DK163125B - Analogifremgangsmaade til fremstilling af chroman-, thiochroman- eller quinolinderivater - Google Patents

Analogifremgangsmaade til fremstilling af chroman-, thiochroman- eller quinolinderivater Download PDF

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DK163125B
DK163125B DK188683A DK188683A DK163125B DK 163125 B DK163125 B DK 163125B DK 188683 A DK188683 A DK 188683A DK 188683 A DK188683 A DK 188683A DK 163125 B DK163125 B DK 163125B
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dimethyl
ethyl
water
chroman
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Michael Klaus
Peter Loeliger
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Hoffmann La Roche
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D215/04—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/60—Quinoline or hydrogenated quinoline ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
    • C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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    • C07—ORGANIC CHEMISTRY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655363—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a six-membered ring
    • C07F9/655372—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems

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  • Quinoline Compounds (AREA)
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Description

i
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Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte chroman-, thiochroman- eller quinolinderivater med den almene formel I
hvor X betegner 0, S, SO, eller NR^; 5 Ri betegner lavere alkyl, R^ betegner hydrogen eller lavere alkyl, eller salte deraf.
I nærvarende beskrivelse betegner udtrykket "lavere" grupper med op til 6 carbonatomer. Foretrukne lavere grupper indeholder 1-4 10 carbonatomer.
Alkylgrupper kan være forgrenede eller uforgrenede, fx methyl, ethyl, isopropyl eller 2-methylpropyl.
Fremgangsmåden ifølge opfindelsen til fremstilling af forbindelserne med formlen I er ejendommelig ved, at man omsætter en forbindelse med 15 den almene formel II
Η3°ΝχΧ0Η3 A
OCT - 2
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med en forbindelse med den almene formel III
^coor1 XJ 1,1 hvor enten A betegner en triarylphosphoniumethylgruppe med formlen CH3-CH-P[Q]3+Y", hvor Q betegner phenyl, og Y betegner anionen af en organisk eller uorganisk syre, og B betegner formyl; 5 eller A betegner acetyl, og B betegner en dialkoxyphosphinylmethyl-gruppe til dannelse af en forbindelse med den almene formel I, og om ønsket oxiderer svovlatomet i en forbindelse, hvor X betegner S, til dannelse af en sulfoxylgruppe, og en vunden forbindelse, om ønsket, 10 isoleres som et salt deraf.
Af de uorganiske syreanioner Y foretrækkes chlor- og bromionen eller hydrosulfationen, og af de organiske syreanioner foretrækkes tosyloxyionen.
Alkoxygrupperne i B er først og fremmest lavere alkoxygrupper med 1-6 15 carbonatomer, fx methoxy eller ethoxy.
Udgangsforbindelseme med formlen II kan, såfremt fremstillingen deraf ikke er kendt eller beskrevet nedenfor, fremstilles analogt med kendte eller analogt med de nedenfor beskrevne metoder.
Omsætningen mellem forbindelserne med formlerne II og III kan fore-20 tages efter kendte metoder som Wittig- eller Homer-reaktion.
Ved Wittig-reaktionen, dvs. ved anvendelse af en forbindelse med formlen III, hvor A = triarylphosphoniumethyl, omsættes komponenterne i nærværelse af et syrebindende middel, fx i nærværelse af en stærk base, fx butyllithium, natriumhydrid eller natriumsaltet af 3
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dimethylsulfoxid, men først og fremmest i nærværelse af et eventuelt med lavere alkyl substitueret ethylenoxid, fx 1,2-butylenoxid, eventuelt i et opløsningsmiddel, fx i en ether såsom diethylether eller tetrahydrofuran eller i et aromatisk carbonhydrid såsom benzen i et 5 temperaturområde, der ligger mellem stuetemperatur og reaktionsblandingens kogetemperatur.
Ved Horner-reaktionen, dvs. ved anvendelse af en forbindelse med formlen III, hvor B = dialkoxyphosphinylmethyl, kondenseres komponenterne ved hjælp af en base og fortrinsvis i nærværelse af et inert 10 organisk opløsningsmiddel, fx ved hjælp af natriumhydrid i benzen, toluen, dimethylformamid, tetrahydrofuran, dioxan eller 1,2-dimetho-xyalkan, eller ved hjælp af et natriumalkoholat i en alkanol, fx natriummethylat i methanol, i et temperaturområde, der ligger mellem 0°C og reaktionsblandingens kogetemperatur.
