AT375360B - METHOD FOR PRODUCING NEW 1,3-BENZODIOXOL DERIVATIVES AND THEIR SALTS - Google Patents

METHOD FOR PRODUCING NEW 1,3-BENZODIOXOL DERIVATIVES AND THEIR SALTS

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Publication number
AT375360B
AT375360B AT467182A AT467182A AT375360B AT 375360 B AT375360 B AT 375360B AT 467182 A AT467182 A AT 467182A AT 467182 A AT467182 A AT 467182A AT 375360 B AT375360 B AT 375360B
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Austria
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solution
benzodioxole
nitro
hydroxy
dimethyl
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AT467182A
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German (de)
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ATA467182A (en
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Ludwig H Dr Schlager
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Gerot Pharmazeutika
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Priority to AT467182A priority Critical patent/AT375360B/en
Priority to EP83890068A priority patent/EP0095454A3/en
Priority to CA000427476A priority patent/CA1233181A/en
Priority to AU14409/83A priority patent/AU566107B2/en
Priority to NO831680A priority patent/NO831680L/en
Priority to DK210483A priority patent/DK210483A/en
Priority to JP58081827A priority patent/JPS58206581A/en
Publication of ATA467182A publication Critical patent/ATA467182A/en
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Publication of AT375360B publication Critical patent/AT375360B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/24—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with two or more hetero atoms
    • A01N43/26—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with two or more hetero atoms five-membered rings
    • A01N43/28—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with two or more hetero atoms five-membered rings with two hetero atoms in positions 1,3
    • A01N43/30—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with two or more hetero atoms five-membered rings with two hetero atoms in positions 1,3 with two oxygen atoms in positions 1,3, condensed with a carbocyclic ring
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A01N43/38—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Dentistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Plant Pathology (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

  

   <Desc/Clms Page number 1> 
 



   Die Erfindung betrifft ein Verfahren zur Herstellung von neuen Benzodioxol-Derivaten der allgemeinen Formel 
 EMI1.1 
 worin R, und   Hz   gleich oder verschieden sein können und Wasserstoff, niederes Alkyl oder Phenyl bedeuten, X, Y und Z nur für die Bedeutung von Wasserstoff nicht gleich sein können und ausser Wasserstoff auch Halogen oder Nitro bedeuten, sowie deren Salzen mit Basen, mit der Massgabe, dass für den Fall, dass   R,, R , X   und Z Wasserstoff bedeuten, das Y keine NO 2-Gruppe sein kann, und deren Salzen mit Basen, das dadurch gekennzeichnet ist, dass man 4-Hydroxy-1, 3-benzodioxole der allgemeinen Formel 
 EMI1.2 
 worin R, und   R   die obige Bedeutung haben,

   vorzugsweise in einem inerten Lösungsmittel oder Lösungsmittelgemisch in ein- oder zweistufiger Reaktion mit halogenierend und/oder nitrierend wirkenden Agentien behandelt, wobei gegebenenfalls auch säurebindende Zusätze und/oder Katalysatoren verwendet werden, und gegebenenfalls eine erhaltene Verbindung in ein Salz überführt. 



   Die nach dem erfindungsgemässen Verfahren erhältlichen neuen Verbindungen der allgemeinen Formel (I) sind einerseits wertvolle Rohstoffe zur Herstellung von Agrochemikalien oder stellen selbst solche dar, anderseits können sie-nach hydrolytischer Aufspaltung des Dioxolanringes-dazu dienen, ansonsten schwer zugängliche kernstubstituierte Pyrogallol-Derivate zu gewinnen. Sie können zur Herstellung von Arzneimitteln, Röntgenkontrastmitteln und Photosensibilisatoren verwendet werden. 



   Die Ausgangsprodukte der allgemeinen Formel (II) sind entweder bekannt oder können nach 
 EMI1.3 
 192700c   [1976] ;   86, 51598j   [1977]).   



   Obwohl die Bedeutung einer Kernsubstitution mit Halogen- oder Nitrogruppen im Bereich der Agrochemikalien bekannt ist   (vgl.   :"Wirkstoffe in Pflanzenschutz- und Schädlingsbekämpfungsmitteln", l. Aufl. 1982, Industrieverband Pflanzenschutz e. V.), und kernhalogenierte Folgeprodukte 
 EMI1.4 
 mel (I) ausser einem durch Nitrierung von Myristicinaldehyd erhaltenen Produkt   (J. Chem. Soc. 95,   1161 [1909]) bisher nicht in der Fachliteratur. 



