NO123948B - - Google Patents

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Publication number
NO123948B
NO123948B NO163240A NO16324066A NO123948B NO 123948 B NO123948 B NO 123948B NO 163240 A NO163240 A NO 163240A NO 16324066 A NO16324066 A NO 16324066A NO 123948 B NO123948 B NO 123948B
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Norway
Prior art keywords
acid
octane
pyridyl
pyridylbicyclo
bicyclo
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Application number
NO163240A
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English (en)
Inventor
Gregory W Adelman
J C Kauer
Original Assignee
Du Pont
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Publication date
Priority claimed from US467705A external-priority patent/US3367941A/en
Application filed by Du Pont filed Critical Du Pont
Publication of NO123948B publication Critical patent/NO123948B/no

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/40—Acylated substituent nitrogen atom
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    • A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
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    • A47G9/00—Bed-covers; Counterpanes; Travelling rugs; Sleeping rugs; Sleeping bags; Pillows
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
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Description

Analogifremgangsmåte til fremstilling av antidepressivt virkspmme 4-pyridylbicyclo-[2, 2 , 2} -
octan-l-aminer eller salter derav.
Foreliggende oppfinnelse angår en anålogifremgahgsmåte til fremstilling av hittil ukjente antidepressivt virksomme 4-pyridylbicyclo-[ 2, 2,2]-octan-l-aminer med den i kravets innledning angitte generelle formel, hvor R og R har de angitte betydninger, eller salter derav.
Forbindelsenes antidepressive virkning fremgår av deres ev-ne til å antagonisere -tetrabenzain-indusert sedasjon hos mus, til å potensiere norépinéfrih-pressorvirkningen hos ganglionblokkerte anesthetiserte hunder, og til å antagonisere fenethylamin-pressorvirkningen hos ganglionblokkerte, anesthetiserte hunder. Sterkest anti-depressiv virkning har forbindelser hvor R og R1" er hydrogen.
Som eksempler på syrer med hvilke forbindelsene kan omdannes til salter skal nevnes saltsyre, svovelsyre, fosforsyre, eddiksyre, ravsyre, adipinsyre, propionsyre, vinsyre, citronsyre og carbonsyre. De foretrukne salter er slike med anioner avledet av saltsyre, eddiksyre og ravsyre.
De ved fremgangsmåten ifolge oppfinnelsen fremstillede frie aminer er i alminnelighet farvelose krystallinske, faste stof-fer som er opplpselige i polare organiske opplosningsmidler. De er moderat basiske og er i denne henseende sammenlignbare med alkylami-nene. Saltene er som regel farvelose, hoytsmeltende krystallinske materialer som er særdeles oppløselige i vann og uopploselige i organiske opplosningsmidler.
Fremgangsmåten ifolge oppfinnelsen er kjennetegnet ved det som er angitt i kravets karakteriserende del.
Til fremstilling av utgangsmaterialet kan man redusere en 4-pyridylbicyclo-[2,2,2]-oct-2^en-lrCarboxylsyre eller ester ved rys ting i hydrpgenatmosfære under anvendelse av en platinakatalysa-tor. Oppldsningsmidlet for denne hydrogenéring er en vandig syre-opplosning.
Det ved denne reaksjon fremkomne produkt,. 4-pyridiy-bicyc-lo-[2,2,2]-octan-l-carboxylsyreethylester kan omdannes til det onskede amin på flere forskjellige måter. Den kan hydrolyseres til den tilsvarende carboxylsyre,og denne underkastes Schmidt's reaksjon med natriumazid i en blanding av konsentrert svovelsyre og kloroform; eller esteren kan omdannes med hydrazinhydrat til dannelse av det tilsvarende hydrazid som derpå, fortrinnsvis ved O - 5°C, behandles med natriumnitrit i fortynnet eddiksyreopplosning for å gi azidet, som efter opplosning i f.eks. toluen eller xylen oppvarmes og hydrolyseres til dannelse av aminet (Curtius' reaksjon); hydrolysen skjer fortrinnsvis ved tilsetning av methanol under tilbakelop med saltsyre eller annen vandig mineralsyre. Man kan også gå frem på den måte at esteren omsettes med hydroxylamin til dannelse av den tilsvarende hydroxamsyre; hydroxamsyren underkastes en Lossen-omgruppering til dannelse av vedkommende amin; herunder skjer pyrolysen eventuelt i nærvær av thionylklorid eller eddiksyreanhydrid. 4-pyridylbicyclo-[2,2,2]-octari-1-aminet kan omdannes til et morioalkyl- eller dialkyl-derivat på flere forskjellige måter. Hvis aminet omsettes med formaldehyd og maur syre, får mari det tilsvarende dimethylaminderivat.
