DE948333C - Process for the production of new, anticholinergic quaternary ammonium salts - Google Patents

Description

Process for the production of new, anticholinergically active quaternary ammonium salts The invention relates to the production of quaternary ammonium salts of the general formula in which Alk is an alkylene radical having 2 to 6 carbon atoms, R is identical or different alkyl radicals having 1 to 5 carbon atoms and X is an anion. Alk means ethylene, propylene, butylene; and. Amylene or polymethylene with 2 to 6 carbon atoms. X means an anion, e.g. B. chloride, bromide, iodide, methyl sulfate, ethyl sulfate, benzenesulfonate, toluenesulfonate, tartrate, succinate, malate, acetate, citrate, nitrate, sulfate and phosphate.

These compounds are obtained by reacting corresponding dialkylaminoalkyl xanthene-9-carboxylates in a manner known per se mi. ttelss corresponding haloalkyls or dialkyl sulfates. These conversions are preferably at increased Temperatures ranging from 50 to roo in an inert solvent, e.g. B.

Acetone, methyl ethyl ketone, a lower alcohol, or chloroform Nitromethane.

However, lower temperatures from 0 to 500 are also sufficient. in the In general, these conversions are preferably carried out in a closed system performed when a lower alkyl halide is used for the reaction mostly the crystalline salt precipitates from the cooled reaction mixture and can through Filter to be isolated and dried. In certain cases it is necessary that Salt by adding a solvent. z. B. of ether or a low boiling point aliphatic or aromatic hydrocarbon, precipitate in order to increase solubility of the salt in the selected solvent.

Optionally you can the anion of the ammonium salts obtained in in a manner known per se by other monovalent or divalent inorganic or organic Replace acid residues.

The compounds of the invention are generally in water or in aqueous solutions of alcohols and add water-soluble organic solvents soluble. They are valuable as medicines, and indeed as excellent anticholineargics Means, d. that is, they have the property of not just passing nerve impulses through the ganglia, but also through the postganglionic, cholinergic nerve endings and by blocking the somatic myoneural nerve endings. The connections should primarily find therapeutic use.

The following examples describe methods of making some of those quaternary bases that especially have these anticholinergic properties demonstrate.

Example I 70 parts of ß-diethylaminoethyl ester hydrochloride of xanthene-9-carboxylic acid who. those dissolved in the smallest possible amount of water, with an excess more concentrated Sodium carbonate solution reacted, whereupon the forming bubble is pulled out with ether, thoroughly dried and the ether evaporated. The remaining ß-diethylaminoethyl ester is dissolved in 240 parts of anhydrous acetone and treated with 22 parts of methyl chloride in implemented in a closed system at 1000 2 hours. Fall out on cooling the reaction mixture crystals of the methyl chloride of the ß-diethylaminoethyl ester the xanthene-9-carboxylic acid. This connection is hygroscopic.

The crystals melt at around 1620.

B e i s p i e l 2-A solution of 34 parts of γ-diethylaminopropyl, esters of xanthene-9-carboxylic acid and 25 parts of dimethyl sulfate in 170 parts of methyl ethyl ketone is heated in a closed vessel for 8 hours at 60 to 650. The implementation mix it is cooled and the precipitate of the methyl sulfate of the γ-diethylaminopropyl ester separated off the xanthene-9-carboxylic acid and dried.

Example 3 17 parts of the ß-dimethylaminoethyl ester hydrochloride of Xanthene-9-carboxylic acids are converted to the base by the procedure of Example I. The base thus formed is dissolved in 50 parts of anhydrous containing 14 parts of methyl chloride Dissolved acetone. The crystalline quaternary salt falls after a short time at room temperature Stand out.

It is filtered and washed on the filter with methyl ethyl ketone The methyl chloride of the ß-dimethylaminoethyl ester dier xanthene-9-carboxylic acid melts at 130 °.

