DK142851B - Analogous process for the preparation of octahydroindolo (2,3-a) quinolizines or acid addition salts thereof. - Google Patents
Analogous process for the preparation of octahydroindolo (2,3-a) quinolizines or acid addition salts thereof. Download PDFInfo
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(11) FREMLÆGGELSESSKRIFT 1^2851 DANMARK (51) Int. Cl.3 C 07 D 471/14 (21) Ansøgning nr. 273^/78 (22) Indleveret den 1 6. jun. 19^8 (24) Løbedaø 1 Jun· 1978 (44) Ansøgningen fremlagt og , . Qn.(11) PUBLICATION NOTICE 1 ^ 2851 DENMARK (51) Int. Cl.3 C 07 D 471/14 (21) Application No. 273 ^ / 78 (22) Filed on 1 6 Jun. 19 ^ 8 (24) Løbedaø 1 Jun · 1978 (44) The application presented and,. Qn.
fremlæggelsesskriftet offentliggjort den 9· *®“*the petition published on 9 · * ® “*
DIREKTORATET FORDIRECTORATE OF
PATENT- OG VAREMÆRKEVÆSENET (3°) Pr,oritet Ugæret fra den (71) RICHTER GEDEON VEGYESZETI GYAR RT., 21, Gyoemroei u., Budapest X., HU.PATENT AND TRADEMARKET (3 °) Pr, ority Undeterred from the (71) RICHTER GEDEON VEGYESZETI GYAR RT., 21, Gyoemroei u., Budapest X., HU.
(72) Opfinder: Csaba Szantay, 8 Zsornbolyai u., Budapest XI., HU: Lajos Szabc, 38/b Visegradi u., Budapest XIII, HU: Gyoergy Kalaus, 101 Vecsey u., Buda= pest IV, HU: Egon Karpatl, 35 Krisztina krt., Budapest XI, HU: Laszlo Szporny, 2 Szabolcska M. u., Budapest XI, HU.(72) Inventor: Csaba Szantay, 8 Zsornbolyai u., Budapest XI., HU: Lajos Szabc, 38 / b Visegradi u., Budapest XIII, HU: Gyoergy Kalaus, 101 Vecsey u., Buda = Plague IV, HU: Egon Karpatl, 35 Krisztina Karta., Budapest XI, HU: Laszlo Szporny, 2 Szabolcska M. u., Budapest XI, HU.
(74) Fuldmægtig under sagens behandling:(74) Plenipotentiary in the proceedings:
Kontor for Industriel Eneret v. Svend schønning._ (54) Analogif remgangs måde til fremstilling af oktahydroindolo(2,3-a)kino= liziner eller syreadditionssalte deraf.Office of Industrial Energetic v. Svend Schönning._ (54) Analogous remedial procedure for producing octahydroindolo (2,3-a) cinema = lizines or acid addition salts thereof.
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte oktahydroindolo[2,3-a]-kinoliziner eller syreadditionssalte deraf. Disse oktahydroindolo [2 , 3-a]kinoliziner indeholder i 1-stillingen en cyanætyl-gruppe eller en alkoxykarbonylætylgruppe, eller to cyanætyl-grupper eller to alkoxykarbonylætylgrupper, og de har den almene formel la og Ib 2 142851 ΓηΟ ΠγΡ L I] JL Η ' /V /Ν eller ΤΓ ^ Η ΗThe present invention relates to an analogous process for the preparation of novel octahydroindolo [2,3-a] quinolizines or acid addition salts thereof. These octahydroindolo [2,3-a] quinolizines contain at the 1-position a cyanethyl group or an alkoxycarbonylethyl group, or two cyanethyl group or two alkoxycarbonylethyl group, and they have the general formula Ia and Ib 2 142851 ΓηΟ ΠγΡ LI] JL Η ' / V / Ν or ΤΓ ^ Η Η
a-ch?-ch a-ch2-ch2Xa-ch? -ch a-ch2-ch2X
2 2 i CH0 Η ι 2 CH„ I 22 2 i CH0 Η ι 2 CH „I 2
AA
la lb hvori A betegner en cyangruppe eller en gruppe med den almene formel COOR hvor R er en alkylgruppe med 1-6 kulstofatomer.la 1b wherein A represents a cyano group or a group of the general formula COOR wherein R is an alkyl group of 1-6 carbon atoms.
Som alkylgruppe R kommer både lige og grenede alkylgrupper med 1-6 kulstofatomer på tale, således fx metyl, ætyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, amyl, isoamyl, n-hexyl og isohexyl.As alkyl group R, both straight and branched alkyl groups having 1-6 carbon atoms are discussed, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, amyl, isoamyl, n-hexyl and isohexyl.
Sådanne forbindelser med den almene formel la foretrækkes, hvor A er en cyangruppe, metoxykarbonylgruppe eller ætoxykarbonyl-gruppe. Desuden foretrækkes sådanne forbindelser med den almene formel Ib, hvor A er en metoxykarbonylgruppe. Hertil kommer fysiologisk acceptable syreadditionssalte af begge disse slags forbindelser.Such compounds of general formula Ia are preferred where A is a cyano group, methoxycarbonyl group or ethoxycarbonyl group. Furthermore, such compounds of general formula Ib are preferred, wherein A is a methoxycarbonyl group. In addition, physiologically acceptable acid addition salts of both of these compounds.
Forbindelser med de almene formler la og Ib er, som det fremgår af deres struktur, chirale molekyler. Deres racemater kan på i og for sig kendt måde opdeles i de optiske antipoder. Opfindelsen omfatter både fremstilling af racematerne og fremstilling af enkelte optisk aktive forbindelser med de almene formler la og Ib.Compounds of the general formulas 1a and 1b are, as can be seen from their structure, chiral molecules. Their racemates can be divided into optical antipodes in a manner known per se. The invention encompasses both the preparation of the racemates and the preparation of single optically active compounds of the general formulas Ia and Ib.
Forbindelserne med de almene formler la og Ib, hvor betydningen af A er som anført ovenfor, samt deres fysiologisk acceptable syreadditionssalte har karudvidende virkning. Disse forbindelser kan derfor bruges til fremstilling af lægemiddelpræparater der som virksom bestanddel indeholder en sådan forbindelse eller syreadditionssalte deraf.The compounds of the general formulas Ia and Ib, where the meaning of A is as indicated above, as well as their physiologically acceptable acid addition salts, have vasodilatory effect. These compounds can therefore be used for the preparation of pharmaceutical compositions containing as an active ingredient such a compound or acid addition salts thereof.
Ved fremgangsmåden ifølge opfindelsen fremkommer der som mellemprodukter hexahydroindolo[2,3-a]kinoliziner med de nedenfor viste almene formler Ila og Ilb, hvor A har den ovenfor angivne 3 142851 betydning.In the process of the invention, as intermediates hexahydroindolo [2,3-a] quinolizines of the general formulas Ila and Ilb are shown below, where A has the meaning given above.
γύ~0® OwO>γύ ~ 0® OwO>
Ay A-CH -CAAy A-CH -CA
a-ch2-ch2 ?H2 H CH2a-ch2-ch2? H2 H CH2
AA
Ha libHa lib
En del af disse forbindelser, der i og for sig ikke har nogen farmakologisk virkning, kendes allerede fra US patentskrift nr. 3.536.721.Some of these compounds, which in themselves have no pharmacological effect, are already known from U.S. Patent No. 3,536,721.
I de der beskrevne forbindelser betegner A en cyangruppe. Ved den kendte fremgangsmåde til fremstilling af disse forbindelser må de renses kromatografisk; udbytterne ligger under 30%. Ved fremgangsmåden ifølge den foreliggende opfindelse vindes disse hexahydro-mellemprodukter, der indeholder en eller to cyangrupper, i- op mod et normalt udbytte på 86%. De mellemprodukter med de almene formler Ila og Ilb, hvor A betegner COOR hvor R er en alkylgruppe med 1-6 kulstofatomer, er hidtil ukendte forbindelser.In the compounds described, A denotes a cyano group. In the known process for preparing these compounds, they must be purified chromatographically; yields are below 30%. In the process of the present invention, these hexahydro intermediates containing one or two cyano groups are recovered up to a normal yield of 86%. The intermediates of the general formulas IIa and IIb, where A represents COOR where R is an alkyl group of 1-6 carbon atoms, are novel compounds.
