DK142949B - ANALOGY PROCEDURE FOR PREPARATION OF 8-OXO2,3,5,8-TETRAHYDRO-FURO (2,3-G) QUINOLIN-7-CARBOXYLIC ACID DERIVATIVES - Google Patents

ANALOGY PROCEDURE FOR PREPARATION OF 8-OXO2,3,5,8-TETRAHYDRO-FURO (2,3-G) QUINOLIN-7-CARBOXYLIC ACID DERIVATIVES Download PDF

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DK142949B
DK142949B DK300076AA DK300076A DK142949B DK 142949 B DK142949 B DK 142949B DK 300076A A DK300076A A DK 300076AA DK 300076 A DK300076 A DK 300076A DK 142949 B DK142949 B DK 142949B
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furo
carboxylic acid
tetrahydro
quinoline
oxo
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DK300076A (en
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R Albrecht
H J Kessler
E Schroeder
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Schering Ag
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems
    • C07D491/044Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

142949142949

Opfindelsen angår en analogifremgangsmåde til fremstilling af hidtil ukendte 8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]qui= nolin-7-carboxylsyrederivater med den almene formel IThis invention relates to an analogous process for the preparation of novel 8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid derivatives of the general formula I

0 I1 5 hvori R"^ betyder en umættet, ligekædet eller forgrenet hy= 2 drocarbongruppe med 2-6 carbonatoroer, og R betyder hydro= gen eller en mættet eller umættet ligekædet eller forgrenet hydrocarbongruppe med 1-6 carbonatomer, eller, når R betegner hydrogen, fysiologisk acceptable salte deraf med uor-10 ganiske eller organiske baser.Wherein R "represents an unsaturated, straight-chain or branched hy = 2 drocarbon group of 2-6 carbon atoms, and R means hydrogen or a saturated or unsaturated straight-chain or branched hydrocarbon group of 1-6 carbon atoms, or when R represents hydrogen, physiologically acceptable salts thereof with inorganic or organic bases.

Med de nævnte ligekædede eller forgrenede umættede hydro= carbongrupper med 2-6 carbonatomer skal forstås grupper såsom vinyl-, allyl-, 1-propenyl-, 1-butenyl-, 2-butenyl-, pentenyl-, hexenyl-, propadienyl-, butadienyl-, hexadienyl-, 15 isopropenyl-, 1-methylpropenyl-, 2-methylpropenyl-, 2-methyl= allyl-, isopentenyl-, 3,3-dimethylallyl-, ethynyl-, propar= gyl-, butynyl-, hexynyl-, l-methyl-2-propynyl-, 2-methyl-3-pentenyl-, 2-penten-4-ynyl-, l-methyl-2-penten-4-ynyl- og 2-methyl-l,3-butadienylgruppen, idet sådanne grupper med 20 2-4 carbonatomer foretrækkes.The said straight or branched unsaturated hydrocarbon groups having 2-6 carbon atoms are meant groups such as vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, pentenyl, hexenyl, propadienyl, butadienyl -, hexadienyl, isopropenyl, 1-methylpropenyl, 2-methylpropenyl, 2-methyl = allyl, isopentenyl, 3,3-dimethylallyl, ethynyl, propar = gyl, butynyl, hexynyl, the 1-methyl-2-propynyl, 2-methyl-3-pentenyl, 2-penten-4-ynyl, 1-methyl-2-penten-4-ynyl and 2-methyl-1,3-butadienyl group, such groups having 20 to 4 carbon atoms being preferred.

Blandt de nævnte ligekædede eller forgrenede mættede hydro= carbongrupper foretrækkes grupper som methyl-, ethyl-, pro= pyl-, butyl-, sek.-butyl-, tert,-buty1-, isobutyl-, pentyl-, isopentyl-, neopentyl- og hexylgruppen, idet sådanne grup-25 per med 1-4 carbonatomer foretrækkes.Among the said straight or branched saturated hydrocarbon groups, groups such as methyl, ethyl, propyl, butyl, sec.-butyl, tert, butyl, isobutyl, pentyl, isopentyl, neopentyl, and the hexyl group, such groups having 1-4 carbon atoms being preferred.

Når R betegner hydrogen, kan de omhandlede forbindelser anvendes i form af deres fysiologisk acceptable salte med uorganiske eller organiske baser.When R represents hydrogen, the compounds of this invention may be used in the form of their physiologically acceptable salts with inorganic or organic bases.

2 U29492 U2949

Til saltdannelse kommer uorganiske og organiske baser/ såsom de af fagmanden på sædvanlig måde benyttede, på tale.For salt formation, inorganic and organic bases / such as those used by one of ordinary skill in the art come into play.

Som baser, der som bekendt foretrækkes til saltdannelse, kommer eksempelvis følgende i betragtning: Natriumhydroxid, 5 kaliumhydroxid, lithiumhydroxid, calciumhydroxid, magnesium= hydroxid, glucamin, N-methylglucamin, N,N-dimethylglucamin, ethanolamin, diethanolamin, morfolin, N-methylmorfolin og tris-(hydroxymethyl)-methylamin osv..For example, as bases that are known to be preferable to salt formation, the following are considered: and tris (hydroxymethyl) methylamine, etc.

Era beskrivelsen til tysk patentansøgning nr. P 20 30 899.0 er det kendt, 10 at 2,3-dihydrofuro [2,3-g] quinolin-7-carboxylsyrer, scm i 5-stillingen eventuelt indeholder en mættet hydrocarbongruppe, har gode hæiningsværdier mod grampositive og gramnegative bakterier og derfor egner sig som urinvejsterapeutika. Forbindelser til denne indikation må have en tilstrækkelig udskillelse i urin, og doseringen afhæn-15 ger heraf. Kun i tilfælde af en forøgelse af urinspejlet kan indtagelsen af et virksomt stof foregå i lavere dosering, for så vidt som dets virkning ikke reduceres i tilsvarende grad, som udskillelsen forøges.In German Patent Application No. P 20 30 899.0, it is known that 2,3-dihydrofuro [2,3-g] quinoline-7-carboxylic acids, scm in the 5-position optionally containing a saturated hydrocarbon group, have good retention values against gram-positive and gram-negative bacteria and are therefore suitable as urinary tract therapies. Compounds for this indication must have a sufficient urinary excretion and the dosage depends on it. Only in the case of an increase in urine levels can the intake of an active substance take place at a lower dosage, insofar as its effect is not reduced to an equivalent degree as the excretion is increased.

