CH471774A - Process for the preparation of cycloalkylmethylamino-benzhydrols - Google Patents

Process for the preparation of cycloalkylmethylamino-benzhydrols

Info

Publication number
CH471774A
CH471774A CH1156467A CH1156467A CH471774A CH 471774 A CH471774 A CH 471774A CH 1156467 A CH1156467 A CH 1156467A CH 1156467 A CH1156467 A CH 1156467A CH 471774 A CH471774 A CH 471774A
Authority
CH
Switzerland
Prior art keywords
sep
preparation
formula
cyclopropylmethylamino
cycloalkylmethylamino
Prior art date
Application number
CH1156467A
Other languages
German (de)
Inventor
Hager Mcmilland Freeman
Pattison Ian
Original Assignee
Warner Lambert Pharmaceutical
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 claimed from US262221A external-priority patent/US3192199A/en
Application filed by Warner Lambert Pharmaceutical filed Critical Warner Lambert Pharmaceutical
Priority claimed from CH249064A external-priority patent/CH446357A/en
Publication of CH471774A publication Critical patent/CH471774A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • C07D243/30—Preparation including building-up the benzodiazepine skeleton from compounds already containing hetero rings
    • C07D243/32—Preparation including building-up the benzodiazepine skeleton from compounds already containing hetero rings containing a phthalimide or hydrogenated phthalimide ring system

Description

  

  Verfahren zur Herstellung von Cycloalkylmethylamino-benzhydrolen    Die vorliegende Erfindung betrifft ein Verfahren  zur Herstellung von neuen Zwischenprodukten, die für    die Herstellung von substituierten 1,4-Benzodiazepinen  der Formel:  
EMI0001.0000     
    verwendet werden, können, worin R, eine     Cycloalkyl-          methylgruppe,    wie beispelsweise Cyclopropylmethyl,  Cyclobutylmethyl oder Cyclopentylmethyl, und R2 Was  serstoff, niederes Alkyl, niederes Alkoxy oder Halo  gen, wie beispielsweise Chlor oder Brom, bedeuten.  



  Die Verbindungen,     der    obigen Formel, sind, als Be  ruhigungsmittel verwendbar. Beispielsweise zeigen sie  Wirksamkeit gegen Angstgefühle und sedative Wirkung    ohne unerwünschte Nebenwirkungen, wie beispielsweise  Hypnose. Ausserdem sind sie als Zwischenprodukte für  die Herstellung von anderen substituierten.     Benzodiaze-          pinen    brauchbar.  



  Somit betrifft die vorliegende Erfindung ein Ver  fahren zur Herstellung von     Cycloalkylmethylaminobenz-          hydrolen    der Formel:  
EMI0001.0008     
    worin R, Cycloalkylmethyl und R2 Wasserstoff, Halo  gen, niederes Alkyl oder niederes Alkoxy bedeuten,    welches dadurch gekennzeichnet ist, dass man ein     2-          Cyclopropyl-carbonylamino-5-benzophenon    der Formel:    
EMI0002.0000     
    worin R3 Cycloalkyl bedeutet in einem inerten Lösungs  mittel mit Lithiumaluminiumhydrid umsetzt.  



  In einer speziellen Ausführungsform, des Verfah  rens gemäss der Erfindung wird z. B. ein     2-Cyclopro-          pylcarbonylamino-5-halogenbenzophenon,    wie.     2-Cyclo-          propylcarbonylamino-5-chlorbenzophenon    der Formel:  
EMI0002.0005     
    mit einem Überschuss von Lithiumaluminiumhydrid  reduziert, worauf man eine wässrige Hydrolyse vor  nimmt, um das entsprechende     2-Cycloalkylmethylamino-          halogenbenzhydrol,    wie beispielsweise     2-Cyclopropyl-          methylamino-5-chlorbenzhydrol    der Formel:  
EMI0002.0010     
    herzustellen.

