CH365064A - Process for the production of quaternary ammonium compounds - Google Patents

Process for the production of quaternary ammonium compounds

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Publication number
CH365064A
CH365064A CH3987256A CH3987256A CH365064A CH 365064 A CH365064 A CH 365064A CH 3987256 A CH3987256 A CH 3987256A CH 3987256 A CH3987256 A CH 3987256A CH 365064 A CH365064 A CH 365064A
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Switzerland
Prior art keywords
radical
methyl
formula
dihydro
radicals
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CH3987256A
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German (de)
Inventor
Kralt Teunis
Jan Van Dijk
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Philips Nv
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Publication of CH365064A publication Critical patent/CH365064A/en

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    • 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
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
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    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
    • C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
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    • C07C211/16—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings
    • C07C211/17—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings containing only non-condensed rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C211/20—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
    • C07C211/21—Monoamines
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C211/25—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/18—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

  

  
 



  Verfahren zur Herstellung von quarternären Ammoniumverbindungen
Die Erfindung bezieht sich auf ein Verfahren zur Herstellung von quarternären Ammoniumverbindungen der Formel
EMI1.1     
 worin Q ein gesättigtes oder ungesättigtes, aliphatisches oder gemischt aliphatisch-alicyclisches Radikal bedeutet, dessen Kohlenstoffgerüst zwei Isoprenradikalen entspricht und R3 einer der Reste
EMI1.2     
 ist,   Rt,    R2 und R4 Alkylreste mit 1 bis 6 Kohlenstoffatomen oder Aralkylreste oder gemischt aliphatisch-alicyclische Reste sind und Z- ein anorganischer Säurerest, z. B. ein Halogen- oder HSO4-Ion bedeutet.



   Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man Amine der Formel
EMI1.3     
 mit einer Verbindung der Formel    R4-Z    III reagieren lässt. Von den erfindungsgemäss erhältlichen Verbindungen der Formel I sind namentlich diejenigen von Interesse, bei denen   Q-R,    ein   oder      S-    Jonyl- oder ein Pseudojonylrest ist, oder ein entsprechender   Hydrojonyl oder    Hydropseudojonylrest, z. B. ein   Dihydro-g-jonyl-    oder ein Tetrahydropseudojonylrest ist.



   Ausserdem kann insbesondere auf diejenigen Verbindungen der Formel I hingewiesen werden, bei denen   Rt    und R2 je ein Alkylradikal mit 1 bis 6 Kohlenstoffatomen, z. B. ein   Methyl-, Äthyl-,    Isoamyl- oder Hexylradikal und R4 ein gemischt aliphatisch-alicyclisches Radikal ist, vorzugsweise ein Dihydrojonylradikal oder ein Aralkylradikal, z. B. der   1-Methyl-2-phenyläthylrest.   



     R1, R2,    R4 können alle drei dieselbe Bedeutung haben, alle z. B. ein Alkylradikal mit 1 bis 6 Kohlenstoffatomen, wie Methyl oder   Methyl.   



   Z- ist vorzugsweise ein Halogenion, z. B. ein Jodion oder ein Bromion. Die Tertiäramine der Formel II haben eine spasmolytische Wirkung ausgeprägter muskulotroper Art. Die quarternären Ammoniumverbindungen der Formel I haben gegenüber Bariumchlorid als Spasmogen eine Wirkung, die etwas geringer ist als die der vorerwähnten Tertiäramine, sie weisen jedoch eine stärkere Wirkung gegenüber   Äthylcholin    als Spasmogen auf, so dass die erfindungsgemäss erhältlichen Verbindungen auch eine spasmolytische Wirkung neurotroper Art haben.



