CH426809A - Process for the preparation of new derivatives of 1,2,3,6-tetrahydropyridine - Google Patents

Process for the preparation of new derivatives of 1,2,3,6-tetrahydropyridine

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Publication number
CH426809A
CH426809A CH932563A CH932563A CH426809A CH 426809 A CH426809 A CH 426809A CH 932563 A CH932563 A CH 932563A CH 932563 A CH932563 A CH 932563A CH 426809 A CH426809 A CH 426809A
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CH
Switzerland
Prior art keywords
radical
hydrogen
carbon atoms
acid
methyl
Prior art date
Application number
CH932563A
Other languages
German (de)
Inventor
Herbert Dr Kuehnis Hans
Hugo Dr Ryf
Rolf Dr Denss
Original Assignee
Geigy Ag J R
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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 CH932563A priority patent/CH426809A/en
Priority to US382955A priority patent/US3366638A/en
Priority to NL6408223A priority patent/NL6408223A/xx
Priority to NL6408218A priority patent/NL6408218A/xx
Priority to AT636465A priority patent/AT252916B/en
Priority to BE650736D priority patent/BE650736A/xx
Priority to BE650738D priority patent/BE650738A/xx
Priority to BE650737D priority patent/BE650737A/xx
Priority to NL6408219A priority patent/NL6408219A/xx
Priority to DE19641445838 priority patent/DE1445838A1/en
Priority to DE19641445836 priority patent/DE1445836A1/en
Priority to DE19641445837 priority patent/DE1445837A1/en
Priority to FR982320A priority patent/FR1414820A/en
Priority to FR982318A priority patent/FR1423686A/en
Priority to FR982319A priority patent/FR1415585A/en
Priority to ES0302395A priority patent/ES302395A1/en
Priority to GB30575/64A priority patent/GB1062714A/en
Priority to GB30577/64A priority patent/GB1062715A/en
Priority to GB30574/64A priority patent/GB1062713A/en
Priority to FR991817A priority patent/FR3662M/en
Priority to FR991816A priority patent/FR3760M/en
Priority to FR991815A priority patent/FR3759M/en
Priority to FI00066/66A priority patent/FI46846B/fi
Priority to US520093A priority patent/US3408357A/en
Priority to DE19661695054 priority patent/DE1695054A1/en
Priority to NO161258A priority patent/NO121781B/no
Priority to NL6600523A priority patent/NL6600523A/xx
Priority to BE675145D priority patent/BE675145A/xx
Priority to DK20266AA priority patent/DK114973B/en
Priority to BR176431/66A priority patent/BR6676431D0/en
Priority to IL24971A priority patent/IL24971A/en
Priority to SE00500/66A priority patent/SE327986B/xx
Priority to GB1774/66A priority patent/GB1116326A/en
Priority to FR46020A priority patent/FR1463646A/en
Priority to FR57638A priority patent/FR5343M/fr
Priority to US562533A priority patent/US3338910A/en
Publication of CH426809A publication Critical patent/CH426809A/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

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—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 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • 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
    • C07D211/36—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 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • 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
    • C07D211/36—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 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—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 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
    • C07D211/74—Oxygen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

  

  



  Verfahren zur Herstellung von neuen Derivaten des   l2,    3, 6-Tetrahydro-pyridins
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von neuen Derivaten des 1,2,3,6  Tetrahydropyridins    mit wertvollen pharmakologischen Eigenschaften.



   Es wurde überraschenderweise gefunden, dass Derivate des 1,2,3,6-Tetrahydropyridins entsprechend der Formel I,
EMI1.1     
 in welcher   Ri    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,   R3    Wasserstoff oder einen Alkylrest mit höchstens
3 Kohlenstoffatomen, den Phenylrest oder einen    Phenylalkylrest    mit 7-8 Kohlenstoffatomen, und R4 Wasserstoff oder den Methylrest bedeutet, und ihre Salze mit anorganischen und organischen Säuren wertvolle pharmakologische Eigenschaften,

   insbesondere eine ausgezeichnete analgetische Wirk  samkeit    bei oraler wie parenteraler Applikation und starke antitussive Wirksamkeit besitzen. Im Gegensatz zu andern   Analgetica    besitzen sie keine para  sympathicolytischen    Eigenschaften, sondern wirken eher   parasympathicomimetisch.    Sie sind zugleich relativ wenig toxisch und eignen sich deshalb z. B. zur Linderung und Behebung von Schmerzen verschie  dener    Genese und auch des Hustenreizes.



