DE1810137B - Process for the preparation of derivatives of o alkoxyphenols - Google Patents

Description

It is known from German Patent 839 938 that the dialkylamides of vanillic acid, especially the vanillic acid diethylamide, therapeutic use as a respiratory and circulatory agent can find. These compounds were produced, for example, by converting Vanillic acid or its derivatives with amines by customary methods, the free phenolic Hydroxyl group optionally protected during the reaction by acylation or etherification and these protective groups were split off from the amide formed on a case-by-case basis.

For the practical implementation of the synthesis of these amides, however, only those of the mentioned methods in question, which start from the vanillic acid chloride, the phenolic hydroxyl at most is protected during the reaction. For example, according to the above cited German patent these dialkylamides of vanillic acid by reaction of vanillic acid chloride are made with a protected hydroxyl group with secondary amines in benzene, while according to French patent specification 1 096 209 (JjeUnSjpung des correspondingly acylated Vanillinsaiirea ^ tOrias with the amine in aqueous Solution effolg * i 'w $ at the same time the protective Acetyl group is split off by excess amine. The manufacture of vanillic acid chloride, however is difficult and time consuming, and so is the manufacture of vanillic acid by melting Vanillin with potassium hydroxide is uncomfortable to handle in practice.

The preparation of the vanillic acid chloride could be carried out by the method for the preparation of vanillic acid dialkylamides according to German patent 1,086,690, according to the acetylvanillic acid be reacted with dialkylcarbamic acid halides, whereupon after cleavage of the Acetyl group the desired dialkylamides can be obtained. The production of vanillic acid is, however also a prerequisite for this procedure.

It is also known that, after the so-called Willgerodt-Kindler reaction, oxo compounds, primarily ketones, can be converted into thioamides by reaction with sulfur and amines in an anhydrous medium, with an elevated temperature, usually 140 to 160 ^° C. , is being worked on. The recommended ratio of sulfur to amine to ketone is 1.5: 1.5: 1. In attempts to transfer this reaction to the conversion of vanillin and the analogous alkoxy-hydroxybenzaldehydes, however, it was found that mixtures of the new corresponding thioamides with other thio compounds are obtained which can hardly be separated. Apart from that, the yield was also by no means satisfactory.

Surprisingly, it has now been found that it is possible to obtain the new dialkylamides of alkoxy-substituted phenolthiocarboxylic acids in good yields, and it is also possible to produce dialkylamides of alkoxy-substituted phenolcarboxylic acids of satisfactory purity via these thioamides in good yield if such an excess of dialkylamine is used that the new dialkylamides of the alkoxy Phenolthiocarbonsäuren precipitate as a salt of the corresponding dialkylamine from the reaction mixture and further the reaction is carried out at 65 to 8O ⁰ C. If, during the oxidation of the thioamides to the corresponding carboxamides, care is taken to ensure that the reaction of the thioamides with the oxidizing agent H ₂ O _{2 is carried out} in an alkaline range of at most pH 11, the carboxylic acid dialkylamides are obtained in such a purity that, for example, the Most of the vanillic acid dialkylamide obtained in this way can dispense with the distillation which is otherwise always necessary for purification. Only the fractions isolated from the mother liquors have to be distilled, as has been customary up to now. This fact also means that the process for its production is considerably simpler and cheaper.

The present invention accordingly provides a process for the preparation of derivatives of o-alkoxyphenols of the general formula

OH

OR,

CX-N

, R ₁

in which X is oxygen or sulfur, R _{1 is} an alkyl radical and R _{2 is} a methyl or ethyl radical, characterized in that benzaldehyde derivatives of the general formula

OR,

(H)

CHO

in which R _{2 has} the meaning given above, in the presence of anhydrous, lower aliphatic alcohols as a solvent with more than 1 mole of sulfur and at least 4 moles of a dialkylamine of the general formula NH ■ (R ₁ J ₂ , in which R _{1 is} the above meaning, at temperatures from 65 to 8O ⁰ C, which thereby determines the resulting dialkylamine salts Thiosäureamide separating, therefrom by treatment with acids having a pH between 3 and 4.5 in aqueous solution, the Thiosäureamide of the general formula

OH

(III)

CS-N

have the meaning given above in which R ₂ and R _1, is in this freedom and, if desired, by treatment with hydrogen peroxide at temperatures of 30 to 6O ⁰ C in an alkaline medium

at a maximum pH of 11 into the carboxamides the general formula

OH

OC-N

in which R ₁ and R _{2 have} the meaning given above, converted.

