CH481870A - Process for the preparation of 5H-dibenzo (a, d) cycloheptene derivatives - Google Patents

Process for the preparation of 5H-dibenzo (a, d) cycloheptene derivatives

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Publication number
CH481870A
CH481870A CH1477869A CH1477869A CH481870A CH 481870 A CH481870 A CH 481870A CH 1477869 A CH1477869 A CH 1477869A CH 1477869 A CH1477869 A CH 1477869A CH 481870 A CH481870 A CH 481870A
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Switzerland
Prior art keywords
hydrochloride
lower alkyl
hydrogen atom
oxalate
dibenzo
Prior art date
Application number
CH1477869A
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German (de)
Inventor
Hamish Dr Russel Jeff
Original Assignee
Wander Ag Dr A
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 Wander Ag Dr A filed Critical Wander Ag Dr A
Priority to CH1477869A priority Critical patent/CH481870A/en
Publication of CH481870A publication Critical patent/CH481870A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C07C209/70—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by reduction of unsaturated amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

  

  



  Verfahren zur Herstellung von   5H-Dibenzo    [a, d] cyclohepten-Derivaten    GegenstandL der Erfindung    ist ein Verfahren zur Herstellung von neuen   5-aminomethylierten 5H-Dibenzo-      [a,      d]      cycloheptenen    der Formel :
EMI1.1     
 sowie von Säure-Additionssalzen davon. In Formel I bedeutet   Rr    ein Wasserstoffatom oder eine niedrige   Alkylgruppe, Rs    stellt eine niedrige Alkyl-, Alkenyloder Alkinylgruppe   dar, und R3 bedeutet    eine niedrige Alkylgruppe. Von den Resten   R4    und   R    bedeutet der eine ein Wasserstoffatom und der andere ein Wasser  stoffatom,    ein Halogenatom oder eine niedrige Alkylgruppe.

   Unter einer niedrigen Alkyl-, Alkenyl-oder Alkinylgruppe wird eine solche mit höchstens 3 C Atomen verstanden.



   Die genannten Verbindungen zeigen, wie dies beim   Elektroschock-Test    [Methode von Goodman et al., J.



  Pharmacol,   108,    168 (1953)] ersichtlich ist, starke antikonvulsive Wirksamkeit und kommen daher insbesondere als Antiepileptika in Betracht.



   Die gewünschten Verbindungen der Formel I werden erhalten, wenn man primäre oder sekundäre Amine der Formel :
EMI1.2     
 worin   RI,      Rz    und   R@   die genannte Bedeutung haben und   R'ein Wasserstoffatom    oder eine e niedrige Alkyl-, Alkenyl-oder Alkinylgruppe darstellt, zum gewünschten tertiären Amin alkyliert, alkenyliert oder alkinyliert.



   Die Alkylierung kann durch Umsetzen mit   entspre-      chenden    Aldehyden unter Verwendung eines Reduktionsmittels, wie Ameisensäure, oder, wie auch eine Alkenylierung oder Alkinylierung, durch Umsetzen mit reaktionsfähigen Estern von entsprechenden Alkoholen, insbesondere den Halogeniden, erfolgen.



   Die als Ausgangsstoffe benötigten primären Amine werden vorzugsweise durch Reduktion entsprechender Nitrile mit Lithiumaluminiumhydrid/Aluminiumchlorid erhalten. Die sekundären Amine entstehen z. B. beim Umsetzen von reaktionsfähigen Estern von Alkoholen der Formel :
EMI2.1     
 worin   RI,    R4 und   R,    die genannte Bedeutung haben, mit Aminen der Formel   H2N-R-..   



   Die nach diesem Verfahren erhaltenen Verbindungen entsprechend Formel I können sowohl als freie Basen als auch in Form ihrer   Additionssalze mit geeigneten Säu-    ren,, wie Halogenwasserstoffsäuren, Toluolsulfonsäuren, Schwefelsäure, Salpetersäure, Phosphorsäure, Essigsäure, Oxalsäure, Malonsäure, Bernsteinsäure, Apfelsäure, Maleinsäure oder Weinsäure, gewonnen und verwendet werden.



