DE834698C - Process for the preparation of soluble compounds of the sulfonamide series - Google Patents

Process for the preparation of soluble compounds of the sulfonamide series

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Publication number
DE834698C
DE834698C DEF2504A DEF0002504A DE834698C DE 834698 C DE834698 C DE 834698C DE F2504 A DEF2504 A DE F2504A DE F0002504 A DEF0002504 A DE F0002504A DE 834698 C DE834698 C DE 834698C
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Germany
Prior art keywords
sulfonamide
preparation
bisulfite
solution
soluble compounds
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Expired
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DEF2504A
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German (de)
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Dr Robert Behnisch
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Bayer AG
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Bayer AG
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Publication date
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Priority to DEF2504A priority Critical patent/DE834698C/en
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Publication of DE834698C publication Critical patent/DE834698C/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/69—Benzenesulfonamido-pyrimidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C07D263/50—Benzene-sulfonamido oxazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Verfahren zur Herstellung von löslichen Verbindungen der Sulfonamidreihe Es ist bekannt, daß wasserlösliche, chemotherapeutisch wirksame Abkömmlinge des 4.Aminobenzolsulfonamids erhalten werden, wenn man Bisulfite und 4-Aminobenzolsulfonamid auf ungesättigte aliphatische oder araliphatische Aldehyde, die eine ungesättigte Seitenkette aufweisen, einwirken läßt. So gewinnt man beispielsweise durch Umsetzung von Natriumbisulfit, 4-Aminobenzolsulfonamid und Zimtaldehyd im molekularen Verhältnis 2 : r : i (in wäßriger Lösung bei go°) das Natriumsalz der 4-(y-Phenylpropyl)-aminobenzolsulfonamid-a, y-disulfosäure in sehr guter Ausbeute als leicht wasserlösliche Substanz.Process for the preparation of soluble compounds of the sulfonamide series It is known that water-soluble, chemotherapeutically effective derivatives of 4. Aminobenzenesulfonamides are obtained by using bisulfites and 4-aminobenzenesulfonamides to unsaturated aliphatic or araliphatic aldehydes, which are an unsaturated Have side chain, can act. For example, you win through implementation of sodium bisulfite, 4-aminobenzenesulfonamide and cinnamaldehyde in a molecular ratio 2: r: i (in aqueous solution at go °) the sodium salt of 4- (y-phenylpropyl) -aminobenzenesulfonamide-a, y-disulfonic acid in very good yield as a readily water-soluble substance.

Versuche, das Verfahren in der vorbeschriebenen Form auf die besonders wertvollen in der Sulfonamidgruppe heterocyclisch substituierten 4-Aminobenzolsulfonamide zu übertragen, sind ergebnislos verlaufen. Erhitzt man nämlich Natriumbisulfit und ein solches Sulfonamid, z. B. das 2-(p-Aminobenzolsulfonamido)-pyrimidin; mit Zimtaldehyd oder Acrolein oder Crotonaldehyd im molekularen Verhältnis 2 : r : r in wäßriger Lösung zum Rochen, so bleibt das 2-(p-Aminobenzolsulfonamido)-pyrimidin größtenteils ungelöst. Man kann zwar eine wäßrige Lösung erzielen, wenn man unter sonst gleichen Bedingungen an Stelle des freien 2-(p-Aminobenzolsulfonamido)-pyrimidins dessen Natriumsalz verwendet. Die so erhältliche wäßrige Lösung reagiert aber alkalisch und scheidet beim Versuch, sie zu neutralisieren, einen Teil des gelüsten Sulfonamids wieder ab. Genau so verhalten sich Lösungen, die aus 2-(p-Aminobenzolsulfonamido)-thiazol, thiodiazol, -pyridin und ähnlich heterocvchsch substituierten Sulfonamiden unter Verwendung der Natriumsalze hergestellt werden. Nach den bisher bekannten Methoden lassen sich demnach keine Lösungen herstellen, die den gestellten Forderungen nach Stabilität und neutraler Reaktion genügen würden.Attempts to apply the procedure in the form described above to the particular valuable 4-aminobenzenesulfonamides which are heterocyclically substituted in the sulfonamide group to transfer have been fruitless. If you heat sodium bisulfite and such a sulfonamide, e.g. B. 2- (p-aminobenzenesulfonamido) pyrimidine; with cinnamaldehyde or acrolein or crotonaldehyde in a molecular ratio of 2: r: r in aqueous Solution to the skate, so the 2- (p-aminobenzene sulfonamido) pyrimidine remains for the most part unsolved. It is true that an aqueous solution can be achieved if one is otherwise the same Conditions in place of the free 2- (p-aminobenzenesulfonamido) pyrimidine Sodium salt used. The aqueous solution thus obtainable, however, has an alkaline reaction and divorces one while trying to neutralize them part of lust for sulfonamides again. This is exactly how solutions behave that consist of 2- (p-aminobenzenesulfonamido) -thiazole, thiodiazole, pyridine and similarly heterocyclically substituted sulfonamides Use of the sodium salts are made. According to the previously known methods it is therefore not possible to produce solutions that meet the requirements Stability and neutral reaction would suffice.