Aminet kan omsettes med maiar syre i' nærvær av eddiksyreanhydrid til dannelse av formylderivatet som kan reduseres til mono-methylaminet ved anvendelse åv lithiumaluminiumhydrid. Hoyere al-kylderivater kan fremstilles ved acylering av aminogruppen med det angjeldende syreklorid efterfulgt av reduksjon med lithiumaluminiumhydrid. Ved en annen fremgangsmåte ved alkylering kan man behandle det primære amin i et vandig basisk medium med et passende alkyler-ingsmiddel, som al-kylhalogenid eller alkylsulfat.
De ved fremgangsmåten fremstillede forbindelser med den generelle formel I har dibasisk karakter og kan omdannes til mono-eller disure salter. F.-eks. kan monohydrokloridet fremstilles ved opplosning av basen i et passende opplosningsmiddel, som ethanol og tilsetning av en ekvivalent tort hydrogenklorid. Hvis der tilsettes to ekvivalenter, dannes et dihydroklorid. •' .
Fremgangsmåten ifolge oppfinnelsen skal i det folgende be-lyses nærmere ved noen eksempler i hvilke angivelser deler og pro-senter alltid er vektdeler og vektprosenter med mindre annet uttryk-, kelig er angitt.
Eksempel i
A. Utgangsmateriale
En opplosning av lOO g ■4-(4-pyridyl)-bicyclo-[2,2,2]-oet.-2-en-1-carboxylsyreethylester i 300 ml vann og lOO ml eddiksyre rystes med 7 g 4 %'s platina på trekull i hydrogenatmosfære inntil hyd-rogenabsorpsjonen opphorer. Opplbsningen filtreres og inndampes til tbrrhet. Residuet opplbses i vann, og opplbsningen gjbres basisk ved tilsetning av 40 %'s vandig natriumhydroxyd. Produktet utskiller sig som hvite krystaller og filtreres og vaskes med vann. Utbyt-tet er 95 g, smp. 83 - 88°C. Dette produkt er 4-(4-pyridyl)-bicyclo-[2,2,2]-octan-l-carboxylsyreethylester. 90 g av denne ester kokes under tilbakelbp i 15 timer i 2000 ml 2N natriumhydroxyd. Efter avkjbling til romtemperatur tilsettes et lite volum 2N saltsyre. : Produktet utskilles som fine krystaller og filtreres og vaskes med vann. IJtbyttet er 69 g, smp. 385 - 387°C {spaltning, forseglet kapilTar). Ytterligere materiale kan utvinnes ved konsentrering av. filtratet. Denne forbindelse, 4-(4-pyridyl)-bicyclo-[2 j 2, 2-3-octan-l-carboxylsyre er uopplbselig i de fleste opplbsningsmidlér, men kan opplbses i vandig syre eller base og kan utvinnes ved regulering av pH-verdien til det isoelektri-ske punkt.
B. Fremgangsmåte ifolge oppfinnelsen
En opplosning av 60 g av syren i 500 ml konsentrert svovelsyre og 800 ml kloroform omrores ved 40 - 50°C, mens der langsomt tilsettes 30 g natriumazid. Reaksjonen er eksoterm, og der utvikles gass. Efter ,at. hele mengden, av natriumazidet er tilsatt holdes reaksjonsblandingen på 45°C i 1 time. Blandingen avkjoles, helles på is, og kloroformskiktet fraskilles og kastes. Det vandige skikt avkjoles og gjores sterkt basisk, hvorefter produktet ekstraheres med ether. Etherekstrakten torkes med kaliumhydroxyd-kaliumcarbonat-blanding. Etheren fjernes ved vakuuminndampning og gir 4-(4-pyridyl)-bicyclo-[2,2,2]-octan-l-amin med smp. 84 - 90°C. Denne forbindelse kan sublimeres til hvite krystaller med smp. 90 - 93°C.
For overforing av aminet til dihydrokloridet opploses det i absolutt alkohol, og torr hydrogenkloridgass tilsettes inntil der er et svakt overskudd. Produktet utskilles som et krystallinsk fast stoff med smp. over 350°C.
