CH423776A - Process for the preparation of new piperidine derivatives - Google Patents

Process for the preparation of new piperidine derivatives

Info

Publication number
CH423776A
CH423776A CH905263A CH905263A CH423776A CH 423776 A CH423776 A CH 423776A CH 905263 A CH905263 A CH 905263A CH 905263 A CH905263 A CH 905263A CH 423776 A CH423776 A CH 423776A
Authority
CH
Switzerland
Prior art keywords
radical
methyl
carbon atoms
formula
hydrogen
Prior art date
Application number
CH905263A
Other languages
German (de)
Inventor
Herbert Dr Kuehnis Hans
Hugo Dr Ryf
Rolf Dr Denss
Original Assignee
Geigy Ag J R
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
Priority to NL124853D priority Critical patent/NL124853C/xx
Application filed by Geigy Ag J R filed Critical Geigy Ag J R
Priority to CH905263A priority patent/CH423776A/en
Priority to US382955A priority patent/US3366638A/en
Priority to NL6408219A priority patent/NL6408219A/xx
Priority to BE650738D priority patent/BE650738A/xx
Priority to BE650736D priority patent/BE650736A/xx
Priority to NL6408223A priority patent/NL6408223A/xx
Priority to DE19641445837 priority patent/DE1445837A1/en
Priority to DE19641445836 priority patent/DE1445836A1/en
Priority to AT616164A priority patent/AT247328B/en
Priority to DK357764A priority patent/DK109200C/en
Priority to NL6408218A priority patent/NL6408218A/xx
Priority to ES0302228A priority patent/ES302228A1/en
Priority to AT616064A priority patent/AT246739B/en
Priority to ES0302229A priority patent/ES302229A1/en
Priority to DE19641445838 priority patent/DE1445838A1/en
Priority to BE650737D priority patent/BE650737A/xx
Priority to FR982319A priority patent/FR1415585A/en
Priority to FR982318A priority patent/FR1423686A/en
Priority to FR982320A priority patent/FR1414820A/en
Priority to GB30577/64A priority patent/GB1062715A/en
Priority to GB30575/64A priority patent/GB1062714A/en
Priority to GB30574/64A priority patent/GB1062713A/en
Priority to FR991815A priority patent/FR3759M/en
Priority to FR991816A priority patent/FR3760M/en
Priority to FR991817A priority patent/FR3662M/en
Priority to FI00066/66A priority patent/FI46846B/fi
Priority to US520093A priority patent/US3408357A/en
Priority to DK20266AA priority patent/DK114973B/en
Priority to DE19661695054 priority patent/DE1695054A1/en
Priority to SE00500/66A priority patent/SE327986B/xx
Priority to GB1774/66A priority patent/GB1116326A/en
Priority to IL24971A priority patent/IL24971A/en
Priority to NL6600523A priority patent/NL6600523A/xx
Priority to NO161258A priority patent/NO121781B/no
Priority to BR176431/66A priority patent/BR6676431D0/en
Priority to BE675145D priority patent/BE675145A/xx
Priority to FR46020A priority patent/FR1463646A/en
Priority to FR57638A priority patent/FR5343M/fr
Priority to US562533A priority patent/US3338910A/en
Publication of CH423776A publication Critical patent/CH423776A/en
Priority to DK104067AA priority patent/DK114622B/en
Priority to US660909A priority patent/US3456060A/en
Priority to US671549A priority patent/US3498994A/en
Priority to US800012*A priority patent/US3509258A/en
Priority to MY1971123A priority patent/MY7100123A/en

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74Oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic 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
    • C07D211/36Heterocyclic 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 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
    • C07D211/40Oxygen atoms
    • C07D211/44Oxygen atoms attached in position 4
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic 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
    • C07D211/36Heterocyclic 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 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
    • C07D211/40Oxygen atoms
    • C07D211/44Oxygen atoms attached in position 4
    • C07D211/48Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

  

  Verfahren zur Herstellung von neuen     Piperidinderivaten       Die vorliegende Erfindung betrifft ein Verfahren  zur Herstellung neuer     Piperidinderivate    und ihrer  Salze mit wertvollen pharmakologischen Eigen  schaften.  



  Es wurde überraschenderweise gefunden, dass       Piperidinderivate    der Formel I,  
EMI0001.0004     
    in welcher       R,    Wasserstoff, einen     Alkylrest    mit höchstens 12       Kohlenstoffatomen,    einen     Alkenylrest    mit 3-5       Koblenstoffatomen,    den     Cyclopropy1methylrest     oder einen     Phenylalkyl        mit    7-9 Kohlenstoff-,       atomen,

            R-    Wasserstoff oder den     Methyirest    und       R3    einen     Alkylrest    mit höchstens 4     Kohlenstoff-          atomen,    einen     Phenylalkylrest    mit 7-9 Kohlen  Stoffatomen, den     Styrylres.t,    der     zusammen    mit       R,    einen gegebenenfalls     methylsubstituierten        Tri-          methylen-    bis     Hexamethylenrest    bilden     kann,

      und       R4        Wasserstoff    oder     Methylrest        bedeuten,     und ihre Salze mit anorganischen und organischen  Säuren wertvolle pharmakologische Eigenschaften,  insbesondere     analgetische    Wirksamkeit bei oraler wie       parenteraler    Applikation, und     zugleich        eine    relative    geringe Toxizität besitzen. Ferner dämpfen Verbin  dungen der Formel I den Hustenreiz.  