15 En forbindelse med formlen I, hvor X betegner S, kan oxideres på i og for sig kendt måde til dannelse af en forbindelse med formlen I, hvor X betegner SO. Oxidationen til en sulfoxidgruppe kan foretages med oxidationsmidler såsom periodater, fx NaJO^, eller med organiske persyrer, fx m-chlorperbenzoesyre. Ved oxidationen med organiske 20 persyrer anvendes ca. ét ækvivalent persyre til dannelse af en sulfoxidforbindelse (X = SO).
Forbindelserne med formlen I kan foreligge i trans- eller cis-form.
Ved fremstillingen forekommer de overvejende i trans-form. Eventuelt forekommende cis-andele kan på i og for sig kendt måde, om ønsket, 25 fraskilles.
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser med formlen I og de fysiologisk tolerable salte deraf er farmakodyna-misk værdifulde forbindelser. De kan anvendes til topisk og systemisk terapi af benigne og maligne neoplasier, af præmaligne læsioner samt 30 til systemisk og topisk profylakse af den nævnte lidelser.
De er endvidere egnede til topisk og systemisk terapi af acne, psoriasis og andre med forøget eller patologisk forandret forhorning forbundne dermatoser, samt af betændelsesagtige og allergiske derma-
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.4 tologiske lidelser. Forbindelserne med formlen I kan endvidere anvendes til bekæmpelse af slimhindesygdomme med betændelsesagtige eller degenerative eller metaplastiske forandringer. I papillomtesten (Europ. J. Cancer bind 10, side 731-737, 1974) har forbindelserne den 5 i tabel I angivne virkning
Tabel I
Forbindelse dosis Forandring af ifølge eksempel (mg/kg) papillomerne (%) 10 1 12.5 - 43 2 50 - 41 3 400 - 35 6 3 - 46
Til behandling af de ovennævnte lidelser administreres de omhandlede 15 forbindelser oralt, hensigtsmæssigt i en dosis til voksne på ca. 1-100 mg/dag, fortrinsvis 5-30 mg/dag. En mulig overdosering kan ytre sig i form af en Vit-A-hypervitaminose og er let at erkende på symptomerne (skældannelse og håraffald).
Dos administreres som enkeltdosis eller fordelt på flere del- 20 doser.
Forbindelserne med formlen I og salte deraf kan derfor anvendes som lægemidler, fx i form af farmaceutiske præparater.
De til systemisk anvendelse tjenlige præparater kan fx fremstilles ved, at en forbindelse med formlen I eller et salt deraf som aktiv 25 bestanddel sættes til ikke-toxiske, inerte, i sig selv i sådanne præparater sædvanlige faste eller flydende bærestoffer.
Midlerne kan administreres enteralt, parenteralt eller topisk. Til enteral applikation kan midlerne fx anvendes i form af tabletter, kapsler, dragéer, sirupper, suspensioner, opløsninger eller 5
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suppositorier. Til parenteral applikation kan midlerne anvendes i form af infusions- eller injektionsopløsninger.
De doseringer, i hvilke præparaterne administreres, kan varieres alt afhængig af anvendelsesmåden og -vejen samt efter patienternes be-5 hov.
Præparaterne kan administreres i én eller flere doser. En foretrukken administrationsform er kapsler med et indhold på ca. 0,5-20 mg aktivstof.
Præparaterne kan indeholde inerte eller farmakodynamisk virksomme 10 tilsætningsstoffer. Tabletter eller granula kan fx indeholde en række bindemidler, fyldstoffer, bærestoffer eller fortyndingsmidler.
Flydende præparater kan fx foreligge i form af en steril, med vand blandbar opløsning. Kapsler kan foruden aktivstoffet indeholde fyldmateriale eller fortykkelsesmiddel. Endvidere kan der forekomme 15 smagsforbedrende tilsætningsstoffer samt de sædvanligvis som konserveringsmidler, stabilisatorer, fugtighedsbevarende midler og emulgeringsmidler anvendte stoffer samt salte til ændring af det osmotiske tryk, puffere og andre tilsætningsstoffer.