   Geeignete Tertiäramine der Formel II kann man beispielsweise dadurch herstellen, dass ein Primäramin der Formel   QR3-NH2    in Anwesenheit einer Lauge, z. B. Natronlauge oder Kalilauge oder Kalkwasser, und eines Lösungsmittels, z. B. eines aliphatischen Alkohols, mit einer solchen Menge eines Halogenierungsmittels der Formel   R, Z    zur Reaktion gebracht wird, wobei zwei gleiche Alkylradikale an dem Stickstoffatom gebunden werden. Man kann auch zunächst ein Wasserstoffatom des Primär  amins durch ein Alkylradikal ersetzen und durch Anwendung eines zweiten Alkylierungsmittels das entstandene Sekundäramin in ein Tertiäramin mit zwei unterschiedlichen Alkylresten umwandeln.



   Man kann zur Herstellung der Ausgangsstoffe der Formel II auch von Sekundäraminen ausgehen.



   Die Alkylierungsreaktion zur Herstellung der genannten Ausgangsstoffe kann in Anwesenheit eines Lösungsmittels für die beiden Reaktionskomponenten durchgeführt werden. Als solche kommen z. B. in Betracht: niedrige aliphatische Alkohole, z. B.



  Methanol, Äthanol, Propanol, Isopropanol oder Butanol. Die Reaktion kann jedoch auch sehr gut ohne Lösungsmittel durchgeführt werden.



   Bei dieser Alkylierungsreaktion werden ein oder zwei Säuremoleküle frei, je nachdem man aus Primäraminen unmittelbar Tertiäramine der Formel II oder zunächst Sekundäramine herstellt. Zum Erzielen einer möglichst hohen Ausbeute des Tertiäramins ist es empfehlenswert, die freigewordene Säuremenge mit einer gleichen Menge Lauge, z. B. mit Natron- oder Kalilauge, zu binden. Das letztere Reaktionsmittel kann sowohl vor als auch während der Alkylierungsreaktion zugesetzt werden. Soll z. B. aus Dihydro-a-jonylamin das entsprechende   N,N-Di-    methyl-tertiäramin hergestellt werden, ohne Isolierung des entsprechenden N-Methylsekundäramins, so kann man unmittelbar beim Anfang der Reaktion zwei Äquivalente Natron- oder Kalilauge zusetzen.



  Grössere Mengen können naturgemäss auch verwendet werden, aber dies ist nicht erforderlich. Man kann jedoch auch das Alkylierungsmittel dem Dihydro-a-jonylamin zusetzen, gegebenenfalls in Anwesenheit eines Lösungsmittels; die erzeugte Säure kann abgeführt werden, nachdem etwa ein   Squiva-    lent derselben gebildet worden ist.



   Zweckmässig erfolgt die erfindungsgemässe   Re    aktion nicht in Anwesenheit von Lauge, da bei der Bildung von quarternären Ammoniumsalzen keine Säure gebildet wird. Diese Quaternisierung kann sowohl durch Anwendung eines Lösungsmittels als auch durch unmittelbare Mischung der Reaktionsbestandteile stattfinden. In Anwesenheit eines Lösungsmittels kann es empfehlenswert sein, das Reaktionsgemisch während einiger Zeit bei Zimmertemperatur aufzubewahren, z. B. während einer Stunde, worauf es gekocht wird. Wenn die Reaktion ohne Anwendung eines Lösungsmittels durchgeführt wird, kann es erwünscht sein, die Reaktion bei erhöhter Temperatur stattfinden zu lassen, z. B. indem die Reaktionsbestandteile an einem Rückflusskühler gekocht werden.



   Geeignete Quaternisierungsmittel der Formel III sind: Halogenide, Chloride, Bromide, Jodide, z. B.



  Benzylchlorid, Methyljodid oder -bromid,   Methyljodid    oder -bromid, 3-Methylbutyljodid oder -bromid,   l-Jod(oder      Brom)- 1 -methyl-2-phenyläthan    oder Di  hydro-fl-jonyljodid      oder -bromid.    Man kann auch HSO4-ionen abgebende Mittel verwenden, z. B. Dialkylsulfate, wie Dimethyl- oder Diäthylsulfat.