   In den Verbindungen der Formel I und den zugehörigen, weiter unten genannten Ausgangsstoffen ist   Ri    z. B. durch Wasserstoff, Alkylreste, wie den
Methyl-,   Äthyl-,    n-Propyl-,   Isopropyl-,    n-Butyl-,   Isobutyl-,      sek.-Butyl-,    n-Amyl-,    Isoamyl-,    n-Hexyl-,   n-Octyl-,    n-Decyl-oder n-Dodecyl-rest ; durch Alkenylreste, wie den
Allyl-, Crotyl-oder    y, y-Dimethylalkylrest    ; durch den Cyclopropylmethylrest oder durch Phenyl  alkylre'ste,    wie den
Benzyl-,   ss-Phenyläthyl-oder    y-Phenylpropylrest verkörpert.



     Rg    ist z. B. Wasserstoff, der Methyl-, Äthyl, n-Propyl-, Isopropyl-, Phenyl-, Benzyl-,   a-Phenyl-      äthyl-oder ss-Phenyläthylrest.   



   Zur erfindungsgemässen Herstellung der Verbindungen der Formel   1    behandelt man eine Verbindung der Formel II
EMI1.2     
 in welchen   Ri,      R2,      R3    und   R4    die oben angegebene Bedeutung haben, mit   Quecksilberionen    enthaltender Schwefelsäure. Die Behandlung zum Zwecke der   Wasseranl'agerung    an die Dreifachbindung und Wasserabspaltung erfolgt unter Verwendung von mindestens 84%iger Schwefelsäure bei Raumtemperatur oder mässig erhöhten Temperaturen, z. B. bis etwa   60 .    Die Reaktionstemperatur kann bei höherer Säurekonzentration niedriger gewählt   und/oder    die Reaktionsdauer verkürzt werden.



   Einzelne Vertreter von Ausgangsstoffen der Formel II mit Wasserstoff als   Ra    und R3 sind in der französischen Patentschrift Nr. 665 M beschrieben, und. weitere sind ebenfalls in der dort angegebenen Weise, das heisst durch Umsetzung von Propargylbromid mit   amalgamiertem Magnesium,    Zink oder Aluminium in einem Gemisch von Tetrahydrofuran und Toluol, und Kondensation der entstandenen metallorganischen Verbindung mit einem entsprechend der Definition von Ri und R4 substituierten 4-Piperidon herstellbar. Anstelle des Propargylbromids können auch analoge Verbindungen, wie z.

   B. das   3-Brom-l-butin    oder das   l-Brom-2-butin,    eingesetzt werden, die Ausgangsstoffe der Formel   II    mit von Wasserstoff verschiedenem Rest R2   und/oder    R3 liefern. Das in der genannten französischen Patentschrift beschriebene Verfahren wird mit Vorteil dadurch modifiziert, dass man anstelle von bloss mit   Quecksilberchlorid      amalgamiertem    Aluminiumgries solches verwendet, das zunächst mittels metallischem Quecksilber   amalgamiert    und hierauf mit Quecksilberchlorid behandelt wurde.



   Die Herstellung von Ausgangsstoffen der Formel   II,    die als Ri ein Wasserstoffatom enthalten, kann   z.    B. nach dem vorstehend genannten Verfahren unter Verwendung der doppelt molaren Menge Pro  pargylbromid    oder eines Analogen und entsprechend erhöhter   Metallmengei    erfolgen.



   Als anorganische und organische Säuren, die zur Salzbildung mit den erfindungsgemässen Basen für die Herstellung von kristallisierten analgetischen und antitussiven Wirkstoffen und teilweise auch für die Reinigung der Basen in Frage kommen, seien beispielsweisegenannt :
Salzsäure, Bromwasserstoffsäure, Schwefelsäure,
Salpetersäure, Phosphorsäure, Methansulfonsäure,  Äthandisulfonsäure,   ss-Hydroxyäthansulfonsäure,   
Essigsäure, Propionsäure, Maleinsäure,
Fumarsäure, Milchsäure, Äpfelsäure, Weinsäure,
Citronensäure, Benzoesäure, Salicylsäure,
Phenylessigsäure und Mandelsäure.