   Beispiel 1
3, 8 g 5-Aminomethyl-11-methyl-5H-dibenzo [a, d]  cyclohepten    (Smp. 77-78  C) werden mit 4, 5 ml   35% iger Formaldehydlösung    und 12, 8 g Ameisensäure während 6 Stunden auf Rückfluss erhitzt. Hierauf wird das Reaktionsgemisch mit 2n Salzsäure verdünnt und am Vakuum eingedampft. Der Rückstand wird in Wasser aufgenommen, mit 2n Natronlauge alkalisch gestellt und viermal mit Chloroform ausgeschüttelt. Die Chloroformauszüge werden einmal mit Wasser gewaschen, mit Natriumsulfat getrocknet und eingedampft.

   Der ölige Rückstand wird ins Oxalat übergeführt, wobei man nach Kristallisation aus   Aceton/Ather    4, 7 g   (82%    der Theorie) 5-Dimethylaminomethyl-11-methyl-5H-dibenzo [a,   d]-      cyclohepten-Oxalat    in Form von farblosen Nadeln vom   Schmelzpunkt 157-160  C erhält.   



   Bei analogem Vorgehen wie im vorerwähnten Bei spiel erhält man aus den entsprechenden Ausgangs stoffen weiterhin z. B. die in der folgenden Tabelle an gegebenen Produkte. In der Tabelle haben Rl,   Ra,    R3, R4 und   R5    die genannte Bedeutung.



  



  Process for the preparation of 5H-dibenzo [a, d] cycloheptene derivatives The invention relates to a process for the preparation of new 5-aminomethylated 5H-dibenzo- [a, d] cycloheptenes of the formula:
EMI1.1
 as well as acid addition salts thereof. In formula I, Rr represents a hydrogen atom or a lower alkyl group, Rs represents a lower alkyl, alkenyl or alkynyl group, and R3 represents a lower alkyl group. Of the radicals R4 and R, one is a hydrogen atom and the other is a hydrogen atom, a halogen atom or a lower alkyl group.

   A lower alkyl, alkenyl or alkynyl group is understood to be one with a maximum of 3 carbon atoms.



   The compounds mentioned show how this occurs in the electric shock test [method by Goodman et al., J.



  Pharmacol, 108, 168 (1953)], strong anticonvulsant activity and are therefore particularly suitable as antiepileptic agents.



   The desired compounds of the formula I are obtained by using primary or secondary amines of the formula:
EMI1.2
 in which RI, Rz and R @ have the meanings mentioned and R 'represents a hydrogen atom or a lower alkyl, alkenyl or alkynyl group, alkylated, alkenylated or alkynylated to the desired tertiary amine.



   The alkylation can be carried out by reacting with appropriate aldehydes using a reducing agent such as formic acid, or, like an alkenylation or alkynylation, by reacting with reactive esters of corresponding alcohols, in particular the halides.



   The primary amines required as starting materials are preferably obtained by reducing corresponding nitriles with lithium aluminum hydride / aluminum chloride. The secondary amines arise z. B. when converting reactive esters of alcohols of the formula:
EMI2.1
 wherein RI, R4 and R, have the meaning mentioned, with amines of the formula H2N-R- ..



   The compounds according to formula I obtained by this process can be used both as free bases and in the form of their addition salts with suitable acids, such as hydrohalic acids, toluenesulfonic acids, sulfuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid or Tartaric acid, extracted and used.



   example 1
3.8 g of 5-aminomethyl-11-methyl-5H-dibenzo [a, d] cycloheptene (melting point 77-78 ° C.) are refluxed with 4.5 ml of 35% formaldehyde solution and 12.8 g of formic acid for 6 hours heated. The reaction mixture is then diluted with 2N hydrochloric acid and evaporated in vacuo. The residue is taken up in water, made alkaline with 2N sodium hydroxide solution and extracted four times with chloroform. The chloroform extracts are washed once with water, dried with sodium sulfate and evaporated.

   The oily residue is converted into the oxalate, after crystallization from acetone / ether, 4.7 g (82% of theory) of 5-dimethylaminomethyl-11-methyl-5H-dibenzo [a, d] - cycloheptene oxalate are obtained in the form of colorless Needles with a melting point of 157-160 ° C. are obtained.



   Using an analogous procedure as in the aforementioned example, you still get z from the corresponding starting materials. B. the products given in the following table. In the table, Rl, Ra, R3, R4 and R5 have the meaning mentioned.