   Zweckmässig werden die aus Primär- oder Sekundäraminen durch Alkylierung erhaltenen Ausgangsstoffe der Formel II zunächst gereinigt, z. B. indem die etwa im Reaktionsgemisch noch vorhandene Lauge entfernt wird oder indem der Überschuss an Alkylierungsmittel oder an Lösungsmittel abdestilliert wird.



   Beispiel I    N,N,N-Triäthyl-N-(dihydro-fl-jonyl)-    ammoniumjodid
Einer Lösung von 1,25 g N,N-Diäthyl-dihydro  fl-jonylamin    (0,005 Mol) in 10 ml absolutem Alkohol wurde 2,4   g Äthyljodid    (0,015 Mol) zugesetzt.



  Diese Lösung wurde dann während 14 Stunden an einem Rückflusskühler gekocht und nach Abkühlung mit 250 ml absolutem Äther verdünnt. Der entstandene Niederschlag wurde abgesaugt und in Vakuo getrocknet. Ausbeute 1,25 g, Schmelzpunkt (nach Umkristallisierung aus Wasser) 133 bis   13 4o C    Analyse: gefunden:   9,380/o    H   54, 05 /o    C 32,880/0 J berechnet:   9,340/o    H   56,020/o    C   31, 20X/o.      T   
Beispiel II    N,N-Dimethyl-N,N-bis-(dihydro-fl-jonyl)-    ammoniumjodid
Einer Lösung von 4,1 g   bis-(Dihydro-ssjonyl)-    amin (0,011 Mol) in 15 ml Methanol wurde 1,8 g Methyljodid (0,013 Mol) zugesetzt.

   Nachdem diese Lösung während 24 Stunden bei Zimmertemperatur aufbewahrt worden war, wurden in der angegebenen Reihenfolge zugesetzt: 2,0 ml 6,3n Natronlauge, 50 ml Methanol und 2,3 g Methyljodid, und das Reaktionsgemisch wurde während zwei Stunden an einem Rückflusskühler gekocht. Darauf wurde wieder 2,3 g Methyljodid zugesetzt und wieder während zwei Stunden gekocht. Dann wurde das Lösungsmittel und das Übermass an Methyljodid in Vakuo verdampft, und das Residuum wurde durch Erwärmung in 10 ml Aceton gelöst. Das nach Abkühlung auskristallisierende Produkt wurde abfiltriert, und aus dem Filtrat wurde noch ein zweites Kristallisat gewonnen. Die beiden Kristallisate wurden aus Wasser umkristallisiert. Ausbeute 1,0 g   (17 0/o),    Schmelzpunkt   194-195"    C.



  Analyse: gefunden:    10,060/o    H   62,990/o    C 2,640/0 N   24, 1apo    J berechnet:    9,8401o    H   63,700/o    C   2,650/o    N   24,001o    J
Beispiel III   
N-Sithyl-N-methyl-N-phenylisopropyl-N-(dihydro-
XB-jonyl)-ammoniumjodid   
Ein Gemisch aus 1,5 g   N-Athyl-N-phenylisopro-      pyl-N-(dihydro-ss-jonyl)-amin    und 11 g Methyljodid wurde während drei Stunden an einem Rückflusskühler gekocht und dann mit 50 ml Petroleumäther ver  dünnt. Das so niedergeschlagene Öl wurde von vorerwähnter Flüssigkeit durch Ab schütten getrennt, worauf es dreimal mit 20 ml Petroleumäther gewaschen wurde.

   Die ganze Menge Lösungsmittel wurde dann aus dem niedergeschlagenen Öl entfernt durch Verdampfung in Vakuo, so dass das Produkt fest wurde. Ausbeute 1,8 g.



  Analyse: gefunden:    8,640/o    H   59, 98eo    C   3,07 O/o    N   26,9 O/o    J berechnet:    8,708/o    H   62,] 10/o    C   2, 90 /o    N   26,3 ovo    J
Beispiel IV    N,N,N-Trimethyl-N-tetrahydro-pseudojonyl    ammoniumjodid
Eine Lösung von 7 g N-Methyl-tetrahydropseudojonylamin (0,03 Mol) und 17 g Methyljodid in 50 ml absolutem Äthanol wurde während zwei Stunden an einem Rückflusskühler gekocht, worauf 1,7 g Kaliumhydroxyd und nochmals 50 ml absolutes Äthanol der Lösung zugesetzt wurden. Nachdem dieses Gemisch während anderthalb Stunden gekocht hatte, wurde das durch Abkühlung und Eindampfung auskristallisierte Kaliumjodid durch Filtrierung entfernt.