  In den Verbindungen der Formel I und den zu  gehörigen, weiter unten genannten Ausgangsstoffen  ist     R1    beispielsweise durch Wasserstoff,     Alkylreste,     wie den       Methyl-,    Äthyl-,     n-Propyl-,        Isopropyl-,        n-Butyl-,          Isohutyl-,    sek.     Butyl-,        n-Amyl-,        n-Hexyl-,          n-Octyl-,        n-Decyl-    oder     n-Dodecylrest;

       durch     Alkenylreste,    wie den     Allyl-,        Crotyl-    oder       Methallylrest;     durch     Cyclopropylmethylrest    oder durch     Phenylalkyl-          reste,    wie den     Benzyl-,        ss-Phenyl-äthyl-    oder       y-Phenyl-propylrest,    verkörpert.  



  R3 ist für sich allein z. B. ein     Methyl-,    Äthyl-,       n-Propyl    ,     Isopropyl-,        n-Butyl-,        Isobutyl-,     sek.     Butyl,        tert.        Butyl-,        Phenyl-,        Benzyl-,          o-Methyl        benzyl-,        a-Phenyl-äthyl-,          ss-Phenyl        äthyl    oder     Styrylrest        (ss-Phenyl-vinyl-          rest).     



       R3        bildet    ferner zusammen mit     R2    z. B.     einen          Trimethylen-,        Tetramethylen-,          1-Methyl-tetramethylen-,        Pentamethylen-    oder       Hexamethylenrest.     



  Die Verbindungen der Formel I lassen sich in  überraschend einfacher Weise herstellen, indem man  ein     4-Piperidon    der Formel     1I,     
EMI0001.0089     
    mit einem     Keton    der Formel I11,           R3-CO-CH2--R2        (III)     wobei     R1,        R2,    R3 und     R4    die unter der     Formel    I an  gegebene Bedeutung haben, in     Gegenwart    einer in  homogener oder heterogener Phase vorliegenden  Base umsetzt. Als Reaktionsmedium können je  nach der Löslichkeit der Ausgangsstoffe z. B.

    Wasser,     wässrige    und schliesslich auch wasserfreie  niedere     Alkanole    Verwendung     finden.        Als    Konden  sationsmittel können einerseits anorganische Basen,  wie     Natriumhydroxyd,    und organische Basen, wie       Piperidin,        Piperazin    und in     wasserfreiem    Medium  oder in Abwesenheit von     Lösungsmitteln    auch       Alkalialkoholate,    und anderseits basische     Ionen-          austauscher,

          vorzugsweise    solche mit     quatemären          Ammoniumgruppen,    wie z. B.     Amberlite    IRA 400  (OHG), aber auch schwächer     basische,    wie     Amber-          lite    IR 413, in Frage, welche in     ansatzweisem    oder  gegebenenfalls auch kontinuierlichem     Verfahren    an  gewendet werden können. Die Kondensationen wer  den bei Raumtemperatur bis mässig erhöhter Tempe  ratur     durchgeführt.     



  Bei den Ausgangsstoffen der Formel     II    handelt  es sich um die in     1-Stellung    gegebenenfalls defini  tionsgemäss     substituierten.        4-Piperidone    und 3     Methyl          4-piperidone.    Verbindungen dieser Formel sind be  reits bekannt und weitere in analoger Weise     herstell-          bar.        Geeignete        Ausgangsstoffe    der Formel     III    sind  beispielsweise     Methyl-alkyl-ketone    mit     geradkettiger     oder verzweigter     Alkylgruppe,    wie z.

   B.  



  Aceton,     Butanon,        Methyl-n-propyl-keton,          Methyl-isopropyl-keton,        Methyl-n-butyl-keton,          Methyl-isobutyl-keton,        Methyl    sek.

       butyl        keton,          Pinakolin,     bei deren Verwendung Verbindungen mit einem  Wasserstoffatom     R2    entstehen, weiter     prim.        Alkyl-          sek.        alkyl        ketone,    wie     Äthyl        isopropyl-keton    und       n-Propyl-isopropyl-keton,    welche Verbindungen der  Formel I mit einem     primären        Alkylrest    als     R2        liefern,     und weiter z.

   B. symmetrische     Dialkylketone,    wie       Diäthyl        keton,        Di-n-propyl-keton,          Di-n-butylketon,          Diisobutyl-keton;          Cycloalkanone,    wie z. B.  



       Cyclopentanon,        Cyclohexanon,          Cycloheptanon    und     Cyclooctanon,     sowie     aromatisch-aliphatische    und     araliphatisch-ali-          phatische        Ketone,    wie       Acetophenon,        Propionphenon,        Butyrophenon,          Benzyl-methyl-keton,          (a-Phenyl        äthyl)-methyl-keton,          (ss        Phenyl-äthyl)-methyl-keton,

            Benzalaceton     und deren entsprechend der     Definition    von R3       substituierte    Derivate.  



