CH377347A - Process for the production of new N-substituted piperidines - Google Patents

Process for the production of new N-substituted piperidines

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Publication number
CH377347A
CH377347A CH1290662A CH1290662A CH377347A CH 377347 A CH377347 A CH 377347A CH 1290662 A CH1290662 A CH 1290662A CH 1290662 A CH1290662 A CH 1290662A CH 377347 A CH377347 A CH 377347A
Authority
CH
Switzerland
Prior art keywords
piperidine
benzyl
reacted
halide
formula
Prior art date
Application number
CH1290662A
Other languages
German (de)
Inventor
John Cavallito Chester
Poe Gray Allan
Original Assignee
Irwin Neisler & Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Irwin Neisler & Company filed Critical Irwin Neisler & Company
Publication of CH377347A publication Critical patent/CH377347A/en

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Description

  

  



  Verfahren zur Herstellung neuer N-substituierter Piperidine
Die vorliegende Erfindung bezieht sich auf ein Verfahren zur Herstellung neuer N-substituierter Piperidine der Formel I
EMI1.1     
 in welcher A eine Alkylenbrücke mit 1-3 Kohlenstoffatomen, B eine Alkylenbrücke mit 2-3 Kohlenstoffatomen, R und R'niedere Alkylgruppen oder R und   R'zusammen mit dem    N-Atom einen   hetero-    cyclischen Rest,   R"Wasserstoff    oder eine entweder in 2-Stellung oder in   3-Stellung    des Piperidinringes befindliche niedere Alkylgruppe und R1 eine gegebenenfalls substituierte Phenylgruppe bedeuten, das dadurch gekennzeichnet ist, dass eine   Piperidinver-    bindung der Formel II
EMI1.2     
 mit einer Verbindung der Formel III
EMI1.3     
 in welcher X ein Chlor-,

   Brom-oder Jodatom bedeutet, in Gegenwart mindestens eines   Siquivalentes    eines Säureakzeptors umgesetzt wird.



   Erfindungsgemäss herstellbare Verbindungen können als aktive Bestandteile   pharmazeutischer Prä-    parate verwendet werden, die menschlichen Organismen zur Verbesserung der Blutzirkulation in den   Herzgefässen und    der Funktion der Herzgefässe zugeführt werden können, falls diese beeinträchtigt sind.



  Dar ber hinaus zeigen erfindungsgemäss herstellbare Verbindungen eine   antiatheroscierotische    Wirkung in menschlichen Organismen und potenzieren die antihypertensive Wirkung der Veratrum-alkaloide, wie durch klinische Versuche festgestellt werden konnte.



   Erfindungsgemäss herstellbare Verbindungen stellen in Form der   freien Base entweder Flüssig-    keiten hohen Siedepunktes oder weisse kristalline Feststoffe mit niedrigem Schmelzpunkt dar, sind in Wasser unlöslich, löslich in wässrigen Mineralsäuren oder organischen Säuren, wobei aus diesen erhaltenen wässrigen Lösungen durch Verdampfung des Wassers die Säureadditionssalze erhalten werden können, und sind in polaren und unpolaren L¯sungsmitteln, wie beispielsweise niedrigen aliphatischen Alkoholen, Chloroform, Benzol und   Petroläther,    löslich.



   Die Strukturformel der einfachsten erfindungsgemäss herstellbaren Verbindung, nämlich des 4-Benzyl-1-(¯-dimethylaminoÏthyl)-piperidns, ist
EMI1.4     

Der Piperidinring kann ebenso wie die   Phenyl-    alkylgruppe   RA-niedere Alkylgruppen als Substi-      tuenten    aufweisen. Solche Substituenten im   Piperidin-    ring aufweisende Verbindungen stellen vollkommene   Aquivalente    von im   Pyridmnng unsubstituierten Ver-    bindungen dar. 