   Aus dem eingedampften Reaktionsgemisch wurde nach Entfernen des Kaliumjodids und Auflösen in 10 ml absolutem Äthanol durch Zusatz von 150 ml absolutem Äther die unreine quarternäre Verbindung niedergeschlagen. Diese wurde dadurch gereinigt, dass sie in Chloroform gelöst wurde, die Lösung wurde filtriert, und die reine Verbindung wurde mit Äther niedergeschlagen. Ausbeute 6 g. Schmelzpunkt   248-250     C.



  Analyse: gefunden:    9,51o    H   51, 81 /o    C   3,71/o    N   34,20/o    J berechnet:    9,260/o    H   52,310/o    C   3,810/o    N   34,60/o    J
Beispiel V   
N-Athyl-N-isoamyl-N-methyl-N-tetrahydropseudo-    jonyl-ammoniumjodid
Ein Gemisch aus 6 g   N-Äthyl-N-isoamyl-tetra-    hydropseudojonylamin (0,02 Mol) und 6 ml Methyljodid (0,1 Mol) wurde während anderthalb Stunden gekocht. Darauf wurde noch 6   ml    Methyljodid zugesetzt und wieder während anderthalb Stunden gekocht.



   Das Reaktionsgemisch wurde darauf fünfmal mit jeweils 25 ml Petroleumäther gewaschen, und dann wurde aus der verbleibenden, gewaschenen Quarternärverbindung das Lösungsmittel durch Verdampfen in Vakuo entfernt, so dass die Substanz fest wurde.



  Ausbeute quantitativ.



   Gefunden   28,9 O/o    J (berechnet 29,1   1 /o).   



   Beispiel VI    N,N,N-Trimethyl-N-(dihydro-fi-jonyl)-    ammoniumjodid
Ein Gemisch aus 2,2 g (0,01 Mol)   Dihydro-ss-    jonylamin, 2 ml (0,032 Mol) Methyljodid und 10 ml Methanol wurde während einer halben Stunde gekocht. Dem Reaktionsgemisch wurde dann 2 ml 6n Natronlauge zugesetzt. Diese Flüssigkeit wurde noch während einer Stunde gekocht. Die Lösung reagierte neutral. Nach Verdampfen des Methanols und des Überschusses an Methyljodid wurde das Residuum in 5 ml Aceton gelöst. Nach mehr als 12 Stunden wurde der Niederschlag abfiltriert und mit Aceton gewaschen. Aus dem Filtrat wurde ein neues Kristallisat gewonnen. Die Ausbeute betrug 2,7 g (700/0).



  Nach Umkristallisierung aus Aceton und dann aus Wasser war der Schmelzpunkt   221-225"    C.



   Gefunden   34,60/0    Jod (berechnet   34,8Q/o).   



   Beispiel VII   
N-Methyl-N-äthyl-N4so amyl-N-(dihydro--jonyl)-    ammoniumjodid
Ein Gemisch aus 0,8 g (0,0029 Mol) N-Methyl  N-isoamyl-dihydro-P-jonylamin,    1 ml (0,012 Mol) Äthyljodid und 3 ml Äthanol wurde während drei Stunden gekocht. Nach Abdampfen des Lösungsmittels und des Übermasses an Äthyljodid verblieb 1,25 g Ö1 (das heisst 1000/o des theoretischen Wertes), das sich nicht kristallisieren liess.



   Gefunden   30,0o    Jod (berechnet   29,20/o).   



