CH422758A - Process for the production of new quaternary ammonium compounds - Google Patents

Process for the production of new quaternary ammonium compounds

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Publication number
CH422758A
CH422758A CH270760A CH270760A CH422758A CH 422758 A CH422758 A CH 422758A CH 270760 A CH270760 A CH 270760A CH 270760 A CH270760 A CH 270760A CH 422758 A CH422758 A CH 422758A
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Switzerland
Prior art keywords
ethanol
radical
formula
methanol
isopropanol
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CH270760A
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German (de)
Inventor
Charles Copp Frederick
George Coker Geoffrey
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Wellcome Found
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Publication of CH422758A publication Critical patent/CH422758A/en

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    • 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
    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
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    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
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    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • 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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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/28—Halogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Textile Engineering (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Furan Compounds (AREA)

Description

  

  



  Verfahren zur Herstellung neuer quaternärer Ammoniumverbindungen    Pie Erfindung betrifft ein. Verfahren    zur Herstellung neuer   quaternärer    Ammoniumverbindungen der Formel
EMI1.1     
 worin R einen in   meta-oder para-Stellung mit einem      Halogenatom oder eine Alkyl-, Alikoxy-,    Hydroxy-,   Forrnyl-, Acetyl-, Alkoxycarbonyl-,    Amino-, Acetamido-, Cyan- oder Nitrogruppe substiierten Phenylrest ; L einen gegebenenfalls in der   ortho-,      m. eta- oder    Para-Stellung mit einem Halogenatiom doder einer    Avkyl-, Alkoxy-, Cyan-oder Nitrogruppe substituier-    ter Phenylrest oder r einen gegebenenfalls in   S-.

   Stellung    mit einem Halogenatom oder eine Nitrogruppe substtuierten Thienylrest; W da. s SauenstofEatom oder eine gerade, gesättigte Kette, die   1    bis 3 nicht   nebenein-    ander liegende   Sauersltoffatlome und 1    bis 16 Kohlen  stolfatame enthält    ;

   X   und Y,    die   gleich oder ver-      schied den sind. je eine Alikyl-,    die Allyl-, Propargyl  odereine/?-,-oder(5-Hydroxyalkylgru.ppeoder    XY auch zusammen verbunden   dieTetr, amethylen-,      Penta-    methylen oder 3-Oxa-pantzamethylengruppe; und Aein einwertiges Anion oder ein   normal-Aquivalent      ei, n, es anehrwentigen Antoms bedeuten,    wobei alle obgenannten Alkyl- bzw. Alkoxyreste höchstens 4 C Atome enthalten.



   Solche Verbindungen bekämpfen wirksam Nematoden, z. B. Syphacia obvelata, Aspiculuris tetraptera oder Trichureis muris in Mäusen,   Toxocara    cati in Katzen, Toxocara canis, Trischuris vulpis oder   Ancylo-    stoma canum in Hunden, Ascaridia galli in   Hühnern    oder töten   Ascaris. lufmtbricoides    bei Schweinen in vitro.



     Pas erfindungsgemässe Verfahren ist) dadurch    gekennzeichnet, dass man ein tertiäres Amin, welches drei der vier an das N-Atom der Formal I gebundenen Gruppen enthält, mit einem die noch fehlende vierte Gruppe enthaltenden Quaternisierungsmittel umsetzt oder dass man ein   tertiäres Amin cLer Formel   
EMI1.2     
 worin Q   die Tetramethylien-, Pentamethylen-oder    3-Oxa-pentsamethylengruppe und z, einen abspaltbaren, das Ion A- bildenden Rest bedeutet, durch   intramolekulareUmsetzungquatemisiert.   



   Die   Verbindungen der Fonmel 1    sind neu, mit   Ausnahmederjenigen,welchedieMgemden    Kationen aufweisen : N-5-(p-Chlor-phenoxy)-3-oxapently-N-p-chlorbenzyl   N,N-dimethylammonium,    N-Benzyl-N-5-(p-methyl-phenoxy)-3-oxapently
N, N-dimethylammonium,    N-'Banzyl-N,N-diäthyl-N-2-(m-methoxy-p'henoxy)-     äthylammonium und   N-Benzyl-N, N-diäthyl-N-2- (m-butoxy-ph, enoxy)-     äthylammoni um.



   Das Anion   A"kan'n der    Rest einer therapeutisch   verwendbaren.Säuresein,    z.   B.    ein   Chlorid-,      Bromid-,    Jodid-,   Sulfat-oder MethylensulfatmAnioni.   



     Ausobigem    ist   ersichtlich,:dass.    die Kette    -W-CHs-CH-z.B..einsdierfolgendenGruppen    sein kann :  -O-(CH2)a    -      (CH2)    b-O-(CH2)c    -0- (CH2) a-O- (CH2) e-       -      (CH2)    f-O-(CH2)g-O-(CH2)h    -0-    (CH2i)-O-(CH2)j-O-(CH2)k    -    (CH2)l-O-(CH2)m-O-(CH2)n-O-(CH2)o    n    diesen Formeln bedeuten die an die   CH2-    Gruppen gehängten Buchstaben, ganze Zahlen ; a, c, e,   h,    k und o sind je mindestens 2 ;

   a oder die Summe von b und c oder die Summe von d und e oder die Summe von f, g und h oder die Summe von i, j und k oder die   Summe von 1,    m,   n    und   o    ist nicht mehr als
18. So kann   z.      B. W--CH2-CH2-eine    der folgenden   Gruppent sein    :    3-Oxatrimethylen, 8-Oxaoctamethylen,    6-Oxasdecamethylen, 3,   5-Dioxapentamefhylen,      779-Dioxanonamethylen,    5,   8-Dioxadecamethylen,      81l-Dioxatridecamethylen,    3, 5,   7-TrioxaheEtamethylen,    4, 7,   10-Trioxadecamethylen,    3, 5, 7-Trioxao. ctamethylen,.



  6, 9,   13-Trioxapentadecamethylen.   



   N-5-   (p-Cblorphenoxy)-3-oxapentyl-N-p-chlor-    benzyl-N,   N-dimethylammoniumsulfat islt in der Lite-    ratur erwähnt,   aberin'keinerWeisebeschrieben.   



  Folgende Verbindungen. sind beschrieben, aber ihre   wurmtotendeWiriksaim'kei.tnichterkannt:worden    :   N-Benzyl-N-5-(pmethylnphenoxy) ^3-oxapentyl-   
N, N, dimethylammonium-n-dodecyloxyacetat, N-Benzyl-N,N-diäthyl-N-2-(m-methoxy-phenoxy)   äthylammoniumchlond und    N-Benzyl-N,N-diäthyl-N-2-(m-tent.-butoxy-phenoxy)  , äthylammoniumchlorid.



   Besonders brauchbar haben   sich'von den    erfin  dungsgemäsaerhältlichenVerbindungan    diejenigen für die Bekämpfung von Syphacia obvelata und Aspi  culuris    tetraptera in Mäusen erwiesen, in denen R ein p-Bromphenylrest ist, oder ein p-Chlorphenylrest, wenn   W    nur ein Sauerstoffeation entält ; zur wirksamen Bekämpfung von Trichuris muris in Mäusen diejenigen, in welchen R ein n p-Nitrophenylrest ist, und   zum A, btoton    von   Ascaris lumb, ricoides in vitro       diejenigen,dea-enKationN-p-'Nitrobenzyl-N-2-(p- nitrophenoxyäthyl)-pyrrolidunium oder N-p-Chlor- 'benzyl-N-2-()p-cblorphenoxyäthyl)-pyrrolidiniumist.   



   Die Kette   W enthält vorzugsweise nur ein    Sauer  stoffattomundnichttmehr    als aoht Kohlenstoffatome.



     Bevorzugt werden diejenigen Sal ! ze der Formel    I, die in   Wasserschwerlöstichsind,    z. B. weniger als   2, 0  /o Gew./Vol.    bei 20 C. Die wurmtötende Wirkung bleibt   besbehen    und die toxischen Effekte auf den Wirt   sind stank vermindert.

   Besonders brauchbare    Salze bilden bzw. ergeben:   BorRuorid,    Perchlorat, Laurylsulfat, Dodecylbenzolsulfonat,   p-Toluylsulfo. nat,    p-Chlorbenzolsulfonat, p-Brombenzolsulfonat, p-Acylamidbenzolsulaonat,   N-Acylatmidosäure,    Diphanyl-4-sulfonat, Napthalin-1-sulfonat,    Naphthalin-2-sulfomät, Naphthaliii-1, 5 disulfo. nat, NaphthaHn-2,7-disul & }a;at,    1-Naphthol-3,6-disulfonat, 2-Naphthol-3,6-disulfonat, 1-Npathoat, 2-Naphthoat,   2-Hydroxy-3-n aphthoat,    4, 4'-Dihydroxy-diphenylmethan-3,3'-dicarboxylat, 2,   2'-Dihydroxy-'l,l'-dm.aphthylniethan-3,    3' dicarboxylat, Piperazin-1,4-bis-carbodithiat, 4, 4'-Dimainostilen-2,2'-disulfoat oder Phenate, wie 2, 4,5-Trichlorpheenat.   



   GeeigneteSalzederFormel1sinidbeispielsweise    die   Chloride, Bmmide oder Jbdide    der solbhe, die eine Sulfonestergrupe -O-SO2-E- enthlaten, worin E   em substituierter und'unsubstituierter Kohlen-      wasserstoffres°,    z.   B. die Tolyl, gcuppe,    ist.    tDieQuatemisierungeimastertiärenAminsder    Formel
EMI2.1     
 mit einem den   Benzyl-oder Thenylhest    abgebenden Mittel, sowie die intramolekulare Quaternisierung des Amins der Formel II wird   zweckmässig    in einem Lösungsmittel durchgeführt, z. B. in   Propan-2-ol oder    in Aceton. Die erstgenannte Umsetzung geht leicht vor sich   ;    die zweite hingegen erfordert   fortgesetztes    Erwärmen.

   Auclh lässt sich die   Quaternifsierungdurch      gameinsames Erhitzen von Verbindungen    der Formel   R-W-CHg-CH-ZundderFormelXYN-CHL    ohne Lösungsmittel durchführen.



   Wie   gesajgt,kanmmantertiäreAmine    der Formel   R-W-CH2-CH2-NX#CH2L z.    B.   ma°    einem Alkylie  ruogsmittel      quaternisieren.    Sind X und Y gleich, kann man auch ein sekundäres Amin der Formel   R-W-CH2-CH2-CNH-CH2#L    mit zwei Aquivalenten   einas      Alkylierungsmittel. s. der    Formel YZ in Gegen  wart eines säure (b ! ndenden Mittels,    z. B. von Soda oder   Pottasche,umsetzen.    Bei dieser Reaktion bildet    aichintermediärda.stertiäreAmAnderFormel R-W-CH2-CH2-NX#CH2L, so dass die Bildung    des   tertiärenAminsunddessenQuaternisierung    in einem Arbeitsgang vor sich geht.

   B. eispiele der für   dieseUmsetzungbrauchbarenAlkylierungsmittelsind    methyljodid, Dimethylsulfat, methyl-p0-toluylsufonat,   Athyljodid,    id, Äthyl-p-tolulsulfonat und 2-Hydroxy  äthyljodid.    Es ist zweckmässig, vom Alkylierungsmittel mehr als die theoretische Menge zu verwenden, um gute Ausbeuten zu erzielen. Beide Reaktionen können in einem Lösungsmittel, z.   B.    in Methanol oder in Aceten, Durchgeführt werden. 



   Verbindungen, in denen NXY die Pyrrolidino-, Piperidino- oder Morpholinogruppe ist, können, wie gesagt, derart   hergestellt werden, dass man ! eine    Verbindung der Formel II intramolekular   quaternisiert.   



  Diese Amine kömen   inFormihrer    Salze hergestellt werden, indem man die entspechende Hydroxy-Verbindung der Formel   R-W-CH2-CH2-N[XY#OH]-    CH2   miteinemHalogenisierungsmittel,    z. B. mit   ThionylchTorid,      Bro.mwa.sserstoff,Jodwasserstoff    oder mit einem   Sulfonylchlorid,    z. B. mit   p-ToluyIsulfonyl-      chloxid, umsetzt.    Das Salz wird am besten in die freie Base übergeführt und die innere   Quatemisierung    be  wirkt man, indem, mam die    freie Base   zweckmäasig    entweder an, sich oder in einem   Lösungsmittel, z.    B. in Isobutanol oder in einem Gemisch von Benzol und Äthanol. erhitzt.

   Die Geschwindigkeit der Reaktion hängt von der Natur von Z   ab.   



     Edindungsgemäss erhältliche Verbindungen,    in denen NXY die Pyrrolidino-   Piperidino-oder    Mor  pholinogruppe    ist, kann man auch herstellen, indem man ein sekundäres Amin des Formel R-W-CH2  CH2-NH#CH2L mit einem a,#=disustituen      Butan,Pentanoder3-Oxapentan    der FormelZ1-Q-Z2, worin   Zt    und   Z2      abspalfbare Reste bedeuten, wobei    einer davon, der das lon A-bildende Rest ist, umsetzt.



     Ales.    Beispiele seien genannt :   1,    4-Dibrombutan,
1,   4-DicMorbutam,   
1,   4-Diniethylsulfonn.yloxyb.utan),    1, 4-Di-p-toluylsulfonloxy-bozan, 1-Brom-4-chlorbutn,    l,5-Di-p-toluyIsulfonyloxybutanund       1,    5-Di-p-toluyl-sulfonyloxy-3-oxapentan.



   Die Reaktion wird vorzugsweise in Gegenwart eines   isäurebindenden Mittels durchgeführt,    z. B. von Soda oder Pottasche, indem man die Ausgangsstoffe an sich oder in einem Lösungsmittel, z. B. in   Iso-      butanoloderineinemGemischvonBenzol    und Athanol erwärmt. Die Reaktion geht unter Bildung des tertiären Amins der Formel II vor sich, so dass die   Bildung des genannten tentiären Amins    und dessen   intramolekulare Quaternisierung gleichzeitig erfolgen.   