Fremgangsmåden ifølge opfindelsen til fremstilling af forbindelserne med de almene formler la og Ib eller fysiologisk acceptable syreadditionssalte deraf er ejendommelig ved det i patentkravets kendetegnende del anførte.The process according to the invention for the preparation of the compounds of the general formulas Ia and Ib or physiologically acceptable acid addition salts thereof is characterized by the characterizing part of the patent claim.
Den som udgangsmateriale nødvendige forbindelse med formel III kan fremstilles på den i J. Heterocyclic Chemistry 3, 101, 1966 beskrevne måde.The starting material required for formula III may be prepared in the manner described in J. Heterocyclic Chemistry 3, 101, 1966.
Omsætningen af forbindelsen med formel III med en forbindelse med den almene formel IV gennemføres hensigtsmæssigt i et inert organisk opløsningsmiddel, fx i en halogeneret kulbrinte såsom di-klormetan.The reaction of the compound of formula III with a compound of the general formula IV is conveniently carried out in an inert organic solvent, for example in a halogenated hydrocarbon such as dichloromethane.
Ved udgangsforbindelser hvor A er en gruppe med den almene formel COOR anvender man hensigtsmæssigt en opløsningsmiddelblanding som foruden det nævnte inerte opløsningsmiddel også indeholder en 142851 4 til gruppen R svarende alkohol med den almene formel R-OH. Reaktionstemperaturen er med hensyn til reaktionens forløb ikke kritisk, men der arbejdes dog hensigtsmæssigt under milde betingelser, ved stuetemperatur. Reaktionstiden ligger mellem 1/2 dag og 3 dage, men påvirker ligeledes ikke reaktionen som sådan og afhænger af reaktionstemperaturen. Eventuelt kan der arbejdes under en inert gasatmosfære, fx under nitrogen eller argon.In starting compounds where A is a group of the general formula COOR, a solvent mixture is suitably used which, in addition to the said inert solvent, also contains an alcohol corresponding to the group R of the general formula R-OH. The reaction temperature is not critical with respect to the course of the reaction, but it is, however, conveniently worked under mild conditions, at room temperature. The reaction time is between 1/2 day and 3 days, but also does not affect the reaction as such and depends on the reaction temperature. Optionally, it can be operated under an inert gas atmosphere, for example under nitrogen or argon.
Reaktionsblandingen oparbejdes på i og for sig kendt måde, fx således at man afdamper opløsningsmidlet eller opløsningsmiddelblandingen og fra remanensen fjerner den eventuelt i overskud foreliggende forbindelse med den almene formel IV ved behandling med et passende opløsningsmiddel, fx petroleumsæter. De vundne forbindelser med de almene formler Ila og/eller Ilb, der hyppigst forefindes i krystallinsk tilstand, omsættes eventuelt til dannelse af syreadditionssalte. Det kan fx ske ved at man opløser basen i et inert organisk opløsningsmiddel, fortrinsvis en alifatisk alkohol, og tilsætter den ønskede syre, fortrinsvis en uorganisk syre såsom et halogenhydrid eller en perhalogensyre.The reaction mixture is worked up in a manner known per se, for example to evaporate the solvent or solvent mixture and remove from the residue any optionally present compound of the general formula IV by treatment with a suitable solvent, eg petroleum ether. The obtained compounds of the general formulas Ila and / or Ilb, most frequently found in crystalline state, are optionally reacted to form acid addition salts. This can be done, for example, by dissolving the base in an inert organic solvent, preferably an aliphatic alcohol, and adding the desired acid, preferably an inorganic acid such as a halohydride or a perhalogenic acid.
Reduktionen af forbindelserne med de almene formler Ila og/ eller Ilb eller reduktionen af syreadditionssaltene af disse forbindelser kan udføres ved hjælp af katalytisk aktiveret hydrogen eller med kemiske reduktionsmidler. I begge tilfælde - dvs. ved reduktion af den frie base såvel som ved reduktion af syreadditionssaltene - kan både de mono- og de disubstituerede forbindelser hver for sig såvel som blandinger af mono- og disubstituerede forbindelser reduceres.The reduction of the compounds of the general formulas IIa and / or Ilb or the reduction of the acid addition salts of these compounds can be carried out by catalytically activated hydrogen or with chemical reducing agents. In both cases - ie. by reducing the free base as well as by reducing the acid addition salts - both the mono- and the disubstituted compounds can be reduced separately as well as mixtures of mono- and disubstituted compounds.
Reduktionsmidlet og de betingelser hvorunder reduktionen gennemføres vælges på en sådan måde at mætningen af indolokinolizin-ringen sker uden reduktion af den eventuelt tilstedeværende cyangruppe .The reducing agent and the conditions under which the reduction is carried out are selected in such a way that the saturation of the indoloquinolizine ring occurs without reducing the cyan group present.
I det tilfælde at reduktionen gennemføres med kemiske midler, anvender man som reduktionsmiddel hensigtsmæssigt et komplekst metalhydrid, fortrinsvis et borhydrid, fx litiumborhydrid, kalium-borhydrid eller natriumborhydrid.In case the reduction is carried out with chemical agents, a complex metal hydride, preferably a borohydride, e.g. lithium borohydride, potassium borohydride or sodium borohydride, is suitably used as a reducing agent.
Reduktionerne med borhydrider udføres i et i forhold til reaktionen inert opløsningsmiddel eller fortyndingsmiddel. Fortrinsvis anvender man alifatiske alkoholer såsom metanol eller vandige alkdioler såsom vandig metanol.The reductions with borohydrides are carried out in an inert solvent or diluent relative to the reaction. Preferably, aliphatic alcohols such as methanol or aqueous alkydiols such as aqueous methanol are used.
142851 5142851 5
Borhydridet sættes til reaktions bl andingen i overskud, hensigtsmæssigt i en 1,5-7 gange så stor molær mængde. Reaktionstemperaturen og reaktionstiden er ikke af afgørende betydning for reaktionens forløb; de afhænger i første række af de pågældende udgangsstoffers reaktionsdygtighed. I almindelighed arbejder man ved temperaturer omkring 0°C, og efter sammenbringningen af reaktanterne omrører man blandingen i en periode på fra 15 minutter til ca. 3 timer.The borohydride is added to the reaction mixture in excess, suitably in a molar amount of 1.5-7 times. The reaction temperature and reaction time are not crucial to the course of the reaction; they depend primarily on the reactivity of the starting materials concerned. In general, at temperatures of about 0 ° C, the mixture is stirred and after stirring the reactants, the mixture is stirred for a period of from 15 minutes to approx. 3 hours.
Hvis reduktionen foretages med katalytisk aktiveret hydrogen anvender man som hydreringskatalysator mest hensigtsmæssigt metaller såsom palladium, platin, nikkel, jern, kobber, kobolt, krom, zink, molybdæn, wolfram eller oxider eller sulfider deraf. Den katalytiske reduktion kan også udføres i nærværelse af katalysatorer, der i forvejen er afsat på overfladen af en passende bærer; på denne måde behøves der til den ønskede reduktion en væsentligt mindre mængde af de dyre ædle metaller end ellers. Som egnede bærere kan nævnes kul, først og fremmest aktive kul, desuden sili-ciumdioxyd, aluminiumoxyd og sulfater og karbonater af jordalkali-metallerne.If the reduction is carried out with catalytically activated hydrogen, as a hydration catalyst, metals such as palladium, platinum, nickel, iron, copper, cobalt, chromium, zinc, molybdenum, tungsten or oxides or sulfides thereof are most suitably used. The catalytic reduction may also be carried out in the presence of catalysts already deposited on the surface of a suitable support; in this way, a much smaller amount of the precious precious metals is needed for the desired reduction than otherwise. Suitable carriers include coal, primarily activated carbon, in addition silica, alumina and sulfates and carbonates of the alkaline earth metals.