   Nach dem erfindungsgemässen Verfahren kann ein   4-Hydroxy-1, 3-benzodioxol   entweder nur halogeniert oder nitriert oder zuerst halogeniert und anschliessend nitriert bzw. zuerst nitriert und danach halogeniert werden. Ein zunächst eingeführter Kernsubstituent kann auch in der darauf folgenden Stufe durch einen andern ersetzt werden. Bei den Agentien, die zur Halogenierung bzw. Nitrierung verwendet werden, handelt es sich um solche, die zur Umsetzung mit aromatischen Kohlenwasserstoffen oder Phenolen an sich bekannt sind. 



   Kernsubstituierte Pyrogallol-Derivate der allgemeinen Formel (I) können auch als Zwischenprodukte zur Synthese pharmakologisch wirksamer Verbindungen dienen   (vgl. AT-Pat.-Anm. A   1888/82) 

 <Desc/Clms Page number 2> 

 oder zur Gewinnung von Photosensibilisatoren   (vgl. GB. Pat. 1, 109, 305).   Im Kern jodierte Substanzen der allgemeinen Formel (I) sind   z. B.   zur Herstellung von Röntgenkontrastmitteln verwendbar. 



   Die Möglichkeit des Einsatzes derartiger Derivate in der Humanmedizin wird durch die Erkenntnis gefördert, dass der Heteroring im Human-Test nicht aufgespalten wird   (Pestic. Sci. 12,   638,645 [1981]). 



   Durch die folgenden Beispiele soll die Erfindung näher erläutert, aber nicht auf diese beschränkt werden. Temperaturangaben beziehen sich jeweils auf Celsiusgrade. 



   Beispiel 1 : Zu einer bei   0'gerührten   Suspension von 10 g 2, 2-Dimethyl-4-hydroxy-1, 3- - benzodioxol und 22 g   NaHCOa   in 150 ml Tetrachlorkohlenstoff tropft man langsam 19, 24 g Brom. 



  Die erfolgte Umsetzung ist am Dünnschicht-Chromatogramm (Schicht : Kieselgel 60 F 254, Laufmittel : Chloroform/Methanol = 9 : 1) zu erkennen. Nach Filtration der Mischung wird das Filtrat am Rotationsverdampfer eingedampft. Der Rückstand kristallisiert beim Stehen und ist aus Petroläther umzukristallisieren. Das erhaltene   2, 2-Dimethyl-4-hydroxy -5, 7 -dibrom -1, 3-benzodioxol   schmilzt bei 59 bis   61 .   



   Das Natriumsalz dieser Verbindung wird erhalten, wenn man eine methanolische Lösung mit einem Äquivalent einer 30%igen Lösung von Natrium-methylat in Methanol versetzt, die Mischung eindampft und den festen Rückstand mit Isopropyläther behandelt. Das getrocknete Natriumsalz schmilzt bis   3200 nicht,   sondern färbt sich nur braun. 



   Beispiel 2 : Eine   auf-5 C   gekühlte Lösung von 30 g 2, 2-Dimethyl-4-hydroxy-1, 3-benzodioxol in 600 ml Chloroform wird unter Rühren tropfenweise mit 14, 8 ml einer 65%igen Salpetersäure   (D   : 1, 40) versetzt, wobei die Temperatur bis auf-2  ansteigt. Am Dünnschicht-Chromatogramm (Schicht : Kieselgel 60 F 254, Laufmittel : Chloroform/Methanol = 9 : 1) sind dann zwei neue Produkte zu erkennen, wovon eines oberhalb (5-Nitro-Derivat) und eines knapp unterhalb (7-Nitro- - Derivat) vom Ausgangsprodukt erscheint. Man lässt bei   10  ausreagieren   und schüttelt dann dreimal mit Wasser aus, wobei beginnende Kristallisation festzustellen ist. Beim Einengen der mit Aktivkohle und Celite erwärmten und filtrierten Lösung kristallisiert das schwerer lösliche 2, 2-Dimethyl-4-hydroxy-7-nitro-1, 3-benzodioxol aus.

   Dieses schmilzt nach dem Umkristallisieren aus CHCl, bei 193 bis   1950.   