De ovenfor omtalte bærestoffer og fortyndingsmidler kan bestå af or-20 ganiske eller uorganiske stoffer, fx af vand, gelatine, lactose, stivelse, magnesiumstearat, talkum, gummi arabicum, polyalkylen-glycoler og lignende. Det er en forudsætning, at alle til fremstillingen af præparaterne anvendte hjælpestoffer er ikke-toxiske.
Til topisk anvendelse bruges aktivstofferne hensigtsmæssigt i form af 25 salver, tinkturer, cremer, opløsninger, lotioner, spraymidler og suspensioner. Der foretrækkes salver og cremer samt opløsninger. De til topisk anvendelse bestemte præparater kan fremstilles ved, at man blander de ved fremgangsmåden ifølge opfindelsen fremstillede produkter som aktiv bestanddel med ikke-toxiske, inerte, til topisk behand-30 ling egnede, i sig selv i sådanne præparater sædvanlige faste eller flydende bærestoffer.
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Til topisk administration anvendes hensigtsmæssigt ca. 0,1-5%'s, fortrinsvis 0,3-2%'s, opløsninger, samt ca. 0,1-5%'s, fortrinsvis ca.
0,3-2%'s, salver eller cremer.
Til præparaterne kan der eventuelt være sat et antioxidationsmiddel, 5 fx tocopherol, N-methyl-7-tocopheramin samt butyleret hydroxyanisol eller butyleret hydroxytoluen.
Fremgangsmåden ifølge opfindelsen belyses nærmere ved nedenstående eksempler: EKSEMPEL 1 10 15,9 g [1-(4,4-dimethyl-6-chromanyl)ethyl]triphenylphosphoniumbromid opvarmes til kogning under tilbagesvaling med 5,5 g 4-ethoxycarbon-ylbenzaldehyd i 150 ml buty lenoxid natten over. Blandingen afkøles, hældes ud på 500 ml methanol/vand (6:4) og ekstraheres tre gange med hexan, og den organiske fase vaskes med vand, tørres over natrium-15 sulfat og inddampes. Der fås 8,1 g af en gullig olie, som renses ved filtrering over silicagel (elueringsmiddel: hexan/ether 9:1). Efter omkrystallisation'af hexan/ether fås 5,7 g ethyl-p-[(E)-2-[4,4-di-methyl-6-chromanyl]propenyl]benzoat i form af farveløse krystaller, smeltepunkt 86-87°C.
20 Det som udgangsmateriale anvendte phosphoniumsalt kan fremstilles på følgende måde: 3,4 g acetylchlorid opløses i 30 ml nitrobenzen, og ved 0-5°C tilsættes der portionsvis 5,7 g aluminiumtrichlorid. Til denne blanding dryppes ved 0-5°C en opløsning af 6,9 g 4,4-dimethyl-chroman 25 i 15 ml nitro-benzen. Efter 1 times omrøring hældes blandingen ud på isvand og ekstraheres med ether, og den organiske fase vaskes med IN NaOH og mættet kogsaltopløsning, tørres over natriumsulfat og inddampes. Den som remanens vundne sorte olie destilleres i høj -vakuum. Der fås 5,1 g 4,4-dimethyl-6-acetylchroman i form af en 30 blålig olie, kogepunkt 110°C/0,02 mm Hg.
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7 20,4 g 4,4-dimethyl-6-acetylchroman opløses i 400 ml methanol, og under isafkøling tilsættes portionsvis 3,3 g natriumborhydrid. Der omrøres natten over ved stuetemperatur, hældes ud på is/vand og ekstraheres med ether. Efter vask med vand, tørring af den organiske 5 fase med natriumsulfat og afdampning af opløsningsmidlet fås 19,4 g af en brun olie, som yderligere kan renses ved filtrering over silicagel (elueringsmiddel: hexan/20% ether). Der fås 18,2 g 4,4-di-methyl-6-(l-hydroxyethyl)chroman i form af en farveløs olie.