   Wenn R ein eine Aminogruppe tragender Phenylrest ist,   mussmainmeistens,beiderHerstellung    der   erfindunjgsgemäss erhältlichen Verbindungen    diese Gruppen mit einer Gr. uppe G schützen, z. B. mit einer Acyl-oder Alkoxycarbonylgruppe oder einer Sulfon  estergru uppe-OSO2E. Bei sollchen Reaktionen    ist daher R ein   Gruppe NHG@Ph-, wobei    Ph den   Pbenyking bedeutet.    Nach Bildung der   quatemären    Verbindung wird die schützende Gruppe   G.    durch Hydrolyse wieder entfernt.



   Die   erfindungsgemässerhältlichen    Salze können während oder nach der erfindungsgemässen Reaktion durch doppelte Umsetzung, z.   B..    in   Lösung o, der    mit einem   Anionenaustausicher,    in das Salz eines anderen Anions übergeführt werden. Dies ist besonders dann   erwunscht,    wenn man ein in Wasser schwer lösliches Salz herstellen will oder   wenn man eine α,#-disubsti-    tuierte Verbindung g der Formel   Zl-Q-Z2 verwendet    hat und   Zt    und   Z2    voneinander verschieden sind.



     Pie    erfindungsgemäss erhältlichen Verbindungen können   infesterFomioralveraMolgtwerden.   



   Beispiel 1
Ein Gemische von 139 g p-nitrophenol, 259 g   1,    4-Dibrombutan und 40 ml Isopropanol und 1 Liter Wasser wird unter Rühren auf Rückfluss erhitzt. Im Verlauf von 3 Stunden wird eine Lösung von   34 g      Natriumhydroxyd    in 300   mt Wasser zugegeben.    Das Gemisch wird. dann weitere 3. Stunden gerührt. Nach dem Erhitzen wird die wässrige   Schichtentfernt    und mit   Ather    extrahiert. Die vereinigten organischen Schichten wäscht man dreimal mit 2 n Natronlauge, um   unreagiertes p-Nitrophenol    zu entfernen. Die e ätherische Lösung wird mit Wasser gewaschen, über   Pottasche    getrocknet, filtriert und eingedampft.

   Der Rückstand ergibt nach einer Vakuumdestillation 1-Brom-4-(p-nitrophenoxy)-butran, Kp.   144-146     C 0, 06   mm.   



   Eine Lösung von 62   g    dieses Athers in 154 g   äthanolischem Dmethytairnin    (33   Gew.- /o)    wird in einem Autoklaven 6   Stunden auf 80  C.    erhitzt. Das entstehende   Reaktionsgemisoh    wird auf dem Dampfbad eingedampft. Den Rückstand löst man in überschüssiger 4n Salzsäure und entfernt die nichtbasischen Nebenprodukte mit Ather. Nach Zugabe von überschüssigem) Ammoniak zu der sauren Schicht   scheideteinÖlaus,daismitÄfberextrahiertwird.   



  Die ätherische Lösung wird mit Wasser gewaschen, über.   Pottasche    getrocknet, filtriert und eingedampft.



     Das01wirdinüberschüssiger4mSalzsäure    wieder gelöst und die Lösung in Vakuum eingedampft. Dieser Rückstand   liefert nach zweimaligem Umkristallisieren    aus Methanol 1-Dimethylamino-4-(p-nbitrophenoxy)butan-hydroxchlorid, Fp. 173  C. Die reine Base wird   mitüberschüssigemAmmoniakwieder    freigesetzt und mit Ather als gelbes Öl isoliert, das langsam fest wird, Fp.   20  C.   



   4 g Benzylbromid gibt man zu einer Lösung von   5    g dieser Base in 10   ml    Aceton. Die Lösung erwärmt sich und wird   dann 30 Minuten unter Rüokfluss er-    wärmt. Beim Abkühlen scheidet sich ein kristalliner fester Stoff aus, der aus   laopnopanol    umkristallisiert wird.   N-Benzyl-N,N-jdimethyl-N-4-'(p-nitrophenoxy)-      butylammomiumbromid,    Fp.   152     C.



   Beispiel 2
Man gibt 4, 1 g   5-Chlorthenylchlorid (5-Chlor-2'-      chlonmetthylthiophon)    zu einer Lösung von 3, 52 g   Jodnatrium    in 10 ml Aceton und erwärmt das Ge  misch.    Nach 30 Minuten wird das ausgeschieden Chlornatrium abfiltriert und mit wenig frischem Aceton gewaschen. Zum Filtrat gibt man 5, 7 g   l-Dimethylamino-4-(p-nitrophenoxy)-butan    und erhitzt die Lösung 30 minuten unter   Rückfluss.    Nach dem Abkühlen werden die ausgeschiedenen Kristalle abfiltriert und mit Athylacetat gewaschen. Das ! feste N (5-Chlorthenyl)-N,N-dimethyl-N-4-(p-nitrophenoxy) butylammoniumjodid wird aus Methanol umkristalli  siert, Fp. 139-140     C.



   Beispiel 3
Eine Lösung von 7, 8 g 1-Brom-2-(P-chlorphenoxy)-äthan und 15 g Benzylamin in 15 ml Benzol wird 5 Stunden auf   demDampfbaderwärmt.    Nach dem   KaltwerdenwirddasGemischfiltriertund    der Rückstand mit frischem Benzol gewaschen. Das mit der   Waschflüssigkeitvereinigte    Filtrat wird mit über  schüssiger4nSalzsäuregeschüttelt,wobeisichfestes    1-Benzylamino-2-(p-chlorphenxoy)-äthan-hydrochlorid ausscheidet. Dieses wird abfiltriert und aus   10 ouzo      Athanol    enthaltendem Isopropanol in Form von farblosen Nadeln umkristallisert, Fp. 190-191  C.



   Dieser Hydrochlorid (5, 96   g)    wind mit wässrigem Ammoniak behandelt, um die frische Base zu   erhal-    ben, welche mit Äther isoliert wird. Man gibt diese Base zu   einerAufschlämmfungvon5,    3 g Soda in 15 ml Methanol, gefolgt von 14,. 5   g      Matbyljodid.    Das entstandene Gemisch wird 2 Stunden unter Rückfluss erhitzt und warm filtrier.t Zum Filtrat gibt man Äther und gewinnt N-Benzyl-N-2-(p-Chlorphenoxy)-äthyl  N,      N-dimethylammoniumjodid,dasman    aus Athanol   umkr. istallisiert,    Fp. 166 C.



   Beispiel 4
Ein Gemisch von   20    g 1-Brom-2-(p-chlorphenoxy)-äthan und 22 g Benzylmethylamin wird auf   70 Cerwärmt,woraufeinerasche'exotherme    Reaktion erfolgt. Nach dem, Abkühlen löst man die halbfeste   Masseinüberschüssiger.Salzsäureundwäscht    die Lösung mit Ather. Eine Behandlung mit Natronlauge, Extraktion mit   2ither    und Eindampfen des getrockneten Extrakts gibt ein basisches Öl, das man    durch.EraktionienteDestillationinBenzykn'ethylamin    und d 1-Benzylmethylamin-2-p-chlorphenoxyäthan, Kp. 158  C/0,01 mm, scheidet.



   Diese Base   (5      g)    und die gleiche Menge Äthyl-p  toluyisulfonat werden    3   Stfunden    in   50    mil siedendem Aceton erwärmt. Abkühlen und Zugabe von Äther   läs. st    das N-Benzyl-N-2-(p-chlorphenoxy)-äthyl-N äthyl-N-methyl-ammonium-p-tolulsulfonat ausscheiden,, das aus Äthylacetat umkristallisiert farblose Plättchen bildet,   Fp.      121- < 122     C.



   Tabelle I enthält weitere   quatemäEe    Ammonium  verbindunlgen,    die nach, den oben beschriebenen Methoden hergestellt wurden. Die Tabelle II enthält die physikalischen   Eigenscihaften    von   Ausgangsverbin-      dungen,diefürdieHerstellungderinTabelle1    enthaltenen Stoffe verwendet worden sind, soweit sie nicht in der Literatur beschrieben sid.



   In den Tabellen I und II bedeuten R2, R3, R4 und   Rg    die   Substituenben dler Ringe ; in Tablelle I Ibedeutet    A-das Anion.



  Tabelle   I      (A)   
EMI4.1     
 Beispiel   WCHsCHa X Y Ri A-kriatail'lisiert aus Fp.  C    Nr.



     5    O (CH2) 2 CH3 CH3 p-NO2 Cl Äthanol/Methanol 228-229
6 O (CH2)2 C2H5 C2H5 p-NO2 J Methandol 172-173
7 O (CH2) 2 -(CH2)4- p-NO2 Cl Äthanol 199-200
8 O   (CH-(CHa)e-p-NOaJÄthanol193-193,    5
9   O      (CH2)    2 -(CH2)2O(CH2)- p-NO2 J Methanol 191-192
10 O   (CH2)    s CH3 CHs p-NO2 Cl   Äthanol 202-203   
11 O (CH2)3 - (CH2)4- p-NO2   J    Methanol 203
12 O (CH2) 3 -(CH2)5- p-NO2 J wäser.

   Methanol 201
13 O   (CH2)    2 CH3 CH3 p-Cl Cl Methanol   225-226   
14 O (CH2) 2 C2H5   C2Hs    p-Cl J   Athanol 163-164   
15 O   (CH2)    2 -(CH2)4- p-Cl Cl Äthanol 183-184
16 O (CH2)   (CH,).- p-Cl    J Methanol   200-201   
17 O(CH2)2 -(CH2)2O(CH2)2-p-Cl J Methandol 177-178
18 O(CH2)3 CH3 CH3 p-Cl Cl Methanol 127-128
19 O (CH2)   cHeCsHgp-CIJ-VsHaOÄthanol145-146   
20 O (CH2) 3 -(CH2)4- p-Cl J Methanol 175
21 O (CH2)3 -(CH2)5- p-Cl J Methanol   170-171   
22 0 (CH2)3 -(CH2)2O(CH2)2- p-Cl J Metanol 199-200
23 O   (CH2)      CH3 Ch3 p-Cl Cl#¸H@O Äthanol/Äthylacetat    137    24 O(CH2)5 CH3 CH3 p-Cl Cl Äthanol 158-159
25 O(CH2)

  6 CH3 CH3 p-Cl Cl Äthanol/Äthylacetat 157    
Tabelle (A) (Fortsetzung) Beispiel   WCHzCBb      X      Y    Ri A- kristallisiert aus Fp. o c Nr.



   26   CH20    (CH2)   2 CHS CH3    p-Cl J   Methanol/Äthanol 180-182   
27 O (CH2) 3 CH3 CH3 p-Br Br   Mothanol/Athylacetat 179-180   
28 O (CH2)   s      C2H5 C2Hs p-Br    Br   Athanol 206   
29 O (CH2)3 -(CH2)4- p-Br Br   Methaml/Ather    140
30 O (CH2)5 CH3 CH3 p-Br Br Metanol 165
3.   CHO(CHCHsCH,p-BrBrAthamol200-203   
32 O   (CH2)    3 CH3 CH3 p-F   Cl#2H2O Äthanol/Äther    85
33 O (CH2) 3 -(CH2)4- p-F J   Athanot/Methamol    171
34 O (CH2) 4 CH3 CH3 p-F J Äthanol 165
35 O (CH2) 5 CH3   CHS      p-F    J Äthanol 117
36 O (CH2)3 CH3 CH3 p-J Br wässr.

   Methanol 209
37 O (CH2) 3 C2H5   C2Hs    p-J Br Methanol   220   
38 O (CH2)3 -(CH2)4- p-J Br Methanol 208
39 O   (CH2)    5 CH3 CH3 p-J Br Methanol   203   
40 O   (CH2) CHS CHs PJ    Br   Methanol 153-154   
41 O   (CH2)    2 CH3 CH3 p-CN Cl Methanol 222-223
42 O (CH2)   a- (CH2) 4- m-Cl    Br Athanol 212
43 O (CH2)   2 CH3 Ch3 o-Cl Cl#H2O Äthanol/Isopropanol 112-113   
44 O (CH2) 3 CH3 CH3 o-Cl J   Athanol    118
45 O (CH2)3 C2H5 C2H5 o-Cl J   Methanol 173-174   
46 O (CH2)3 -(CH2)4- o-Cl J Methanol 133    47      O    O(CH2) 2 CH3   CHS    H Br Äthanol/Isopropzanol 159-160
48 0 (CH2)

  2 C2H5 C2H5 H Br Äthanol   139-140   
49 O   (CH2) 2- (CH2) 4- H    Br   Äthajiol    164-165    50    O (CH2)2 -(CH2)5- H J Methanol 197-198
51 O (CH2)3 CH3 CH3 H   Br    Äthanol/Äther 113
52 O (CH2) s   C2H,    C2H5 H Br   Athanol      130   
53 O (CH2)3 -(CH2)4- H Br Äthanol 155    54    O   (CH2)    s   CHS      CHS    H Br Äthanol 168-169
55 O (CH2)6 CH3 CH3 H Br Äther/ Isopropanol 112
Tabelle I(B)
EMI5.1     
 Beispiel   w#CH2CH2 X Y R1 A- kristallisiert aus Fp.  C    Nr.



   55 (b)   0(CH,)sCH,CH,p-NOClAthanol/Methamol208-209   
56 O (CH23)   2 -(CH2)4- p-NO2 Cl#H2O Isopropanol/Äthylacetat    98-99
57 O   (CH2)    2   CH,    CH3 p-Cl   G11    Isopropanol./Äther 185, 5-187    58    O   (CH2)    2 -(CH2)4- p-Cl Cl Isopropanol/Äther 154-155
59 O   (CH2)    2   CH,      CHS      m-Cl    Br.

   Isopropanol 163-164
60 O   (CH2)2 CH3 Ch3 o-Cl Cl#H2O Isopropanol/Äther 114-115       61    1 O(CH2)2 CH3 CH3 H   CL      Isopropanol/Äthylacetat164-165   
62 O (CH2) 2 -(CH2)4- H J isopropanol/Äthylacetat 124-125  Tabelle   Z (C)   
EMI6.1     
 Beispiel   WCBbCHz      X      Y    Ri A1 kristallisiert aus Fp.  C Nr.