Claims (1)

Tabelle Beispiel Ri R2 Rs R4 R5 Schmelzpunkt 2 H-CH3-CH3 1-Cl H Hydrochlorid : 220-222 C 3 H -CH3 -CH3 H H Hydrochlorid : 207-209 C 4 H -C2H5 -C2H5 H H Hydrochlorid : 185-186 C 5 H -CH3 -CH3 2-Cl H Oxalat 153-154 C 6-CHs-CH3-CH3 H 7-Cl Hydrochlorid : 230-232 C 7 H-CH3 WH3 H 7-a Hydrochlorid : 218¯m0 C 8 H -CH2-CH = CH2 - CH3 H H Hydrochlorid : 218-219 C 9 H -CH2-C # CH -CH3 H H Hydrochlorid : 205-206 C 10 H-CHg-CHs 2-CHg H Oxalat : 162-162 C 11 H -CH3 -CH3 H 7-CH3 Hydrochlorid : 198-203 C 12 -C2H5 -CH3 -CH3 H H Oxalat : Table Example Ri R2 Rs R4 R5 Melting point 2 H-CH3-CH3 1-Cl H hydrochloride: 220-222 C 3 H -CH3 -CH3 H H hydrochloride: 207-209 C 4 H -C2H5 -C2H5 H H hydrochloride: 185-186 C 5 H -CH3 -CH3 2-Cl H oxalate 153-154 C 6-CHs-CH3-CH3 H 7-Cl hydrochloride: 230-232 C 7 H-CH3 WH3 H 7-a hydrochloride: 218¯m0 C 8 H -CH2-CH = CH2 -CH3 H H hydrochloride: 218-219 C 9 H -CH2-C # CH -CH3 H H hydrochloride: 205-206 C 10 H-CHg-CHs 2-CHg H oxalate: 162-162 C 11 H -CH3 -CH3 H 7-CH3 hydrochloride: 198-203 C 12 -C2H5 -CH3 -CH3 H H Oxalate: 173-174 C 13 H-CsHs-CHs H H Oxalat : 163-164 C PATENTANSPRUCH Verfahren zur Herstellung von 5-aminomethylierten 5H-Dibenzo[a,d]cycloheptenen der Formel EMI2.2 worin Ri ein Wasserstoffatom oder eine niedrige Alkylgruppe, RL eine niedrige Alkyl-, Alkenyl-oder Alkinylgruppe und Rs eine niedrige Alkylgruppe darstellt, von den Resten R4 und R, der eine ein Wasserstoffatom und der andere ein Wasserstoffatom, ein Halogenatom oder eine niedrige Alkylgruppe bedeutet, sowie von Säure-Additionssalzen davon, dadurch gekennzeichnet, dass man primäre oder sekundäre Amine der Formel EMI3.1 worin Rl, R und R, 173-174 C 13 H-CsHs-CHs H H oxalate: 163-164 C PATENT CLAIM Process for the preparation of 5-aminomethylated 5H-dibenzo [a, d] cycloheptenes of the formula EMI2.2 wherein Ri is a hydrogen atom or a lower alkyl group, RL is a lower alkyl, alkenyl or alkynyl group and Rs is a lower alkyl group, of the radicals R4 and R, one is a hydrogen atom and the other is a hydrogen atom, a halogen atom or a lower alkyl group , and acid addition salts thereof, characterized in that primary or secondary amines of the formula EMI3.1 where Rl, R and R, die genannte Bedeutung haben und R'ein Wasserstoffatom oder eine niedrige Alkyl-, Alkenyl-oder Alkinylgruppe darstellt, zum gewünschten tertiären Amin alkyliert, alkenyliert oder alkinyliert, worauf man das erhaltene Reaktionsprodukt al, s freie Base oder in Form eines Säure-Additionssalzes isoliert. have the meaning mentioned and R 'represents a hydrogen atom or a lower alkyl, alkenyl or alkynyl group, alkylated, alkenylated or alkynylated to the desired tertiary amine, whereupon the reaction product obtained is isolated as a free base or in the form of an acid addition salt.
CH1477869A 1967-03-22 1967-03-22 Process for the preparation of 5H-dibenzo (a, d) cycloheptene derivatives CH481870A (en)

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CH1477869A CH481870A (en) 1967-03-22 1967-03-22 Process for the preparation of 5H-dibenzo (a, d) cycloheptene derivatives

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CH1477869A CH481870A (en) 1967-03-22 1967-03-22 Process for the preparation of 5H-dibenzo (a, d) cycloheptene derivatives
CH410467A CH481054A (en) 1967-03-22 1967-03-22 Process for the preparation of 5H-dibenzo (a, d) cycloheptene derivatives

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CH410467A CH481054A (en) 1967-03-22 1967-03-22 Process for the preparation of 5H-dibenzo (a, d) cycloheptene derivatives

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