DE1810137A1 - Process for the preparation of derivatives of o-alkoxyphenols - Google Patents

Description

Leritia limited liability company Chemical and pharmaceutical products - industrial supplies Munich 15, Schwanthalerstraße 39

Process for the preparation of derivatives of o-alkoxyphenols

It is known from German patent specification 839.938; that the Dialkylamides of vanillic acid, in particular the vanillic acid diethylamide, as a respiratory and circulatory agent therapeutic use can find. These compounds were produced, for example, by converting vanillic acid or its derivatives mit.Aminen by customary methods, with the free phenolic Hydroxyl group was optionally protected during the reaction by acylation or etherification and this 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 methods mentioned have hitherto been considered which start from the vanillic acid chloride, the phenolic hydroxyl possibly being protected during the reaction. For example according to the German patent cited above, these dialkylamides made of vanillic acid by reacting vanillic acid chloride with a protected hydroxyl group with secondary amines in benzene while according to French patent 1,096,209 the implementation of the corresponding acylated vanillic acid chloride takes place with the amine in aqueous solution, at the same time the protective acetyl group is split off by excess amine will. The production of vanillic acid chloride, however, is difficult and time-consuming, as is the production of vanillic acid melting vanillin with potassium hydroxide is uncomfortable in practice.

The preparation of the vanillic acid chloride could be carried out by the process for the preparation of Vanillinsäuredialkylamiden according to

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DBP 1 “086.690 avoided”, according to which acetylvanillic acid is reacted with dialkylcarbamic acid halides, whereupon the desired dialkylamides are obtained after splitting off the acetyl group. The production of vanillic acid is also a prerequisite for this process »

It is also known that after what is known as the Illgerodt-Kind ~ ler reaction, oxo compounds, primarily ketones, are converted into thio- _; Acid amides can be converted, working at an elevated temperature, usually at 140-160 ° C. A ratio of 1.5: 1 »5: 1 is recommended as the most favorable ratio of sulfur amine ketone. However, attempts to transfer this reaction to the conversion of vanillin and the analogous alkoxy-hydroxybenzaldehydes have shown that mixtures of the new corresponding Thioamides are obtained with other thio compounds that can hardly be separated. Apart from that it was. the yield is also by no means satisfactory.

Surprisingly, it has now been found "that it is possible that new dialkylamides alkoxysubstituierter'Phenolthiocarbonsäuren in good yields to obtain and aniBerdem is possible to produce a satisfactory leg of knowledge about these thioamides in good yield dialkyl amides alkoxysubstito * FOURTH phenolic acids ₅ when to produce the Thiosäurearaide Such an excess of dialkylamine is used that the new dialkylamides of the alkoxy-substituted phenolthiocarboxylic acid precipitate out of the reaction mixture as the salt of the corresponding dialkylamine and the reaction is also carried out at 65-80 ° C. If, in the oxidation of the thioamides to the corresponding carboxamides, attention is paid to the fact that the reaction of the thioamides with the oxidizing agent HgO _{2 is carried out} in an alkaline range of fflascimal P _H 11, the carboxylic dialkyl fiiides are obtained in such purity that, for example in the case of the bulk of the vanillic acid dialkylamide obtained in this way, the distillation, which is otherwise always necessary for purification, must be removed. Only the portion isolated from the mother liquors must be removed

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common to be distilled. This circumstance also means a substantial simplification and cheaper of the process for its production.

The present invention accordingly provides a process for the preparation of derivatives of o-alkoxyphenols in general Formula I:

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In 4 <& r X is oxygen _{or sulfur, E 1 is} an alkyl radical and R _{2 is} a methyl or ethyl radical, which is characterized in that benzaldehyde derivatives of the general formula II:

OR ₂ , (II)

in which R ^ is defined as above, in anhydrous, lower aliphatic alcohols as a solvent with more than 1 mole of sulfur and at least 4 moles of a dialkylamine of the formula HN. (R ₁ )., in which Ej is defined as above, at temperatures of 65 - 80 ° C converted from the solid dialkylamine salts of the thioamides, the new thioamides of the general formula III:

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in which R ₁ and R 'are as defined above, are set by treatment with acids in freedom, followed, if desired, the thiocarboxamide group is converted by treatment with hydrogen peroxide in alkaline medium at a p _H of at most 11 in the carboxylic acid amide.

