NO760764L - - Google Patents

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Publication number
NO760764L
NO760764L NO760764A NO760764A NO760764L NO 760764 L NO760764 L NO 760764L NO 760764 A NO760764 A NO 760764A NO 760764 A NO760764 A NO 760764A NO 760764 L NO760764 L NO 760764L
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formula
compounds
methyl
hours
manner known
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NO760764A
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Norwegian (no)
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J Nadelson
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Sandoz Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/60—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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

Fremgangsmåte for fremstilling av nye organiske forbindelser. Procedure for the production of new organic compounds.

Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av nye 3-(o<-iminobenzyl)-4-hydroksy-2(1H)-pyridoner med formel I The present invention relates to a process for the production of new 3-(o<-iminobenzyl)-4-hydroxy-2(1H)-pyridones of formula I

hvori R^, og R. er like eller forskjellige og i det enkelte tilfelle betyr hydrogen, fluor, klor, trifluormetylgruppen, en alkyl- eller alkoksygruppe med 1 til 4 karbonatomer, og R^ står for en alkylgruppe med 1 til 4 karbonatomer. in which R^, and R. are the same or different and in the individual case means hydrogen, fluorine, chlorine, the trifluoromethyl group, an alkyl or alkoxy group with 1 to 4 carbon atoms, and R^ stands for an alkyl group with 1 to 4 carbon atoms.

Det ses at forbindelsene med formel I kan opptre i tautomere former med formler Ia, Ib og Ic It is seen that the compounds of formula I can occur in tautomeric forms with formulas Ia, Ib and Ic

hvori R-^, R3 0<3 R4^ar ^en ovennevnte betydning. wherein R-^, R3 0<3 R4^are ^a above-mentioned meaning.

For enkelhets skyld omhandles i det følgende bare forbindelsene i form av formel I henholdsvis deres kjemiske betegnelse, men oppfinnelsen er ikke begrenset til denne tautomere form. For the sake of simplicity, only the compounds in the form of formula I and their chemical designation are dealt with in the following, but the invention is not limited to this tautomeric form.

Det særegne ved fremgangsmåten i henhold til oppfinnelsen er at forbindelser med formel II The peculiarity of the method according to the invention is that compounds of formula II

hvori R^, R2 / R3og R^har den ovennevnte betydning, reduseres i et inert organisk løsningsmiddel. Fremgangsmåten kan gjennomføres på i og for seg kjent måte, f.eks. ved katalytisk hydrogener ing. Egnede katalysatorer omfatter palladiumkull, platinaoksyd og Raney-nikkel, foretrukket palladiumkull. Hensiktsmessig anvendes et inert organisk løsningsmiddel, som en lavere alkanol, f.eks. metanol eller foretrukket etanol. Hydrogeneringen gjennomføres hensiktsmessig ved temperaturer mellom 10 og 50°C, foretrukket mellom 20 og 30°C. Reaksjonstiden utgjør f.eks. 1 til 10 timer og ligger vanlig ved 2 til 3 timer. in which R 1 , R 2 / R 3 and R 3 have the above meaning, is reduced in an inert organic solvent. The procedure can be carried out in a manner known per se, e.g. by catalytic hydrogener ing. Suitable catalysts include palladium charcoal, platinum oxide and Raney nickel, preferably palladium charcoal. An inert organic solvent, such as a lower alkanol, e.g. methanol or preferably ethanol. The hydrogenation is conveniently carried out at temperatures between 10 and 50°C, preferably between 20 and 30°C. The reaction time is e.g. 1 to 10 hours and usually lies at 2 to 3 hours.

De ved fremgangsmåten i henhold til oppfinnelsen erholdte forbindelser med formel I kan isoleres og renses på i og for seg kjent måte. Forbindelsene med formel I kan på i og for seg kjent måte overføres The compounds of formula I obtained by the method according to the invention can be isolated and purified in a manner known per se. The compounds of formula I can be transferred in a manner known per se

i sine syreaddisjonssalter og omvendt.in their acid addition salts and vice versa.

