DE134234C

DE134234C -

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Publication number: DE134234C
Application number: DENDAT134234D
Authority: DE

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KAISERLICHESIMPERIAL

PATENTAMT.PATENT OFFICE.

M 134234 KLASSE 12 (j. M 134234 CLASS 12 (j.

Das Studium der Anhydride der Salicylsäure hat bereits verschiedene Forscher beschäftigt. Kraut erhielt (Ann. d. Chemie, Bd. 74 [neue Reihe], S. 13) durch Erhitzen von Acctylchlorid mit Salicylsäure auf 130 bis 140° ein hellgelbes, zu einer harzartigen Masse erstarrendes OeI, welches er für identisch hält mit dem durch Erhitzen von Acetylsalicylsäure auf 140 bis 170⁰ unter Austritt von Acetanhydrid gebildeten Körper. Kraut.hält diese Verbindung, die er offenbar in reinem Zustande nicht in Händen gehabt hat, nicht für ein Sa'üreanhydrid, sondern für eine der Äcetosalicylsäure entsprechende Salicylosalicylsäure. Thatsä.chlich zeigt der nach Kraut's Angaben hergestellte Körper, in Weingeist gelösf und mit Wasser verdünnt, noch saure Eigenschaften. Von seiner Salicylosalicylsäure bezw. auch direct von der Acetylsalicylsäure gelangte Kraut zu seiner Trisalicylosalicylsäure, wenn er die Temperatur auf 2oo° steigerte, wobei die Anhydridbildung sich zwischen mehreren Molecülen vollzog, aber augenscheinlich so, dafs im Endkörper noch immer eine Hydroxyl-(Phenol-)Gruppe und somit auch eine Carboxylgruppe intact geblieben waren. Kraut's Trisalicylosalicylsäure ist sehr leicht löslich in Alkohol und Aether. Schiff (Ann. 87 [neue Reihe] S. 218), der darauf hinweist, dafs Salicylsäureanhydrid mit Eisenchlorid keine Färbung giebt, will das Anhydrid durch Erwärmen von Salicylsäure mit Phosphoroxychlorid erhalten haben, doch giebt er an, dafs hierbei ein in kochendem Alkohol löslicher und ein darin unlöslicher Körper entstehen; ersleren hält er für Salicylid, letzteren für Tetrasalicylid. Schiff bezweifelt auch, dafs Kraut reine Verbindungen unter Händen gehabt habe, womit auch die Versuche des Erfinders in Einklang stehen. Weiter,hat H. W. Perkin (Berichte 1883, S. 339) versucht, das Anhydrid der Salicylsäure darzustellen, indem er Salicylsäure mit Essigsäure anhydrid erhitzte. Als Zwischenproduct erhielt er eitle zähe Masse, von der er annimmt, dafs sie zum grofsen Theil aus Salicylid besteht; dieselbe liefert bei der Destillation in allerdings schlechter Ausbeute Xanthon. Salicylid · zu isoliren hat Perkin nicht versucht.The study of the anhydrides of salicylic acid has already occupied various researchers. Kraut received (Ann. D. Chemie, Vol. 74 [new series], p. 13) by heating acctyl chloride with salicylic acid to 130 to 140 ° a light yellow oil that solidifies to a resinous mass, which he considers to be identical to the through Heating of acetylsalicylic acid to 140 to 170 ⁰ with the escape of acetic anhydride. Kraut. Considers this compound, which he evidently did not have in his hands in the pure state, not to be an acid anhydride, but rather a salicylosalicylic acid corresponding to acetosalicylic acid. In fact, the body produced according to Kraut's information, dissolved in alcohol and diluted with water, still shows acidic properties. From his salicylosalicylic acid respectively. Kraut also got its trisalicylosalicylic acid directly from acetylsalicylic acid when he raised the temperature to 200 °, the anhydride formation taking place between several molecules, but evidently so that there was still a hydroxyl (phenol) group in the end body and thus also one Carboxyl group remained intact. Kraut's trisalicylosalicylic acid is very easily soluble in alcohol and ether. Schiff (Ann. 87 [new series], p. 218), who points out that salicylic anhydride does not give any coloration with ferric chloride, claims to have obtained the anhydride by heating salicylic acid with phosphorus oxychloride, but he states that it is more soluble in boiling alcohol and a body insoluble in it arise; The former he considers salicylid, the latter tetrasalicylid. Schiff also doubts that Kraut had pure compounds in its hands, with which the inventor's experiments are also in accord. Furthermore, HW Perkin (reports 1883, p. 339) tried to represent the anhydride of salicylic acid by heating salicylic acid with acetic anhydride. As an intermediate product he received a vain, viscous mass, which he assumes to consist for the most part of salicylide; the same gives xanthone in the distillation, however, in poor yield. Perkin did not attempt to isolate salicylide.