   Beispiel VIII
N-Methyl-N-äthyl-N-phenylisopropyl-N-(tetra hydro-pseudojonyl)-ammoniumjodid
Ein Gemisch aus 1,75 g   N-Athyl-N-phenyliso-    propyl-tetrahydro-pseudojonylamin und 10 g Methyljodid wurde während drei Stunden gekocht. Darauf wurde der Lösung 50 ml Petroleumäther zugesetzt.



  Es entstand ein steifes Öl, das einige Male mit Petroleumäther gewaschen wurde. Schliesslich wurde das Lösungsmittel in Vakuo abgedampft. Die Ausbeute war quantitativ.



   Analyse: Jodgehalt   26,00/0    (berechnet   26,2 1/o).      



  
 



  Process for the production of quaternary ammonium compounds
The invention relates to a process for the preparation of quaternary ammonium compounds of the formula
EMI1.1
 where Q is a saturated or unsaturated, aliphatic or mixed aliphatic-alicyclic radical, the carbon structure of which corresponds to two isoprene radicals and R3 is one of the radicals
EMI1.2
 is, Rt, R2 and R4 are alkyl radicals with 1 to 6 carbon atoms or aralkyl radicals or mixed aliphatic-alicyclic radicals and Z- is an inorganic acid radical, e.g. B. means a halogen or HSO4 ion.



   The inventive method is characterized in that amines of the formula
EMI1.3
 can react with a compound of the formula R4-Z III. Of the compounds of the formula I obtainable according to the invention, those of particular interest are those in which Q-R is a or S-ionyl or pseudojonyl radical, or a corresponding hydrojonyl or hydropseudojonyl radical, e.g. B. is a dihydro-g-ionyl or a tetrahydropseudojonyl radical.



   In addition, reference can be made in particular to those compounds of the formula I in which Rt and R2 each represent an alkyl radical having 1 to 6 carbon atoms, e.g. B. a methyl, ethyl, isoamyl or hexyl radical and R4 is a mixed aliphatic-alicyclic radical, preferably a dihydrojonyl radical or an aralkyl radical, e.g. B. the 1-methyl-2-phenylethyl radical.



     R1, R2, R4 can all three have the same meaning, all e.g. B. an alkyl radical having 1 to 6 carbon atoms, such as methyl or methyl.



   Z- is preferably a halogen ion, e.g. B. an iodine ion or a bromine ion. The tertiary amines of the formula II have a spasmolytic effect of a pronounced musculotropic nature. The quaternary ammonium compounds of the formula I have an effect on barium chloride as a spasmogen which is somewhat less than that of the tertiary amines mentioned above, but they have a stronger effect on ethylcholine as a spasmogen, see above that the compounds obtainable according to the invention also have a spasmolytic effect of a neurotropic type.



   Suitable tertiary amines of the formula II can be prepared, for example, by using a primary amine of the formula QR3-NH2 in the presence of an alkali, e.g. B. caustic soda or potassium hydroxide or lime water, and a solvent, e.g. B. an aliphatic alcohol, is reacted with such an amount of a halogenating agent of the formula R, Z, whereby two identical alkyl radicals are bonded to the nitrogen atom. You can also first replace a hydrogen atom of the primary amine with an alkyl radical and convert the resulting secondary amine into a tertiary amine with two different alkyl radicals by using a second alkylating agent.



   For the preparation of the starting materials of the formula II, it is also possible to start from secondary amines.



   The alkylation reaction for the preparation of the starting materials mentioned can be carried out in the presence of a solvent for the two reaction components. As such come z. B. considered: lower aliphatic alcohols, e.g. B.



  Methanol, ethanol, propanol, isopropanol or butanol. However, the reaction can also be carried out very well without a solvent.



   During this alkylation reaction, one or two acid molecules are released, depending on whether tertiary amines of the formula II or secondary amines are first prepared from primary amines. To achieve the highest possible yield of the tertiary amine, it is advisable to mix the amount of acid released with an equal amount of lye, e.g. B. with sodium or potassium hydroxide to bind. The latter reactant can be added both before and during the alkylation reaction. Should z. B. the corresponding N, N-dimethyl-tertiary amine can be prepared from dihydro-α-ionylamine without isolating the corresponding N-methyl secondary amine, two equivalents of sodium hydroxide or potassium hydroxide solution can be added immediately at the beginning of the reaction.