   Die nachfolgenden Beispiele erläutern die Durchführung   der tezfindungsgemässen    Verfahren, stellen jedoch keineswegs die einzigen Ausführungsformen derselben vor. Die Temperaturen sind in Celsiusgraden angegeben.



   Beispiel 1 a) 4,05 g Aluminiumgries werden mit 10 g Quecksilber versetzt und mit einem Rührer gut vermischt. Dann wird das unverbrauchte Quecksilber abdekantiert. Das amalgamierte Aluminium wird in 25 ml abs. Tetrahydrofuran und 15 ml abs. Benzol mit 15 mg Quecksilberchlorid kurz aufgekocht und anschliessend 15 Minuten weitergerührt. Hierauf werden bei   50-60  von    insgesamt 20,5   ml    Propargylbromid. so viel ohne Lösungsmittel zugegeben, bis die Reaktion in Gang kommt und die Temperatur gegen   70  steigt ;    nachher wird das restliche Propargylbromid, verdünnt mit 35 ml abs. Benzol, zugefügt. Das Gemisch wird 30 Minuten gerührt. Hierauf werden bei   20-25  50    g 1-   (ss-Phenyl-äthyl)-4-piperi-    don in 150 ml abs.

   Benzol unter Eiskühlung langsam zugetropft und das Gemisch weitere 15 Stunden gerührt. Dann wird es mit Eis und 2n Salzsäure zersetzt, die wässrige Phase abgetrennt, mit Chloroform gewaschen und mit konz. Natronlauge alkalisch gemacht, und die freigesetzte Base in Chloroform aufgenommen. Die   Chloroformlösung    wird getrocknet und eingedampft und der Rückstand destilliert, wobei das   1- (, B-Phenyl-äthyl)-4- (2'-propinyl)-4-piperi-    dinol vom Kp.   003 130-140     erhalten wird.



   Auf analoge Weise erhält man z. B. :
1-Benzyl-4-   (2'-propinyl)-4-piperidinol,   
Kp.   003 128135     ;    1-Methyl- (2'-propinyl)-4-piperidinol,   
Smp.   91-93     ;   
1-Methyl-441'-methyl-2'-propinyl)-4-piperidinol,
Kp. 0, 0175-78  ;       1-Äthyl-4-      (2'-propinyl)-4-piperidinol    ;    1-n-Butyl-4-      (2'-propinyl)-4-piperidinol    ;

      1-n-Dodecyl-4-      (2'-propinyl)-4-piperidinol    ;    1- (a-Methyl-ss-phenyl-äthyl)-4-(2'-propinyl)-   
4-piperidinol ;    1- (y-Phenyl-propyl)-4-(2'-propinyl)-4-piperidinol.    b) 12 g   1 tss-Phenyl-äthyl)-4-(2'-propinyl)-4-pi-    peridinol werden langsam in 35   ml    konz. Schwefelsäure, die 350 mg Quecksilbersulfat enthält, eingetragen und das Gemisch 6 Stunden auf   50  erhitzt.   



  Dann wird es auf Eis gegossen, mit konz. Natronlauge alkalisch gemacht und mit Chloroform extrahiert. Die Chloroformlösung wird mit gesättigter Natriumchloridlösung gewaschen, getrocknet und eingedampft, und der Rückstand im Hochvakuum destilliert. Das   l-[l'g'-Phenyl-äthyl)-1', 2', 3', 6'-tetra-      hydro-4'-pyridyl]-2-propanon    geht unter 0,01 Torr bei   140  über.   



   Das aus einer Lösung der Base in Isopropanol/ Äther mittels ätherischer Chlorwasserstofflösung ausgefällte Hydrochlorid schmilzt nach Umkristallisation aus   Isopropanol/Äther    bei   177-179 .   