   63 O   (CH2)    2 CH3 CH3 p-NO2 Cl   Athanol    211-212
64 O   (CH2)    2   C2H5 C2H5 p-NO2    J Methanol   184   
65 O   (CH2)    2 -(CH2)4- p-NO2 J Methanol 199
66   O      (CH2)      2 -(CH2)5- p-NO2 Cl#¸H2O Isopropanol/Äther    198
67 O (CH2) 2O(CH2)2 CH3 CH3 p-NO2 Cl Isopropanol 156-157
68 O   (CH2)    2   CHS    CH3 p-Cl Cl Methanol 214-2145
69 O (CH2)2 C2H5 C2H5 p-Cl J Methanol 185
70 O (CH2) 2 -(CH2)4- p-Cl J Methanol   170       7.    1 O(CH2)2 -(CH2)5- p-Cl Cl Äthanol/Äther 154
72 O (CH2)   3 CH3 CH3 p-Cl Cl#H2O Isopropanol/Äthylacetat 104-105   
73 O (CH2)

  3 C2h5 C2H5 p-Cl J   Isopropanol/Äthanol166-167   
74 O (CH2)   3 -(CH2)4- p-Cl Cl#H2O Isopropanol/Äthylacetat    145-146
75 O (CH2)4 CH3 CH3 p-Cl Cl   Isopropanol/Äthylacetat 176-177   
76   O      (CH2)    4 C2H5 C2h5 p-Cl J isopropanol/Äthylacetat 150-151
77 O (CH2)   4 -(CH2)4- p-Cl Cl#H2O Isopropanol/.Äther    78-79
78 O   (CH2)5 CH3 CH3 p-Cl cl#H2O Ispropanol/Äthylacetat 126-127   
79 O   (CH2)    5   C2H5      C2HS    p-Cl   Cl.,      Äthanol/Äther140-141   
80 O (CH2)   5 -(CH2)4- p-Cl Cl#H2O Isopropanol/Äther 157-158       810(0)

  .CHsCHgp-ClClIsopropanol160-161   
82 O   (CH2)      6    CH3 CHg p-Cl   J-1/2H2O    Methanol 190
83 O (CH2)6 C2H5 C2H5 p-Cl Cl Isopropal 169
84   OCCHJe-(CHs)-p-ClClIsopropanol/Äther101   
85 O (CH2) 40 CH3 CH3 p-Cl   J    Methanol 161-162
86 O (CH2)-10 -(CH2)4- p-Cl J Methanol   123       87    O   (CHO(CHCHgCHgp-0.01Isopropanol/Äfhar    124-125
88 O (CH2)2O (CH2)   2-(CH2) 5-p-Cl    J Isopropanol   133-134   
89 O (CH2)6 CH3 CH3 m-Cl Br Äthanol 155-156
90 O   (CH2)    6-(CH2) 4-m-Cl Br Methanol   141-142   
91 O (CH2) 2O(Ch2)2 CH3 CH3 m-Cl Br   IsQpropa.noI/Äther93-94   
92 O   (CH2)

      2 CH3 CH3 o-Cl   Cl-HsO Äthanol    127
93 O (CH2) 2 C2H5 C2H5 o-Cl J Isopropanol   124   
94 O (CH2) 2 -(CH2)4- o-Cl J Methanol 159-160
95 O (CH2) 2 -(CH2)5- o-Cl J Metanol 167
96 O (CH2) C2H5 C2H5 o-Cl J Isopropanol 1360-137
97 O (CH2)6 CH3 Ch3 o-Cl Cl Methanol 178-179
98 O (CH2)6 C2h5 C2H5 o-Cl J Athanol 136-137
99 O   (CH2)    6 -(CH2)4- o-Cl Cl Isopropanol/ Äther 153-154 100 O   (CHs)20(CHCHgCHso-ClClIsopropanol/Äther129-130    101 O (CH2)2 CH3 Ch3 p-Br Br Methanol 226   102      O      (CH2)    2 C2H5 C2H5 p-Br Br   Athanol    195 103 O (CH2)2 -(CH2)4- p-Br Br Athanol 176   104    O (CH2)2   (CH2)

      5- p-Br Cl Äthanol/Äthylacetat 156 erweichtbei 150 105 O (CH2) 2 CH3 CH3 p-CN J Methanol 225   106      O    (CH2)2 -(CH2)4- o-Br Br   ithanol/lither    125   107      O      (CH2)    2 CH3 CH3 H Br Methanol   206    108 O (CH2)   2 C2H5 C2H5    H Br   Isopopanol/Äther 150-151    109 O (CH2) 2 -(CH2)4- H Br Äthanol   158-159      110 O O(CH2)2 - (CH2)5- H Br Isopropanol 187    111 O   (CH2)    2 CH2 CH :

   CH2 H Br Aceton/Athylacetat 115 112 O   (CH2)    2 CH3 C2H5 H J Isopropanol   121, 123    
Tabelle I(C) (Fortsetzung) Beispiel WCH2CH2 X   Y    Ri   A-kristallisiert    aus Fp.    C    Nr.



  113 O (CH2)   CHg CHg    H   Cl#H2O Ispropanol/ Äthylacetat    118-119 114 O   (CHJsQHgCHs    H J Isopropanol/Äthanol 140-141 115 O (CH2) 3 -(CH2)4- H Cl-2H2O Isopropanol/Äthylacetat 78-79 116 O   (CH2)    4 CH3 Ch3 H   Cl#¸ H2O Isopropopaol/Äthylacetat    150-151 117 O (CH2)4 C2H5 C2H5 H J Isopropanol 142-143 118 O (CH2)   4 -(CH2)4- H Cl#H2O Isopropanol/Äther    91-92 119 O   (CH2)      5    CH3 CH3 H Cl.

   H2O   Iso, propanol/ Athylacetat    167-168   120      O    (CH2) 5 C2H5   C2H6    H Cl Isopropanol/Nthylacetat 199-200   121    O   (CHJg-(CHHCl.HaOIsopropanoVÄther    105-106 122 O (CH2)6 CH3 CH3 H Br Athaniol 157-158 123 O   (CH2)      C2H5 C2H6    H Br Äthanol   139-140    124 O(CH2)6 -(CH2)4- H Br isopropanol 145 125 O (CH2)10 CH3 CH3 H Br Athanol 125 126 O(CH2)10 C2H5 C2H5 H Br   Äthanol/Äther    121-122 127 O   (CH2)    10 -(Ch2)4- H Br Äthanol/Äthylacetat 115-118 128 O (CH2)2O(CH2)2 CH3 CH3 H   ci      Isopmpaiiol/Äther119-120    129 O (CH2) 2O (CH2)   2-(CH2)

   4-H J Isopropanol    124-125    Tabelle I (D)   
EMI7.1     
   Beispiel WCHzCH2 X Y Ri A-kristallisiertaus Fp.  C    Nr.



  130 O(CH2)2 CH3 CH3 p-NO2 Cl   Methanol 229-230    131 O   (CH2)      2 C2h5 C2ht p-NO2 J#¸H2O Metanol      164-165    132 O   (CH,),-(CH)-p-NOgC1-2HOIsopro)panol/Äther    175 133 O   (CH2)    2 -(CH2)5- p-NO2 Cl Äthanol/Äther 194 134 O (CH2) 2 -(CH2)2O(CH2)2- p-NO2 J Wasser 187 135 O (CH2)2 CH3 CH3 p-Cl Cl Äthandol 228-229 136 O (CH2)2 C2H5 C2H5 p-Cl J   Äthanol 186-187    137 O (CH2)   2 -(CH2)4- p-Cl Cl#¸H2O n-Butanol/Äther 156    138 O   (CH2)    2 -(CH2)5- p-Cl Cl Isopropanol/Äther 189 139 O   (CH2)      0(CH-p-ClJ.lV,HsOÄthanol    197   140    CH20   (CH2)

        CHCHgp-ClJÄthanol    178-181 141 O   (CH2)    2 CH3 CH3 p-Br Br Methanol 232-233   142    O (CH2)   2 CH, CH3 p-J    Br Methanol 223-224 143 O   (CH2)      2 4CH2) 4-p-CN    J Athanol 189-192 144 (CH2O (CH2)2 CH3 CH3 p-CN J Äthano9l 147-150 145 O (CH2) 2 CH3 Ch3 o-Cl Cl   Athanol/Ather    115-117 146 O   (CH2)2 -(CH2)4- o-cl Cl#H2O n-Butanol/Äther      84-85    147 O   (CH2)    2 -(CH2)5- o-Cl J Metahanl 151 148 O   (CH2)2 -(CH2)2O(CH2)2- o-Cl Cl#¸H2O Metahanol 142    149 O (CH2)   2 CH3 CH3 H    Br   2ithanol    194-195   150    0 O(CH2)

  2 C2H5 C2h5 H Br Äthanol 137-138 151 O   (CH2)    2 -(CH2)4- H Br   Äthanol/Äth & r    124 152 O   (CH2) 2- (CH2) 5- H    Br Äthanol 184 153 O (CH2) 2 H Br Athanol/Ather 178-179 154 O (CH2)2 CH3 C3H7 H J Äther/Äthylacetat 128-130 155 O   (CH2)    2   CH3CH2-CH    CH: CH2H J Isopropanol 106-108 156 CH2O(CH2)2 CH3 CH3 H J Äthandol 149-151   Tabelle I (E)   
EMI8.1     
 Nr. Natur u. Stellung   X      Y    Naturu.

   A- kristalisiertaus Fp.é C Beispiel   vonRa Stellung    von Rs 157 p-CN C2h5 C2h5 p-NO2 J Metannol 196-998   (Zers.)    158 p-CN   C2Hs C2H5 p-CN    J   Math.anot    189-193 159 p-CHs CH3 CH3 p-NO2 Cl Methanol 217-218 160 p-CH3 CH3 CH3   p-Cll C1 Athanol 222-223    161 p-Ch3 CH3 CH3 o-Cl   ClH,

  0Äthanol110-112      162    p-CH3 CH3 CH3   Cl#H2O Br Äthanol    147-148 163 p-CH3O CH3 CH3 Br   ci      Äthanol 177-178    164 p-CH30 CH3 CH3   d Cl Methanol    167-168 165 p-CH3O CH3   CH5    Cl   Cl#H2O Isopropanol/Äthylacetat 82-83    166 p-CH3O CH3 CH3 o-Cl J   Athanol    133-136 167   p-CH3CONH    CH3 CH3 H Cl   Athawol    183-184 168   p-CHO    CH3 CH3 p-Cl J Methanol   205-208    169 p-CHeCo CH3 CH3   P-NO2      J      Athanol    177-178 170 p-CH3CO CH3 Ch3 p-NO2 J Äthanol 122-123 171   p-CH30CO    -(CH2)2O(CH2)

  2-H J Methanol 168-170 172 p-C2H5O   #CO -(CH2)5- J J Äthanol/Äthylactat 130-132    173 p-OH CH3 CH3 p-NO2   J    Äthanol 178-180   174    m-CH3 CH3 CH3 p-Cl Cl Äthanol 178-179 175 m-CH3 CH3 CH3 J Methanol 169-170   176    m-CH3 C2H5   C2H5    p-NO2 Cl Isopropanol 154-155 177   m-CH3 C2H5 C2H5    p-Cl Cl Isopropanol 202-203 178 m-CH3 CH,

     CH3 o-Cl Cl#H2O Isopropanol    93-94 179 m-CH3   C2H5 C2HS    H Br Äthanol 124-152 180   m-CH30    CH3 CH3 p-Cl Cl   Athanol      173-174    181 m-Ch3O CH3 CH3 p-NO2 Cl Isopropanol 147-148 182 m-CH3O C2H5 C2h5 p-NO2 Cl Äthanol/Isopropanol 159-161 183 m-CHO C2H5   C2HS    p-Cl   Cl    Äthanol/Isopropanol 177-178 184 m-CH3O -(CH2)4- p-NO2 Cl Äthanol 158-159 185 m-CH3O -(CH2)4- p-Cl Cl Äthanol/isopropanol 161-162 186   m-CHj)    CH3 CH3 o-Cl Cl Isopropanol 150-151 187 m-CHeO CH3 CH3 H J Äthanol 130-131 188   m-CH3O-(CH2) 4-H    Br   IsopDopanoI/Äthylacetat    95-96
Tabelle   f       (F)

     
EMI8.2     
 Beispiel R4   WCHzCHs    X   Y    Rs A- kristallisiert aus Fp.  C Nr.



  189 Cl O (CH2) 2 CH3) CH3 H C1 Isopropanol   142    190 Cl O(CH2)2 C2H5 C2H5 H J Äthanol 1609 191 Br O(CH2)2 CH3 CH3 H Cl Äthanol./Äter 179-180 192 Br O(CH2)2 -(CH2)5- H J Methanol 196-199 193 Br O(CH2)2 CH3 CH3 Cl Cl Äthanol/Äther 195-196   194      Br    O (CH2)   2 C2H5 C2H5 Cl Cl-H20 Isopnopanol 114    
Tabelle I(E) (Fortsetzung) Beispiel R4 WCH2CH2 X   Y    Ri   A-kristal'lisiertaus'Fp. C    Nr.



  195 Br O (CH2)2 -(CH2)4- Cl J Methanol 179-180 196 Br O   (CH2)      2- (CH2) 5- Cl Cl Athanol/Ather      202-203    197 N02 O (CH2)   2 CH3 CH3 C1 J Methanol    158-159 198 N02 O   (CH2) 2 C2H5 C2H5    Cl J Methanol   139-140    0 199 No2 O   (CH2)      s    CH3 CH3   ci    J Methanol   160-161    200 N02 O (CH2)   3      C2HS    C2H5 Cl J Methanol 164   201      N02    O   (CH2)      3-(CH2) 4-Cl J Athanol    152 202   N02    O (CH2)4 CH3 CH3 Cl J Methanol 139-140
Tabelle II, Ausgangsamine
EMI9.1     
 natur u. Stellung WCH2CH2 X Y Kp.