Det har nu vist sig, at de omhandlede forbindelser med den 20 almene formel I samtidig med at have en god hæmningsvirkning over for grampositive og gramnegative bakterier viser en forøget urinudskillelse i forhold til de tilsvarende kendte forbindelser, som indeholder en mættet hydrocarbongruppe i 5-stillingen, f.eks. 5-ethyl-2,3,5,8-tetrahydro-8-oxo-furo-25 [2,3-g]quinolin-7-carboxylsyre (kendt fra beskrivelsen til ovennævnte tyske patentansøgning nr. P 20 30 899.0), hvilket den efterfølgende tabel med forbindelserne fremstillet ifølge eksempel 3 og eksempel 4 som eksempel viser i sammenligning med 5-ethyl-2,3,5,8-tetrahydro-8-oxo-furo[2,3-g]-30 quinolin-7-carboxylsyre. Talværdierne angiver det procentuelle indhold af en indtaget dosis, som i løbet af 6 timer udskilles i rotters urin efter en dosering på 100 mg/kg pr. os.It has now been found that the compounds of the general formula I, while having a good inhibitory effect on gram-positive and gram-negative bacteria, show an increased urinary excretion over the corresponding known compounds which contain a saturated hydrocarbon group at the 5-position. , eg. 5-ethyl-2,3,5,8-tetrahydro-8-oxo-furo-25 [2,3-g] quinoline-7-carboxylic acid (known from the specification of the above-mentioned German patent application No. P 20 30 899.0), which the following table of the compounds prepared according to Example 3 and Example 4 as an example shows, in comparison with 5-ethyl-2,3,5,8-tetrahydro-8-oxo-furo [2,3-g] -30 quinoline-7- carboxylic acid. The numerical values indicate the percentage content of an ingested dose which is excreted in the urine of rats over a period of 6 hours following a dose of 100 mg / kg per day. U.S.

142949 3142949 3

Forbindelse 5-ethyl-2,3,5,8- 8-oxo-5-(l-pro= 8-oxo-2,3,5,8- tetrahydro-8-oxo- penyD-2,3,5,8- tetrahydro-5- furo [2,3-g] quino= tetxahydro-furo- vinyl-furo[2, lin-7-carboxylsyre [2,3-g]guinolin- 3-g]quinolin- 5 7-carboxylsyre 7-carbcotylsyre (eksecpel 3) (eksempel 4)Compound 5-Ethyl-2,3,5,8-8-oxo-5- (1-pro = 8-oxo-2,3,5,8-tetrahydro-8-oxopyrene-2,3,5, 8- tetrahydro-5-furo [2,3-g] quino = tetxahydro-furovinyl-furo [2, lin-7-carboxylic acid [2,3-g] guinoline-3-g] quinoline-7-carboxylic acid 7-Carbcotyl Acid (Example 3) (Example 4)

Udskillelse% 0,48% 2,1% 3,4%Excretion% 0.48% 2.1% 3.4%

For urinvejsterapeutika, såsom de ifølge opfindelsen frem-10 stillede forbindelser, er foruden virkningen (udtrykt som den minimale haanningskoncentration MHK) også den aktive forbindelses udskillelsesgrad i urinen (i procent af den administrerede dosis) af betydning. Begge størrelser afviger stærkt indbyrdes blandt forskellige forbindelser, 15 så at kvotienten mellem udskillelse og MHK er at anbefale til en meningsfuld vurdering af urinvejsterapeutika, idet MHK-værdien for den vigtigste kim Eschericcia coli blev benyttet. For oxolinsyre, som er det bedste for tiden i handelen gående urinvejsterapeutikum, og for forbindelsen 20 5-ethyl-2,3,5,8-tetrahydro-8-oxo-furo[2,3-g]guinolin-7- carboxylsyre blev følgende værdier fastslået og sammenlignet med de tilsvarende værdier for nogle af de ifølge opfindelsen fremstillede forbindelser. Talværdierne for udskillelsen angiver procentdelen af en indtaget dosis, som udskilles 25 i rotters urin inden for 6 timer i tilfælde af en dosering på 100 mg/kg pr. os.For urinary tract therapies, such as the compounds of the invention, in addition to the effect (expressed as the minimum MHK concentration), the excretion rate of the active compound in the urine (as a percentage of the dose administered) is also important. Both sizes differ widely among different compounds, so that the quotient between excretion and MHK is to recommend a meaningful assessment of urinary tract therapies, using the MHK value for the main germ Eschericcia coli. For oxolinic acid, which is currently the most commercially available urinary tract therapeutic, and for compound 20 5-ethyl-2,3,5,8-tetrahydro-8-oxo-furo [2,3-g] guinoline-7-carboxylic acid, The following values are determined and compared with the corresponding values for some of the compounds of the invention. The excretion numbers indicate the percentage of an ingested dose which is excreted in the urine of rats within 6 hours in the case of a dose of 100 mg / kg per day. U.S.

4 1429494 142949

Forbindelse MHK E.coli Udskil- Kvotient _mg/ml_lelse %_Compound MHK E.coli Excretion Quotient _mg / ml_l%% _

Oxolinsyre 0,1 0,32 3,2 5-ethyl-2,3,5,8-tetrahydro-8-5 oxo-furo[2,3-g]quinolin-7- carboxylsyre (kendt fra tysk offentliggørelsesskrift nr.Oxolinic acid 0.1 0.32 3.2 5-Ethyl-2,3,5,8-tetrahydro-8-5 oxo-furo [2,3-g] quinoline-7-carboxylic acid (known from German publication no.

20 30 899) 0,05 0,48 9,6 8-ΟΧΟ-5-(1-propenyl)-2,3,5,8-10 tetrahydro-furo[2,3-g]quinolin- 7- carboxylsyre (eksempel 3) 0,2 2,1 10,5 8- OXO-2,3,5,8-tetrahydro-5-vinyl-furo[2,3-g]quinolin-7- carboxylsyre (eksempel 4) 0,05 3,4 68 15 8-oxo-2,3,5,8-tetrahydro-5- vinyl-furo[2,3-g]quinolin-7-carboxylsyre, Na-salt (eksempel li) 0,05 4,1 82899) 0.05 0.48 9.6 8-β-5- (1-propenyl) -2,3,5,8-10 tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid ( Example 3) 0.2 2.1 10.5 8- OXO-2,3,5,8-tetrahydro-5-vinyl-furo [2,3-g] quinoline-7-carboxylic acid (Example 4) 0.05 3,4 68 15 8-oxo-2,3,5,8-tetrahydro-5-vinyl-furo [2,3-g] quinoline-7-carboxylic acid, Na salt (Example 1I) 0.05 4.1 82

Af sammenligningen mellem de terapeutiske kvotienter for de 20 urinvejsvirksomme forbindelser fremgår overlegenheden af de ifølge opfindelsen fremstillede forbindelser i forhold til oxolinsyre samt de fra tysk offentliggørelsesskrift nr.From the comparison of the therapeutic quotients for the 20 urinary tract compounds, the superiority of the compounds of the invention with respect to oxolinic acid as well as those of German publication no.