Til reduktion med katalytisk aktiveret hydrogen anvendes som katalysator fortrinsvis palladium, hensigtsmæssigt palladium på aktive kul, eller Raney-Nlckel; men valget af katalysatoren afhænger dog stedse af egenskaberne hos det til hydrogenering værende stof og af reaktionsbetingelserne.For reduction with catalytically activated hydrogen, catalyst is preferably used as palladium, suitably palladium on activated charcoal, or Raney-Nckel; however, the choice of the catalyst will always depend on the properties of the hydrogenation substance and on the reaction conditions.
Den katalytiske hydrogenering gennemføres hensigtsmæssigt i et i forhold til reaktionen inert opløsningmiddel, fx i en alkohol, halogeneret kulbrinte, ætylacetat, iseddikesyre eller en blanding af to eller flere sådanne opløsningsmidler. Foretrukne opløsningsmidler til denne reaktion er alifatiske alkoholer, fx metanol eller ætanol, og halogenerede kulbrinter såsom diklormetan, diklorætan eller blandinger deraf. For det tilfælde at der som katalysator anvendes platin arbejder man fortrinsvis i et neutralt eller bedre surt medium. Ved anvendelse af Raney-nikkel som katalysator er det hensigtsmæssigt at arbejde i neutralt eller alkalisk medium.The catalytic hydrogenation is conveniently carried out in a solvent inert to the reaction, for example in an alcohol, halogenated hydrocarbon, ethyl acetate, glacial acetic acid or a mixture of two or more such solvents. Preferred solvents for this reaction are aliphatic alcohols, e.g. methanol or ethanol, and halogenated hydrocarbons such as dichloromethane, dichloroethane or mixtures thereof. If platinum is used as a catalyst, it is preferably employed in a neutral or better acidic medium. When using Raney nickel as a catalyst, it is appropriate to work in neutral or alkaline medium.
Temperaturen ved den katalytiske hydrogenering såvel som trykket og reaktionstiden dertil afhænger af de anvendte udgangsmaterialer og varierer inden for vide grænser, men fortrinsvis 6 142851 arbejdes der dog ved stuetemperatur og atmosfæretryk indtil der ikke længere sker hydrogenoptagelse. Dette kan vare fra 10 minutter til cirka 5 timer.The temperature of the catalytic hydrogenation as well as the pressure and reaction time thereof depend on the starting materials used and vary within wide limits, but preferably at room temperature and atmospheric pressure, however, hydrogen uptake is no longer effected. This can last from 10 minutes to about 5 hours.
Reaktionsblandingen oparbejdes på i og for sig kendt måde, fx ved at man efter afslutning af hydrogenoptagelsen filtrerer reaktionsblandingen og inddamper filtratet til tørhed.The reaction mixture is worked up in a manner known per se, for example, after completion of the hydrogen uptake, the reaction mixture is filtered and the filtrate is evaporated to dryness.
Ved en foretrukken udførelsesform for reduktionen med katalytisk aktiveret hydrogen forhydreres først en med vand og det ved hydreringen anvendte opløsningsmiddel, fortrinsvis metanol, udvasket katalysator, hvorefter opløsningen af forbindelsen med den almene formel Ila og/eller Ilb eller opløsningen af syreadditionssalte deraf i nævnte opløsningsmiddel tilsættes, hvorpå der hydrogeneres fortrinsvis ved stuetemperatur og atmosfæretryk indtil hydrogenoptagelsen ophører.In a preferred embodiment of the reduction with catalytically activated hydrogen, a water and the solvent used, preferably methanol, are washed out before the hydrogenation of the catalyst, after which the solution of the compound of general formula IIa and / or Ilb or the solution of acid addition salts thereof is added in said solvent. , which is preferably hydrogenated at room temperature and atmospheric pressure until hydrogen uptake ceases.
Hvis der ved reduktionen vindes en blanding af forbindelser med de almene formler la og Ib, kan denne blanding på i og for sig kendt måde opdeles i de enkelte komponenter. Dette kan fx ske ved præparativ lagkromatografi, da Rf-værdien for den disubstituerede forbindelse, dvs. en forbindelse med formel Ib, er større end R^-værdien for den tilsvarende monosubstituerede forbindelse.If, upon reduction, a mixture of compounds of the general formulas 1a and 1b is obtained, this mixture can be divided into the individual components known per se. This can be done, for example, by preparative layer chromatography, since the Rf value of the disubstituted compound, i.e. a compound of formula Ib, is greater than the R 2 value of the corresponding monosubstituted compound.
Som adsorptionsmiddel anvendes hensigtsmæssigt Merck-silikagel PF254-366' som eluerin9smiddel ^an forskellige opløsningsmiddel-kombinationer komme på tale, fx benzen/metanol, fortrinsvis i forholdet 14:2 (H. Halpaap: Chemie-Ing.-Techn. 35, 488, 1963).As adsorbent, Merck silica gel PF254-366 'is suitably used as an eluent in various solvent combinations, for example benzene / methanol, preferably in a ratio of 14: 2 (H. Halpaap: Chemie-Ing. Techn. 35, 488, 1963).
Ved strukturundersøgelser over forbindelser med de almene formler la og Ib tillader Bohlmann-båndene i IR-spektret den slutning at hydrogenatomet i 12β-stillingen og hydrogenatomet henholdsvis gruppen A-CH2-CH2~ i 1-stillingen står i β-stilling i forhold til hinanden, dvs. at forbindelserne med de almene formler la og Ib udviser trans-konfiguration.In structural studies of compounds of the general formulas 1a and 1b, the Bohlmann bands in the IR spectrum allow the conclusion that the hydrogen atom in the 12β position and the hydrogen atom, respectively, the group A-CH2-CH2 ~ in the 1 position, is in the β position relative to each other. , ie that the compounds of the general formulas 1a and 1b exhibit trans-configuration.
De forbindelser med de almene formler la og Ib, hvor A er en gruppe COOR hvor R = C^_g alkylgruppe, kan på i og for sig kendt måde underkastes omestringsreaktioner; således kan der af en fremstillet ester om ønsket fremstilles en vilkårlig anden ester ved at man koger esteren med den almene formel la eller Ib i den alkohol, der svarer til den ønskede estergruppe, sammen med et al-kalimetalalhoholat af samme alkohol, fortrinsvis natriumalkoholatet deraf, og under kogningen kontinuerligt afdestillerer den ved om- 142851 7 estringen opstående alkohol, der har lavere kogepunkt end den til den nye estergruppe svarende alkohol, fra reaktionsblandingen.The compounds of the general formulas Ia and Ib, where A is a group of COOR where R = C1-6 alkyl group, can be subjected in a manner known per se to transesterification reactions; thus, any desired ester can be prepared from any ester, if desired, by boiling the ester of the general formula Ia or lb in the alcohol corresponding to the desired ester group, together with an alkali metal alcoholate of the same alcohol, preferably the sodium alcoholate thereof. and, during boiling, continuously distills the alcohol obtained by the esterification having a lower boiling point than the alcohol corresponding to the new ester group from the reaction mixture.
