CH522668A - Verfahren zur Herstellung neuer heterocyclischer Aminoketone - Google Patents

Verfahren zur Herstellung neuer heterocyclischer Aminoketone

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Publication number
CH522668A
CH522668A CH1717968A CH522668DA CH522668A CH 522668 A CH522668 A CH 522668A CH 1717968 A CH1717968 A CH 1717968A CH 522668D A CH522668D A CH 522668DA CH 522668 A CH522668 A CH 522668A
Authority
CH
Switzerland
Prior art keywords
mol
phenyl
hcl
paraformaldehyde
yield
Prior art date
Application number
CH1717968A
Other languages
English (en)
Inventor
Klaus Dr Posselt
Kurt Dr Thiele
Original Assignee
Degussa
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 DE1966D0051910 external-priority patent/DE1543538A1/de
Application filed by Degussa filed Critical Degussa
Publication of CH522668A publication Critical patent/CH522668A/de

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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C07D231/18—One oxygen or sulfur atom
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
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    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D307/70—Nitro radicals
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Description


  



  Verfahren zur Herstellung neuer heterocyclischer   Aminoketone   
Die Erfindung betrifft ein Verfahren zur Herstellung von neuen heterocyclischen   Aminoketonen    der allgemeinen Formel
EMI1.1     
 ihrer Salze und ihrer optisch aktiven Isomeren bzw.



  Diastereomeren. In dieser Formel bedeuten die Reste   R-R4    Wasserstoff, Halogen, niedriges Alkyl, Aralkyl, Phenyl, Hydroxyl, niedriges Alkoxy, Nitro oder niedriges Carbalkoxy, die Reste   R5    und R, Wasserstoff oder Methyl, die Reste R7 und   R8    Wasserstoff, Halogen oder niedriges Alkoxy und das Symbol X ein heterocyclisches Ringsystem, das monocyclisch oder konden   siert bicyclisch ist, 1 Heteroatome aufweist und das    auch eine oder mehrere Oxogruppen enthalten kann und dessen   Einzelringe    vorzugsweise aus 5 oder 6 Gliedern bestehen.



   Als Heteroatome kommen in Betracht, Sauerstoff, Stickstoff und Schwefel. Als Beispiele für das Symbol X seien folgende heterocyclische Ringsysteme genannt: Furan, Thiophen, Pyrrol, Pyrazol, Thiazol, Pyridin, Pyrimidin, Triazin, Pyrazolon, Benzofuran, Benzthiophen, Indol, Chinolin, Isochinolin, Benzdioxol, Benzdioxan, Dechydroisochinolin, Benzthiazol, Benzimidazol.



   Es hat sich gezeigt, dass diese Verbindungen wertvolle pharmazeutische Eigenschaften besitzen und sich zur Herstellung von   Azzneäniitteln,    insbesondere zur Behandlung von Herz- und Kreislaufkrankheiten, eignen.



   Die Herstellung der heterocyclischen Aminoketone der oben angegebenen allgemeinen Formel erfolgt dadurch, dass man eine Verbindung der allgemeinen Formel
EMI1.2     
 mit einer Verbindung der allgemeinen Formel 
EMI2.1     
 in Gegenwart von Formaldehyd oder eines Formaldehyd liefernden Stoffes in einem Lösungsmittel umsetzt.



   In den erhaltenen Verbindungen kann man in an sich bekannter Weise die Carbonylgruppe zur Hydroxygruppe reduzieren und gegebenenfalls die Basen in ihre Salze überführen.



   Das Verfahren wird üblicherweise in einem Temperaturbereich zwischen   20     und   150"C    durchgeführt.



  Als Lösungsmittel kommen hierfür beispielsweise Alkohole, Dioxan, Eisessig usw. in Betracht.



   Die erhaltenen Verbindungen, die optisch aktive Kohlenwasserstoffatome enthalten und in der Regel als Racemate anfallen, können in an sich bekannter Weise z. B. mittels einer optisch aktiven Säure in die optisch aktiven Isomeren gespalten werden. Es ist aber auch möglich, von vornherein optisch aktive bzw. auch disstereomere Ausgangsstoffe einzusetzen, wobei dann als Endprodukt eine entsprechende reine optisch aktive Form bzw. diastereomere Konfiguration erhalten wird.