De som utgangsforbindelser anvendte forbindelser med formel II kan fremstilles, ved at forbindelser med formel III hvori R^; R2, R3og R^har den ovennevnte betydning, ringsluttes i nærvær av en syre og et løsningsmiddel. The compounds of formula II used as starting compounds can be prepared by compounds of formula III in which R^; R 2 , R 3 and R 3 have the above-mentioned meaning, are ring-closed in the presence of an acid and a solvent.

Ringslutningen kan gjenn&mførés^.: på i og for seg kjent måte,The circular conclusion can be repeated in a manner known in and of itself,

f.eks. ved behandling av forbindelser med formel III med en syre, som saltsyre, p-toluensulfonsyre, polyfosforsyre eller foretrukket svovelsyre, hensiktsmessig i et inert løsningsmiddel, som et aromatisk hydrokarbon,, som f.eks. benzen ell.iT toluen. Foretrukket kan et overskudd av syre anvendes som reaksjonsmedium. Fremgangsmåten gjennomføres hensiktsmessig ved temperaturer mellom 80 og 150°C, foretrukket ved .tilbakeløpstemperaturen for reaksjons-blandingen. Reaksjonstiden kan utgjøre f.eks. 12 til 36 timer og ligger vanlig ved 20 til 36 timer. e.g. by treating compounds of formula III with an acid, such as hydrochloric acid, p-toluenesulfonic acid, polyphosphoric acid or preferably sulfuric acid, suitably in an inert solvent, such as an aromatic hydrocarbon, such as e.g. benzene or toluene. Preferably, an excess of acid can be used as reaction medium. The process is conveniently carried out at temperatures between 80 and 150°C, preferably at the reflux temperature for the reaction mixture. The reaction time can be e.g. 12 to 36 hours and usually lies at 20 to 36 hours.

De erholdte forbindelser med formel II kan isoleres og rensesThe obtained compounds of formula II can be isolated and purified

på i .og for seg kjent måte.in a manner known in and of itself.

Forbindelsene med formel III lar seg fremstille ved at forbindelser med formel IV hvori R^, R2, R^ og R 4 har den ovennevnte betydning, oksyderes. The compounds of formula III can be prepared by oxidizing compounds of formula IV in which R 1 , R 2 , R 1 and R 4 have the above meaning.

Oksydasjonen kan gjennomføres på i og for seg kjent måte, f.eks. med kaliumpermanganat eller foretrukket kromtrioksyd, og under vandig sure betingelser. De foretrukne syrer omfatter mineralsyrer som svovelsyre eller saltsyre og foretrukket organiske syrer, spesielt eddiksyre. Reaksjonstemperaturen ligger hensiktsmessig mellom 10 og 50°C, foretrukket mellom 20 og 30°C, og reaksjonstiden kan f.eks. utgjøre 1 til 5 timer, og ligger vanlig mellom 1.5 og 2.5 timer. The oxidation can be carried out in a manner known per se, e.g. with potassium permanganate or preferably chromium trioxide, and under aqueous acidic conditions. The preferred acids include mineral acids such as sulfuric acid or hydrochloric acid and preferred organic acids, especially acetic acid. The reaction temperature is conveniently between 10 and 50°C, preferably between 20 and 30°C, and the reaction time can e.g. amount to 1 to 5 hours, and is usually between 1.5 and 2.5 hours.

De erholdte forbindelser med formel III kan isoleres og rensesThe obtained compounds of formula III can be isolated and purified

på i og for seg kjent måte.in a manner known per se.

Forbindelsene med formel IV kan fremstilles ved at forbindelser med formel V The compounds of formula IV can be prepared by making compounds of formula V

hvori R^og R^har den ovennevnte betydning, i et inert organisk løsningsmiddel omsettes med forbindelser med formel VI wherein R^ and R^ have the above meaning, in an inert organic solvent react with compounds of formula VI

hvori R2og R4 har den ovennevnte betydning. wherein R 2 and R 4 have the above meaning.