   Zur Gewinnung des 5-Nitro-Derivates wird die   CHC1,-Mutterlauge   zur Trockne eingedampft und der Rückstand in Isopropanol aufgenommen. Beim Stehen der Lösung in der Kälte kristallisiert das   2, 2-Dimethyl-4-hydroxy-5-nitro-1, 3-benzodioxol   aus, das bei 150 bis   1510 schmilzt.   



   Die Stellung der Nitrogruppen ergibt sich aus den NMR-Spektren der beiden Isomeren : Während die OH-Gruppe des 5-Nitro-Derivates in   CDCl   bei 250 MHz ein Signal bei 10, 42 ppm zeigt, ergibt die OH-Gruppe der 7-Nitro-Verbindung unter gleichen Bedingungen eine gleitende Resonanz zwischen 4, 6 und 6, 2 ppm. 



   Beide Isomeren liefern beim Erhitzen in wässeriger Lösung infolge Hydrolyse des Dioxolanringes das bekannte 4-Nitro-pyrogallol,   Fp. :   165 bis   166    (Literatur   : Fp. 162O).   



   Beispiel 3 : Eine Lösung von 5 g des gemäss Beispiel 1 erhältlichen Natriumsalzes von   2, 2-Dimethyl-4-hydroxy-5, 7-dibrom-1, 3-benzodioxol   in 100 ml Chloroform wird bei 0 bis   5  tropfen-   weise mit 2, 4 ml konz. HNO, versetzt. Dabei fällt zunächst ein Niederschlag aus, der sich dann weitgehend wieder auflöst. Die organgerote Mischung wird mehrmals mit Wasser ausgeschüttelt, die Chloroform-Phase mit   Na. SO.   getrocknet, nach Verrühren mit Aktivkohle filtriert und im Vakuum eingedampft. Das zurückbleibende Öl kristallisiert beim Verrühren mit Wasser. Nach dem 
 EMI2.1 
    2-Dimethyl-4-hydroxy-5-nitro-7-- brom-1, 3-benzodioxol   als gelbes Pulver mit einem Fp. 93 bis 95 . 



   Die Abspaltung von Bromid während der Umsetzung ist durch Reaktion mit ARNO, nachzuweisen. Die Stellung der NO. -Gruppe ergibt sich aus den NMR-Spektrum   (CDC1,,   250 MHz), weil die benachbarte OH-Gruppe ein Signal bei 10, 27 ppm zeigt (vgl. Beispiel 2). 



   Beispiel 4 : Zu einer bei 00 gerührten Mischung von 3 g des gemäss Beispiel 2 erhältlichen   2, 2-Dimethyl-4-hydroxy-7-nitro-1, 3-benzodioxols,   7 g   NaHCO,   und 200 ml   CC1   tropft man eine Lösung von 4 g Brom in 20 ml   Cri..   Nach dem Erwärmen auf Raumtemperatur lässt man das Gemisch über Nacht stehen. Am Dünnschicht-Chromatogramm ist dann völlige Umsetzung festzustellen. Nach Filtration von anorganischem Material wird das Filtrat im Vakuum eingedampft und der kristalline 

 <Desc/Clms Page number 3> 

 Rückstand aus wenig Chloroform umkristallisiert. Das erhaltene   2, 2-Dimethyl-4-hydroxy-5-brom-     - 7-nitro-1, 3-benzodioxol   schmilzt bei 185 bis   188 ,   nachdem es bei 1550 eine Kristallumwandlung zeigt. 



   Beim Erhitzen einer wässerigen Lösung dieser Verbindung bildet sich infolge Hydrolyse des Dioxolanringes das gleiche 4-Brom-6-nitro-pyrogallol (Fp. 133 bis   135 ),   das auch durch Hydrolyse gemäss Beispiel 3 erhältlichen Isomeren entsteht. 



   Beispiel 5 : Eine Lösung von 10 g 2, 2-Dimethyl-4-hydroxy-1, 3-benzodioxol in 100 ml Chloroform wird unter Rühren bei 12 bis 140 tropfenweise mit 10 ml   65%iger HNO.   versetzt, nach 15 min bei gleicher Temperatur mit weiteren 48 ml   65%iger HNO..   Am Dünnschicht-Chromatogramm (vgl. Beispiel 2) ist ersichtlich, dass die zunächst gebildeten mono-nitrierten Produkte in eines übergehen, das noch unterhalb des 7-Nitro-Derivats erscheint. Man schüttelt die Chloroform-Lösung nach weiteren 15 min Reaktionsdauer dreimal mit Wasser aus, trocknet über   NA, SO"   und dampft das Filtrat im Vakuum ein. Der Rückstand kristallisiert beim Anreiben mit Isopropanol. Aus Äthanol umkristallisiert, schmilzt das erhaltene 2, 2-Dimethyl-4-hydroxy-5,7-dinitro-1, 3-benzodioxol bei 203 bis 2050. 