As a solvent for the reaction of the aldehydes of the general formula II with sulfur and Dialkylamines can be named, for example, methanol, ethanol and isopropanol, with Methanol usually gives the best results. Furthermore, there has been a dialkylamine amount from about 5 moles to 1 mole of aldehyde of the general formula II has proven very useful. The reaction can by the presence of a small amount of triethylamine, for example 0.5 mol per mole of aldehyde, be favored. It has also been shown that it is advantageous to use the sulfur in excess the amount of aldehyde of the general formula II to be used, preferably 2 moles of sulfur per Mole of aldehyde applied.

The solid dialkylamine salt of the thioic acid dialkylamides of the general type which precipitates out in this reaction Formula III is isolated, for example by filtering or centrifuging. From these salts you can by treatment with acids, expediently with those which have a pH value in aqueous solution have between 3 and 4.5, obtained the free thioic acid dialkylamides of the general formula III that have not yet been described. Weak organic acids are best suited for this such as acetic acid or propionic acid.

The conversion of the thioamides of the general formula III into the corresponding carboxamides is expediently carried out at temperatures from 30.degree. To 60.degree. As alkalis which are suitable as the alkaline reaction medium for this oxidation, there can be mentioned aqueous solutions of alkali hydroxides, such as sodium and potassium hydroxide, and of alkali carbonates, such as sodium and potassium carbonate. The carboxylic acid dialkylamides resulting directly from precipitation, such as the dialkylamides of vanillic acid and ethylvanillic acid, can be purified simply by falling over or by recrystallization. In the case of Vanillinsäurediäthylamids this is achieved by dissolving it in acetone at boiling heat, filtered with charcoal and cases at 20 ⁰ C and petroleum ether. The product obtained after two reprecipitations then meets the purity requirements for a pharmaceutical. The products obtained from the mother liquors are expediently subjected to the customary vacuum distillation for purification.

The new thiosäuredialkylamides of the general formula III are not only intermediates in the Manufacture of the dialkylamides of vanillic acid and ethylvanillic acid, they also have interesting ones themselves pharmacological properties.

example 1

1 mol of vanillin, 0.5 mol of triethylamine and 5 mol of diethylamine are introduced into 400 ml of absolute methanol and mixed with 2 gram atoms of sulfur while stirring. The mixture is heated for 40 hours under reflux, which corresponds to a reaction temperature of 70 ⁰ C. When the reaction has ended, the mixture is cooled to -5 ° C. and the yellow-brown crystals which precipitate, the diethylamine salt of thiovanillic acid diethylamide, are isolated by centrifugation. The salt is then dissolved at 40 ° C in 270 ml of glacial acetic acid, mixed with an equal amount of water, stirred with charcoal and filtered at 40 ⁰ C. The resulting brownish solution is ^{cooled to 0 °} C. with stirring, yellow crystals separating out. After the precipitation has been completed by adding 270 ml of water, the thiovanillic acid diethylamide is centrifuged off, washed with water and dried. In this way, 0.61 mol of thiovanillic acid diethylamide with a melting point of 83 ° C. is obtained.

Example 2

0.61 mol of the set according to example 1 are dissolved Thiovanillinsäurediäthylamids sodium hydroxide solution at 40 ⁰ C in 462 ml of 10%. 117 ml of water and 1.5 g of activated charcoal are added to this solution, the charcoal is filtered off and the filtrate is mixed in portions with 263 ml of 33% perhydrol over the course of 3 hours. After the reaction has ended, the reaction mixture is acidified with concentrated hydrochloric acid until a pH of 6 is reached, crude vanillic acid diethylamide separating out, which is isolated, washed with water and dried. 0.52 mol of crude product with a melting point of 94 ° C. is obtained in this way.

This 0.52 mol of crude product is dissolved in acetone and heated to boiling with charcoal under reflux conditions. After 10 minutes, the charcoal is filtered off while hot, the filtrate is cooled to 20 ° C., petroleum ether is added dropwise and then cooled to -10 ° C. The crystals obtained in this way are purified further by repeated reprecipitation from acetone and petroleum ether as described above. This gives 0.373 mol of pure vanillic acid diethylamide with a melting point of 93 to 96 ^° C.