6,2 g 4,4-dimethyl-6-(l-hydroxyethyl)chroman opløses i 3 ml absolut 10 ether og 20 ml hexan og tilsættes 3 dråber pyridin. Ved en temperatur på 0-5°C tildryppes langsomt en opløsning af 5,4 g phosphortri,-bromid i 20 ml hexan. Der omrøres i yderligere 3 timer ved 0eC, hældes ud på is og ekstraheres med ether. Den organiske fase vaskes med fortyndet natriumhydrogencarbonatopløsning og vand, tørres over 15 natriumsulfat og inddampes. Der fås 4,5 g 4,4-dimethyl-6-(1-brometh-yl)chroman i form af en rødlig olie. Den omdannes uden yderligere rensning til phosphoniumbromidet.
4.6 g 4,4-dime thyl-6-(1-bromethyl) chroman opløses i 40 ml xylen og tilsættes 5,3 g triphenylphosphin. Blandingen opvarmes natten over 20 til 100°C og afkøles, og de udfældede krystaller sugefiltreres og vaskes med hexan. Til yderligere rensning kan phosphoniumsaltet opløses i methylenchlorid og på ny udfældes ved tilsætning af ethylacetat. Der fås 3,5 g [l-(4,4-dimethyl-6-chromanyl)ethyl]tri-phenylphosphoniumbromid som farveløse krystaller, smeltepunkt 142-25 148°C.
EKSEMPEL 2 2.6 g af en 50%'s dispersion af natriumhydrid i mineralolie vaskes tre gange med pentan, tørres i vakuum og suspenderes i 100 ml dimethylformamid. Ved stuetemperatur tildryppes en opløsning af 16,4 30 g diethyl-4-ethoxycarbonyl-benzylphosphonat i 100 ml dimethylformamid. Efter 30 minutters omrøring ved stuetemperatur tildryppes en opløsning af 10 g 3,4-dihydro-4,4-dimethyl-2H-l-benzothiopyran-6-ylmethylketon i 80 ml dimethylformamid, og der opvarmes derefter i 2,5 time til 70°C. Efter afkøling hældes der ud 8
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på isvand, syrnes med 2N saltsyre og ekstraheres med ether. Den organiske fase vaskes flere gange med vand, tørres og inddampes. Der fås en gul olie, som efter chromatografi på silicagel (elueringsmiddel: hexan/ethylacetat =4:1) og krystallisation af 5 hexan giver 9,8 g ethyl p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-l-benzothiopyran-6-yl)propenyl]benzoat i form af svagt gullige krystaller, smeltepunkt 91-92°C.
EKSEMPEL 3 4,0 g ethyl p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-l-benzothiopyran-10 6-yl)propenyl]benzoat opløses i 100 ml chloroform. Under omrøring tildryppes langsomt ved 0-5°C en opløsning af 2,5 g m-chlorper-benzoesyre (ca. 90%) i 100 ml chloroform, og der efteromrøres natten over ved 0-5°C. Reaktionsblandingen fortyndes med chloroform, vaskes to gange med fortyndet sodaopløsning og vand, tørres og inddampes.
15 Efter filtrering af råproduktet over silicagel (elueringsmiddel: hexan/ethylacetat = 1:2) og krystallisation af hexan/ethylacetat 2,8 g ethyl p-[(E)-2-(3',4'-dihydro-4',4'-dimethyl-2'H-l'-benzo-thiopyran- 6'-yl)propenyl]benzoat-l'-oxid, smeltepunkt 97-99eC.
EKSEMPEL 4 20 I analogi med eksempel 1 fås ud fra [1-(4,4-dimethyl-6-thiochroman-yl) ethyl ] triphenylphosphoniumbromid og 4-ethoxycarbonylbenzaldehyd ethyl p- [ (E) -2- [4,4-dimethyl-6-thiochromanyl]propenyl]benzoat, smeltepunkt 9l-92eC.
Det som udgangsmateriale anvendte phosphoniumsalt kan fremstilles ud 25 fra 4,4-dimethylthiochroman i analogi med den i afsnit 2-4 i eksempel 1 beskrevne måde.
