise new corresponding acids, namely 2,4,5,6-tetraiodobenzoic acid, 3-amino-2,4,5,6-tetraj odbenzoic acid, 3-acylamino-2,4,5,6-tetraiodobenzoic acid and 2,3,4,5,6-pentaiodobenzoic acid, can be obtained with thionyl chloride. In the preparation of 3-amino-2,4,5,6-tetraiodobenzoyl chloride The intermediate product is 3-thionylamino-2,4,5,6-tetraiodobenzoyl chloride, which is either separated from the reaction mixture or immediately without separation in the reaction mixture by alkali or acid treatment into the 3-amino-2,4,5,6-tetraiodobenzoyi chloride can be transferred.

The 2,4,5,6-tetraiodobenzoic acid is obtained from the 5-amino-2,4,6-triiodobenzoic acid by diazotizing the amino group and reacting with potassium iodide.

The 3-amino-2,4,5,6-tetraiodobenzoic acid can be produced by iodination of 3-iodo-5-aminobenzoic acid can be obtained with Na Cl-ClI solution, which in turn can be obtained by acylation into the 3-acylamino-2,4,5,6-tetraiodobenzoic acids, by diazotization and treatment convert with potassium iodide into pentaiodobenzoic acid.

For the preparation of the abovementioned starting compounds Protection is not sought within the scope of the present invention.

The new 0- or N-3-amino-2,4,5,6-tetraiodo-, -3-acylamino-2,4,5,6-tetraiodo-, -2,4,5,6-Tetraiodo- and -pentajodobenzoic acid esters or amides are valuable intermediates for the manufacture of pharmaceutical preparations.

In addition, a number of these compounds are highly choleretic Effectiveness.

The following examples show how the process is carried out explained on the basis of a few representatives from the individual compound classes.

Example 1 3.22 g of 2,4,5,6-tetraiodobenzoyl chloride (m.p. = 1090 C) become Boiled under reflux with 25 ccm of methanol for 21 /, hours. The solution filtered hot and evaporated. 2.1 g of 2,3,4,6-Tetraj are obtained as residue methyl odbenzoate with a melting point of 149 ° to 150 ° C. The yield is 65.64% Theory.

Example 2 3.22 g of 2,3,4,6-tetraiodobenzoyl chloride (0.005 mol) are used dissolved in 20 cc of benzene and treated with 0.85 g of piperidine (0.01 mol). The reaction starts immediately and is stopped by heating in a water bath for 10 minutes. The reaction mixture is then allowed to cool and filtered off with suction while cold. Man receives 3.25 g of colorless reaction product, which after boiling with water and Drying at 100 "C in vacuo 2.65 g of pure 2,3,4,6-tetraiodobenzoylpiperidide vom F. = 232 to 2340 C delivers. When the benzene mother liquor is evaporated, it remains an evaporation residue of 0.81 g, from which after boiling with 50 ccm of water still about 0.7 g of tetraiodobenzoyl piperidide can be obtained. The yield of pure piperidide is 76.5% of theory.

Example 3 3.22 g of 2,3,4,6-tetraiodobenzoyl chloride (0.005 mole) will be used mixed with 0.93 g of aniline. The mixture is slowly warmed. Accelerated from around 80 ° C the reaction changes in such a way that self-warming occurs. After the reaction has ended the mixture is heated for 10 minutes on a water bath and then twice with Boiled 50 ccm of water each. This gives 3.25 g of crystallized 2,3,4,6-tetraiodobenzanilide as residue; that's 92.75 01o of theory. F. = 285 to 289 "C.

Example 4 3.22 g of 2,3,4,6-tetraiodobenzoyl chloride are with 0.62 g phenol mixed and heated. The reaction starts with self-heating and Escape from HC1. After the reaction subsided, the mixture was left for 1 hour warmed in a water bath, then taken up in 2.5 ccm of pyridine and in 50 ccm Let water flow in. The water-insoluble reaction product becomes in ether added, the essential solution to remove the pyridine and the excess Phenol washed repeatedly with dilute hydrochloric acid and dilute alkali lye, dried and evaporated. The residue obtained from evaporation after drying is 2.96 g of phenyl 2,3,4,6-tetraiodobenzoate; that is 84.4% of theory. Melting point F. = 172 to 175 ° C.

Example 5 9.2 g of o; -aminobutyric acid ethyl ester are cold with 22 g of crude 2,3,4,6-tetraiodobenzoyl chloride are mixed and the mixture is made by adding brought into solution by about 6 com acetone. As a result of the exothermic reaction, the The temperature of the reaction solution increases rapidly. After 10 minutes the mixture becomes 10 minutes heated to 700 ° C and a further 15 minutes to 1000 ° C. From that obtained in the reaction The soluble precipitates are made by intensive stirring with about 250 ccm of water Parts washed out. The crystals are then removed from the aqueous solution severed. 24.75 g of N-2,3,4,6-tetraiodobenzoyl-o; - aminobutyric acid ethyl ester are obtained; the are 98% of theory. M.p. = 161 "C (from ethanol).