Omsetningen gjennomføres hensiktsmessig ved temperaturer mellomThe turnover is suitably carried out at temperatures between

-75 og -55°C, foretrukket mellom -65 og -60°C. Egnede løsnings-midler omfatter alifatiske hydrokarboner som pentan, heksan og heptan, og foretrukket etere som dietyleter eller spesielt tetrahydrofuran. Reaksjonstiden kan f.eks. utgjøre mellom 1 og 5 timer, spesielt mellom 2.5 og 3.5 timer.. Forbindelsene med formel V fremstilles hensiktsmessig in situ på i og for seg kjent måte fra de tilsvarende 3-fenyl-N-alkyl-5-metyl-isoksazol-4-karboksamider ved omsetning ved f.eks. et C^_^-alkyllitium, spesielt n-butyllitium f.eks. under betingelsene for den etter-følgende fremgangsmåte for fremstilling av forbindelsene med formel IV. -75 and -55°C, preferably between -65 and -60°C. Suitable solvents include aliphatic hydrocarbons such as pentane, hexane and heptane, and preferably ethers such as diethyl ether or especially tetrahydrofuran. The reaction time can e.g. be between 1 and 5 hours, especially between 2.5 and 3.5 hours. The compounds of formula V are suitably prepared in situ in a manner known per se from the corresponding 3-phenyl-N-alkyl-5-methyl-isoxazole-4-carboxamides in case of turnover by e.g. a C^_^-alkyllithium, especially n-butyllithium e.g. under the conditions of the following process for the preparation of the compounds of formula IV.

De erholdte forbindelser med formel IV kan isoleres og rensesThe obtained compounds of formula IV can be isolated and purified

på i og for seg kjent måte.in a manner known per se.

Forbindelsene med formel VI og de for fremstilling av forbindelser med formel V nødvendige utgangsforbindelser er enten kjente eller kan fremstilles fra kjente utgangsforbindelser på i og for seg kjent måte. The compounds of formula VI and the starting compounds necessary for the preparation of compounds of formula V are either known or can be prepared from known starting compounds in a manner known per se.

Forbindelsene med formel I utmerker seg ved farmakodynamiske egenskaper. Spesielt har forbindelsene med formel I en søvn-innledende og lett beroligende virkning, påvist f.eks. ved resultatene av forsøk som er beskrevet av Winter (J.Pharmacol. and Exp. Therap. 94, 7-11, (1948)), av S. Irwin (Gordon Research Conference, The compounds of formula I are distinguished by their pharmacodynamic properties. In particular, the compounds of formula I have a sleep-inducing and slightly sedative effect, demonstrated e.g. by the results of experiments described by Winter (J.Pharmacol. and Exp. Therap. 94, 7-11, (1948)), by S. Irwin (Gordon Research Conference,

Medicinal Ghemistry,(1959)) og Chen (Symposium on Sedative and Hypnotic Drugs, Williams and Wilkins (1954)), av Reed-Muench (American Journal of Hygiene 27, 493-497, (1938)) og av I. Geiler (Psychopharmacologia, I, 42-492 (1960)). Medicinal Ghemistry,(1959)) and Chen (Symposium on Sedative and Hypnotic Drugs, Williams and Wilkins (1954)), by Reed-Muench (American Journal of Hygiene 27, 493-497, (1938)) and by I. Geiler ( Psychopharmacologia, I, 42-492 (1960)).

Forbindelsene med formel I kan derfor anvendes for søvninnledningThe compounds of formula I can therefore be used for sleep induction

og som lett beroligende middel. Den for innledning av søvnen tilførte daglige dose bør utgjøre mellom 35 og 1000 mg og kan tilføres i flere delmengder på mellom 8 og 500 mg 2-4 ganger daglig, men foretrukket som en engangsdose før man skal sove. For anvendelse som lett beroligende middel skal forbindelsene med formel I tilføres i en daglig dose på mellom 30 og 1500 mg, hensiktsmessig i flere and as a mild sedative. The daily dose given for the initiation of sleep should be between 35 and 1000 mg and can be given in several sub-quantities of between 8 and 500 mg 2-4 times a day, but preferably as a single dose before going to sleep. For use as a mild sedative, the compounds of formula I must be administered in a daily dose of between 30 and 1500 mg, suitably in several

delmengder på mellom 7.5 og 750 mg 2 til 4 ganger daglig eller i retardform. partial amounts of between 7.5 and 750 mg 2 to 4 times a day or in retard form.

