DE1058522B - Process for the production of new, therapeutically effective basic ethers - Google Patents

Description

Process for the production of new, therapeutically effective basic Ether The invention relates to a method for the production of new, therapeutic effective basic ether.

Basically substituted phenyl ethers, especially ß-disubstituted ones Aminoethyl-o-aralkylphenyl ethers, among other things, have an excellent antihistamine effect. They are conveniently obtained by using an aminoethyl halide with a metal salt, z. B. an alkali salt of an aralkylphenol, implemented. The so obtained basic Ethers are then converted into suitable salts for therapeutic administration, which are generally obtained using inorganic acids.

The previously known manufacturing processes for the named basic ethers and their salts by means of inorganic acids exhibit a number of Disadvantages. First of all, the one reaction component, the o-aralkylphenol, be reacted in a highly purified form. But this cleaning is with associated significant losses. Metallic phenates are then used to produce the phenates Sodium, sodium hydride or sodium alcoholates, their use or production but is not harmless.

Furthermore, the other reaction component must be in the form of the free basic chloride can be used for condensation. These basic chlorides are, however, not very stable, apart from the fact that the condensation under absolutely anhydrous Conditions must be carried out.

Finally, it must be taken into account that the basic ethers obtained must be purified by fractional distillation, and that the salts thereof with inorganic acids, e.g. B. their hydrochlorides, are very hygroscopic. In addition they are too easily soluble in solvents containing hydroxyl groups, so that it is difficult to purify by recrystallization from water or alcohol, if not impossible.

It has now been found that pure, non-hygroscopic salts of such ß-disubstituted aminoethyl-o-aralkylphenolether in a cheap and simple way can be prepared if, generally speaking, o-aralkylphenols directly in a "one-step process," d. H. without isolating the intermediates into the salts of the ß-disubstituted aminoethyl-o-aralkylphenol ethers mentioned with organic Polycarboxylic acids transferred.

Compounds made by the process of the invention have the following general formula In this formula, R1 and R3 are hydrogen or lower alkyl groups, halogen or alkoxy groups, R2 is hydrogen or a methyl group, Z is a phenyl, pyridyl, 2-thienyl or 2-furyl radical, R4 and R5 are alkyl radicals or together with the N- Atom of a heterocyclic ring, to the remainder of a polybasic carboxylic acid.

According to the invention, o-substituted ones are then converted accordingly Phenols in an anhydrous organic solvent in alkali phenolates they in the presence of an acid-binding substance with appropriately basic substituted Ethyl halide hydrohalides - or first with ethylene dihalide and then with an amino compound corresponding to the above formula; adds the reaction mixture with water and a polybasic, non-toxic carboxylic acid and isolates the precipitating one Salt, which is optionally recrystallized.

Shown a little more concretely, one proceeds according to the invention as follows: that the starting material is in an inert, non-aqueous organic solvent dissolves, the solution is heated with an excess of alkali metal hydroxide, by filtration the insoluble alkali salt of the isomeric p-aralkylphenol, provided one is from a mixture started from o- and p-aralkylphenol, removed the filtrate, which is essentially contains the more soluble alkali salt of o-aralkylphenol, with a ß-disubstituted Aminoethyl chloride hydrochloride uni --- A1- ., alihydroxide or carbonate heated until the basic phenol ether has formed, and finally an excess its organic polycarboxylic acid, dissolved in water, to form the reaction mixture added. The salt of the basic ether falls with the organic polycarboxylic acid the end. Impurities remain in solution. The precipitated salt is made from water or crystallized in an alcohol, whereby any salt still present les corresponding p-isomer, which has a higher solubility, is completely removed.

The inventive method has been used to produce basic Ethers of o-aralkylphenols, the n p-position in the phenol ring no substituents wear, proven to be particularly beneficial. It is known that direct alkylation provides of an alkali phenolate with an alkyl halide by the Claisen method und his co-workers, -Annalen der Chemie ”, Vol. 442, 3. 210 (1925), in a non-polar Solvent to prevent substitution, quite low yields in o-aralkylphenols, while considerable amounts of difficult to separate p-isomers are formed. Man Incidentally, according to the method according to the invention, not only the isomer mixture obtained use directly, but it is also possible to use the p-aralkylihenol in the pure state to cut down as a valuable by-product.