Es wurde gefunden, daß man zu leicht und neutral wasserlöslichen, chemotherapeutisch hoch wirksamen Verbindungen gelangt, wenn man Bisulfite und in der Stilfonamidgruppe heterocyclisch substituierte a-Aminobenzolsulfonamide auf ungesättigte aliphatische oder araliphatische Aldehyde, die eine ungesättigte Seitenkette aufweisen, in einem solchen Verhältnis aufeinander einwirken läßt, daß auf i Molekül der Sulfonamidverbindung mehr als i Molekül des Aldehyds und mehr als 2 Moleküle des Bisulfits zur Umsetzung gelangen. Die Umsetzung wird zweckmäßig in wäßriger Lösung bei Temperaturen über ioo durchgeführt. Im Gegensatz zur früheren Versuchsanordnung geht man hier nicht von den Natriumsalzen, sondern von den freien Sulfonamiden aus und erhält hochkonzentrierte Lösungen, die bei Einstellung auf genau neutrale Reaktion keine Abscheidung ergeben. Als Sulfonamide im Sinne der vorliegenden 1?rfinclung können die verschiedenen bekannten lieterocyclisch substituierten Sulfonamide Verwendung finden, als Aldehyde z. B. Zimtaldehyd, Acro>lein, Crotonaldehyd und ihre Abkömmlinge. Die zur Umsetzung erforderliche Temperatur von über ioo- kann durch möglichst konzentriertes Lösen der Umsetzungsteilnehmer in wenig Wasser und Kochen der Lösung erreicht werden. Noch günstiger ist, besonders bei Verwendung leicht flüchtiger Aldehyde, das Arbeiten im Rührautoklaven. Die Höhe der Umsetzungstemperatur hängt von der Natur des Aldehyds ab und wird vorteilhaft zwischen iio und 16o' gewählt. Die Umsetzung wird zweckmäßig so durchgeführt, daß der Aldehyd zunächst mit dem Bisulfit und die entstandene Anlagerungsverbindung mit dem Sulfonamid umgesetzt wird. Die Erfindung ist jedoch auf diese Arbeitsweise nicht beschränkt. Man kann statt dessen auch das Sulfonamid zunächst mit dem Aldehvd umsetzen und anschließend Bistilfit anlagern oder alle Komponenten zugleich zur Umsetzung bringen. Die anfallende Lösung kann nach Filtration, Einstellung auf einen bestimmten Gehalt und pii-Wert, sowie Sterilisation zur Injektion verwendet werden. Man kann aber auch z. B. durch Eindampfen im Vakuum oder durch Ausfällen mit organischen Lösungsmitteln das entstandene Produkt in fester Form isolieren.It has been found that too easily and neutrally water-soluble, chemotherapeutically highly effective compounds come from bisulfites and in the stilfonamidgruppe on heterocyclically substituted α-aminobenzene sulfonamides unsaturated aliphatic or araliphatic aldehydes, which have an unsaturated side chain have, can act on each other in such a ratio that on i molecule of the sulfonamide compound more than 1 molecule of the aldehyde and more than 2 molecules of the bisulfite to implement. The reaction is expediently in aqueous Solution carried out at temperatures above 100. In contrast to the earlier test arrangement one does not proceed here from the sodium salts, but from the free sulfonamides and receives highly concentrated solutions, which when adjusted to exactly neutral reaction result in no separation. As sulfonamides within the meaning of the present refinement the various known lieterocyclically substituted sulfonamides can be used find, as aldehydes z. B. cinnamaldehyde, acrolein, crotonaldehyde and their derivatives. The temperature of over 100% required for the implementation can be achieved by as concentrated as possible Dissolving the reactants in a little water and boiling the solution can be achieved. Working is even cheaper, especially when using volatile aldehydes in a stirred autoclave. The level of the reaction temperature depends on the nature of the aldehyde from and is advantageously chosen between iio and 16o '. The implementation becomes appropriate carried out so that the aldehyde initially with the bisulfite and the resulting addition compound is reacted with the sulfonamide. However, the invention is based on this mode of operation not restricted. Instead, the sulfonamide can first be mixed with the aldehyde implement and then add Bistilfit or all components at the same time Bring implementation. The resulting solution can after filtration, adjustment to a certain content and pii value, as well as sterilization for injection can be used. But you can also z. B. by evaporation in vacuo or by precipitation with organic Solvents isolate the resulting product in solid form.