   In analoger Weise werden z. B. folgende Verbindungen erhalten :    l-    (l'-Benzyl-1', 2', 3',   6'-tetrahydro-4'-pyridyl)-   
2-propanon, Hydrochlorid, Smp.   184-186     ;    1- (1'-Methyl-1', 2', 3', 6'-tetrahydro-4'-pyridyl)-   
2-propanon, Kp.   o,      o,      65-68 ,   
Citrat Smp.   153-154     ;    3- (1'-Methyl-1', 2', 3', 6'-tetrahydro-4'-pyridyl) ¯   
2-butanon, Kp. 0, 01   55 ,   
Citrat Smp. 105-107  ;

       1- (1'-Äthyl-1', 2',    3',   6'-tetrahydro-4'-pyridyl)-   
2-propanon, Citrat Smp.   131-132     ;    1- (1'-n-Butyl-1', 2', 3', 6'-tetrahydro-4'-pyridyl)-   
2-propanon ;    1- (1'-n-Dodecyl-1', 2', 3', 6'-tetrahydro-4'pyridyl)-   
2-propanon ;    l-    [l'-(a-Methyl-ss-phenyl-äthyl)-1', 2',   3',      6'-tetra-       hydro-4'-pyridyl]-2-propanon    ;    1- [1'- (7-Phenyl-propyl)-11, 21,    3', 6'-tetrahydro   4'-pyridyl]-2-propanon.   



   Beispiel 2
8,35 g   1-Methyl-4-(1'-methyl-2'-propinyl) 4pi-    peridinol (vgl. Beispiel   1    a) werden langsam unter Kühlung in 25 g   84%    ige Schwefelsäure und 0,4 g   Quecksilbersulfat    eingetragen und 24 Stunden bei Zimmertemperatur gerührt. Hierauf wird das Gemisch auf Eis gegossen, mit konz. Natronlauge   alka-    lisch gemacht und mit Chloroform extrahiert. Die   Chloroformlösung    wird mit gesättigter Natriumchloridlösung gewaschen, getrocknet, eingedampft und der Rückstand destilliert.

   Das   3-(1'-Methyl-      1',      2',    3',   6'-tetrahydro-4'-pyridyl)-2-butanon    geht unter 0,01 Torr bei   55  über.    Citrat Smp.   105-107     (vgl. auch Beispiel   1    b).



   Nach der in den Beispielen   1    und 2 beschriebenen Arbeitsweise können z. B. auch die folgenden Verbindungen erhalten werden :    1- (1'-Methyl-1', 2', 3', 6'-tetrahydro-4'-pyridyl)-       2-butanon,    Citrat Smp.   135-136     ;    1- (1'-Methyl-1', 2', 3', 6'-tetrahydro-4'-pyridyl)-   
2-pentanon, Citrat Smp.   131-133  ;       1- (1'-Methyl-1', 2', 3', 6'-tetrahydro-4'-pyridyl)-   
2-hexanon, Citrat Smp. 117-119  ;    1- (1'-n-Propyl-1',    2', 3',   6'-tetrahydro-4'-pyridyl)-   
2-propanon, Hydrochlorid Smp.   148-149 .   



   Beispiel 3 a) 8,85 g   1-Äthyl-4- (2'-propinyl)-4-piperidinol    werden in 90 ml abs. Chloroform gelöst und unter Rühren 4 ml Thionylchlorid langsam zugetropft.



  Unter Selbsterwärmung färbt sich die Lösung dunkel.



  Sie wird anschliessend 4 Stunden unter Rückfluss gekocht. Nach dem Eindampfen im Rotationsverdampfer wird der Rückstand mit konz. Natronlauge alkalisch gestellt und mit Äther ausgegossen.



  Die   Atherlösung    wird getrocknet und eingedampft.



  Bei der Destillation des Rückstandes im Hochvakuum wird das   l-Athyl-4-(2'-propinyl)-1,    2,3,6tetrahydro-pyridin vom Kp.   o,      ol 60-66  erhalten.   



  Citrat Smp.   127-128 .    b)   1    g rohes   1-Athyl-4-(2'-propinyl)-1,    2,3,6  tetrahydropyridin,    das durch   1-Athyl-4-(2'-propinyl-    iden)-piperidin verunreinigt ist, wird mit 4 ml   25 % iger    Schwefelsäure und 50 mg Quecksilber-IIsulfat 4 Stunden unter Rühren auf   60  erhitzt.    Nach dem Erkalten wird das Gemisch alkalisch gestellt und mit Chloroform extrahiert, die Chloroformlösung getrocknet und eingedampft und der Rückstand im Vakuum destilliert. Die Fraktion von 95-100 /12 Torr wird in Aceton gelöst und mit acetonischer Citronensäurelösung bis pH 4 versetzt.