EKSEMPEL 5 I analogi med eksempel 1 fås ud fra l-(4,4-dimethyl-l,2,3,4-tetrahy-dro-6-quinolinyl]ethyl]triphenylphosphoniumbromid og 4-30 ethoxycarbonylbenzaldehyd ethyl p-[(E)-2-(4,4-dimethyl-l,2,3,4-tetrahydro-6-quinolinyl]propenylJbenzoat.
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Det som udgangsmateriale anvendte phosphoniumsalt kan fremstilles ud fra 4,4-dimethyl-l,2,3,4-tetrahydroquinolin i analogi med den i afsnit 2-4 i eksempel 1 beskrevne måde.
EKSEMPEL* 6 5 I analogi med eksempel 1 fås ud fra [l«(l,4,4-trimethyl-l,2,3,4-tetra-hydro-6-quinolinyl)ethyl]triphenylphosphoniumbromid og 4-ethoxycarbonylbenzaldehyd ethyl p-[(E)-2-(l,4,4-trimethyl-l,2,3,4-tetrahydro-6-quinolinyl]propenyl]benzoat, smeltepunkt 100-1010C.
Det som udgangsmateriale anvendte phosphoniumsalt kan fremstilles ud 10 fra 1,4,4-trimethylquinolin i analogi med den i afsnit 2-4 i eksempel 1 beskrevne måde.
EKSEMPEL A
Kapsler til oral administration kan have følgende sammensætning:
Pr. kapsel 15 Forbindelse med formlen I 0,5 mg
Voksblanding 50,5 mg
Vegetabilsk olie 98,9 mg
Trinatriumsalt af ethylendiamintetra-eddikesyre 0,5 mg
20 EKSEMPEL B
En salve kan have følgende sammensætning:
Forbindelse med formlen I 0,2 g
Cetylalkohol 2,7 g
Uldfedt 6,0 g 25 Vaseline 15,0 g
Destilleret vand q.s. ad 100,0 g
DK 163125B
10 EKSEMPEL 7 74.5 mg natriumhydrid (50%'s i mineralolie) vaskes med absolut pen-tan, tørres i vandstrålevakuum og suspenderes i 5 ml absolut dime thylformamid. Ved stuetemperatur tildryppes en opløsning af 465 mg 5 diethyl-4-ethoxycarbonyl-benzylphosphonat i 5 ml absolut dimethyl-formamid. Efter 10 minutters omrøring tilsættes en opløsning af 410 mg 6-acetyl-l,2,3,4-tetrahydro-l,4,4-trimethyl-quinolin i 5 ml dimethylformamid, og der opvarmes i 1 time til 706C og derefter i yderligere 2 timer til 90°C. Efter afkøling hældes reaktionsblan-10 dingen ud i is, ekstraheres flere gange med ether, vaskes med vand, tørres over natriumsulfat og inddampes. Efter chromatografi af råproduktet på silicagel (elueringsmiddel: hexan/ether =4:1) fås ethyl p-[(E)-2-(l,2,3,4-tetrahydro-l,4,4-trimethyl-6-quinolinyl)propenyl]benzoat i form af bleggule krystaller, 15 smeltepunkt 100-101°C.
Det som udgangsmateriale anvendte 6-acetyl-l,2,3,4-tetrahydro-l,4,-4-trimethyl-quinolin kan fremstilles på følgende måde: 21.5 g 3,4-dihydro-l,4,4-trimethyl-2(lH)-quinolinon opløses i 43 g carbondisulfid og tilsættes 85 g aluminiumchlorid. Under isafkøling 20 og kraftig omrøring tildryppes langsomt 17,8 g acetylchlorid.
Derefter opvarmes der til kogning under tilbagesvaling i 1 1/2 time, afkøles og tilsættes forsigtigt isvand. Der ekstraheres tre gange med ethylacetat, vaskes med vand, tørres og inddampes. Den således vundne brunlige olie filtreres over silicagel (elueringsmiddel: 25 hexan/ethylacetat = 2:1) og omkrystalliseres derefter af hexan/ethylacetat. Der fås 19,5 g 6-acetyl-3,4-dihydro-l,4,4-trimethyl-2(lH)-quinolinon i form af farveløse krystaller, smeltepunkt 75-77°C.