   Die erfindungsgemässen Verbindungen sind zur Herstellung pharmazeutischer   Zusalrunensetzungen    geeignet. Die pharmazeutischen Zusammensetzungen bzw. Medikamente, die eine oder mehrere der erfindungsgemässen Verbindungen oder auch Mischungen derselben mit anderen pharmazeutisch wirksamen Stoffen enthalten sowie gegebenenfalls Zusätze weiterer pharmazeutischer Trägermittel, können enteral, parenteral, oral oder perlingual angewandt werden.



   Beispiel I   l-(2-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-äthyl } -thienyl-(2)-keton   
EMI2.2     

12,6 g (0,1 Mol) 2-Acetyl-thiophen, 18,7 g (0,1 Mol) l-Norephedrin-HC1 und 4 g (0,13 Mol) Paraformaldehyd werden in 20 ml Isopropanol gelöst und nach Zugabe von 0,2 ml HC1 konz. 2 Stunden unter Rückfluss gekocht. Danach wird die noch warme Lösung mit 100 ml Aceton versetzt. Das beim Erkalten auskristallisierte Hydrochlorid wird durch Umkristallisieren aus   Äthanol    gereinigt.



  Fp.   191-192     C, Ausbeute 17 g
Beispiel 2   
1-(2-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-äthyl)-furyl-(2)-keton   
EMI2.3     

11 g (0,1 Mol) 2-Acetyl-furan, 18,7 g (0,1 Mol) I-Norephedrin-HC1 und 4 g (0,13 Mol) Paraformaldehyd werden in 20 ml Isopropanol unter Zusatz von 5 Tropfen äthanolischer HC1 2 Stunden am Rückfluss erhitzt. Das bereits ausgefallene Hydrochlorid wird mit 50 ml Aceton gut durchgerührt und abgesaugt. Es wird durch Umkristallisieren aus Äthanol gereinigt.



  Fp.   186-187     C, Ausbeute 10,5 g.



   Beispiel 3
1-   {    2- [3-Phenyl-3-hydroxy-propyl-(2)  amino]-äthyl}-[4-methyl-thiazolyl-(2)}-keton   
EMI2.4     

7 g (0,05 Mol) 4-Methyl-2-acetyl-thiazol, 9,4 g (0,5 Mol)   l-Norephedrin-HCl,    2 g (0,067 Mol) Paraformaldehyd und 5 Tropfen isopropanolische HC1 werden in 15 ml Isopropanol wie in Beispiel 2 umgesetzt und aufgearbeitet. Das Hydrochlorid wird aus Methanol umkristallisiert.



  Fp.   197-1990    C. Ausbeute 7 g 
Beispiel 4   l-{2-[3-Phenyl-3-hydroxy-propyl-(2)-    amino]   -äthyl} -antipyryl-(4)-keton   
EMI3.1     

11,5 g 4-Acetyl-antipyrin (0,05 Mol), 9,5 g   l-Norephedrin-HCl    (0,05 Mol) und 2 g Paraformaldehyd (0,67 Mol) werden in 20 ml Isopropanol mit 5 Tropfen isopropanolischer HCI versetzt und   insgs    samt 5 Stunden unter Rückfluss gekocht, wobei nach 3 Stunden noch 1 g Paraformaldehyd zugesetzt wird.



  Danach wird das Lösungsmittel abdestilliert und der Rückstand mit Sodalösung behandelt. Die als   Öl    anfallende Mannichbase wird mit Äther zur Kristallisation gebracht. Mit 2 Mol   HC1    bildet sie ein   Dihydrochlo-    rid, das aus Äthanol umkristallisiert wird.



  Fp.   206-208     C, Ausbeute 9 g.