20 30 899 kendte dermed strukturanaloge forbindelser énty digt.20 30 899 thus known structurally analogous compounds.

De omhandlede forbindelser kan administreres i de farmaceu-25 tisk sædvanlige administrationsformer, såsom tabletter, dragéer, kapsler, piller, opløsninger osv..The compounds of the invention may be administered in the pharmaceutically conventional forms of administration such as tablets, dragees, capsules, pills, solutions, etc.

De omhandlede forbindelser fremstilles ved fremgangsmåden ifølge opfindelsen, der er ejendommelig ved, at man omsætter en forbindelse med den almene formel II, som kan fore-30 ligge i de tautomere former A eller B, /0 coor2 ^ 0 j ^ i—CX i (ii)The compounds of this invention are prepared by the process of the invention, characterized by reacting a compound of the general formula II which may be present in the tautomeric forms A or B, O (ii)

HH

II A II BII A II B

2 142949 5 hvori R har den ovenfor anførte betydning, med en forbindelse med den almene formel R"X, hvori R" har den for R1 ovenfor anførte betydning eller betyder en mættet, ligekædet eller forgrenet alkylgruppe med 2-6 carbonatomer, som indehol-5 der et eller to halogenatomer, hydroxygrupper, acyloxygrup-per med 1-4 carbonatomer, benzoyloxygrupper, alkansulfonyl= oxygrupper med 1-4 carbonatomer i alkyldelen eller benzen= sulfonyloxygrupper, som i kernen kan være substitueret med halogenatomer eller med alkylgrupper indeholdende 1-4 car= 10 bonatomer, og X har betydningen et halogenatom, en alkansul= fonyloxygruppe med 1-4 carbonatomer i alkyldelen eller en benzensulfonyloxygruppe, som kan være substitueret med ha= logenatomer eller med alkylgrupper indeholdende 1-4 carbon= atomer, og derpå eller samtidig på i og for sig kendt måde fraspalter i 15 R" tilstedeværende substituenter under dannelse af umættede bindinger og derefter i vilkårlig rækkefølge fores trer en fri carboxylgzrppe til dannelse af en ester af den i kravets indledning angivne art eller hydrolyserer en fores tret carboxylgruppe og/eller på i og for sig kendt måde alt efter det til sidst ønskede slutprodukt endej rer carbon- carbon- fler-20 dobbeltbindingen i R1 og cm ønsket overfører en fri carboxylsyre til et fysiologisk acceptabelt salt deraf med en uorganisk eller organisk base.Wherein R is as defined above, with a compound of the general formula R "X, wherein R" is as defined for R 1 above, or is a saturated, straight-chain or branched alkyl group of 2-6 carbon atoms containing Wherein one or two halogen atoms, hydroxy groups, acyloxy groups having 1-4 carbon atoms, benzoyloxy groups, alkanesulfonyl = oxy groups having 1-4 carbon atoms in the alkyl moiety or benzene = sulfonyloxy groups which may be substituted at the core by halogen atoms or with alkyl groups containing 1-4 car = 10 bone atoms, and X has the meaning of a halogen atom, an alkanesulphonyloxy group having 1-4 carbon atoms in the alkyl moiety or a benzenesulfonyloxy group which may be substituted by halogen atoms or with alkyl groups containing 1-4 carbon atoms and then or simultaneously in a manner known per se, decomposes into 15 R "substituents present to form unsaturated bonds, and then randomly forms a free carboxyl group. to form an ester of the kind set forth in the preamble of the claim or hydrolyze a substituted carboxyl group and / or in a manner known per se according to the final desired product, the carbon-carbon multiple-double bond in R1 and cm is desired. transfers a free carboxylic acid to a physiologically acceptable salt thereof with an inorganic or organic base.

Når R" betyder en mættet ligekædet eller forgrenet alkyl= gruppe med 1 eller 2 substituenter, som elimineres til indføring af flerdobbelte bindinger, har alkylgruppen den ov-25 ennævnte for ligekædede eller forgrenede mættede alkylgrupper anførte betydning,bortset fra methyl.Søm substituenter kommer følgende i betragtning: Halogenerne fluor, chlor, brom og jod, hvoraf fluor, chlor og brom er særlig foretrukne, hydroxygruppen, acyloxygrupperne formyloxy-, acetoxy-, propionyloxy- og 30 butyryloxygruppen, alkansulfonyloxygrupper, såsom methan- eller ethansulfonyloxygruppen,hvoraf methansulfonyloxygruppen foretrækkes, o-, m- eller p-halogenbenzensulfonyloxygrupper, hvoraf p-stillingen og blandt halogenerne fluor, chlor, brom og jod halogenerne chlor og brom er særlig foretrukne, 35 og o-, m- eller p-alkylbenzensulfonyloxygrupper, hvor p-stillingen er særlig foretrukken, og blandt alkylgrupperne 142949 6 methyl, ethyl, propyl, butyl, hvoraf sådanne med 1-2 carbon« atomer har forrang. Hvad antallet af substituenter angår foretrækkes 1 substituent i alkylgruppen i resten R".When R "means a saturated straight or branched alkyl = group of 1 or 2 substituents which is eliminated for introduction of multiple bonds, the alkyl group has the above meaning for straight chain or branched saturated alkyl groups, except methyl. Considering: The halogens fluorine, chlorine, bromine and iodine, of which fluorine, chlorine and bromine are particularly preferred, the hydroxy group, the acyloxy groups formyloxy, acetoxy, propionyloxy and butyryloxy group, alkanesulfonyloxy groups, such as methane or ethanesulfonyloxy group, -, m- or p-halobenzenesulfonyloxy groups, of which the p-position and of the fluorine, chlorine, bromine and iodine halogens chlorine and bromine are particularly preferred, and the o-, m- or p-alkylbenzenesulfonyloxy groups where the p-position is particularly preferred and from the alkyl groups 142949 6 methyl, ethyl, propyl, butyl, of which those having 1-2 carbon 'atoms take precedence. In the number of substituents, 1 substituent in the alkyl group of the residue R "is preferred.

