DE1238485C2 - Process for the preparation of quaternary ammonium salts - Google Patents

Process for the preparation of quaternary ammonium salts

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Publication number
DE1238485C2
DE1238485C2 DE1960W0027453 DEW0027453A DE1238485C2 DE 1238485 C2 DE1238485 C2 DE 1238485C2 DE 1960W0027453 DE1960W0027453 DE 1960W0027453 DE W0027453 A DEW0027453 A DE W0027453A DE 1238485 C2 DE1238485 C2 DE 1238485C2
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ethanol
methanol
ether
isopropanol
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DE1238485B (en
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Geoffrei George Coker
Frederick Charles Copp
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Wellcome Foundation Ltd
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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
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    • 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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    • 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
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
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    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • 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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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—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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    • 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
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    • 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

Description

BUNDESREPUBLIK DEUTSCHLANDFEDERAL REPUBLIC OF GERMANY

Int. Cl.:Int. Cl .:

C07cC07c

DEUTSCHESGERMAN

PATENTAMT C07d
Deutsche Kl.: 12 q-32/01 PATENT OFFICE C07d
German class: 12 q- 32/01

PATENTSCHRIFTPATENT LETTERING

Nummer:Number:

Aktenzeichen:File number:

Anmeldetag:Registration date:

Auslegetag:Display day:

Ausgabetag:Issue date:

W27453IVb/12q 14. März 1960 13. April 1967 26. Oktober 1967W27453IVb / 12q March 14, 1960 April 13, 1967 October 26, 1967

Patentschrift stimmt mit der Auslegeschrift übereinThe patent specification corresponds to the patent specification

Es wurde festgestellt, daß quartäre Ammoniumsalze der allgemeinen FormelIt was found that quaternary ammonium salts of the general formula

Ri
R — O — (CH2)„ — N — CH2 — Ra Ri
R - O - (CH 2 ) "- N - CH 2 - Ra

R2 R 2

worin R einen in p-Stellung halogen- oder nitrosubstituierten Phenylrest, R] und R2 niedermolekulare Alkylreste oder zusammen die Tetramethylengruppe, R3 einen gegebenenfalls in beliebiger Stellung halogensubstituierten Phenylrest oder eine gegebenenfalls in 5-Stellung halogensubstituierte Thienylgruppe, ΑΘ ein Anion und η eine ganze Zahl von 2 bis 5 bedeutet, wirkungsvoll dem Befall mit Nematoden entgegenwirken und z. B. Syphacia obvelata, Aspiculuris tetraptera oder Trichuris muris bei Mäusen, von Toxocara cati in Katzen, von Toxocara canis, Trichuris vulpis oder Ancylostoma caninum in Hunden oder von Ascaridia galli in Küken von Hühnern oder Ascaris lumbricoides von Schweinen in vitro abtöten.where R is a phenyl radical which is halogen or nitro-substituted in the p-position, R] and R 2 are low molecular weight alkyl radicals or together the tetramethylene group, R3 is a phenyl radical which is optionally halogen-substituted in any position or a thienyl group which is optionally halogen-substituted in the 5-position, Α Θ an anion and η a Whole number from 2 to 5 means, effectively counteract the infestation with nematodes and z. B. Syphacia obvelata, Aspiculuris tetraptera or Trichuris muris in mice, of Toxocara cati in cats, of Toxocara canis, Trichuris vulpis or Ancylostoma caninum in dogs or of Ascaridia galli in chicks of chickens or Ascaris lumbricoides of pigs in vitro.

Die aus der deutschen Patentschrift 1 117 600 bekannten konstitutionell ähnlichen quartären Ammoniumsalze besitzen, wie Versuche mit verschiedenen Nematodenarten bei Tieren gezeigt haben, keine oder nur geringe Wirkung gegen Nematoden. So wird, wie Versuche mit Syphacia obvelata zeigten, bei Verwendung der dort beschriebenen orthosubstituierten Derivate bei mehrtägiger, meist 3tägiger Anwendung selbst so beachtlicher Mengen wie 300 bis 500 mg/kg täglich nur ein Teil der Würmer entfernt, während bei Verwendung der erfindungsgemäß hergestellten Verbindungen bereits bei einer ltägigen Verabfolgung entsprechender Mengen eine praktisch 100°/()ige Wurmbefreiung erzielt wird.The constitutionally similar quaternary ammonium salts known from German Patent 1,117,600 as experiments with various nematode species in animals have shown, little or no action against nematodes. As experiments with Syphacia obvelata have shown, when using the orthosubstituted derivatives described there for multi-day, usually 3-day periods Applying even as considerable amounts as 300 to 500 mg / kg daily only removes part of the worms, while when using the compounds prepared according to the invention already for an everyday Administering appropriate amounts practically 100% worm clearance is achieved.

Auch bei Versuchen mit Trichuris muris zeigte sich die hohe Aktivität der erfindungsgemäß hergestellten Verbindung im Vergleich zu den gleichmäßig unwirksamen oder nur gering wirkenden bekannten quartären Ammoniumverbindungen.Tests with Trichuris muris also showed the high activity of those produced according to the invention Compound in comparison to the equally ineffective or only slightly effective known quaternary ammonium compounds.

Das Verfahren der Erfindung ist dadurch gekennzeichnet, daß in an sich bekannter Weise ein tertiäres Amin, welches drei der im Endprodukt gewünschten Stickstoffsubstituenten enthält, unter Einführung des vierten gewünschten Substituenten quaterniert wird und gegebenenfalls das so erhaltene Salz in das Salz eines anderen Anions übergeführt wird.The method of the invention is characterized in that in a known manner a tertiary amine, which three of the desired in the end product Contains nitrogen substituents, is quaternized with the introduction of the fourth desired substituent and optionally the salt thus obtained is converted into the salt of another anion.