As solvents for the reaction of the aldehydes of the formula II with sulfur and dialkylamines, for example, methanol, ethanol and isopropane oil can be mentioned, with methanol generally being able to achieve the best results. Further, "Ine has proven Dialkylaminmenge of about 5 moles, to 1 ° ^M l aldehyde of the formula II * The reaction may very by the presence of a small amount Triäthylämin, for example 0.5 mole per mole of aldehyde, are favored. It has also been shown that it is advantageous to use the sulfur in excess, based on the amount of aldehyde of the formula II; preference is given to using 2 moles of sulfur per mole of aldehyde.

The solid dialkylamine salt of the thioic acid dialkylamides of the formula III which precipitates in this reaction is, for example, by filter or centrifuge, isolated. From these salts you can by treatment with acids, expediently with those in aqueous solution have a p ^ value between 3 and 4.5, the free thioic acid dialkylamides of the formula in are obtained, which have not yet been described. It is best to do it yourself weak organic acids such as acetic acid or propionic acid.

The conversion of the thioamides of the formula into the corresponding Carboxamides Is expediently carried out at temperatures of 30 - 60 ° C. As alkalis that as alkaline Reaction medium suitable for this oxidation can be aqueous solutions of alkali hydroxides, such as sodium and potassium hydroxide, as well as alkali carbonates such as sodium and potassium carbonate. The immediate result of failure Accruing carboxylic acid dialkylamides, such as the dialkylamides of 'Vaniliiniäure and Äthylvanillinsäure can easily by Um- • precipitate or through, recrystallize be purified. In the event of

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This is achieved by dissolving the ¹ vanillic acid diethylamide in acetone at the boiling point, filtering with cabbage and precipitating at 20 ° C. with 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 usual vacuum distillation for purification.

The new thioic acid dialkylamides of the formula III are not just intermediates in the manufacture of the dialkylamides of vanillic acid and ethylvanillic acid, they also have interesting ones in their own right 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, while stirring, with 2 Gram atoms of sulfur mixed in. The mixture is refluxed for 40 hours, which corresponds to a reaction temperature of 70.degree. 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 in 270 ml of glacial acetic acid at 40 ° C., the same amount of water is added, the mixture is stirred with charcoal and filtered at 40 ° C. The resulting brownish solution becomes cooled to 0 ° C. with stirring, yellow crystals separating out. After the precipitation is completed by adding 270 ml of water the thiovanillic acid diethylamide is centrifuged off, washed with water and dried '. In this way, Mari receives 0.61 mol of the thiovanillic acid diethylamide with a melting point of 83 ° C.

Example 2:

0.61 mol of the thiovanillic acid diethylamide adjusted according to Example 1 are dissolved in 462 ml of 10% sodium hydroxide solution at 40 ° C. This 117 ml of water and 1.5 g of activated charcoal are added to the solution, the charcoal is filtered off and the filtrate is removed over the course of 3 hours

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263 ml of 33% perhydrol are added in portions. After loading 'the reaction has ended the reaction mixture is acidified with concentrated hydrochloric acid until reaching a p _H of 6 to give crude Vanillinsäurediäthylamid deposited which was isolated, washed with water and dried. This gives 0.52 mol of crude product with a melting point of 94 ° C.

This 0.52 mol of crude product is dissolved in acetone and washed with charcoal heated to reflux. After 10 minutes, the charcoal is filtered off while hot, the filtrate is cooled to 20 ° C. and added dropwise mixed with petroleum ether, and then cooled to -10 ° C. The crystals obtained in this way are removed by repeated reprecipitation Acetone and petroleum ether are further purified as described above. This gives 0.373 moles of pure vanillic acid diethylamide with a melting point 93 - 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 added to 400 ml of absolute alcohol and 2 gram atoms of sulfur mixed. The mixture is refluxed for 40 hours, what corresponds to a reaction temperature of 75 ° C. After cooling it will the separated crystal pulp is centrifuged, the solid parts dissolved in 250 ml of glacial acetic acid, filtered with charcoal and mixed with the same amount of water. Separate after cooling to about 0 ° C yellow crystals form, the precipitation of which is completed by adding water dropwise »obtained after suctioning off and drying 0.6 mol of thiovanillic acid diethylamide with a melting point of 84 ° C.

