DE3210701A1 - 2-Azabicycloalkane-3-carboxylic acids and process for their preparation - Google Patents

2-Azabicycloalkane-3-carboxylic acids and process for their preparation

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DE3210701A1
DE3210701A1 DE19823210701 DE3210701A DE3210701A1 DE 3210701 A1 DE3210701 A1 DE 3210701A1 DE 19823210701 DE19823210701 DE 19823210701 DE 3210701 A DE3210701 A DE 3210701A DE 3210701 A1 DE3210701 A1 DE 3210701A1
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formula
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carbon atoms
hydrogen
integer
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German (de)
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Holger Gaul
Volker Dr Teetz
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Hoechst AG
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Hoechst AG
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Priority to DE19823210701 priority Critical patent/DE3210701A1/en
Priority to NZ21487782A priority patent/NZ214877A/en
Priority to IE3065/82A priority patent/IE55867B1/en
Priority to GR70162A priority patent/GR78413B/el
Priority to CA000418453A priority patent/CA1341296C/en
Priority to NZ202903A priority patent/NZ202903A/en
Priority to IE1904/88A priority patent/IE56170B1/en
Priority to DE8585103730T priority patent/DE3280014D1/en
Priority to AT82112007T priority patent/ATE25244T1/en
Priority to DE8282112007T priority patent/DE3275293D1/en
Priority to LU88263C priority patent/LU88263I2/xx
Priority to EP82112007A priority patent/EP0084164B1/en
Priority to EP85103730A priority patent/EP0170775B2/en
Priority to AU91931/82A priority patent/AU559140B2/en
Priority to AT85103730T priority patent/ATE47838T1/en
Priority to ES518574A priority patent/ES8308850A1/en
Priority to MA19890A priority patent/MA19672A1/en
Priority to FI824474A priority patent/FI80017C/en
Priority to KR8205823A priority patent/KR890003424B1/en
Priority to IL67572A priority patent/IL67572A/en
Priority to PH28321A priority patent/PH18918A/en
Priority to JP57227179A priority patent/JPS58118569A/en
Priority to NO824394A priority patent/NO156786C/en
Priority to DK576782A priority patent/DK170444B1/en
Priority to HU844653A priority patent/HU194167B/en
Priority to DZ826743A priority patent/DZ490A1/en
Priority to PT76052A priority patent/PT76052B/en
Priority to ES521740A priority patent/ES521740A0/en
Priority to NO832741A priority patent/NO158799C/en
Publication of DE3210701A1 publication Critical patent/DE3210701A1/en
Priority to PH30781A priority patent/PH19771A/en
Priority to CA000461836A priority patent/CA1206478A/en
Priority to US06/673,605 priority patent/US5008400A/en
Priority to AR85299524A priority patent/AR247571A1/en
Priority to IL84058A priority patent/IL84058A0/en
Priority to FI883456A priority patent/FI80675C/en
Priority to SG13/89A priority patent/SG1389G/en
Priority to JP1007870A priority patent/JPH01301695A/en
Priority to JP1007871A priority patent/JPH064586B2/en
Priority to US07/346,339 priority patent/US4933361A/en
Priority to HK749/89A priority patent/HK74989A/en
Priority to US07/468,567 priority patent/US5101039A/en
Priority to CS914095A priority patent/CS409591A3/en
Priority to DK119992A priority patent/DK171232B1/en
Priority to NL930048C priority patent/NL930048I2/en
Priority to BG098551A priority patent/BG60936B2/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • 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
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • 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
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D209/52—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 condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a process for the preparation of compounds of the formula I <IMAGE> in which n represents an integer from 4 to 13 and R<1> represents hydrogen, which is characterised in that enamines of cyclic ketones are reacted with N-acylated beta -halo- alpha -aminopropionic acid esters or with acrylic acid esters, then a ring closure is performed with acylamine and ester cleavage, and the intermediates of the formula VIIa or VIIb defined in the description resulting in this way are reduced to compounds of the formula I. The invention furthermore relates to intermediates of the formulae VIIa and VIIb.

Description

2-Azabicycloalkan-3-carbonsäuren und Verfahren zu ihrer2-Azabicycloalkane-3-carboxylic acids and processes for their

Herstellung 2-Azabicycloalkan-3-carbonsäuren der Formel Ia, in der n eine qanze Zahl von 4 bis 13 bedeutet, und ihre Ester sind Aminosäurederivate mit lipophilen Eigenschaften. Sie stellen wertvolle Synthesebausteine in der Peptidchemie oder als Teilstruktur von ACE-Inhibitoren dar.Preparation of 2-azabicycloalkane-3-carboxylic acids of the formula Ia, in which n is a qanze number from 4 to 13, and their esters are amino acid derivatives with lipophilic properties. They represent valuable synthetic building blocks in peptide chemistry or as part of the structure of ACE inhibitors.

Die Titelverbindungen sind nach bekannten Verfahren nur in schlechten Ausbeuten synthetisierbar. Die Synthese der Octahydroindol-2-carbonsäure kann beispielsweise durch katalytische Reduktion des bekannten Indolin-2-carbonsäureäthyiesters (Am. Soc. 92 (1970), 2476) erfolgen, der aus Idol-2-carbonsäurederivate durch Reduktion mit Phosphoniun.'-jodid (Austr. J. Chem. 20 (1965), 1935) oder durch Reduktion mit Zinn in konzentrierter Salzsäure (Am. Soc. 92 (1970) 2476) nur schlecht zugänglich ist.According to known processes, the title compounds are only in poor quality Yields can be synthesized. The synthesis of octahydroindole-2-carboxylic acid can, for example by catalytic reduction of the well-known indoline-2-carboxylic acid ethyl ester (Am. Soc. 92 (1970), 2476) made from idol-2-carboxylic acid derivatives by reduction with Phosphoniun .'-iodide (Austr. J. Chem. 20 (1965), 1935) or by reduction with Tin in concentrated hydrochloric acid (Am. Soc. 92 (1970) 2476) is difficult to access is.