   Beispiel 5 1-(2-[3-Phenyl-3-hydroxy-propyl-(2) amino]   -äthyl) -pyridyl-(3)-keton   
EMI3.2     

40 g (0,33 Mol) 3-Acetyl-pyridin, 18,7 g (0,1 Mol)   l-Norephedrin-HCI    und 3 g (0,1 Mol)   Paraforrnalde-    hyd werden in 15 ml Isopropanol insgesamt 3 Stunden unter Rückfluss gekocht, wobei nach 1 Stunde 1 g Paraformaldehyd zugegeben wird. Anschliessend wird mit 300 ml Aceton verdünnt. Das ausfallende Hydrochlorid wird aus   Methanol/Äthanol    (1:2) umkristallisiert.



  Fp.   187-189     C, Ausbeute 7 g.



   Beispiel 6   1-(2- [3-Phenyl-3-hydroxy-propyl(2)-amino]-  äthyl}-[2,4-dimethyl-thiazolyl-(5)]-keton   
EMI3.3     

25 g (0,16 Mol) 2,4-Dimethyl-5-acetyl-thiazol, 30 g (0,16 Mol)   l-Norephedrin-HCl    und   5 g (0,16    Mol) Paraformaldehyd werden in 50 ml Isopropanol mit 15 Tropfen isopropanolischer HCI versetzt und insgesamt 1 Stunde am Wasserbad gekocht. Nach   t/2    Stunde werden weitere 1,5 g Paraformaldehyd zugegeben. Die noch warme Lösung wird mit 100 ml Aceton verdünnt.



  Das ausfallende Hydrochlorid wird aus 80 proz. Athanol umkristallisiert.



  Fp.   208-2100    C. Ausbeute 6,6 g. 



     Beispiel    7    l-(2-[3-Phenyl-3-hydroxy-propyl-(2)-aminoj- äthyl)-[4-methyl-2 -hydroxy-thiazolyl -(5)1-keton   
EMI4.1     

5 g (0,035 Mol)   4-Methyl-2-hydroxy-5-acetyl-thia-    zol, 6,6 g (0,035) Mol)   l-Norephedrin-HCI    und 1,5 g (0,05 Mol) Paraformaldehyd werden 2 Stunden in 20 ml Eisessig am   Rüclcfluss    gekocht. Das beim Erkalten ausfallende Hydrochlorid wird aus   Methanol/Ätha-    nol (1:1) umkristallisiert.



  Fp.   209-2100    C. Ausbeute 4,5 g.



   Beispiel 8   l-{ 2- [3-Phenyl-3 -hydroxy-propyl-(2)- amino]-äthyl)-cumaronyl-keton   
EMI4.2     

40g (0,25 Mol) 2-Acetyl-cumaron, 46,5 g (0,25 Mol) l-Norephedrin-HCI und 7,5 g (0,25 Mol) Paraformaldehyd werden in 200 ml Isoamylalkohol gelöst und nach Zugabe von 10 Tropfen äthanolischer   HCl    1/2 Stunde am Rückfluss gekocht. Dann werden weitere 2,5 g (0,083 Mol) Paraformaldehyd zugesetzt und noch 1/4 Stunde erhitzt. Die noch warme Lösung wird mit 100 ml Aceton verdünnt. Beim Erkalten kristallisiert das Hydrochlorid aus, das aus Äthanol umgelöst wird.



  Fp.   199-200     C, Ausbeute 31,5 g.



   Beispiel 9   1-3-( 3-[3-Phenyl-3-hydroxy-propylg2)- amino]-propionyl) -thionaphthen   
EMI4.3     

17,6 g (0,1 Mol) 3-Acetyl-thionaphthen, 18,7 g (0,1 Mol) l-Norephedrin-HCl und 4,5 g (0,15 Mol) Paraformaldehyd werden 2 Stunden in 50 ml Isopropanol am Rückfluss gekocht. Die noch warme Lösung wird mit 100 ml Aceton verdünnt. Beim Erkalten fällt das Hydrochlorid aus, das aus Methanol umkristallisiert wird.



  Fp.   220-2210    C, Ausbeute 18,5 g.