Resten X i forbindelsen R"X kan være halogenatomerne fluor, 5 chlor, brom og jod, idet fluor, chlor og jod foretrækkes, en alkansulfonyloxygruppe med 1-4 carbonatomer, f.eks. med methan eller ethan som alkan, hvorhos methan foretrækkes, eller en arylsulfonyloxygruppe med aryl som phenyl, o-, m- eller p-alkylphenyl (alkyl = methyl eller ethyl), o-, m- eller 10 p-halogenphenyl osv..The residue X of the compound R "X may be the halogen atoms fluorine, chlorine, bromine and iodine, with fluorine, chlorine and iodine being preferred, an alkanesulfonyloxy group having 1-4 carbon atoms, for example with methane or ethane as alkane, where methane is preferred, or an arylsulfonyloxy group with aryl such as phenyl, o-, m- or p-alkylphenyl (alkyl = methyl or ethyl), o-, m- or 10-halogenophenyl, etc.

Alkyleringen gennemføres fortrinsvis i alkalisk medium, fortrinsvis i vand eller i organiske opløsningsmidler, såsom eksempelvis alkohol, dimethylsulfoxid, dioxan, tetra= hydrofuran o.a. eller blandinger deraf med vand ved 0-150°C, 15 fortrinsvis ved 0-100°C med en reaktionstid fra 0,5 timer til 5 dage. Som alkalisk medium anvender man f.eks. 1-10 ækvivalenter alkali, fortrinsvis NaOH eller KOH, i forhold til benyttet alkyleringsreagens, især 2-6 ækvivalenter i vandig alkohol eller dimethylsulfoxid.The alkylation is preferably carried out in alkaline medium, preferably in water or in organic solvents such as, for example, alcohol, dimethylsulfoxide, dioxane, tetrahydrofuran and the like. or mixtures thereof with water at 0-150 ° C, preferably at 0-100 ° C with a reaction time of 0.5 hours to 5 days. As an alkaline medium, e.g. 1-10 equivalents of alkali, preferably NaOH or KOH, relative to the alkylating reagent used, especially 2-6 equivalents in aqueous alcohol or dimethyl sulfoxide.

20 N-alkyleringen kan foregå med et alkyleringsreagens R"X, hvori R" allerede foreligger i den til sidst ønskede betydning for R^·, eller også - hvilket af eksperimentelle grunde kan være hensigtsmæssigt eller også nødvendigt (f.eks.The N-alkylation may be carried out with an alkylation reagent R "X, wherein R" is already present in the last desired meaning for R 2, or also - which for experimental reasons may be appropriate or also necessary (e.g.

R·*· i betydningen en vinylgruppe) - gennemføres med et alky= 25 leringsmiddel R"X, hvori R" betyder en mættet alkylgruppe, som er substitueret med en af ovennævnte substituenter, der er let at eliminere under dannelse af den til sidst ønskede umættede C-C-binding i Rx. Går man ud fra sådanne substituerede R"X-alkylerings-reagenser, forløber elimineringen under alkyleringsbeting-30 eiserne i reglen spontant til dannelse af de ønskede slutprodukter med den almene formel I. Fraspaltes tilstedeværende substituenter i R" ikke samtidig under alkyleringsbetingelserne, gennemføres den påfølgende eliminering,f.eks. med basiske reagenser, såsom NaOH, KOH, K-tert.-butylat, NaH, ^CO^, 142949 7 pyridin, aminer i opløsningsmidler, såsom vand, alkohol, di= methylformamid eller dimethylsulfoxid, ved temperaturer mellem 0 og 150°C, fortrinsvis mellem 20 og 100°C, i løbet af 0,5 til 10 timer, fortrinsvis i løbet af 0,5-5 timer.R ·, in the meaning of a vinyl group) - is carried out with an alkylating agent R "X, wherein R" unsaturated CC bond in Rx. Assuming such substituted R "X alkylation reagents, the elimination under the alkylation conditions usually proceeds spontaneously to form the desired end products of general formula I. Substituents present in R" are not simultaneously cleaved under the alkylation conditions, the subsequent elimination, for example. with basic reagents such as NaOH, KOH, K-tert-butylate, NaH, CO 2, pyridine, amines in solvents such as water, alcohol, dimethylformamide or dimethylsulfoxide, at temperatures between 0 and 150 ° C, preferably between 20 and 100 ° C, within 0.5 to 10 hours, preferably within 0.5-5 hours.

5 Hvis primærproduktet ved fremgangsmåden ifølge opfindelsen endjnu ikke indeholder den umættede C-C-binding i gruppen R1 i den til sidst ønskede stilling, foretages dens forskydning ved hjælp af metoder, βομ for fagmanden er almindelig kendt til sådanne omlejringsreaktioner.If the primary product of the process according to the invention does not yet contain the unsaturated C-C bond in the group R1 at the last desired position, its displacement is carried out by methods βομ of the artisan is generally known for such rearrangement reactions.

10 ' Reaktionen kan foregå under alkaliske eller sure reaktionsbetingelser. Som basiske omlejringskatalysatorer kommer f.eks. alkalier såsom NaOH, KOH eller K-tert.-butylat på tale, og som sur katalysator f.eks, trifluoreddikesyre.The reaction may take place under alkaline or acidic reaction conditions. As basic rearrangement catalysts, e.g. alkalis such as NaOH, KOH or K-tert-butylate in speech, and as an acid catalyst, for example, trifluoroacetic acid.

Den basiske omlejring foretrækkes. Den foregår f.eks. ved 15 temperaturer mellem 0 og 180°C, fortrinsvis ved 0-130°C, i løbet af 0,5-24 timer, fortrinsvis i løbet af 2-4 timer, med 3-7 N NaOH eller KOH i opløsningsmidler, såsom vand, ethylenglycol, dimethylformamid eller lignende.The basic rearrangement is preferred. It takes place, for example. at 15 temperatures between 0 and 180 ° C, preferably at 0-130 ° C, within 0.5-24 hours, preferably 2-4 hours, with 3-7 N NaOH or KOH in solvents such as water , ethylene glycol, dimethylformamide or the like.

22

Den 7-stiIlede -COOR -gruppe i fremgangsmådeproduktet kan 20 være en fri eller forestret carboxylgruppe. Hvis R i udgangsproduktet er et H-atom, kan der under alkyleringsbetingelserne også samtidig finde en forestring af den frie carboxylgruppe sted, især når R" i alkyleringsmidlet er lig med R1.The 7-membered -COOR group in the process product may be a free or esterified carboxyl group. If R in the starting product is an H atom, under the alkylation conditions an esterification of the free carboxyl group may also occur, especially when R "in the alkylating agent is equal to R1.