Forbindelser med de almene formler la eller Ib, hvor A er en cyangruppe, kan på i og for sig kendt måde omdannes til estere hvor A står for en gruppe COOR hvor R = C^g-alkylgruppe. Dette kan fx ske ved at man koger den eller de forbindelser, der som substituent eller substituenter A indeholder en cyangruppe, i en fortyndet mineralsyre, fx saltsyre eller svovlsyre, eller i en fortyndet uorganisk base, fx natrium- eller kaliumhydroxyd, og derefter forestrer den dannede karboxylsyre på i og for sig kendt måde. Til dette formål kan man fx koge den vundne karboxylsyre med den til den ønskede estergruppe svarende alkohol. En anden mulighed består i at man af karboxylsyrerne fremstiller sølvsaltet og derefter omsætter dette med et til den ønskede gruppe R svarende alkylhalogenid, fortrinsvis alkyljodidet. Endelig kan man gå frem på den måde at man af karboxylsyren danner et reaktionsdygtigt derivat, fx karboxylsyrehalogenidet eller karboxyl-syreanhydridet, og derefter omsætter dette med den til den ønskede gruppe R svarende alkohol R-OH. Det er ydermere muligt at omsætte de ved fremgangsmåden ifølge opfindelsen vundne cyanforbindelser med overskud af den til den ønskede gruppe R svarende alkohol og saltsyre og derefter vinde den ønskede ester over den som mellemprodukt dannede iminoæter.Compounds of the general formulas Ia or Ib, where A is a cyano group, can in a manner known per se be converted to esters where A stands for a group COOR where R = C 1-6 alkyl group. This can be done, for example, by boiling the compound (s) containing as substituent or substituents A a cyano group, in a dilute mineral acid, eg hydrochloric or sulfuric acid, or in a dilute inorganic base, e.g. sodium or potassium hydroxide, formed carboxylic acid in a manner known per se. For this purpose, for example, the carboxylic acid obtained can be boiled with the alcohol corresponding to the desired ester group. Another option consists in preparing the silver salt of the carboxylic acids and then reacting it with an alkyl halide corresponding to the desired group R, preferably the alkyl iodide. Finally, one can proceed by forming a reactive derivative of the carboxylic acid, for example the carboxylic acid halide or carboxylic acid anhydride, and then reacting it with the alcohol R-OH corresponding to the desired group R. Furthermore, it is possible to react the cyan compounds obtained by the process according to the invention with excess of the alcohol and hydrochloric acid corresponding to the desired group R and then to obtain the desired ester over the intermediate imino ether.
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser med de almene formler la og Ib kan eventuelt renses yderligere, fx ved omkrystallisation. Til denne behandling egner sig sådanne opløsningsmidler som fx alifatiske alkoholer såsom metanol og ætanol, eller alifatiske ætere, som fx diætylæter.The compounds of the general formulas 1a and 1b prepared by the process according to the invention can optionally be further purified, for example by recrystallization. Suitable for this treatment are such solvents as, for example, aliphatic alcohols such as methanol and ethanol, or aliphatic ethers such as diethyl ether.
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser kan også renses ved præparativ lagkromatografi. Som adsorptionsmiddel anvendes hensigtsmæssigt silikagel af mærket Merck PF254-366' som flYdeiniddel kommer forskellige opløsningsmiddel landinger på tale, fx benzen/metanol, fortrinsvis i forholdet 14:2 eller 14:3, og som elueringsmiddel fortrinsvis alifatiske ætere, fx diætylæter, eller alifatiske ketoner, som fx acetone i betragtning.The compounds of the process according to the invention can also be purified by preparative layer chromatography. As the adsorbent, silica gel of the brand Merck PF254-366 'is suitably used as a fluid agent, various solvent landings are discussed, e.g. , such as, for example, acetone.
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser med de almene formler la eller Ib kan om ønsket omsættes med syre til fysiologisk acceptable syreadditionssalte deraf.The compounds of the general formulas 1a or 1b prepared by the process according to the invention can, if desired, be reacted with acid to physiologically acceptable acid addition salts thereof.
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Egnede syrer er fx uorganiske syrer såsom hydrogenklorid eller hydrogenbromid, svovlsyre eller fosforsyre, og desuden organiske karboxylsyrer såsom myresyre, eddikesyre, propionsyre, oxalsyre, glykolsyre, maleinsyre, fumarsyre, ravsyre, vinsyre, ascorbin-syre, citronsyre, æblesyre, salicylsyre, mælkesyre, benzoesyre, kanelsyre, eller alkylsulfonsyrer såsom metansulfonsyre, og desuden cyklohexyIsulfonsyre, asparaginsyre, glutaminsyre, N-acetyl-asparaginsyre, eller N-acetylglutaminsyre.Suitable acids are e.g. benzoic acid, cinnamic acid, or alkyl sulfonic acids such as methanesulfonic acid, and in addition cyclohexyl sulfonic acid, aspartic acid, glutamic acid, N-acetyl-aspartic acid, or N-acetylglutamic acid.
Saltdannelsen gennemføres fortrinsvis i et inert opløsningsmiddel, hensigtsmæssigt i en alifatisk alkohol såsom metanol,ved at man opløser basen med den almene formel la og/eller Ib i det ønskede opløsningsmiddel og derefter omsætter den så længe med den ønskede syre, at blandingens pH-værdi bliver svagt sur (ca. 6). Det dannede syreadditionssalt kan isoleres ved udfældning med et ublandbart organisk opløsningsmiddel som fx. diætylæter.The salt formation is preferably carried out in an inert solvent, suitably in an aliphatic alcohol such as methanol, by dissolving the base of the general formula Ia and / or Ib in the desired solvent and then reacting it with the desired acid for as long as the pH of the mixture becomes slightly acidic (about 6). The acid addition salt formed can be isolated by precipitation with an immiscible organic solvent such as e.g. diethyl ether.
Hvis forbindelserne med de almene formler la eller Ib ved fremgangsmåden ifølge opfindelsen vindes i form af syreadditionssalte, kan man af disse om ønsket frisætte de frie forbindelser med de almene fonnier la og/eller Ib på i og for sig kendt måde ved omsætning med en base i et passende opløsningsmiddel. Herved kan man i enkeltheder fx gå således frem at syreadditionssaltet opløses i et passende opløsningsmiddel eller en opløsningsmiddelblanding, fx en blanding af acetone og vand, hvorefter der til opløsningen sættes den beregnede mængde base, fx koncentreret ammoniakvand.If the compounds of the general formulas 1a or 1b are obtained in the form of acid addition salts in the process according to the invention, they may, if desired, release the free compounds with the general forms 1a and / or 1b in a manner known per se by reaction with a base. in a suitable solvent. Hereby, for example, it can be stated, for example, that the acid addition salt is dissolved in a suitable solvent or solvent mixture, for example a mixture of acetone and water, and then the calculated amount of base, for example concentrated ammonia water is added to the solution.
Forbindelser med de almene formler la og Ib vindes ved fremgangsmåden ifølge opfindelsen med højt udbytte og i godt identificerbar form. Resultaterne af elementæranalysen viser god overensstemmelse med de beregnede værdier. Båndene for de karakteristiske grupper i IR-spektret, værdierne for signalerne af den magnetiske kærneresonans og data for massespektret beviser entydigt at der er tale om de strukturer der gengiver de almene formler la og Ib.Compounds of the general formulas 1a and 1b are obtained by the high-yielding and well-identifiable form of the invention. The results of the elemental analysis show good agreement with the calculated values. The bands of the characteristic groups in the IR spectrum, the values of the signals of the magnetic nuclear resonance, and the data for the mass spectrum unequivocally prove that these are the structures representing the general formulas Ia and Ib.
Ved farmakologiske undersøgelser har det vist sig at forbindelser med de almene formler la og Ib har væsentlig karudvidende virkning. Denne virkning viser sig frem for alt ved kraftig stigning af blodgennemløbet i hjerne og lemmer.In pharmacological studies it has been found that compounds of the general formulas Ia and Ib have substantial vasodilatory effect. This effect is especially evident by a sharp increase in the blood flow in the brain and limbs.
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Det skal bemærkes at der fra DK fremlæggelsesskrift nr. 139.431 kendes nærbeslægtede forbindelser med formlen χχ.- uuIt should be noted that, from DK Presentation No. 139,431, there are known closely related compounds of the formula χχ.- uu
' XX'XX
NC-CH2CH2^ ^ hvor R er en alkylgruppe med 1-6 kulstofatomer, og fra DK fremlæggelsesskrift nr. 139,432 andre nærbeslægtede forbindelser med formlenNC-CH 2 CH 2 + where R is an alkyl group of 1-6 carbon atoms, and from DK Publication No. 139,432 other closely related compounds of the formula
X_XXX_XX
CjZkXCjZkX
HH
nh2-ch2ch2ch2'NH2-CH2CH2CH2 '
RR
hvor R ligeledes er en alkylgruppe med 1-6 kulstofatomer. Begge de to typer forbindelser har karudvidende virkning.wherein R is also an alkyl group of 1-6 carbon atoms. Both types of compounds have a vasodilatory effect.