   Beispiel 10 1-3- { 3- [3-Phenyl-3-hydroxy-propyl-(2)   amino] -p ropionyl) -l-m ethyli ndol   
EMI4.4     
 
25 g (0,13 Mol) 1-Methyl-3-acetyl-indol, 24,3 g (0,13 Mol)   I-Norephedrin-HCI    und 5 g (0,17 Mol) Paraformaldehyd werden in 100 ml Isopropanol gelöst und insgesamt 6 Stunden am Wasserbad erhitzt. Nach jeweils 2 Stunden werden noch 2,5 g Paraformaldehyd zugegeben. Danach wird das Lösungsmittel abdestilliert und der Rückstand in warmem Aceton gelöst. Das beim Erkalten ausfallende Hydrochlorid wird aus Äthanol umkristallisiert.



  Fp.   194-195     C, Ausbeute 22 g.



   Beispiel 11   l-5-( 3-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-propionyl) -benzdioxol-(1,3)   
EMI5.1     

8 g (0,048 Mol) 5-Acetyl-benzdioxol-(1,3), 9,1 g (0,048 Mol)   l-Norephedrin-HCl    und 2,9 g (0,097 Mol) Paraformaldehyd werden in 30 ml Isopropanol unter Zusatz von 5 Tropfen isopropanolischer   HCt    2 Stunden auf dem Wasserbad gekocht.



   Nach Zugabe von 100 ml Aceton zur warmen Reaktionslösung fällt das Hydrochlorid aus, das aus Äthanol umkristallisiert wird.



  Fp.   195-1970    C, Ausbeute 9 g.



   Beispiel 12   1-4-(3-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-propionyl)-l,3-dimethylpyrazol    und   -1,5-dimethyl-pyrazol    (Gemisch).
EMI5.2     




   26 g (0,19 Mol) des bei der Synthese anfallenden Isomerengemisches von 1,3- und 1,5-Dimethyl-4-acetylpyrazol, 37,4 g (0,2 Mol) l-Norephedrin-HCl und 9 g (0,3 Mol) Paraformaldehyd werden in 150 ml Isopropanol 3 Stunden unter   N,-Atmosphäre    gekocht.



  Beim Erkalten kristallisiert das Hydrochlorid, das aus Isopropanol und anschliessend 2mal aus Äthanol umkristallisiert wird.



  Fp.   196     C, Ausbeute 11 g.



   Beispiel 13   1-(2-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-äthyl)-chinolyl-(3)-keton   
EMI5.3     
 
10 g (0,058 Mol) 3-Acetylchinolin, 11,2 g (0,058 Mol)   l-Norephedrin-HCl    und 1,6 g (0,058 Mol) Paraformaldehyd werden 2,5 Stunden in 75 ml Isopropanol auf dem Wasserbad gekocht, wobei nach 1 Stunde weitere 0,8 g (0,026 Mol) Paraformaldehyd zugegeben werden. Beim Versetzen mit 150 ml Aceton fällt das Hydrochlorid aus, das aus 800/oigem Methanol umkristallisiert wird.



  Fp.   205-2060    C, Ausbeute 5 g.



   Beispiel 14   1-(2-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-äthyl) -isochinolyl-(4)-keton   
EMI6.1     
    S g    (0,024 Mol)   4-AcetylisochinoJin-HCI,    4,6 g (0,024 Mol)   l-Norephedrin-HCl    und 0,7 g (0,024 Mol) Paraformaldehyd werden in 50 ml Äthanol-Iso  propanol-Gemisch    (1:1) 2,5 Stunden auf dem Wasserbad gekocht, wobei nach 1 Stunde weitere 0,4 g (0,012 Mol) Paraformaldehyd zugegeben werden. Beim Erkalten fällt das Dihydrochlorid aus, das aus Äthanol umkristallisiert wird.



  Fp.   208O    C, Ausbeute 3 g.



   Beispiel 15    1-{2-[3-Phenyl-3-hydroxy-propyl- (2)-amino]-äthyl)-[ 1,2,4-trimethyl-   
5 -carbäthoxypyrrolyl-(3)] -keton
EMI6.2     

18 g (0,081 Mol)   1,2,4-Trimethyl-3-acetyl-5 carb-    äthoxypyrrol, 15,2 g (0,081 Mol) l-Norephedrin  HC1    und 2,4 g (0,081 Mol)   Paraforma1:1ehyd    werden in 50 ml Isopropanol 1,5 Stunden auf dem Wasserbad gekocht, wobei nach 0,5 Stunden weitere 1,2 g (0,04 Mol) Paraformaldehyd zugegeben werden. Beim Versetzen mit 100 ml Aceton fällt das Hydrochlorid aus, das aus Äthanol umkristallisiert wird.