Nach dem Verfahren der Erfindung werden bevorzugt Verbindungen hergestellt, in denen R ein Bromphenylrest, ein Chlorphenylrest oder ein p-Nitrophenylrest, die den Befall von Mäusen mit Syphacia Verfahren zur Herstellung von quartären AmmoniumsalzenAccording to the process of the invention, compounds are preferably prepared in which R is a bromophenyl radical, a chlorophenyl residue or a p-nitrophenyl residue, which can infest mice with syphacia Process for the preparation of quaternary ammonium salts

Patentiert für:Patented for:

The Wellcome Foundation Limited, LondonThe Wellcome Foundation Limited, London

Vertreter:Representative:

Dr. M. EuleDr. M. Owl

und Dipl.-Chem. Dr. rer. nat. W. J. Berg, Patentanwälte, München 2, Hilblestr. 20and Dipl.-Chem. Dr. rer. nat. W. J. Berg, Patent Attorneys, Munich 2, Hilblestr. 20th

Als Erfinder benannt:
Frederick Charles Copp,
Geoffrei George Coker, LondonNamed as inventor:
Frederick Charles Copp,
Geoffrei George Coker, London

Beanspruchte Priorität:Claimed priority:

Großbritannien vom 13. März 1959 (8878, 8879),Great Britain March 13, 1959 (8878, 8879),

vom 20. November 1959dated November 20, 1959

(39 558, 39 559)(39 558, 39 559)

obvelata oder Aspiculuris tetraptera wirksam vermindern, ferner Verbindungen mit einem N-p-Nitrobenzol-N-2-p-nitrophenoxyäthylpyrrolidinium- oder N-p-Chlorobenzyl-N-2-p-chlorophenoxyäthylpyrrolidinium - Kation, die Ascaris lumbricoides von Schweinen in vitro abtöten, sowie ganz allgemein Salze, die wenig in Wasser löslich sind, z. B. weniger als 2,0% Gewicht/Volumen bei 200C. Dabei bleibt die anthelmintische Aktivität des Kations erhalten, während die toxischen Eigenschaften auf das Wirttier sehr vermindert sind.obvelata or Aspiculuris tetraptera, as well as compounds with an Np-nitrobenzene-N-2-p-nitrophenoxyethylpyrrolidinium or Np-chlorobenzyl-N-2-p-chlorophenoxyethylpyrrolidinium cation that kill Ascaris lumbricoides in pigs in vitro, as well as in general Salts that are sparingly soluble in water, e.g. B. less than 2.0% weight / volume at 20 0 C. The anthelmintic activity of the cation is maintained while the toxic properties are very reduced to the host animal.

Die nachfolgenden Beispiele erläutern die Erfindung. The following examples illustrate the invention.

Beispiel 1example 1

N-Benzyl-N,N-dimethyl-N-4-p-nitrophenoxybutylammon iumbromidN-Benzyl-N, N-dimethyl-N-4-p-nitrophenoxybutylammonium bromide

Eine Mischung aus 139 g p-Nitrophenol, 259 g 1,4-Dibrombutan, 40 ml Isopropanol und 11 Wasser wurde unter Rühren mit Rückfluß erhitzt, wobei eine Lösung von 34 g Natriumhydroxyd in 300 ml Wasser im Verlauf von 3 Stunden langsam zugegeben wurde. Das Gemisch wurde dann noch weitere 3 Stunden gerührt. Nach Abkühlen wurde die wäßrige Schicht entfernt und mit Äther extrahiert. Die kombinierten organischen Schichten wurden dreimal mit 2 n-Natronlauge gewaschen, um unverändert gebliebenesA mixture of 139 g of p-nitrophenol, 259 g of 1,4-dibromobutane, 40 ml of isopropanol and 1 liter of water was heated to reflux with stirring, a solution of 34 g of sodium hydroxide in 300 ml of water was added slowly over 3 hours. The mixture was then left for an additional 3 hours touched. After cooling, the aqueous layer was removed and extracted with ether. The combined organic layers were washed three times with 2N sodium hydroxide solution to leave unchanged

709 703/282709 703/282

p-Nitrophenol zu entfernen. Die ätherische Lösung wurde mit Wasser gewaschen, über Kaliumcarbonat getrocknet, filtriert und eingedampft. Der Rückstand wurde unter reduziertem Druck destilliert und ergab dabei l-Brom-4-p-nitrophenoxybutan; Kp.oo(>144 bis 146°C.Remove p-nitrophenol. The ethereal solution was washed with water over potassium carbonate dried, filtered and evaporated. The residue was distilled under reduced pressure to give l-bromo-4-p-nitrophenoxybutane; Bp oo (> 144 to 146 ° C.

Eine Lösung dieses Äthers (62 g) in einer Lösung von Dimethylamin in Äthanol (154 g; 35% Gewicht/ Gewicht) wurde bei 800C 6 Stunden lang in einem Autoklav erhitzt. Das resultierende Reaktionsgemisch wurde auf einem Dampfbad eingedampft. Der Rückstand wurde in 4 η-Salzsäure im Überschuß aufgelöst, und die nicht basischen Nebenprodukte wurden mit Äther entfernt. Bei Zusatz von Ammoniak im Überschuß zu der Säureschicht wurde ein öl ausgefällt, das mit Äther extrahiert wurde. Die ätherische Lösung wurde mit Wasser gewaschen, über Kaliumcarbonat getrocknet, filtriert und eingedampft. Das restliche öl wurde wiederum in 4n-Salzsäure im Überschuß aufgelöst, und die Lösung wurde unter reduziertem Druck eingedampft. Der Rückstand wurde zweimal aus Methanol auskristallisiert und ergab dabei 1-Dimethylamino-4-p-nitrophenoxybutanhydrochlorid; F. = 173°C. Die reine Base wurde mit Ammoniak im Überschuß regeneriert und mit Äther als ein gelbes öl isoliert, das anschließend erstarrte; F. = 200C.A solution of this ether (62 g) in a solution of dimethylamine in ethanol (154 g; 35% weight / weight) was heated in an autoclave at 80 ° C. for 6 hours. The resulting reaction mixture was evaporated on a steam bath. The residue was dissolved in excess 4η hydrochloric acid and the non-basic by-products were removed with ether. When ammonia was added in excess to the acid layer, an oil was precipitated which was extracted with ether. The ethereal solution was washed with water, dried over potassium carbonate, filtered and evaporated. The remaining oil was again dissolved in excess 4N hydrochloric acid, and the solution was evaporated under reduced pressure. The residue was crystallized twice from methanol to give 1-dimethylamino-4-p-nitrophenoxybutane hydrochloride; M.p. = 173 ° C. The pure base was regenerated with excess ammonia and isolated with ether as a yellow oil, which then solidified; F. = 20 0 C.

Einer Lösung von 5 g dieser Base in 10 ml Aceton wurden 4 g Benzylbromid hinzugesetzt, wobei das Gemisch heiß wurde. Es wurde schließlich 30 Minuten lang unter Rückfluß erhitzt. Beim Abkühlen schieden sich rasch Kristalle aus, welche aufgesammelt und aus Isopropanol umkristallisiert wurden. Man erhielt N-Benzyl-N,N-dimethyl-N-4-p-nitrophenoxybutylammoniumbromid; F. = 152°C..4 g of benzyl bromide were added to a solution of 5 g of this base in 10 ml of acetone, the Mixture got hot. It was finally refluxed for 30 minutes. When cooling down Crystals quickly separated out, which were collected and recrystallized from isopropanol. N-benzyl-N, N-dimethyl-N-4-p-nitrophenoxybutylammonium bromide was obtained; F. = 152 ° C ..