   Beispiel   6 : Eine   Lösung von 10 g 2, 2-Dimethyl-4-hydroxy-1, 3-benzodioxol in 200 ml   CCI,   wird mit 20 g eines pulverisierten Kationenaustauschers   (mit -COONa   als aktive Gruppen) versetzt und dazu unter Rühren bei Raumtemperatur eine Lösung von 5, 4 ml Sulfurylchlorid in 20 ml CCl getropft. Nach 3 h tropft man noch eine Lösung von 2, 7 ml   SO. Cl.   in 10 ml   CCl,   zu. Nach weiteren 3 h Rühren zeigt das Dünnschicht-Chromatogramm (vgl. Beispiel   1)   nahezu vollständige Umsetzung an. Die vom Ionenaustauscher abgesaugte Lösung wird mit Wasser gewaschen, über 
 EMI3.1 
 vom Fp. 81 bis   830.   



   Die Stellung des Chloratoms ergibt sich daraus, dass die beiden aromatischen Protonen im NMR-Spektrum   (CDC1, 250   MHz) auch nach Bildung des Natrionphenolats in CD OD oder eines Komplexes mit einer Europium-Verbindung praktisch   keinen "shift"-Effekt   zeigen. 



   Beispiel 7 : Eine Lösung von 5 g 2, 2-Dimethyl-4-hydroxy-1, 3-benzodioxol in 100 ml   CCI,   wird mit einem Jodkristall und 10 g Natriumbicarbonat versetzt und auf   0'gekühlt,   Dazu tropft man unter Rühren bei 0 bis   30 eine   Lösung von 8, 5 g Chlor in 80   CC1,..   Sobald am Dünnschicht-Chromatogramm (vgl. Beispiel   1)   kein Ausgangsprodukt mehr erscheint, entfernt man überschüssiges Chlor durch Einblasen von Stickstoff. Das Filtrat der Reaktionsmischung wird im Vakuum eingedampft und der Rückstand mit Petroläther verrührt, worauf Kristallisation einsetzt. Das Rohprodukt wird unter Verwendung von Aktivkohle aus Methanol/Wasser umgefällt.

   So erhält man ein farbloses Pulver von 2,2-Dimethyl-4-hydroxy-5,6,7-trichlor-1,3-benzodioxol, das bei 150 bis   152    schmilzt. 



   Im NMR-Spektrum dieser Verbindung erscheinen keine Signale von Kernprotonen. 



   Beispiel 8 : Zu einer Lösung von   8,   4   g 2, 2-Dimethyl-4-hydroxy-1, 3-benzodioxol   in 400 ml 0, 5 n NaOH tropft man unter Rühren bei Raumtemperatur eine Lösung von 25, 4 g Jod und 30 g Kaliumjodid in 150 ml Wasser. Nach dem Stehen über Nacht ist am Dünnschicht-Chromatogramm (Schicht : Kieselgel 60 F 254, Laufmittel : Äthylacetat/Methanol/2n   NU, OH   =   25 : 8 :   3) die Bildung eines neuen Produkts festzustellen. Die filtrierte Lösung wird bei 2 bis   5    mit gesättigter wässeriger   NaHSO-Lösung   bis PH 5 verührt, dann mit Chloroform ausgeschüttelt. Die mit   Na ; ; SO,   getrocknete und nach Zusatz von Aktivkohle filtrierte Chloroformlösung hinterlässt nach dem Eindampfen ein gelbes Öl.

   Nach dem Umfällen aus Methanol/Wasser oder Umkristallisieren aus Petrol- 
 EMI3.2 
 spiel 8) vollständige Umsetzung anzeigt, wird die Mischung filtriert und das Filtrat eingedampft. 



  Der Rückstand wird nach Filtration der Lösung mit Aktivkohle aus Methanol/Wasser umgefällt, dann aus Isopropyläther/Petroläther umkristallisiert. Man erhält so   2, 2-Dimethyl-4-hydroxy-5, 7-     - dichlor-1, 3-benzodioxol   vom Fp. 172 bis   174 .   