  Fp.   179-1800    C, Ausbeute 10 g.



   Beispiel 16   1-6-(3-[3-Phenyl-3-hydroxy-propyl-(2)-    amino]-propionyl}-benzdioxan-(1 ,4)
EMI6.3     

11,7 g (0,066 Mol)   6-Acetyl-1,4-benzdioxan,    12,3 g (0,066 Mol)   I-Norephedrin-HCI    und 2g (0,067 Mol) Paraformaldehyd werden in 33 ml Isopropanol 2 Stunden auf dem Wasserbad gekocht, wobei nach 1 Stunde weitere 2 g (0,067 Mol) Paraformaldehyd zugegeben werden. Das Lösungsmittel wird abdestilliert und der Rückstand mit Aceton behandelt. Das anfallende Hydrochlorid wird aus Äthanol umkristallisiert.



  Fp.   201O    C, Ausbeute 7,5 g. 



   Beispiel 17   1-2-(3-[3-Phenyl-3-hydroxy-propyl-(2)- aminol-propionyl) -benzdioxan-(1,4)   
EMI7.1     

11 g (0,061 Mol) 2-Acetyl-1,4-benzdioxan, 11,6 g (0,062 Mol)   l-Norephedrin-HCl    und 1,85 g (0,062 Mol) und 1,85 g Paraformaldehyd werden in 30 ml Isopropanol wie in Beispiel 16 umgesetzt und aufgearbeitet.



  Fp. 1780 C, Ausbeute 8 g.



   Beispiel 18    1-(2-[3-PhenyI-3-hydroxy-propyl- (2)-amino]-äthyi)-[2-benzyl-lO-hydroxy- decahydroisochinolyl-(4)] -keton.   
EMI7.2     




   11 g (0,0339 Mol) 2-Benzyl-4-acetyl10-hydroxy-decahydroisochinolin. HC1, 6,5 g (0,035 Mol) l-Norephedrin.HCl und 1,4 g (0,047 Mol) Paraformaldehyd werden 2 Stunden in 35 ml Isopropanol auf dem Wasserbad gekocht, wobei nach 1 Stunde weitere 1,4 g Paraformaldehyd zugegeben werden. Anschliessend wird das Lösungsmittel abdestilliert und der Rückstand mit Aceton und Essigester versetzt. Das anfallende Dihydrochlorid wird aus   Athanol    umkristallisiert.



  Fp.   182-183     C, Ausbeute 7 g.



   Beispiel 19   l-f2-[3-Phenyl-3-hydroxy-propyl-(2). amrno]-äthyl}-5-nitrofuryl.(2)j-keton   
EMI7.3     

11,6 g (0,075 Mol) 2-Acetyl-5-nitro-furan, 14 g (0,075 Mol)   l-Norephedrin.HC1    und 3 g (0,1 Mol) Paraformaldehyd werden in 50 ml Isopropanol 3 Stunden auf dem Wasserbad   erhitzt.    Das beim Erkalten ausfallende Hydrochlorid wird aus   800/oigem    Äthanol umkristallisiert.



  Fp.   210     C unter Zersetzung. Ausbeute 3 g. 



   Beispiel 20    1-4-(3-[3-Phenyl-3-hydroxy-propyl-(2)-      amino]-propionyl}-1    ,3,5-trimethyl-pyrazol
EMI8.1     

27 g (0,178 Mol)   1 ,3,5-Trimethyl-4-acetyl-pyrazol,    33 g (0,177 Mol)   l-Norephedrin.HCl    und 10,8 g (0,36 Mol) Paraformaldehyd werden in 150 ml Isopropanol 2 Stunden auf dem Wasserbad erhitzt. Danach wird das Lösungsmittel abdestilliert und der Rückstand mit 100 ml Aceton versetzt. Das ausgefallene Hydrochlorid wird aus Isopropanol umkristallisiert.



  Fp. 1910 C; Ausbeute 14,5 g.