  Mit anorganischen und organischen Säuren, wie  Salzsäure,     Bromwasserstoffsäure,    Schwefelsäure,  Salpetersäure, Phosphorsäure,     Methansulfonsäure,          Äthandisulfonsäure,        ss-Hydroxy        äthansulfonsäure,     Essigsäure,     Propionsäure,        Maleinsäure,          Fumarsäure,        Milchsäure,        Äpfelsäure,    Weinsäure,         Citronensäure,        Benzoesäure,        Salicylsäure,

            Phenylessigsäure    und Mandelsäure  bilden die Verbindungen der Formel I     Salze,    die  teilweise gut wasserlöslich sind.  



  Die nachfolgenden Beispiele erläutern die Durch  führung des     erfindungsgemässen    Verfahrens, stellen  jedoch keineswegs die einzigen Ausführungsformen  desselben vor. Die Temperaturen sind in Celsius  graden angegeben.    <I>Beispiel 1</I>  Zu einer Mischung von 226 g     1-Methly-4-piperi-          don    und 120 g Aceton in 700 ml Wasser gibt. man  300 g neutral gewaschenes     Amberlite    400 (OHG),  welches zuvor während 15     Stunden    mit 2n Natron  lauge bei Raumtemperatur     gerührt    wurde, und rührt  die Mischung während 20 Stunden bei 30 .

   Dann  wird der     Ionenaustauscher        abfiltriert    und das Filtrat  am Rotationsverdampfer im Vakuum eingedampft.  Der Rückstand wird     in    Chloroform aufgenommen,  die Lösung mit     Natriumsulfat    getrocknet und einge  dampft. Das Rohprodukt wird     im    Vakuum destil  liert, wobei man das     1-(1'-Methyl-4'-piperidyl)-2-          propanon    vom     Kp.12    125-130  erhält (vgl. Bei  spiel 2).  



  Die obige Base wird- in einem Gemisch von  Äther und     Isopropanol    5 : 1 gelöst und die Lösung  mit so viel absolut ätherischer     Chlorwasserstoff-          lösung    versetzt, bis kein weiteres Hydrochlorid mehr  ausfällt. Das Hydrochlorid wird     abfiltriert    und aus.       Isopropanol        umkristallisiert,        Smp.    125-127 .  



  <I>Beispiel 2</I>  In eine Mischung von 120 g     neutral    gewaschenem       Amberlite    IRA 400 (OHG), welches zuvor während  15 Stunden mit 2n     Natronlauge    bei Raumtemperatur       gerührt    wurde, und 176 g Aceton wurden     unter          gutem        Rühren    innerhalb 5 Stunden 67,8 g     1-Methyl-          4-piperidon    bei Zimmertemperatur     zutropfen    gelas  sen und das Gemisch anschliessend 19 Stunden wei  tergerührt.

   Dann wird der     Ionenaustauscher        abfil-          triert,    mit Methanol gewaschen und das Filtrat am  Rotationsverdampfer im Vakuum     eingedampft.    Das  Rohprodukt wird im Hochvakuum     destilliert,    wobei  man das     1-(1'-Methyl        4'-hydroxy-4'-piperidyl)-2-pro-          panon    vom     Kp.o,o1    75  erhält (vgl. Beispiel 1).  



  Die obige Base wird in Aceton gelöst und unter  Rühren so lange mit einer     gesättigten    Lösung von       Citronensäure    in Aceton versetzt, bis die Lösung  sauer     (pH    4)     reagiert.    Das ausgefallene Salz wird ab  filtriert und aus     Aceton/Methanol    umkristallisiert.  Das     1-(1'-Methyl-4'-hydroxy-4'-piperidyl)-2-propa-          non-citrat    zeigt einen     Smp.    von 103-105 .  



  In     analoger    Weise werden hergestellt:       1-(1'-Methyl-4'-hydroxy-4'-piperidyl)-2-butanon,     KP.     o,o1    95 ,     Citrat,        Smp.    145-146 ;  1-(1'     Methyl-4'        hydroxy-41-piperidyl)-2-pentanon,          Kp.o,oos,    119-121 ,     Citrat,        Smp.    126-128 ;       1-(1'-Methyl-4'-hydroxy-4'-piperidyl)-2-hexanon,     KP.     o,o1,    116-l18 ;

             1-(1'-Methyl-4'-hydroxy-4'-piperidyl)-3-methyl-          2-butanon,        Kp.0,005,    85 ,     Citrat,        Smp.    132  bis 134 ;       2-(1'-Methyl-4'        hydroxy-4'-piperidyl)-cyclo-          hexanon,        Kp.0,0i,    125 ,     Smp.    95-96 ;

         2-(1'-Methyl-4'-hydroxy-4'-piperidyl)-cyclo-          pentanon,        Kp.        o.oos,    115-118 ,     Smp.    70 ,       Citrat,        Smp.    157-158 ;  1-(1'     Methyl-4'-hydroxy-4'-piperidyl)-3-phenyl-          2-propanon,        Kp.0,003    132-135 ;

         a-(1'-Methyl-4'-hydroxy-4'-piperidyl)-aceto-          phenon,        Kp.        o,ol,    123-125 , Hydrochlorid,       Smp.    146-147 ; _       2-(1'-Methyl-4'-hydroxy-4'-piperidyl)-3-pentanon,          Kp.        o,oos,    95-100 ,     Citrat,    130-132 .