   Die drei kernchlorierten Derivate von Beispiel 6,7 und 9 lassen sich auch durch ihre 

 <Desc/Clms Page number 4> 

 Rf-Werte unterscheiden. Unter den Bedingungen des in Beispiel 8 beschriebenen Dünnschicht-Chromatogramms ergibt sich : 
 EMI4.1 
 
<tb> 
<tb> Derivat <SEP> : <SEP> Beispiel: <SEP> Rf-Wert:
<tb> 5-Chlor- <SEP> 6 <SEP> 0, <SEP> 82
<tb> 5, <SEP> 7-Dichlor- <SEP> 9 <SEP> 0, <SEP> 73
<tb> 5,6, <SEP> 7-Trichlor- <SEP> 7 <SEP> 0,67
<tb> 




   <Desc / Clms Page number 1>
 



   The invention relates to a process for the preparation of new benzodioxole derivatives of the general formula
 EMI1.1
 wherein R, and Hz may be the same or different and denote hydrogen, lower alkyl or phenyl, X, Y and Z cannot be the same only for the meaning of hydrogen and besides hydrogen also denote halogen or nitro, and their salts with bases, with the proviso that in the event that R ,, R, X and Z are hydrogen, the Y cannot be a NO 2 group, and their salts with bases, which is characterized in that 4-hydroxy-1, 3 -benzodioxoles of the general formula
 EMI1.2
 where R, and R have the above meaning,

   preferably treated in an inert solvent or solvent mixture in a one- or two-stage reaction with halogenating and / or nitrating agents, optionally also using acid-binding additives and / or catalysts, and optionally converting a compound obtained into a salt.



   The new compounds of the general formula (I) obtainable by the process according to the invention are on the one hand valuable raw materials for the production of agrochemicals or are themselves such, on the other hand they can serve - after hydrolytic splitting of the dioxolane ring - to obtain otherwise difficult to access core-substituted pyrogallol derivatives . They can be used in the manufacture of drugs, X-ray contrast media and photosensitizers.



   The starting products of the general formula (II) are either known or can be according to
 EMI1.3
 192700c [1976]; 86, 51598j [1977]).



   Although the importance of a core substitution with halogen or nitro groups in the field of agrochemicals is known (cf. "Active ingredients in crop protection and pesticides", 1st edition 1982, Industrial Association of Plant Protection eV), and nuclear halogenated secondary products
 EMI1.4
 mel (I), apart from a product obtained by nitration of myristicinaldehyde (J. Chem. Soc. 95, 1161 [1909]), has not previously been found in the specialist literature.



   According to the process according to the invention, a 4-hydroxy-1,3-benzodioxole can either only be halogenated or nitrided or first halogenated and then nitrided or first nitrided and then halogenated. An initially introduced core substituent can also be replaced by another in the subsequent stage. The agents used for halogenation or nitration are those which are known per se for reaction with aromatic hydrocarbons or phenols.



   Nuclear-substituted pyrogallol derivatives of the general formula (I) can also serve as intermediates for the synthesis of pharmacologically active compounds (cf. AT-Pat. Note A 1888/82)

 <Desc / Clms Page number 2>

 or to obtain photosensitizers (cf. GB Pat. 1, 109, 305). Essentially iodinated substances of the general formula (I) are e.g. B. usable for the production of X-ray contrast media.



   The possibility of using such derivatives in human medicine is promoted by the knowledge that the heteroring is not split in the human test (Pestic. Sci. 12, 638,645 [1981]).



   The following examples are intended to explain the invention in more detail, but not to limit it. Temperatures refer to degrees Celsius.



   Example 1: 19.24 g of bromine are slowly added dropwise to a suspension of 10 g of 2,2-dimethyl-4-hydroxy-1,3-benzodioxole and 22 g of NaHCOa in 150 ml of carbon tetrachloride, stirred at 0 '.



  The reaction can be seen from the thin-layer chromatogram (layer: silica gel 60 F 254, eluent: chloroform / methanol = 9: 1). After filtering the mixture, the filtrate is evaporated on a rotary evaporator. The residue crystallizes on standing and is to be recrystallized from petroleum ether. The 2, 2-dimethyl-4-hydroxy -5, 7-dibromo -1, 3-benzodioxole obtained melts at 59 to 61.



   The sodium salt of this compound is obtained by adding an equivalent of a 30% solution of sodium methylate in methanol to a methanolic solution, evaporating the mixture and treating the solid residue with isopropyl ether. The dried sodium salt does not melt until 3200, but only turns brown.