   Das rohe Citrat wird abgesaugt und aus   Aceton/Methanol      umkristaJlisiert,    das erhaltene Citrat des   l-(l'-Äthyl-1',    2', 3',   6'-tetra-      hydro-4-pyridyl)-2-propanon    schmilzt bei   131-132     (vgl. Beispiel   1).   



   Die Mutterlauge enthält das Citrat des   1- (1'-      Athyl-4'-hydroxy-'4 !-piperidyl)-2-propanons.  



  



  Process for the preparation of new derivatives of l2, 3, 6-tetrahydropyridine
The present invention relates to a process for the preparation of new derivatives of 1,2,3,6 tetrahydropyridine with valuable pharmacological properties.



   It has surprisingly been found that derivatives of 1,2,3,6-tetrahydropyridine corresponding to the formula I,
EMI1.1
 in which Ri is hydrogen, an alkyl radical with at most 12
Carbon atoms, an alkenyl radical with 3-5
Carbon atoms, the cyclopropylmethyl radical or a phenylalkyl radical with 7-9 carbon atoms, R2 is hydrogen or the methyl radical, R3 is hydrogen or an alkyl radical with at most
3 carbon atoms, the phenyl radical or a phenylalkyl radical with 7-8 carbon atoms, and R4 denotes hydrogen or the methyl radical, and their salts with inorganic and organic acids have valuable pharmacological properties,

   in particular have excellent analgesic efficacy for oral and parenteral administration and strong antitussive effectiveness. In contrast to other analgesics, they have no para-sympathicolytic properties, but rather have a parasympathicomimetic effect. At the same time, they are relatively less toxic and are therefore suitable for. B. to relieve and remedy pain of various origins and also the coughing stimulus.



   In the compounds of formula I and the associated starting materials mentioned below, Ri is z. B. by hydrogen, alkyl radicals, such as the
Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-amyl, isoamyl, n-hexyl, n-octyl, n-decyl or n-dodecyl radical; by alkenyl residues such as the
Allyl, crotyl or y, y-dimethylalkyl radical; by the Cyclopropylmethylrest or by Phenyl alkylre'ste, like the
Benzyl, ss-phenylethyl or y-phenylpropyl radical embodied.



     Rg is e.g. B. hydrogen, the methyl, ethyl, n-propyl, isopropyl, phenyl, benzyl, a-phenyl, ethyl or ss-phenylethyl radical.



   For the preparation according to the invention of the compounds of formula 1, a compound of formula II is treated
EMI1.2
 in which Ri, R2, R3 and R4 have the meaning given above, with sulfuric acid containing mercury ions. The treatment for the purpose of water attachment to the triple bond and elimination of water is carried out using at least 84% sulfuric acid at room temperature or at moderately elevated temperatures, e.g. B. to about 60. With a higher acid concentration, the reaction temperature can be selected to be lower and / or the reaction time can be shortened.



   Individual representatives of starting materials of the formula II with hydrogen as Ra and R3 are described in French patent specification No. 665 M, and. others can also be prepared in the manner indicated there, i.e. by reacting propargyl bromide with amalgamated magnesium, zinc or aluminum in a mixture of tetrahydrofuran and toluene, and condensing the resulting organometallic compound with a 4-piperidone substituted according to the definition of Ri and R4 . Instead of the propargyl bromide, analog compounds, such as.

   B. 3-bromo-l-butyne or l-bromo-2-butyne can be used, which supply starting materials of formula II with a radical R2 and / or R3 other than hydrogen. The method described in the French patent mentioned is advantageously modified in that instead of aluminum grit amalgamated merely with mercury chloride, such powder is used which was first amalgamated with metallic mercury and then treated with mercury chloride.



   The preparation of starting materials of the formula II which contain a hydrogen atom as Ri can, for. B. by the above-mentioned method using twice the molar amount of Pro pargylbromid or an analog and a correspondingly increased amount of metal.



   Inorganic and organic acids that can be used for salt formation with the bases according to the invention for the production of crystallized analgesic and antitussive active ingredients and in some cases also for cleaning the bases are, for example:
Hydrochloric acid, hydrobromic acid, sulfuric acid,
Nitric acid, phosphoric acid, methanesulphonic acid, ethane disulphonic acid, ss-hydroxyethanesulphonic acid,
Acetic acid, propionic acid, maleic acid,
Fumaric acid, lactic acid, malic acid, tartaric acid,
Citric acid, benzoic acid, salicylic acid,
Phenylacetic acid and mandelic acid.