Forbindelsene med formel I kan anvendes i den fri hydroksyformThe compounds of formula I can be used in the free hydroxy form

eller i form av farmasøytisk tålbare salter, idet saltene størrelses-ordenmessig har den samme virkning som de tilsvarende fri former. Egnede saltformer er f.eks. alkalimetallsaltené/spesielt litiuni7, natrium-, kaliumsaltene, og jordalkalimetallsaltene, spesielt magnesium- eller kalsiumsaltene. or in the form of pharmaceutically tolerable salts, the salts having in terms of order of magnitude the same effect as the corresponding free forms. Suitable salt forms are e.g. alkali metal salts/especially lithium, the sodium, potassium salts, and the alkaline earth metal salts, especially the magnesium or calcium salts.

Forbindelsene med formel I kan blandes med vanlige farmasøytisk tålbare fortynnings- og bærermidler og eventuelt tilføres også med andre vanlige farmasøytiske tilsetningsstoffer, i form av hårdt fylte kapsler eller tabletter. The compounds of formula I can be mixed with usual pharmaceutically acceptable diluents and carriers and optionally also added with other usual pharmaceutical additives, in the form of hard-filled capsules or tablets.

De foretrukne forbindelser med formel I er dem hvori og R4harThe preferred compounds of formula I are those in which and R 4 have

de følgende betydninger:the following meanings:

R^= hydrogen, klor, fluor, trifluormetyl, metyl eller metoksy, R^= hydrogen, chlorine, fluorine, trifluoromethyl, methyl or methoxy,

spesielt hydrogen eller klor og helt spesielt hydrogenespecially hydrogen or chlorine and especially hydrogen

R^= hydrogen,R^= hydrogen,

R^= hydrogen, klor, fluor, trifluormetyl, metyl eller metoksy, R^= hydrogen, chlorine, fluorine, trifluoromethyl, methyl or methoxy,

spesielt hydrogen, klor, trifluormetyl, metyl eller metoksyespecially hydrogen, chlorine, trifluoromethyl, methyl or methoxy

R^= metyl.R 1 = methyl.

De spesielt foretrukne forbindelser med formel I er dem hvori en kombinasjon av de ovenfor som foretrukket nevnte betydninger foreligger. Den mest foretrukne forbindelse er 3-(c<-iminobenzyl) - 4-hydroksy-6-fenyl-l-metyl-2(1H)-pyridon. The particularly preferred compounds of formula I are those in which a combination of the meanings mentioned above as preferred exists. The most preferred compound is 3-(c<-iminobenzyl)-4-hydroxy-6-phenyl-1-methyl-2(1H)-pyridone.

Eksempel 1: 3- -iminobenzyl)-4.-hydroksy.-6.-f enyl-l-metyl-2 (1H) -py r. i do Example 1: 3- (iminobenzyl)-4.-hydroxy.-6.-phenyl-1-methyl-2(1H)-pyrr.i do

a) 3-f§nYlz53_(^.zhY^£2]S§Yf§2§tYiil^ZS§£Yli§23S§§52llållS§£^2]S§§mi^ a) 3-f§nYlz53_(^.zhY^£2]S§Yf§2§tYiil^ZS§£Yli§23S§§52llållS§£^2]S§§mi^

(forbindelse med formel IV)(compound of formula IV)

Til en til -65°C avkjølt suspensjon av 75 g (0.348 mol) 3-fenyl-5,N-To a suspension cooled to -65°C of 75 g (0.348 mol) 3-phenyl-5,N-