   Example 2: A solution of 30 g of 2,2-dimethyl-4-hydroxy-1,3-benzodioxole in 600 ml of chloroform, cooled to -5 ° C., is added dropwise with 14.8 ml of a 65% nitric acid (D: 1 , 40), the temperature rising to -2. The thin-layer chromatogram (layer: silica gel 60 F 254, eluent: chloroform / methanol = 9: 1) shows two new products, one above (5-nitro derivative) and one just below (7-nitro- Derivative) from the starting product appears. Allow to react at 10 and then shake out three times with water, with the beginning of crystallization being ascertained. When the solution heated and filtered with activated carbon and Celite is concentrated, the less soluble 2, 2-dimethyl-4-hydroxy-7-nitro-1, 3-benzodioxole crystallizes out.

   This melts after recrystallization from CHCl, at 193 to 1950.



   To obtain the 5-nitro derivative, the CHC1 mother liquor is evaporated to dryness and the residue is taken up in isopropanol. When the solution is left in the cold, the 2, 2-dimethyl-4-hydroxy-5-nitro-1, 3-benzodioxole crystallizes, which melts at 150 to 1510.



   The position of the nitro groups results from the NMR spectra of the two isomers: While the OH group of the 5-nitro derivative in CDCl at 250 MHz shows a signal at 10.42 ppm, the OH group of the 7-nitro Connection under the same conditions a sliding resonance between 4, 6 and 6, 2 ppm.



   When heated in aqueous solution as a result of hydrolysis of the dioxolane ring, both isomers give the known 4-nitro-pyrogallol, mp: 165 to 166 (literature: mp 162O).



   Example 3: A solution of 5 g of the sodium salt of 2,2-dimethyl-4-hydroxy-5,7-dibromo-1,3-benzodioxole obtainable according to Example 1 in 100 ml chloroform is added dropwise with 0 to 5 with 2 , 4 ml conc. ENT, offset. Precipitation initially occurs, which then largely dissolves again. The orange-red mixture is shaken out several times with water, the chloroform phase with Na. SO. dried, filtered after stirring with activated carbon and evaporated in vacuo. The remaining oil crystallizes when mixed with water. After this
 EMI2.1
    2-Dimethyl-4-hydroxy-5-nitro-7-- bromo-1, 3-benzodioxole as a yellow powder with an mp. 93 to 95.



   The elimination of bromide during the reaction can be demonstrated by reaction with ARNO. The position of the NO. Group results from the NMR spectrum (CDC1 ,, 250 MHz) because the neighboring OH group shows a signal at 10, 27 ppm (cf. Example 2).



   Example 4: A solution of is added dropwise to a mixture of 3 g of the 2, 2-dimethyl-4-hydroxy-7-nitro-1, 3-benzodioxole, 7 g of NaHCO, which is obtainable according to Example 2, and 200 ml of CC1 4 g of bromine in 20 ml of cri. After warming to room temperature, the mixture is left to stand overnight. Complete conversion can then be determined on the thin-layer chromatogram. After filtration of inorganic material, the filtrate is evaporated in vacuo and the crystalline

 <Desc / Clms Page number 3>

 Crystallized residue from a little chloroform. The 2, 2-dimethyl-4-hydroxy-5-bromo-7-nitro-1, 3-benzodioxole obtained melts at 185 to 188 after it shows a crystal transformation at 1550.



   When an aqueous solution of this compound is heated, hydrolysis of the dioxolane ring forms the same 4-bromo-6-nitro-pyrogallol (mp. 133 to 135), which is also obtained by hydrolysis according to Example 3.



   Example 5: A solution of 10 g of 2,2-dimethyl-4-hydroxy-1,3-benzodioxole in 100 ml of chloroform is added dropwise with 10 ml of 65% HNO at 12 to 140. added, after 15 min at the same temperature with a further 48 ml of 65% ENT. The thin-layer chromatogram (see Example 2) shows that the initially formed mono-nitrided products pass into one that is still below the 7-nitro -Derivats appears. After a further 15 min reaction time, the chloroform solution is shaken out three times with water, dried over NA, SO "and the filtrate is evaporated in vacuo. The residue crystallizes on trituration with isopropanol. Recrystallized from ethanol, the 2,2-dimethyl obtained melts -4-hydroxy-5,7-dinitro-1,3-benzodioxole at 203 to 2050.