   C von R2 p-NO2 O   (CH2)    2 -(CH2)5- nicht destilliert p-NO2 O (CH2)3 CH3 CH3 nicht destilliert p-NO2 O(CH2)3 C2H5 C2H5 nicht destilliert p-NO2 O(CH2)3 -(CH2)4- nicht destilliert p-NO2 O(CH2)3 -(CH2)5- 168-194 /0,001 mm   p-N02    O   (CH2)    4 CH3 CH3   nitcht destilliert Fp. # 20     p-NO2 O(CH2)5 CH3 CH3 nicht destillert Fp. 35  P-NO2 O(CH2)6 CH3 CH3 nicht destiliert Fp. 35  p-NO2 CH2O(CH2)2 CH3 CH3 110-112 /0,05 mm   m-N02    O (CH2)   CHs CH, 101-105 /0, 01mm      m-N02    O   (CH2)    2 -(CH2)4- 128-135 /0,01 mm p-Br O(CH2)2 CH3 CH3 150-152 /15 mm p-Br O(CH2)2 C2H5 C2H5 104-108 /0,1mm p-Br O   (CH2)2 Ch2#CH   : CH2 CH2 CH :

   CH2   1.14-,118 /0,07mm    p-Br O   (CH2)    2 -(CH2)4- 116-120 /0,1 mm p-Br O(CH2)2 -(Ch2)5- 124-128 /0,06 mm p-Br   O (CH2) 3 CH3 CHs 94-98 /0, 2mm    p-Br O   (CH2)    3 C2H5 C2H5 108-11 /0,1 mm p-Br O (CH2)3 -(CH2)4- 108-112 /0,01 mm p-Br O (CH2) 4 CH3 CH3 98-150 /0,15 mm p-Br O   (CH2)    4   C2H5    C2Hs   111-ill7 /0, 08mm    p-Br O(CH2)4 -(CH2)4- 113-119 /0,05 mm p-Br O(CH2)5 CH3 CH3 105-110 /0,08 mm p-Br O(CH2)5 C2H5 C2h5 118-122 C/0,01 mm p-Br O(CH2)5 -(CH2)4- 126-131 /0, 06 mm p-Br O   (CH2)    6 CH3 CH3 108-115 /0,01 mm p-Br O(CH2)6 C2H5 C2H5 120-125 é/0,02 mm p-Br O (CH2)6 -(CH2)4- 18-132 /0,02 mm p-Br O(CH2)10 CH3 CH3 162-170 /.0, 2 mm p-Br O(CH2)10 C2H5 C2H5 175 /0,

  25 mm p-Br   0    (CH2)10 -(CH2)4- 176-186 é/0,15 mm p-Br O(CH2)2O(CH2)2CH3 CH3 136-138 /0,08 mm   p-Br0(CH,),0(CHJ,-(CH,),-160-164 /0,7mm    p-Cl O (CH2) 2 CH3 Ch3 139-145 é/16 mm p-Cl O(CH2)2 C2H5 C2H5 160-180 /30mm   p-CX    O   (CH2)      (CH)-107-110 /0,4mm    p-Cl O (CH2)2 -(CH2)5- 1760-178 /13 mm p-cl O   (CH2)    2 -(CH2)O(CH2)- 130-125é /0,15 mm 
Tabelle II Ausgangamine (Fortsetzung) Natur u. Stellung WCH2CH2 X Y Kp.

   C von R2 p-Cl CH2O   (CH2)    2 CH6 CH3   144-150 /10    mm   p-CN0(CHCaHgCHg120-.126 /0mm    p-Ch3CONH O(CH2) 2   CHs    CH3   nichtdestilliert       p-CHO O(CH2)2 CH3 CH3 108 /0,2 mm p-CH3O#CO O(CH2)2 -(CH2)2O(CH2)2- 166 /0,05 mm      p-C2H5O    -CO O(CH2)2 -(CH2)5- 160-165 /0,1 mm p-CH3 O (CH2) 2   CHa    CH3   121'/16 mm    m-CH3 O(CH2)2 CH3 CH3 119 /12 mm m-C H3 O   (CHCCHg141 /17.mm    m-CH3O O(CH2)2 CH3 CH3 85-87 /0, 08 mm   m-CH3O    O (CH2)2 -(CH2)4- 104 /0,05 mm 1-Benzylamino-2-(m-methoxyphenoxy)-äthan 1-(N-methyl-N-m-methylbenzylamino)-2-phenoxy hat einen Kp=176-182  C/0,5 mm äthan hat einen Kp=124-128  C/0,

  1 mm    Beispiel 203   
Man   gibteineLösungvom250gN-'o-Chlor-    benzyl-N-2-(p-chlorphenoxy)-äthyl-N,H-dimethyl ammoniumchlorid. (Vgl. Beispiel 145) in 500 ml Was ser langsam unter Rühren zu einer   Lösung von. 191g    Natium-p-tolulsulfonat in 400 ml asser, In dem Masse, wie die Zugabe fortschreitet, scheidet sich ein kristalliner fester Stoff aus.   Dann Jässt man.    das Ge  misch    17 Stunden stehen und filtriert. Der Filterkuchen wird mit   Wassler    gewaschen und aus einem   Gemisch von Isopropanol und Ather umkristallisiert.   



  N-o-Chlorbezyl-N-2-(p-chlorphenoes)-äthyl-N, Ndimethylammonium-toluylsulfonat, Fp. 1460-147  C.



   Beispiel 204
Nach der in   Beispiel 203 beschrieibenen Methode    wird N-p-Chlorpbenzyl-N,N-dimetnjhyl-N-2-(p-nirophenoxy--äthyl-ammoniumchloir (Beinpisl 13) in folgende Salze umgewandlet:    I.    p-Chlorbenzolsulfonat, Fp.   238-23-90    C ;    Löslichikeit    bei   20  C etwa 0,. l"/o Gew./Vol.   



     II.    p-Toluylsulfonat, Fp. 226-227  C;
Löslichkeit bei 20  etwa 0,2 %
III. 4,   4'-Diaminostilben"2,2disu!!fbnat-mjonfohyd.rat,   
Fp. 181-182  C ;   Löslichkeitbei 20  etwa    0, 1    /o    ;
IV. 2-Hydroxy-3-naphatosat, Fp. 129-130  ;    LösRchkeit    bei 20  C etwa 0, 1   zozo    ;
V. Emponat monohldry, Fp. 185-186  C ;
Löslichkeit bei   20 etwa0,,1c/o    ;
VI. Jodid, Fp. 201-202 C ;
Löslickhleit bei 20  etwa 0,2 %, und VII. 2, 4, 2-5Triclorphenat, FP. 125-125 é C.



   Beispiel 205    Man gitbt eine Lösung    von   100      g      p-Hydroxy-    acetophenon in 100   ml'Ätthanol stufenweise zn einer      Lösungvom    16, 9   g    Natrum in 500 i Äthanol. Dann gibt man   174    g   Äthylendibromid(25''Überschuss)    zu. Das   Gemischwirdjetzt    5 Stunden unter Riiakfluss erhitzt, abgekühlt und in Wasser gelossen. Das Öl wird mit   Ather    extrahiert und der Extrakt mit 2n Natronlauge erschöpfend gewaschen. Die ätherische Lösung trocknet man über wasserfreier Pottasche, filtriert und. dampft ein.

   Der Rückstand wird im Vakuum   destilliertund'gibtp-(2-Bromäfhoxy)-acoto-    phenon, Kp. 128-136  C/0,2 mm dieser Stoff ver  festigtsichbei55     C.



   Eine Lösung von 20 g dieser Verbindung gibt   man in 10 ml Äthanol zu    56 g alkoholischem Di  methylamin(33Gew.-"/o).    Das Gemsich wird 6   Stun-    den auf 60  C   erwärt    und dann auf dem Dampfbad eingedampft. Man   gijbtzumRückstandüberschüssige      2n      SalzsäureundentferntdasunlöslicheÖl    mit Äther.



  Die saure Lösung wird   mit überschüssigem konzen-      triertem    Ammoniak behandelt und das ausgeschiedene    O1 mitÄtherextrahiert.DerExtraktwirdüberPott- asche getrocknet, filtriert und eingedampft. Der Rück-    stand   wirdimVakumndestilliertundliefertp-(2-Di-       mefhylaminoätboxy-acetophenon,Kp.128-'132 C/    0, 25 mm.



   , 3, 86 g   feingepulvertes Jodkali gibt    man zu einer Lösung von 3,   8    g   Chlorbenzylchlorid    in 5.   ml}    Aceton und dann 4,0 g p-(2-Dmiethylaminoäthoxy)-acetophenon und erhitzt das Gemisch 1¸ Stunden unter   RückQiuss.    Das Gemisch von festen Stoffen wird abfiltriert, mit Äthylacetat gewaschen und mit Wasser die anorganischen Stoffe entfernt. Der unlösliche Teil wird abfiltriert, mit freischem Wasser gewaschen und wiederholt aus Athanol   umkristaeisiert.   



   N-2-(p-Acethylphenopxy)-äthyl-N-p-chlobenzyl N, N-dimethylammoniumjodid, Fp. 133-134  C.



   Beispiel 206
Ein   Gemischvon14,    3 g p-Cyan-phenol, 23 g 2-Chloräthyldimethylamin-hydrochlorid und 12, 8 g    NatrmmhydBoxydS. ocken wird erhitzt und 20 Stunden in100ml.siedendemToluolgerührt.Man'extrahiert    das erkaltete Gemisch mit verdünnter Salzsäure und   wäscht den Extrakt mit Ätiher.    Durch Behandlung des    saurenExtraiktsmit)Natronlaugesetztman2-(p-Cyan-    phenoxy)-äthyl-dimethylamin als Öl freit, das man mit Äther isoliert und destilliert, Kp.

   108-110  C/0, 2 mm, 
Die Behandlung dieser Base (3,   3    g) mit   einein      ÜberschussvonCyambenzyljodid    (6, 5 g) in 50 ml sieden Aceton ergibt   N-      (p-Cyan-benzyl)-N- [2- (p-    cyan-phenoxy)-äthyl]-N,N-dimethylaminoiumjodid, das aus Methanol in farblosen Prismen kristallisiert, Fp. 213-214  C.



   Beispiel 207
Man löst 3, 25 g metallisches Natrium in 60 ml trockenem Äthanol, gibt erst eine Lösung von 10 g   Athyhp-hydrcxybenzoat    in 25 ml Äthanol und dann eine Suspension vo 15 g N-(CHloräthyl)-morpholinhydrochlorid in   50    ml des gleichen Lösungsmittels zu.



     MankoohtdasGemischzweiStunden    unter   Rück-      fLuss    und lässt es dann über nacht stehen. Man filtriert von den ausgeschiedenen Salzen ab, verdampft den Alkohol, gibt Wasser zu und basifiziert die Lösung in   GegenwartvonEismitAmmoniak.    Die Ex  traktion mit Chloroform und    eine Destillation liefert N-2-(p-Äthoxycarbonyl-phenoxy)-öäthylmorpholin das zählflüssiges Öl, Kp. 178  C/0, 2 mm.



   Die Umsetzung von 5,   0gdieser    Base mit 7, 5 g   p-Chlorbenzyljodid    in 50 ml Aceton lefert N-p   CMo!ibenzyl-N-2-(p-äthoxycacbonyl-pbsnoxy)-äthyl- morpholiniumjodid. Aus einer Mischung von Äthanol      und Äthylacetat umikdstallisiert bildet    es Nadeln, Fp.



  157-158  C.



   Beispiel   208      
EineSuspensionvon13gN-2-(p-Acetamino-    phenxoy)-äthyl-N-p-chlorbenzyl-N,N-dimethylammoniumchlorid (vgl. Beispeil 168) in 100   ml    Methanol wird mit Chlorwasserstoff gesättigt und die Lösung 3 Stunden unter Rückflues erwärmt. Das Eindampfen. der Mischung ergibt einen gummiartigen   Stoff, der durch Zerireiben    mit   Äthylaoetat    fest wird.



  Man kristallisiert das   N-2- (p-Aminophenoxy)-äthyl-       N-p-. chlortbenzyl-'N,N-.dimethyl'ammoniumchlorifd-    hydrochlorid aus Äthanol um, Fp.   172-174  C (unter    Verwendung eines auf   140  C vorgeheizten Bades).   



  Eine   wässrige Losung dieses    festen Stoffes wird mit   Ammoniakbis    pH 8-9 behandelt und Jodkali   zuge-    füht, um N-2-(p-Aminophenoxy)-äthyl-2-p-chlor  benzyl-N,N-dimethylammoniumJ!odidzuerhalten    ; aus   IsopropanolumkristalliertFp.163-164 C.   



   Beispiel 209
Man gibt 43 g 1-Brom-2-(m-methyl-phenoxy) äthan zu einer Lösung von   510    g Benzylamin in Benzol und erhitzt die Mischung 4 Stunden auf   dem Dampf-    bad. Nach dem Erkalten filtriort man den unlöslichen festen Stoff ab und wäscht   ihnmitfrischem    Benzol.



  Das mit der   Waschflussiigkeit    kombinierte Filtrat schüttelt man mit überschüssiger 4n Natronlauge. Die wässrige Schicht wird abgetrennt, die restliche Benzolschicht über festem Kaliumhydroxyd getrocknet, filtriert und eingedampft. Der Rückstand wird im Vakuum destilliert und liefert   l-Benzylamino-2- (m-    methylphenoxy)-äthaqn, Kp. 134-145  C/0, 5   rnm.   



   13   g    dieser Base gibt man langsam zu einer gekühlten Mischung von 7 ml Ameisensäure (98%)   und 6, 8 ml Formalin    (35 Gew.-%). Die erhaltene   Mischung enwärmt man    8 Stunden auf dem   Dampf-    bad, behandelt sie mit 8 ml   konzentrierterSalzsäure    und Dampft sie dann im Vakuum ein. Das 1- (N   Benzyl-N-m!ethylamino)-2-(m-mssthyl-phenoxy)-äthan    wird mit   Ammoniak. freigesetzt und mit Äther    als farblose Flüsigkeit isoliert, Kp.   138-142  C/0,    08   mm.   



   2 g dieser Base werden in   10    ml Aceton gelöst und 2 g Methyljodid zugegeben. Nach 4 Stunden gibt man Athylacetat bis zur beginnendem Trübung zu,    waraufdannN-Benzyl-N-2-(m-methyl-phenoxy)-    äthyl-N,   N-dimethylammonium:jodidlangsamaus-    kristallisiert. Es wird gesammelt und aus einer Mi  schung    von   Aceton und Äther umikristallisiert,    Fp.



  107-108  C.



   Beispiel 210
Eine Lösung von 20 g 1-(p-Acetamid-phenoxy)  2-brom-ätJhanund36gBaozylmethylamin    in 40 ml Benzol wird 3 Stunden unter Rückfluss erwärmt.



  Nach dem   Abkühlenwirdderausgeschiedenefeste    Stoff abfilrtiert und mit Benzol gewaschen. Das mit der   Wascbflüssigk'eit vereinigte Filtrat wird mit über-      schüssiger 2n Salzsäure extrahiert. Das    Basisch  macben des Extrakts    mit   überschüssigem.Ammoniak    liefert   1-      (p-Acetamido-, phenoxy)-2-    (N-benzyl-N  methylamino)-äthanalsÖl,    das in der Folge fest wird.