Instead of the etherification of the aralkylphenol substituted with a base Carrying out alkyl halide hydrohalide in one stage, you can also in one 7, has step process the alkali salt of aralkylphenol 5 first with a dihaloalkyl compound etherify and then etherify the monohalogen ether obtained with an appropriate amine convert into a basic substituted uher, which is then converted into a polycarboxylic acid salt is converted.

The terms "" aralkylphenol "and" aralkylphenylithera, as used in the description and the claims are used, do not only refer to the pure @ralkylphenols and aralkylphenyl ethers, such as 2-benzyl -.) henol and 2-benzylphenyl ether, but also to other similarly constituted compounds in which the benzyl radical z. B. by a substituted benzyl or another aralkyl radical or by a heterocyclic radical, such as a thiophene, pyridyl and furan radical, with the phenol radical is linked by an alkylene intermediate member, is replaced. the Formula images given above in the description illustrate which connections preferably come into question.

Under the expression #> basic substituted ethyl halide hydrohalide « should be understood not only dialkyliminoethyl halide hydrohalides, but also ethyl halide hydrohalides, which are in the 3-position to the nitrogen atom of a heterocyclic best are bound.

Akimoff (U.S. Patent 2016848) has shown that p-benzylphenol can be separated from o-benzylphenol by dissolving the mixture of isomers in a inert, non-aqueous solvent and adding the aqueous solution of an alkali metal hydroxide, with alkali metal salts being formed , the water is removed by distillation and then the alkali metal salt of p-benzylphenol, which is insoluble in the non-aqueous solvent, is separated off by filtration, while the soluble alkali metal salt of o-benzyldhenol remains in solution. It has been found that the slight peculiar solubility behavior also applies quite generally to analogous aralkylphenols and that these can easily be obtained in pure form by Akimoff's process. In contrast, however, it has been found that the separation process proposed by Akimoff does not produce pure o-benzylphenol or pure o-aralkylphenols, since considerable amounts of p-isomers remain in the filtrate.

However, the p-isomer which cannot be separated off in this way can be reduced remove the method of the present invention by learning from the surprising Difference in the solubility of the salts of the two isomeric basic ethers with Makes use of polycarboxylic acids in solvents. So it was found that the solubility of the primary citrate of o-benzylphenyl-ß-dimethylaminoethyl ether at room temperature in water less than one twentieth the solubility of the citrate of that of p-benzylphenol derived isomeric basic ether is. The solubility of the former Compound in water at room temperature is e.g. B. 10 / "that of the p-isomers Connection more than 20 ° / o. As a result, the contaminating p-isomer can pass through Recrystallization from water is completely eliminated and the citrate is obtained of the pure o-benzyl-ß-dimethylaminoethyl ether in a very high yield. In each The cases investigated so far have been the salts derived from an o-aralkylphenol basic ether with polycarboxylic acids in hydroxylated solvents as essential proved to be less soluble than the corresponding p-isomeric compounds.

Salts derived from inorganic acids, such as the hydrochlorides, however, do not follow this rule. It is amazing that according to the invention Process excellent yields of basic ethers are obtained, although none anhydrous conditions for the Williamson condensation are maintained; because ß-disubstituted aminoethylchloride is known to be easy, especially in Presence of polar solvents, for dimerization and polymerization.

Notable advantages of the present invention include the following Process listed: 1. In the production process according to the invention, a cheap mixture of isomeric o- and p-aralkylphenols instead of the much more expensive ones pure o-aralkylphenols can be used as starting material.

2. One can for the production of phenates instead of alkali metals, Alkali hydrides, alkali alcoholates or alkali amides use an alkali hydroxide. It is well known that the means used earlier require the observation of special safety measures.

3. It is not necessary to use the free basic chloride for condensation in a separate operation.

4. It is also not necessary to use the basic ether for purification to distill. This saves equipment and significantly reduces labor costs humiliated.

5. The salts of the basic ethers with polycarboxylic acids obtained according to the invention are not hygroscopic and can be easily cleaned by recrystallization.