      <I>Beispiel 3</I>    17,4g Aceton werden mit 18,9 g     1-Benzyl        4-          piperidon    und 15 g neutral gewaschenem     Amberlite     IRA 400 (OHO), welches vorher während 15 Stunden  mit 2n     Natronlauge    bei Raumtemperatur gerührt  wurde, 24 Stunden bei 50  gerührt.

   Dann wird der       Ionenaustauscher        abfiltriert    und mit Methanol ge  waschen und das Filtrat am Rotationsverdampfer im  Vakuum eingedampft.     Der    Rückstand wird im Hoch  vakuum     destilliert.    Das     1-(1'-Benzyl-4'-hydroxy-4'-          piperidyl)-2-propanon    siedet unter 0,01 mm Druck  bei 125 . Das analog Beispiel 1 bereitete     Hydro-          chlorid    schmilzt bei 166-168 .  



  In analoger Weise erhält man unter Verwendung  von 20,3 g       1-(ss-PhenyT-äthyl)-4-piperidon    das       1-[1'-(ss        Phenyl-äthyl)-4'-hydroxy-4'-piperidyll-          2-propanon,    Hydrochlorid     Smp.    127-129 ,  und unter Verwendung von 14,1 g       1-n-Propyl-4-piperidon    das       1-(1'-n-Propyl-4'        hydroxy-4'-piperidyl)-          2        propanon    vom     Kp.0,01,    80-82 ,     Hydro-          chlorid        Smp.    137-139 .

      <I>Beispiel 4</I>    In einem Kolben werden 17,4 g Aceton und  20 g     Amberlite    IR 4B vorgelegt. Hierauf werden  innerhalb 5 Stunden 11,3 g     1-Methyl-l-piperidon     unter Rühren     zugetropft    und das Reaktionsgemisch  anschliessend 19     Stunden    gerührt.

   Der     Ionenaustau-          scher    wird     abfiltriert    und mit Methanol gewaschen,  das Filtrat im Vakuum eingedampft und der Rück  stand im Vakuum     destilliert.    Das     1-(1'-Methyl4'-          hydroxy-4'-piperidyl)-2-propanon    geht unter 0,005 mm  Druck bei 80  über.     Citrat        Smp.    103-105 .  



  <I>Beispiel 5</I>  Zu 23,2 g Aceton und 20 g     Amberlite    IRA 400,  (OHG-Form) in 20 ml Methanol werden unter  Rühren innerhalb 5 Stunden 11,3 g     1-Methyl-4-pi-          peridin        zugetropft    und das Gemisch anschliessend 19  Stunden weitergerührt. Der     Ionenaustauscher    wird       abfiltriert    und mit Methanol gewaschen. Das Filtrat  wird im Rotationsverdampfer eingedampft und das    zurückbleibende 1-     (Y-        Methyl-4'-hydroxy-4'-piperi-          dyl)-2-propanon    im Hochvakuum destilliert.  



       Kp.o,ool    70-85 ,     Citrat        Smp.    103-105 .  <I>Beispiel 6</I>  Zu 11,3 g     1-Methyl-4-piperidon    und 5,8g Ace  ton werden unter Rühren 0,10 g     Natriummethylat     gegeben, wobei sich das Reaktionsgemisch auf 40   erwärmt. Nach 8 Stunden Stehenlassen bei Raum  temperatur wird das nun     dickflüssige    Reaktions  gemisch in 80 ml Chloroform gelöst und die Lö  sung mit wenig Wasser     sowie    zweimal mit gesättigter       Natriumchloridlösung    extrahiert.

   Dann wird die       Chloroformlösung    mit     Natriumsulfat    getrocknet und  eingedampft und der Rückstand im Hochvakuum  destilliert, wobei das     1-(1'-Methyl-4'-hydroxy-4'-pi-          peridyl)-2-propanon    vom     Kp.        o.o5,    80  erhalten wird.       Citrat        Smp.    103-104 .

      <I>Beispiel 7</I>    Zu einer Lösung von 7,2 g Aceton in 50 ml  2n Natronlauge werden innerhalb 5 Stunden 11,3 g       1-Methyl-4-piperidon        zugetropft.    Man rührt das Ge  misch weitere 24 Stunden, zieht es dann mit Chloro  form aus, trocknet die     Chloroformlösung    mit Na  triumsulfat und dampft sie ein. Bei der Destillation  des Rückstandes erhält man das.     1-(1'-Methyl-4'-hy-          droxy-4'-piperidyl)-2-propanon    vom     Kp.o,oo170-85 .  



  Process for the preparation of new piperidine derivatives The present invention relates to a process for the preparation of new piperidine derivatives and their salts with valuable pharmacological properties.



  It has surprisingly been found that piperidine derivatives of the formula I,
EMI0001.0004
    in which R, hydrogen, an alkyl radical with a maximum of 12 carbon atoms, an alkenyl radical with 3-5 carbon atoms, the cyclopropylmethyl radical or a phenylalkyl with 7-9 carbon atoms,

            R is hydrogen or the methyl radical and R3 is an alkyl radical with a maximum of 4 carbon atoms, a phenylalkyl radical with 7-9 carbon atoms, the styryl radical, which, together with R, can form an optionally methyl-substituted trimethylene to hexamethylene radical,

      and R4 is hydrogen or a methyl radical, and their salts with inorganic and organic acids have valuable pharmacological properties, in particular analgesic activity in oral and parenteral administration, and at the same time have a relatively low toxicity. Furthermore, compounds of the formula I dampen the urge to cough.