Der er foretaget undersøgelser over den karudvidende ’ virkning af nogle af de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser med den almene formel la eller Ib (stofferne A, B, C og D) i sammenligning med dels apovin-caminsyreætylester som referenceforbindelse, dels med repræsentanter for forbindelserne med de almene formler V og VI.Studies have been conducted on the vasodilating effect of some of the compounds of the general formula Ia or Ib (substances A, B, C and D) prepared by the process according to the invention in comparison with partly apovin-caminoic acid ethyl ester as a reference compound and partly with representatives of the compounds of general formulas V and VI.
Undersøgelserne foretoges på hunde der var narkotiserede med kloralose-uretan. Blodgennemstrømningen gennem leddene måltes på arteria femoralis, mens man til blodgennemstrømningen igennem hjernen optog data ved måling af blodstrømningen i arteria carotis interna og arteria vertebralis. Åremodstanden i kredsløbet beregnedes udfra de tilsvarende værdier for blodtryk og blodstrømning.The studies were conducted on dogs anesthetized with chloralose-urethane. Blood flow through the joints was measured on arterial femoralis, while for blood flow through the brain, data were obtained by measuring blood flow in the arterial carotid artery and arterial vertebral artery. The annual resistance in the circuit was calculated from the corresponding values for blood pressure and blood flow.
Stofferne blev indgivet i en dosis på 1 mg/kg intravenøst. Forandringerne opstilledes procentuelt. De som gennemsnit for seks dyr opnåede værdier er sammenstillet i nedenstående tabel sammen med data der opnåedes ved anvendelse af den med held i farmakologien anvendte apovinkaminsyreætylester.The drugs were administered at a dose of 1 mg / kg intravenously. The changes were made as a percentage. The values obtained for six animals averaged are summarized in the table below, together with data obtained using the apovarcamic acid ethyl ester successfully used in pharmacology.
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Stof Blod- Puls Blodstrøm- Åremod- Blodstrøm- Åremodtryk ning________stand____ning________stand___ i hjernen i leddene A -8 +12 Q -3 +148 -65 B -52 -5 +2 -7 +140 -65 C -25 +35 +78 -54 +93 -61 D -18 +27 +41 -43 +120 -54Substance Blood - Pulse Blood flow - Vascularity - Blood flow - Ventricular depression ________stand ___________________________________ in the brain of the joints A -8 +12 Q -3 +148 -65 B -52 -5 +2 -7 +140 -65 C -25 +35 +78 -54 +93 -61 D -18 +27 +41 -43 +120 -54
Reference -28 +14 +16 -20 +58 -35Reference -28 +14 +16 -20 +58 -35
Formel RFormula R
V C0Hc -43,5 +43,5 +56,2 -44,4 +53,8 -38,4V COHc -43.5 +43.5 +56.2 -44.4 +53.8 -38.4
L DL D
V n-C4H9 -11,1 +33,1 +44,9 -30,2 +76,8 -49,5 VI C-H,- -22.6 +6,3 +1 -5,3 +301,5 -60,30 2. o A: 1-(2'-metoxykarbonylæty1)-1,2,3,4,6,7,12,12b-oktahydroindolo [2,3-a]kinolizin B: 1,1-di-(2'-metoxykarbonylætyl)-1,2,3,4,6,7,12,12b-oktahydro-indolo[2,3-a]kinolozin C: 1-(2,-ætoxykarbonylætyl)-l,2,3,4,6,7,12,12b-oktahydroindolo [2,3-a]kinolizin B: 1-(2'-cyanætyl)-1,2,3,4,6,7,12,12b-oktahydroindolo[2,3-a]kinolizinV n-C4H9 -11.1 +33.1 +44.9 -30.2 +76.8 -49.5 VI CH, - -22.6 +6.3 +1 -5.3 +301.5 -60 2. A: 1- (2'-methoxycarbonylethyl) -1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizine B: 1,1-di- ( 2'-methoxycarbonylethyl) -1,2,3,4,6,7,12,12b-octahydro-indolo [2,3-a] quinolozin C: 1- (2, -ethoxycarbonylethyl) -1,2,3, 4,6,7,12,12b-octahydroindolo [2,3-a] quinolizine B: 1- (2'-cyanethyl) -1,2,3,4,6,7,12,12b-octahydroindolo [2, 3-a] quinolizine
Af tabellen fremgår det at navnlig forbindelserne A og B bevirker stigning af blodgennemstrømningen i leddene og i den henseende har ca. 2 1/2 gang så kraftig virkning som referenceforbindelsen. Virkningen med hensyn til øgning af blodgennemstrømningen gennem hjernen af forbindelserne C og D er henholdsvis 2,5 og 5 gange så høj som tilsvarende virkning af referenceforbindelsen.It can be seen from the table that, in particular, compounds A and B cause an increase in blood flow in the joints and in this respect have approx. 2 1/2 times as powerful as the reference compound. The effect of increasing the blood flow through the brain of compounds C and D is 2.5 and 5 times, respectively, as high as the corresponding effect of the reference compound.
Tabellen viser desuden at den ved fremgangsmåden ifølge opfindelsen fremstillede forbindelse C har væsentlig stærkere cerebral vasodilaterende virkning (78% stigning i den cerebrale blodstrøm) end de to afprøvede forbindelser med formel VThe table further shows that the compound C prepared by the process according to the invention has a significantly stronger cerebral vasodilating effect (78% increase in the cerebral blood flow) than the two compounds of formula V tested.
142851 11 (henholdsvis 56 og 45% stigning i den cerebrale blodstrøm) , mens den afprøvede forbindelse med formel VI slet ikke har cerebral vasodilaterende virkning (1% stigning af blodstrømmen gennem hjernen).(56 and 45% increase in cerebral blood flow, respectively), while the tested compound of formula VI has no cerebral vasodilating effect (1% increase in blood flow through the brain).
Den ved fremgangsmåden ifølge opfindelsen fremstillede forbindelse D giver 41% stigning i den cerebrale blodstrøm, altså af samme eller omtrent samme størrelsesorden som de to afprøvede forbindelser med formel V.The compound D prepared by the method according to the invention gives a 41% increase in the cerebral blood flow, ie of the same or approximately the same order of magnitude as the two compounds of formula V tested.
Alle de afprøvede, ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser giver væsentlig større forøgelse af blodstrømmen til lemmerne (forøgelser på 93 til 148%) end de afprøvede forbindelser med formel V (henholdsvis 54 og 77% stigning) ; de var dog i denne henseende af mindre effekt end den afprøvede forbindelse med formel VI, men den havde som nævnt ingen cerebral vasodilatorisk virkning.All the compounds prepared by the process according to the invention give a substantially greater increase in blood flow to the limbs (increases of 93 to 148%) than the tested compounds of formula V (54 and 77% increase respectively); however, they were less effective in this regard than the tested compound of Formula VI, but as mentioned, it had no cerebral vasodilatory effect.
Den ved fremgangsmåden ifølge opfindelsen fremstillede forbindelse har en meget gunstig systematisk kardiovaskulær virkning i sammenligning med den afprøvede forbindelse med formel VI, hvis virkning den ellers ligger nærmest, nemlig med et blodtrykfald på kun 8%, sammenlignet med det af nævnte forbindelse VI fremkaldte blodtrykfald på 23%; den blodtryksænkende virkning under den vasodilaterende behandling er en uønsket bivirkning fordi blodtilførslen kan aftage i nogle organer som følge af nedgangen i perfusionstrykketThe compound of the present invention has a very favorable systematic cardiovascular effect in comparison with the tested compound of formula VI, the effect of which is otherwise closest, namely with a blood pressure drop of only 8%, compared with the blood pressure drop of said compound VI. 23%; the blood pressure lowering effect during the vasodilating treatment is an undesirable side effect because the blood supply may decrease in some organs due to the decrease in perfusion pressure
Sammenfattende har de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser således gunstige egenskaber i sammenligning med de afprøvede kendte, nærbeslægtede forbindelser.In summary, the compounds prepared by the process of the invention thus have favorable properties in comparison with the tested known, closely related compounds.