Due to its low toxicity and excellent physical properties Properties of the primary citrates is advantageous citric acid as a polycarboxylic acid used in carrying out the claimed method. But you can too Use other polycarboxylic acids such as malic acid, tartaric acid, succinic acid, maleic acid and fumaric acid. The acids can be in solid form or in Form of their aqueous solutions or suspensions of those containing the basic ether Reaction mixture are added. Inert, non-aqueous solvents, e.g. B. toluene, Xylene, chlorobenzene, o-dichlorobenzene and others are found in the process of the invention Use. Although sodium hydroxide is preferably used, so can other alkali hydroxides or, if desired, alkali hydrides, alkali amides or the Use alkali metals yourself. If you leave an alkali hydroxide with the appropriate phenol react, you do not need to remove the water that has formed. In the cases in which a relatively pure o-aralkylphenol is used as the starting material for the claimed method is used, especially when another substituent in the 'position of the phenol ring the possibility of the presence of a p-isomer excludes all reactants that lead to the formation of the basic ether are required, mix together in the reaction kettle at the same time.

It is of course possible to use the above procedure to some extent to change. So z. B. a ß-halogenated ethyl-o-aralkylphenyl ether as an intermediate and then with a secondary amine to the corresponding basic ether implemented. This is then, as described above, with the help of an organic Polycarboxylic acid, e.g. B. citric acid, precipitated and purified.

The process products obtained according to the invention are highly effective Antihistamines, local anesthetics, fungicides, and the like.

The following examples serve to illustrate the invention: Example 1 Primary citrate of 2-benzylphenyl-β-dimethylaminoethyl ether 25 g of sodium hydroxide are added in flakes to a solution of 92.1 g of a mixture of about 57 ° / ° o-benzylphenol and 43 ° / ° p-benzylphenol in 350 cc of toluene. The reaction mixture is refluxed with stirring for 11/2 hours and then filtered through a coarse fritted glass filter while still hot, with gentle suction. The relatively insoluble sodium salt of p-benzylphenol is washed thoroughly on the filter with a total of 350 cc of toluene. 12 g of sodium hydroxide in the form of scales and 43.3 g of β-dimethylaminoethyl chloride hydrochloride are added to the filtrate, which contains the soluble sodium salt of o-benzylphenol and also a considerable proportion of the sodium salt of the p-isomer. The reaction mixture is refluxed overnight (20 hours) while stirring vigorously. A solution of 105 g of citric acid monohydrate in 400 cc of water is then added. The mixture is then heated to 90 to 100 ° C on the steam bath. The acidic aqueous layer is separated, 13.7 g of decolorizing charcoal are added, and the mixture is then digested on the steam bath for a further 15 minutes. The decolorizing charcoal is filtered off and the hot filtrate is cooled to 50C. The white primary citrate crystallizes out. The crude product has a melting point between 112 and 125 ° C. After suction, it is recrystallized from 450 ccm of water in order to separate any p-isomer still present. The moist filter cake from the second recrystallization is roughly crushed, covered with benzene and then subjected to an azeotropic distillation to completely remove the water.

After complete removal of the benzene by distillation under the distillation residue obtained is boiled in 360 cc under reduced pressure Dissolved methanol. The solution is filtered and then cooled in an ice bath. The white crystalline primary citrate of 2-benzyl-phenyl-ß-dimethylaminoethyl ether is sucked off and dried in the air. It melts at 139 to 140 ° C with evolution of gas. Yield: 88.5 g.