     Erfinduogsgemäss    herstellbare   N- (Dialkylamino-    alkyl)-piperidine werden auch als   4-Phenylalkyl-1-      (dialkylaminoalky !)-piperidine bezeichnet    und Beispiele für solche Verbindungen sind
4-p-ChlorphenylÏthyl-1-(¯-diisopropyl   aminoäthyl)-piperidin,   
4-(3,4-MethylendioxyphenylÏthyl)   1-(γ-piperidinopropyl)-piperidin,       4- (3,    4,   5-Trimethoxy-phenyläthyl)-3-äthyl-      
1- (, B-diäthylaminoäthyl)-piperidin,
4-(α-Phenylpropyl)-1 -(γ-pyrrolidinopropyl)-    piperidin,
4-(¯-Phenylpropyl)-1-(¯-diÏthylaminopropyl) piperidin,    4-(α -PhenylÏthyl)-1 -(¯-piperidinopropyl)-    piperidin.



   Die Säureadditionssalze erfindungsgemäss herstellbarer Verbindungen können in   iiblicher    Weise durch Umsetzung der freien Basen mit den   gebräuch-    lichen anorganischen Säuren, z. B. SalzsÏure, BromwasserstoffsÏure, JodwasserstoffsÏure, SchwefelsÏure oder Phosphorsäure, oder den gebräuchlichen organischen SÏuren, wie z. B. EssigsÏure, GerbsÏure, ZitronensÏure, MalonsÏure, ¯thansulfonsÏure, Cyclohexylsulfaminsäure und dergleichen hergestellt werden. Diese Salze stellen völlige Äquivalente der freien Basen dar und sind lediglich besonders geeignete Verabreichungsformen.



   Beispiel 1
4-Benzyl-l-   (-dimethytaminoäthyI)-piperidin   
Eine Lösung von Dimethylaminoäthylchlorid, welche aus 180 g (1, 25 Mol) Dimethylaminoäthyl  chlorid-hydrochlorid    erhalten wurde, in Xylol, wurde tropfenweise ei. ner auf Rückfluss erhitzten Suspension von 175 g (1, 0 Mol) 4-Benzylpiperidin, 104 g (0, 75 Mol) Kaliumcarbonat und 80 g (0, 75 Mol) Natriumcarbonat in 250 cm3 Xylol zugesetzt. Die erhaltene AufschlÏmmung wurde 20 Stunden auf Rückfluss erhitzt, gekühlt, worauf so lange Wasser r zugesetzt wurde, bis alle anorganischen Salze in L¯sung gegangen waren. Die wässrige Schicht wurde sodann verworfen und die Xylollösung eingeengt.



  Der erhaltene ölige Rückstand wurde destilliert, wobei entsprechend einer 53, 5    /oigen    Ausbeute 132 g 4-Benzyl-1-   (} 5-dimethylaminoäthyl)-piperidin bei    einem Siedepunkt von Kp =   110-114°C    bei 0, 1 mm Hg und einem Brechungsindex n24D = 1, 5160 erhalten wurden.



   Beispiel 2
4-Benzyl-1-(¯-dimethylaminoÏthyl)-piperidin
Eine Suspension, bestehend aus 28, 0 g (0, 16 Mol) 4-Benzylpiperidin   [(W.    L. C.   Veer    und St. Goldschmidt,   Rec.    Trav. Chim. 65. 793 (1946) ; C. A.



     41,    3101 (1947)], 34, 6 g (0, 24   Mol) -Di-      methylaminoäthylchlorid-Hydrochlorid    und 50 g wasserfreiem, pulverförmigem Natriumcarbonat und 200 cm3 n-Butylalkohol wurde unter R hren 24 Stunden auf Rückfluss erhitzt. Anschliessend wurde gekühlt und filtriert, worauf das Filtrat im Vakuum eingeengt wurde. Der Rückstand wurde hierauf mit Äther verdünnt, der erhaltene Niederschlag abfiltriert und das Filtrat im Vakuum eingeengt. Bei Vakuumdestillation wurde eine geringe Menge eines Vorlaufes und, entsprechend einer Ausbeute von 31% der Theorie, 12, 3 g   4-Benzyl-1-(,-dimethylamino-      äthyl)-piperidin    erhalten.

   Das 4-Benzyl-l-   B-dimethyl-      aminoäthyl)-piperidin    besass einen Siedepunkt Kp = 135-140  C bei 0, 5 mm Hg und einen Brechungsindex   n 24    =   1,    5167.