    Die gewünschten, oben beschriebenen substituierten  1,4-Benzodiazepine können dann hergestellt werden,  indem man-  
EMI0002.0011     
  
    1. <SEP> in <SEP> der <SEP> im <SEP> schweizerischen <SEP> Patent <SEP> Nr. <SEP> 466,272 <SEP> be  schriebenen <SEP> Weise <SEP> die, <SEP> Benzhydrolgruppe <SEP> des <SEP> Pro  duktes <SEP> des <SEP> Verfahrens <SEP> gemäss <SEP> der <SEP> Erfindung <SEP> mit     
EMI0002.0012     
  
    einem <SEP> Überschuss <SEP> Mangandioxyd <SEP> unter <SEP> Bildung <SEP> von.
<tb>  beispielsweise <SEP> 2-Cyclopropylmethylamino- <SEP> 5 <SEP> -chlor  benzophenon <SEP> oxydiert,
<tb>  2. <SEP> in <SEP> der <SEP> im <SEP> schweizerischen <SEP> Patent <SEP> Nr.

   <SEP> 459 <SEP> 205 <SEP> be  schriebenen <SEP> Weise <SEP> 1 <SEP> Mol <SEP> des <SEP> so <SEP> erhaltenen <SEP> 2-Cyclo  propylmethylamino-5-chlorbenzophenons <SEP> in <SEP> Tetra  hydrofuran <SEP> mit <SEP> 2 <SEP> Mol <SEP> Phthalimidoacetylchlorid <SEP> zum
<tb>  Rückfluss <SEP> erhitzt <SEP> und
<tb>  3. <SEP> das <SEP> so <SEP> erhaltene <SEP> Phthalimidoacetylderivat <SEP> in <SEP> der <SEP> im
<tb>  schweizerischen <SEP> Patent <SEP> Nr. <SEP> 446 <SEP> 357 <SEP> beschriebenen
<tb>  Weise <SEP> mit <SEP> Hydrazinhydrat <SEP> umsetzt.       Beispiel  2-Cyclopropylmethylamino-5-chlorbenzhydrol  Zu einer Aufschlämmung von 94,8 g (2,47 Mol)  Lithiumaluminiumhydrid in 1,2 Liter Tetrahydrofuran  wird unter Rühren eine Lösung von 356 g (1,18 Mol)  2 -Cyclopropylcarbonylamino- 5 -chlorbenzophenon in  1,8 Liter Tetrahydrofuran gegeben.

   Die Zugabe dauert  80 Minuten, wobei man gelinde am Rückfluss kocht,  und dann lässt man das Reaktionsgemisch über Nacht  am Rückfluss kochen und während eines Zeitraumes;  von<B>3</B> Tagen auf Zimmertemperatur abkühlen. Der in  dem Reaktionsgemisch gebildete Komplex wird dann  mit Wasser hydrolysiert. Während der Hydrolyse. wer  den 500 cm3 Tetrahydrofuran zugegeben, um das,  Rühren zu erleichtern. Wenn der flockige weisse  Niederschlag sich schnell absetzt, hört man zu rühren  auf, filtriert das, Gemisch, Wäscht den Filterkuchen. mit  Lösungsmittel, trocknet die vereinigten Filtrate über  Magnesiumsulfat, filtriert und entfernt das Lösungs  mittel im Vakuum, wobei man     2-Cyclopropylmethyl-          amino-5-chorbenzhydrol    als Rückstand erhält.

   Der  Rückstand wird aus 1300 cm3  Skelly B  umkristalli  siert und ergibt 315 g     2-Cyclopropylmethylamino-5-          chlorbenzhydrol    vom Schmelzpunkt 85 bis 85,5' C  (Ausbeute 93 %).  
EMI0002.0017     
  
    Analyse:
<tb>  Berechnet: <SEP> <B>C <SEP> 70:395</B> <SEP> H <SEP> <B>6,30 <SEP> Cl <SEP> 12,32</B>
<tb>  Gefunden: <SEP> C <SEP> 70,80 <SEP> H <SEP> 6,45 <SEP> Cl <SEP> 12,31, <SEP> 12,44



  Process for the preparation of cycloalkylmethylamino-benzhydrols The present invention relates to a process for the preparation of new intermediates which are used for the preparation of substituted 1,4-benzodiazepines of the formula:
EMI0001.0000
    can be used, in which R is a cycloalkylmethyl group, such as cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, and R2 is hydrogen, lower alkyl, lower alkoxy or halogen, such as chlorine or bromine.