Beispiel 2Example 2

N-S-Chlorthienyl-NjN-dirnethyl-N^-p-nitrophenoxybutylammoniumjodid N-S-chlorothienyl-NjN-dirnethyl-N ^ -p -nitrophenoxybutylammonium iodide

4,1 g 5-Chlorthienylchlorid (5-ChIor-2'-chlormethylthiophen) wurden in einer Lösung von 3,52 g Natriumiodid in 10 ml Aceton hinzugesetzt; das Gemisch wurde erwärmt. Nach ^stündigem Stehenlassen wurde das ausgefällte Natriumchlorid abfiltriert und mit ein wenig frischem Aceton gewaschen. Dem Filtrat wurden 5,7 g l-Dimethylamino-4-p-nitrophenoxybutan hinzugesetzt, und die Lösung wurde 30 Minuten unter Rückfluß erhitzt. Nach dem Abkühlen wurden die ausgeschiedenen Kristalle abfiltriert und mit Äthylacetat gewaschen. Das verbleibende N-5-Chlorthienyl-N,N-dimethyl-N-4-p-nitrophenoxybutylammoniumjodid wurde aus Methanol auskristallisiert; F. = 139 bis 1400C.4.1 g of 5-chlorothienyl chloride (5-chloro-2'-chloromethylthiophene) were added to a solution of 3.52 g of sodium iodide in 10 ml of acetone; the mixture was heated. After standing for hours, the precipitated sodium chloride was filtered off and washed with a little fresh acetone. To the filtrate was added 5.7 g of 1-dimethylamino-4-p-nitrophenoxybutane, and the solution was refluxed for 30 minutes. After cooling, the precipitated crystals were filtered off and washed with ethyl acetate. The remaining N-5-chlorothienyl-N, N-dimethyl-N-4-p-nitrophenoxybutylammonium iodide was crystallized from methanol; F. = 139 to 140 0 C.

Beispiel 3Example 3

N-Benzyl-N-2-p-chlorphenoxyäthyl-N,N-dimethylammoniumjodid N-benzyl-N-2-p-chlorophenoxyethyl-N, N-dimethylammonium iodide

Eine Lösung von 7,8 g l-Brom-2-p-chlorphenoxymethan und 15 g Benzylamin in 15 ml Benzol wurde 5 Stunden lang auf einem Dampfbad erhitzt. Nach dem Abkühlen wurde das Gemisch filtriert, und der Rückstand wurde mit frischem Benzol gewaschen. Filtrat und Waschlaugen wurde miteinander mit 4 η-Salzsäure im Überschuß geschüttelt, wobei sich festes l-Benzylamino-2-p-chlorphenoxyäthanhydrochlorid ausschied. Nach dem Abfiltrieren und Umkristallisieren aus 10% Äthanol enthaltendem Isopropanol erhielt man farblose Nadeln; F. = 190 bis 1910C.A solution of 7.8 g of 1-bromo-2-p-chlorophenoxymethane and 15 g of benzylamine in 15 ml of benzene was heated on a steam bath for 5 hours. After cooling, the mixture was filtered and the residue was washed with fresh benzene. The filtrate and wash liquor were shaken together with excess 4η hydrochloric acid, solid 1-benzylamino-2-p-chlorophenoxyethane hydrochloride separating out. After filtering off and recrystallization from isopropanol containing 10% ethanol, colorless needles were obtained; F. = 190 to 191 0 C.

5,96 g dieses Hydrochlorids wurden mit wäßriger Ammoniaklösung behandelt und ergaben dabei die freie Base, welche mit Äther isoliert wurde. Einer Schlämme von 5,3 g Natriumcarbonat in 15 ml Methanol setzte man zunächst diese Base und dann 14,5 g Methyljodid hinzu. Das resultierende Gemisch wurde 2 Stunden lang unter Rückfluß erhitzt und heiß filtriert. Nach dem Zusatz von Äther zu dem Filtrat erhielt man N-Benzyl-N-2-p-chlorphenoxyäthyl-^N-dimethylammoniumjodid, das aus Äthanol umkristallisiert wurde; F. = 166°C.5.96 g of this hydrochloride were treated with aqueous ammonia solution and gave the free base, which was isolated with ether. A slurry of 5.3 g of sodium carbonate in 15 ml This base and then 14.5 g of methyl iodide were added to methanol. The resulting mixture was refluxed for 2 hours and filtered hot. After adding ether to the The filtrate was obtained N-benzyl-N-2-p-chlorophenoxyethyl- ^ N-dimethylammonium iodide, which was recrystallized from ethanol; M.p. = 166 ° C.

Beispiel 4Example 4

N-Benzyl-N-2-p-chlorphenoxyäthyl-N-äthyl-N-methylammonium-p-toluolsulfonat N-Benzyl-N-2-p-chlorophenoxyethyl-N-ethyl-N-methylammonium-p-toluenesulfonate

Ein Gemisch aus 20 g l-Brom-2-p-chlorphenoxyäthan und 22 g Benzylmethylamin wurde auf 700C erwärmt, wobei eine schnelle exotherme Reaktion erfolgte. Nach dem Abkühlen wurde die halbfeste Masse in verdünnter Salzsäure im Überschuß aufgelöst, worauf die Lösung mit Äther gewaschen wurde. Die Behandlung mit Natriumhydroxyd, die Extraktion mit Äther und das Eindampfen der getrockneten Lösung ergaben ein basisches öl, das durch fraktionierte Destillation in Benzylmethylamin und 1-Benzylmethylamin - 2 - ρ - chlorphenoxyäthan geschieden wurde; Kp.0,1 1580C.
5 g dieser Base und eine gleiche Menge Äthylp-toluolsulfonat wurden 3 Stunden lang in 50 ml siedendem Aceton erhitzt. Beim Abkühlen und Zusatz von Äther wurde N-Benzyl-N-2-p-chlorphenoxyäthyl-N-äthyl-N-methylammonium-p-toluolsulfonat ausgefällt, das aus Äthylacetat auskristallisierte und dabei farblose Blättchen bildete; F. = 121 bis 122°C.A mixture of 20 g of 1-bromo-2-p-chlorophenoxyethane and 22 g of benzylmethylamine was heated to 70 ° C., a rapid exothermic reaction taking place. After cooling, the semi-solid mass was dissolved in excess dilute hydrochloric acid, whereupon the solution was washed with ether. Treatment with sodium hydroxide, extraction with ether and evaporation of the dried solution gave a basic oil which was separated into benzylmethylamine and 1-benzylmethylamine - 2 - ρ - chlorophenoxyethane by fractional distillation; Bp 0.1 158 0 C.
5 g of this base and an equal amount of ethyl p-toluenesulfonate were heated in 50 ml of boiling acetone for 3 hours. Upon cooling and the addition of ether, N-benzyl-N-2-p-chlorophenoxyethyl-N-ethyl-N-methylammonium-p-toluenesulfonate was precipitated, which crystallized from ethyl acetate and formed colorless flakes; F. = 121 to 122 ° C.