Die erfindung betrifft ein Verfahren zur Herstellung von Verbindungen der Formel I, in welcher n für eine ganze Zahl von 4 bis 13 und R1 für Wasserstoff steht, sowie ihrer Alkyl- und Aralkylester, das dadurch gekennzeichnet ist, daß Enamine der Formel ai, in welcher n vorstehende Bedeutung hc.t und X1für Dialkyl- amino mit 2 bis 10 C-Atomen oder für einen Rest der Formel III, worin m und o eine ganze Zahl von 1 bis 3, (m + o)# 3 und A CH2, NH, 0 oder S bedeutet, steht, mit N-acylierten ß-Halogen- α amino-propionsäureestern der Formel IV, in welcher X2 für Chlor oder Brom, Y für Alkanoyl mit 1 bis 5 C-Atomen, Aroyl mit 7 bis 9 C-Atomen oder andere, in der Peptidchemie übliche, sauer abspaltbare Schutz gruppen und R2 für Alkyl mit 1 bis 5 C-Atomen oder Aralkyl mit 7 bis 9 C-Atoraen steht oder mit Acrylsäureestern der formel V, in welcher Y und R2 vorstehende Bedeutung haben Verbindungen der Formel VI, in welcher R2 und Y vorstehende Bedeutung haben, umsetzt, diese mit Hilfe starker Säuren unter Acylamid- und Esterspaltung zu Verbindungen der Formel VIIa, die auch in der tautomeren Form der Formel VIIb vorliegen können, in welchen n vorstehende Bedeutung hat, cyclisiert, die Verbindungen der Formel VIIa oder b, gegebenenfalls nach überführung in ihre C1-C18-Alky3.- oder C7-C10-Aralkylester, durch katalytische Hydrierung in Gegenwart von Ubergangsmetallkatalysatoren oder durch Reduktion mit Boran-Amin-Komplexen oder komplexen Borhydriden in Verbindungen der Formel I, in welcher n vorstehende Bedeutung hat und für Wasserstoff, Alkyl mit 1 bis 18 C-Atomen oder Aralkyl mit 7 bis 10 C-Atomen steht, überführt, und diese, falls R1 Wasserstoff ist, gegebenenfalls zu Verbindungen der Formel I, in welcher n vorstehende Bedeutung hat und R1 für Alkyl mit 1 bis 18 C-Atomen oder Aralkyl mit 7 bis 10 C-Atomen steht, verestert.The invention relates to a process for the preparation of compounds of the formula I in which n is an integer from 4 to 13 and R1 is hydrogen, and their alkyl and aralkyl esters, which is characterized in that enamines of the formula ai, in which n the preceding meaning hc.t and X1 for dialkylamino with 2 to 10 carbon atoms or for a radical of the formula III, in which m and o are an integer from 1 to 3 , (m + o) # 3 and A is CH2, NH, 0 or S, with N-acylated ß-halo-α-amino-propionic acid esters of the formula IV, in which X2 stands for chlorine or bromine, Y for alkanoyl with 1 to 5 carbon atoms, aroyl with 7 to 9 carbon atoms or other common ones in peptide chemistry , protective groups that can be split off under acidic conditions and R2 represents alkyl with 1 to 5 carbon atoms or aralkyl with 7 to 9 carbon atoms or with acrylic acid esters of the formula V, in which Y and R2 have the preceding meaning Compounds of the formula VI, in which R2 and Y have the preceding meaning, converts, these are cyclized with the aid of strong acids with acylamide and ester cleavage to give compounds of the formula VIIa, which can also be present in the tautomeric form of the formula VIIb, in which n has the above meaning, the compounds of the formula VIIa or b, optionally after conversion into their C1-C18-alkyl or C7-C10-aralkyl esters, by catalytic hydrogenation in the presence of transition metal catalysts or by reduction with borane-amine complexes or complex borohydrides in compounds of the formula I, in which n has the above meaning and represents hydrogen, alkyl having 1 to 18 carbon atoms or aralkyl having 7 to 10 carbon atoms, and these, if R1 is hydrogen, optionally to compounds of the formula I in which n has the above meaning and R1 is alkyl having 1 to 18 carbon atoms or aralkyl having 7 to 10 carbon atoms, esterified.

In Am. Soc. 81 (1956) 2596 wird die Reaktion von 3-Brompropylamin mit einem Enamin des Cyclohexanons beschrieben.In Am. Soc. 81 (1956) 2596 is the reaction of 3-bromopropylamine described with an enamine of cyclohexanone.

Es wird weiter ausgeführt, daß für den Ablauf der Alkylierung eine freie NH2-Gruppe notwendig sei. Es ist daher überaus überraschend, daß auch Halogenpropionsäure-Derivate mit acylierter Aminogruppe, wie sie die vorstehend beschriebenen Verbindungen der Formel IV darstellen, zur Alkylierung von Enaminen eingesetzt werden können. Dabei werden vorzugsweise Enamine des Cyclohexanons, Cycloheptanons eingesetzt. Als Aminkomponente kommt beispielsweise Diethylamin, Pyrrolidin, Piperidin oder Morpholin in Frage.It is further stated that a for the course of the alkylation free NH2 group is necessary. It is therefore extremely surprising that halopropionic acid derivatives with acylated amino group, such as the compounds described above Formula IV represent, can be used for the alkylation of enamines. Included enamines of cyclohexanone and cycloheptanone are preferably used. As an amine component For example, diethylamine, pyrrolidine, piperidine or morpholine can be used.