   Beispiel 21    l-4-3-[3-Phenyl-3-hydroxy-propyl-(2)-      amino] -propionyl)-l    -benzyl3 ,5 -dimethyl-pyrazol
EMI8.2     

13,5 g (0,0624 Mol)   3,5-Dimethyl-1-benzyl-4-acetyl-pyrazol,    11,1 g (0,0593 Mol   l-Norephedrin-HCl    und 3,6 g (0,12 Mol) Paraformaldehyd werden 2 Stunden auf dem Wasserbad erhitzt. Beim Versetzen der Reaktionslösung mit 100 ml Aceton fällt das Hydrochlorid aus, das aus Äthanol umkristallisiert wird.



  Fp. 2000 C; Ausbeute 11 g.



   Beispiel 22 d,l- { 2-[3-(3-Fluor-4-methoxy-phenyl)
3-hydroxy-propyl-(2)-amino]    äthyl } -thienyl{2)-keton   
EMI8.3     

28 g (0,119 Mol) d,l-3-(3-Fluor-4-methoxy-phenyl)3-hydroxy-propyl-(2)-amin.HC1, 15 g (0,119 Mol) 2-Acetylthiophen und 7,2 g (0,24 Mol) Paraformaldehyd werden in 200 ml Isopropanol wie in Beispiel 21 umgesetzt und aufgearbeitet. Das Hydrochlorid wird aus Äthanol umkristallisiert.



  Fp. 2080 C; Ausbeute 10 g. 



   Beispiel 23    I-(l-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-propyl-(2))-thienyl-(2)-keton   
EMI9.1     

43g (0,307 Mol) 2-Propionylthiophen, 57,7 g (0,308 Mol)   l-Norealiedrin.HCl    und 18,4 g (0,614 Mol) Paraformaldehyd werden in 60 ml Isopropanol 1 Stunde wie in Beispiel 21 umgesetzt und aufgearbeitet.



  Das Hydrochlorid wird aus Äthanol umkristallisiert.



  Fp.   208     C; Ausbeute 16,5 g.



   Beispiel 24    1-(2-[3-Phenyl-3-hydroxy-propyl-(2)-      aminoj-äthyl    }-[5-chlor-thienyl-(2)] -keton
EMI9.2     

30 g (0,187 Mol) 2-Acetyl-5-chlor-thiophen, 35 g (0,187 Mol)   l-Norephedrin.HCI    und 5,6 g (0,187 Mol) Paraformaldehyd werden in 50   ml    Isopropanol 1 Stunde wie in Beispiel 21 umgesetzt und auf gearbeitet.



  Das Hydrochlorid wird aus Äthanol umkristallisiert.



  Fp.   198     C; Ausbeute 16 g.



   Beispiel 25   d,l-(2-[2-(2-Chlor-phenyl)-2-hydroxy- äthylamino]-äthyl)-thienyl-(2)-keton   
EMI9.3     

12,6 g (0,1 Mol) 2-Acetyl-thiophen, 20,8 g (0,1 Mol)   d,l-2-(2-Chlor-phenyl)-      2-hydroxy-äthylamin.HCl    und 4,5 g (0,15 Mol) Paraformaldehyd werden in 100 ml Isopropanol 2 Stunden auf dem Wasserbad erhitzt.



  Danach wird das Lösungsmittel abdestilliert und der Rückstand mit Essigester zur Kristallisation gebracht.



  Das Hydrochlorid wird aus   Athanol    umkristallisiert.



  Fp.   158-160     C; Ausbeute 4 g.



   Beispiel 26   [3-Phenyl-3-hydroxy-propyl-(2)]-{3-[4-phenyl thiazolyl-(2)]-3-hydroxypropyl(1)y amin   
EMI9.4     
 
6 g (0,015 Mol)   1-(2-[3-Phenyl-3-hydroxypropyl-(2)-amino    äthyl}-[4-phenyl-thiazolyl-(2)-]keton.HCl werden in 60 ml Methanol aufgeschlämmt und durch Zugabe von 0,6 g (0,016 Mol) Natriumborhydrid reduziert. Nach 1 Stunde wird das Lösungsmittel abdestilliert und der Rückstand in Aceton gelöst. Aus dieser Lösung wird mit Fumarsäure das Fumarat gefällt und anschliessend mit Natronlauge wieder die Base freigesetzt. Die ölige Base wird in Äther aufgenommen, mit isopropanolischer Salzsäure in das Hydrochlorid übergeführt und das Salz aus Äthanol umkristallisiert.