Eksempel 2
A. Utgangsmateriale
En opplosning av 128,5 g (0,50 mol) 4-(3-pyridyl)-bicyclo [2,2,2]-oet.-2-en-l-carboxylsyreethylester i 300 ml vann og lOO ml eddiksyre rystes med 8 g 4 %'s platina/trekull i hydrogenatmosfære inntil der ikke absorberes mere hydrogen. Opplbsningen filtreres, konsentreres tii tbrrhet, fortynnes med vann og gjores basisk ved tilsetning av 40 %'s vandig natriumhydroxyd. Den basiske opplosning ekstraheres med ether, og etherekstrakten tbrres over magnesiumsulfat. Etheren fjernes ved vakuuminndampning til dannelse av 4-(3-pyridyl) -bicyclo-[2,2,2]-octan-l-carboxylsyreethylester, smp. 88-89°C.
129,5 g (0,5 mol) 4-(3-pyridyl)-bicyclo-[2,2,2]-octan-1-carboxylsyreethylester kokes under tilbakelbp i 2000 ml 2N natrium-hydroxydopplbsning i 15 timer. Efter avkjbling til romtemperatur tilsettes et like stort volum 2N saltsyre, og produktet utskilles som et krystallinsk fast stoff. Dette består av 4-(3-pyridyl)_-bi-cyclo-[2,2,2]-octan-l-carboxyisyre, smp.286,5 - 287,5°C.
B. Fremgangsmåte ifolge oppfinnelsen
En opplosning av 115,5 g (0,50 mol) 4-(3-pyridyl)-bicyc-lo- [ 2, 2,2]-octan-l-carbbxylS'yre i en blanding av lOO ml konsentrert svovelsyre og 1600 ml kloroform omrores ved 40 - 50°C mens der langsomt tilsettes■65 g (1,0 mol) natriumazid. Efter at alt natrium azid er tilsatt, holdes reaksjonsblandingen på 45°C i 1 time. Blandingen avkjoles, helles på is, og kiorofermlaget fraskilles og kastes. Det vandige skikt avkjoles og gjores sterkt basisk, og produktet ekstraheres over i ether. Etherekstrakten torres over kaliumhydroxyd, filtreres og mettes med tort hydrogenklorid. Dihydrokloridet av 4-(3-pyridyl)-bicycXo-[2,2,2]-octan-l-amin.utskilles som et krystallinsk stoff med smp. 349 - 352°C (spaltning).
Eksempel 3
A. Utgangsma teriale
En opplosning av 128,5 g (0,50 mol) 4-(2-pyridyl)-bicyc-lo- [2,2,2]-oct-2-en-1-carboxylsyreethylester i en blanding av 300 ml vann og 100 ml eddiksyre rystes med 8 g 4 %'s platina/trekull i hydrogenatmosfære inntil der ikke absorberes mere hydrogen. Oppløsnin-gen filtreres, konsentreres til torr.het, fortynnes med vann og gjores basisk ved tilsetning av 40 %'s vandig natriumhydroxyd. Den basiske opplosning ekstraheres med ether, og etherekstrakten torres over magnesiumsulfat. Etheren fjernes ved vakuuminndampning til dannelse av 4-(2-pyridyl)-bicyclo-{2,2,2]-octan-1-carboxylsyreethyles ter, smp. 52 - 54°C.
129,5 g (0,5 mol 4-(2-pyridyl)-bicyclo-[2,2,2]-octan-l-carboxylsyreethylester kokes under tilbakelbp i 2000 ml 2N natrium-hydroxydopplasning i 15 timer. Efter avkjoling til romtemperatur tilsettes der et like stort volum.2N saltsyre, og produktet utskilles som et krystallinsk fast stoff. Det erholdte produkt er 4-(2-pyridyl)-bicyclo-[2,2,2]-l-carboxylsyre, smp. 226 - 228°C.
B. Fremgangsmåte ifolge oppfinnelsen
En opplosning av 115,5 g (0,50 mol) 4-(2-pyridyl)-bicyc-lo- [2,2,2]-octan-l-carboxylsyre i en blanding av lOOO ml konsentrert svovelsyre og 1600 ml kloroform omrores ved 40 - 50°C, mens der langsomt tilsettes 65 g (0,1 mol) natriumazid.- Efter at alt natriumazid er tilsatt, holdes reaksjonsblandingen på 45°C i 1 time. Blandingen avkjoles og helles på is, og kloroformskiltet fraskilles og kastes.