Aber auch andere sekundäre Amine sind geeignet. Bevorzugt sind Pyrrolidirocycloalkylene.But other secondary amines are also suitable. Pyrrolidirocycloalkylenes are preferred.

Formyl, Acetyl, Propionyl oder Benzoyl oder andere sauer abspaltbare Schutzgruppen wie z.B. tert.Butyloxycarbonyl sind besonders geeignete Gruppen Y der ß-Brom bzw. Chlord-amino-carbonsäure-ester der Formel IV. Vorzugsweise setzt man C1-C3-Alkyl- oder die Benzylester ein.Formyl, acetyl, propionyl or benzoyl or other acid cleavable Protecting groups such as tert-butyloxycarbonyl are particularly suitable Y groups the β-bromine or chloro-aminocarboxylic acid ester of the formula IV. Preference is given to setting one C1-C3-alkyl or the benzyl ester.

Die unter den basischen Versuchsbedingungen aus den ß-Halogen- OG -aminopropionsäureestern intermediär entstehenden AcrylsXurederivate der Formel V sind ebenfalls als Ausgangsverbindungen geeignet. Sie werde. z.B. durch Behandeln der Halogenaminopropionsäurederivate oder der analogen 0-Tosyl-Serin-derivate mit Basen hergestellt. Vorzugsweise werden tertiäre organische Basen wie z.B. Triäthylamin verwendet.The under the basic test conditions from the ß-halogen OG -aminopropionic acid esters intermediate acrylicsxure derivatives of the formula V are also suitable as starting compounds. She becomes. e.g. by treating the haloaminopropionic acid derivatives or the analogous 0-tosyl-serine derivatives with Bases made. Tertiary organic bases such as triethylamine are preferred used.

Es ist von Vorteil, unter Zusatz geringer Mengen von Polymerisati.onsirwhiLi.torcn wie z.B. Ifydrochinon in organischen Lösemitteln zu arbeiten. Die Acrylsäurederivate der Formel V können an Stelle der llalogenpropionsäurederivate unter identischen Reaktionsbedingungen eIngesetzt werden.It is advantageous, with the addition of small amounts of Polymerisati.onsirwhiLi.torcn such as ifydroquinone to work in organic solvents. The acrylic acid derivatives of the formula V can be used instead of the llalogenpropionic acid derivatives under identical Reaction conditions are used.

Als Lösungsmittel für die Enaminsynthese eignen sich nicht alkylierbare organische Lösemittel, wie beispielsweise Dimethylacetamid, DMSO, THF oder Toluol. Besonders geeignet ist Dimethyiformamid.Suitable solvents for the enamine synthesis are non-alkylatable ones organic solvents such as dimethylacetamide, DMSO, THF or toluene. Dimethylformamide is particularly suitable.

Es empfiehlt sich, die Enamine der Formel II im Überschuß einzusetzen und so N-Acyl-acrylester als Verunreinigung im Endprodukt zu vermeiden.It is advisable to use the enamines of the formula II in excess and so avoid N-acyl-acrylic ester as an impurity in the end product.

Die zur Oyclisierung notwendige Hydrolyse der N-Acylgruppe wird im allgemeinen gemeinsam mit einer Spaltung der Esterfunktion durch starke wäßrigen Mineralsäuren wie Schwefelsäure oder bevorzugt Salzsäure bewirkt. Im Falle der N-tert.Butyloxycarbonyl-Derivate der Formel IV ist es bei Verwendung von Dioxan/HCl oder wasserfreier Trifluoressigsäure beispielsweise möglich, die Esterfunktion zu erhalten, die Ester der Dehydrocarbonsäuren VIIa oder VIIb zu isolieren. Diese lassen sich durch Hydrierung oder Umsetzung mit Boran-AnIin-Kornplexen oder komplexen Borhydriden in die Azabicyclocarbonsäureester der Formel I überführen.The hydrolysis of the N-acyl group necessary for the cyclization is carried out in the generally together with a cleavage of the ester function by strong aqueous Mineral acids such as sulfuric acid or, preferably, hydrochloric acid. In the case of the N-tert-butyloxycarbonyl derivatives of formula IV it is when using dioxane / HCl or anhydrous trifluoroacetic acid for example possible to obtain the ester function, the esters of the dehydrocarboxylic acids Isolate VIIa or VIIb. These can be hydrogenated or reacted with Borane-AnIin complexes or complex borohydrides in the azabicyclocarboxylic acid ester of formula I convert.

Dehydrocarbonsäuren der Formel VIIa oder VIIb, in welcher n vorstehende Bedeutung hat. lassen sich katalytisch in Gegenwart von Ubergangsmetallkatalysatoren zu Verbindungen der Formel I, in welcher n für eine ganze Zahl von 4 bis 13 und R1 für Wasserstoff steht, mit einem überwiegenden Gehalt an endo-cis-Isomeren der Formel VIII, in welcher n vorstehene Bedeutung hat, hydrieren. Dehydrocarboxylic acids of the formula VIIa or VIIb, in which n has the preceding meaning. can be catalytically in the presence of transition metal catalysts to compounds of the formula I in which n is an integer from 4 to 13 and R1 is hydrogen, with a predominant content of endo-cis isomers of the formula VIII, in which n has the above meaning , hydrogenate.