Die vorstehend angeführten und sonst noch vorhandenen Literaturangaben enthalten wohl Muthmafsungen und Widersprüche bezüglich der Constitution der Salicylsäureanhydride, geben aber kein Verfahren zur glatten Darstellung eines von Salicylsäure und sonstigen Verunreinigungen freien Salicylids. Für die Therapeutik hat aber ein derartiges Verfahren ein wesentliches Interesse, denn seit der Einführung der Salicylsäure in den Arzneischatz ist man bestrebt, ein Salicylsäuredcrivat darzustellen, das den Magen nicht belästigt, frei von unangenehmen Nebenwirkungen ist und erst in Berührung mit der Darmwand Salicylsäure regenerirt. Die Salicylate werden durchweg bereits im Magen gespalten und auch die Acetsalicylsäure erleidet bereits durch verdünnte Säure Spaltung. Am meisten resistent sind von den bislang für medicinische Anwendung vorgeschlagenen Salicylsäurederivaten noch die Salicylphenolester oder Salole, doch kommt denselben neben der Salicylwirkung noch die oft unangenehm empfundene specitische Wirkung der Phenole zu. Von diesen Nachlheilen frei ist das Salicylid.The literature references cited above and otherwise available probably contain There are assumptions and contradictions regarding the constitution of salicylic anhydrides but not a method of smoothly displaying any of salicylic acid and other impurities free salicylids. For therapeutics, however, such a method has an essential interest, because since its introduction of the salicylic acid in the medicinal treasure, efforts are made to represent a salicylic acid derivative, that does not bother the stomach, is free from unpleasant side effects and only in Contact with the intestinal wall regenerates salicylic acid. The salicylates are consistently already split in the stomach and the acetalicylic acid also suffers from being diluted Acid cleavage. The most resistant are those for medicinal use up to now proposed salicylic acid derivatives nor the salicylphenol esters or salols, but comes in addition to the salicylic effect, there is also the specitic effect, which is often perceived as unpleasant of phenols too. Salicylid is free from these after-healing effects.

Es wurde nun gefunden, dafs die Acetsalicylsäure bereits beim Erhitzen auf 150 bis i6o° , sehr allmählich unter Essigsäureabspaltung Sa-It has now been found that the acetalicylic acid already on heating to 150 to 160 ° , very gradually with elimination of acetic acid

Claims

licylid begins to deliver, but the reaction is only after 5 to 6 hours of heating at 200 to 2io ° a complete respectively. almost quantitative. The raw product obtained, which in the heat becomes a viscous, rapidly solidifying when cooling and then easy to powder Forms mass, is formed in order to remove and reverse acetalicylic acid still adhering Salicylic acid repeatedly boiled with water, possibly also with diluted alcohol, and then for further purification dissolved in benzene, glacial acetic acid, chloroform or, best of all, acetone, whereupon the salicylid is extracted from the saturated acetone solution, most expediently by pouring it into the water in cold water, fails.