   The following examples explain the implementation of the method according to the invention, but by no means represent the only embodiments thereof. The temperatures are given in degrees Celsius.



   Example 1 a) 4.05 g of aluminum powder are mixed with 10 g of mercury and mixed well with a stirrer. Then the unused mercury is decanted off. The amalgamated aluminum is in 25 ml abs. Tetrahydrofuran and 15 ml of abs. Benzene briefly boiled with 15 mg of mercury chloride and then stirred for a further 15 minutes. This is followed by 50-60 of a total of 20.5 ml of propargyl bromide. so much added without solvent until the reaction starts and the temperature rises to 70; then the remaining propargyl bromide, diluted with 35 ml of abs. Benzene, added. The mixture is stirred for 30 minutes. Then at 20-25 50 g of 1- (ss-phenyl-ethyl) -4-piperidone in 150 ml of abs.

   Benzene was slowly added dropwise with ice cooling and the mixture was stirred for a further 15 hours. Then it is decomposed with ice and 2N hydrochloric acid, the aqueous phase is separated off, washed with chloroform and acidified with conc. Sodium hydroxide solution made alkaline, and the released base was taken up in chloroform. The chloroform solution is dried and evaporated and the residue is distilled, the 1- (, B-phenyl-ethyl) -4- (2'-propynyl) -4-piperidinol of boiling point 003 130-140 being obtained.



   In an analogous way one obtains z. B.:
1-benzyl-4- (2'-propynyl) -4-piperidinol,
Bp 003 128135; 1-methyl- (2'-propynyl) -4-piperidinol,
M.p. 91-93;
1-methyl-441'-methyl-2'-propynyl) -4-piperidinol,
B.p. 0, 0175-78; 1-ethyl-4- (2'-propynyl) -4-piperidinol; 1-n-butyl-4- (2'-propynyl) -4-piperidinol;

      1-n-dodecyl-4- (2'-propynyl) -4-piperidinol; 1- (a-methyl-ss-phenyl-ethyl) -4- (2'-propynyl) -
4-piperidinol; 1- (γ-phenyl-propyl) -4- (2'-propynyl) -4-piperidinol. b) 12 g of 1 tss-phenyl-ethyl) -4- (2'-propynyl) -4-piperidinol are slowly concentrated in 35 ml. Sulfuric acid, which contains 350 mg of mercury sulfate, entered and the mixture heated to 50 for 6 hours.



  Then it is poured onto ice, with conc. Sodium hydroxide solution made alkaline and extracted with chloroform. The chloroform solution is washed with saturated sodium chloride solution, dried and evaporated, and the residue is distilled in a high vacuum. The 1- [l'g'-phenyl-ethyl) -1 ', 2', 3 ', 6'-tetrahydro-4'-pyridyl] -2-propanone goes over at 140 below 0.01 torr.



   The hydrochloride precipitated from a solution of the base in isopropanol / ether by means of an ethereal hydrogen chloride solution melts after recrystallization from isopropanol / ether at 177-179.



   In an analogous manner, for. B. obtained the following compounds: l- (l'-Benzyl-1 ', 2', 3 ', 6'-tetrahydro-4'-pyridyl) -
2-propanone, hydrochloride, m.p. 184-186; 1- (1'-methyl-1 ', 2', 3 ', 6'-tetrahydro-4'-pyridyl) -
2-propanone, b.p. o, o, 65-68,
Citrate m.p. 153-154; 3- (1'-methyl-1 ', 2', 3 ', 6'-tetrahydro-4'-pyridyl) ¯
2-butanone, b.p. 0, 01 55,
Citrate m.p. 105-107;

       1- (1'-ethyl-1 ', 2', 3 ', 6'-tetrahydro-4'-pyridyl) -
2-propanone, citrate m.p. 131-132; 1- (1'-n-butyl-1 ', 2', 3 ', 6'-tetrahydro-4'-pyridyl) -
2-propanone; 1- (1'-n-dodecyl-1 ', 2', 3 ', 6'-tetrahydro-4'pyridyl) -
2-propanone; 1- [l '- (a-methyl-ss-phenyl-ethyl) -1', 2 ', 3', 6'-tetrahydro-4'-pyridyl] -2-propanone; 1- [1'- (7-phenyl-propyl) -11, 21, 3 ', 6'-tetrahydro 4'-pyridyl] -2-propanone.