In der nachfolgenden Tabelle I sind weitere quar-In the following table I are further quarters

täre Ammoniumverbindungen angeführt, welche nach ähnlichen Verfahren, wie sie im vorstehenden beschrieben worden sind, hergestellt wurden. Die Tabellen II und III geben die physikalischen Eigenschaften der Ausgangsstoffe an, die zur Synthese der in Tabelle I angeführten Verbindungen erforderlich waren.Tary ammonium compounds listed, which by procedures similar to those in the preceding have been described. Tables II and III give the physical properties the starting materials required for the synthesis of the compounds listed in Table I. was.

Tabelle I (A)
RiTable I (A)
Ri

NO2 NO 2

Bei
spielat
game Y .Y. RiRi R2 R 2 R1 R 1 ΑΘ Α Θ Lösungsmittel für
KristallisationSolvent for
Crystallization F.
°CF.
° C 5
65
6th 0(CH2)O
0(CHa)2 O (CH 2 ) O
0 (CHa) 2 CH3
C2H5CH 3
C2H5 CH3
C2H5 CH 3
C 2 H 5 p-Cl
P-Clp-Cl
P-Cl Cl
JCl
J Methanol
ÄthanolMethanol
Ethanol 225 bis 226
163 bis 164225 to 226
163 to 164

Fortsetzungcontinuation

Beiat VV RiRi P„P " CH3 CH 3 CH3 CH 3 CH3 CH 3 CH3 CH 3 CH3 CH 3 CH3 CH 3 CH3 CH 3 CH3 CH 3 R.R. ΛΘΛΘ Lösungsmittel fürSolvent for F.F. spielgame II. 1M 1 st 1XZ 1 XZ CH3 CH 3 CH3 CH 3 CH3 CH 3 — (CH2)4 —- (CH 2 ) 4 - CH3 CH 3 C2H5 C 2 H 5 CaH5 CaH 5 1X41X4 /Λ/ Λ KristallisationCrystallization 0C 0 C 77th O(CHa)aO (CHa) a -(CF- (CF Ia)4-Ia) 4 - CH3 CH 3 - (CH2)4 -- (CH 2 ) 4 - CH3 CH 3 CH3 CH 3 C2H5 C 2 H 5 — (CHa)4 —- (CHa) 4 - -(CHa)4-- (CHa) 4 - p-Clp-Cl ClCl ÄthanolEthanol 183 bis 184183 to 184 88th O(CH2)3 O (CH 2 ) 3 CH3 CH 3 CH3 CH 3 C2H5 C 2 H 5 CH3 CH 3 C2H5 C 2 H 5 CH3 CH 3 — (CHa)4 —- (CHa) 4 - CH3 CH 3 CH3 CH 3 p-Clp-Cl ClCl MethanolMethanol 127 bis 128127 to 128 99 0(CHa)3 0 (CHa) 3 C2H5 C 2 H 5 C2H5 C 2 H 5 — (CHa)4 —- (CHa) 4 - CH3 CH 3 — (CH2)4 —- (CH 2 ) 4 - CaH5 CaH 5 CH3 CH 3 C2H5 C 2 H 5 p-Clp-Cl J ■ Va H2OJ ■ Va H 2 O ÄthanolEthanol 145 bis 146145 to 146 1010 0(CHa)3 0 (CHa) 3 -(CHa)4-- (CHa) 4 - CH3 CH 3 CH3 CH 3 CH3 CH 3 C2H5 C 2 H 5 p-Clp-Cl JJ MethanolMethanol 175175 1111th 0(CHa)4 0 (CHa) 4 CH3 CH 3 CH3 CH 3 C2H5 C 2 H 5 p-Clp-Cl Cl- VaH2OCl-VaH 2 O Äthan öl—ÄthylacetatEthane oil - ethyl acetate 137137 1212th 0(CHa)5 0 (CHa) 5 CH3 CH 3 p-Clp-Cl ClCl ÄthanolEthanol 158 bis 159158 to 159 1313th 0(CHa)3 0 (CHa) 3 CH3 CH 3 p-Brp-Br BrBr Methanol—ÄthylacetatMethanol-ethyl acetate 179 bis 180179 to 180 1414th O(CH2)3 O (CH 2 ) 3 C2H5 C 2 H 5 p-Brp-Br BrBr ÄthanolEthanol 206206 1515th 0(CHa)3 0 (CHa) 3 p-Brp-Br BrBr Methanol—ÄtherMethanol — ether 140140 1616 O(CH2)5 O (CH 2 ) 5 p-Brp-Br BrBr MethanolMethanol 165165 1717th O(CH2)3 O (CH 2 ) 3 0-F0-F Cl ■ 2H2OCl ■ 2H 2 O Äthanol—ÄtherEthanol — ether 8585 1818th O(CH2)3 O (CH 2 ) 3 p-Fp-F JJ Äthanol—MethanolEthanol — methanol 171171 1919th 0(CHa)4 0 (CHa) 4 p-Fp-F JJ ÄthanolEthanol 165165 2020th 0(CHa)5 0 (CHa) 5 p-Fp-F JJ ÄthanolEthanol 117117 2121 0(CH2)s0 (CH 2 ) s p-Fp-F BrBr wäßriges Methanolaqueous methanol 209209 2222nd 0(CHa)3 0 (CHa) 3 p-Ipi BrBr MethanolMethanol 220220 2323 O(CH2)3 O (CH 2 ) 3 p-Ipi BrBr MethanolMethanol 208208 2424 0(CHa)5 0 (CHa) 5 p-Ipi BrBr MethanolMethanol 203203 2525th O(CH2)3 O (CH 2 ) 3 m-Clm-Cl BrBr ÄthanolEthanol 212212 2626th 0(CH2)a0 (CH 2 ) a o-Clo-Cl Cl · H2OCl · H 2 O Äthanol—IsopropanolEthanol-isopropanol 112 bis 113112 to 113 2727 0(CHa)3 0 (CHa) 3 o-Clo-Cl J ■J ■ ÄthanolEthanol 118118 2828 O(CH2)3 O (CH 2 ) 3 o-Clo-Cl JJ MethanolMethanol 173 bis 174173 to 174 2929 0(CHa)3 0 (CHa) 3 o-Clo-Cl JJ MethanolMethanol 133133 3030th O(CH2)aO (CH 2 ) a HH BrBr Äthanol—IsopropanolEthanol-isopropanol 159 bis 160159 to 160 3131 O(CH2)2 O (CH 2 ) 2 HH BrBr ÄthanolEthanol 139 bis 140139 to 140 3232 O(CH2)2 O (CH 2 ) 2 HH BrBr ÄthanolEthanol 164 bis 165164 to 165 3333 0(CHa)3 0 (CHa) 3 HH BrBr Äthanol—ÄtherEthanol — ether 113113 3434 0(CHa)3 0 (CHa) 3 HH BrBr ÄthanolEthanol 130130 3535 0(CHa)3 0 (CHa) 3 HH BrBr ÄthanolEthanol 155155 3636 0(CHa)5 0 (CHa) 5 HH BrBr ÄthanolEthanol 168 bis 169168 to 169