   Example 6: A solution of 10 g of 2, 2-dimethyl-4-hydroxy-1, 3-benzodioxole in 200 ml of CCI is mixed with 20 g of a powdered cation exchanger (with -COONa as active groups) and with stirring at room temperature a solution of 5.4 ml of sulfuryl chloride in 20 ml of CCl was added dropwise. After 3 h, a solution of 2.7 ml of SO is added dropwise. Cl. in 10 ml CCl, too. After stirring for a further 3 h, the thin-layer chromatogram (see Example 1) shows almost complete conversion. The solution extracted by the ion exchanger is washed with water, over
 EMI3.1
 from mp. 81 to 830.



   The position of the chlorine atom results from the fact that the two aromatic protons in the NMR spectrum (CDC1, 250 MHz) show practically no "shift" effect even after formation of the sodium phenolate in CD OD or a complex with a europium compound.



   Example 7: A solution of 5 g of 2, 2-dimethyl-4-hydroxy-1, 3-benzodioxole in 100 ml of CCI is mixed with an iodine crystal and 10 g of sodium bicarbonate and cooled to 0 '. The solution is added dropwise with stirring at 0 to 30 a solution of 8.5 g of chlorine in 80 CC1, .. As soon as the starting product no longer appears on the thin-layer chromatogram (cf. Example 1), excess chlorine is removed by blowing in nitrogen. The filtrate of the reaction mixture is evaporated in vacuo and the residue is stirred with petroleum ether, whereupon crystallization begins. The crude product is reprecipitated from methanol / water using activated carbon.

   This gives a colorless powder of 2,2-dimethyl-4-hydroxy-5,6,7-trichloro-1,3-benzodioxole, which melts at 150 to 152.



   No signals of nuclear protons appear in the NMR spectrum of this compound.



   Example 8: A solution of 25.4 g of iodine and 30 is added dropwise to a solution of 8.4 g of 2,2-dimethyl-4-hydroxy-1,3-benzodioxole in 400 ml of 0.5N NaOH with stirring at room temperature g of potassium iodide in 150 ml of water. After standing overnight, the formation of a new product can be determined on the thin-layer chromatogram (layer: silica gel 60 F 254, eluent: ethyl acetate / methanol / 2n NU, OH = 25: 8: 3). The filtered solution is stirred at 2 to 5 with saturated aqueous NaHSO solution to pH 5, then shaken out with chloroform. The one with Na; ; SO, dried and filtered after the addition of activated carbon chloroform solution leaves a yellow oil after evaporation.

   After reprecipitation from methanol / water or recrystallization from petroleum
 EMI3.2
 game 8) indicates complete reaction, the mixture is filtered and the filtrate evaporated.



  After filtration of the solution with activated carbon, the residue is reprecipitated from methanol / water and then recrystallized from isopropyl ether / petroleum ether. This gives 2, 2-dimethyl-4-hydroxy-5, 7- - dichloro-1, 3-benzodioxole, mp. 172 to 174.



   The three core chlorinated derivatives of Examples 6, 7 and 9 can also be identified by their

 <Desc / Clms Page number 4>

 Differentiate RF values. Under the conditions of the thin-layer chromatogram described in Example 8, the following results:
 EMI4.1
 
<tb>
<tb> Derivative <SEP>: <SEP> Example: <SEP> Rf value:
<tb> 5-chlorine- <SEP> 6 <SEP> 0, <SEP> 82
<tb> 5, <SEP> 7-dichloro- <SEP> 9 <SEP> 0, <SEP> 73
<tb> 5.6, <SEP> 7-trichloro- <SEP> 7 <SEP> 0.67
<tb>

Claims (1)