Durch katalytische Hydrierung mit Metallkatalysatoren wie z.B Platin ode Raney-Nickel erhält man Gemische von 70 - 90 % endo-cis- und 10 - 30 % trans-Azabicyclo-alkan-2- carbonsäure. Geeignet sind auch andere Edelmetall- oder Nickel-Katalysatoren. Das bei der katalytischen Hydrierung auftretende Isomerenverhältnis ist von den Reaktionsbedingungen und der Art des verwendeten Katalysators abhängig.Through catalytic hydrogenation with metal catalysts such as platinum or Raney nickel, mixtures of 70 - 90% endo-cis and 10 - 30% trans-azabicyclo-alkane-2- carboxylic acid. Other noble metal or nickel catalysts are also suitable. That with the catalytic Isomer ratio occurring depends on the reaction conditions and the hydrogenation Depending on the type of catalyst used.

Neben Rh/Al 203 ist auch Pt/C zur Reduktion gut geeignet, jedoch wird etwas mehr trans-Produkt erhalten. Eine Verkürzung der Reduktionszeit durch höheren Wasserstoffdruck ist möglich, jedoch sollte die Temperatur niedrig gehalten werden. Als Lösemittel für die katalytische Hydrierung eignen sich beispielsweise Ethanol, Methanol, Essigester, Dioxan, Eisessig oder Gemische dieser Lösemittel.In addition to Rh / Al 203, Pt / C is also well suited for reduction, but is get some more trans product. A shortening of the reduction time through higher Hydrogen pressure is possible, but the temperature should be kept low. Suitable solvents for the catalytic hydrogenation are, for example, ethanol, Methanol, ethyl acetate, dioxane, glacial acetic acid or mixtures of these solvents.

Verbindungen der Formel I, in welcher n für eine ganze Zahl von 4 bis 13 und R1 für Wasserstoff steht, mit einem Gehalt von mehr als 50 % an trans-Isomeren der Formel IX, in welcher n vorstehende Bedeutung hat, sind dagegen durch Reduktion von Verbindungen der Formel VII, in welcher n vorstehende Bedeutung hat, mit Boran-Amin-Komplexen oder komplexen Borhydriden in niederen Alkoholen zugänglich.Compounds of the formula I in which n is an integer from 4 to 13 and R1 is hydrogen, with a content of more than 50% of trans isomers of the formula IX, in which n has the above meaning, are, however, accessible by reducing compounds of the formula VII, in which n has the above meaning, with borane-amine complexes or complex borohydrides in lower alcohols.

Als Reduktionsmittel ist Natriumborhydrid in Alkoholen, insbesondere in Methanol, Ethanol oder Isopropanol, bevorzugt.Sodium borohydride is used as a reducing agent in alcohols, in particular in methanol, ethanol or isopropanol, is preferred.

Ebenso verwendbar sind Amin-Boran-Komplexe in Eisessig.Amine-borane complexes in glacial acetic acid can also be used.

Die Isolierung der reinen endo-cis- und trans-Verbindungen der Formel VII bzw. IX kann beispielsweise durch chromatographische Verfahren oder Kristallisolationsverfahren erfolgen.Isolation of the pure endo-cis and trans compounds of the formula VII or IX can, for example, by chromatographic processes or crystal isolation processes take place.

Als besonders vorteilhaft hat sich die Abtrennung der reinen endo-cis-Verbindung der Formel VIII aus dem Diastereomerengemisch der katalytischen Hydrierung durch fraktionierende Kristallisation erwiesen.The separation of the pure endo-cis compound has proven to be particularly advantageous of the formula VIII from the diastereomer mixture of the catalytic hydrogenation fractional crystallization proved.

Die rei.ne trans-Verbindung der Formel IX wird vorteilhafter weise durch fraktionierte Kristallisation aus dem Diastereomerengemisch der Amin-Boran-Komplex- oder Boranat-Reduktion abgetrennt.The pure trans compound of the formula IX is advantageously used by fractional crystallization from the mixture of diastereomers of the amine-borane complex or boranate reduction separated.

Die Verbindungen der Formeln VIII oder IX oder ihre Gemische können gegebenenfalls nach Methoden, wie sie z.B.The compounds of the formulas VIII or IX or their mixtures can if necessary by methods such as those e.g.

im Houben-Weyl, Bd. VIII (1952) beschrieben sind, in die C1- C18-Alkyl- oder C7-C10 -Aralkylester überführt werden.are described in Houben-Weyl, Vol. VIII (1952), in the C1- C18-alkyl or C7-C10 aralkyl esters are converted.

Die Erfindung betrifft weiterhin Verbindungen der Formel X, in welcher n für eine ganze Zahl von 4 bis 13, R1 für Wasserstoff, Alkyl mit 1 bis 18 C-Atomen oder Aralkyl mit 7 bis 10 C-Atomen und R3, R4 und/oder R5 für Wasserstoff stehen oder R3 und R4 bzw. R4 und R5jeweils gemei.nsam eine chemische Bindung bedeuten.The invention further relates to compounds of the formula X in which n is an integer from 4 to 13, R1 is hydrogen, alkyl having 1 to 18 carbon atoms or aralkyl having 7 to 10 carbon atoms and R3, R4 and / or R5 stand for hydrogen or R3 and R4 or R4 and R5 each jointly mean a chemical bond.

In bevorzugte Verbindungen der Formel X bedeuten n, 4, 5, 6 oder 7 und R1, R2, R3, R4 und R5 stehen jeweils für Wasserstoff.Preferred compounds of the formula X are n, 4, 5, 6 or 7 and R1, R2, R3, R4 and R5 each represent hydrogen.

Bevorzuyt sind auch Ester der Formel X, in den R für C1-C6-Alkyl, insbesondere Methyl oder Ethyl, steht.Preference is also given to esters of the formula X, in which R stands for C1-C6-alkyl, especially methyl or ethyl.