  In the compounds of the formula I and the associated starting materials mentioned below, R1 is, for example, by hydrogen, alkyl radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isohutyl, sec. Butyl, n-amyl, n-hexyl, n-octyl, n-decyl or n-dodecyl radical;

       by alkenyl radicals, such as the allyl, crotyl or methallyl radical; embodied by cyclopropylmethyl radicals or by phenylalkyl radicals, such as the benzyl, β-phenyl-ethyl or γ-phenyl-propyl radical.



  R3 is z. B. a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl, tert. Butyl, phenyl, benzyl, o-methyl benzyl, a-phenyl-ethyl, s-phenyl-ethyl or styryl radical (s-phenyl-vinyl radical).



       R3 also forms together with R2 z. B. a trimethylene, tetramethylene, 1-methyl-tetramethylene, pentamethylene or hexamethylene radical.



  The compounds of the formula I can be prepared in a surprisingly simple manner by adding a 4-piperidone of the formula 1I,
EMI0001.0089
    with a ketone of the formula I11, R3-CO-CH2-R2 (III) where R1, R2, R3 and R4 have the meaning given under the formula I, in the presence of a base present in a homogeneous or heterogeneous phase. As a reaction medium, depending on the solubility of the starting materials, for. B.

    Water, aqueous and finally anhydrous lower alkanols are used. Inorganic bases such as sodium hydroxide and organic bases such as piperidine, piperazine and, in an anhydrous medium or in the absence of solvents, also alkali alcoholates, and on the other hand, basic ion exchangers, can be used as condensation agents.

          preferably those with quaternary ammonium groups, such as. B. Amberlite IRA 400 (OHG), but also weaker basic ones such as Amberlite IR 413, which can be used in batches or, if necessary, also continuously. The condensations are carried out at room temperature to moderately elevated temperatures.



  The starting materials of the formula II are those optionally substituted in the 1-position according to the definition. 4-piperidone and 3 methyl 4-piperidone. Compounds of this formula are already known and others can be prepared in an analogous manner. Suitable starting materials of the formula III are, for example, methyl-alkyl-ketones with a straight-chain or branched alkyl group, such as.

   B.



  Acetone, butanone, methyl-n-propyl-ketone, methyl-isopropyl-ketone, methyl-n-butyl-ketone, methyl-isobutyl-ketone, methyl sec.

       butyl ketone, pinacolin, the use of which creates compounds with a hydrogen atom R2, further prim. Alkyl sec. alkyl ketones, such as ethyl isopropyl ketone and n-propyl isopropyl ketone, which provide compounds of the formula I with a primary alkyl radical as R2, and further z.

   B. symmetrical dialkyl ketones such as diethyl ketone, di-n-propyl ketone, di-n-butyl ketone, diisobutyl ketone; Cycloalkanones, such as. B.



       Cyclopentanone, cyclohexanone, cycloheptanone and cyclooctanone, as well as aromatic-aliphatic and araliphatic-aliphatic ketones, such as acetophenone, propionphenone, butyrophenone, benzyl-methyl-ketone, (a-phenyl-ethyl) -methyl-ketone, (ss phenyl-ethyl) -methyl-ketone,

            Benzalacetone and their derivatives substituted according to the definition of R3.



  With inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethane disulfonic acid, ß-hydroxyethanesulfonic acid, acetic acid, propionic acid, maleic acid, fumaric acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid,

            Phenylacetic acid and mandelic acid form the compounds of the formula I salts, some of which are readily soluble in water.



  The following examples explain the implementation of the process according to the invention, but by no means represent the only embodiments thereof. The temperatures are given in degrees Celsius. <I> Example 1 </I> Add to a mixture of 226 g of 1-methyl-4-piperidone and 120 g of acetone in 700 ml of water. 300 g of amberlite 400 (OHG) washed neutrally, which has previously been stirred for 15 hours with 2N sodium hydroxide solution at room temperature, and the mixture is stirred for 20 hours at 30.

   The ion exchanger is then filtered off and the filtrate is evaporated in vacuo on a rotary evaporator. The residue is taken up in chloroform, the solution is dried with sodium sulfate and evaporated. The crude product is distilled in vacuo, giving 1- (1'-methyl-4'-piperidyl) -2-propanone with a boiling point of 125-130 (cf. Example 2).



  The above base is dissolved in a mixture of ether and isopropanol 5: 1 and the solution is mixed with an amount of absolutely ethereal hydrogen chloride solution until no more hydrochloride precipitates. The hydrochloride is filtered off and off. Isopropanol recrystallized, m.p. 125-127.



  <I> Example 2 </I> In a mixture of 120 g of neutral washed Amberlite IRA 400 (OHG), which had previously been stirred for 15 hours with 2N sodium hydroxide solution at room temperature, and 176 g of acetone were 67, 8 g of 1-methyl-4-piperidone are added dropwise at room temperature and the mixture is then stirred for 19 hours.