PATENTANSPRUCH : Verfahren zur Herstellung von neuen 1, 3-Benzodioxol-Derivaten der allgemeinen Formel EMI4.2 worin R, und R ;, gleich oder verschieden sein können und Wasserstoff, niederes Alkyl oder Phenyl bedeuten, X, Y und Z nur für die Bedeutung von Wasserstoff nicht gleich sein können und ausser Wasserstoff auch Halogen oder Nitro bedeuten, sowie deren Salzen mit Basen, mit der Massgabe, EMI4.3 allgemeinen Formel EMI4.4 worin R, und R die obige Bedeutung haben, vorzugsweise in einem inerten Lösungsmittel oder Lösungsmittelgemisch in ein- oder zweistufiger Reaktion mit halogenierend und/oder nitrierend wirkenden Agentien behandelt, wobei gegebenenfalls auch säurebindende Zusätze und/oder Katalysatoren verwendet werden, PATENT CLAIM: Process for the preparation of new 1,3-benzodioxole derivatives of the general formula  EMI4.2  wherein R, and R;, may be the same or different and denote hydrogen, lower alkyl or phenyl, X, Y and Z cannot be the same only for the meaning of hydrogen and, apart from hydrogen, also denote halogen or nitro, and their salts with bases with the proviso  EMI4.3  general formula  EMI4.4  wherein R and R have the meaning given above, preferably treated in an inert solvent or solvent mixture in a one- or two-stage reaction with halogenating and / or nitrating agents, acid-binding additives and / or catalysts also optionally being used, und gegebenenfalls eine erhaltene Verbindung mit einer Base in ein Salz überführt.  and optionally converting a compound obtained with a base into a salt.
AT467182A 1982-05-13 1982-12-23 METHOD FOR PRODUCING NEW 1,3-BENZODIOXOL DERIVATIVES AND THEIR SALTS AT375360B (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AT467182A AT375360B (en) 1982-12-23 1982-12-23 METHOD FOR PRODUCING NEW 1,3-BENZODIOXOL DERIVATIVES AND THEIR SALTS
EP83890068A EP0095454A3 (en) 1982-05-13 1983-05-02 Nuclens-substituted pyrogallol derivatives
CA000427476A CA1233181A (en) 1982-05-13 1983-05-04 Ring-substituted derivatives of pyrogallol
AU14409/83A AU566107B2 (en) 1982-05-13 1983-05-10 Ring-substituted derivatives of pyrogallol
NO831680A NO831680L (en) 1982-05-13 1983-05-11 PYROGALL-DERIVATIVES.
DK210483A DK210483A (en) 1982-05-13 1983-05-11 PYROGALLOOL DERIVATIVES, THEIR USE AND THE PROCEDURES FOR PRODUCING THEREOF
JP58081827A JPS58206581A (en) 1982-05-13 1983-05-12 Novel ring-substituted derivative of pyrogallol

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA90A (en) * 1869-10-01 C.H. Waterous A set gauge for sawing machines
CA91A (en) * 1869-10-09 W. Baker A machine for moulding and carrying bricks
GB1220056A (en) * 1967-02-21 1971-01-20 Fisons Pest Control Ltd Substituted benzodioxoles
US3736338A (en) * 1967-02-21 1973-05-29 Fisons Ltd Benzodioxole derivatives useful as pesticides
US3948952A (en) * 1967-02-21 1976-04-06 Fisons Limited Benzodioxole derivatives useful as pesticides
DE2611042A1 (en) * 1975-03-18 1976-10-07 Hoffmann La Roche PHENYLCARBAMATE
US4067883A (en) * 1971-05-04 1978-01-10 Fisons Limited Process for preparing a 4-hydroxy-benzodioxol
DE2816474A1 (en) * 1978-04-15 1979-10-25 Bayer Ag DICHLORBENZODIOXOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS SYNERGIS IN INSECTICIDES AND ACARICIDES
US4183861A (en) * 1976-01-30 1980-01-15 Brichima S.P.A. Process for preparing aromatic methylene-dioxy compounds

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA90A (en) * 1869-10-01 C.H. Waterous A set gauge for sawing machines
CA91A (en) * 1869-10-09 W. Baker A machine for moulding and carrying bricks
GB1220056A (en) * 1967-02-21 1971-01-20 Fisons Pest Control Ltd Substituted benzodioxoles
US3736338A (en) * 1967-02-21 1973-05-29 Fisons Ltd Benzodioxole derivatives useful as pesticides
US3948952A (en) * 1967-02-21 1976-04-06 Fisons Limited Benzodioxole derivatives useful as pesticides
US4067883A (en) * 1971-05-04 1978-01-10 Fisons Limited Process for preparing a 4-hydroxy-benzodioxol
DE2611042A1 (en) * 1975-03-18 1976-10-07 Hoffmann La Roche PHENYLCARBAMATE
US4183861A (en) * 1976-01-30 1980-01-15 Brichima S.P.A. Process for preparing aromatic methylene-dioxy compounds
DE2816474A1 (en) * 1978-04-15 1979-10-25 Bayer Ag DICHLORBENZODIOXOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS SYNERGIS IN INSECTICIDES AND ACARICIDES

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