Im folgenden wird das Verfahren anhand von Beispielen erläutert: Beispiel 1: l-Acetylamino-2- (2-oxocyclohcxyl) -äthan-carbonsäure methylester 269 g 3-Chlor-2-acetylamino-propionsäuremethylester und 282 g Pyrrolidinocyclohexan werden in 1,5 1 DMF 24 Stunden bei Raumtemperatur gehalten. Man engt im Vakuum ein, nimmt den Rückstand in wenig Wasser auf, stellt mit konzentrierter Salzsäure auf pH 2 und axtrahiert 2 mal mit je 3 1 Essigester. Beim Einengen der über wasserfreiem Natriumsulfat getrockneten organischen Phase hinterbleibt ein hellgelbes öl.The process is explained below using examples: example 1: 1-Acetylamino-2- (2-oxocyclohxyl) -ethane-carboxylic acid methyl ester 269 g of 3-chloro-2-acetylamino-propionic acid methyl ester and 282 g of pyrrolidinocyclohexane are in 1.5 1 DMF for 24 hours at room temperature held. It is concentrated in vacuo, the residue is taken up in a little water, and the solution is set with concentrated hydrochloric acid to pH 2 and extracted 2 times with 3 1 ethyl acetate each time. On concentration of the organic phase, dried over anhydrous sodium sulfate a light yellow oil remains.

Ausbeute etwa 300 g.Yield about 300 g.

H-NMR (0D0l3) Werte: 2,01 (s,3H); 3,76 (s,3H) ; 4,35-4,8 (m,1H) Analyse: C H N 12 19 4 59,73 7,94 5,81 ber.H-NMR (0D013) values: 2.01 (s, 3H); 3.76 (s, 3H); 4.35-4.8 (m, 1H) Analysis: C H N 12 19 4 59.73 7.94 5.81 calc.

60,1 7,5 6,2 gef. 60.1 7.5 6.2 found.

Beispiel 2: endo-cis-Octahydroi.ndol-2-carbonsäure 290 g des in Beispiel 1 hergestellten Acetylamino-Derivates werden in 1,5 1 2n Salzsäure 45 Minuten am Rückfluß erhitzt. Man engt im Vakuum ein, nimmt den Rückstand in Eisessig auf versetzt mit 5 g Rh/Alz03 (5% Rh) und hydriert bei 5 bar Wasserstoffdruck. Die Reduktion kann auch bei Normaldruck erfolgen, jedoch ist die Reduktion unter Druck schneller und bei größeren Ansätzen vorzuziehen. Nach beendeter Wasserstoffaufnahme wird filtriert, gut eingeengt und der Rückstand unter Verwendung von Impfkristallen aus Chioroform/Diisopropyläther kristallisiert.Example 2: endo-cis-octahydroi.ndol-2-carboxylic acid 290 g of the in example 1 prepared acetylamino derivatives are in 1.5 1 2N hydrochloric acid 45 minutes on Heated to reflux. It is concentrated in vacuo, and the residue is taken up in glacial acetic acid with 5 g of Rh / Alz03 (5% Rh) and hydrogenated at 5 bar hydrogen pressure. The reduction can also take place at normal pressure, but the reduction is faster under pressure and preferable for larger approaches. After the uptake of hydrogen has ended, it is filtered, well concentrated and the residue using seed crystals from chloroform / diisopropyl ether crystallized.

Schmp. 230 - 23300 Zers. (filzige Nadeln) Ausbeute ca. 20 g Aus der Mutterlauge kann bis zu 10 g weiteres Produkt gewonnen werden, daß jedoch mit trans-Octahydro-indol-2-carbonsäure verunreinigt ist. Aus der letzten Mutterlauge kristallisieren 10 - 20 g leicht verunreinigte trans-Octahydroindolcarbonsäure aus. M.p. 230 - 23300 decomp. (felted needles) Yield approx. 20 g from the Up to 10 g of further product can be obtained from mother liquor, but that with trans-octahydro-indole-2-carboxylic acid is contaminated. From the last mother liquor 10-20 g slightly contaminated crystallize trans-octahydroindolecarboxylic acid.

Schmp. 225 - 230° Zers. (kompakte Kristalle) In gleicher Weise lassen sich endo-cis-2-Azabicyclo-(5.3.0) decan-3-carbonsäure und endo-cis-2-Azabicyclo-(6.3.0)undecan-3-carbonsäure herstellen. M.p. 225-230 ° decomp. (compact crystals) Leave in the same way endo-cis-2-azabicyclo- (5.3.0) decane-3-carboxylic acid and endo-cis-2-azabicyclo- (6.3.0) undecane-3-carboxylic acid produce.

Beispiel 3: trans-Octahydroindol-2-carbonsäure 290 g des nach Beispiel 1 erhaltenen Acylamino-Derivates werden wie in Beispiel 2 angegeben mit 2n Salzsäure erhitzt. Man engt im Vakuum ein, nimmt in 1 1 Isopropanol auf und reduziert mit etwa 35 g NaBH4, das portionsweise in 30 Minuten zugesetzt wird. Die Reaktionstemperatur sollte 40 - 500C betragen. Man läßt ca. 4 Stunden reagieren, engt im Vakuum ein, stellt mit verdünnter Salzsäure auf pH 6,5, sättigt mit festem Natriumchlorid und extrahiert die Aminosäuren mehrfach mit n-Butanol. Der nach Einengen der organischen Phase hinterbleibende Rückstand wird aus Chloroform/Diisopropyläthex wie im Beispiel 2 beschrieben, fraktioniert kristallisiert. Example 3: trans-octahydroindole-2-carboxylic acid 290 g of the according to example 1 obtained acylamino derivatives are given as in Example 2 with 2N hydrochloric acid heated. It is concentrated in vacuo, taken up in 1 l of isopropanol and reduced with it about 35 g NaBH4, which is added in portions over 30 minutes. The reaction temperature should be 40 - 500C. It is allowed to react for approx. 4 hours, concentrated in vacuo, adjusts to pH 6.5 with dilute hydrochloric acid, saturates with solid sodium chloride and extracts the amino acids several times with n-butanol. The one after narrowing the organic Phase remaining residue is made from chloroform / diisopropylethyl as in the example 2 described, fractionally crystallized.