5,0 g 6-acetyl-3,4-dihydro-l,4,4-trimethyl-2(lH)-quinolinon opløses i 30 200 ml benzen, tilsættes 2,1 g ethylenglycol og nogle krystaller p- toluensulfonsyre og koges derefter i 5 timer under fraskillelse af vand. Efter afkøling fortyndes der med ethylacetat, vaskes med fortyndet natriumhydrogencarbonatopløsning, tørres og inddampes. Der fås 5,6 g 3,4-dihydro-l,4,4-trimethyl-6-(2-methyl-l,3-dioxolan-2-
DK 163125B
11 yl)-2-(lH)-quinolinon i form af en farveløs olie, som størkner ved henstand i køleskab, smeltepunkt 81-83eC. Forbindelsen anvendes til næste trin uden yderligere rensning.
0,14 g lithiumaluminiumhydrid suspenderes i 10 ml absolut ether, og 5 ved stuetemperatur tildryppes en opløsning af 1,0 g 3,4-dihydro- 1,4,4-crimetyl-6-(2-methyl-1,3-dioxoloan-2-yl)-2(IH)-quinolinon i 15 ml absolut tetrahydrofuran. Efter 2 timers omrøring ved stuetemperatur dryppes under afkøling isvand langsomt til reaktionsblandingen, der ekstraheres tre gange med ethylacetat, og 10 den organiske fase vaskes med vand, tørres og inddampes. Den således vundne brunlige olie opløses i 10 ml tetrahydrofuran og omrøres i 1 1/2 time ved stuetemperatur efter tilsætning af 5 ml IN svovlsyre.
Derefter hældes blandingen ud på isvand, indstilles på alkalisk reaktion ved tilsætning af IN natriumhydroxidopløsning og ekstraheres 15 med ethylacetat. Den organiske fase vaskes med vand, tørres og inddampes. Dette råprodukt renses yderligere ved chromatografi på silicagel (elueringsmiddel: hexan/ethylacetat = 9:1), og der fås 460 mg 6-acetyl~l,2,3,4-tetrahydro-l,4,4-trimethyl-quinolin i form af en grønlig, viskos olie.

Claims (1)

  1. 5 R·^· betegner lavere alkyl, betegner hydrogen eller lavere alkyl, eller salte deraf, kendetegnet ved, at man omsætter en forbindelse med den almene formel II H3C>. ^0Η3 Cct " 10 med en forbindelse med den almene formel III ^^^^COOR1 JTJ 1,1 DK 163125 B hvor rA og X har den ovenfor anførte betydning, og enten Å betegner en triarylphosphoniumethylgruppe med formlen CH3-CH-PfQjj^Y*, hvor Q betegner phenyl, og Y betegner anionen af en organisk eller uorganisk syre, og B betegner formyl; 5 eller A betegner acetyl, og B betegner en dialkoxyphosphinylmethyl-gruppe; til dannelse af en forbindelse med den almene formel I, og om ønsket oxiderer svovlatomet i en forbindelse, hvor X betegner S, til dannelse af en sulfoxylgruppe, og en vunden forbindelse, om ønsket, 10 isoleres som et salt deraf.
DK188683A 1982-05-12 1983-04-27 Analogifremgangsmaade til fremstilling af chroman-, thiochroman- eller quinolinderivater DK163125C (da)

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CH2956/82A CH651034A5 (de) 1982-05-12 1982-05-12 Chroman-, thiochroman- oder 1,2,3,4-tetrahydrochinolinderivate und ihre verwendung als arzneimittel-wirkstoffe.
CH295682 1982-05-12

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US4788213A (en) 1988-11-29
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AT380244B (de) 1986-04-25
IE55264B1 (en) 1990-07-18
DK163125C (da) 1992-06-09
ZA833215B (en) 1984-02-29
IT1212739B (it) 1989-11-30
DE3316932C2 (da) 1992-07-02
CH651034A5 (de) 1985-08-30
NL8301661A (nl) 1983-12-01
US4678793A (en) 1987-07-07
PH23005A (en) 1989-02-24
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