Det vandige skikt civkjbles og gjores sterkt basisk, og produktet ekstraheres over i ether. Etherekstrakten torres over kaliumhydroxyd, filtreres og mettes med torr hydrogenkloridgass. Dihydrokloridet av 4-(2-pyridyl)-bicyclo-[2,2,2]-octan-l-amin utskilles som et krystallinsk fast stoff med smp. 357°C (spaltning).
Eksempel 4
En ethanolopplosning av O,10 ml 4-(4-pyridyi)-bicyclo-[ 2,2, 2]-octan-l-amin, fremstillet som angitt i eksempel 1, omrores mens der,tilsettes O,IO mol tort hydrogenklorid i ethanol. Det bunn-fall som utskiller seg filtreres, vaskes med ethanol og torres. Det består av 4-(4-pyridyl)-bicyclo-[2, 2, 2]-octan-l-aminhydrokloirid med smp. 385 - 387°C (spaltning).
Eksempel 5
En ethanolopplosning av 0,IO mol 4-(4-pyridyl)-bicyclo-[2,2,2]-octan-l-amin, fremstillet som angitt i eksempel 1, omrores,
og der tilsettes O,IO mol eddiksyre. Opplosningen konsentreres ved vakuuminndampning og fortynnes med ethylether. Produktet krystalliserer og filtreres, vaskes med ethylether og tbrres. Det består av 4-(4-pyridyl)-bicyclo-[2,2,2]-octan-1-amin-monoacetat med smp. 206 - 209°C.
Eksempel 6
En opplosning av 0,10 mol 4-(2-pyridyl)-bicyclo-[2,2,2]-octan-l-amin, fremstillet som angitt i eksempel 3, i absolutt ethanol omrores mens der tilsettes O,10 mol ravsyre. Opplosningen inndampes i vakuum og gir den krystallinske forbindelse 4-(2-pyridyl)-bicyclo-[2,2,2]-octan-l-amin-monosuccinat med smp. 234 - 235°C.
Eksempel 7
N-methyl-4-(3-pyridyl)-bicyclo-[2,2,2]-octan-1-amin fremstilles på folgende måte: en suspensjon av 3,4 g 4-(3-pyridyl)-bi-cyclo- [2,2,2J-octan-l-amin fremstillet som angitt i eksempel 2, i 50 ml triethylamin avkjoles til -5°C, og der tilsettes langsomt 1,4 ml methylklorf ormiat. Efter omroring i 2 timer ved isbadtemparatur helles blandingen i 200 ml vann; triethylaminet' fjernes under nedsatt trykk. Det hvite faste stoff filtreres og vaskes med vann. Efter rensning av dette produkt smelter det ved 201 - 202°C. Det består av 4-(3-pyridyl)-bicyclo-[2,2,2]-octan-1-carbamidsyremethyles ter.
En opplosning av 1„2g av denne forbindelse i 100 mo tetrahydrofuran omrores mens der tilsettes 1,0 g lithiumaluminiumhydrid. Blandingen avkjoles under tilbakelbp i 4 1/2 time. Blandingen oppld-ses i ether behandlet med torr HCl-gass, hvorved man får hydroklorid-et av forbindelsen som et hvitt salt med smp. 287 - 291°C.
Eksempel 8
N,N-dimethyl-4-(3-pyridyl)-bicyclo-[2,2,2]-octan-l-amin fremstilles på folgende måte:, en blanding av 5, 6. g 4-(3-pyridyl)-bicyclo-[2,2,2]-octan-l-amin, fremstillet som angitt i eksempel 2, 20 ml 90 %'s maursyre og 16 ml 35 %'s vandig formaldehyd oppvarmes på dampbad i 28 timer. Opplosningen heldes derpå på is, gjores basisk med natriumhydroxyd og ekstraheres med benzen. Benzenekstrak-ten torres og konsentreres til en lysegul olje. Denne opploses i ether og behandles med HC1, hvorved man får dihydrokloridet med smp. 287 - 288°C.
Eksempel 9
En suspensjon av 20 g 4-(4-pyridyl)-bicyclo-[2,2,2]-octan-l-carboxylsyreethylester i 300 ml hydrazinhydrat kokes under tilbakeldp natten over, ca. 15 timer. Blandingen avkjoles og fortynnes med ether, hvorved man får et hvitt krystallinsk fast stoff med smeltepunkt 200 - 203°C. Det omkrystalliseres fra ethanol og gir et produkt med smeltepunkt 202 - 204°C; det består av 4- (4-pyridyl.) -bi-cyclo- [2,2,2]-octan,1-carboxylsyrehydrazid.