Ausbeuten: 40 - 60 y cis-Produkt 20 g Mischfraktion 100 -130 g trans-Produkt, Schmp. ca, 2300 (Zers.) In gleiche Weise lassen sich trans-2-Azabicyclo (5.3.0) decan-3-carbonsäure und trans-2-Azabicyclo(6.3.0)undecan--3-carbonsäure herstellen.Yields: 40-60 y cis product 20 g mixed fraction 100-130 g trans product, Mp. Approx. 2300 (decomp.) In the same way, trans-2-azabicyclo (5.3.0) decane-3-carboxylic acid and trans-2-azabicyclo (6.3.0) undecane-3-carboxylic acid produce.

Claims (8)

2-Azabicycloalkan-3-carbonsäuren und Verfahren zu ihrer Herstellung Patentansprüche: 1. Verfahren zur Herstellung von Verbindungen der Formel I, in welcher n für eine ganze Zahl von 4 bis 13 und R1 für Wasserstoff steht, dadurch gekennzeichnet, daß Enamine der Formel II, in welcher n vorstehende Bedeutung hat und X1 für Dialkylamino mit 2 bis 10 C-Atomen oder für einen Rest der Formel III, worin m und o eine ganze Zahl von 1 bis 3, (m + 0) ) 3 und A CII2, NH, 0 oder S bedeutet, steht, mit N-acylierten ß-Haloen-:h -amino-propionsäureestern der Formel IV, in welcher X2 für Chlor oder Brom, Y für Alkanoyl mit 1 bis 5 C-Atomen, Aroyl mit 7 bis 9 C-Atomen oder andere, in der Peptidchemie übliche, sauer abspaltbare Schutzgruppen und R2 für Alkyl mit 1 bis 5 C-Atomen oder Aralkyl mit 7 bis 9 C-Atomen steht oder mit Acrylsäureestern der Formel V, in welcher Y und R2 vorstehende Bedeutung haben zu Verbindungen der Formel VI, in welcher R2 und Y vorstehende Bedeutung haben, umsetzt, diese mit Hilfe starker Säuren unter Acylamid- und Esterspaltung zu Verbindungen der Formel VII a oder b, in weicher n vorstehende Bedeutung hat, cyclisiert, diese, gegebenenfalls nach Überführung- in ihre 010 18 Alkyl- oder C7-C1O-Aralkylester durch katalytische Hydrierung in Gegenwart von Ubergangsmetallkatalysatoren oder durch Reduktion mit Boran-nmin-omplexen oder komplexen Borhydriden in Verbindungen der Formel I, in welcher n vorstehende Bedeutung hat, und R1 für Wasserstoff, Alkyl mit 1 bis 18 C-Atomen oder Aralkyl mit 7 bis 10 C-Atomen steht, überführt und diese, falls R1 Wasserstoff ist, gegebenenfalls zu Verbindungen der Formel I, in welcher n vorstehende Bedeutung hat und R1 für Alkyl mit 1 bis 18 C-Atomen oder Aralkyl mit 7 bis 10 C-Atomen steht, verestert.2-Azabicycloalkane-3-carboxylic acids and process for their preparation Patent claims: 1. Process for the preparation of compounds of the formula I in which n is an integer from 4 to 13 and R1 is hydrogen, characterized in that enamines of the formula II, in which n has the preceding meaning and X1 for dialkylamino with 2 to 10 carbon atoms or for a radical of the formula III, in which m and o are an integer from 1 to 3, (m + 0 )) 3 and A is CII2, NH, 0 or S, stands, with N-acylated ß-halo: h -amino-propionic acid esters of the formula IV, in which X2 for chlorine or bromine, Y for alkanoyl with 1 to 5 carbon atoms, aroyl with 7 to 9 carbon atoms or others, in which Protecting groups which can be split off under acidic conditions, customary in peptide chemistry, and R2 stands for alkyl with 1 to 5 carbon atoms or aralkyl with 7 to 9 carbon atoms or with acrylic acid esters of the formula V, in which Y and R2 have the above meanings to compounds of the formula VI, in which R2 and Y have the above meaning, these are cyclized with the help of strong acids with acylamide and ester cleavage to give compounds of the formula VII a or b, in which n has the above meaning, these, optionally after conversion into their 010 18 alkyl or C7 -C10 aralkyl esters by catalytic hydrogenation in the presence of transition metal catalysts or by reduction with borane-nmin complexes or complex borohydrides in compounds of the formula I, in which n has the preceding meaning, and R1 represents hydrogen, alkyl having 1 to 18 carbon atoms or aralkyl having 7 to 10 carbon atoms, and these, if R1 is hydrogen, optionally to compounds of the formula I in which n has the preceding meaning and R1 is alkyl with 1 to 18 carbon atoms or aralkyl with 7 to 10 carbon atoms, esterified. 2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß n für eine ganze Zahl von 4 bis 7 steht.2. The method according to claim 1, characterized in that n is for one is an integer from 4 to 7. 3. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß Verbindungen der Formel VII, in welcher n vorstehende Bedeutung hat, durch katalytische Hydrierung in Gegenwart von übergangsmetallkatalysatoren in Verbindung der Formel I, in welcher n für eine ganze Zahl von 4 bis 13 und R1 für Wasserstoff steht, mit einem überwiegenden Gehalt an endocis-Isomeren der Formel VIII, in welcher n vorstehende Bedeutung hat, überführt. 3. The method according to claim 1, characterized in that compounds of formula VII, in which n has the preceding meaning, by catalytic hydrogenation in the presence of transition metal catalysts in compound of formula I, in which n is an integer from 4 to 13 and R1 is Is hydrogen, with a predominant content of endocis isomers of the formula VIII, in which n has the above meaning, converted. 4. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß Verbindungen der Formel VII, in welcher n vorstehende Bedeutung hat, durch Reduktion mit Boran-Amin-Komplexen oder komplexen Borhydriden in niederen Alkoholen in Verbindungen der Formel I, in welcher n für eine ganze Zahl von 4 bis 13 und R1 für Wasserstoff steht, mit einem Gehalt von mehr als 50 % an trans-Isomeren der Formel IX, in welcher n vorstehende Bedeutung hat, überführt. 4. The method according to claim 1, characterized in that compounds of the formula VII, in which n has the preceding meaning, by reduction with borane-amine complexes or complex borohydrides in lower alcohols in compounds of the formula I, in which n is an integer from 4 to 13 and R1 represents hydrogen, with a content of more than 50% of trans isomers of the formula IX, in which n has the preceding meaning, converted. 5. Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß die reine endo-cis-Verbindung der Formel VIII durch fraktionierte Kristallisation abgetrennt wird.5. The method according to claim 3, characterized in that the pure endo-cis compound of formula VIII separated by fractional crystallization will. 6. Verfahren nach Anspruch 4, dadurch gekennzeichnet, daß die reine trans-Verbindung der Formel IX durch fraktionierte Kristallisation abgetrennt wird.6. The method according to claim 4, characterized in that the pure trans compound of the formula IX is separated off by fractional crystallization. 7. Verbindungen der Formel X in welcher n für eine ganze Zahl von 4 bis 13, R1 für Wasserstoff, Alkyl mit 1 bis 18 C-Atomen oder Aralkyl mit 7 bis 10 C-Atomen und R3, R4 und/oder R5 für Wasserstoff stehen oder R3 und R4 bzw. R4 und R5 jeweils gemeinsam -eine chemische Bindung bedeuten.7. Compounds of Formula X in which n is an integer from 4 to 13, R1 is hydrogen, alkyl with 1 to 18 carbon atoms or aralkyl with 7 to 10 carbon atoms and R3, R4 and / or R5 are hydrogen or R3 and R4 or R4 and R5 each together mean a chemical bond. 8. Verbindungen nach Anspruch 7, dadurch gekennzeichnet, daß n Zür 5, 6 oder 7 und R1, R3 und R4 jeweils für Wasserstoff stehen.8. Compounds according to claim 7, characterized in that n Zür 5, 6 or 7 and R1, R3 and R4 each represent hydrogen.
DE19823210701 1981-12-29 1982-03-24 2-Azabicycloalkane-3-carboxylic acids and process for their preparation Withdrawn DE3210701A1 (en)