2 25 Hvis -COOR i udgangsproduktet er en forestret carboxyl= gruppe, afhænger bestandigheden af denne estergruppe af betingelserne ved alkylerings- og/eller elimineringsreaktionen. Hvis disse omsætninger foretages ved særlig høj reaktionstemperatur, medhydrolyseres estergruppen helt 30 eller i det mindste delvis. Alt efter den til sidst ønske- o de betydning af R forestres eller efterforestres en fri carboxylgruppe på i og for sig kendt måde, og en forestret carboxylgruppe hydrolyseres.If -COOR in the starting product is an esterified carboxyl group, the resistance of this ester group depends on the conditions of the alkylation and / or elimination reaction. If these reactions are carried out at particularly high reaction temperatures, the ester group is fully hydrolyzed to 30 or at least partially. Depending on the desired meaning of R, a free carboxyl group is esterified or post-esterified in a manner known per se, and an esterified carboxyl group is hydrolyzed.

8 1429498 142949

Saltdannelsen foretages på i og for sig kendt måde, f.eks. ved omsætning med en 1 normal opløsning af de tilsvarende uorganiske eller organiske baser, idet den opnåede opløs-5 ning inddampes, og den tilbageblivende rest omkrystalliseres, f.eks. fra alkohol/vand-blandinger (5-9:5-1).Salt formation is carried out in a manner known per se, e.g. by reaction with a 1 normal solution of the corresponding inorganic or organic bases, evaporating the resulting solution and recrystallizing the residue, e.g. from alcohol / water mixtures (5-9: 5-1).

Sædvanligvis udfældes reaktionsproduktet på grund af den 1 2 flerdobbelte binding i R og eventuelt også i R i form af cis/trans-isomere blandinger deraf, som på sædvanlig 10 måde kan separeres i cis- og trans-formen, f.eks. ved hjælp af fraktioneret krystallisation eller kromatografi.Usually, the reaction product is precipitated due to the 1 2 multiple bond in R and optionally also in R in the form of cis / trans isomeric mixtures thereof, which in the usual manner can be separated into the cis and trans forms, e.g. by fractional crystallization or chromatography.

De omhandlede forbindelser skal i forbindelse med de i den galeniske farmaci sædvanlige tilsætninger tjene til eksempelvis fremstilling af midler mod urinvejsinfektioner. An-15 vendeisen kan foregå i de farmaceutisk sædvanlige administrationsformer. Forbindelserne fremstillet ifølge opfindelsen er særlig egnede til oral administration, f.eks. i tabletter, dragéer, kapsler, piller og suspensioner. Tabletter indeholder eksempelvis 0,1-1 g virksomt stof og 0,1 til 5 g 20 af - et farmakologisk indifferent hjælpestof. Som hjælpestof fer anvendes eksempelvis til tabletter: mælkesukker, stivelse, talkum, gelatine, magnesiumstearat osv..The compounds of the present invention must, in connection with the usual additives in the Galenic pharmacy, serve, for example, in the preparation of agents for urinary tract infections. The application may be carried out in the pharmaceutically conventional forms of administration. The compounds of the invention are particularly suitable for oral administration, e.g. in tablets, dragees, capsules, pills and suspensions. Tablets contain, for example, 0.1-1 g of active substance and 0.1 to 5 g 20 of - a pharmacologically inert auxiliary. As an excipient, for example, tablets are used: milk sugar, starch, talc, gelatin, magnesium stearate, etc.

Forbindelserne fremstillet ifølge opfindelsen er anvendelig på såvel det humanmedicinske som det veterinærmedicinske 25 område.The compounds of the invention are useful in both the human and veterinary fields.

De omhandlede aktive stoffer skal anvendes i mængder mellem 0,1 og 4,0 g pr. patient og pr. dag.The active substances in question must be used in amounts between 0.1 and 4.0 g per liter. patient and per. day.

Fremgangsmåden ifølge opfindelsen belyses nærmere i de følgende eksempler.The process according to the invention is illustrated in more detail in the following examples.

1429AO1429AO

99

Eksempel 1.Example 1.

5-allyl-8-oxo-2,3,5,8-tetrahydro-furo f 2,3-g]quinolin-7-carboxylsyre.5-Allyl-8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

a) 5-allyl-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]quinolin-7- 5 carboxylsyre-allylester.a) 5-Allyl-8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7- carboxylic acid allyl ester.

3,8 g pulveriseret natriumhydroxid suspenderes i 27 ml di= methylsulfoxid, derpå indføres 3,1 g 8-hydroxy-2,3-dihydro-furo[2,3-g]quinolin-7-carboxylsyre, og der pmrøres i 10 minutter ved stuetemperatur. Derpå tilsættes 5,67 ml allylbro-10 mid, der omrøres i 2 timer ved stuetemperatur og der udhældes i vand. Det faste produkt frafiltreres og omkrystalliseres fra ethanol. Smeltepunkt 100°C, udbytte 2,5 g.3.8 g of powdered sodium hydroxide are suspended in 27 ml of di-methylsulfoxide, then 3.1 g of 8-hydroxy-2,3-dihydro-furo [2,3-g] quinoline-7-carboxylic acid is added and stirred for 10 minutes. at room temperature. Then 5.67 ml of allyl bromide is added, which is stirred for 2 hours at room temperature and poured into water. The solid product is filtered off and recrystallized from ethanol. Melting point 100 ° C, yield 2.5 g.

b) 5-allyl-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]quinolin-7-carboxylsyre.b) 5-Allyl-8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

15 1/0 g 5-allyl-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]quinolin- 7- carboxylsyre-allylester koges under tilbagesvaling med 10 ml 2n NaOH i 10 minutter. Opløsningen filtreres og syrnes.1/0 g of 5-allyl-8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid allyl ester is refluxed with 10 ml of 2n NaOH for 10 minutes. The solution is filtered and acidified.

Det udfældede produkt omkrystalliseres fra DMF. Smeltepunkt 264-279°C. Udbytte 0,55 g.The precipitated product is recrystallized from DMF. Melting point 264-279 ° C. Yield 0.55 g.

20 Eksempel 2.Example 2.

8- ΟΧΟ-5-(1-propeny1)-2,3,5,8-tetrahydro-furo[2,3-g]quinolin- 7-carboxylsyre.8- [5- (1-propenyl) -2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

500 mg 5-allyl-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]qulnolin-7-carboxylsyre opvarmes til 130°C i 5 ml 5n NaOH og 2 1/2 25 ml ethylenglycol i 3 timer. Der tilsættes vand og koncentreret saltsyre, og det fældede materiale omkrystalliseres fra dimethylformamid. Smeltepunkt 263°C. Udbytte 0,30 g.500 mg of 5-allyl-8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid is heated to 130 ° C in 5 ml of 5n NaOH and 2 1/2 25 ml ethylene glycol for 3 hours. Water and concentrated hydrochloric acid are added and the precipitated material is recrystallized from dimethylformamide. Melting point 263 ° C. Yield 0.30 g.