Tabelle I (B)Table I (B)

Beiat γγ RiRi R2 R 2 CH3 CH 3 CH3 CH 3 R.4R.4 ΑΘ Α Θ Lösungsmittel fürSolvent for F.F. spielgame KristallisationCrystallization 0C 0 C 3737 0(CHa)2 0 (CHa) 2 CH3 CH 3 CH3 CH 3 C2H5 C 2 H 5 C2H5 C 2 H 5 p-Clp-Cl ClCl MethanolMethanol 214 bis 215214 to 215 3838 O(CH2)2 O (CH 2 ) 2 C2H5 C 2 H 5 C2H5 C 2 H 5 p-Clp-Cl JJ MethanolMethanol 185185 3939 O(CH2)2 O (CH 2 ) 2 (CHa)4 (CHa) 4 p-Clp-Cl JJ MethanolMethanol 170170 4040 O(CH2)3 O (CH 2 ) 3 p-Clp-Cl Cl · H2OCl · H 2 O Isopropanol—ÄthylIsopropanol-ethyl 104 bis 105104 to 105 acetatacetate 4141 O(CH2)3 O (CH 2 ) 3 p-Clp-Cl JJ Isopropan öl—ÄthanolIsopropane oil - ethanol 166 bis 167166 to 167

Fortsetzungcontinuation

Bei
spielat
game YY RiRi R2 R 2 CH3 CH 3 CH3 CH 3 C2H5 C 2 H 5 CH3 CH 3 CH3 CH 3 CH3 CH 3 CH3 CH 3 p-Clp-Cl Cl · H2OCl · H 2 O Lösungsmittel für
KristallisationSolvent for
Crystallization F.
0CF.
0 C 4242 0(CHa)3 0 (CHa) 3 -(Ci-- (Ci- Ia)4-Ia) 4 - C2H5 C 2 H 5 C2H5 C 2 H 5 CH3 CH 3 C2H5 C 2 H 5 C2H5 C 2 H 5 CH3 CH 3 C2H5 C 2 H 5 p-Clp-Cl ClCl Isopropanol—Äthyl
acetatIsopropanol-ethyl
acetate 145 bis 146145 to 146 4343 O(CH2)4 O (CH 2 ) 4 CH3 CH 3 CH3 CH 3 — (CHa)4 —- (CHa) 4 - -(CHa)4-- (CHa) 4 - CaH5 CaH 5 — (CH2)4 —- (CH 2 ) 4 - C2H5 C 2 H 5 — (CHa)4 —- (CHa) 4 - p-Clp-Cl JJ Isopropanol—Äthyl
acetatIsopropanol-ethyl
acetate 176 bis 177176 to 177 4444 0(CHa)4 0 (CHa) 4 C2H5 C 2 H 5 C2H5 C 2 H 5 CH3 CH 3 C2H5 C 2 H 5 — (CHa)4 —- (CHa) 4 - CH3 CH 3 -ia)4 —-ia) 4 - p-Clp-Cl Cl · 2H2OCl • 2H 2 O Isopropanol—Äthyl
acetatIsopropanol-ethyl
acetate 150 bis 151150 to 151 4545 O(CH2)4 O (CH 2 ) 4 — (CHa)4 —- (CHa) 4 - CaH5 CaH 5 CH3 CH 3 (CHa)4 (CHa) 4 CH3 CH 3 CH3 CH 3 p-Clp-Cl Cl ■ H2OCl · H 2 O Isopropanol—ÄtherIsopropanol ether 78 bis 7978 to 79 4646 O(CH2)5 O (CH 2 ) 5 CH3 CH 3 C2H5 C 2 H 5 C2H5 C 2 H 5 C2H5 C 2 H 5 p-Clp-Cl ClCl Isopropanol—Äthyl
acetatIsopropanol-ethyl
acetate 126 bis 127126 to 127 4747 0(CHa)5 0 (CHa) 5 C2H5 C 2 H 5 -(CI- (CI — (CHa)4 —- (CHa) 4 - p-Clp-Cl Cl · H2OCl · H 2 O Äthanol—ÄtherEthanol — ether 140 bis 141140 to 141 4848 0(CHa)5 0 (CHa) 5 CH3 CH 3 CH3 CH 3 o-Clo-Cl Cl · H2OCl · H 2 O Isopropan öl—ÄtherIsopropane oil — ether 157 bis 158157 to 158 4949 0(CHa)2 0 (CHa) 2 C2H5 C 2 H 5 C2H5 C 2 H 5 o-Clo-Cl JJ ÄthanolEthanol 127127 5050 0(CHa)2 0 (CHa) 2 o-Clo-Cl JJ IsopropanolIsopropanol 124124 5151 0(CH2)a0 (CH 2 ) a o-Clo-Cl JJ MethanolMethanol 159 bis 160159 to 160 5252 0(CHa)5 0 (CHa) 5 p-Brp-Br BrBr IsopropanolIsopropanol 136 bis 137136 to 137 5353 O(CH2)2 O (CH 2 ) 2 p-Brp-Br BrBr MethanolMethanol 226226 5454 O(CH2)2 O (CH 2 ) 2 p-Brp-Br BrBr ÄthanolEthanol 195195 5555 0(CHa)2 0 (CHa) 2 o-Bro-br BrBr ÄthanolEthanol 176176 5656 0(CHa)2 0 (CHa) 2 HH BrBr Äthanol—ÄtherEthanol — ether 125125 5757 O(CH2)2 O (CH 2 ) 2 HH BrBr MethanolMethanol 206206 5858 0(CHa)2 0 (CHa) 2 HH BrBr Isopropanol—ÄtherIsopropanol ether 150 bis 151150 to 151 5959 0(CHa)2 0 (CHa) 2 HH JJ ÄthanolEthanol 158 bis 159158 to 159 6060 0(CHa)2 0 (CHa) 2 HH Cl · H2OCl · H 2 O IsopropanolIsopropanol 121 bis 123121 to 123 6161 0(CHa)3 0 (CHa) 3 HH JJ Isopropanol—Äthyl
acetatIsopropanol-ethyl
acetate 118 bis 119118 to 119 6262 0(CHa)3 0 (CHa) 3 HH Cl ■ 2H2OCl ■ 2H 2 O Isopropan öl—ÄthanolIsopropane oil - ethanol 140 bis 141140 to 141 6363 0(CHa)3 0 (CHa) 3 HH Cl- !/2H2OCl-! / 2H 2 O Isopropanol—Äthyl
acetatIsopropanol-ethyl
acetate 78 bis 7978 to 79 6464 0(CHa)4 0 (CHa) 4 HH JJ Isopropanol—Äthyl
acetatIsopropanol-ethyl
acetate 150 bis 151150 to 151 6565 O(CH2)4 O (CH 2 ) 4 HH Cl · H2OCl · H 2 O IsopropanolIsopropanol 142 bis 143142 to 143 6666 O(CH2)4 O (CH 2 ) 4 HH Cl ■ H2OCl · H 2 O Isopropanol—ÄtherIsopropanol ether 91 bis 9291 to 92 6767 0(CHa)5 0 (CHa) 5 HH ClCl Isopropanol—Äthyl
acetatIsopropanol-ethyl
acetate 167 bis 168167 to 168 6868 0(CHa)5 0 (CHa) 5 HH Cl ■ H2OCl · H 2 O Isopropanol—Äthyl
acetatIsopropanol-ethyl
acetate 199 bis 200199 to 200 6969 0(CHa)5 0 (CHa) 5 Isopropanol—ÄtherIsopropanol ether 105 bis 106105 to 106