The sodium salt of p-benzylphenol obtained as a by-product is immediately dissolved in 300 cc of water in order to avoid discoloration, which easily occurs with prolonged exposure to atmospheric air, and the solution is acidified by adding 40 cc of 20 0% sulfuric acid. Any toluene still present is removed by passing steam through the mixture. This is then cooled and filtered. The p-benzylphenol thus obtained is washed with water and air-dried. Melting point: 80.5 to 83.5 ° C. Yield: 34.5 g. Example 2 Primary citrate of β-dimethylaminoethyl 2- (2'-thenyl) phenyl ether According to the procedure of Example 1, a mixture of o- and p- (2-thenyl) -phenol, instead of the mixture of o- and p-benzylphenol, is converted into the primary citrate of ß-dimethylaminoethyl-2- (2'- thenyl) phenyl ethers. Melting point: 150 to 151 ° C (with decomposition). Example 3 Primary citrate of β-dimethylaminoethyl-2-furfurylphenyl ether In accordance with the procedure of Example 1, o-furfurylphenol and an equimolecular amount of ß-dimethylaminoethyl chloride hydrochloride are converted to the primary citrate of ß-dimethylaminoethyl-2-furfurylphenyl ether. The basic ether obtained is a white crystalline solid mass. Example 4 Acid dl-malate of 2-benzylphenylß-dimethylaminoethyl ether According to the method described in Example 1, the above salt is obtained by using an equimolecular amount of dl-malic acid (67 g) and about half as much water for the reaction instead of citric acid. Melting point of the salt obtained: 129.5 to 131'C. Example 5 Primary citrate of 2-benzylphenyl-ß-diethylaminoethyl ether According to the process described in Example 1, the abovementioned salt is obtained by using an equimolecular amount of -ß-diethylaminoethyl chloride hydrochloride instead of ß-dimethylaminoethyl chloride hydrochloride. Melting point of the primary citrate: 127.5 to 128.5 ° C. Example 6 Primary citrate of 2-benzylphenyl-β-1- (pyrrolidyl) ethyl ether According to the process described in the example, the abovementioned salt is obtained by using an equimolecular amount of ß- (1-pyrrolidyl) ethyl chloride hydrochloride instead of ß-dimethylaminoethyl chloride hydrochloride. Melting point of the primary citrate: 135 to 136 ° C with decomposition. Example 7 Primary citrate of 2-benzylphenyl-ß- (1-piperidyl) ethyl ether In accordance with the process described in Example 1, the abovementioned salt is obtained by using an equimolecular amount of ß- (1-piperidyl) ethyl chloride hydrochloride instead of ß-dimethylaminoethyl chloride hydrochloride. Melting point of the primary citrate: 145.5 to 146.0 ° C with decomposition. Example 8 Primary citrate of 2-benzylphenyl-ß- (4-morpholinyl) ethyl ether According to the process described in Example 1, the above-mentioned salt is obtained by using an equimolecular amount of β- (4-morpholino) ethyl chloride hydrochloride instead of β-dimethylaminoethyl chloride hydrochloride: melting point of the primary citrate: 125 to 126 ° C. with decomposition . EXAMPLE 9 Acid d-tartrate of 2-benzylphenyl-ß-dimethylaminoethyl ether According to the process described in Example 1, the above salt is obtained by using an equimolecular solution of dW monic acid in the same weight of water instead of the citric acid solution. Example 10 Acid succinate of 2-benzylphenyl-β-dimethylaminoethyl ether According to the procedure described in Example 1. the above salt is obtained by replacing the citric acid solution with a solution of 59 g of succinic acid in the least possible amount of boiling water. The reaction mixture obtained is cooled, the precipitated acid succinate is filtered off, dried and recrystallized from isopropanol. It has a melting point of 104 to 105 ° C. Example 11 Acid maleate of 2-benzylphenyl-ß-dimethylaminoethyl ether A solution of 58 g of maleic acid in the same weight is added to a hot solution of the corresponding basic ether, obtained by the process of Example 1 Water added. The precipitated acidic maleate is filtered off from the cooled solution and recrystallized from water or isopropanol. Melting point: 118 to 119 ° C. Example 12 Acid fumarate of 2-benzylphenyl-ß-dimethylaminoethyl ether To a xylene solution of the corresponding basic ether, as can be obtained by the method of Example 1 using xylene instead of toluene as the reaction medium 60 g of finely powdered fumaric acid and 100 cc of water were added. The mixture is heated on the steam bath for 15 minutes while stirring, then cooled and filtered. The acid fumarate obtained melts after recrystallization from water or isopropanol at 144 to 145 ° C. Example 13 Primary citrate of 2-benzyl-4-chlorophenyl-β-diethylaminoethyl ether A mixture of 109 g of o-benzyl-p-chlorophenol, 300 cc of toluene, 86.5 g of β-dimethylaminoethyl chloride hydrochloride and 50 g of sodium hydroxide in flakes is heated under a reflux condenser with stirring for about 17 hours. A solution of 150 g of anhydrous citric acid in 500 cc of water is then added to the reaction mixture which contains the basic ether formed. The toluene layer is separated and discarded. After the aqueous layer has cooled down vigorously, the precipitated solid is filtered off. By recrystallization from the smallest possible amount of water and treatment with 7.5 g of decolorizing charcoal, 193 p, colorless crystals with a melting point of 143 to 144 ° C. are obtained. Example 14 Primary