Beispiel i i32 g Zimtaldehyd werden bei 70 bis 80- unter Rühren langsam zti einer Lösung von 2o8 g Natriumbisulfit in 800 ccm Wasser getropft und st) lange erhitzt, bis klare Lösung eingetreten ist. Durch Zugabe einiger Tropfen Natronlauge wird die Lösung genau neutralisiert und sodann mit 125 g 2-(p-Amitiobenzolsulfonamido)-pyrimidin versetzt. Man erhitzt 12 Stunden auf i2o° Innentemperatur und erhält nach Abkühlen eine klare goldgelbe Lösung. Diese wird blank filtriert und mit destilliertem Wasser zii 1,251 aufgefüllt. Sie reagiert neutral, kann aber durch Zusatz von Lauge auf schwach alkalische oder von Säure auf schwach saure Reaktion eingestellt werden, ohne daß Zersetzung cintiitt. Sie erleidet auch beim Sterilisieren keine Zersetzung.EXAMPLE I 32 g of cinnamaldehyde are slowly added dropwise at 70 to 80 g with stirring to a solution of 208 g of sodium bisulfite in 800 cc of water and heated for a long time until a clear solution has formed. The solution is precisely neutralized by adding a few drops of sodium hydroxide solution, and then 125 g of 2- (p-amitiobenzene sulfonamido) pyrimidine are added. The mixture is heated to an internal temperature of 120 ° for 12 hours and, after cooling, a clear, golden-yellow solution is obtained. This is filtered blank and made up to 1.251 with distilled water. It reacts neutrally, but can be adjusted to a weakly alkaline or acidic to a weakly acidic reaction by adding lye, without causing any decomposition. It does not deteriorate even during sterilization.