The salicylid thus obtained forms a white powder that is practically insoluble in water and ether, very sparingly soluble in hot alcohol, and completely tasteless. Elementary analysis showed 69.73 pCt. C and 3.5 pCt. H (calculated for C ₁ H ₁₁ O ₂ 70 pCt. C and 3.33 pCl. //). Boiled with alcohol, the solution gives no reaction to salicylic acid. The salicylid is easily soluble in chloroform, glacial acetic acid, benzene and especially in acetone. It starts with iio ° to sinter is waxy at 130 ^0, viscous at I6O ° to finally at 210 ⁰ to. melt. It cannot be distilled without decomposition. Provides cooked with caustic alkalis. it, going completely into solution, rapidly and slightly salicylic acid salt; Also, carbonic alkalies decompose it in the heat, and even in a 2 to 5 per cent. solution on prolonged standing at ordinary temperature. With the exception of concentrated sulfuric acid, when it is converted into sulfosalicylic acid, it is not cleaved by acids. In nitric acid, which is 20 to 25 pCt. fuming acid are added, it dissolves under nitration to form trinitrosalicylide. It crystallizes from water in beautiful crystals melting at 121.5 °, and tastes very bitter. The solutions of the nitro body likewise do not react with ferric chloride. The salicylid present, which arises smoothly and almost quantitatively, differs sharply from the above-mentioned trisalicylosalicylic acid, to which the herb came because it did not complete the reaction when the acetalicylic acid was heated, but broke it off prematurely, in that it is very difficult in alcohol is soluble, is insoluble in ether, and does not give the salicylic acid reaction, while trisalicylosalicylic acid gives this reaction, owing to the presence of the free plicnol group in a small spiritual solution.

Example: 10 kg of acetalicylic acid are used in in an open vessel slowly heated to 200 to 21 o ° and at this temperature 5 to 6 hours received. After this time the reaction is ended. You let it cool down and the obtained, previously crushed raw salicylide boils (6.3 to 6.5 kg in weight) with 4 to 6 times the amount of water 2 to 3 times. That which always quickly hardens Product is then dissolved in 4 to 5 times the amount of acetone and the clear solution in poured 20 to 30 times the amount of water. Here the salicylid falls in white cheesy Flakes, which are dried.

Finally, the patent 68960, which is related to a publication by Richard Anschütz (reports 25, p. 3056). Anschütz provided two crystallizing salicylides, namely a "chloroform-soluble" salicylide of the formula

CnH ^ p 4 ", his tetrasalicylid, and a polysalicylide insoluble in chloroform. Apart from the fact that, when he presented his salicylides, Anschütz did not start from acetalicylic acid, but like Schiff (Ann. 158) from salicylic acid and phosphorus oxychloride, the end products also differ from this present Salicylid by higher-lying melting points ·, as well as in other ways. Anschiitz 'Polisalicylid is insoluble in chloroform. the Tetrasalicylid Anschiitz' patent specification 68960 melts at 260 to 261 °, so it is the melting point over that of the displayed here Salicylids 50 ⁰ The salicylid Anschütz, according to his statements, provides a splendidly crystallizing salicylid-chloroform compound with chloroform. The salicylid in question dissolves very easily in chloroform (3 parts of salicylid dissolve in 10 parts of chloroform), but the solution does not separate either when standing or when walking slowly Evaporation of crystals of salicylide chloroform, probe The chloroform gradually evaporates. leaving behind a syrupy liquid which, however, becomes hard and solid again when the chloroform is completely evaporated.

The salicylid is used in pharmacy and should also be used as a starting material for other derivatives, e.g. B. Nitrosalicylid, serve.

Patent-A ν SPR υ cn:
Process for the preparation of salicylid, consisting in that acetalicylic acid is heated for 5 to 6 hours at 200 to 210 °, the reaction product is boiled with water, it is then dissolved in acetone or similar solvents and precipitated with water.