) )

dimetyl-isoksazol-4-karboksamid og 1 liter tetrahydrofuran tilsettes dråpevis 478 ml 1,6 M n-butyllitiumløsning i heksan Dimethyl-isoxazole-4-carboxamide and 1 liter of tetrahydrofuran are added dropwise to 478 ml of 1.6 M n-butyllithium solution in hexane

(0.765 mol), idet temperaturen holdes mellom -60 og -70°C; Etter avsluttet tilsetning omrøres den orangefargede suspensjon i v : (0.765 mol), the temperature being kept between -60 and -70°C; After the addition is complete, the orange-coloured suspension is stirred in v:

1 1/2 time ved -60 til -70°C og tilsettes så dråpevis 37.2 g1 1/2 hours at -60 to -70°C and then add dropwise 37.2 g

(0.350 mol) benzaldehyd i 375 ml tetrahydrofuran, idet temperaturen holdes ved -60 til -70°C. Etter avsluttet tilsetning omrøres blandingen i 1 1/2 time ved -60.til -70°C, oppvarmes deretter til -30°C og tilsettes hurtig mettet ammoniumkloridløsning. < Blandingen fortynnes med tetrahydrofuran og lagene skilles. Tetra-hydrof uranlaget vaskes to ganger med 50% natriumkloridløsning og en gang med mettet natriumkloridløsning, tørres over vannfritt magnesiumsulfat, filtreres og inndampes til tørrhet i vakuum. Den faste rest utgnis i en blanding av eter og petroleter (50:50), filtreres og vaskes med kold eter hvorved den i overskriften nevnte forbindelse, smp. 183 - 184°C, erholdes. (0.350 mol) of benzaldehyde in 375 ml of tetrahydrofuran, the temperature being maintained at -60 to -70°C. After the addition is complete, the mixture is stirred for 1 1/2 hours at -60 to -70°C, then heated to -30°C and saturated ammonium chloride solution is quickly added. < The mixture is diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% sodium chloride solution and once with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo. The solid residue is triturated in a mixture of ether and petroleum ether (50:50), filtered and washed with cold ether whereby the compound mentioned in the title, m.p. 183 - 184°C, is obtained.

b) N-metYl-5-fenacylzS^fenYlisoksazol-4-karbgksamid (forbindelse med formel III) b) N-methyl-5-phenacyl2S2-phenylisoxazole-4-carbhexamide (compound of formula III)

En suspensjon av 50 g (0.155 mol) 3-fenyl-5-(P-hydroksyfenetyl)~N-metyl-isoksazol-4-karboksamid og 800 ml eddiksyre tilsettes dråpevis ved romtemperatur 18.4 g (0.185 mol) kromtrioksyd i 185 ml vann. Den erholdte løsning omrøres i 2 timer ved romtemperatur og en del av eddiksyren fjernes i vakuum. Resten uthelles i isblandet vann og ekstraheres med metylenklorid. Metylenkloridlaget vaskes med 2N natriumhydroksyd, tørres over vannfritt magnesium-sulf at, filtreres og inndampes i vakuum.. Den faste rest utrives med varm eter, avkjøles til 0°C og filtreres, hvorved den i overskriften nevnte forbindelse, smp. 125 til 128°C, erholdes. A suspension of 50 g (0.155 mol) 3-phenyl-5-(P-hydroxyphenethyl)~N-methyl-isoxazole-4-carboxamide and 800 ml acetic acid is added dropwise at room temperature to 18.4 g (0.185 mol) chromium trioxide in 185 ml water. The resulting solution is stirred for 2 hours at room temperature and part of the acetic acid is removed in vacuo. The residue is poured into ice-cold water and extracted with methylene chloride. The methylene chloride layer is washed with 2N sodium hydroxide, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with hot ether, cooled to 0°C and filtered, whereby the compound mentioned in the title, m.p. 125 to 128°C, is obtained.