   Example 2
8.35 g of 1-methyl-4- (1'-methyl-2'-propynyl) 4piperidinol (cf. Example 1 a) are slowly introduced into 25 g of 84% strength sulfuric acid and 0.4 g of mercury sulfate with cooling Stirred for 24 hours at room temperature. The mixture is then poured onto ice, with conc. Sodium hydroxide solution made alkaline and extracted with chloroform. The chloroform solution is washed with saturated sodium chloride solution, dried and evaporated, and the residue is distilled.

   The 3- (1'-methyl-1 ', 2', 3 ', 6'-tetrahydro-4'-pyridyl) -2-butanone goes over below 0.01 torr at 55. Citrate melting point 105-107 (cf. also Example 1b).



   According to the procedure described in Examples 1 and 2, for. B. the following compounds can also be obtained: 1- (1'-methyl-1 ', 2', 3 ', 6'-tetrahydro-4'-pyridyl) -2-butanone, citrate mp 135-136; 1- (1'-methyl-1 ', 2', 3 ', 6'-tetrahydro-4'-pyridyl) -
2-pentanone, citrate m.p. 131-133; 1- (1'-methyl-1 ', 2', 3 ', 6'-tetrahydro-4'-pyridyl) -
2-hexanone, citrate m.p. 117-119; 1- (1'-n-propyl-1 ', 2', 3 ', 6'-tetrahydro-4'-pyridyl) -
2-propanone, hydrochloride m.p. 148-149.



   Example 3 a) 8.85 g of 1-ethyl-4- (2'-propynyl) -4-piperidinol in 90 ml of abs. Dissolved chloroform and slowly added dropwise with stirring 4 ml of thionyl chloride.



  The solution turns dark when it warms itself.



  It is then refluxed for 4 hours. After evaporation in a rotary evaporator, the residue is treated with conc. Sodium hydroxide solution made alkaline and poured out with ether.



  The ether solution is dried and evaporated.



  When the residue is distilled in a high vacuum, the l-ethyl-4- (2'-propynyl) -1, 2,3,6-tetrahydropyridine of boiling point o, ol 60-66 is obtained.



  Citrate m.p. 127-128. b) 1 g of crude 1-ethyl-4- (2'-propynyl) -1, 2,3,6 tetrahydropyridine, which is contaminated by 1-ethyl-4- (2'-propynylidene) piperidine, is with 4 ml of 25% sulfuric acid and 50 mg of mercury (II) sulfate were heated to 60 for 4 hours while stirring. After cooling, the mixture is made alkaline and extracted with chloroform, the chloroform solution is dried and evaporated and the residue is distilled in vacuo. The fraction of 95-100 / 12 Torr is dissolved in acetone and acetone citric acid solution to pH 4 is added.

   The crude citrate is filtered off with suction and recrystallized from acetone / methanol, the obtained citrate of 1- (l'-ethyl-1 ', 2', 3 ', 6'-tetrahydro-4-pyridyl) -2-propanone melts 131-132 (see Example 1).



   The mother liquor contains the citrate of 1- (1'-ethyl-4'-hydroxy-'4! -Piperidyl) -2-propanone.