10 1429Α910 1429Α9

Eksempel 3.Example 3

8-oxo-5-(l-propenyl) -2,3,5,8-tetrahydro-furo[2,3-g]quinolin- 7- carboxylsyre.8-oxo-5- (1-propenyl) -2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

500 mg 5-allyl-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]quinolin-5 7-carboxylsyre opløses i 1,1 ml In NaOH. Der inddampes, og resten omkrystalliseres fra isopropanol/vand 8:2. Smeltepunkt 235°C. Udbytte 0,20 g.Dissolve 500 mg of 5-allyl-8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-5-7-carboxylic acid in 1.1 ml of In NaOH. Evaporate and the residue is recrystallized from isopropanol / water 8: 2. Melting point 235 ° C. Yield 0.20 g.

Eksempel 4.Example 4

8- OXO-2,3,5,8-tetrahydro-5-vinyl-furo[2,3-g]quinolin-7-10 carboxylsyre.8- OXO-2,3,5,8-tetrahydro-5-vinyl-furo [2,3-g] quinoline-7-10 carboxylic acid.

a) 6,0 g pulveriseret natriumhydroxid suspenderes i 45 ml dimethylsulfoxid, 5,0 g 8-hydroxy-2,3-dihydro-furo[2,3-g]-quinolin-7-carboxylsyre indføres deri, og der omrøres i 10 minutter ved stuetemperatur. 8,2 g l-brom-2-fluor-ethan til- 15 sættes, og der omrøres derpå i 2 timer. Der udhældes i vand, og der syrnes med koncentreret saltsyre. Det opnåede faste produkt kromatograferes over 200 g kiselgel med dioxan/ koncentreret NH^OH/vand 8:1:2, og det rene materiale omkrystalliseres fra dimethylformamid. Smeltepunkt 300-304°C (de-20 komponering). Udbytte 0,3 g. 1 2,8 g pulveriseret natriumhydroxid suspenderes i 20 ml dimethylsulfoxid, 2,3 g 8-hydroxy-2,3-dihydro-furo[2,3-g]-quinolin-7-carboxylsyre indføres deri, og der omrøres i 10 minutter ved stuetemperatur. 2,6 ml 1,2-dibrom-ethan tilsæt- 25 tes, og der omrøres i 24 timer ved stuetemperatur. Der udhældes i vand og syrnes med koncentreret saltsyre. Det opnåede faste produkt kromatograferes over kiselgel med dioxan/ koncentreret NH^OH/vand 8:1:2, og det rene materiale omkry-stalliseres fra dimethylformamid. Smeltepunkt 300-304°C (de-30 komponering). Udbytte 0,04 g.a) 6.0 g of powdered sodium hydroxide is suspended in 45 ml of dimethyl sulfoxide, 5.0 g of 8-hydroxy-2,3-dihydro-furo [2,3-g] quinoline-7-carboxylic acid is introduced therein and stirred for 10 minutes. minutes at room temperature. 8.2 g of 1-bromo-2-fluoro-ethane are added and stirred for 2 hours. Pour into water and acidify with concentrated hydrochloric acid. The solid product obtained is chromatographed over 200 g of silica gel with dioxane / concentrated NH 4 OH / water 8: 1: 2 and the pure material is recrystallized from dimethylformamide. Melting point 300-304 ° C (decomposition). Yield 0.3 g. 1.8 g of powdered sodium hydroxide are suspended in 20 ml of dimethyl sulfoxide, 2.3 g of 8-hydroxy-2,3-dihydro-furo [2,3-g] -quinoline-7-carboxylic acid is introduced therein. and stirring for 10 minutes at room temperature. 2.6 ml of 1,2-dibromo-ethane are added and stirred for 24 hours at room temperature. Pour into water and acidify with concentrated hydrochloric acid. The solid product obtained is chromatographed over silica gel with dioxane / concentrated NH 4 OH / water 8: 1: 2 and the pure material is recrystallized from dimethylformamide. Melting point 300-304 ° C (decomposition). Yield 0.04 g.

142949 11 c) 2,3 g 8-hydroxy-2,3-dihydro-furo[2,3-g]quinolin-7-carb= oxylsyre Indføres i en blanding af 2,04 g kaliumhydroxid, 14,8 ml vand, 46 ml ethanol og 7,5 g l-brom-2-fluorethan, og der koges i 5 dage under tilbagesvaling. Det opnåede faste 5 produkt frafiltreres og kromatograferes over 200 g kiselgel med dioxan/koncentreret NH^OH/vand 8:1:2, hvorefter der om»-krystalliseres fra ethanol. Der opnås 0,36 g 5-(2’fluorethyl)- 8-OXO-2,3,5,8-tetrahydro-furo[2,3-g]qulnQlin-7-carboxylsyr© med dekomponeringspunktet 308-314°C. 0,36 g 5-(2-fluor-ethyl)-10 8-ΟΧΟ-2,3,5,8-tetrahydro-furo[2,3-g]quinolin-7-carboxylsyre indføres i en blanding af 4,8 g NaOH og 3,5 ml dimethylsulf-oxid, og der omrøres i 2 timer ved 25°C. Der udhældes i vand, syrnes med koncentreret saltsyre, og det opnåede faste produkt kromatograferes over kiselgel med dioxan/koncentreret 15 NH4OH/vand 8:1:2. Der opnås 0,20 g 8-oxo-2,3,5,8-tetrahydro- 5-vinylfuro[2,3-g]quinolin-7-carboxylsyre med smeltepunkt 300-304°C (dekomponering).C) 2.3 g of 8-hydroxy-2,3-dihydro-furo [2,3-g] quinoline-7-carb = oxylic acid Introduced into a mixture of 2.04 g of potassium hydroxide, 14.8 ml of water, 46 ml of ethanol and 7.5 g of 1-bromo-2-fluoroethane and boil for 5 days under reflux. The obtained solid product is filtered off and chromatographed over 200 g of silica gel with dioxane / concentrated NH 4 OH / water 8: 1: 2, then crystallized from ethanol. 0.36 g of 5- (2'-fluoroethyl) -8-OXO-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid is obtained with the decomposition point 308-314 ° C. 0.36 g of 5- (2-fluoro-ethyl) -10 8-ΟΧΟ-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid are introduced into a mixture of 4.8 g of NaOH and 3.5 ml of dimethyl sulfoxide and stir for 2 hours at 25 ° C. It is poured into water, acidified with concentrated hydrochloric acid and the obtained solid product is chromatographed over silica gel with dioxane / concentrated NH 4 OH / water 8: 1: 2. There are obtained 0.20 g of 8-oxo-2,3,5,8-tetrahydro-5-vinyl furo [2,3-g] quinoline-7-carboxylic acid, mp 300-304 ° C (decomposition).