The resulting mother liquors are evaporated, the residue is ^{distilled at 170 °} C. and a vacuum of 0.5 mm Hg. After subsequent dissolution in acetone and precipitation with petroleum ether, as described above, a further 0.122 mol of pure vanillic acid diethylamide is obtained. The total yield is 0.495 mol of analytically pure product, which corresponds to a yield, based on vanillin, of 49.5% of theory.

Example 3

1 mol of vanillin, 0.5 mol of triethylamine and 5 mol of diethylamine are dissolved in 400 ml of absolute alcohol entered and mixed with 2 gram atoms of sulfur. The mixture is refluxed for 40 hours heated, which corresponds to a reaction temperature of 75 ° C. After cooling, the deposited Centrifuged crystal pulp, dissolved the solid portions in 250 ml of glacial acetic acid, filtered with charcoal and mixed with the same amount of water. After leaving

cool to about 0 ° C yellow crystals separate, the precipitation of which is completed by adding water drop by drop. After vacuuming and drying 0.6 mol of thiovanillic acid diethylamide with a melting point of 84 ° C. is obtained.

If the reaction according to Example 3 is carried out in isopropanol instead of ethanol as the reaction medium, a reaction ^{temperature of 80 °} C. is established. After working up as described in Example 3, 0.43 mol of thiovanillic acid diethylamide with a melting point of 84 ° C. is obtained.

Example 4

1 mole of ethyl vanillin is added to 400 ml of methanol. The mixture is then added with cooling mixed with 0.5 moles of triethylamine and 5 moles of diethylamine and then with 2 gram atoms of sulfur. The The mixture is heated under reflux conditions for 48 hours and then cooled to -5 ° C., with a solid substance is deposited. It is isolated by suction, in 160 ml of glacial acetic acid with warming dissolved, diluted with 116 ml of water and filtered after adding 3% animal charcoal. It becomes the mixture then cooled again and sucked off the solid product.

This gives 0.59 mol of thioäthylvanillinsäurediäthylamid, which corresponds to a yield of 59% the theory.

The Thioäthylvanillinsäurediäthylamid can by dissolving in ethanol, filtering over animal charcoal and Cooling can be further cleaned.

Example 5

0.517 mol of thioäthylvanillinsäurediethylamid prepared according to Example 4 are dissolved at a temperature of 60 ⁰ C in 220 ml of 10% sodium hydroxide solution and 1500 ml of water. After adding 5 g of charcoal, the solution is filtered. The filtrate is then gradually admixed with 485 ml of perhydrol and 60 ml of 50% sodium hydroxide solution over the course of 5 hours and at a temperature of 40 ° C., the reaction temperature being maintained by cooling. After the addition has ended, a pH of 6 is set by adding 80 ml of concentrated hydrochloric acid. The precipitated product is isolated by suction, washed with water and dried. This gives 0.468 mol of crude ethylvanillic acid diethylamide. This amide can be purified by dissolving it in acetone, adding animal charcoal and filtering and precipitating it with petroleum ether. This gives 0.335 mol of pure ethylvanillic acid diethylamide with a melting point of 91 ° C.

Claims (3)

Patent claims: 1. Process for the preparation of derivatives of o-alkoxyphenols of the general formula OH (I) CX-N in which X is oxygen or sulfur, R _{1 is} an alkyl radical and R _{2 is} a methyl or ethyl radical, 55 characterized in that one benzaldehyde derivatives of the general formula OH (Π) CHO in which R _{2 has} the meaning given above, in the presence of anhydrous, lower aliphatic alcohols as a solvent with more than 1 mole of sulfur and at least 4 moles of a dialkylamine of the general formula NH · (R ₁ ^, in which R _{1 has} the meaning given above has, at temperatures of 65 to 80 ⁰ C, separates the solid dialkylamine salts of the thioamides, therefrom by treatment with acids which have a pH between 3 and 4.5 in aqueous solution, the thioamides of the general formula OH OR, CS-N (III) have the meaning given above in which R ₂ and R _1, is in this freedom and, if desired, by treatment with hydrogen peroxide at temperatures of 30 to 6O ⁰ C in an alkaline medium at a pH value of at most 11 in the carboxamides of the general formula OH OC-N the R ₁ and R _{2 are} those given above Have meaning convicted. 2. The method according to claim 1, characterized in that the reaction of the benzaldehyde derivatives carried out with sulfur and dialkylamine in the presence of a small amount of triethylamine. 3. The method according to claim 1, characterized in that the reaction of the benzaldehyde derivatives carried out with sulfur and dialkylamine with 2 moles of sulfur per mole of benzaldehyde derivative.