En suspensjon av 14 g av dette hydrazid "omrores i 150 ml vann, og der tilsettes IO ml konsentrert HC1 inntil pH-verdien er 2,0. Det faste stoff opploses herved.
Opplosningen avkjoles til O - 5°C, og der tilsettes en opplosning av 4,3 g natriumnitrit i 14 ml vann i lopet av 1/2 time. Der tilsettes 12,5 ml triethylamin; ved tilsetningens avslutning er pH-verdien 11, og der kan utskilles et hvitt fast stoff. Der tilsettes ether for å opplose det faste stoff, og vannet ekstraheres flere gan-ger med ether. Etherekstrakten torres over magnesiumsulfat og filtreres, og der tilsettes lOO ml tort toluen. Etheren avdestilleres og toluenopplosningen kokes under tilbakelop inntil der ikke utvikles ytterligere nitrogen. Der tilsettes en blanding av 50 ml torr methanol inneholdende O,5 g 1,4-diazobicyclo-[2,2,2]-octan, og hele blandingen kokes under tilbakelop i 3 tims r. Derefter fjernes opp-losningsmidlene under vakuum, og produktet, methylurethanet, kan hydrolyseres uten ytterligere rensning.
Det ovennevnte résiduum opploses i 150 ml n-butanol, og der tilsettes 25 g kaliumhydroxyd. Blandingen kokes under tilbakelop i 18 timer, fortynnes med vann Og surgjores med konsentrert saltsyre, hyorefter n-butanolen fjernes ved destillasjon under vakuum. Vannet gjores sterkt basisk med kaliumhydroxyd, og der ekstraheres derpå med en blanding av diethylether og tetrahydrofuran. Ekstraktentorres over en blanding av kaliumcarbonat og kaliumhydroxyd, filtreres og 'konsentreres. Det derved erholdte produkt er 4-(4-pyridyl) -bicyclo- [2, 2, 2]-octan-l-amin, som kan sublimeres og gir hvite krystaller med smeltepunkt 90 - 93<?>C.
Eksempel IQ
A. Utgangsnrateriale
En suspensjon av 23,1 g 4-(3-pyridylJ-bicyclo--[2, 2, 2]-octan-l-carboxylsyre i 200 ml vann omrores mens der tilsettes 5,6 g kaliumhydroxyd. Den resulterende opplosning konsentreres under vakuum og gir kaliumsaltet av 4-(3-pyridyl)-bicyclo-[2,2,2]-octan-1-carboxylsyre. Dette torres i vakuum ved lO0°C for å fjerne alt vann. Saltet suspenderes i benzen, og der tilsettes 15 g oxalylklorid, hvorpå blandingen kokes under tilbakelop inntil der- ikke lenger utvikles gass. Derefter konsentreres benzenopplosningen, hvorved der fremkommer 4-(3-pyridyl)-bicyclo-[2,2,2]-octan-1-carboxylsyreklorid. Dette tilsettes til en blanding av 15 g hydroxylaminacetat i 200 ml tort pyridiri, idet temperaturen foldes på 5 - 10°C. Derefter omrores blandingen ved romtemperatur i 3 timer. Blandingen heldes på is og vann, og der tilsettes syre inntil produktet krystalliserer. Det består av 4-(3-pyridyl)-bicyclo-[2,2,2]-octan-1-hydroxamsyre.
B. Fremgangsmåte ifolge oppfinnelsen
En opplosning av 5 g ketondimethyl i 10 ml ethylacetat tilsettes dråpevis til en suspensjon av 12 g 4-(3-pyridyl)-bicyclo-[2,2,2]-octan-l-hydroxamsyre i 20 ml ethylacetat ved romtemperatur. Blandingen oppvarmes til 50°C il time, opplosning smidlet fjernes ved destillasjon under vakuum og residuet krystalliseres. Dette produkt pyrolyseres i et loddrett ror av ildfast glass pakket med skår av ildfast glass, idet pyrolysen skjer i nitrogenstrom under vakuum og ved 300 - 400°C. Forbindelsen tilsettes til roret med en hastighet på 0,2 g pr. minutt. Pyrolysatet oppsamles i en kolbe som avkjoles i et bad av fase CO^og aceton.