Fremgangsmåden ifølge opfindelsen skal i det følgende belyses nærmere ved nogle eksempler.The process according to the invention will now be described in more detail by some examples.
Eksempel 1 a) 1-(2'-Metoxykarbonylætyl)-2,3,4,6,7,12-hexahydro-lH-indolo [2,3-a]kinolizinium-perklorat og 1,1-di-(2'-metoxykarbonylætyl)-2,3,4,6,7,12-hexahydro-lH-indolo[2,3-a]-kinolizinium-perklorat (blanding) 2,24 g (10,0 mMol) 2,3,4,6,7,12-hexahydroindolo[2,3-a]kinol-izin opløses i 100 ml diklormetan og til opløsningen sættes der 12 142851 0,2 ml metanol og 2,10 g (24,4 mMol) acrylsyremetylester. Reaktionsblandingen henstår i 2 dage ved stuetemperatur. Derefter fjernes opløsningsmidlet i vakuum og remanensen rives med petroleumsæter for at fjerne overskydende acrylsyremetylester. Den faste remanens opløses i 15 ml metanol, opløsningen syrnes med 70%'s perklor-syre til pH 6 og det udskilte salt frafiltreres og vaskes med æter. Der vindes 4,0 g af blandingen af de ovennævnte hexahydroforbindel-ser. Produktet smelter ved 135-160°C.Example 1 a) 1- (2'-Methoxycarbonylethyl) -2,3,4,6,7,12-hexahydro-1H-indolo [2,3-a] quinolizinium perchlorate and 1,1-di- (2 ') (methoxycarbonylethyl) -2,3,4,6,7,12-hexahydro-1H-indolo [2,3-a] quinolizinium perchlorate (mixture) 2.24 g (10.0 mMol) 2.3.4 , 6,7,12-Hexahydroindolo [2,3-a] quinol-azine is dissolved in 100 ml of dichloromethane and to the solution is added 0.2 ml of methanol and 2.10 g (24.4 mMol) of acrylic acid methyl ester. The reaction mixture is left at room temperature for 2 days. Then, the solvent is removed in vacuo and the residue is triturated with petroleum ether to remove excess acrylic acid methyl ester. The solid residue is dissolved in 15 ml of methanol, the solution is acidified with 70% perchloric acid to pH 6 and the separated salt is filtered off and washed with ether. 4.0 g of the mixture of the above hexahydro compounds are obtained. The product melts at 135-160 ° C.
IR-spektrum (i KBr); 3200 (indol-NH), 1735, 1718 (CC^CH^, 1630 og 1550 cm-1 (C=N).IR spectrum (in KBr); 3200 (indole-NH), 1735, 1718 (CC ^CH ^, 1630 and 1550 cm-1 (C = N).
b) 1-(21-Metoxykarbonylætyl)-1,2,3,4,6,7,12,12b-oktahydroindolo [2,3-a]kinolizin og 1,1-di-(21-metoxykarbonylætyl)-1,2,3,4,6,7,12, 12b-oktohydroindolo[2,3-a]kinolizin 4,0 g af den i henhold til afsnit a) fremstillede blanding hydrogeneres i 100 ml metanol i nærværelse af 2,0 g palladium/aktiv kul. Efter afslutning af hydrogenoptagelsen frafiltreres katalysatoren, filtratet inddampes til tørhed og inddampningsremanensen opløses i vandig metanol. Opløsningen gøres alkalisk med 5%*s vandig natriumkarbonatopløsning og ekstraheres med diklormetan. Ekstrakterne forenes, tørres og filtreres og filtratet inddampes til tørhed.b) 1- (21-Methoxycarbonylethyl) -1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizine and 1,1-di- (21-methoxycarbonylethyl) -1; 2,3,4,6,7,12, 12b-octohydroindolo [2,3-a] quinolizine 4.0 g of the mixture prepared according to paragraph a) is hydrogenated in 100 ml of methanol in the presence of 2.0 g of palladium /active coal. After completion of the hydrogen uptake, the catalyst is filtered off, the filtrate is evaporated to dryness and the evaporation residue is dissolved in aqueous methanol. The solution is made alkaline with 5% aqueous sodium carbonate solution and extracted with dichloromethane. The extracts are combined, dried and filtered and the filtrate is evaporated to dryness.
Den vundne blanding renses ved præparativ lagkromatografi (på Kieselgel Merck ^254-366' flydemiddel benzen/metanol 14:2; elue-ring med acetone; R^-værdien af det disubstituerede produkt er større end R^-værdien af det monosubstituerede produkt).The obtained mixture is purified by preparative layer chromatography (on Kieselgel Merck ^ 254-366 'liquid benzene / methanol 14: 2; elution with acetone; the R₂ value of the disubstituted product is greater than the R₂ value of the monosubstituted product) .
Der vindes 1,6 g (40%) 1,1-di-(21-metoxykarbonylætyl)-1,2, 3,4,6,7,12,12b-oktahydroindolo[2,3-a]kinolizin som smelter ved 226°C efter omkrystallisation fra metanol.1.6 g (40%) of 1,1-di- (21-methoxycarbonylethyl) -1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizine are obtained, 226 ° C after recrystallization from methanol.
IR-spektrum (KBr): 3300 (NH), 2790, 2740 (Bohlman-bånd), 1732, 1720 (C02CH3).IR spectrum (KBr): 3300 (NH), 2790, 2740 (Bohlman band), 1732, 1720 (CO 2 CH 3).
Massespektrum m/e (%): 398(16,M), 397(11), 383(1), 339(2), 325(100), 311(4), 237(15), 197(50), 185(35), 170(50), 169(75). Kernemagnetisk resonansspektrum (CDCl^): 5=9,00 (lH-s, indol-NH), 730 (4H-m, aromatiske protoner), 3,80 (3H-s, CC^CH^), 3,56 (3H-s, C02CH3).Mass Spectrum m / e (%): 398 (16, M), 397 (11), 383 (1), 339 (2), 325 (100), 311 (4), 237 (15), 197 (50), 185 (35), 170 (50), 169 (75). Nuclear Magnetic Resonance Spectrum (CDCl3): 5 = 9.00 (1H-s, indole-NH), 730 (4H-m, aromatic protons), 3.80 (3H-s, CC1 CH2), 3.56 ( 3H-s, CO 2 CH 3).
Desuden vindes 0,8 g (25%) l-(2-metoxykarbonylætyl)-l,2,3,4,6,7,12,12b-oktahydroindolo[2,3,-a]kinolizin, hvis hydro-klorid smelter ved 245°C under sønderdeling.In addition, 0.8 g (25%) of 1- (2-methoxycarbonylethyl) -1,2,3,4,6,7,12,12b-octahydroindolo [2,3- a] quinolizine whose hydrochloride melts at 245 ° C with decomposition.
142851 13 IR-spektrum (i KBr) : 2780 (Bohlmand-bånd), 1725 cm ^((302(3^). Massespektrum m/e (%): 312 (90,M), 311(100)/ 297(3), 281(10), 253(2), 239(70), 225(10), 197(40), 170(22), 169(23).IR spectrum (in KBr): 2780 (Bohlmand band), 1725 cm 2 ((302 (3)). Mass spectrum m / e (%): 312 (90, M), 311 (100) / 297 ( 3), 281 (10), 253 (2), 239 (70), 225 (10), 197 (40), 170 (22), 169 (23).