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DE19823210701 DE3210701A1 (en) 1982-03-24 1982-03-24 2-Azabicycloalkane-3-carboxylic acids and process for their preparation
NZ21487782A NZ214877A (en) 1981-12-29 1982-12-23 Cepyrrol-2-ylcarboxylic acid derivatives
IE3065/82A IE55867B1 (en) 1981-12-29 1982-12-23 New derivatives of bicyclic aminoacids,processes for their preparation,agents containing these compounds and their use,and new bicyclic aminoacids as intermediates and processes for their preparation
GR70162A GR78413B (en) 1981-12-29 1982-12-23
CA000418453A CA1341296C (en) 1981-12-29 1982-12-23 2-azabicycloalkane-3-carboxylic acid derivatives, processes for their preparation, agents containing these compounds and their use
NZ202903A NZ202903A (en) 1981-12-29 1982-12-23 1-- pe pyrrol-2-yl-carboxylic acid derivatives and pharmaceutical compositions
IE1904/88A IE56170B1 (en) 1981-12-29 1982-12-23 Derivatives of bicyclic aminoacids,processes for their preparation,agents containing these compounds and their use,and new bicyclic aminoacids as intermediates and processes for their preparation
DE8585103730T DE3280014D1 (en) 1981-12-29 1982-12-24 Derivatives of bicyclic amino acids, processes for their preparation, agents containing them and their use as well as bicyclic amino acids as intermediates and process for their preparation
AT82112007T ATE25244T1 (en) 1981-12-29 1982-12-24 NEW DERIVATIVES OF BICYCLIC AMINO ACIDS, PROCESS FOR THEIR PREPARATION, COMPOSITIONS CONTAINING THEM AND THEIR USE, AS WELL AS NEW BICYCLIC AMINO ACIDS AS INTERMEDIATE STAGES AND PROCESS FOR THEIR PREPARATION.
DE8282112007T DE3275293D1 (en) 1981-12-29 1982-12-24 Derivatives of bicyclic amino acids, process for their preparation, agents containing them and their use, as well as bicyclic amino acids as intermediates, and process for preparing them
LU88263C LU88263I2 (en) 1981-12-29 1982-12-24
EP82112007A EP0084164B1 (en) 1981-12-29 1982-12-24 Derivatives of bicyclic amino acids, process for their preparation, agents containing them and their use, as well as bicyclic amino acids as intermediates, and process for preparing them
EP85103730A EP0170775B2 (en) 1981-12-29 1982-12-24 Derivatives of bicyclic amino acids, processes for their preparation, agents containing them and their use as well as bicyclic amino acids as intermediates and process for their preparation
AU91931/82A AU559140B2 (en) 1981-12-29 1982-12-24 Perhydrobicyclopyrtolyl-aminoacid derivatives
AT85103730T ATE47838T1 (en) 1981-12-29 1982-12-24 DERIVATIVES OF BICYCLIC AMINO ACIDS, PROCESS FOR THEIR MANUFACTURE, AGENTS CONTAINING THEM AND THEIR USE, AS WELL AS NEW BICYCLIC AMINO ACIDS AS INTERMEDIATE STAGES AND PROCESS FOR THEIR MANUFACTURE.
ES518574A ES8308850A1 (en) 1981-12-29 1982-12-27 Derivatives of bicyclic amino acids, process for their preparation, agents containing them and their use, as well as bicyclic amino acids as intermediates, and process for preparing them.
MA19890A MA19672A1 (en) 1981-12-29 1982-12-27 Process for the preparation of new bicyclic amino acid derivatives
FI824474A FI80017C (en) 1981-12-29 1982-12-27 Process for the preparation of azabicycloalkanecarboxylic acid derivatives
KR8205823A KR890003424B1 (en) 1981-12-29 1982-12-27 Processes for preparation of bicyclic amino acid derivatives
IL67572A IL67572A (en) 1981-12-29 1982-12-27 Trans-2-aza bicyclo(3.(3+n).o)alkane-3-carboxylic acid derivatives,processes for their preparation and pharmaceutical compositions containing them
PH28321A PH18918A (en) 1981-12-29 1982-12-27 2-acyl-azabicycloalkane-3-carboxylic acid derivatives,pharmaceutical compositions containing these compounds and their use