  Larger amounts can of course also be used, but this is not necessary. However, the alkylating agent can also be added to the dihydro-α-ionylamine, if appropriate in the presence of a solvent; the acid generated can be discharged after approximately one squivalent of the same has been formed.



   The reaction according to the invention does not expediently take place in the presence of alkali, since no acid is formed during the formation of quaternary ammonium salts. This quaternization can take place both by using a solvent and by directly mixing the reaction components. In the presence of a solvent, it may be advisable to keep the reaction mixture for some time at room temperature, e.g. B. during an hour, after which it is cooked. If the reaction is carried out without the use of a solvent, it may be desirable to allow the reaction to take place at an elevated temperature, e.g. B. by boiling the reaction ingredients on a reflux condenser.



   Suitable quaternizing agents of the formula III are: halides, chlorides, bromides, iodides, e.g. B.



  Benzyl chloride, methyl iodide or bromide, methyl iodide or bromide, 3-methylbutyl iodide or bromide, 1-iodine (or bromine) -1-methyl-2-phenylethane or dihydroflu-ionyl iodide or bromide. One can also use HSO4 ion releasing agents, e.g. B. dialkyl sulfates, such as dimethyl or diethyl sulfate.



   The starting materials of the formula II obtained from primary or secondary amines by alkylation are expediently first purified, e.g. B. by removing any alkali still present in the reaction mixture or by distilling off the excess of alkylating agent or solvent.



   Example I N, N, N-triethyl-N- (dihydro-fl-ionyl) ammonium iodide
2.4 g of ethyl iodide (0.015 mol) were added to a solution of 1.25 g of N, N-diethyl-dihydrofl-ionylamine (0.005 mol) in 10 ml of absolute alcohol.



  This solution was then boiled in a reflux condenser for 14 hours and, after cooling, diluted with 250 ml of absolute ether. The resulting precipitate was filtered off with suction and dried in vacuo. Yield 1.25 g, melting point (after recrystallization from water) 133 to 13 4o C Analysis: found: 9.380 / o H 54.05 / o C 32.880 / 0 J calculated: 9.340 / o H 56.020 / o C 31.20X / O. T
Example II N, N-Dimethyl-N, N-bis (dihydro-fl-ionyl) ammonium iodide
To a solution of 4.1 g of bis (dihydro-ssjonyl) amine (0.011 mol) in 15 ml of methanol was added 1.8 g of methyl iodide (0.013 mol).

   After this solution had been stored at room temperature for 24 hours, the following were added in the order given: 2.0 ml of 6.3N sodium hydroxide solution, 50 ml of methanol and 2.3 g of methyl iodide, and the reaction mixture was boiled on a reflux condenser for two hours. Then another 2.3 g of methyl iodide were added and the mixture was boiled again for two hours. Then the solvent and excess methyl iodide were evaporated in vacuo and the residue was dissolved in 10 ml of acetone by heating. The product which crystallized out after cooling was filtered off and a second crystallizate was obtained from the filtrate. The two crystals were recrystallized from water. Yield 1.0 g (17 0 / o), melting point 194-195 "C.



  Analysis: found: 10.060 / o H 62.990 / o C 2.640 / o N 24.1 apo J calculated: 9.8401o H 63.700 / o C 2.650 / o N 24.001o J
Example III
N-Sithyl-N-methyl-N-phenylisopropyl-N- (dihydro-
XB-jonyl) ammonium iodide
A mixture of 1.5 g of N-ethyl-N-phenylisopropyl-N- (dihydro-ss-jonyl) amine and 11 g of methyl iodide was boiled in a reflux condenser for three hours and then diluted with 50 ml of petroleum ether. The oil so precipitated was separated from the aforementioned liquid by pouring it off, whereupon it was washed three times with 20 ml of petroleum ether.