citrate of 2-benzyl-4-ethoxyphenyl-ß-dimethylaminoethyl ether If equimolecular amounts of o-benzylp-ethoxyphenol and ß-diethylaminoethyl chloride hydrochloride are used as starting materials and the procedure is as described in Example 13 , the above-mentioned compound is obtained as a white crystalline solid. Example 15 Primary citrate of β-diethylaminoethyl 2- (α-methylbenzyl) phenyl ether According to the process described in Example 1, the above-mentioned primary citrate with a melting point of 126 to 129 ° C. is obtained from o- (a-methylbenzyl) phenol and ß-diethylaminoethyl chloride hydrochloride. Example 16 Primary citrate of ß-diethylaminoethyl-2- (a -methylbenzy l) -4-methyl-phenyl ether If you work according to the method described in Example 13 and use p-methyl-o- (a-methylbenzyl) phenol and ß-diethylaminoethyl chloride hydrochloride instead of o-benzyl-p-chlorophenol and ß-dimethylaminoethyl chloride hydrochloride, the above-mentioned is used Compound obtained as a white, crystalline solid mass with a melting point of 125 to 128 ° C. Example 17 Primary citrate of β-dimethylaminoethyl 2- (2'-pyridylmethyl) phenyl ether If you work according to the method described in Example 13 and use 92.5 g of o- (2-pyridylmethyl) phenol instead of o-benzylp-chlorophenol and only 150 ccm of water instead of 500 ccm for the preparation of the citric acid solution, so the above-mentioned primary citrate is obtained, which melts at 149 to 150 ° C. with evolution of gas. Example 18 Acid malate of 2- (4'-bromobenzyl) phenyl-ß-dimethylaminoethyl ether If you work according to the method described in Example 13 and use 0.5 mol of o- (4'-bromobenzyl) phenol in place of o-benzyl-p-chlorophenol and 0.75 mol of malic acid dissolved in the same weight of water in place of the aqueous citric acid solution, the above-mentioned acidic malate is obtained as a crystalline solid mass. Example 19 Primary citrate of β-diethylaminoethyl 2- (4'-isopropylbenzyl) phenyl ether If the procedure described in Example 13 is followed and o- (4'-isopropylbenzyl) phenol is used in place of o-benzyl-p-chlorophenol and 0.5 mol of ß-diethylaminoethyl chloride hydrochloride is used in place of ß-dimethylaminoethyl chloride hydrochloride , the above-mentioned primary citrate is obtained as a crystalline solid mass. Example 20 Acid maleate of β-dimethylaminoethyl 2- (4'-methoxybenzyl) phenyl ether If the procedure described in Example 13 is followed and o- (4'-methoxybenzyl) phenol is used instead of o-benzyl-p-chlorophenol and 90 g of maleic acid, dissolved in 100 cc of water, instead of the aqueous citric acid solution, so the above-mentioned acidic maleate is obtained as a crystalline solid mass. Example 21 Primary citrate of β-dimethylaminoethyl 2- (3'-thenyl) phenyl ether If the procedure described in Example 13 is followed and o- (3'-thenyl) -phenol, which is obtained by reacting 3-thenyl bromide with sodium phenolate in toluene suspension, is used instead of o-benzyl-p-chlorophenol, then o-benzyl-p-chlorophenol is used the above-mentioned primary citrate, which, after recrystallization from a mixture of methanol and ether, melts at 136 to 137.5 ° C. Example 22 Primary citrate of 2-benzylphenyl-ß-dimethylaminoethyl ether To the toluene filtrate obtained by the process of Example 1, which essentially contains the sodium salt of o-benzylphenol and also a certain amount of the sodium salt of p-benzylphenol, 400 cc of ethylene dichloride and 12 g of sodium hydroxide are added in flakes. The reaction mixture is refluxed overnight with stirring. Solvent and excess ethylene chloride are then removed by distillation under reduced pressure. The residue is dissolved in 700 ccm of toluene, the solution is poured into a sealed tube and cooled to 10 ° C. Gaseous dimethylamine is passed into the solution at this temperature until about 68 g have been absorbed by it. The bomb tube is then melted shut and heated at 150 ° C. for 7 hours, cooled, opened and the contents washed thoroughly with water in order to remove the unreacted dimethylamine and its hydrochloride. The toluene solution obtained is then treated with a 25% strength aqueous citric acid solution while stirring until no more precipitation occurs. The primary citrate is suctioned off and recrystallized from water. This completely removes the more soluble p-isomer. The above-mentioned primary citrate with a melting point of 139 to 140 ° C. is obtained. Example 23 Primary citrate of 4-chloro-2-benzylphenyl-β-dimethylamino ether To a solution of 218 g (1.0 mol) of 4-chloro-2-benzylphenol in 750 cc of toluene, 46 g (1.15 mol) of scales of sodium hydroxide are added all at once with thorough stirring. The reaction mixture is heated under the reflux condenser for about 13 /, hours until no more water can be removed with the aid of a Dean-Stark trap. A solution of 60 g (1.5 mol) of sodium hydroxide in 60 cc of water is added to a cooled slurry of 173 g (1.2 mol) of β-dimethylaminoethyl chloride hydrochloride in 200 cc of toluene. After stirring for about 10 minutes, the salt is completely decomposed and the toluene solution is decanted. The remaining aqueous sludge is extracted in a similar manner five times with 80 cc of fresh toluene each time. The decanted toluene solutions are purified and dried over anhydrous potassium carbonate for 2 hours. The potassium carbonate is then removed by filtration.