Example 4 2.0 parts of the hydrochloride of the β-diethylaminoethyl ester the xanthene-9-carboxylic acid are dissolved in the smallest possible amount of water and treated with an excess of a concentrated sodium hydroxide solution. The thus obtained The suspension is extracted with ether. The ethereal solution is washed with water, dried and filtered. An excess of methyl iodide is added to the filtrate, and the solution thus obtained is kept at 0 ° for 2 days. The crystalline methyl iodide is recrystallized from isopropanol and then melts at I78 to I79P.

Example 5 1.8 parts of the ß- (di-n-butylamino) ethyl ester of xanthene-9-carboxylic acid are dissolved in a solution of 18 parts of butyl bromide in 85 parts of methyl ethyl ketone and heated in a closed vessel to 6o to 650 for 8 hours. The implementation mix is thoroughly cooled and a non-crystalline precipitate of the forms Butyl bromide of ß- (di-n-butylamino) ethyl ester of xanthene-9-carboxylic acid. He is sparingly soluble in water.

Example 6 I30 parts of the 3-diethylaminoethyl ester of xanthene-9-carboxylic acid and 73 parts of methyl p-toluenesulfonate are dissolved in 400 parts of methyl ethyl ketone. The solution is held at about 0 ° for about 15 hours; crystallized during this time the quaternary ammonium salt.

This salt is filtered and washed on the filter with ether. It melts at I37 to I380.

Example 7 The methyl iodide of the β-diethylaminoethyl ester of xanthene-9-carboxylic acid is converted to the corresponding sulfate when 1 mole of the quaternary ammonium iodide is mixed with 0.5 mol of silver sulfate in methanol at room temperature. The silver iodide is filtered off and the filtrate is evaporated. The salt obtained in this way is in oily form and could not be made to crystallize.

Example 8 The methyl bromide Ides ß-diethylaminoethyl ester of xanthene-9-carboxylic acid is converted to the corresponding acetate when 1 mole of the quaternary ammonium bromide is mixed with 0.5 mol of silver acetate in absolute methanol. The silver bromide will removed and the liquid evaporated in vacuo. The acetate is an oily salt, that did not crystallize.

Example g The methyl bromide of the ß-diethylaminoethyl ester of xanthene-9-carboxylic acid is converted into the corresponding acidic tartrate by the action of 1 mole of the bromide to 0.5 mol of silver tartrate and 0.5 mol of tartaric acid in cold methanol. The silver bromide is filtered off and the filtrate is evaporated in vacuo.

The salt thus obtained is washed with ether and methyl ethyl ketone, but could not be made to crystallize.

Example 10 210 parts of the methyl bromide of β-diethylaminoethyl ester of the xanthene-9-carboxylic acid are anhydrous with 87 parts of silver citrate and 63.3 parts Citric acid and 1350 parts of methanol mixed and at room temperature about I. Shaken for an hour. The silver bromide is filtered off and the filtrate in vacuo evaporated. The oily residue of the citric acid salt is washed with ether and then covered with dioxane.

It crystallizes in a short time and is then triturated and treated with dioxane and isopropanol. It is dried at 70 to 800 and forms white 96 to 980 melting crystals.

The yield is 265 parts, which is almost quantitative. The salt is sparingly soluble in acetone, isopropanol and methyl ethyl ketone.

Example 11 25 parts of the methyl bromide of 8-diethylaminoethyl ester the xarithene-9-carboxylic acid and 38 parts of tartaric acid are in 1900 parts of methanol dissolved at room temperature. 91 parts of silver tartrate are added to this solution, and this suspension is shaken at room temperature for 15 minutes. The silver bromide is filtered off and the filtrate is evaporated in vacuo. The residue of acid Tartrate is washed several times with ether and placed in a vacuum desiccator 250 dried. It consists of, a white powder that is hygroscopic and could not be recrystallized.