   The ion exchanger is then filtered off, washed with methanol and the filtrate is evaporated in vacuo on a rotary evaporator. The crude product is distilled in a high vacuum, 1- (1'-methyl-4'-hydroxy-4'-piperidyl) -2-propanone of boiling point 0.175 being obtained (see Example 1).



  The above base is dissolved in acetone and a saturated solution of citric acid in acetone is added while stirring until the solution is acidic (pH 4). The precipitated salt is filtered off and recrystallized from acetone / methanol. 1- (1'-Methyl-4'-hydroxy-4'-piperidyl) -2-propanone citrate has a melting point of 103-105.



  The following are prepared in an analogous manner: 1- (1'-methyl-4'-hydroxy-4'-piperidyl) -2-butanone, KP. o, o1 95, citrate, m.p. 145-146; 1- (1 'methyl-4' hydroxy-41-piperidyl) -2-pentanone, b.p. o, oos, 119-121, citrate, m.p. 126-128; 1- (1'-methyl-4'-hydroxy-4'-piperidyl) -2-hexanone, KP. o, o1, 116-118;

             1- (1'-methyl-4'-hydroxy-4'-piperidyl) -3-methyl-2-butanone, b.p. 0.005, 85, citrate, m.p. 132 to 134; 2- (1'-methyl-4 'hydroxy-4'-piperidyl) -cyclohexanone, bp 0.0i, 125, m.p. 95-96;

         2- (1'-methyl-4'-hydroxy-4'-piperidyl) cyclopentanone, b.p. o.oos, 115-118, m.p. 70, citrate, m.p. 157-158; 1- (1 'methyl-4'-hydroxy-4'-piperidyl) -3-phenyl-2-propanone, b.p. 0.003 132-135;

         a- (1'-methyl-4'-hydroxy-4'-piperidyl) -acetophenone, b.p. o, ol, 123-125, hydrochloride, mp. 146-147; _ 2- (1'-methyl-4'-hydroxy-4'-piperidyl) -3-pentanone, b.p. o, oos, 95-100, citrate, 130-132.

      <I> Example 3 </I> 17.4 g of acetone are mixed with 18.9 g of 1-benzyl 4-piperidone and 15 g of amberlite IRA 400 (OHO) washed neutrally, which has previously been stirred for 15 hours with 2N sodium hydroxide solution at room temperature, Stirred at 50 for 24 hours.

   The ion exchanger is then filtered off and washed with methanol and the filtrate is evaporated on a rotary evaporator in vacuo. The residue is distilled in a high vacuum. The 1- (1'-benzyl-4'-hydroxy-4'-piperidyl) -2-propanone boils under 0.01 mm pressure at 125. The hydrochloride prepared analogously to Example 1 melts at 166-168.



  In an analogous way, using 20.3 g of 1- (ss-phenyl-ethyl) -4-piperidone, 1- [1 '- (ss-phenyl-ethyl) -4'-hydroxy-4'-piperidyll-2 is obtained propanone, hydrochloride mp 127-129, and using 14.1 g of 1-n-propyl-4-piperidone, 1- (1'-n-propyl-4 'hydroxy-4'-piperidyl) -2 propanone of bp 0.01, 80-82, hydrochloride mp 137-139.

      <I> Example 4 </I> 17.4 g of acetone and 20 g of Amberlite IR 4B are placed in a flask. 11.3 g of 1-methyl-l-piperidone are then added dropwise with stirring over the course of 5 hours and the reaction mixture is then stirred for 19 hours.

   The ion exchanger is filtered off and washed with methanol, the filtrate is evaporated in vacuo and the residue is distilled in vacuo. The 1- (1'-methyl-4'-hydroxy-4'-piperidyl) -2-propanone passes over at 80 under 0.005 mm pressure. Citrate m.p. 103-105.



  <I> Example 5 </I> To 23.2 g of acetone and 20 g of Amberlite IRA 400, (OHG form) in 20 ml of methanol, 11.3 g of 1-methyl-4-piperidine are added with stirring over the course of 5 hours was added dropwise and the mixture was then stirred for a further 19 hours. The ion exchanger is filtered off and washed with methanol. The filtrate is evaporated in a rotary evaporator and the remaining 1- (Y-methyl-4'-hydroxy-4'-piperidyl) -2-propanone is distilled in a high vacuum.



       B.p. ool 70-85, citrate mp 103-105. <I> Example 6 </I> 0.10 g of sodium methylate are added to 11.3 g of 1-methyl-4-piperidone and 5.8 g of acetone with stirring, the reaction mixture warming to 40%. After 8 hours of standing at room temperature, the now viscous reaction mixture is dissolved in 80 ml of chloroform and the solution extracted with a little water and twice with saturated sodium chloride solution.

   The chloroform solution is then dried with sodium sulfate and evaporated and the residue is distilled in a high vacuum, the 1- (1'-methyl-4'-hydroxy-4'-piperidyl) -2-propanone having a boiling point of o.o5, 80 is obtained. Citrate m.p. 103-104.