  Es wird gesammelt und aus wässrigem Methanol oder einer Mischung von Athylacetat   undPetroläther    (Kp.



     40-60 C)umkristallisiert,Fp.62-64     C,   klarwer-      den-d    bei   72  C.   



   , 11 g dieser Base wenden mit 8 g Methyljodid in   40      mfl    Aceton   umgesetzt und liefern N-2- (p-Acet-      amidophenoxy)-äthyl-N-benzyl-N,.N-di.methylammo- niumjodid, Fp. 230-23 l  C.   



   Man leitet Chlorwasserstoff in 8   g    des so   erhalte-    nen Jodids in 80 ml Methanol bis zur Sätigug. Man erh, itzt die Losung 6   Stundsm. unter Rückfluss. Beim    Eindampfen   bleibt ein gummiantiger Stoff zurück,    der beim Kochen. mit Äthanol kristallisiert. Man Sammelt   dem festen. Stoff    und kristallisiert ihn durch Abscheiden aus warmem   MethanolmittelsÄtiber,    um   N-2-    (p-Aminophenoxy)-äthyl-N-benzyl-N,N-dimethyl  ammonium-hydrochloridzuerhalten,Fp.229-280     C.



  



  Process for the preparation of new quaternary ammonium compounds Pie invention relates to a. Process for the preparation of new quaternary ammonium compounds of the formula
EMI1.1
 wherein R is a phenyl radical which is substituted in the meta or para position by a halogen atom or an alkyl, alikoxy, hydroxy, formyl, acetyl, alkoxycarbonyl, amino, acetamido, cyano or nitro group; L one optionally in the ortho-, m. eta or para position with a halogen atom d or an alkyl, alkoxy, cyano or nitro group substituted phenyl radical or r an optionally in S-.

   Position with a halogen atom or a nitro group substituted thienyl radical; W there. s Oxygen atom or a straight, saturated chain that contains 1 to 3 non-adjacent oxygen atoms and 1 to 16 carbon atoms;

   X and Y, which are the same or different. an allyl, allyl, propargyl or a /? -, - or (5-hydroxyalkyl group or XY also linked together the tetr, amethylene, penta-methylene or 3-oxa-pantzamethylene group; and A is a monovalent anion or a normal- Equivalent to ei, n, es mean several antoms, all of the above-mentioned alkyl or alkoxy radicals containing a maximum of 4 carbon atoms.



   Such compounds are effective in controlling nematodes, e.g. B. Syphacia obvelata, Aspiculuris tetraptera or Trichureis muris in mice, Toxocara cati in cats, Toxocara canis, Trischuris vulpis or Ancylostoma canum in dogs, Ascaridia galli in chickens or kill Ascaris. lufmtbricoides in pigs in vitro.



     The process according to the invention is characterized in that a tertiary amine which contains three of the four groups bonded to the N atom of formula I is reacted with a quaternizing agent which still contains the fourth group, or a tertiary amine of the formula
EMI1.2
 where Q is the tetramethyliene, pentamethylene or 3-oxapentamethylene group and z, a cleavable radical which forms the ion A-, quaternizes by intramolecular conversion.



   The compounds of formula 1 are new, with the exception of those which have the Mgemden cations: N-5- (p-chloro-phenoxy) -3-oxapently-Np-chlorobenzyl N, N-dimethylammonium, N-benzyl-N-5- (p -methyl-phenoxy) -3-oxapently
N, N-dimethylammonium, N-'Banzyl-N, N-diethyl-N-2- (m-methoxy-p'henoxy) -ethylammonium and N-benzyl-N, N-diethyl-N-2- (m- butoxy-ph, enoxy) - äthylammoni um.



   The anion A "can be the remainder of a therapeutically usable acid, for example a chloride, bromide, iodide, sulfate or methylene sulfate anion.



     From the above it can be seen: that. the chain -W-CHs-CH- can be, for example, one of the following groups: -O- (CH2) a - (CH2) bO- (CH2) c -0- (CH2) aO- (CH2) e- - (CH2) fO - (CH2) gO- (CH2) h -0- (CH2i) -O- (CH2) jO- (CH2) k - (CH2) lO- (CH2) mO- (CH2) nO- (CH2) on these formulas the letters attached to the CH2 groups mean whole numbers; a, c, e, h, k and o are each at least 2;

   a or the sum of b and c or the sum of d and e or the sum of f, g and h or the sum of i, j and k or the sum of 1, m, n and o is not more than
18. For example B. W - CH2-CH2- be one of the following groups: 3-oxatrimethylene, 8-oxaoctamethylene, 6-oxasdecamethylene, 3, 5-dioxapentamethylene, 779-dioxanonamethylene, 5, 8-dioxadecamethylene, 81l-dioxatridecamethylene, 3, 5 , 7-TrioxaheEtamethylene, 4, 7, 10-Trioxadecamethylene, 3, 5, 7-Trioxao. ctamethylene ,.



  6, 9, 13-trioxapentadecamethylene.



   N-5- (p-Cblophenoxy) -3-oxapentyl-N-p-chlorobenzyl-N, N-dimethylammonium sulfate is mentioned in the literature, but not described in any way.



  The following connections. have been described, but their worm-killing effects are not recognized: N-Benzyl-N-5- (pmethylnphenoxy) ^ 3-oxapentyl-
N, N, dimethylammonium-n-dodecyloxyacetate, N-benzyl-N, N-diethyl-N-2- (m-methoxy-phenoxy) ethylammonium chloride and N-benzyl-N, N-diethyl-N-2- (m- tent.-butoxy-phenoxy), ethylammonium chloride.



   Particularly useful of the compounds obtainable according to the invention have proven to be those for the control of Syphacia obvelata and Aspi culuris tetraptera in mice in which R is a p-bromophenyl radical, or a p-chlorophenyl radical if W contains only one oxygen ation; for effective control of Trichuris muris in mice those in which R is an n p -nitrophenyl residue, and for A, btoton of Ascaris lumb, ricoides in vitro those, dea-enKationN-p-'nitrobenzyl-N-2- (p- nitrophenoxyethyl) pyrrolidinium or Np-chloro- 'benzyl-N-2 - () p-chlorophenoxyethyl) pyrrolidinium.



   The chain W preferably contains only one oxygen atom and no more than no more carbon atoms.



     Preferred are those Sal! ze of formula I which are in water-difficult solids, e.g. B. less than 2.0 / o w / v. at 20 C. The worm-killing effect remains and the toxic effects on the host are odorless.

   Particularly useful salts form or result in: boron fluoride, perchlorate, lauryl sulfate, dodecyl benzene sulfonate, p-toluyl sulfo. nat, p-chlorobenzenesulfonate, p-bromobenzenesulfonate, p-acylamidbenzenesulaonate, N-acylamido acid, diphanyl-4-sulfonate, napthalene-1-sulfonate, naphthalene-2-sulfomate, naphthalene-1, 5 disulfo. nat, NaphthaHn-2,7-disulfonate, 1-naphthol-3,6-disulfonate, 2-naphthol-3,6-disulfonate, 1-npathoate, 2-naphthoate, 2-hydroxy-3-n aphthoate, 4,4'-dihydroxy-diphenylmethane-3,3'-dicarboxylate, 2,2'-dihydroxy-'l, l'-dm.aphthylniethan-3, 3 'dicarboxylate, piperazine-1,4-bis-carbodithiate , 4, 4'-Dimainostilen-2,2'-disulfoate or phenates, such as 2, 4,5-trichloropheenate.



   Suitable salts of the formula are, for example, the chlorides, ammides or amides of the solbhe which contain a sulfonic ester group -O-SO2-E-, in which E is a substituted and unsubstituted hydrocarbon residue, e.g. B. the tolyl group is. tThe quaternization of the master’s amine formula
EMI2.1
 with an agent releasing the benzyl or thenyl hest, and the intramolecular quaternization of the amine of the formula II is expediently carried out in a solvent, e.g. B. in propan-2-ol or in acetone. The former implementation is easy; the second, however, requires continued heating.

   Quaternification can also be carried out by heating compounds of the formula R-W-CHg-CH-Z and the formula XYN-CHL together without a solvent.



   As said, tertiary amines of the formula R-W-CH2-CH2-NX # CH2L e.g. B. quaternize an alkyl radical. If X and Y are the same, one can also use a secondary amine of the formula R-W-CH2-CH2-CNH-CH2 # L with two equivalents of an alkylating agent. s. of the formula YZ in the presence of an acidic binding agent, e.g. soda or potash. In this reaction, aichintermediate-tertiary amine forms the formula RW-CH2-CH2-NX # CH2L, so that the formation of the tertiary amine and its quaternization in one Operation is going on.

   B. Examples of the alkylating agents that can be used for this reaction are methyl iodide, dimethyl sulfate, methyl p0-toluyl sulfonate, ethyl iodide, id, ethyl p-toluene sulfonate and 2-hydroxyethyl iodide. It is advisable to use more than the theoretical amount of the alkylating agent in order to achieve good yields. Both reactions can be carried out in a solvent, e.g. B. in methanol or in acetene, carried out.



   Compounds in which NXY is the pyrrolidino, piperidino or morpholino group can, as said, be prepared in such a way that! a compound of formula II quaternized intramolecularly.



  These amines can be prepared in the form of their salts by treating the corresponding hydroxy compound of the formula R-W-CH2-CH2-N [XY # OH] - CH2 with a halogenating agent, e.g. B. with ThionylchTorid, Bro.mwa.sserstoff, hydrogen iodide or with a sulfonyl chloride, z. B. with p-ToluyIsulfonyl- chloxid, implemented. The salt is best converted into the free base and the internal quaternization be works by, mam the free base either on, itself or in a solvent, e.g. B. in isobutanol or in a mixture of benzene and ethanol. heated.

   The rate of the reaction depends on the nature of Z.



     Compounds obtainable according to the invention in which NXY is the pyrrolidino, piperidino or morpholino group can also be prepared by converting a secondary amine of the formula RW-CH2 CH2-NH # CH2L with a, # = disustituen butane, pentane or 3-oxapentane Formula Z1-Q-Z2, in which Zt and Z2 denote radicals which can be split off, one of which, being the radical which forms ion A, converts.



     Ales. Examples are: 1,4-dibromobutane,
1, 4-DicMorbutam,
1,4-Diniethylsulfonn.yloxyb.utan), 1,4-Di-p-toluylsulfonloxy-bozan, 1-Bromo-4-chlorobutene, 1,5-Di-p-toluyIsulfonyloxybutan und 1,5-Di-p-toluyl- sulfonyloxy-3-oxapentane.



   The reaction is preferably carried out in the presence of an acid binding agent, e.g. B. of soda or potash, by the starting materials per se or in a solvent, for. B. in isobutanol or a mixture of benzene and ethanol. The reaction proceeds with the formation of the tertiary amine of the formula II, so that the formation of the said tentiary amine and its intramolecular quaternization take place simultaneously.



   If R is a phenyl radical bearing an amino group, in most cases, when preparing the compounds obtainable according to the invention, these groups must have a size. protect group G, e.g. B. with an acyl or alkoxycarbonyl group or a sulfonic ester group-OSO2E. In such reactions, R is therefore a group NHG @ Ph-, where Ph means Pbenyking. After the quaternary compound has been formed, the protective group G. is removed again by hydrolysis.



   The salts obtainable according to the invention can during or after the reaction according to the invention by double reaction, e.g. B .. in solution o, which is converted with an anion exchanger into the salt of another anion. This is particularly desirable when one wants to prepare a salt that is sparingly soluble in water or when one has used an α, # -disubstituted compound g of the formula Z1-Q-Z2 and Zt and Z2 are different from one another.



     The compounds obtainable according to the invention can be followed in more rigid form.



   example 1
A mixture of 139 g of p-nitrophenol, 259 g of 1,4-dibromobutane and 40 ml of isopropanol and 1 liter of water is heated to reflux with stirring. A solution of 34 g of sodium hydroxide in 300 ml of water is added in the course of 3 hours. The mixture will. then stirred for a further 3 hours. After heating, the aqueous layer is removed and extracted with ether. The combined organic layers are washed three times with 2N sodium hydroxide solution in order to remove unreacted p-nitrophenol. The ethereal solution is washed with water, dried over potash, filtered and evaporated.

   After vacuum distillation, the residue gives 1-bromo-4- (p-nitrophenoxy) -butran, boiling point 144-146 C 0.06 mm.



   A solution of 62 g of this ether in 154 g of ethanolic demethytairnin (33% by weight) is heated to 80 ° C. in an autoclave for 6 hours. The resulting reaction mixture is evaporated on the steam bath. The residue is dissolved in excess 4N hydrochloric acid and the non-basic by-products are removed with ether. When excess ammonia is added to the acidic layer, an oil louse separates out, which is used to over-extract.



  The essential solution is washed over with water. Potash dried, filtered and evaporated.



     The oil is redissolved in excess 4m hydrochloric acid and the solution is evaporated in vacuo. After recrystallizing twice from methanol, this residue yields 1-dimethylamino-4- (p-n-nitrophenoxy) butane-hydroxchloride, melting point 173 ° C. The pure base is released again with excess ammonia and isolated with ether as a yellow oil which slowly solidifies, melting point 20 C.



   4 g of benzyl bromide are added to a solution of 5 g of this base in 10 ml of acetone. The solution heats up and is then refluxed for 30 minutes. On cooling, a crystalline solid separates out, which is recrystallized from laopnopanol. N-Benzyl-N, N-dimethyl-N-4 - '(p-nitrophenoxy) -butylammomium bromide, m.p. 152 C.



   Example 2
4.1 g of 5-chlorothenyl chloride (5-chloro-2'-chlonmetthylthiophone) are added to a solution of 3.52 g of sodium iodine in 10 ml of acetone and the mixture is heated. After 30 minutes, the precipitated sodium chloride is filtered off and washed with a little fresh acetone. 5.7 g of l-dimethylamino-4- (p-nitrophenoxy) butane are added to the filtrate and the solution is refluxed for 30 minutes. After cooling, the precipitated crystals are filtered off and washed with ethyl acetate. The ! solid N (5-chlorothenyl) -N, N-dimethyl-N-4- (p-nitrophenoxy) butylammonium iodide is recrystallized from methanol, melting point 139-140 C.