Tabelle I (C) RiTable I (C) Ri

Beiat γγ RiRi CH3 CH 3 CH3 CH 3 CH3 CH 3 p-Clp-Cl ClCl Lösungsmittel fürSolvent for F.F. spielgame C2H5 C 2 H 5 p-Clp-Cl JJ KristallisationCrystallization CC C C 7070 O(CH2)2 O (CH 2 ) 2 CH3 CH 3 (CHa)4 (CHa) 4 p-Clp-Cl Cl- -ι/ζ H2O Cl- -ι / ζ H 2 O ÄthanolEthanol 228 bis 229228 to 229 7171 0(CHa)2 0 (CHa) 2 C2H5 C 2 H 5 p-Brp-Br BrBr ÄthanolEthanol 186 bis 187 186 to 187 7272 O(CH2)2 O (CH 2 ) 2 n-Butanol—Äthern-butanol ether 156156 7373 0(CHa)2 0 (CHa) 2 MethanolMethanol 232 bis 233232 to 233

Fortsetzungcontinuation

1010

Bei
spielat
game YY RiRi R2 R 2 CH3 CH 3 R4 R 4 Ae A e Lösungsmittel für
KristallisationSolvent for
Crystallization F.
°CF.
° C 7474 O<CH2)2 O <CH 2 ) 2 CH3 CH 3 CH3 CH 3 C2H5 C 2 H 5 p-Ipi BrBr MethanolMethanol 223 bis 224223 to 224 7575 O(CH2)2 O (CH 2 ) 2 CH3 CH 3 CH3 CH 3 -(CHa)4-- (CHa) 4 - o-Clo-Cl ClCl Äthanol—ÄtherEthanol — ether 115 bis 117115 to 117 7676 O{CH2)2 O {CH 2 ) 2 -(CHa)4-- (CHa) 4 - o-Clo-Cl Cl · H2OCl · H 2 O n-Butanol—Äthern-butanol ether 84 bis 8584 to 85 7777 O(CH2)2 O (CH 2 ) 2 CH3 CH 3 HH BrBr ÄthanolEthanol 194 bis 195194 to 195 7878 O(CH2)2 O (CH 2 ) 2 C2H5 C 2 H 5 HH BrBr ÄthanolEthanol 137 bis 138137 to 138 7979 O(CH2)2 O (CH 2 ) 2 HH BrBr Äthanol—ÄtherEthanol — ether 124124

Tabelle I (D) RiTable I (D) Ri

/V/ V

LH2"LH2 "

R5 ΑΘR 5 ΑΘ

RaRa

Beiat χχ γγ RiRi CH3 CH 3 CH3 CH 3 CH3 CH 3 RsRs Ae A e Lösungsmittel fürSolvent for F.F. spielgame C2H5 C 2 H 5 CaH5 CaH 5 KristallisationCrystallization °C° C 8080 ClCl O(CH2)2 O (CH 2 ) 2 CH3 CH 3 CH3 CH 3 CH3 CH 3 HH ClCl IsopropanolIsopropanol 142142 8181 ClCl O(CH2)2 O (CH 2 ) 2 C2H5 C 2 H 5 CH3 CH 3 C2H5 C 2 H 5 HH JJ ÄthanolEthanol 160160 8282 BrBr 0(CHa)2 0 (CHa) 2 CH3 CH 3 C2H5 C 2 H 5 -(CHa)4-- (CHa) 4 - HH ClCl Äthanol—ÄtherEthanol — ether 179 bis 180179 to 180 8383 BrBr O(CH2)2 O (CH 2 ) 2 CH3 CH 3 -(CHa)4-- (CHa) 4 - CH3 CH 3 ClCl ClCl Äthanol—ÄtherEthanol — ether 195 bis 196195 to 196 8484 BrBr 0(CHa)2 0 (CHa) 2 C2H5 C 2 H 5 CH3 CH 3 ClCl Cl · H2OCl · H 2 O IsopropanolIsopropanol 114114 8585 BrBr 0(CHa)2 0 (CHa) 2 C2H5 C 2 H 5 ClCl JJ MethanolMethanol 179 bis 180179 to 180 86,86 NO2 NO 2 O(CH2)2 O (CH 2 ) 2 CH3 CH 3 ClCl JJ MethanolMethanol 158 bis 159158 to 159 8787 NO2 NO 2 0(CHa)2 0 (CHa) 2 C2H5 C 2 H 5 ClCl JJ MethanolMethanol 139 bis 140139 to 140 8888 NO2 NO 2 G(CHa)3 G (CHa) 3 ClCl JJ MethanolMethanol 160 bis 161160 to 161 8989 NO2 NO 2 O(CH2)3 O (CH 2 ) 3 ClCl JJ MethanolMethanol 164164 9090 NO2 NO 2 0(CHa)3 0 (CHa) 3 ClCl JJ ÄthanolEthanol 152152 9191 NO2 NO 2 0(CHa)4 0 (CHa) 4 ClCl JJ MethanolMethanol 139 bis 140139 to 140