Example 6 6.44 g of 2,3,4,6-tetraiodobenzoyl chloride are dissolved in 7 g of dioxane dissolved and a heated to 80 to 90 "C solution of 2.1 g of 2-amino-thiazole in 9 g of dioxane and 1.2 g of triethylamine were added. After heating for about 20 minutes Most of the dioxane is distilled off in vacuo on the steam bath and the residue heated for another 2 hours on the steam bath. The reaction mixture is used for working up with excess 4N hydrochloric acid and 500 ccm of ether and the resulting Separated precipitate. 6.75 g of N- (2,3,4,6-tetraiodobenzoyl) -2'-aminothiazole are obtained; that is 95.3% of theory. Decomposition point after recrystallization from n-propanol about 180 "C.

Example 7 5 g of 2,3,4,6-tetraiodobenzoyl chloride are mixed with 4 g of 3-oxy-pyridine hydrochloride mixed and then mixed with 10 com dioxane. The resulting mixture is heated in an open vessel to 130C for 16 hours, then with it after cooling Ether digests and the insoluble fraction is separated off. This will then go through sequential treatment with water, dilute NaOH, dilute H Cl and Further purified water at the boiling point. After drying the precipitate is obtained 2.77 g of O- (2,3,4,6-tetraiodobenzoyl) -3'-oxypyridine; that is 39.4% of theory.

The compound can be recrystallized from glycol monoethyl ether and then shows a melting point of 226 to 234 ° C.

Example 8 6.44 g of 2,3,4,6-tetraiodobenzoyl chloride are in 100 cc dissolved in dry ether and then within a minute with a solution of 1.08 g of phenylhydrazine were added to 40 cc of ether. After refluxing for 20 minutes, become 2.4 g of K2 C Oil were added and the mixture was refluxed for a further 2 hours while stirring cooked. The reaction mixture is then partially mixed with about 100 cc of water offset. The resulting precipitate is filtered off and replaced by successive Boil with 15 ccm 1 n-NaO H, 50 ccm H2O and excess dilute hydrochloric acid cleaned. After boiling, the precipitate is filtered off with suction, chlorine-free with water washed and dried. 6.4 g of 2,3,4,6-tetraiodobenzoyl-phenylhydrazide are obtained obtained with a decomposition point of 223 to 228 "C, which corresponds to a yield of 89.5 01o of theory. The hydrazide can be dissolved in glycol monoethyl ether, Add water in the heat until it remains turbid and recrystallized will. The substance purified in this way then shows a decomposition point of 231 to 235 "C.

Example 9 6.59 g of 3-amino-2,4,5,6-tetraiodobenzoyl chloride (F.

= 162 to 163 "C) are refluxed with 50 cc of methanol for 13/4 hours boiled, the resulting precipitate is filtered off after cooling and from about 750 cc of methanol redissolved. 4.38 g are obtained 3-amino-2,4,5,6-tetraiodobenzoic acid methyl ester as yellow crystals; that is 66.85 per cent of theory. F. = 121 to 123 "C.

Example 10 3.0 g of pentaiodobenzoyl chloride (m.p. 315-317 "C) will be used refluxed with 15 cc of n-butanol for 4 hours. The mixture is cooled the precipitated crystals are filtered off and washed with petroleum ether. 2.2 g of n-butyl pentaiodobenzoate are obtained; that's 700 / o of theory.

F. = 149 to 150 ° C.

Example 11 10 g of phenol are heated to 105 to 110 ° C., slowly 3 g of pentaiodobenzoic acid chloride are added and the mixture is heated to 115 to 120 ° C. for 15 minutes. After cooling, the reaction mixture is triturated with ether. The one left behind Precipitation is sucked off and washed with a lot of ether. 2.68 is obtained g of 83.3% of theory.

By evaporating the ether extract washed with sodium hydroxide solution and water 0.10 g of impure ester can still be obtained.

Example 12 6.59 g of 3 - amino - 2,4,5,6 - tetraiodobenzoyl chloride (F. = 162 to 163 "C) are mixed with 4.5 g of aniline and heated to 80 to 100" C, the sudden formation of a precipitate indicating the onset of the reaction. After brief warming, the reaction mixture is cooled with water and a little hydrochloric acid digested, boiled and the insoluble fraction filtered off. 6.96 g of 3-amino-2,4,5,6-tetraiodobenzoylanilide are obtained; that's 990 / o of theory. Melting point m.p. = 281 to 283 "C.

Example 13 2.08 g of pentaiodobenzoyl chloride (m.p. = 315 to 317 "C) and 2 g of aniline are slowly heated together until the reaction occurs with a rise in temperature and precipitation begins. After the reaction subsides, the mixture becomes boiled with water, then with acetone, suction filtered the solid portion and dried.

1.4 g of pentaiodobenzanilide are obtained; that's 62.8 ovo of theory. F. = 345 to 347 ° C.