c) 5-metyl-3,6-difenyl-isoksazolo/4 ,5-c7pyridin-4(5H)-on c) 5-methyl-3,6-diphenyl-isoxazolo[4,5-c7pyridin-4(5H)-one

(Forbindelse med formel II)(Compound of formula II)

En blanding av 26.1 g (0.0815 mol) N-metyl-5-fenacyl-3-fenylisoksazol-4-karboksamid og 261 ml 2M svovelsyre oppvarmes i 24 timer til koking (tilbakeløp). Blandingen avkjøles og ekstraheres med metylenklorid. Metylenkloridlaget vaskes med vann og deretter med mettet natriumkloridløsning, tørres over vannfritt magnesium sulfat, filtreres og inndampes i vakuum. Resten utrives med eter og omkrystalliseres fra etanol, hvorved den i overskriften nevnte forbindelse, smp. 149 - 151.5°C, erholdes. A mixture of 26.1 g (0.0815 mol) of N-methyl-5-phenacyl-3-phenylisoxazole-4-carboxamide and 261 ml of 2M sulfuric acid is heated for 24 hours to boiling (reflux). The mixture is cooled and extracted with methylene chloride. The methylene chloride layer is washed with water and then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is triturated with ether and recrystallized from ethanol, whereby the compound mentioned in the title, m.p. 149 - 151.5°C, is obtained.

<d>) 3-iminobenzyl )_-4-hYdrgksYz6-f <d>) 3-Iminobenzyl )_-4-hYdrgksYz6-f

(Forbindelse med formel I)(Compound of formula I)

En blanding av 16.5 g (0.0545 mol) N-metyl-3,6-difenyl-isoksazolo-/4,57pyridin-4(5H)-on, 330 ml etanol og 1.65 g 10% palladium-kull-katalysator hydrogeneres ved romtemperatur og 3.4 atmosfærer. Hydrogeneringen avsluttes så snart en ekvivalent hydrogen er absorbert (ca. 2.5 timer). Blandingen tilsettes metylenklorid og katalysatoren fjernes ved filtrering. Løsningen inndampes i vakuum til ca. 50 ml og tilsettes eter for utskilling av faststoffer, A mixture of 16.5 g (0.0545 mol) N-methyl-3,6-diphenyl-isoxazolo-[4,57pyridin-4(5H)-one, 330 ml of ethanol and 1.65 g of 10% palladium-charcoal catalyst is hydrogenated at room temperature and 3.4 atmospheres. The hydrogenation ends as soon as one equivalent of hydrogen has been absorbed (approx. 2.5 hours). Methylene chloride is added to the mixture and the catalyst is removed by filtration. The solution is evaporated in vacuum to approx. 50 ml and add ether to separate solids,

som frafiltrert gir den i overskriften nevnte forbindelse med smp. 238 - 240°C. Forbindelsen løses i metanol og tilsettes natriumhydroksydløsning, idet man etter inndamping erholder natriumsaltet av 3-((3-iminobenzyl)-4-hydroksy-6-fenyl-l-metyl-2(1H)-pyridon.. which, filtered off, gives the compound mentioned in the title with m.p. 238 - 240°C. The compound is dissolved in methanol and sodium hydroxide solution is added, obtaining after evaporation the sodium salt of 3-((3-iminobenzyl)-4-hydroxy-6-phenyl-1-methyl-2(1H)-pyridone..

Eksempel 2:Example 2:

Analogt eksempel 1 og under anvendelse av egnede utgangsforbindelser i omtrent ekvivalente mengder kommer man frem til forbindelser med formel IV, III, II og I, hvori R^, R2, R-^ og R^har de i den følgende tabell angitte betydninger: Analogous to example 1 and using suitable starting compounds in approximately equivalent amounts, compounds of formula IV, III, II and I are arrived at, in which R^, R2, R-^ and R^ have the meanings indicated in the following table:

Claims (1)