Eksempel 2 a) 1-(21-Ætoxykarbonylætyl)-2,3,4,6,7,12-hexahydro-lH-lndolo [2,3-a3kinolizinium-perklorat 10,1 g (45 mMol) 2,3,4,6,7,12-hexahydroindolo[2,3-a]kinolizin opløses i 230 ml diklormetan og til opløsningen sættes 4,5 ml ætanol og 5,1 g (mMol) akrylsyreætylester. Reaktionsblandingen henstår ved stuetemperatur i 2 dage. Derefter fjernes opløsningsmidlet i vakuum, remanensen opløses i 70 ml ætanol og opløsningens pH-værdi reguleres til 6 med 70%'s perklorsyre. Den udfældede hexahydroforbindelse frafiltreres og vaskes først med ætanol og derefter med æter. Der vindes 12,5 g (65%) 1-(2'-ætoxykarbonylætyl)-2,3,4,6,7,12-hexahydro-lH-indolo[2,3-a]kinolizinium-perklorat som smelter ved 166°C. IR-spektrum (i KBr): 3240 (indol-NH), 1725 (C02C2Hg), 1630, 1550 cm 1 (C=N) .Example 2 a) 1- (21-Ethoxycarbonylethyl) -2,3,4,6,7,12-hexahydro-1H-indolo [2,3-a] quinolizinium perchlorate 10.1 g (45 mMol) 2.3.4 , 6,7,12-Hexahydroindolo [2,3-a] quinolizine is dissolved in 230 ml of dichloromethane and to the solution is added 4.5 ml of ethanol and 5.1 g (mMol) of acrylic acid ethyl ester. The reaction mixture is left at room temperature for 2 days. Then, the solvent is removed in vacuo, the residue is dissolved in 70 ml of ethanol and the pH of the solution is adjusted to 6 with 70% perchloric acid. The precipitated hexahydro compound is filtered off and washed first with ethanol and then with ether. 12.5 g (65%) of 1- (2'-ethoxycarbonylethyl) -2,3,4,6,7,12-hexahydro-1H-indolo [2,3-a] quinolizinium perchlorate are obtained, melting at 166 ° C. IR spectrum (in KBr): 3240 (indole-NH), 1725 (CO 2 CO 2 Hg), 1630, 1550 cm -1 (C = N).
b) 1-(21-Ætoxykarbonylæty1)-1,2,3,4,6,7,12,12-oktahydroindolo [2,3-a3kinolizin-hydroklorid 6,0 g (14 mMol) af den ifølge afsnit a) fremstillede forbindelse opløses i en blanding af 90 ml ætanol og 30 ml diklormetan og hydrogeneres i nærværelse af 10 g palladium/aktiv kul. Efter optagelse af den beregnede mængde hydrogen (ca. 1 time) frafiltreres katalysatoren og filtratet inddampes i vakuum. Til remanensen sættes der 50 ml vand og blandingen gøres alkalisk med 5%'s vandig natriumkarbonatopløsning, hvorpå den ekstraheres med diklormetan og ekstrakten tørres over magniumsulfat og derpå inddampes. Den vundne olie opløses i 20 ml ætanol, opløsningen syrnes med saltsur ætanol til pH 6 og den udskilte forbindelse frafiltreres og vaskes først med en smule alkohol og derefter med æter. Der vindes 3,4 g (68%) hydroklorid som efter afkrystallisation fra ætanol smelter ved 244°C.b) 1- (21-Ethoxycarbonylethyl) -1,2,3,4,6,7,12,12-octahydroindolo [2,3-a] quinolizine hydrochloride 6.0 g (14 mMol) of the prepared according to section a) compound is dissolved in a mixture of 90 ml of ethanol and 30 ml of dichloromethane and hydrogenated in the presence of 10 g of palladium / activated carbon. After taking up the calculated amount of hydrogen (about 1 hour), the catalyst is filtered off and the filtrate is evaporated in vacuo. To the residue is added 50 ml of water and the mixture is made alkaline with 5% aqueous sodium carbonate solution, then extracted with dichloromethane and the extract is dried over magnesium sulfate and then evaporated. The oil obtained is dissolved in 20 ml of ethanol, the solution is acidified with hydrochloric acid ethanol to pH 6 and the separated compound is filtered off and washed first with a little alcohol and then with ether. 3.4 g (68%) of hydrochloride is obtained which after crystallization from ethanol melts at 244 ° C.
14 142851 IR-spektrum (i KBr): 3145 (indol-NH), 2790, 2730 (Bohlman-bånd), 1724 cm-1 (C/2C2H5).IR spectrum (in KBr): 3145 (indole-NH), 2790, 2730 (Bohlman band), 1724 cm-1 (C / 2C2H5).
Kernemagnetisk resonansspektrum (CDCl^): 6=8,80 (ΙΗ-s, indol-NH), 7,30 (4H-m, aromatiske protoner), 4,18 (2H-q, CO^CH^CH.,), 1,25 (3H-t, C02CH2CH3).Nuclear Magnetic Resonance Spectrum (CDCl3): 6 = 8.80 (ΙΗ-s, indole-NH), 7.30 (4H-m, aromatic protons), 4.18 (2H-q, CO , 1.25 (3H-t, CO 2 CH 2 CH 3).
Massespektrum m/e (%): 326(85,M), 325(95), 296(17), 281(18), 253(3), 239 (100), 225(14), 197(40), 185(13), 170(35).Mass Spectrum m / e (%): 326 (85, M), 325 (95), 296 (17), 281 (18), 253 (3), 239 (100), 225 (14), 197 (40), 185 (13), 170 (35).
169(35) .169 (35).
Eksempel 3 a) 1-(21-Ætoxykarbonylatyl)-2,3,4,6,7,12-hexahydro-lH-indolo [2,3-a]kinolizin 2,2 g (10 mMol) 2,3,4,6,7,12-hexahydroindolo[2,3-a]kinolizin opløses i 100 ml diklormetan og til opløsningen sættes der 0,5 ml ætanol og 2,3 g (25 mMol) akrylsyreætylester. Reaktionsblandingen henstår i 2 dage under argonatmosfære ved stuetemperatur. Derefter fjernes opløsningsmidlet i vakuum og remanensen rives med 3x3 ml petroleumsæter. Efter dekantering tørres produktet. Der vindes 2,75 g (86 %) 1-(2'-ætoxykarbonylætyl)-2,3,4,6,7,12-hexahydro-lH-indolo [2,3-a]kinolizin som smelter ved 72-74°C.Example 3 a) 1- (21-Ethoxycarbonylatyl) -2,3,4,6,7,12-hexahydro-1H-indolo [2,3-a] quinolizine 2.2 g (10 mMol) 2.3.4 , 6,7,12-Hexahydroindolo [2,3-a] quinolizine is dissolved in 100 ml of dichloromethane and to the solution is added 0.5 ml of ethanol and 2.3 g (25 mMol) of acrylic acid ethyl ester. The reaction mixture is left under argon atmosphere at room temperature for 2 days. Then, the solvent is removed in vacuo and the residue is triturated with 3x3 ml of petroleum ether. After decanting, the product is dried. 2.75 g (86%) of 1- (2'-ethoxycarbonylethyl) -2,3,4,6,7,12-hexahydro-1H-indolo [2,3-a] quinolizine melting at 72-74 are obtained. ° C.
b) 1-(21-ÆtoxykarbonyIstyl)-1,2,3,4,6,7,12-12b-oktahydroindolo [2,3-a]kinolizin-hydroklorid 2,5 g (7,7 mMol) af den ifølge afsnit a) fremstillede forbindelse opløses i 150 ml ætanol og hydrogeneres i nærværelse af 2 g palladium/aktiv kul. Efter optagelse af den beregnede mængde hydrogen, ca. 30 minutter, frafiltreres katalysatoren og filtratet inddampes i vakuum. Inddampningsremanensen opløses i 10 ml ætanol og opløsningens pH-værdi indstilles på 5 ved tilsætning af saltsur metanol. De udfældede bundfald frafiltreres og vaskes først med ætanol og derefter med æter. Efter tørring vindes 1,2 g (50%) af ovennævnte hydroklorid. Produktets fysiske konstanter stemmer fuldstændigt med konstanterne af produktet ifølge eksempel 2b) .b) 1- (21-Ethoxycarbonylstyle) -1,2,3,4,6,7,12-12b-octahydroindolo [2,3-a] quinolizine hydrochloride 2.5 g (7.7 mMol) section a) the compound prepared is dissolved in 150 ml of ethanol and hydrogenated in the presence of 2 g of palladium / activated carbon. After taking up the calculated amount of hydrogen, approx. 30 minutes, the catalyst is filtered off and the filtrate is evaporated in vacuo. The evaporation residue is dissolved in 10 ml of ethanol and the pH of the solution is adjusted to 5 by the addition of hydrochloric acid methanol. The precipitated precipitates are filtered off and washed first with ethanol and then with ether. After drying, 1.2 g (50%) of the above hydrochloride is obtained. The physical constants of the product completely agree with the constants of the product of Example 2b).