   Example 3
A solution of 7.8 g of 1-bromo-2- (P-chlorophenoxy) -ethane and 15 g of benzylamine in 15 ml of benzene is heated on the steam bath for 5 hours. After getting cold, the mixture is filtered and the residue washed with fresh benzene. The filtrate combined with the washing liquid is shaken with excess 4N hydrochloric acid, whereupon solid 1-benzylamino-2- (p-chlorophenoxy) -ethane hydrochloride separates out. This is filtered off and recrystallized from isopropanol containing 10 ouzo ethanol in the form of colorless needles, melting point 190-191 C.



   This hydrochloride (5.96 g) is treated with aqueous ammonia to obtain the fresh base, which is isolated with ether. This base is added to a slurry of 5.3 g of soda in 15 ml of methanol, followed by 14. 5 g matbyl iodide. The resulting mixture is heated under reflux for 2 hours and filtered warm. Ether is added to the filtrate and N-benzyl-N-2- (p-chlorophenoxy) ethyl N, N-dimethylammonium iodide, which is recirculated from ethanol, is obtained. crystallized, m.p. 166 C.



   Example 4
A mixture of 20 g of 1-bromo-2- (p-chlorophenoxy) -ethane and 22 g of benzylmethylamine is heated to 70 C, whereupon a quick, exothermic reaction takes place. After cooling, dissolve the semi-solid mass in excess hydrochloric acid and wash the solution with ether. Treatment with sodium hydroxide solution, extraction with 2ither and evaporation of the dried extract gives a basic oil which is separated by partial distillation in benzyne-ethylamine and 1-benzylmethylamine-2-p-chlorophenoxyethane, b.p. 158 C / 0.01 mm.



   This base (5 g) and the same amount of ethyl p toluyisulfonate are heated in 50 mils of boiling acetone for 3 hours. Let cool and add ether. If the N-benzyl-N-2- (p-chlorophenoxy) -ethyl-N-ethyl-N-methyl-ammonium-p-tolulsulphonate separates out, which forms colorless platelets when recrystallized from ethyl acetate, melting point 121- <122 C.



   Table I contains further quaternary ammonium compounds which were prepared by the methods described above. Table II contains the physical properties of starting compounds which have been used for the production of the substances contained in Table 1, insofar as they are not described in the literature.



   In Tables I and II, R2, R3, R4 and Rg denote the substituents on the rings; in table I I means A-the anion.



  Table I (A)
EMI4.1
 Example WCHsCHa X Y Ri A-kriatail'lized from Fp. C No.



     5 O (CH2) 2 CH3 CH3 p-NO2 Cl ethanol / methanol 228-229
6 O (CH2) 2 C2H5 C2H5 p-NO2 J Methandol 172-173
7 O (CH2) 2 - (CH2) 4- p-NO2 Cl ethanol 199-200
8 O (CH- (CHa) e-p-NOaJethanol193-193, 5
9 O (CH2) 2 - (CH2) 2O (CH2) - p-NO2 J methanol 191-192
10 O (CH2) s CH3 CHs p-NO2 Cl ethanol 202-203
11 O (CH2) 3 - (CH2) 4- p-NO2 J methanol 203
12 O (CH2) 3 - (CH2) 5- p-NO2 J water.

   Methanol 201
13 O (CH2) 2 CH3 CH3 p-Cl Cl methanol 225-226
14 O (CH2) 2 C2H5 C2Hs p-Cl J Ethanol 163-164
15 O (CH2) 2 - (CH2) 4- p-Cl Cl ethanol 183-184
16 O (CH2) (CH,) .- p-Cl J methanol 200-201
17 O (CH2) 2 - (CH2) 2O (CH2) 2-p-Cl J Methandol 177-178
18 O (CH2) 3 CH3 CH3 p-Cl Cl methanol 127-128
19 O (CH2) cHeCsHgp-CIJ-VsHaOethanol145-146
20 O (CH2) 3 - (CH2) 4- p-Cl J methanol 175
21 O (CH2) 3 - (CH2) 5- p-Cl J methanol 170-171
22 0 (CH2) 3 - (CH2) 2O (CH2) 2- p-Cl J Metanol 199-200
23 O (CH2) CH3 Ch3 p-Cl Cl # ¸H @ O ethanol / ethyl acetate 137 24 O (CH2) 5 CH3 CH3 p-Cl Cl ethanol 158-159
25 O (CH2)

  6 CH3 CH3 p-Cl Cl ethanol / ethyl acetate 157
Table (A) (continued) Example WCHzCBb X Y Ri A- crystallized from mp. O c no.



   26 CH20 (CH2) 2 CHS CH3 p-Cl J methanol / ethanol 180-182
27 O (CH2) 3 CH3 CH3 p-Br Br Mothanol / ethyl acetate 179-180
28 O (CH2) s C2H5 C2Hs p-Br Br Ethanol 206
29 O (CH2) 3 - (CH2) 4- p-Br Br methamine / ether 140
30 O (CH2) 5 CH3 CH3 p-Br Br Metanol 165
3. CHO (CHCHsCH, p-BrBrAthamol200-203
32 O (CH2) 3 CH3 CH3 p-F Cl # 2H2O ethanol / ether 85
33 O (CH2) 3 - (CH2) 4- p-F J Athanot / Methamol 171
34 O (CH2) 4 CH3 CH3 p-F J ethanol 165
35 O (CH2) 5 CH3 CHS p-F J ethanol 117
36 O (CH2) 3 CH3 CH3 p-J Br aq.

   Methanol 209
37 O (CH2) 3 C2H5 C2Hs p-J Br methanol 220
38 O (CH2) 3 - (CH2) 4- p-J Br methanol 208
39 O (CH2) 5 CH3 CH3 p-J Br methanol 203
40 O (CH2) CHS CHs PJ Br methanol 153-154
41 O (CH2) 2 CH3 CH3 p-CN Cl methanol 222-223
42 O (CH2) a- (CH2) 4- m-Cl Br Ethanol 212
43 O (CH2) 2 CH3 Ch3 o-Cl Cl # H2O ethanol / isopropanol 112-113
44 O (CH2) 3 CH3 CH3 o-Cl J Ethanol 118
45 O (CH2) 3 C2H5 C2H5 o-Cl J methanol 173-174
46 O (CH2) 3 - (CH2) 4- o-Cl J methanol 133 47 O O (CH2) 2 CH3 CHS H Br ethanol / isopropzanol 159-160
48 0 (CH2)

  2 C2H5 C2H5 H Br ethanol 139-140
49 O (CH2) 2- (CH2) 4- H Br Ethajiol 164-165 50 O (CH2) 2 - (CH2) 5- H J methanol 197-198
51 O (CH2) 3 CH3 CH3 H Br ethanol / ether 113
52 O (CH2) s C2H, C2H5 H Br ethanol 130
53 O (CH2) 3 - (CH2) 4- H Br ethanol 155 54 O (CH2) s CHS CHS H Br ethanol 168-169
55 O (CH2) 6 CH3 CH3 H Br ether / isopropanol 112
Table I (B)
EMI5.1
 Example w # CH2CH2 X Y R1 A- crystallized from mp. C No.



   55 (b) O (CH,) sCH, CH, p -NOClAthanol / Methamol 208-209
56 O (CH23) 2 - (CH2) 4- p-NO2 Cl # H2O isopropanol / ethyl acetate 98-99
57 O (CH2) 2 CH, CH3 p-Cl G11 isopropanol / ether 185, 5-187 58 O (CH2) 2 - (CH2) 4- p-Cl Cl isopropanol / ether 154-155
59 O (CH2) 2 CH, CHS m-Cl Br.

   Isopropanol 163-164
60 O (CH2) 2 CH3 Ch3 o-Cl Cl # H2O isopropanol / ether 114-115 61 1 O (CH2) 2 CH3 CH3 H CL isopropanol / ethyl acetate164-165
62 O (CH2) 2 - (CH2) 4- H J isopropanol / ethyl acetate 124-125 Table Z (C)
EMI6.1
 Example WCBbCHz X Y Ri A1 crystallizes from mp. C no.



   63 O (CH2) 2 CH3 CH3 p-NO2 Cl Ethanol 211-212
64 O (CH2) 2 C2H5 C2H5 p-NO2 J methanol 184
65 O (CH2) 2 - (CH2) 4- p-NO2 J methanol 199
66 O (CH2) 2 - (CH2) 5- p-NO2 Cl # ¸H2O isopropanol / ether 198
67 O (CH2) 2O (CH2) 2 CH3 CH3 p-NO2 Cl isopropanol 156-157
68 O (CH2) 2 CHS CH3 p-Cl Cl methanol 214-2145
69 O (CH2) 2 C2H5 C2H5 p-Cl J methanol 185
70 O (CH2) 2 - (CH2) 4- p-Cl J methanol 170 7. 1 O (CH2) 2 - (CH2) 5- p-Cl Cl ethanol / ether 154
72 O (CH2) 3 CH3 CH3 p-Cl Cl # H2O isopropanol / ethyl acetate 104-105
73 O (CH2)

  3 C2h5 C2H5 p-Cl J isopropanol / ethanol 166-167
74 O (CH2) 3 - (CH2) 4- p-Cl Cl # H2O isopropanol / ethyl acetate 145-146
75 O (CH2) 4 CH3 CH3 p-Cl Cl isopropanol / ethyl acetate 176-177
76 O (CH2) 4 C2H5 C2h5 p-Cl J isopropanol / ethyl acetate 150-151
77 O (CH2) 4 - (CH2) 4- p-Cl Cl # H2O Isopropanol / .ether 78-79
78 O (CH2) 5 CH3 CH3 p-Cl cl # H2O Ispropanol / Ethyl acetate 126-127
79 O (CH2) 5 C2H5 C2HS p-Cl Cl., Ethanol / ether 140-141
80 O (CH2) 5 - (CH2) 4- p-Cl Cl # H2O isopropanol / ether 157-158 810 (0)

  .CHsCHgp-ClClIsopropanol160-161
82 O (CH2) 6 CH3 CHg p-Cl J-1 / 2H2O methanol 190
83 O (CH2) 6 C2H5 C2H5 p-Cl Cl Isopropal 169
84 OCCHJe- (CHs) -p-ClClIsopropanol / ether 101
85 O (CH2) 40 CH3 CH3 p-Cl J methanol 161-162
86 O (CH2) -10 - (CH2) 4- p-Cl J methanol 123 87 O (CHO (CHCHgCHgp-0.01Isopropanol / Äfhar 124-125
88 O (CH2) 2O (CH2) 2- (CH2) 5-p-Cl J isopropanol 133-134
89 O (CH2) 6 CH3 CH3 m-Cl Br Ethanol 155-156
90 O (CH2) 6- (CH2) 4-m-Cl Br methanol 141-142
91 O (CH2) 2O (Ch2) 2 CH3 CH3 m-Cl Br IsQpropa.noI / ether93-94
92 O (CH2)

      2 CH3 CH3 o-Cl Cl-HsO ethanol 127
93 O (CH2) 2 C2H5 C2H5 o-Cl J isopropanol 124
94 O (CH2) 2 - (CH2) 4- o-Cl J methanol 159-160
95 O (CH2) 2 - (CH2) 5- o-Cl J Metanol 167
96 O (CH2) C2H5 C2H5 o-Cl J isopropanol 1360-137
97 O (CH2) 6 CH3 Ch3 o-Cl Cl methanol 178-179
98 O (CH2) 6 C2h5 C2H5 o-Cl J Ethanol 136-137
99 O (CH2) 6 - (CH2) 4- o-Cl Cl isopropanol / ether 153-154 100 O (CHs) 20 (CHCHgCHso-ClClIsopropanol / ether 129-130 101 O (CH2) 2 CH3 Ch3 p-Br Br methanol 226 102 O (CH2) 2 C2H5 C2H5 p-Br Br Ethanol 195 103 O (CH2) 2 - (CH2) 4- p-Br Br Ethanol 176 104 O (CH2) 2 (CH2)

      5- p-Br Cl ethanol / ethyl acetate 156 softens at 150 105 O (CH2) 2 CH3 CH3 p-CN J methanol 225 106 O (CH2) 2 - (CH2) 4- o-Br brithanol / lither 125 107 O (CH2 ) 2 CH3 CH3 H Br methanol 206 108 O (CH2) 2 C2H5 C2H5 H Br isopopanol / ether 150-151 109 O (CH2) 2 - (CH2) 4- H Br ethanol 158-159 110 OO (CH2) 2 - ( CH2) 5- H Br Isopropanol 187 111 O (CH2) 2 CH2 CH:

   CH2 H Br acetone / ethyl acetate 115 112 O (CH2) 2 CH3 C2H5 H J isopropanol 121, 123
Table I (C) (continued) Example WCH2CH2 X Y Ri A-crystallized from mp. C No.



  113 O (CH2) CHg CHg H Cl # H2O Ispropanol / ethyl acetate 118-119 114 O (CHJsQHgCHs HJ isopropanol / ethanol 140-141 115 O (CH2) 3 - (CH2) 4- H Cl-2H2O isopropanol / ethyl acetate 78-79 116 O (CH2) 4 CH3 Ch3 H Cl # ¸ H2O Isopropopaol / Ethyl acetate 150-151 117 O (CH2) 4 C2H5 C2H5 HJ Isopropanol 142-143 118 O (CH2) 4 - (CH2) 4- H Cl # H2O Isopropanol / Ether 91-92 119 O (CH2) 5 CH3 CH3 H Cl.

   H2O isopropanol / ethyl acetate 167-168 120 O (CH2) 5 C2H5 C2H6 H Cl isopropanol / ethyl acetate 199-200 121 O (CHJg- (CHHCl.HaOIsopropanoVäther 105-106 122 O (CH2) 6 CH3 CH3 H Br Athaniol 157- 158 123 O (CH2) C2H5 C2H6 H Br Ethanol 139-140 124 O (CH2) 6 - (CH2) 4- H Br isopropanol 145 125 O (CH2) 10 CH3 CH3 H Br Ethanol 125 126 O (CH2) 10 C2H5 C2H5 H Br Ethanol / Ether 121-122 127 O (CH2) 10 - (Ch2) 4- H Br Ethanol / Ethyl acetate 115-118 128 O (CH2) 2O (CH2) 2 CH3 CH3 H ci Isopmpaiiol / Ether 119-120 129 O ( CH2) 2O (CH2) 2- (CH2)

   4-H J Isopropanol 124-125 Table I (D)
EMI7.1
   Example WCHzCH2 X Y Ri A-crystallized from mp. C No.