Fremgangsmåte for fremstilling av nye 3- (c< -iminobenzyl)-4- hydroksy-2(1H)-pyridoner med formel I Process for the preparation of new 3-(c<-iminobenzyl)-4- hydroxy-2(1H)-pyridones of formula I hvori R^ , R2 og R4 er like eller forskjellige og i det enkelte tilfelle betyr hydrogen, fluor, klor, trifluormetylgruppe, en alkyl- eller alkoksygruppe med 1-4 karbonatomer, og R^ står for en alkylgruppe med 1-4 karbonatomer, karakterisert ved at forbindelser med formel II in which R^ , R2 and R4 are the same or different and in the individual case means hydrogen, fluorine, chlorine, trifluoromethyl group, an alkyl or alkoxy group with 1-4 carbon atoms, and R^ stands for an alkyl group with 1-4 carbon atoms, characterized in that compounds of formula II hvori R^ , R2 , R^ og R4 har den ovennevnte betydning, reduseres i et inert organisk løsningsmiddel.wherein R 1 , R 2 , R 1 and R 4 have the above meaning, is reduced in an inert organic solvent.
NO760764A 1975-03-14 1976-03-05 NO760764L (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US55841975A 1975-03-14 1975-03-14
US58476475A 1975-06-09 1975-06-09

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NO760764L true NO760764L (en) 1976-09-15

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JP (1) JPS51113877A (en)
AT (1) AT358590B (en)
AU (1) AU505460B2 (en)
CA (1) CA1064038A (en)
CH (1) CH601241A5 (en)
DE (1) DE2609127A1 (en)
DK (1) DK98176A (en)
ES (1) ES446035A1 (en)
FI (1) FI760572A (en)
FR (2) FR2303545A1 (en)
GB (3) GB1545576A (en)
HK (2) HK46581A (en)
IE (1) IE43907B1 (en)
IL (1) IL49202A (en)
MY (2) MY8200142A (en)
NL (1) NL7602494A (en)
NO (1) NO760764L (en)
NZ (1) NZ180299A (en)
PT (1) PT64899B (en)
SE (1) SE7602542L (en)
YU (1) YU63676A (en)

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US4179566A (en) * 1975-08-06 1979-12-18 Sandoz, Inc. Substituted hydroxy pyridones
US4238616A (en) * 1977-01-19 1980-12-09 Sandoz, Inc. 3-(Substituted)phenyl-5-(β-hydroxyphenethyl)-N-(alkyl)-isoxazole-4-carboxamides
JPWO2002102807A1 (en) * 2001-06-14 2004-09-30 萬有製薬株式会社 Novel isoxazolopyridone derivatives and uses thereof
GB0119911D0 (en) 2001-08-15 2001-10-10 Novartis Ag Organic Compounds

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YU63676A (en) 1982-02-28
CA1064038A (en) 1979-10-09
MY8200141A (en) 1982-12-31
FR2303545B1 (en) 1982-03-19
GB1545576A (en) 1979-05-10
SE7602542L (en) 1976-09-15
ES446035A1 (en) 1977-09-16
HK46581A (en) 1981-09-25
IE43907L (en) 1976-09-14
FR2371435B1 (en) 1980-03-07
JPS51113877A (en) 1976-10-07
CH601241A5 (en) 1978-06-30
AU1201276A (en) 1977-09-22
HK46681A (en) 1981-09-25
GB1545577A (en) 1979-05-10
PT64899B (en) 1977-08-18
FR2371435A1 (en) 1978-06-16
DK98176A (en) 1976-09-15
GB1545575A (en) 1979-05-10
IL49202A0 (en) 1976-05-31
MY8200142A (en) 1982-12-31
ATA181576A (en) 1980-02-15
IE43907B1 (en) 1981-07-01
FI760572A (en) 1976-09-15
NL7602494A (en) 1976-09-16
DE2609127A1 (en) 1976-09-23
PT64899A (en) 1976-04-01
AU505460B2 (en) 1979-11-22
IL49202A (en) 1979-09-30
NZ180299A (en) 1978-07-28
FR2303545A1 (en) 1976-10-08
AT358590B (en) 1980-09-25

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