  Fp.   178-181     C, Ausbeute 2,5 g.



   Beispiel 27   [1 -Phenyl-1-hydroxy-propyl-(2)] - (    1-[4-methyl   thiazolyl- < 2) ]-1-hydroxy-propyl-(3)}-amin   
EMI10.1     

15 g (0,044 Mol) {2-[1-Phenyl-1-hydroxy-propyl-(2)-amino]- äthyl}-[4-methyl-thiazolyl-(2)]-keton.HCl werden in 150 ml Methanol mit 1 g Natriumboranat bei Raumtemperatur reduziert. Nach Stehenlassen über Nacht wird mit konz. HCI angesäuert, das Lösungsmittel abdestilliert und der Rückstand mit kochendem Äthanol extrahiert. Beim Abkühlen kristallisiert das HCl-Salz aus.



  Fp.   201-202     C; Ausbeute 5,5 g.



   Beispiel 28   [l-Phenyl-l-hydroxy-propyl-(2)1-( 1-[2,4-dime- thyl-thiazolyl-(5)].1-hydroxy-propyl-(3)}-amin   
EMI10.2     

10,7 g (0,03 Mol) (2-[1-Phenyl-1-hydroxy-propyl-(2)-amino]-   äthyl }-[2,4dimethyl-thiazolyl-(5)]-keton.llCl    werden in 100 ml Methanol mit 1 g Natriumboranat wie in Beispiel 5 reduziert und aufgearbeitet.



     HCl-Salz.   



  F.   217-218 ,    Ausbeute 5 g.



   Beispiel 29   [3-Phenyl-3-hydroxy-propyl-(2)]-{2-[thienyl-     (2)]-3-hydroxypropyl-(1)}-amin
EMI10.3     

63 g (0,2 Mol)   1-(2-[3-Phenyl-3-hydroxy-propyl- (2)-amiao]-äthyl) -thienyl < 2)-keton-HCI    und 300 g Aluminiumisopropylat werden in 21 Isopropanol auf   1300    erhitzt und das bei der Reduktion entstehende Aceton über eine Kolonne abdestilliert. Nach 7 Stunden wird die erkaltete Lösung mit Zitronensäure (100 g in 200 ml Wasser) zersetzt und anschliessend mit 30prozentiger Natronlauge stark alkalisch gemacht.



  Die organische Phase wird über Calciumoxyd getrocknet, das Lösungsmittel im Vakuum abdestilliert und der Rückstand mit Äther zur Kristallisation gebracht.



  Der Aminoalkohol schmilzt bei   123-125 ,    nachdem er aus 50prozentigem Alkohol umkristallisiert wurde. Mit 1 Mol HC1 entsteht ein Hydrochlorid, das aus Dioxan umkristallisiert, bei   152-155     schmilzt.



  Ausbeute 13 g. 



   Beispiel 30   [3-Phenyl-3-hydroxy-propyl-(2)] - {    3-[comaronyl   (2)]-3-hydroxy-propyl-(1)}-amin   
EMI11.1     

18 g (0,05 Mol) 1-(2-[3-Phenyl-3-hydroxy-propyl  (2)-aminoj-äthyl Ycumaronyl-keton-HCl    werden in 100 ml Äthanol aufgeschlämmt und mit 2 g Natriumborhydrid, gelöst in   50 mal      äthanol,    bei Zimmertemperatur reduziert. Nach 1 Stunde wird mit 5 ml HCl (konzentriert) zersetzt, vom NaCI abfiltriert, das Lösungsmittel i.v. abdestilliert und der Rückstand aus Isopropanol/Essigester (1:1) umkristallisiert. Das Hydrochlorid schmilzt bei   210-2150    unter Zersetzung, Ausbeute 11 g.