  The compounds of the above formula are useful as sedatives. For example, they show effectiveness against feelings of anxiety and sedative effects without undesirable side effects, such as hypnosis. They are also substituted as intermediates for the manufacture of others. Benzodiazepines can be used.



  The present invention thus relates to a process for the preparation of cycloalkylmethylaminobenzhydrols of the formula:
EMI0001.0008
    where R, cycloalkylmethyl and R2 are hydrogen, halogen, lower alkyl or lower alkoxy, which is characterized in that a 2-cyclopropyl-carbonylamino-5-benzophenone of the formula:
EMI0002.0000
    wherein R3 is cycloalkyl in an inert solvent reacts medium with lithium aluminum hydride.



  In a special embodiment, the procedural rens according to the invention, for. B. a 2-Cyclopro- pylcarbonylamino-5-halobenzophenone, such as. 2-Cyclo-propylcarbonylamino-5-chlorobenzophenone of the formula:
EMI0002.0005
    reduced with an excess of lithium aluminum hydride, whereupon an aqueous hydrolysis is carried out in order to obtain the corresponding 2-cycloalkylmethylaminohalobenzhydrol, such as 2-cyclopropylmethylamino-5-chlorobenzhydrol of the formula:
EMI0002.0010
    to manufacture.

    The desired substituted 1,4-benzodiazepines described above can then be prepared by-
EMI0002.0011
  
    1. <SEP> in <SEP> the <SEP> in the <SEP> Swiss <SEP> patent <SEP> No. <SEP> 466,272 <SEP> described <SEP> way <SEP> the <SEP> benzhydrol group < SEP> of the <SEP> product <SEP> of the <SEP> method <SEP> according to <SEP> of the <SEP> invention <SEP> with
EMI0002.0012
  
    a <SEP> excess <SEP> manganese dioxide <SEP> under <SEP> formation <SEP> of.
<tb> for example <SEP> 2-Cyclopropylmethylamino- <SEP> 5 <SEP> -chlor benzophenone <SEP> oxidized,
<tb> 2. <SEP> in <SEP> the <SEP> in the <SEP> Swiss <SEP> patent <SEP> No.

   <SEP> 459 <SEP> 205 <SEP> be written <SEP> manner <SEP> 1 <SEP> mol <SEP> of the <SEP> thus <SEP> obtained <SEP> 2-cyclopropylmethylamino-5-chlorobenzophenone <SEP > in <SEP> tetrahydrofuran <SEP> with <SEP> 2 <SEP> mol <SEP> phthalimidoacetyl chloride <SEP> for
<tb> reflux <SEP> heated <SEP> and
<tb> 3. <SEP> the <SEP> so <SEP> received <SEP> phthalimidoacetyl derivative <SEP> in <SEP> the <SEP> im
<tb> Swiss <SEP> patent <SEP> No. <SEP> 446 <SEP> 357 <SEP>
<tb> way <SEP> reacts with <SEP> hydrazine hydrate <SEP>. Example 2-Cyclopropylmethylamino-5-chlorobenzhydrol A solution of 356 g (1.18 mol) of 2-cyclopropylcarbonylamino-5-chlorobenzophenone is added with stirring to a suspension of 94.8 g (2.47 mol) of lithium aluminum hydride in 1.2 liters of tetrahydrofuran placed in 1.8 liters of tetrahydrofuran.