   Analyse :
Berechnet : N (basisch) 11, 37
Gefunden : 11, 22
Das Dihydrochlorid des 4-Benzyl-1-(¯-dimethyl  aminoäthyl)-piperidins    wurde in üblicher Weise hergestellt und besass einen Schmelzpunkt von 270¯ C.



   Analyse :
Berechnet : C C60, 18%; H 8,84 %; Cl 22,21 %
Gefunden : 60, 50 8, 71 22, 11
Weitere erfindungsgemäss herstellbare 4-Phenylalkyl-1-dialkylaminoalkyl-piperidine werden in der folgenden Tabelle angegeben :
Tabelle
C Wasserstoff Chlorion    Verbindung physikalische Konstinten Gew.%Gew.%Gew.%Gew.%Gew.% Gew.% berechnet gefunden berechnet gefunden berechnet gefunden    4-PhenylÏthyl-1- Kp. 123-153¯ C - - - - -  (¯-dimethyl-aminoÏthyl)- bei 0,6 mm Hg piperidin n 25D = 1,5125 Dihydrochlorid Fp.   279  C    61, 25 61, 34 9, 07 9, 11   21,    27 21, 20 4-Benzyl-l-(¯-diÏthyl- Kp. 111-126¯ C   aminoäthyl)-piperidin    bei 0, 1 mm Hg    n 21    = 1, 5130 - - - - -  Dihydrochlorid Fp.

   237-239¯ C 62, 23   61,    80 9, 29 9, 28 20, 41 20, 42   4-Benzyl-l-(γ-dimethyl- Kp. 130-133¯ C    aminopropyl)-piperidin bei 0, 15 mm Hg    D =    1,   5123------    Dihydrochlorid Fp. 280-282¯ C 61, 25   61,    37 9, 07 9, 12 21, 27 21, 33



  



  Process for the production of new N-substituted piperidines
The present invention relates to a process for the preparation of new N-substituted piperidines of the formula I.
EMI1.1
 in which A is an alkylene bridge with 1-3 carbon atoms, B an alkylene bridge with 2-3 carbon atoms, R and R 'lower alkyl groups or R and R' together with the N atom a heterocyclic radical, R "hydrogen or either in The lower alkyl group in the 2-position or in the 3-position of the piperidine ring and R1 is an optionally substituted phenyl group, which is characterized in that a piperidine compound of the formula II
EMI1.2
 with a compound of the formula III
EMI1.3
 in which X is a chlorine,

   Bromine or iodine atom means, is implemented in the presence of at least one equivalent of an acid acceptor.



   Compounds which can be prepared according to the invention can be used as active constituents of pharmaceutical preparations which can be supplied to human organisms to improve the blood circulation in the cardiac vessels and the function of the cardiac vessels if these are impaired.



  In addition, compounds which can be prepared according to the invention show an antiatherosclerotic effect in human organisms and potentiate the antihypertensive effect of the Veratrum alkaloids, as has been established by clinical trials.



   Compounds which can be prepared according to the invention are in the form of the free base either liquids with a high boiling point or white crystalline solids with a low melting point, are insoluble in water, soluble in aqueous mineral acids or organic acids, the aqueous solutions obtained from these being given the acid addition salts by evaporation of the water and are soluble in polar and non-polar solvents such as lower aliphatic alcohols, chloroform, benzene and petroleum ether.



   The structural formula of the simplest compound which can be prepared according to the invention, namely 4-benzyl-1- (¯-dimethylaminoÏthyl) piperidine, is
EMI1.4

The piperidine ring, like the phenylalkyl group, can have RA lower alkyl groups as substituents. Compounds of this type which have substituents in the piperidine ring represent perfect equivalents of compounds which are unsubstituted in the pyridine ring.



     N- (dialkylaminoalkyl) piperidines which can be prepared according to the invention are also referred to as 4-phenylalkyl-1- (dialkylaminoalkyl) piperidines and are examples of such compounds
4-p-chlorophenylethyl-1- (¯-diisopropyl aminoethyl) piperidine,
4- (3,4-methylenedioxyphenylethyl) 1 - (γ-piperidinopropyl) piperidine, 4- (3, 4, 5-trimethoxyphenylethyl) -3-ethyl-
1- (, B-diethylaminoethyl) piperidine,
4 - (α-phenylpropyl) -1 - (γ-pyrrolidinopropyl) -piperidine,
4- (¯-phenylpropyl) -1- (¯-diÏthylaminopropyl) piperidine, 4 - (α-phenylÏthyl) -1 - (¯-piperidinopropyl) piperidine.