U2851 15U2851 15
Eksempel 4 1— (21 -Ætoxykarbony lætyl )-1,2,3,4,6,7,12,12b-oktahydrolndolo [2,3-a]klnollzln-hydroklorld 0,35 g (1 mMol) 1-(2'-metoxykarbonylætyl)-l,2,3,4,6,7,12,12b-oktahydroindolo[2,3-a]kinolizin-hydroklorid fordeles mellem 10 ml diklormetan og 3 ml 5%'s vandig natriumkarbonatopløsning. Den vandige fase ekstraheres med 2x3 ml diklormetan. Den organiske fase tørres over magniumsulfat og filtreres og filtratet inddampes. Den som inddampningsremanens vundne olie opløses i 15 ml ætanol og til opløsningen sættes der 50 mg natriumætylat. Blandingen koges i 2 timer og afkøles derefter og det resterende natriumætylat sønderdeles med iseddikesyre. Opløsningen inddampes i vakuum til tørhed.Example 4 1- (21-Ethoxycarbonylethyl) -1,2,3,4,6,7,12,12b-octahydroloindolo [2,3-a] chlorobenzene hydrochloride 0.35 g (1 mMol) 1- (2) (methoxycarbonylethyl) -1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizine hydrochloride is partitioned between 10 ml of dichloromethane and 3 ml of 5% aqueous sodium carbonate solution. The aqueous phase is extracted with 2x3 ml of dichloromethane. The organic phase is dried over magnesium sulfate and filtered and the filtrate is evaporated. The oil obtained as the evaporation residue is dissolved in 15 ml of ethanol and 50 mg of sodium ethylate are added to the solution. The mixture is boiled for 2 hours and then cooled and the remaining sodium ethylate is decomposed with glacial acetic acid. The solution is evaporated in vacuo to dryness.
Til inddampningsremanensen sættes der 10 ml 5%'s vandig natriumkarbonatopløsning og blandingen ekstraheres med 20 ml diklormetan. Den organiske fase filtreres, filtratet tørres over magniumsulfat og inddampes derefter i vakuum til tørhed. Som inddampningsremanens vindes der 0,30 g af en olie. Denne opløses i 2 ml ætanol, opløsningens pH-værdi indstilles på 6 med saltsur ætanol og det udfældede salt frafiltreres og vaskes først med ætanol og derefter med æter. Efter tørring vindes 0,25 g (78%) af ovennævnte hydroklorid som smelter ved 244°C.To the evaporation residue is added 10 ml of 5% aqueous sodium carbonate solution and the mixture is extracted with 20 ml of dichloromethane. The organic phase is filtered, the filtrate is dried over magnesium sulfate and then evaporated in vacuo to dryness. As the evaporation residue, 0.30 g of an oil is obtained. This is dissolved in 2 ml of ethanol, the pH of the solution is adjusted to 6 with hydrochloric acid ethanol and the precipitated salt is filtered off and washed first with ethanol and then with ether. After drying, 0.25 g (78%) of the above hydrochloride is obtained which melts at 244 ° C.
Eksempel 5 a) 1-(21-Cyanætyl)-2,3,4,6,7,12-hexahydro-IH-indolo[2,3-a] kinolizinium-perklorat 2,24 g (10 mMol) 2,3,4,6,7,12-hexahydroindolo[2,3-a]kinoli-zin opløses i 100 ml diklormetan og til opløsningen sættes der 1,25 g (23 mMol) akrylnitril. Reaktionsblandingen henstår ved stuetemperatur i 2 dage. Derefter fjernes opløsningsmidlet i vakuum, remanensen opløses i 20 ml metanol og opløsningens pH-værdi indstilles på 6 ved hjælp af 70%'s perklorsyre. Krystallerne frafiltreres og vaskes med æter. Der vindes 3,2 g (86 %) af det i overskriften angivne perklorat, det smelter ved 210°C ved sønderdeling.Example 5 a) 1- (21-Cyanethyl) -2,3,4,6,7,12-hexahydro-1H-indolo [2,3-a] quinolizinium perchlorate 2.24 g (10 mMol) 2.3 , 4,6,7,12-Hexahydroindolo [2,3-a] quinoline is dissolved in 100 ml of dichloromethane and 1.25 g (23 mMol) of acrylonitrile are added to the solution. The reaction mixture is left at room temperature for 2 days. Then, the solvent is removed in vacuo, the residue is dissolved in 20 ml of methanol and the pH of the solution is adjusted to 6 by 70% perchloric acid. The crystals are filtered off and washed with ether. 3.2 g (86%) of the title perchlorate is obtained, it melts at 210 ° C when decomposing.
IR-spektrum (i KBr): 3280 (indol-NH), 2280 (CN), 1625, 1550 cm-1 (C=N).IR spectrum (in KBr): 3280 (indole-NH), 2280 (CN), 1625, 1550 cm -1 (C = N).
142851 16 b) 1-(21-Cyanætyl)-1,2,3,4,6/7,12,12b-oktahydroindolo[2,3-a]ki no lizin-hydroklorid 2,50 g (6,6 mMol) af den ifølge afsnit a) fremstillede forbindelse hydrogeneres i 120 ml metanol i nærværelse af 2,0 g palla-dium/aktiv kul. Efter optagelse af den beregnede mængde hydrogen (cirka 25 minutter) frafiltreres katalysatoren og filtratet inddampes i vakuum. Til remanensen sættes der 30 ml vand. Blandingen gøres alkalisk med vandig natriumkarbonatopløsning og ekstraheres derefter med diklormetan. De forenede diklormetanfaser tørres, filtreres og befries i vakuum ved destillation for opløsningsmiddel.B) 1- (21-Cyanethyl) -1,2,3,4,6 / 7,12,12b-octahydroindolo [2,3-a] quilizine hydrochloride 2.50 g (6.6 mMol) ) of the compound prepared according to paragraph (a) is hydrogenated in 120 ml of methanol in the presence of 2.0 g of palladium / activated carbon. After taking up the calculated amount of hydrogen (about 25 minutes), the catalyst is filtered off and the filtrate is evaporated in vacuo. Add 30 ml of water to the residue. The mixture is made alkaline with aqueous sodium carbonate solution and then extracted with dichloromethane. The combined dichloromethane phases are dried, filtered and freed in vacuo by solvent distillation.
Den vundne olie opløses i 10 ml ætanol og opløsningen syrnes med saltsur metanol til pH 6. Bundfaldet frafiltreredes, vaskedes med æter og tørredes derefter. Der vindes 1,5 g (72%) af det i overskriften angivne hytdroklorid. Saltet smelter under sønderdeling ved 178°C.The obtained oil is dissolved in 10 ml of ethanol and the solution is acidified with hydrochloric acid methanol to pH 6. The precipitate is filtered off, washed with ether and then dried. 1.5 g (72%) of the title hydrochloride is obtained. The salt melts with decomposition at 178 ° C.
IR-spektrum (i KBr): 1610 (aromatisk svingning), 2235 (CN). Massespektrum m/e (%): 279(45,M), 272(38), 239(100), 197(14), 170(11), 169(13).IR spectrum (in KBr): 1610 (aromatic oscillation), 2235 (CN). Mass Spectrum m / e (%): 279 (45, M), 272 (38), 239 (100), 197 (14), 170 (11), 169 (13).
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DK273478A DK142851B (en) | 1978-06-16 | 1978-06-16 | Analogous process for the preparation of octahydroindolo (2,3-a) quinolizines or acid addition salts thereof. |
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DK273478A DK142851B (en) | 1978-06-16 | 1978-06-16 | Analogous process for the preparation of octahydroindolo (2,3-a) quinolizines or acid addition salts thereof. |
DK273478 | 1978-06-16 |
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