Tabelle II
Als Ausgangsstoffe verwendete AmineTable II
Amines used as starting materials

RO · CH2CH2 — NXY RiRO · CH 2 CH 2 - NXY Ri

X-/^^Y—N R2 X - / ^^ Y - N R 2

XX YY RiRi -(CI- (CI CH3 CH 3 R2 R 2 I2)s —I 2 ) s - CH3 CH 3 CH3 CH 3 Kp.Kp. nicht destilliertnot distilled NO2 NO 2 O(CH2)aO (CH 2 ) a C2H5 C 2 H 5 CH3 CH 3 nicht destilliertnot distilled NO2 NO 2 0(CHa)2 0 (CHa) 2 C2H5 C 2 H 5 CH3 CH 3 CH3 CH 3 nicht destilliertnot distilled NO2 NO 2 G(CHa)3 G (CHa) 3 -(CHa)4-- (CHa) 4 - nicht destilliertnot distilled NO2 NO 2 0(CHa)3 0 (CHa) 3 CH3 CH 3 CH3 CH 3 nicht destilliert;not distilled; NO2 NO 2 O(CH2)4 O (CH 2 ) 4 C2H5 C 2 H 5 C2H5 C 2 H 5 Schmelzpunkt ~20°CMelting point ~ 20 ° C nicht destilliert;not distilled; NO2 NO 2 O(CH2)5 O (CH 2 ) 5 Schmelzpunkt ~35°CMelting point ~ 35 ° C 150 bis 152°C/15 mm150 to 152 ° C / 15 mm BrBr 0(CH2)a0 (CH 2 ) a 104 bis 1O8°C/O,1 mm104 to 10 8 ° C / 0.1 mm BrBr 0(CHa)2 0 (CHa) 2

Fortsetzungcontinuation

χχ YY RiRi R2 R 2 — (CH2)4 —- (CH 2 ) 4 - CH3 CH 3 CH3 CH 3 CH3 CH 3 CH3 CH 3 (CH2)4 (CH 2 ) 4 CH3 CH 3 CH3 CH 3 CH3 CH 3 CH3 CH 3 CH3 CH 3 CH3 CH 3 Kp.Kp. BrBr O(CH2)2 O (CH 2 ) 2 C2H5 C 2 H 5 C2H5 C 2 H 5 C2H5 C 2 H 5 C2H5 C 2 H 5 C2H5 C 2 H 5 C2H5 C 2 H 5 C2H5 C 2 H 5 C2H5 C 2 H 5 116 bis 120°C/0,l mm116 to 120 ° C / 0.1 mm BrBr 0(CH2)s0 (CH 2 ) s -(CH2), —- (CH 2 ), - -(CHa)4-- (CHa) 4 - -(CHa)4-- (CHa) 4 - 94 bis 98°C/0,2mm94 to 98 ° C / 0.2mm BrBr 0(CHa)3 0 (CHa) 3 108 bis 1110QO,lmm108 to 111 0 QO, lmm BrBr 0(CHa)3 0 (CHa) 3 108 bis 112°C/0,01mm108 to 112 ° C / 0.01mm BrBr 0(CHa)4 0 (CHa) 4 98 bis 105 0QO, 15 mm98 to 105 0 QO, 15 mm BrBr O(CH2)4 O (CH 2 ) 4 111 bis 117°C/0,08mm111 to 117 ° C / 0.08mm BrBr O(CH2)4 O (CH 2 ) 4 113 bis 119°C/0,05mm113 to 119 ° C / 0.05mm BrBr O(CH2)5 O (CH 2 ) 5 105 bis 110°C/0,08mm105 to 110 ° C / 0.08mm BrBr 0(CHa)5 0 (CHa) 5 118 bis 1220QO5Ol mm118 to 122 0 QO 5 Ol mm BrBr 0(CHa)5 0 (CHa) 5 126 bis 131°C/O,O6mm126 to 131 ° C / O, O6mm ClCl O(CH2)aO (CH 2 ) a 139 bis 145°C/16mm139 to 145 ° C / 16mm ClCl 0(CHa)2 0 (CHa) 2 160 bis 180°C/30mm160 to 180 ° C / 30mm ClCl 0(CHa)2 0 (CHa) 2 107 bis 110°Q0,4mm107 to 110 ° Q0.4mm ClCl CH2O(CHa)2 CH 2 O (CHa) 2 144 bis 150°Q10mm144 to 150 ° Q10mm

Tabelle IIITable III

Als Ausgangsstoffe verwendete Äther — ΖEther used as starting materials - Ζ

XX YY ZZ Kp.Kp. F.F.
0C 0 C NO2 NO 2 0(CHa)4 0 (CHa) 4 BrBr 50 bis 156°C/0,08 mm50 to 156 ° C / 0.08 mm NO2 NO 2 0(CHa)5 0 (CHa) 5 BrBr 170 bis 171°C/0,l mm170 to 171 ° C / 0.1 mm —- BrBr 0(CHa)4 0 (CHa) 4 BrBr 118 bis 125°C/0,l mm118 to 125 ° C / 0.1 mm 28 bis 2928 to 29 BrBr 0(CHa)5 0 (CHa) 5 BrBr 123 bis 13O°C/O,O9 mm123 to 130 ° C / O.09 mm 33 bis 3433 to 34 Beispiel 92Example 92 b) p-Toluolsulfonat; F. = 226 bisb) p-toluenesulfonate; F. = 226 to 227°C; Löslich-227 ° C; Soluble-

N-o-Chlorbenzyl-N-2-p-chlorphenoxyäthyl-N,N-dimethylammonium-p-toluolsulfonat N-o-chlorobenzyl-N-2-p-chlorophenoxyethyl-N, N-dimethylammonium-p-toluenesulfonate