Eksempel 5.Example 5

8-oxo-5-propargyl-2,3,5,8-tetrahydro-furp[2,3-g] guinolin-,7-20 carboxylsyre.8-oxo-5-propargyl-2,3,5,8-tetrahydrofurp [2,3-g] guinoline, 7-20 carboxylic acid.

2,31 g 8-hydroxy-2,3-dihydro-furo[2,3-g]quinolin-7-carboxyl= syre og 4,7 ml 3-brompropyn koges i en opløsning af 1,96 g KOH i 14,2 ml vand og 40 ml ethanol i 5 dage under tilbagesvaling. Det efter køling udkrystalliserede produkt omkrystal-25 liseres fra eddikesyre. Smeltepunkt 308-310°C. Udbytte 1,7 g.2.31 g of 8-hydroxy-2,3-dihydro-furo [2,3-g] quinoline-7-carboxylic acid and 4.7 ml of 3-bromopropylene are boiled in a solution of 1.96 g KOH in 14, 2 ml of water and 40 ml of ethanol for 5 days under reflux. The product crystallized after cooling is recrystallized from acetic acid. Melting point 308-310 ° C. Yield 1.7 g.

Eksempel 6.Example 6

8-oxo-5-propadienyl-2,3,5,8-tetrahydro-furo[2,3-g]quinolin-7-carboxylsyre.8-oxo-5-propadienyl-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

a) 0,54 g 8-oxo-5-propargyl-2,3,5,8-tetrahydro-furo[2,3-g]-30 quinolin-7-carboxylsyre indføres i en suspension af 0,56 g pulveriseret kaliumhydroxid i 11 ml dimethylformamid ved 142949 12 0°C. Der omrøres i 2 timer ved 0°C, udhældes i vand, syrnes med saltsyre, og det opnåede faste produkt omkrystalliseres fra dimethylformamid. Smeltepunkt 257-261°C. Udbytte 0,16 g.a) 0.54 g of 8-oxo-5-propargyl-2,3,5,8-tetrahydro-furo [2,3-g] -quinoline-7-carboxylic acid is introduced into a suspension of 0.56 g of powdered potassium hydroxide. in 11 ml of dimethylformamide at 0 ° C. Stir for 2 hours at 0 ° C, pour into water, acidify with hydrochloric acid and recrystallize the resulting solid product from dimethylformamide. Melting point 257-261 ° C. Yield 0.16 g.

b) 0,20 g oxo-5-propargy1-2,3,5,8-tetrahydro-furo[2,3-g]-5 quinolin-7-carboxylsyre omrøres i 10 ml trifluoreddikesyre i 20 timer ved stuetemperatur, der udhældes i vand, og det opnåede faste produkt omkrystalliseres fra dimethylformamid. Smeltepunkt 257-261°C. Udbytte 0,10 g.b) 0.20 g of oxo-5-propargyl-2,3,5,8-tetrahydro-furo [2,3-g] -5-quinoline-7-carboxylic acid is stirred in 10 ml of trifluoroacetic acid for 20 hours at room temperature, which is poured out in water and the resulting solid product is recrystallized from dimethylformamide. Melting point 257-261 ° C. Yield 0.10 g.

Eksempel 7.Example 7

10 5-(2-butenyl)-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]quinolin- 7-carboxylsyre.5- (2-Butenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

a) 5-(2-butenyl)-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]quinolin-7-carboxylsyre-2-butenylester.a) 5- (2-Butenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid 2-butenyl ester.

2,5 g 8-hydroxy-2,3-dihydro-furo[2,3-g]quinolin-7-carboxyl= 15 syre indføres ved stuetemperatur i en suspension af 3,0 g natriumhydroxid i 21,8 ml dimethylsulfoxid, hvorpå der tilsættes 4,4 g crotylbromid. Der omrøres i 2 timer ved stuetemperatur, udhældes i vand, og det opnåede faste produkt omkrystalliseres fra ethanol. Smeltepunkt 111°C. Udbytte 20 0,85 g.2.5 g of 8-hydroxy-2,3-dihydro-furo [2,3-g] quinoline-7-carboxylic acid are introduced at room temperature into a suspension of 3.0 g of sodium hydroxide in 21.8 ml of dimethyl sulfoxide, whereupon 4.4 g of crotyl bromide are added. The mixture is stirred for 2 hours at room temperature, poured into water and the resulting solid product is recrystallized from ethanol. Melting point 111 ° C. Yield 20 0.85 g.

b) 5-(2-butenyl)-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]quino= lin-7-carboxylsyre.b) 5- (2-Butenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quino = lin-7-carboxylic acid.

0,75 g 5-(2-butenyl)-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]-quinolin-7-carboxylsyre-2-butenylester koges i 10 ml 2n NaOH 25 i 10 minutter under tilbagesvaling. Der filtreres, syrnes med saltsyre og det opnåede faste produkt omkrystalliseres fra dimethylformamid. Smeltepunkt 276-286°C. Udbytte 0,43 g.0.75 g of 5- (2-butenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] -quinoline-7-carboxylic acid 2-butenyl ester is boiled in 10 ml of 2n NaOH 25 for 10 minutes under reflux. It is filtered, acidified with hydrochloric acid and the solid product obtained is recrystallized from dimethylformamide. Melting point 276-286 ° C. Yield 0.43 g.

Eksempel 8.Example 8.

5-(1-butenyl)-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]quinolin- 7-carboxylsyre.5- (1-Butenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

142949 13 0,30 g 5-(2-butenyl)-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]-quinolin-7-carboxylsyre opvarmes 1 3 ml 5n NaOH og 1,5 ml ethylenglycol i 4 timer til 130°C- Der fortyndes med vand, 5 syrnes med saltsyre, og det opnåede faste produkt omkrystalliseres fra dimethylsulfoxid/vand. Smeltepunkt 270-271°C. Udbytte 0,11 g.0.30 g of 5- (2-butenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid is heated in 3 ml of 5n NaOH and 1 5 ml of ethylene glycol for 4 hours to 130 ° C. Dilute with water, acidify with hydrochloric acid and the resulting solid product is recrystallized from dimethylsulfoxide / water. Melting point 270-271 ° C. Yield 0.11 g.

Eksempel 9.Example 9

5-(2-methyl-2-propenyl)-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]-10 quinolin-7-carboxylsyre.5- (2-methyl-2-propenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] -quinoline-7-carboxylic acid.

a) 5-(2-methyl-2-propenyl)-8-oxo-2,3,5,8-tetrahydro-furo-[2,3-g]quinolin-7-carboxylsyre-(2-methyl-2-propenyl)-ester.a) 5- (2-methyl-2-propenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid (2-methyl-2 propenyl) ester.