      <I> Example 7 </I> 11.3 g of 1-methyl-4-piperidone are added dropwise over 5 hours to a solution of 7.2 g of acetone in 50 ml of 2N sodium hydroxide solution. The mixture is stirred for a further 24 hours, then extracted with chloroform, the chloroform solution is dried with sodium sulfate and evaporated. The distillation of the residue gives 1- (1'-methyl-4'-hydroxy-4'-piperidyl) -2-propanone of boiling point 0.0170-85.

 

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung von neuen Piperidin- derivaten der Formel I, EMI0003.0102 in welcher R, Wasserstoff, einen Alkylrest mit höchstens 12 Kohlenstoffatomen, einen Alkenylrest mit 3-5 Kohlenstoffatomen, den Cyclopropylmethylrest oder einen Phenylalkylrest mit 7-9 Kohlenstoff- atomen, R2 Wasserstoff oder den Methylrest, PATENT CLAIM Process for the production of new piperidine derivatives of the formula I, EMI0003.0102 in which R, hydrogen, an alkyl radical with a maximum of 12 carbon atoms, an alkenyl radical with 3-5 carbon atoms, the cyclopropylmethyl radical or a phenylalkyl radical with 7-9 carbon atoms, R2 hydrogen or the methyl radical, R3 einen Alkylrest mit höchstens 4 Kohlenstoff atomen, dem Phenylrest, einen Phenylalkylrest mit 7-9 Kohlenstoffatomen, den Styrylrest oder zusammen mit R2 einen gegebenenfalls methyl- substituierten Trimethylen- bis Hexamethylenrest und R4 Wasserstoff oder Methylrest bedeuten, und ihren Salzen mit anorganischen und organischen Säuren, dadurch gekennzeichnet, R3 is an alkyl radical with a maximum of 4 carbon atoms, the phenyl radical, a phenylalkyl radical with 7-9 carbon atoms, the styryl radical or, together with R2, an optionally methyl-substituted trimethylene to hexamethylene radical and R4 is hydrogen or methyl radical, and their salts with inorganic and organic acids , characterized, dass man ein substi tuiertes 4-Piperidon der Formel II, EMI0004.0001 mit einem Keton der allgemeinen Formel 111, R3-CO-CH2-R2 (III) wobei R1, R2, R3 und R4 die oben angegebene Be deutung haben, in Gegenwart einer in. homogener oder heterogener Phase vorliegenden Base umsetzt. that a substituted 4-piperidone of the formula II, EMI0004.0001 with a ketone of the general formula III, R3-CO-CH2-R2 (III) where R1, R2, R3 and R4 have the meaning given above, in the presence of a base present in homogeneous or heterogeneous phase. UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch, dadurch ge kennzeichnet, dass man die Reaktion in Anwesenheit einer in homogener Phase vorliegenden organischen oder anorganischen Base ausführt. 2. Verfahren nach Patentanspruch, dadurch ge kennzeichnet, dass man die Reaktion in Anwesenheit eines in heterogener Phase vorliegenden basischen Ionenaustauschers ausführt. 3. SUBClaims 1. The method according to claim, characterized in that the reaction is carried out in the presence of an organic or inorganic base present in a homogeneous phase. 2. The method according to claim, characterized in that the reaction is carried out in the presence of a basic ion exchanger present in a heterogeneous phase. 3. Verfahren nach Patentanspruch und Unter ansprüchen 1 und 2, dadurch gekennzeichnet, dass man erhaltene Verbindungen der Formel I mit an organischen oder organischen Säuren in Salze über führt. J. R. Geigy AG Anmerkung <I>des</I> Eidg. <I>Amtes für geistiges Eigen-</I> <I>tum:</I> Sollten Teile der Beschreibung mit der im Pa tentanspruch gegebenen Definition der Erfindung nicht in Einklang stehen, so sei daran erinnert, dass gemäss Art. 51 des Patentgesetzes der Patent anspruch für den sachlichen Geltungsbereich des Pa tentes massgebend ist. Process according to claim and sub-claims 1 and 2, characterized in that compounds of the formula I obtained are converted into salts with organic or organic acids. JR Geigy AG Note <I> by </I> Eidg. <I> Office for Intellectual Property </I> <I> property: </I> Should parts of the description with the definition of the invention given in the patent claim not be included in Are consistent, it should be remembered that according to Art. 51 of the Patent Act, the patent claim is decisive for the material scope of the patent.
CH905263A 1963-07-19 1963-07-19 Process for the preparation of new piperidine derivatives CH423776A (en)

Priority Applications (45)