After the heating of the solution of the sodium salt of 4-chloro-2-benzylphenol has ended the Dean-Stark trap is replaced by an ordinary reflux condenser. On that the dried toluene solution of ß-dimethylaminoethyl chloride becomes this phenolate solution allowed to run in a slow stream, whereupon heating is continued. the The reaction mixture is then heated on the reflux condenser overnight with thorough stirring.

The heating is now stopped and a solution of 240 g (1.25 mol) of anhydrous citric acid in 1 l of water is carefully added to the reaction mixture. After thorough mixing, two clear layers are obtained. The still hot solution is transferred to a separating funnel and the aqueous layer is drawn off as quickly as possible. Crystallization sets in almost immediately. The solution is cooled and the crude product is filtered off. Recrystallization from methanol gives 320 g of the primary citrate of 4-chloro-2-benzylphenyl-ß-dimethylaminoethyl ether with a melting point of 141.5 to 143.5 ° C. Analysis for C "H" 0 $ NCl: Calculated ..... C 57.3 ° / o, H 5.9 ° / o; found ..... C 57.5 ° / o, H 5.8 ° / o. Example 24 Primary citrate of 2-benzylphenyl-β-dimethylaminoethyl ether 46 g (1.15 mol) of flaky sodium hydroxide are added with thorough stirring to a solution of 184 g (1.0 mol) of a mixture of approximately equal amounts of 2-benzylphenol and 4-benzylphenol in 650 cc of toluene. The mixture is heated to boiling in a reflux condenser fitted with a Dean-Stark trap until all of the water formed (18 cc) has been removed, which takes about 2 hours. The water can also be removed by azeotropic distillation with toluene, if care is taken that the toluene distilled off is replaced again. The mixture is filtered while hot through a large-pored sintered glass funnel in order to remove the insoluble sodium salt of 4-benzylphenol. Acidification of this sodium salt gives crude 4-benzylphenol, which can be obtained as a by-product.

At the same time, a suspension of 86.5 g (0.6 mol) of ß-dimethylaminoethyl chloride hydrochloride in 100 cc of toluene in a beaker with cooling all at once with a solution 30 g (0.75 mol) of sodium hydroxide in 30 cc of water are added. The mix will stirred until the salt has completely decomposed and settles at the bottom of the Beakers a homogeneous paste has settled. Then the toluene solution of the free basic Chlorides decanted. The aqueous paste is a total of five times with 40 ccm Extracted toluene and decanted the toluene extract in each case. The combined extracts are dried over anhydrous potassium carbonate for at least 2 hours.