Example I2 The methyl bromide of the β-diethylaminoethyl ester of xanthene-9-carboxylic acid is converted into the corresponding acidic malate when 1 mole of the bromide is 0.5 Moles of silver malate and 0.5 moles of malic acid reacted in methanol at room temperature will. The silver bromide is filtered off and the solution of the acidic malate in vacuo evaporated. It is a hygroscopic powder that is not pure crystalline Shape could be obtained.

B e i s p i e l I3 234 parts of the methyl iodide of the ß-diethylaminoethyl ester the xanthene-9-carboxylic acid and 85 parts of silver nitrate are mixed and poured into tooo Share methanol shaken for 1 hour at room temperature. The silver iodide will filtered off and the filtrate evaporated in vacuo.

The residue of the nitrate salt is washed with ether and with methyl ethyl ketone washed and dried at 70 to 80 °. It melts at I42 to 1430.

Example 14 82 parts of this ß-diethylaminoethyl ester of xanthene-9-carboxylic acid are dissolved in I25 parts of methyl ethyl ketone. Methyl bromide gas is added to this solution until 25 parts have been added. The solution becomes warm, and d'as quaternary The ammonium salt begins to precipitate. The reaction mixture is closed at 75 ° Vessel heated for 18 hours. Then the salt is collected on a filter with methyl ethyl ketone washed and dried. The yield is 9.5%. The methyl bromide thus obtained of the p-diethylaminoethyl ester Ider xanthene-9-carboxylic acid melts at 173 ° to 176 °.

In a similar experiment in which the reaction mixture was 18 hours was kept at room temperature instead of 75 °, a yield of 93% the same, at 176 to 1780 melting salt, after two washes with methyl ethyl ketone, obtain.

This salt can be obtained with a melting point of 180-182 ° by dissolving in hot ethanol, treating with activated charcoal, Filter, evaporate and finally wash the salt with cold methyl ethyl ketone and subsequent drying.

Example 15 A solution of 339 parts of the β-diethylaminoethyl ester of xanthene-9-carboxylic acid and 126 parts of dimethyl sulfate in 4000 parts of methyl ethyl ketone is heated to reflux temperature for 3 hours.

No precipitate forms on cooling. The solution is in vacuo evaporated and the residue of the methyl sulfate of the ß-diethylaminoethyl ester Xanthene-9-carboxylic acid washed with cold isopropanol. It crystallizes soon after and is triturated, washed with isopropanol and dried. It melts at around 114 to 118 °.

B e i s p i e l 16 16 parts of the ß-diethylaminoethyl ester of xanthene-9-carboxylic acid are dissolved in 50 parts of methyl ethyl ketone. This solution is' with 7th Parts of ethyl bromide are added and then in a closed vessel at 75 ° for 15 hours heated.

The precipitate of the ethyl bromide of the ß-diethylaminoethyl ester Xanthene-9-carboxylic acid is filtered and dried. It consists of a white one Powder that is easily soluble in alcohol and water.

Claims (2)

PATENT CLAIMS: I. Process for the preparation of new, anticholinergically active quaternary ammonium salts of the general formula in which Alk denotes an alkylene radical with 2 to 6 carbon atoms, R denotes the same or different alkyl radicals with 1 to 5 carbon atoms and X denotes an anion, characterized in that corresponding dialkylaminoalkyl xanthene-9-carboxylates in a manner known per se by means of corresponding haloalkyls or dialkyl sulfates in one Reacts inert organic solvent and the anion of the ammonium salts obtained is optionally exchanged in a manner known per se for other mono- or divalent inorganic or organic acid residues. 2. The method according to claim I, characterized in that one is an ester of the formula reacted with CH3Br in an inert organic solvent and the salt formed was separated off. Publications considered: Helvetica Chimica Acta, Vol. 24, (1941), pp. 458 to 465; Journal of the Chemical Society, 1947, 5. 55 ff. And Pp. 164 to 168; Journal of Pharmacology and Experim. Therapeutics, Vol. 85, (1945) 5. 85 to Ioa; Journal of the American chemical Society, Vol. 64, (1942), pp. 428ff., and Vol. 68, (1946), pp. 2345-2348.