   The acid addition salts which can be prepared according to the invention can be prepared in the usual way by reacting the free bases with the customary inorganic acids, e.g. B. hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid or phosphoric acid, or the common organic acids such. B. acetic acid, tannic acid, citric acid, malonic acid, ¯thanesulfonic acid, cyclohexylsulfamic acid and the like can be produced. These salts are complete equivalents of the free bases and are merely particularly suitable forms of administration.



   example 1
4-Benzyl-1- (-dimethytaminoethyl) -piperidine
A solution of dimethylaminoethyl chloride, which was obtained from 180 g (1.25 mol) of dimethylaminoethyl chloride hydrochloride, in xylene, was added dropwise to egg. A refluxed suspension of 175 g (1.0 mol) of 4-benzylpiperidine, 104 g (0.75 mol) of potassium carbonate and 80 g (0.75 mol) of sodium carbonate in 250 cm3 of xylene was added. The resulting slurry was heated to reflux for 20 hours, cooled, after which water was added until all the inorganic salts had gone into solution. The aqueous layer was then discarded and the xylene solution was concentrated.



  The oily residue obtained was distilled, with 132 g of 4-benzyl-1- (} 5-dimethylaminoethyl) piperidine at a boiling point of bp = 110-114 ° C. at 0.1 mm Hg and corresponding to a 53.5% yield a refractive index n24D = 1.5160 were obtained.



   Example 2
4-Benzyl-1- (¯-dimethylaminoÏthyl) piperidine
A suspension consisting of 28.0 g (0.16 mol) of 4-benzylpiperidine [(W. L. C. Veer and St. Goldschmidt, Rec. Trav. Chim. 65, 793 (1946); C.A.



     41, 3101 (1947)], 34.6 g (0.24 mol) dimethylaminoethyl chloride hydrochloride and 50 g of anhydrous, powdered sodium carbonate and 200 cm3 of n-butyl alcohol were heated to reflux with stirring for 24 hours. It was then cooled and filtered, whereupon the filtrate was concentrated in vacuo. The residue was then diluted with ether, the resulting precipitate was filtered off and the filtrate was concentrated in vacuo. Vacuum distillation gave a small amount of a first run and, corresponding to a yield of 31% of theory, 12.3 g of 4-benzyl-1 - (, - dimethylamino-ethyl) piperidine.

   The 4-benzyl-1-B-dimethylaminoethyl) piperidine had a boiling point bp = 135-140 ° C. at 0.5 mm Hg and a refractive index n 24 = 1.5167.



   Analysis:
Calculated: N (basic) 11, 37
Found: 11, 22
The dihydrochloride of 4-benzyl-1- (¯-dimethyl aminoethyl) piperidine was prepared in the usual way and had a melting point of 270¯ C.



   Analysis:
Calculated: C C60, 18%; H 8.84%; Cl 22.21%
Found: 60, 50 8, 71 22, 11
Further 4-phenylalkyl-1-dialkylaminoalkyl-piperidines which can be prepared according to the invention are given in the following table:
table
C hydrogen chlorine ion compound physical constants wt.% Wt.% Wt.% Wt.% Wt.% Wt.% Calculated found calculated found calculated found 4-PhenylÏthyl-1 Kp. 123-153¯ C - - - - - (¯ -dimethyl-aminoethyl) - at 0.6 mm Hg piperidine n 25D = 1.5125 dihydrochloride m.p. 279 C 61, 25 61, 34 9, 07 9, 11 21, 27 21, 20 4-benzyl-1- (¯ -diÏthyl- bp. 111-126¯ (aminoethyl) piperidine at 0.1 mm Hg n 21 = 1.5130 - - - - - dihydrochloride mp.