2,3 g 8-hydroxy-2,3-dihydrofuro[2,3“g]quinolin-7-carboxyl*= syre indføres i en suspension af 3,0 g natriumhydroxid i 20 15 ml dimethylsulfoxid, hvorpå der tilsættes 6,0 g methallyl-bromid. Der omrøres i 2 timer ved stuetemperatur, udhældes i vand, og det opnåede faste produkt omkrystalliseres fra methanol. Smeltepunkt 169-172°C. Udbytte 0,80 g.2.3 g of 8-hydroxy-2,3-dihydrofuro [2.3 g] quinoline-7-carboxylic acid are introduced into a suspension of 3.0 g of sodium hydroxide in 15 ml of dimethylsulfoxide, to which 6.0 g of methallyl bromide. The mixture is stirred for 2 hours at room temperature, poured into water and the resulting solid product is recrystallized from methanol. Melting point 169-172 ° C. Yield 0.80 g.

b) 5-(2-methyl-2-propenyl)-8-ΟΧΟ-2,3,5,8-tetrahydro-furo- 20 [2,3-g]quinolin-7-carboxylsyre.b) 5- (2-methyl-2-propenyl) -8-ΟΧΟ-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

0,75 g 5-(2-methyl-2-propenyl)-8-ΟΧΟ-2,3,5,8-tetrahydro-furo [2,3-g]quinolin-7-carboxylsyre-(2-methyl-2-propenyl)-ester suspenderes i 10 ml 2n NaOH og koges i 10 minutter under tilbagesvaling. Der filtreres, syrnes med saltsyre, og 25 det opnåede produkt omkrystalliseres fra dimethylformamid. Smeltepunkt 265-272°C. Udbytte 0,30 g.0.75 g of 5- (2-methyl-2-propenyl) -8-ΟΧΟ-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid (2-methyl-2) (propenyl) ester is suspended in 10 ml of 2n NaOH and refluxed for 10 minutes. It is filtered, acidified with hydrochloric acid and the product obtained is recrystallized from dimethylformamide. Melting point 265-272 ° C. Yield 0.30 g.

Eksempel 10.Example 10.

5-(2-methyl-l-propenyl)-8-oxo-2,3,5,8-tetrahydro-furo[2,3-g]-5- (2-methyl-l-propenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] -

Claims (2)

8-OXO-2,3,5,8-tétrahydro-5-vinyl-furo[2,3-g]quinolin-7-10 carboxylsyre, natriumsalt. 0,23 g 8-ΟΧΟ-2,3,5,8-tetrahydro-5-vinyl-furo[2,3-g]quinolin-7-carboxylsyre opløses i 0,9 ml ln NaOH. Der inddampes i vakuum og resten omkrystalliseres fra isopropanol/vand 8:2. Smeltepunkt 253-257°C. Udbytte 0,13 g.8-OXO-2,3,5,8-tetrahydro-5-vinyl-furo [2,3-g] quinoline-7-10 carboxylic acid, sodium salt. Dissolve 0.23 g of 8-β-2,3,5,8-tetrahydro-5-vinyl-furo [2,3-g] quinoline-7-carboxylic acid in 0.9 ml of 1N NaOH. Evaporate in vacuo and the residue is recrystallized from isopropanol / water 8: 2. Melting point 253-257 ° C. Yield 0.13 g. 15 Patentkrav. — —*» — »—* — »·» Analogifremgangsmåde til fremstilling af 8-oxo-2,3,5,8-te= trahydro-furo[2,3-g]quinolin-7-carboxylsyrederivater med den almene formel I .0 COOR2 T T T «> i,1 20 hvori R"*" hetegner en umættet, ligekædet eller forgrenet 2 hydrocarbongruppe med 2-6 carbonatomer, og R betegner hydrogen eller en mættet eller umættet ligekædet eller for-15 Patent claims. - Analogy Process for the Preparation of 8-Oxo-2,3,5,8-te = Trahydro-Furo [2,3-g] Quinoline-7-Carboxylic Acid Derivatives of General Formula I .0 COOR2 TTT «> i, 1 20 wherein R" * "denotes an unsaturated, straight or branched 2 hydrocarbon group of 2-6 carbon atoms and R represents hydrogen or a saturated or unsaturated straight or branched chain.
DK300076A 1975-07-04 1976-07-02 ANALOGY PROCEDURE FOR PREPARING 8-OXO-2,3,5,8-TETRAHYDRO-FURO (2,3-G) QUINOLIN-7-CARBOXYLIC ACID DERIVATIVES DK142949C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19752530412 DE2530412A1 (en) 1975-07-04 1975-07-04 CHINOLINCARBONIC ACID DERIVATIVES II
DE2530412 1975-07-04

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DK300076A DK300076A (en) 1977-01-05
DK142949B true DK142949B (en) 1981-03-02
DK142949C DK142949C (en) 1981-10-05

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DK300076A DK142949C (en) 1975-07-04 1976-07-02 ANALOGY PROCEDURE FOR PREPARING 8-OXO-2,3,5,8-TETRAHYDRO-FURO (2,3-G) QUINOLIN-7-CARBOXYLIC ACID DERIVATIVES

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JP (1) JPS5223096A (en)
BE (1) BE843738A (en)
CA (1) CA1071209A (en)
CH (1) CH626894A5 (en)
DE (1) DE2530412A1 (en)
DK (1) DK142949C (en)
FR (1) FR2315932A1 (en)
IE (1) IE43256B1 (en)
IL (1) IL49967A0 (en)
LU (1) LU75294A1 (en)
NL (1) NL7607417A (en)
PT (1) PT65299B (en)
SE (1) SE7607515L (en)

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DE2030899A1 (en) * 1970-06-18 1971-12-23 Schering Ag, 1000 Berlin Und 4619 Bergkamen Quinoline carboxylic acid derivatives

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FR2315932B1 (en) 1979-07-20
DK142949C (en) 1981-10-05
PT65299A (en) 1976-07-01
DE2530412A1 (en) 1977-01-20
JPS5223096A (en) 1977-02-21
IE43256L (en) 1977-01-04
FR2315932A1 (en) 1977-01-28
IL49967A0 (en) 1976-09-30
CA1071209A (en) 1980-02-05
BE843738A (en) 1977-01-03
IE43256B1 (en) 1981-01-14
CH626894A5 (en) 1981-12-15
NL7607417A (en) 1977-01-06
SE7607515L (en) 1977-01-05
DK300076A (en) 1977-01-05
LU75294A1 (en) 1977-02-23
PT65299B (en) 1977-12-13

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