  130 O (CH2) 2 CH3 CH3 p-NO2 Cl Methanol 229-230 131 O (CH2) 2 C2h5 C2ht p-NO2 J # ¸H2O Metanol 164-165 132 O (CH,), - (CH) -p-NOgC1- 2HOIsopro) panol / ether 175 133 O (CH2) 2 - (CH2) 5- p-NO2 Cl Ethanol / ether 194 134 O (CH2) 2 - (CH2) 2O (CH2) 2- p-NO2 J water 187 135 O (CH2) 2 CH3 CH3 p-Cl Cl Ethandol 228-229 136 O (CH2) 2 C2H5 C2H5 p-Cl J Ethanol 186-187 137 O (CH2) 2 - (CH2) 4- p-Cl Cl # ¸H2O n -Butanol / ether 156 138 O (CH2) 2 - (CH2) 5- p-Cl Cl isopropanol / ether 189 139 O (CH2) 0 (CH-p-ClJ.lV, HsOethanol 197 140 CH20 (CH2)

        CHCHgp-ClJethanol 178-181 141 O (CH2) 2 CH3 CH3 p-Br Br methanol 232-233 142 O (CH2) 2 CH, CH3 pJ Br methanol 223-224 143 O (CH2) 2 4CH2) 4-p-CN J Ethanol 189-192 144 (CH2O (CH2) 2 CH3 CH3 p-CN J Ethano9l 147-150 145 O (CH2) 2 CH3 Ch3 o-Cl Cl Ethanol / ether 115-117 146 O (CH2) 2 - (CH2) 4- o-cl Cl # H2O n-butanol / ether 84-85 147 O (CH2) 2 - (CH2) 5- o-Cl J Metahanl 151 148 O (CH2) 2 - (CH2) 2O (CH2) 2- o-Cl Cl # ¸H2O Metahanol 142 149 O (CH2) 2 CH3 CH3 H Br 2ithanol 194-195 150 0 O (CH2)

  2 C2H5 C2h5 H Br Ethanol 137-138 151 O (CH2) 2 - (CH2) 4- H Br Ethanol / Eth & r 124 152 O (CH2) 2- (CH2) 5- H Br Ethanol 184 153 O (CH2) 2 H Br Ethanol / ether 178-179 154 O (CH2) 2 CH3 C3H7 HJ ether / ethyl acetate 128-130 155 O (CH2) 2 CH3CH2-CH CH: CH2H J isopropanol 106-108 156 CH2O (CH2) 2 CH3 CH3 HJ Ethandol 149-151 Table I (E)
EMI8.1
 No. nature u. Position X Y Naturu.

   A- crystallized from m.p. e C Example of Ra position of Rs 157 p-CN C2h5 C2h5 p-NO2 J Metannol 196-998 (dec.) 158 p-CN C2Hs C2H5 p-CN J Math. Anot 189-193 159 p-CHs CH3 CH3 p-NO2 Cl methanol 217-218 160 p-CH3 CH3 CH3 p-Cll C1 ethanol 222-223 161 p-Ch3 CH3 CH3 o-Cl ClH,

  0 Ethanol 110-112 162 p-CH3 CH3 CH3 Cl # H2O Br Ethanol 147-148 163 p-CH3O CH3 CH3 Br ci Ethanol 177-178 164 p-CH30 CH3 CH3 d Cl Methanol 167-168 165 p-CH3O CH3 CH5 Cl Cl # H2O Isopropanol / Ethyl acetate 82-83 166 p-CH3O CH3 CH3 o-Cl J Ethanol 133-136 167 p-CH3CONH CH3 CH3 H Cl Athawol 183-184 168 p-CHO CH3 CH3 p-Cl J Methanol 205-208 169 p- CHeCo CH3 CH3 P-NO2 J Ethanol 177-178 170 p-CH3CO CH3 Ch3 p-NO2 J Ethanol 122-123 171 p-CH30CO - (CH2) 2O (CH2)

  2-HJ Methanol 168-170 172 p-C2H5O #CO - (CH2) 5- JJ Ethanol / Ethylactate 130-132 173 p-OH CH3 CH3 p-NO2 J Ethanol 178-180 174 m-CH3 CH3 CH3 p-Cl Cl Ethanol 178-179 175 m-CH3 CH3 CH3 J methanol 169-170 176 m-CH3 C2H5 C2H5 p-NO2 Cl isopropanol 154-155 177 m-CH3 C2H5 C2H5 p-Cl Cl isopropanol 202-203 178 m-CH3 CH,

     CH3 o-Cl Cl # H2O Isopropanol 93-94 179 m-CH3 C2H5 C2HS H Br Ethanol 124-152 180 m-CH30 CH3 CH3 p-Cl Cl Ethanol 173-174 181 m-Ch3O CH3 CH3 p-NO2 Cl Isopropanol 147- 148 182 m-CH3O C2H5 C2h5 p-NO2 Cl Ethanol / Isopropanol 159-161 183 m-CHO C2H5 C2HS p-Cl Cl Ethanol / Isopropanol 177-178 184 m-CH3O - (CH2) 4- p-NO2 Cl Ethanol 158- 159 185 m-CH3O - (CH2) 4- p-Cl Cl Ethanol / isopropanol 161-162 186 m-CHj) CH3 CH3 o-Cl Cl Isopropanol 150-151 187 m-CHeO CH3 CH3 HJ Ethanol 130-131 188 m- CH3O- (CH2) 4-H Br IsopDopanoI / Ethyl acetate 95-96
Table f (F)

     
EMI8.2
 Example R4 WCHzCHs X Y Rs A- crystallized from mp. C No.



  189 Cl O (CH2) 2 CH3) CH3 H C1 Isopropanol 142 190 Cl O (CH2) 2 C2H5 C2H5 HJ Ethanol 1609 191 Br O (CH2) 2 CH3 CH3 H Cl Ethanol. / Ether 179-180 192 Br O (CH2) 2 - (CH2) 5- HJ methanol 196-199 193 Br O (CH2) 2 CH3 CH3 Cl Cl ethanol / ether 195-196 194 Br O (CH2) 2 C2H5 C2H5 Cl Cl-H20 isopnopanol 114
Table I (E) (continued) Example R4 WCH2CH2 X Y Ri A crystallized from Fp. C No.



  195 Br O (CH2) 2 - (CH2) 4- Cl J methanol 179-180 196 Br O (CH2) 2- (CH2) 5- Cl Cl ethanol / ether 202-203 197 N02 O (CH2) 2 CH3 CH3 C1 J methanol 158-159 198 N02 O (CH2) 2 C2H5 C2H5 Cl J methanol 139-140 0 199 No2 O (CH2) s CH3 CH3 ci J methanol 160-161 200 N02 O (CH2) 3 C2HS C2H5 Cl J methanol 164 201 N02 O (CH2) 3- (CH2) 4-Cl J ethanol 152 202 N02 O (CH2) 4 CH3 CH3 Cl J methanol 139-140
Table II, starting amines
EMI9.1
 nature u. Position WCH2CH2 X Y Kp.

   C of R2 p-NO2 O (CH2) 2 - (CH2) 5- not distilled p-NO2 O (CH2) 3 CH3 CH3 not distilled p-NO2 O (CH2) 3 C2H5 C2H5 not distilled p-NO2 O (CH2) 3 - (CH2) 4- not distilled p-NO2 O (CH2) 3 - (CH2) 5- 168-194 / 0.001 mm p-N02 O (CH2) 4 CH3 CH3 not distilled m.p. # 20 p-NO2 O ( CH2) 5 CH3 CH3 not distilled m.p. 35 P-NO2 O (CH2) 6 CH3 CH3 not distilled m.p. 35 p-NO2 CH2O (CH2) 2 CH3 CH3 110-112 / 0.05 mm m-N02 O (CH2) CHs CH, 101-105 / 0, 01mm m-N02 O (CH2) 2 - (CH2) 4- 128-135 / 0.01 mm p-Br O (CH2) 2 CH3 CH3 150-152 / 15 mm p- Br O (CH2) 2 C2H5 C2H5 104-108 / 0.1mm p-Br O (CH2) 2 Ch2 # CH: CH2 CH2 CH:

   CH2 1.14-, 118 / 0.07mm p-Br O (CH2) 2 - (CH2) 4- 116-120 / 0.1 mm p-Br O (CH2) 2 - (Ch2) 5- 124-128 / 0 .06 mm p-Br O (CH2) 3 CH3 CHs 94-98 / 0, 2 mm p-Br O (CH2) 3 C2H5 C2H5 108-11 / 0.1 mm p-Br O (CH2) 3 - (CH2) 4- 108-112 / 0.01 mm p-Br O (CH2) 4 CH3 CH3 98-150 / 0.15 mm p-Br O (CH2) 4 C2H5 C2Hs 111-ill7 / 0.08 mm p-Br O ( CH2) 4 - (CH2) 4- 113-119 / 0.05 mm p-Br O (CH2) 5 CH3 CH3 105-110 / 0.08 mm p-Br O (CH2) 5 C2H5 C2h5 118-122 C / 0.01 mm p-Br O (CH2) 5 - (CH2) 4- 126-131 / 0.06 mm p-Br O (CH2) 6 CH3 CH3 108-115 / 0.01 mm p-Br O (CH2 ) 6 C2H5 C2H5 120-125 é / 0.02 mm p-Br O (CH2) 6 - (CH2) 4- 18-132 / 0.02 mm p-Br O (CH2) 10 CH3 CH3 162-170 /. 0.2 mm p-Br O (CH2) 10 C2H5 C2H5 175/0,

  25 mm p-Br 0 (CH2) 10 - (CH2) 4- 176-186 é / 0.15 mm p-Br O (CH2) 2O (CH2) 2CH3 CH3 136-138 / 0.08 mm p-Br0 ( CH,), 0 (CHJ, - (CH,), - 160-164 / 0.7mm p-Cl O (CH2) 2 CH3 Ch3 139-145 é / 16 mm p-Cl O (CH2) 2 C2H5 C2H5 160 -180 / 30mm p-CX O (CH2) (CH) -107-110 / 0.4mm p-Cl O (CH2) 2 - (CH2) 5- 1760-178 / 13 mm p-cl O (CH2) 2 - (CH2) O (CH2) - 130-125é / 0.15 mm
Table II Starting Amines (continued) Nature & Position WCH2CH2 X Y Kp.

   C of R2 p-Cl CH2O (CH2) 2 CH6 CH3 144-150 / 10 mm p-CN0 (CHCaHgCHg120-.126 / 0mm p-Ch3CONH O (CH2) 2 CHs CH3 undistilled p-CHO O (CH2) 2 CH3 CH3 108 / 0.2 mm p-CH3O # CO O (CH2) 2 - (CH2) 2O (CH2) 2- 166 / 0.05 mm p-C2H5O -CO O (CH2) 2 - (CH2) 5- 160- 165 / 0.1 mm p-CH3 O (CH2) 2 CHa CH3 121 '/ 16 mm m-CH3 O (CH2) 2 CH3 CH3 119/12 mm mC H3 O (CHCCHg141 /17.mm m-CH3O O (CH2 ) 2 CH3 CH3 85-87 / 0.08 mm m-CH3O O (CH2) 2 - (CH2) 4- 104 / 0.05 mm 1-Benzylamino-2- (m-methoxyphenoxy) -ethane 1- (N- methyl-Nm-methylbenzylamino) -2-phenoxy has a Kp = 176-182 C / 0.5 mm ethane has a Kp = 124-128 C / 0,

  1 mm example 203
A solution of 250 g of N-'o-chlorobenzyl-N-2- (p-chlorophenoxy) -ethyl-N, H-dimethylammonium chloride is added. (See Example 145) in 500 ml of water slowly with stirring to a solution of. 191g sodium p-tolulsulphonate in 400 ml water. As the addition progresses, a crystalline solid separates out. Then one jets. the mixture stand for 17 hours and filtered. The filter cake is washed with Wassler and recrystallized from a mixture of isopropanol and ether.



  N-o-chlorobenzyl-N-2- (p-chlorophenoes) ethyl-N, N-dimethylammonium toluylsulfonate, m.p. 1460-147 C.



   Example 204
According to the method described in Example 203, Np-chloropbenzyl-N, N-dimethyl-N-2- (p-nirophenoxy-ethyl-ammonium chloride (Beinpisl 13) is converted into the following salts: I. p-chlorobenzenesulfonate, melting point 238- 23-90 ° C; solubility at 20 ° C about 0.1 "/ o wt / vol.



     II. P-Toluene sulfonate, m.p. 226-227 C;
Solubility at 20 about 0.2%
III. 4,4'-diaminostilbene "2,2disu !! fbnat-mjonfohyd.rat,
M.p. 181-182 C; Solubility at 20 about 0.1 / o;
IV. 2-hydroxy-3-naphatosate, m.p. 129-130; Solubility at 20 C about 0.1 zozo;
V. Emponat monohldry, m.p. 185-186 C;
Solubility at 20 about 0.1 c / o;
VI. Iodide, m.p. 201-202 C;
Löslickhleit at 20 about 0.2%, and VII. 2, 4, 2-5 triclorophenate, FP. 125-125 é C.



   Example 205 A solution of 100 g of p-hydroxyacetophenone in 100 ml of ethanol is added in stages to a solution of 16.9 g of sodium in 500 l of ethanol. Then 174 g of ethylene dibromide (25 '' excess) are added. The mixture is then heated under a flow of air for 5 hours, cooled and poured into water. The oil is extracted with ether and the extract is washed exhaustively with 2N sodium hydroxide solution. The essential solution is dried over anhydrous potash, filtered and. evaporates.

   The residue is distilled in vacuo and p- (2-bromoaphoxy) -acotophenone, boiling point 128-136 C / 0.2 mm, this substance solidifies at 55 C.



   A solution of 20 g of this compound in 10 ml of ethanol is added to 56 g of alcoholic dimethylamine (33% by weight). The mixture is heated for 6 hours at 60 ° C. and then evaporated on the steam bath. Excess 2N hydrochloric acid is added to the residue and the insoluble oil is removed with ether.



  The acidic solution is treated with excess concentrated ammonia and the precipitated O1 is extracted with ether. The extract is dried over pot ash, filtered and evaporated. The residue is vacuum distilled and yields p- (2-dimethylaminoätboxy-acetophenone, boiling point 128-132 C / 0.25 mm.