   237-239¯ C 62, 23 61, 80 9, 29 9, 28 20, 41 20, 42 4-Benzyl-1- (γ-dimethyl- bp 130-133¯ C aminopropyl) piperidine at 0.15 mm Hg D = 1,523 ------ dihydrochloride m.p. 280-282¯ C 61, 25 61, 37 9, 07 9, 12 21, 27 21, 33

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung neuer N-substituierter Piperidi, ne der Formel I EMI3.1 in welcher A eine Alkylenbrücke mit 1-3 Kohlenr stoffatomen, B eine Alkylenbrücke mit 2-3 Kohlenstoffatomen, R und R'niedere Alkylgruppen oder R und R'zusammen mit dem Stickstoffatom einen heterocyclischen Rest, R"Wasserstoff oder eine entweder in 2-Stellung oder in 3-Stellung des Piperidin- ringes befindliche niedere Alkylgrup. PATENT CLAIM Process for the preparation of new N-substituted piperidines of the formula I. EMI3.1 in which A an alkylene bridge with 1-3 carbon atoms, B an alkylene bridge with 2-3 carbon atoms, R and R 'lower alkyl groups or R and R' together with the nitrogen atom a heterocyclic radical, R "hydrogen or one either in the 2-position or lower alkyl group located in the 3-position of the piperidine ring. pe und Rt eine gegebenenfalls substituierte Phenylgruppe bedeuten, wobei die Stickstoffatome an n verschiedene Kohlen- stoffatome der Alkylenbrücke B gebunden sind, dadurch gekennzeichnet, dal3 eine Piperidinverbindung der Formel II EMI3.2 mit einer Verbindung der Formel III EMI3.3 in welcher X ein Chlor-, Brom-oder Jodatom bedeutet, in Gegenwart mindestens eines Äquivalentes eines Säureakzeptors umgesetzt wird. pe and Rt denote an optionally substituted phenyl group, the nitrogen atoms being bonded to n different carbon atoms of the alkylene bridge B, characterized in that a piperidine compound of the formula II EMI3.2 with a compound of the formula III EMI3.3 in which X is a chlorine, bromine or iodine atom, the reaction is carried out in the presence of at least one equivalent of an acid acceptor. UNTERANSPRUCHE 1. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass 4-Benzylpiperidin mit einem p-Dimethylaminoäthylhalogenid zum 4-Benzyl-1 (p-dimethylaminoäthyl)-piperidin umgesetzt wird. SUBCLAIMS 1. The method according to claim, characterized in that 4-benzylpiperidine is reacted with a p-dimethylaminoethyl halide to form 4-benzyl-1 (p-dimethylaminoethyl) piperidine. 2. Verfahren nach Patentanspruch, dadurch ge kennzeichnet, dass 4-Phenyläthylpiperidin mit einem ¯-DimethylaminoÏthylhalogenid zum 4-Phenyläthyl l- (-dimethylaminoäthyl)-piperidin umgesetzt wird. 2. The method according to claim, characterized in that 4-phenylethylpiperidine is reacted with a ¯-dimethylaminoÏthyl halide to give 4-phenylethyl-l- (dimethylaminoethyl) piperidine. 3. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass 4-Benzylpiperidin mit einem ss-Di- äthylaminoäthylhalogenid zum 4-Benzyl-1-(ss-diäthyl- aminoäthyl)-piperidin umgesetzt wird. 3. The method according to claim, characterized in that 4-benzylpiperidine is reacted with an β-diethylaminoethyl halide to form 4-benzyl-1- (β-diethylaminoethyl) piperidine. 4. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass 4-Benzylpiperidin mit einem y-Dimethylaminopropylhalogenid zum 4-Benzyl-1-(y-di- methylaminopropyl)-piperidin umgesetzt wird. 4. The method according to claim, characterized in that 4-benzylpiperidine is reacted with a γ-dimethylaminopropyl halide to give 4-benzyl-1- (γ-dimethylaminopropyl) piperidine. 5. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass solche Verbindungen der Formel II verwendet werden, in denen die Gruppen R und R' zusammen mit dem benachbarten Stickstoffatom einen Pyrrolidin-, Piperidin-oder Morpholinring darstellen. 5. The method according to claim, characterized in that compounds of the formula II are used in which the groups R and R 'together with the adjacent nitrogen atom represent a pyrrolidine, piperidine or morpholine ring.
CH1290662A 1956-06-22 1957-01-31 Process for the production of new N-substituted piperidines CH377347A (en)

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