   Beispiel 31  [3-Phenyl-3-hydroxy-propyl-(2)]-{[3-thionaphthenyl-(3)]-3-hydroxypropyl-(1)}-amin
EMI11.2     

19 g (0,05 Mol)   1-3 - { 3 -[phenyl-3-hydroxy-propyl- (2)-am ino] -prop ionyl) -thionaphthen-HC1    werden in 100 ml Äthanol aufgeschlämmt und mit 2 g Natriumborhydrid, gelöst in   50 mal    Äthanol, bei   Zim-    mertemperatur reduziert. Nach 1 Stunde wird filtriert, das Lösungsmittel abdestilliert und der Rückstand in Äther gelöst. Aus der ätherischen Lösung wird das Hydrochlorid mit äthanolischen   HC1    gefällt. Es wird aus Isopropanol umkristallisiert.



  Fp.   167-1700,    Ausbeute 12 g.



   Beispiel 32
1-4-{3-[3-Phenyl-3-hydroxy-propyl-(2)- amino]-propionyl}-1-phenyl-5-methyl-pyrazol
EMI11.3     

4,5 g (0,0225 Mol) 4-Acetyl-5-methyl-1-phenyl-pyrazol, 2 mal 0,75 g Paraformaldehyd und 4,5 g (0,0248 Mol)   l-Norephedrin.HCl    werden in   40 mg    Isopropanol 2 Stunden unter Rückfluss gekocht, wobei die 2. Portion Paraformaldehyd nach 1 Stunde zugegeben wird. Das HCl-Salz, das aus der Reaktionslösung ausfällt, wird   aus Athanol umkristallisiert.   



  F.   221     C. Ausbeute 2,5 g.

Claims (1)

  1. PATENTANSPRUCH 1 Verfahren zur Herstellung von neuen heterocyclischen Aminoketonen der allgemeinen Fonnel EMI12.1 worin die Reste Rt - R4 gleich oder verschieden sind und Wasserstoff, Halogen, niedriges Alkyl, Aralkyl, Phenyl, Hydroxyl, niedriges Alkoxy, Nitro oder niedriges Carbalkoxy bedeuten, die Reste R5 und R;
    gleich oder verschieden sind und Wasserstoff oder Methyl darstellen, die Reste R7 und R8 gleich oder verschieden sind und Wasserstoff, Halogen oder niedriges Alkoxy sind und das Symbol X ein heterocyclisches Ringsystem ist, das monocyciisch oder kondensiert bicyclisch ist, 14 Heteroatome aufweist und das als weitere Substituenten auch eine oder mehrere Oxogruppen enthalten kann, dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel EMI12.2 mit einer Verbindung der allgemeinen Formel EMI12.3 in Gegenwart von Formaldehyd oder eines Formaldehyd liefernden Stoffes in einem Lösungsmittel umsetzt.
    PATENTANSPRUCH II Verwendung der gemäss Patentanspruch I erhaltenen Verbindungen oder deren Salze zur Herstellung von Verbindungen der allgemeinen Formel EMI12.4 durch Reduktion der Carbonylgruppe zur Hydroxygruppe.
    UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch I, dadurch gekennzeichnet, dass man die erhaltenen Basen in ihre Säuradditionssalze überführt.
    2. Verfahren nach Patentanspruch I, dadurch gekennzeichnet, dass man die erhaltenen racemischen Verbindungen in ihre optisch aktiven Isomeren auftrennt.
    3. Verfahren nach Patentanspruch I, dadurch gekennzeichnet, dass man optisch aktive Isomere bzw.
    Diastereomere als Ausgangsstoffe verwendet.
CH1717968A 1966-12-30 1968-11-18 Verfahren zur Herstellung neuer heterocyclischer Aminoketone CH522668A (de)

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DE1966D0051910 DE1543538A1 (de) 1966-12-30 1966-12-30 Verfahren zur herstellung neuer heterocyclischer aminoalkohole
CH1717968 1968-11-18
US1827970A 1970-03-10 1970-03-10

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AT286978B (de) 1971-01-11
US3715369A (en) 1973-02-06
US3631055A (en) 1971-12-28
US3658845A (en) 1972-04-25
GB1203810A (en) 1970-09-03
FR8021M (de) 1970-08-03
US3686206A (en) 1972-08-22

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