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If the reaction according to Example 3 in isopropanol instead of Xthanol carried out as the reaction medium, it turns out a Reaction temperature of 00 ° C. 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 mixed, with cooling, with 0.5 mol of triethylamine and 5 mol of diethylamine and then with 2 gram atoms of sulfur. The mixture is refluxed for 48 hours and then cooled to -5 ° C., a solid substance separating out. It is isolated by suction, dissolved in 160 ml of glacial acetic acid while warming, diluted with 116 ml of water and, after adding 3 % animal charcoal, filtered. The mixture is then cooled again and the solid product is filtered off with suction.

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

The Thioäthylvanillinsäurediäthylamid can by dissolving in Xthanol, Filtering over animal charcoal and cooling can be further purified.

Example 5J

0.517 thioäthylvanillinsäurediethyl- 'amide prepared according to Example 4 are at a temperature of 60 ° C in 220 ml of 10 Jiiger Sodium hydroxide solution and 1,500 ml of water dissolved. After adding 5 g of charcoal, the solution is filtered. The filtrate is then stirred 485 ml of fethydrol and 60 ml of 50% sodium hydroxide solution are gradually added in the course of 5 hours and at a temperature of 40 ° C., the reaction temperature being maintained by cooling. When the addition is complete, add 80 ml of concentrated hydrochloric acid set a p ^ value of 6 «Dae precipitated product is isolated by suction, washed with water and dried. This gives 0.468 mol of crude xthylvanillic acid diethylamide. This amide can be thrown in acetone, Addition of animal charcoal and filtration and precipitation with petroleum ether can be cleaned. This gives 0.335 mol of pure ethylvanillic acid diethylamide with a temperature of 91 ° C.

909833/1473 ORIGINAL INSPECTED

Claims (11)

_ 8 Ί 610137 ^ jiVi / a Fs ^ patent claims: 1. Process for the preparation of derivatives of o-alkoxyphenols the general formula OH . 1 in which X is oxygen or sulfur, R- is an alkyl radical and Rp denotes a methyl or ethyl radical, characterized in that that benzaldehyde derivatives of the general formula (II) CHO in the Rp is as defined above, in anhydrous, lower ones aliphatic alcohols as solvents with more than 1 mole of sulfur and at least 4 moles of a dialkylamine of the formula NH. (P-) p, in which E- is as defined above, at temperatures from 65 - 80 ° C implemented, the new thioamides from the solid dialkyl amines al zen of the thioamides general formula (in) in which R ₂ and R ₁ are as defined above, are set by treatment with acids in freedom, followed, if desired, the thiocarboxylic? midgruppe by treatment with hydrogen peroxide in alkaline medium at a p _H of at most 11 in the carboxylic acid amide group is transformed. Ö09833 / U73 "" *,. r. . - i! :. [ic! .edorl tfcU.fl. L Γ 'Γ - I · _Μ ._.,. "<,", J, 2. The method according to claim 1, characterized in that in the reaction of the benzaldehyde derivatives of the formula II with sulfur and the dialkylamine methanol is used as a solvent . will. 3. Process according to Claims 1 and 2, characterized in that benzaldehyde derivatives of the formula II with the reaction Sulfur and dialkylamine is worked in the presence of a small amount of triethylamine. 4. Process according to claims 1 to 3, characterized in that there are 2 moles of sulfur per mole of benzaldehyde derivative of the formula II can be used. 5. The method according to claims 1 to 4, characterized in that that to release the thioamides of the formula III from their Dialkylamine salts acetic acid is used. 6. Process according to claims 1 to 5, characterized in that the conversion of the thiocarboxamide group into the carboxamide group is carried out at 30 - 60 ° C. 7. The method according to claims 1 to 6 for the production of Vanillic acid diethylamide, characterized in that vanillin in anhydrous methanol as a solvent with more than 1 mol Sulfur and at least 4 moles of diethylamine reacted at temperatures of 65 - 80 ° C, from the solid Diethylamine salt of the new Thiovanillinsäurediäthylamids that Free Thiovanillinsäurediäthylamid obtained by decomposition with acetic acid and this at temperatures of 30 - 60 ° C in alkaline medium with a p "of a maximum of 11 with hydrogen peroxide is treated. 8. The new dialkyl amides of thiovanilic acid. 9. Thiovanillic acid diethylamide. 10. The new dialkylamides of thioethylvanillic acid. 11. Thioäthylvanillinsäurediethylamid. Lentia limited liability company ? A -Ϊ 2 «*« Chemical and pharmaceutical products - industrial supplies .12.1 .1969 λ / j * -; ÖÖ9833 / U73