Det derved erholdte råprodukt tilsettes til 100 ml methanol inneholdende 0,5 g 1,4-diazabicyclp-[2,2,2]-octan, og blandingen kokes under tilbakelop i 3 timer. Opplbsningen konsentreres, og produktet opploses i vandig syre, avfarves med aktivt kull, filtreres og gjores basisk med IO ^6's vandig natriumhydroxyd. Produktet ekstraheres over kloroform, torres ved hjelp av natriumsulfat og konsentreres.
Dette produkt hydrolyseres ved kokning under tilbakelop i 100 ml n-butanol med IS g kaliumhydroxyd i 18 tima:. Den resulterende blanding fortynnes med 300 ml vann, og blandingen surgjores vedtilsetning av konsentrert HC1. Butanolen fjernes ved destillasjon. Derpå gjores det vandige system sterkt basisk med natriumhydroxyd,
og produktet ekstraheres med en blanding av ether og tetrahydrofuran. Ekstrakten torres over en blanding av kaliumcarbonat og kaliumhydroxyd, filtreres og konsentreres tilslutt under redusért trykk. Herved erholdes et fast stoff med smeltepunkt 74 - 76,5°C, som består av 4-(3-pyridyl)-bicyclo-[2,2,2]-oetan-1-amin.

Claims (1)

  1. Analogifremgangsmåte til fremstilling av antidepressivt virksomme 4-pyridylbicyclo-[2,2,2]-octan-1-aminer med den generelle formel
    eller salter derav, i hvilken formel R og R<1>, som er like eller forskjellige, betegner hydrogenatomer, alkylgrupper med 1-4 carbonato-mer eller allylgrupper,karakterisert vedat man a) omsetter den tilsvarende 4-pyridylbicyclo-[2,2,2]-octan-l-carboxylsyre opplost i et opplosningsmiddel og i nærvær av konsentrert svovelsyre med natriumazid for dannelse av det onskede amin, eller b) omdanner en 4-pyridylbicyclo- [2, 2, 2_/-octan-1-carboxylsyre-ester med hydrazinhydrattil dannelse av hydrazider, som ved lav tem-peratur omsettes med natriumnitrit i eddiksyre, hvorefter man opplo-ft ser reaksjonsproduktet, syreazidet, i et iriert opplbsningsmiddel, torrer og oppvarmer inntil nitrogenutviklingen er fullfort og derpå foretar hydrolyse til dannelse av det frie amin, eller c) oppvarmer en 4-pyridylbicyclo-[2,2,2]-octan-l-hydroxamsyre til fremkallelse av pyrolyse og dannelse av det tilsvarende isocyanat som derpå hydrolyseres for dannelse av det frie amin hvorpå man om onsket alkylerer eller dialkylerer 1-aminogruppen med det onskede alkyl- eller allyleringsmiddel inneholdende gruppen R eller R1 eller begge, samt om onsket omdanner den erholdte-forbindelse til et salt ved omsetning med den onskede syre.
NO163240A 1964-06-22 1966-06-01 NO123948B (no)

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US37713264A 1964-06-22 1964-06-22
US46081265A 1965-06-02 1965-06-02
US460820A US3419598A (en) 1964-06-22 1965-06-02 Derivatives of bicyclo[2.2.2]oct-2-ene and process of preparation
US467705A US3367941A (en) 1965-06-28 1965-06-28 4-pyridyl and 4-substituted pyridylbicyclo-[2.2.2]octane-1-amines

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US3419598A (en) 1968-12-31
NL6507979A (no) 1965-12-23
NL144603B (nl) 1975-01-15
DE1468817A1 (de) 1969-01-09
DE1468817B2 (de) 1977-11-17
BE665701A (no) 1965-10-18
SE341850B (no) 1972-01-17
AT278782B (de) 1970-02-10
GB1146848A (en) 1969-03-26
FR5768M (no) 1968-02-05
DK117633B (da) 1970-05-19
BE681987A (no) 1966-12-02
DK131669C (da) 1976-01-19
CH487103A (de) 1970-03-15
GB1066005A (en) 1967-04-19
CH478797A (de) 1969-09-30
DE1620133A1 (de) 1970-03-12
LU51239A1 (no) 1968-03-06
DE1620133B2 (de) 1977-05-12
NL128186C (no) 1900-01-01
LU48884A1 (no) 1965-08-23
IL25880A (en) 1970-05-21
DK131669B (da) 1975-08-18
SE330529B (no) 1970-11-23
NL6607687A (no) 1966-12-05

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