   All of the solvent was then removed from the precipitated oil by evaporation in vacuo so that the product solidified. Yield 1.8g.



  Analysis: found: 8.640 / o H 59.98eo C 3.07 O / o N 26.9 O / o J calculated: 8.708 / o H 62.1] 10 / o C 2.90 / o N 26.3 ovo J
Example IV N, N, N-Trimethyl-N-tetrahydro-pseudojonyl ammonium iodide
A solution of 7 g of N-methyl-tetrahydropseudojonylamine (0.03 mol) and 17 g of methyl iodide in 50 ml of absolute ethanol was boiled in a reflux condenser for two hours, whereupon 1.7 g of potassium hydroxide and another 50 ml of absolute ethanol were added to the solution . After this mixture had boiled for an hour and a half, the potassium iodide which had crystallized out by cooling and evaporation was removed by filtration.



   After removing the potassium iodide and dissolving it in 10 ml of absolute ethanol, the impure quaternary compound was precipitated from the evaporated reaction mixture by adding 150 ml of absolute ether. This was purified by dissolving it in chloroform, the solution was filtered, and the pure compound was precipitated with ether. Yield 6g. Melting point 248-250 C.



  Analysis: found: 9.51o H 51.81 / o C 3.71 / o N 34.20 / o J calculated: 9.260 / o H 52.310 / o C 3.810 / o N 34.60 / o J
Example V
N-ethyl-N-isoamyl-N-methyl-N-tetrahydropseudo-jonyl-ammonium iodide
A mixture of 6 g of N-ethyl-N-isoamyl-tetrahydropseudojonylamine (0.02 mol) and 6 ml of methyl iodide (0.1 mol) was boiled for one and a half hours. Then 6 ml of methyl iodide were added and the mixture was boiled again for an hour and a half.



   The reaction mixture was then washed five times with 25 ml of petroleum ether each time, and then the solvent was removed from the remaining, washed quaternary compound by evaporation in vacuo, so that the substance became solid.



  Quantitative yield.



   Found 28.9 O / o J (calculated 29.1 1 / o).



   Example VI N, N, N-Trimethyl-N- (dihydro-fi-ionyl) ammonium iodide
A mixture of 2.2 g (0.01 mol) of dihydro-ss-jonylamine, 2 ml (0.032 mol) of methyl iodide and 10 ml of methanol was boiled for half an hour. 2 ml of 6N sodium hydroxide solution were then added to the reaction mixture. This liquid was boiled for another hour. The solution reacted neutrally. After evaporation of the methanol and the excess of methyl iodide, the residue was dissolved in 5 ml of acetone. After more than 12 hours the precipitate was filtered off and washed with acetone. New crystals were obtained from the filtrate. The yield was 2.7 g (700/0).



  After recrystallization from acetone and then from water, the melting point was 221-225 "C.



   Found 34.60 / 0 iodine (calculated 34.8%).



   Example VII
N-methyl-N-ethyl-N4so amyl-N- (dihydro-ionyl) -ammonium iodide
A mixture of 0.8 g (0.0029 mol) of N-methyl N-isoamyl-dihydro-P-ionylamine, 1 ml (0.012 mol) of ethyl iodide and 3 ml of ethanol was boiled for three hours. After evaporation of the solvent and the excess of ethyl iodide, 1.25 g of oil remained (that is, 1000 / o of the theoretical value), which could not be crystallized.



   Found 30.0% iodine (calculated 29.20%).



   Example VIII
N-methyl-N-ethyl-N-phenylisopropyl-N- (tetra-hydro-pseudojonyl) -ammonium iodide
A mixture of 1.75 g of N-ethyl-N-phenylisopropyl-tetrahydropseudojonylamine and 10 g of methyl iodide was boiled for three hours. 50 ml of petroleum ether were then added to the solution.



  A stiff oil resulted which was washed several times with petroleum ether. Finally the solvent was evaporated in vacuo. The yield was quantitative.



   Analysis: iodine content 26.00 / 0 (calculated 26.2 1/0).