M'erden an Stelle de:2-(1)-Aniini)l>enzo@lstilfo>namidc@)-pyrimidins 124,5 g 2-(l)-Ainino@benzoilstilfonamido)-pyridin oder 128 g 2-(l)-:@niiiio@lienz_o@1stilfonamid@i)-thiazol eingesetzt, dann ci-li;ilt man ebenfalls goldgelbe klare Lösungen %-()n neutraler Reaktio»i und hoher Beständigkeit. Beisliiel2 Zti einer Lösung von 2i>s rciileni eisenfreien Natriumbisulfit in Soo ccin Wasser tropft man unter Rühren und guter Iiiililting 56- Acro@lein (frisch destilliert), rührt 2 Stunden unter Kühlung und i Stunde bei 50°, neutralisiert genau mit Natronlauge, setzt 132 g 2-(p-Aminoil)enzolstilfc@namido)-.l-methylpyrimidin zu und erhitzt 12 Stunden auf 16o bis 170' Innentemperatur. Nach Abkühlung wird die Lösung blank filtriert und im Vakuum eingedampft. Der feste Rückstand läßt sich leicht pulvern. Er ist in Wasser sehr leicht und mit neutraler Reaktion löslich. Die Lösung ist sterilisierhar, ()linc# Veränderung zti erleiden.M'erden instead of de: 2- (1) -Aniini) l> enzo @ lstilfo> namidc @) - pyrimidins 124.5 g 2- (l) -Ainino @ benzoilstilfonamido) -pyridine or 128 g 2- (l) -: @ niiiio @ lienz_o @ 1stilfonamid @ i) -thiazole used, then ci-li; ilt one also golden yellow clear solutions% - () n neutral reaction and high stability. For example, a solution of 2% iron-free sodium bisulfite in soocin water is added dropwise with stirring and thorough dilution 132 g of 2- (p-Aminoil) enzolstilfc @ namido) -. L-methylpyrimidine are added and the mixture is heated to an internal temperature of 160 to 170 ° for 12 hours. After cooling, the solution is filtered blank and evaporated in vacuo. The solid residue can easily be powdered. It is very easily soluble in water and has a neutral reaction. The solution is sterilizable, () linc # change zti.

An Stelle des Acroleins kann man auch log Crotonaldehyd einsetzen und erhält ein Pulver mit ähnlichen Eigenschaften. An Stelle des 2-(p-Aminobenzolsulfonamido)-.1-niethvlpyrimiclins können auch andere heterocyclisch substituierte Sulfonamide eingesetzt werden, z. B. solche, die den Thiodiazol-, Pyrazin-, Pyridazin-, Pvrazo@l- (>der Oxazolring enthalten.Log crotonaldehyde can also be used in place of acrolein and receives a powder with similar properties. Instead of 2- (p-aminobenzenesulfonamido) -. 1-niethvlpyrimiclins other heterocyclically substituted sulfonamides can also be used, e.g. B. those that have the thiodiazole, pyrazine, pyridazine, Pvrazo @ l- (> the oxazole ring contain.

Claims (2)

PATENTANSPRÜCHE: i. Verfahren zur Herstellung liisliclier Verbindungen der Stilftmamidreihe, dadurch gekennzeichnet, daß man die in der Sulfonamidgruppe lieterocj#clisch substituierten I-Aminobenzolstilfonamide mit einem ungesättigten aliphatischen oder araliphatischen Aldehyd, der eine ungesättigte Seitenkette aufweist, und mit Bisulfit in einem solchen molekularen Verhältnis zur Umsetzung bringt, daß auf i Mol des Sulfonamids mehr als i Mol des Aldehyds und mehr als 2 'Iol des Bisulfits zur Einwirkung gelangen. PATENT CLAIMS: i. Process for making liisliclier compounds the Stilftmamid series, characterized in that one in the sulfonamide group lieterocj # clically substituted I-aminobenzolstilfonamide with an unsaturated one aliphatic or araliphatic aldehyde, which has an unsaturated side chain, and with bisulfite in such a molecular ratio for implementation that on 1 mole of the sulfonamide more than 1 mole of the aldehyde and more than 2 'Iol of the bisulfite come to action. 2. Verfahren nach Anspruch i, dadurch gekennzeichnet, daß man die Reaktion in wäßriger Lösung bei Temperaturen über ioo" durchführt.2. The method according to claim i, characterized in that the reaction is carried out in aqueous solution at temperatures above 100 ".
DEF2504A 1944-09-08 1944-09-08 Process for the preparation of soluble compounds of the sulfonamide series Expired DE834698C (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE921148C (en) * 1952-09-04 1954-12-09 Nordmark Werke Gmbh Process for the preparation of a condensation product from a p-aminobenzenesulfonamidopyrimidine, cinnamaldehyde and alkali bisulfite

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE921148C (en) * 1952-09-04 1954-12-09 Nordmark Werke Gmbh Process for the preparation of a condensation product from a p-aminobenzenesulfonamidopyrimidine, cinnamaldehyde and alkali bisulfite

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