Application Number Priority Date Filing Date Title
NL124853D NL124853C (en) 1963-07-19
CH905263A CH423776A (en) 1963-07-19 1963-07-19 Process for the preparation of new piperidine derivatives
US382955A US3366638A (en) 1963-07-19 1964-07-15 1-(1'-hydrocarbyl substituted-4'-hydroxy-4'-piperidyl)-2-ketones
AT616164A AT247328B (en) 1963-07-19 1964-07-17 Process for the preparation of new piperidine derivatives
ES0302228A ES302228A1 (en) 1963-07-19 1964-07-17 Procedure for the preparation of new derivatives of piperidine. (Machine-translation by Google Translate, not legally binding)
BE650736D BE650736A (en) 1963-07-19 1964-07-17
NL6408223A NL6408223A (en) 1963-07-19 1964-07-17
DE19641445837 DE1445837A1 (en) 1963-07-19 1964-07-17 Process for the preparation of new piperidine derivatives
DE19641445836 DE1445836A1 (en) 1963-07-19 1964-07-17 Process for the preparation of new derivatives of 1,2,3,6-tetrahydropyridine
NL6408219A NL6408219A (en) 1963-07-19 1964-07-17
DK357764A DK109200C (en) 1963-07-19 1964-07-17 Process for the preparation of piperidine derivatives or salts thereof.
NL6408218A NL6408218A (en) 1963-07-19 1964-07-17
BE650738D BE650738A (en) 1963-07-19 1964-07-17
AT616064A AT246739B (en) 1963-07-19 1964-07-17 Process for the preparation of new piperidine derivatives
ES0302229A ES302229A1 (en) 1963-07-19 1964-07-17 Procedure for the preparation of new derivatives of piperidine. (Machine-translation by Google Translate, not legally binding)
DE19641445838 DE1445838A1 (en) 1963-07-19 1964-07-17 New piperidine derivatives and processes for their preparation
BE650737D BE650737A (en) 1963-07-19 1964-07-17
FR982319A FR1415585A (en) 1963-07-19 1964-07-20 New piperidine derivatives and their preparation
FR982318A FR1423686A (en) 1963-07-19 1964-07-20 Piperidine derivatives and their preparation
FR982320A FR1414820A (en) 1963-07-19 1964-07-20 New derivatives of 1, 2, 3, 6-tetrahydro-pyridine and their preparation
GB30575/64A GB1062714A (en) 1963-07-19 1964-08-04 -ß-(4'-acyloxy-4'-piperidyl)-ketones
GB30577/64A GB1062715A (en) 1963-07-19 1964-08-04 -ß-(4'-tetrahydropyridyl)-ketones
GB30574/64A GB1062713A (en) 1963-07-19 1964-08-04 4'-hydroxy-4'-piperidyl-ketones
FR991815A FR3759M (en) 1963-07-19 1964-10-17 Medicinal product based on new piperidine derivatives, having in particular analgesic and anti-coughing action.
FR991816A FR3760M (en) 1963-07-19 1964-10-17 Medicinal product based on 1.2.3.6-tetrahydropyridine derivatives, having in particular analgesic and anti-cough properties.
FR991817A FR3662M (en) 1963-07-19 1964-10-17 Medicinal product based on new 1.2.3.6-tetrahydropyridine derivatives, having in particular analgesic and anti-cough properties.
FI00066/66A FI46846B (en) 1963-07-19 1966-01-11
US520093A US3408357A (en) 1963-07-19 1966-01-12 Alkyl acid esters of 4-alkyloxy-n-substituted-4-piperidinols
NL6600523A NL6600523A (en) 1963-07-19 1966-01-14
DE19661695054 DE1695054A1 (en) 1963-07-19 1966-01-14 Process for the preparation of new piperidine derivatives
SE00500/66A SE327986B (en) 1963-07-19 1966-01-14
GB1774/66A GB1116326A (en) 1963-07-19 1966-01-14 Piperidine derivatives and processes for their production
IL24971A IL24971A (en) 1963-07-19 1966-01-14 Piperidine derivatives and their preparation
DK20266AA DK114973B (en) 1963-07-19 1966-01-14 Process for the preparation of piperidine derivatives or salts thereof.
NO161258A NO121781B (en) 1963-07-19 1966-01-14
BR176431/66A BR6676431D0 (en) 1963-07-19 1966-01-14 PROCESS TO PRODUCE NEW PIPERIDINIC DERIVATIVES
BE675145D BE675145A (en) 1963-07-19 1966-01-14
FR46020A FR1463646A (en) 1963-07-19 1966-01-15 Piperidine derivatives and their preparation
FR57638A FR5343M (en) 1963-07-19 1966-04-14
US562533A US3338910A (en) 1963-07-19 1966-07-05 Piperidine derivatives of 1-hydrocarbyl-4-alkenylene-isonipecotic acid esters
DK104067AA DK114622B (en) 1963-07-19 1967-02-27 Process for the preparation of piperidine derivatives or salts thereof.
US660909A US3456060A (en) 1963-07-19 1967-08-16 Therapeutic compositions containing piperidine derivatives and methods of treating cough and pain therewith
US671549A US3498994A (en) 1963-07-19 1967-09-29 Certain 1,2,3,6-tetrahydro-4-pyridyl ketones
US800012*A US3509258A (en) 1963-07-19 1968-10-11 Therapeutic compositions containing piperidine derivatives and methods of treating cough therewith
MY1971123A MY7100123A (en) 1963-07-19 1971-12-31 Piperidine derivatives and processes for their production

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH905263A CH423776A (en) 1963-07-19 1963-07-19 Process for the preparation of new piperidine derivatives

Publications (1)

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CH423776A true CH423776A (en) 1966-11-15

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AT (2) AT247328B (en)
CH (1) CH423776A (en)
DK (1) DK109200C (en)
ES (2) ES302229A1 (en)

Also Published As

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ES302228A1 (en) 1965-01-16
ES302229A1 (en) 1965-01-16
DK109200C (en) 1968-04-01
AT247328B (en) 1966-06-10
AT246739B (en) 1966-05-10

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