JP57227179A JPS58118569A (en) 1981-12-29 1982-12-27 Novel derivative of bicycloamino acid
DK576782A DK170444B1 (en) 1981-12-29 1982-12-28 Analogous Process for Preparation of Bicyclic Amino Acid Derivatives and Their Physiologically Harmless Salts
NO824394A NO156786C (en) 1981-12-29 1982-12-28 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DERIVATIVES OF BICYCLIC AMINO ACIDS.
HU844653A HU194167B (en) 1981-12-29 1982-12-28 Process for production og byciclic derivatives of carbonic acid
DZ826743A DZ490A1 (en) 1981-12-29 1982-12-29 New bicyclic amino acid derivatives, process for their preparation, medicaments containing these compounds and their use, new bicyclic amino acids as intermediates and process for their preparation.
PT76052A PT76052B (en) 1981-12-29 1982-12-29 NEW DERIVATIVES OF BICYCLIC AMINO-ASEANES METHOD FOR THE PRODUCTION THEREOF AND THEIR USE, AND NEW BICYCLIC AMINO-ASEANES AS INTERMEDIATES AND METHOD FOR THE PRODUCTION THEREOF
ES521740A ES521740A0 (en) 1981-12-29 1983-04-22 PROCEDURE FOR THE PREPARATION OF NEW BICYCLE AMINO ACIDS.
NO832741A NO158799C (en) 1981-12-29 1983-07-27 BICYCLIC AMINO ACIDS.
PH30781A PH19771A (en) 1981-12-29 1984-06-06 Azabicycloalkane carboxylic acids and esters
CA000461836A CA1206478A (en) 1981-12-29 1984-08-24 Bicyclic amino acid derivatives useful as medical intermediates
US06/673,605 US5008400A (en) 1981-12-29 1984-11-21 Bicyclic aminoacids as intermediates
AR85299524A AR247571A1 (en) 1981-12-29 1985-02-18 Derivatives of bicyclic amino acids, process for their preparation, agents containing them and their use, as well as bicyclic amino acids as intermediates, and process for preparing them
IL84058A IL84058A0 (en) 1981-12-29 1987-10-01 Bicyclic heterocyclic compounds and their preparation
FI883456A FI80675C (en) 1981-12-29 1988-07-21 AZABICYKLOALKANKARBOXYLSYRADERIVAT OCH FOERFARANDE FOER DERAS FRAMSTAELLNING.
SG13/89A SG1389G (en) 1981-12-29 1989-01-07 Derivates of bicyclic amino acids,process for their preparation,agents containing them and their use as well as bicycle amino acids as intermediates,and process for preparing them
JP1007871A JPH064586B2 (en) 1981-12-29 1989-01-18 Novel bicyclic compound
JP1007870A JPH01301695A (en) 1981-12-29 1989-01-18 Novel derivative of bicyclic amino acid
US07/346,339 US4933361A (en) 1981-12-29 1989-04-28 Derivatives of bicyclic aminoacids agents containing these compounds and their use
HK749/89A HK74989A (en) 1981-12-29 1989-09-14 Derivatives of bicyclic amino acids,process for their preparation,agents containing them and their use,as well as bicyclic amino acids as intermediates,and process for preparing them
US07/468,567 US5101039A (en) 1981-12-29 1990-01-23 Azabicycloamino carboxylic acid intermediates
CS914095A CS409591A3 (en) 1981-12-29 1991-12-27 Novel derivatives of bicyclic amino acids, process of their preparation, means comprising said compounds and their application, as well as novel bicyclic amino acids as intermediate products and process for preparing thereof
DK119992A DK171232B1 (en) 1981-12-29 1992-09-28 Azabicyclic compounds and processes for their preparation
NL930048C NL930048I2 (en) 1981-12-29 1993-06-03 Novel bicyclic amino acid derivatives, process for their preparation, agents containing these substances and their use, as well as new bicyclic amino acids as intermediates and processes for their preparation.
BG098551A BG60936B2 (en) 1981-12-29 1994-02-24 New derivatives of bicyclic amino acids, methods for their preparation, compositions containing them and their application, and new bicyclic amino acids as intermediate products, and methods for their preparation

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