Example 14 6.59 g of 3-amino-2,4,5,6-tetraiodobenzoyl chloride become mixed with 1.8 g of piperidine and 50 cc of acetone.

The mixture is refluxed for 11/2 hours and after cooling sucked off by the precipitation. After boiling the precipitate with water and Drying gives 6.4 g of 3-amino-2,4,5,6-tetraiodobenzoylpiperidide; that's 90 01o of theory. F. = 231 to 233 "C.

Example 15 3.12 g of pentaiodobenzoyl chloride are mixed with 1 g of piperidine and 200 cc of acetone are mixed and the mixture is refluxed for 30 minutes.

After the reaction has ended, the acetone is in vacuo removed and the residue first boiled with water, then with acetone. After filtering off and drying the precipitate gives 2.5 g of pentaiodobenzoyl piperidide; the are 75.4 0 /, of theory.

F. = 255 "C (with slow decomposition).

Example 16 22 g of 3-amino-2,4,5,6-tetraiodobenzoyl chloride are mixed with 11 g of N-fl-oxyethyl-ß'-aminopropionic acid methyl ester and 20 ccm of acetone mixed and heated until the reaction starts with a rise in temperature. Distilled in the process the acetone off. After the reaction has ended, the reaction mixture is dissolved in a little dimethylformamide dissolved and the solution, while still warm, in excess dilute hydrochloric acid under strong Stir poured. The ester precipitates out as a precipitate and can be filtered off with suction will. After drying the filter cake, 23.0 g of methyl N- (3-amino-2,4,5,6-tetraiodobenzoyl) -N-p-oxyethyl, B'-aminopropionate are obtained; that's 88.5 / o of theory.

Example 17 1 g of 3-acetylamino-2,4,5,6-tetraiodobenzoylehloride (F. = 181 to 183 "C) is dissolved together with log piperidine in 10 cc of dioxane. The Solution is heated to the boil, whereupon an oil precipitates. After 10 minutes of cooking it will the overlying solution decanted, poured into 150 ccm of water and that at the same time separated as an oil separating piperidide. It is diluted by boiling with H Cl purified and crystallized after prolonged standing.

This gives 0.82 g of 3-acetylamino-2,4,5,6-tetraiodobenzoylpiperidide; that's 76.6 01o of theory.

M.p. = 130 ° C.

Example 18 0.24 g of sodium are dissolved in 15 cc of butanol and mixed with 2.0 g of pentaiodobenzoic acid chloride were added.

The mixture is then refluxed for 24 hours and then left to stand for another 3 days at room temperature. After that, the eliminated yellow crystals collected on the filter.

1.1 g of butyl pentaiodobenzoate are obtained in this way; that's 52.4ovo the theory. F. = 146 to 147 ° C.

Example 19 0.25 g of sodium are dissolved in 10 ccm of methanol and added added to a solution of 3 g of 3-amino-2,4,5,6-tetraiodobenzoic acid chloride in dioxane. The mixture is refluxed for 15 minutes, then the solution in plenty of water poured in and the precipitated methyl ester separated. 2.05 g of 3-amino-2,4,5,6-tetraiodobenzoic acid methyl ester are obtained that's 68.90 / 0 the theory. Melting point of the substance dissolved from methanol 115 to 118 "C.

Claims (3)

PATENT CLAIMS: 1. A process for the preparation of four- or five-fold iodinated benzoic acid esters or amides, characterized in that benzoic acid chlorides of the general formula are used in which X denotes a hydrogen atom, an iodine atom, an amino group, a low molecular weight acylamino group or a thionylamino group, in the presence of inert organic solvents and optionally in the presence of acid-binding agents with organic compounds which contain active hydrogen or metal atoms bonded to oxygen or nitrogen atoms , and subsequently converting any thionylamino groups present into amino groups in a manner known per se by saponification with acidic or alkaline agents. 2. The method according to claim 1, characterized in that the iodinated benzoic acid chlorides with organic compounds containing one or more contain aliphatically, aromatically or heterocyclically bonded hydroxyl groups, or with their metal derivatives. 3. The method according to claim 1, characterized in that the iodinated benzoic acid chlorides with aliphatic, araliphatic or aromatic primary or secondary amines that are substituted in the hydrocarbon radical, or with nitrogen-containing heterocycles which can be acylated on nitrogen or with aliphatic ones or aromatic compounds containing a hydrazino group, or with heterocyclic ones Reacts amino compounds. Publications considered: Beilstein, Handbuch der Organischen Chemistry, 4th edition, 1932, 1st supplementary work, Vol. 10, p. 359, and 2nd supplementary work, Vol. 10, p. 520, as well as 2nd supplementary work, Vol. 5, p. 229; Reports of the German Chemicals Gesellschaft, Vol. 29, pp. 839ff., 1625, 2833ff .; F. Klares, Textbook of Organic Chemie, Vol. II, 1954, p. 520; Journal für Prakt. Chemie, 2nd series, Vol. 121, p. 283.