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung von quarternären Ammoniumverbindungen der Formel EMI3.1 in welcher Q ein gesättigtes oder ungesättigtes, aliphatisches oder gemischt aliphatisch-alicyclisches Radikal bedeutet, dessen Kohlenstoffgerüst zwei Isoprenradikalen entspricht und R einer der Reste EMI4.1 darstellt, R1, R2 und R4 Alkylradikale mit 1 bis 6 Kohlenstoff atomen oder Aralkykadikale oder gemischt aliphatisch-alicyclische Radikale sind und Zein anorganischer Säurerest ist, dadurch gekennzeichnet, dass man ein Amin der Formel EMI4.2 mit einer Verbindung der Formel R4-Z III reagieren lässt. PATENT CLAIM Process for the preparation of quaternary ammonium compounds of the formula EMI3.1 in which Q is a saturated or unsaturated, aliphatic or mixed aliphatic-alicyclic radical, the carbon structure of which corresponds to two isoprene radicals and R is one of the radicals EMI4.1 represents, R1, R2 and R4 are alkyl radicals with 1 to 6 carbon atoms or aralkyl radicals or mixed aliphatic-alicyclic radicals and zein is an inorganic acid radical, characterized in that one is an amine of the formula EMI4.2 can react with a compound of the formula R4-Z III. UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass Q-R3- ein Dihydro-B-jonyl- oder ein Tetrahydropseudojonylrest ist, Rt und R2 gleiche Alkylradikale mit 1 bis 6 Kohlenstoffatomen bedeuten und R4 ein gemischt aliphatisch-alicyclischer Rest, z. B. ein Dihydro-fiionylrest oder ein Aralkylrest, z. B. der l-Methyl-2-phenyl-äthylrest, ist, welcher im aliphatischen Teil 1 bis 6 Kohlenstoffatome enthält. SUBCLAIMS 1. The method according to claim, characterized in that Q-R3- is a dihydro-B-ionyl or a tetrahydropseudojonyl radical, Rt and R2 are the same alkyl radicals with 1 to 6 carbon atoms and R4 is a mixed aliphatic-alicyclic radical, e.g. B. a dihydro-fiionyl radical or an aralkyl radical, e.g. B. the l-methyl-2-phenyl-ethyl radical, which contains 1 to 6 carbon atoms in the aliphatic part. 2. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass Q-R5 ein Dihydro-ssjonylrest, R, und R2 ein Methyl-, Äthyl- oder 3-Methyl-butylrest und R4 ein Dihydro-ssjonyl-oder ein l-Methyl2-phenyl-äthylrest ist. 2. The method according to claim, characterized in that Q-R5 is a dihydro-ssjonyl radical, R, and R2 is a methyl, ethyl or 3-methyl-butyl radical and R4 is a dihydro-ssjonyl or a 1-methyl2-phenyl-ethyl radical is. 3. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass R1, R2 und R4 Alkylradikale mit 1 bis 6 Kohlenstoffatomen sind, z. B. Methyl oder Äthyl. 3. The method according to claim, characterized in that R1, R2 and R4 are alkyl radicals with 1 to 6 carbon atoms, for. B. methyl or ethyl. 4. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass Z- ein Halogenion, vorzugsweise ein Jod- oder Bromion, bedeutet. 4. The method according to claim, characterized in that Z- is a halogen ion, preferably an iodine or bromine ion. 5. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass Z- ein HSO4-Ion ist. 5. The method according to claim, characterized in that Z- is an HSO4 ion. 6. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man ein Tertiäramin der Formel II bei Zimmertemperatur, in einem Alkohol gelöst, mit einem den Rest Z abgebenden Alkylierungsmittel reagieren lässt. 6. The method according to claim, characterized in that a tertiary amine of the formula II, dissolved in an alcohol, is allowed to react with an alkylating agent which releases the radical Z at room temperature.
CH3987256A 1955-11-24 1956-11-22 Process for the production of quaternary ammonium compounds CH365064A (en)

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