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung von neuen Derivaten des 1,2,3,6-Tetrahydropyridins der Formel I, EMI3.1 in welcher Ri 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, R3 Wasserstoff oder einen Alkylrest mit höchstens 3 Kohlenstoffatomen, den Phenylrest oder einen Phenylalkylrest mit 7-8 Kohlenstoffatomen, und R4 Wasserstoff oder den Methylrest bedeutet, und ihre Salze mit anorganischen und organischen Säuren, dadurch gekennzeichnet, dass man eine Verbindung der Formel II, EMI3.2 in welchen Rl, Rs, PATENT CLAIM Process for the preparation of new derivatives of 1,2,3,6-tetrahydropyridine of the formula I, EMI3.1 in which Ri is hydrogen, an alkyl radical with at most 12 Carbon atoms, an alkenyl radical with 3-5 Carbon atoms, the cyclopropylmethyl radical or a phenylalkyl radical with 7-9 carbon atoms, R2 is hydrogen or the methyl radical, R3 is hydrogen or an alkyl radical with at most 3 carbon atoms, the phenyl radical or a phenylalkyl radical with 7-8 carbon atoms, and R4 denotes hydrogen or the methyl radical, and their salts with inorganic and organic acids, characterized in that a compound of the formula II, EMI3.2 in which Rl, Rs, Rg und R4 die oben angegebene Bedeutung haben, mit Quecksilberionen enthaltender Schwefelsäure behandelt. Rg and R4 have the meaning given above, treated with sulfuric acid containing mercury ions. UNTERANSPRUCH Verfahren nach Patentanspruch, dadurch gekenn- zeichnet, dass man erhaltene Verbindungen der Formel I mit anorganischen oder organischen Säuren in Sälze überführt. SUBClaim Process according to patent claim, characterized in that the compounds of the formula I obtained are converted into salts with inorganic or organic acids.
CH932563A 1963-07-19 1963-07-26 Process for the preparation of new derivatives of 1,2,3,6-tetrahydropyridine CH426809A (en)

Priority Applications (42)

Application Number Priority Date Filing Date Title
NL124853D NL124853C (en) 1963-07-19
CH932563A CH426809A (en) 1963-07-26 1963-07-26 Process for the preparation of new derivatives of 1,2,3,6-tetrahydropyridine
US382955A US3366638A (en) 1963-07-19 1964-07-15 1-(1'-hydrocarbyl substituted-4'-hydroxy-4'-piperidyl)-2-ketones
NL6408219A NL6408219A (en) 1963-07-19 1964-07-17
DE19641445837 DE1445837A1 (en) 1963-07-19 1964-07-17 Process for the preparation of new piperidine derivatives
AT636465A AT252916B (en) 1963-07-26 1964-07-17 Process for the preparation of new derivatives of 1,2,3,6-tetrahydropyridine
BE650736D BE650736A (en) 1963-07-19 1964-07-17
BE650738D BE650738A (en) 1963-07-19 1964-07-17
BE650737D BE650737A (en) 1963-07-19 1964-07-17
NL6408223A NL6408223A (en) 1963-07-19 1964-07-17
DE19641445838 DE1445838A1 (en) 1963-07-19 1964-07-17 New piperidine derivatives and processes for their preparation
DE19641445836 DE1445836A1 (en) 1963-07-19 1964-07-17 Process for the preparation of new derivatives of 1,2,3,6-tetrahydropyridine
NL6408218A NL6408218A (en) 1963-07-19 1964-07-17
FR982320A FR1414820A (en) 1963-07-19 1964-07-20 New derivatives of 1, 2, 3, 6-tetrahydro-pyridine and their preparation
FR982318A FR1423686A (en) 1963-07-19 1964-07-20 Piperidine derivatives and their preparation
FR982319A FR1415585A (en) 1963-07-19 1964-07-20 New piperidine derivatives and their preparation
ES0302395A ES302395A1 (en) 1963-07-26 1964-07-24 Procedure for the preparation of new derivatives of 1, 2,3,6-tetrahidro-pyridine. (Machine-translation by Google Translate, not legally binding)
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
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.
FR991815A FR3759M (en) 1963-07-19 1964-10-17 Medicinal product based on new piperidine derivatives, having in particular analgesic and anti-coughing action.
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
IL24971A IL24971A (en) 1963-07-19 1966-01-14 Piperidine derivatives and their preparation
NO161258A NO121781B (en) 1963-07-19 1966-01-14
NL6600523A NL6600523A (en) 1963-07-19 1966-01-14
BE675145D BE675145A (en) 1963-07-19 1966-01-14
DK20266AA DK114973B (en) 1963-07-19 1966-01-14 Process for the preparation of piperidine derivatives or salts thereof.
BR176431/66A BR6676431D0 (en) 1963-07-19 1966-01-14 PROCESS TO PRODUCE NEW PIPERIDINIC DERIVATIVES
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
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)

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CH932563A CH426809A (en) 1963-07-26 1963-07-26 Process for the preparation of new derivatives of 1,2,3,6-tetrahydropyridine

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