Eine Lösung von 250 g N-o-Chlorbenzyl-N-2-p-dimethylammoniumchlorid (Beispiel 75) in 500 ml Wasser wurde langsam und unter Rühren einer Lösung von 191 g Natrium-p-toluolsulfonat in 400 ml Wasser zugesetzt. Bei fortschreitendem Zusatz schieden sich Kristalle aus. Schließlich ließ man das Gemisch 17 Stunden stehen und filtrierte dann. Der Rückstand wurde mit Wasser gewaschen und aus einem Gemisch von Isopropanol und Äther umkristallisiert, wobei man N-o-Chlorbenzyl-N-2-p-chlorphenoxyäthyl-N,N-dimethylammonium-p-toluolsulfbnat erhielt; F. = 146 bis 1470C.A solution of 250 g of no-chlorobenzyl-N-2-p-dimethylammonium chloride (Example 75) in 500 ml of water was added slowly and with stirring to a solution of 191 g of sodium p-toluenesulfonate in 400 ml of water. As the addition progressed, crystals separated out. Finally the mixture was allowed to stand for 17 hours and then filtered. The residue was washed with water and recrystallized from a mixture of isopropanol and ether, resulting in No-chlorobenzyl-N-2-p-chlorophenoxyethyl-N, N-dimethylammonium-p-toluenesulphnate; F. = 146 to 147 0 C.

Beispiel 93Example 93

Nach ähnlichen Methoden, wie im Beispiel 92 beschrieben, wurde N-p-chlorbenzyl-NjN-dimethyl-N - 2 - ρ - nitrophenoxyäthylammoniumchlorid (Beispiel 5) in folgende Salze umgewandelt: Using methods similar to those described in Example 92, N-p -chlorobenzyl-NjN-dimethyl-N - 2 - ρ - nitrophenoxyethylammonium chloride (Example 5) converted into the following salts:

a) p-Chlorbenzolsulfonat;
Löslichkeit bei 200C
Volumen;a) p-chlorobenzenesulfonate;
Solubility at 20 ° C
Volume;

F. = 238 bis 239°C; etwa 0,1% Gewicht/ keit bei 2O0C etwa 0,2% Gewicht/Volumen; c) 4,41-Diaminostilben-2,2'-disulfonat-monohydrat; F. = 181 bis 182°C; Löslichkeit bei 2O0C etwa 0,1% Gewicht/Volumen;M.p. = 238 to 239 ° C; about 0.1% w / wind speed for 2O 0 C about 0.2% weight / volume; c) 4,4 1- diaminostilbene-2,2'-disulfonate monohydrate; M.p. = 181 to 182 ° C; Solubility at 2O 0 C about 0.1% weight / volume;

d) 2-Hydroxy-3-naphthoat; F. = 129 bis 13O0C; Löslichkeit bei 2O0C etwa 0,1% Gewicht/ Volumen;d) 2-hydroxy-3-naphthoate; F. = 129 to 13O 0 C; Solubility at 2O 0 C about 0.1% weight / volume;

e) Embonat-monohydrat; F. = 185 bis 186°C; Löslichkeit bei 2O0C etwa 0,1% Gewicht/ Volumen;e) Embonate monohydrate; M.p. = 185 to 186 ° C; Solubility at 2O 0 C about 0.1% weight / volume;

Jodid; F. = 201 bis 2020C; Löslichkeit bei 20°C etwa 0,2% Gewicht/Volumen;Iodide; Mp = 201-202 0 C; Solubility at 20 ° C about 0.2% weight / volume;

g) 2,4,5-Trichlorphenolat; F. = 154 bis 1550C.g) 2,4,5-trichlorophenate; F. = 154 to 155 0 C.

Claims (1)

Patentanspruch:Claim: Verfahren zur Herstellung quartärer Ammoniumsalze der allgemeinen FormelProcess for the preparation of quaternary ammonium salts of the general formula RiRi R — O — (CHa)n — Ν83— CH2 — R3 R - O - (CHa) n - Ν 83 - CH 2 - R 3 R2
worin R einen in p-Stellung halogen- oder nitro-R 2
wherein R is a halogen or nitro in the p-position substituierten Phenylrest, Ri und R2 niedermolekulare Alkylreste oder zusammen die Tetramethylengruppe, R3 einen gegebenenfalls in beliebiger Stellung halogensubstituierten Phenylrest oder eine gegebenenfalls in 5-Stellung halogensubstituierte Thienylgruppe, Ae ein Anion und η eine ganze Zahl von 2 bis 5 bedeutet, dadurch gekennzeichnet, daß in an sich bekannter Weise ein tertiäres Amin, welches dreisubstituted phenyl radical, Ri and R 2 low molecular weight alkyl radicals or together the tetramethylene group, R3 is a phenyl radical which is optionally halogen-substituted in any position or a thienyl group which is optionally halogen-substituted in the 5-position, A e is an anion and η is an integer from 2 to 5, characterized in that that in a known manner a tertiary amine which three der im Endprodukt gewünschten Stickstoffsubstituenten enthält, unter Einführung des vierten gewünschten Substituenten quaterniert wird und gegebenenfalls das so erhaltene Salz in das Salz eines anderen Anions übergeführt wird.contains the desired nitrogen substituents in the end product, with the introduction of the fourth desired substituents is quaternized and optionally the salt thus obtained into the salt another anion is converted. In Betracht gezogene Druckschriften:
Deutsche Patentschrift Nr. 1 117 600.Considered publications:
German patent specification No. 1 117 600.
DE1960W0027453 1959-03-13 1960-03-14 Process for the preparation of quaternary ammonium salts Expired DE1238485C2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB887959 1959-03-13
GB8878/59A GB924961A (en) 1959-03-13 1959-03-13 Quaternary ammonium compounds, the preparation thereof and pharmaceutical compositions thereof
GB3955859 1959-11-20
GB3955959 1959-11-20

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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
DE2913523A1 (en) 1979-04-04 1980-10-23 Basf Ag SUBSTITUTED ALKYLAMONIUM SALTS, THEIR PRODUCTION AND USE FOR REGULATING PLANT GROWTH
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
KR20130127012A (en) * 2010-09-21 2013-11-21 지이 헬쓰케어 리미티드 Novel precursors 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

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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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ES256264A1 (en) 1960-08-16
NL6909922A (en) 1969-10-27
DK104353C (en) 1966-05-09
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FR558M (en) 1961-05-29
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DE1238485B (en) 1967-04-13
FR1421206A (en) 1965-12-17

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