   The addition takes 80 minutes, refluxing gently, and then allowing the reaction mixture to reflux overnight and for a period; cool down to room temperature within <B> 3 </B> days. The complex formed in the reaction mixture is then hydrolyzed with water. During hydrolysis. who added 500 cm3 of tetrahydrofuran to facilitate stirring. When the flaky white precipitate settles out quickly, the stirring is stopped, the mixture is filtered and the filter cake is washed. with solvent, the combined filtrates are dried over magnesium sulfate, filtered and the solvent is removed in vacuo, 2-cyclopropylmethylamino-5-chlorobenzhydrol being obtained as a residue.

   The residue is recrystallized from 1300 cm3 of Skelly B and gives 315 g of 2-cyclopropylmethylamino-5-chlorobenzhydrol with a melting point of 85 to 85.5 ° C. (yield 93%).
EMI0002.0017
  
    Analysis:
<tb> Calculated: <SEP> <B> C <SEP> 70: 395 </B> <SEP> H <SEP> <B> 6.30 <SEP> Cl <SEP> 12.32 </B>
<tb> Found: <SEP> C <SEP> 70.80 <SEP> H <SEP> 6.45 <SEP> Cl <SEP> 12.31, <SEP> 12.44

Claims (1)

<B>PATENTANSPRUCH</B> Verfahren zur Herstellung von Cycloalkylmethyl- aminobenzhydrolen der Formel: EMI0002.0020 worin R, Cycloalkylmethyl und R2 Wasserstoff, Halo gen, niederes Alkyl oder niederes Alkoxy bedeuten, dadurch gekennzeichnet, dass man ein 2-Cyclopropyl- carbonylamino-5-benzophenon der Formel: EMI0003.0000 worin R3 Cycloalkyl- bedeutet, in einem inerten Lö sungsmittel mit Lithiumaluminiumhydrid umsetzt. UNTERANSPRUCH Verfahren nach Patentanspruch zur Herstellung von 2-Cyclopropylmethylamino-5-chlorbenzhydrol. <B> PATENT CLAIM </B> Process for the production of cycloalkylmethyl aminobenzhydrols of the formula: EMI0002.0020 wherein R, cycloalkylmethyl and R2 are hydrogen, halogen, lower alkyl or lower alkoxy, characterized in that a 2-cyclopropylcarbonylamino-5-benzophenone of the formula: EMI0003.0000 wherein R3 is cycloalkyl, reacts in an inert solvent with lithium aluminum hydride. SUBCLAIM Process according to claim for the production of 2-Cyclopropylmethylamino-5-chlorobenzhydrol.
CH1156467A 1963-03-01 1964-02-28 Process for the preparation of cycloalkylmethylamino-benzhydrols CH471774A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US262221A US3192199A (en) 1963-03-01 1963-03-01 Process for the production of 1-cycloalkyl derivatives of 1, 4-benzodiazepine
CH249064A CH446357A (en) 1963-03-01 1964-02-28 Process for the preparation of substituted 1,4 benzodiazepine compounds
US427079A US3284503A (en) 1963-03-01 1965-01-21 2-cycloalkylmethylamino-benzhydrols and benzophenones
US427141A US3304313A (en) 1963-03-01 1965-01-21 2-(nu-phthalimidoacetyl-nu-cycloalkylmethyl)-aminobenzophenone derivatives

Publications (1)

Publication Number Publication Date
CH471774A true CH471774A (en) 1969-04-30

Family

ID=27428447

Family Applications (2)

Application Number Title Priority Date Filing Date
CH1156467A CH471774A (en) 1963-03-01 1964-02-28 Process for the preparation of cycloalkylmethylamino-benzhydrols
CH1156567A CH476690A (en) 1963-03-01 1964-02-28 Process for the preparation of 2-cycloalkylcarbonylamino compounds

Family Applications After (1)

Application Number Title Priority Date Filing Date
CH1156567A CH476690A (en) 1963-03-01 1964-02-28 Process for the preparation of 2-cycloalkylcarbonylamino compounds

Country Status (1)

Country Link
CH (2) CH471774A (en)

Also Published As

Publication number Publication date
CH476690A (en) 1969-08-15

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