The dark brown toluene solution of the sodium salt of 2-benzylphenol is placed in a three-necked flask equipped with a mechanical stirrer and a reflux condenser. The dried toluene solution of the β-dimethylaminoethyl chloride is filtered off from the desiccant and poured all at once into the three-necked flask. The reaction mixture is then heated to boiling overnight with stirring on the reflux condenser. A solution of 135 g (0.7 mol) of anhydrous citric acid in 350 cc of water is then added, also with thorough stirring, whereupon heat is generated. After a short time, the primary citrate begins to separate out. The mixture is cooled and the crude salt is filtered off. It can be recrystallized from water or methanol. One-time recrystallization from water gives 158 g of the primary citrate of 2-benzylphenyl-ß-dimethylaminoethyl ether with a melting point of 138.5 to 139.5 ° C. Analysis for C23 H29 08N Calculated ..... C 61.8 ° / o, H 6.5 ° / o; found ..... C 62.10 / " H 6.6%. Instead of the aralkylphenols used in the examples, other compounds of this type can also be used as starting materials for the "one-step process" according to the invention, e.g. E.g .: 4-ethoxy-2-benzylphenol, 2- (2'-chlorobenzyl) -phenol, 2- (3'-chlorobenzyl) -phenol, 2- (4'-chlorobenzyl) -phenol, 4-methyl-2- benzylphenol, 4-methoxy-2-benzylphenol, 4-tert. Butyl-2-benzylphenol, 2- (5'-chloro-2'-thenyl) -phenol, 4-chloro-2- (4'-chlorobenzyl) -phenol, 2- (4'-fluorobenzyl) -phenol, 4- Fluoro-2-benzylphenol, 4-bromo-2-benzylphenol, 4-iodo-2-benzylphenol, 2- (2 ', 3'-dimethoxybenzyl) -phenol, 2- (2', 4'-dichlorobenzyl) -phenol.

Also other than those mentioned in the examples ß-disubstituted Aminoethyl chloride hydrochloride can be used for the etherification of aralkylphenols be e.g. B .: ß- (Di-N-n-butyl) -aminoethyl chloride hydrochloride and ß-1- (2-methylpiperidyl) ethyl bromide hydrobromide. Instead of the polycarboxylic acids mentioned in the examples, other acids can also be used of this type, such as phthalic acid, oxalic acid, malonic acid, alkylmalonic acid, pyrocartaric acid, alkylated succinic acid, glutaric acid, adipic acid, citraconic acid, saccharic acid can be used to produce the corresponding salts.

If you follow the procedure of Example 22, you can Dimethylamine by other amines, e.g. B. diethylamine, piperidine, 2-methylpiperidine, Pyrrolidine, replace.

Claims (3)

PATENT CLAIMS: 1. Process for the production of new, therapeutically effective basic ethers of the general formula: where R1 and R3 = hydrogen or lower alkyl groups, halogen or alkoxy groups, R2 = hydrogen or a methyl group, Z a phenyl, pyridyl, 2-thienyl or 2-furyl radical, R4 and R5 alkyl radicals or together with the N atom a heterocyclic ring and An denotes the remainder of a polybasic carboxylic acid, characterized in that correspondingly o-substituted phenols are converted into alkali metal phenols in an anhydrous organic solvent, in the presence of an acid-binding substance with correspondingly basic substituted ethyl halide hydrohalides or first with ethylene dihalide and then with an amino compound corresponding to the above formula is reacted, water and a polybasic, non-toxic carboxylic acid are added to the reaction mixture and the salt which precipitates is isolated and, if necessary, recrystallized. 2. The method according to claim 1, characterized in that one of a corresponding o- runs out in addition to p-substituted phenol-containing mixture and before the addition of the basic substituted component the sparingly soluble alkali salt formed disconnects p-connection. 3. The method according to claim 1 or 2, characterized in that that citric acid is used as the polycarboxylic acid.