   , 3.86 g of finely powdered potassium iodide are added to a solution of 3.8 g of chlorobenzyl chloride in 5. ml of acetone and then 4.0 g of p- (2-diethylaminoethoxy) acetophenone and the mixture is heated under reflux for 1½ hours. The mixture of solid substances is filtered off, washed with ethyl acetate and the inorganic substances are removed with water. The insoluble part is filtered off, washed with free water and repeatedly recrystallized from ethanol.



   N-2- (p-Acethylphenopxy) -ethyl-N-p-chlobenzyl N, N-dimethylammonium iodide, m.p. 133-134 C.



   Example 206
A mixture of 14.3 g of p-cyanophenol, 23 g of 2-chloroethyldimethylamine hydrochloride and 12.8 g of sodium hydroxide BoxydS. The mixture is heated and stirred in 100 ml. boiling toluene for 20 hours. The cooled mixture is extracted with dilute hydrochloric acid and the extract is washed with ether. Treatment of the acidic extract with) sodium hydroxide sets 2- (p-cyano-phenoxy) -ethyl-dimethylamine free as an oil, which is isolated with ether and distilled, bp.

   108-110 C / 0.2 mm,
Treatment of this base (3.3 g) with an excess of cyambenzyl iodide (6.5 g) in 50 ml of boiling acetone gives N- (p-cyano-benzyl) -N- [2- (p-cyano-phenoxy) -ethyl] -N, N-dimethylaminoium iodide, which crystallizes from methanol in colorless prisms, m.p. 213-214 C.



   Example 207
3.25 g of metallic sodium are dissolved in 60 ml of dry ethanol, a solution of 10 g of ethyhp-hydroxybenzoate in 25 ml of ethanol and then a suspension of 15 g of N- (chloroethyl) -morpholine hydrochloride in 50 ml of the same solvent are added.



     The mixture is refluxed for two hours and then left to stand overnight. The precipitated salts are filtered off, the alcohol is evaporated off, water is added and the solution is basified with ammonia in the presence of ice. Extraction with chloroform and distillation gives N-2- (p-ethoxycarbonyl-phenoxy) -öäthylmorpholin the counting liquid oil, boiling point 178 C / 0, 2 mm.



   The reaction of 5.0 g of this base with 7.5 g of p-chlorobenzyl iodide in 50 ml of acetone yields N-p CMo! Ibenzyl-N-2- (p-ethoxycacbonyl-pbsnoxy) -ethyl-morpholinium iodide. Umikdstallized from a mixture of ethanol and ethyl acetate it forms needles, m.p.



  157-158 C.



   Example 208
A suspension of 13 g of N-2- (p-acetaminophenxoy) -ethyl-N-p-chlorobenzyl-N, N-dimethylammonium chloride (cf. Example 168) in 100 ml of methanol is saturated with hydrogen chloride and the solution is heated under reflux for 3 hours. The evaporation. the mixture gives a rubbery substance which solidifies by rubbing it with ethyl acetate.



  The N-2- (p-aminophenoxy) -ethyl-N-p- is crystallized. chlorotbenzyl-'N, N-.dimethyl'ammoniumchlorifd- hydrochloride from ethanol, mp 172-174 ° C. (using a bath preheated to 140 ° C.).



  An aqueous solution of this solid substance is treated with ammonia to pH 8-9 and iodine-potassium is added to obtain N-2- (p-aminophenoxy) -ethyl-2-p-chlorobenzyl-N, N-dimethylammonium iodide; Recrystallized from isopropanol, mp 163-164 C.



   Example 209
43 g of 1-bromo-2- (m-methyl-phenoxy) ethane are added to a solution of 510 g of benzylamine in benzene and the mixture is heated on a steam bath for 4 hours. After cooling, the insoluble solid is filtered off and washed with fresh benzene.



  The filtrate combined with the washing liquid is shaken with excess 4N sodium hydroxide solution. The aqueous layer is separated off, the remaining benzene layer is dried over solid potassium hydroxide, filtered and evaporated. The residue is distilled in vacuo and yields 1-benzylamino-2- (m-methylphenoxy) ethane, bp. 134-145 C / 0.5 mm.



   13 g of this base are slowly added to a cooled mixture of 7 ml of formic acid (98%) and 6.8 ml of formalin (35% by weight). The mixture obtained is heated on a steam bath for 8 hours, treated with 8 ml of concentrated hydrochloric acid and then evaporated in vacuo. The 1- (N benzyl-N-m! Ethylamino) -2- (m-mssthyl-phenoxy) -ethane is treated with ammonia. released and isolated with ether as a colorless liquid, bp 138-142 C / 0.08 mm.



   2 g of this base are dissolved in 10 ml of acetone and 2 g of methyl iodide are added. After 4 hours, ethyl acetate is added until the onset of cloudiness, then N-benzyl-N-2- (m-methyl-phenoxy) -ethyl-N, N-dimethylammonium: iodide slowly crystallized out. It is collected and recrystallized from a mixture of acetone and ether, mp.



  107-108 C.



   Example 210
A solution of 20 g of 1- (p-acetamide-phenoxy) 2-bromo-ethane and 36 g of baozylmethylamine in 40 ml of benzene is heated under reflux for 3 hours.



  After cooling, the precipitated solid is filtered off and washed with benzene. The filtrate combined with the washing liquid is extracted with excess 2N hydrochloric acid. The basic maceration of the extract with excess ammonia gives 1- (p-acetamido-, phenoxy) -2- (N-benzyl-N methylamino) -ethane oil, which then solidifies.



  It is collected and extracted from aqueous methanol or a mixture of ethyl acetate and petroleum ether (bp.



     40-60 C) recrystallized, melting point 62-64 C, clearing-d at 72 C.



   , 11 g of this base are reacted with 8 g of methyl iodide in 40 ml of acetone and yield N-2- (p-acetamidophenoxy) -ethyl-N-benzyl-N, .N-di.methylammonium iodide, melting point 230- 23 l C.



   Hydrogen chloride is passed into 8 g of the iodide thus obtained in 80 ml of methanol until it is saturated. The solution is heated for 6 hours. under reflux. When evaporating, a rubbery substance is left behind, which is what happens when cooking. crystallized with ethanol. One collects the solid. Substance and crystallized by precipitation from warm methanol by means of ether to give N-2- (p-aminophenoxy) ethyl-N-benzyl-N, N-dimethyl ammonium hydrochloride, m.p. 229-280 C.

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung neuer quatemärer Ammoniumverbindungen der Formel EMI11.1 worin R einen in meta-oder pan-Stellung mit einem Halogenatom oder einer Alfkyl-, Alkoxy-, Hydroxy-, Formyl-, Acetyl-, Alkoxycarbonyl-, Aminlo-, Acet amiido-,Cyan-oderNitDogruppesuibstituieiten Phenylrest ; PATENT CLAIM Process for the preparation of new quaternary ammonium compounds of the formula EMI11.1 wherein R is a phenyl radical in the meta or pan position with a halogen atom or an alkyl, alkoxy, hydroxy, formyl, acetyl, alkoxycarbonyl, aminlo, acetamiido, cyano or nitro group having substituents; L einen gegebenenfaNsinderortho-,meta-oder para-.StM'ULHgmiteinemHalogenatoim.oder einer Alkyl-, Alkoxy-, Cyan-oder Nitrogruppe substituierter Pyhenylrest oder einen gegebenefalls in 5-Stellung mit einem Halogenatol oder einer. Nitrogruppe sub- stituierten Thienylrest ; W das. SauerstoiSEatom oder 'einegeradegesättigteKette,diel bis 3 nicht neben- einander liegende Sauerstoffatome und 1 bis 16 Kohlenstoffatome enthält; L is optionally a pyhenyl radical substituted in the 5-position by a halogen atom or an alkyl, alkoxy, cyano or nitro group, or a pyhenyl radical which is optionally substituted in the 5-position by a halogen atom. Nitro group-substituted thienyl radical; W the oxygen atom or a straight saturated chain which contains up to 3 non-adjacent oxygen atoms and 1 to 16 carbon atoms; X und Y, die gleich oder ver schiedensind,jeeineAlkyl-, die Ailyl-, Prqpargyl- oder eine ss-, &gamma;-oder #-Hydroxyalkylgruppe oder XY zusammen eine Tetramethylen-, Rentamethylen-oder 3-Oxapentamethylengruppe ; X and Y, which are the same or different, are each an alkyl, the ailyl, prepargyl or an β, γ or -hydroxyalkyl group or XY together a tetramethylene, rentamethylene or 3-oxapentamethylene group; und A- ein einwertiges Anion oder ein normal-Äquivalent eines mehrwerti- gen Anions bedeuten, wobei alle obegenannten Alkylbzw. Alkoxyrestehöchstens.4C-Atomeenth'alten, dadurch gekennzeichnet, dass s man ein tertiäres Amin, welches drei der vier an'dasN-AtomderFonnel1 gebundene Gruppen enthält, mit einem die noch fehlende vierte Gruppe enthaltenden Quaternisierungsmittel umsetzt oder dass man ein tertiäres Amin der Formel EMI12.1 worin Q die Tetramothylen-, Pentamethylon-oder 3-Oxa-pemtamsthylenjgruppeundZeinenabspalt- baren,dasIonA"bildendenRestbedeutet, durch mtrajnole.kular.eUmsetzungquatermsieit. and A- is a monovalent anion or a normal equivalent of a polyvalent anion, where all of the above-mentioned alkyl or. Alkoxy radicals contain a maximum of 4C atoms, characterized in that a tertiary amine which contains three of the four groups bonded to the N atom of the formula 1 is reacted with a quaternizing agent containing the fourth group which is still missing, or a tertiary amine of the formula EMI12.1 where Q denotes the tetramothylene, pentamethylone or 3-oxa-pemtamsthylenj group and Zeinen cleavable radical forming the ionA ", by mtrajnole.kular.e conversion it is quaterms. UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man ein tertiäres Amin der Formel EMI12.2 mit einem den Benzyl- oder Thenylrest abgebenden Mittel umsetzt. SUBClaims 1. The method according to claim, characterized in that a tertiary amine of the formula EMI12.2 with a benzyl or thenyl radical releasing agent. 2. Verfahren nach Patentanspruch, dadurch ge kensnzeichnet, dass ma ein tertiäres Amin der formel EMI12.3 mit einem den Rest R-W-CH2--CH2-abgebenden Mittel umsetzt. 2. The method according to claim, characterized ge kensnzeich that ma a tertiary amine of the formula EMI12.3 with a remainder R-W-CH2 - CH2-releasing agent. 3. Verfahren n, ach. Patentanspmich, dadurch gekennzeichnet, dass man ein tenäres Afmin der Formel EMI12.4 mit einemAJlkylieriungsmittel'umsetzt. 3. Procedure n, ach. Patent claim, characterized in that a tenary Afmin of the formula EMI12.4 reacted with an alkylating agent. 4. Verfahren nach Patentanspmich, dadutch ge kennzeidhnet, dass R der p-Bromphenylrest ist. 4. The method according to patent application, dadutch ge indicates that R is the p-bromophenyl radical. 5. Verfahren nach Patenftajisprucb, dadurch ge kennzeichniet, dass R der pwNitrophenyltest ist. 5. The method according to Patenftajisprucb, characterized in that R is the pwnitrophenyl test. 6. Verfahren nach Patentanspruch, dadurch ge kennzeichnet, dass R der p-Chlorphenylrest ist und W ein Sauerstoffatom enthält. 6. The method according to claim, characterized in that R is the p-chlorophenyl radical and W contains an oxygen atom. 7. Verfahren nach Patentanspruch, dadurch ge kennzeichnet,dassmandieerhaltenenProdukte durch Austauschen des Anions in schwere wasserunlösliche Salle überführt. 7. Process according to claim, characterized in that the products obtained are converted into heavy water-insoluble salts by exchanging the anion.
CH270760A 1959-03-13 1960-03-10 Process for the production of new quaternary ammonium compounds CH422758A (en)

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EP0017209A1 (en) * 1979-04-04 1980-10-15 BASF Aktiengesellschaft Substituted alkylammonium salts, their preparation and use in plant growth regulation

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ES410734A1 (en) * 1973-01-18 1976-01-01 Rocador Sa Butacaine pamoate
US3956369A (en) * 1973-05-18 1976-05-11 Ozeretskovskaya Natalia Nikola N-β-(2-acetyl-4-chlorophenoxy)-ethyl-N,N-dimethyl-N-benzyl-ammonium-p-chlorobenzene sulphonate, method for preparing same and medicinal preparation based thereon
JPS53144554A (en) * 1977-04-12 1978-12-15 Nattermann A & Cie New basic paraabenzoylether
DE3233828A1 (en) * 1982-09-11 1984-03-15 Basf Ag, 6700 Ludwigshafen ARYLOXYALKYLAMINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE FOR CONTROLLING UNWANTED PLANT GROWTH
GB9321812D0 (en) * 1993-10-22 1993-12-15 Smithkline Beecham Plc Pharmaceuticals
GB9321811D0 (en) * 1993-10-22 1993-12-15 Smithkline Beecham Plc Pharmaceuticals
EP0982300A3 (en) * 1998-07-29 2000-03-08 Societe Civile Bioprojet Non-imidazole alkylamines as histamine H3 - receptor ligands and their therapeutic applications
EP0978512A1 (en) * 1998-07-29 2000-02-09 Societe Civile Bioprojet Non-imidazole aryloxy (or arylthio) alkylamines as histamine H3-receptor antagonists and their therapeutic applications
DE10235312A1 (en) 2002-08-01 2004-02-12 Basf Ag Process for the preparation of aminoalkoxybenzylamines and aminoalkoxybenzonitriles as intermediates
US20130178653A1 (en) * 2010-09-21 2013-07-11 Imperial College Novel precursor of radiolabelled choline analog compounds
MX2022011194A (en) * 2020-03-11 2022-11-08 Nocion Therapeutics Inc Charged ion channel blockers and methods for use.

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DE1117600B (en) * 1956-03-29 1961-11-23 Wellcome Found Process for the preparation of quaternary ammonium salts effective against nematodes

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EP0017209A1 (en) * 1979-04-04 1980-10-15 BASF Aktiengesellschaft Substituted alkylammonium salts, their preparation and use in plant growth regulation
US4350518A (en) 1979-04-04 1982-09-21 Basf Aktiengesellschaft Plant growth regulating substituted alkylammonium salts

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