NO774155L

NO774155L - NEW PHENYL DERIVATIVES.

Info

Publication number: NO774155L
Application number: NO774155A
Authority: NO
Inventors: Ernest Mohacsi
Original assignee: Hoffmann La Roche
Priority date: 1976-12-06
Filing date: 1977-12-05
Publication date: 1978-06-07
Also published as: IE46003B1; IL53532A0; FI773636A; AR219510A1; NL7713432A; IE46003L; SE7713779L; AU3126477A; ATA869277A; FR2372808B1; AU514827B2; ES472573A1; ES472572A1; IL53532A; FR2372808A1; GB1589792A; MC1172A1; NZ185860A; IT1143727B; LU78638A1

Description

Nye fenylderivaterNew phenyl derivatives

Foreliggende oppfinnelse vedrører venstredreiende 3-fenoksy-N-substituerte morfinanderivater med den generelle formel The present invention relates to levorotatory 3-phenoxy-N-substituted morphinan derivatives with the general formula

hvor R betyr halogen, nitro, lavere alkyl, lavere alkoksy, hydroksy eller hydrogen, where R means halogen, nitro, lower alkyl, lower alkoxy, hydroxy or hydrogen,

R-^hydrogen, lavere alkyl, lavere alkenyl, gruppen R-^hydrogen, lower alkyl, lower alkenyl, the group

-CH2(CH2)pR2 eller -CO~(CH2)p-R2,-CH2(CH2)pR2 or -CO~(CH2)p-R2,

R2en hetero-aromatisk eller aromatisk rest eller cyklo-lavere alkyl, R2 a hetero-aromatic or aromatic residue or cyclo-lower alkyl,

p et helt tall fra 0 til 3, ogp an integer from 0 to 3, and

n betyr et helt tall fra 1 til 5,n means an integer from 1 to 5,

samt farmasøytisk anvendelige salter derav.as well as pharmaceutically usable salts thereof.

Uttrykket "halogen" som anvendt i denne beskrivelsen omfatterThe term "halogen" as used in this specification includes

de fire formene brom, klor, fluor og jod, idet fluor og brom er foretrukket. Begrepet "lavere alkyl" omfatter såvel rettkjedete som forgrenete mettete hydrokarbonrester med 1-7 C-atomer, som metyl, etyl, n-propyl, isopropyl, n-butyl, isobutyl og lignende, hvorved metyl er foretrukket. Uttrykket "lavere alkenyl" betegner både rettkjedete og forgrenete alifatiske hydrokarbonrester med 2-7 C-atomer, som har en olefinisk dobbelt-binding, som vinyl, allyl, prop-2-en-l-yl og lignende. De foretrukne lavere alkenylgrupper er -CH2-CH=CH2, the four forms bromine, chlorine, fluorine and iodine, with fluorine and bromine being preferred. The term "lower alkyl" includes both straight-chain and branched saturated hydrocarbon residues with 1-7 C atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, whereby methyl is preferred. The term "lower alkenyl" denotes both straight-chain and branched-chain aliphatic hydrocarbon residues of 2-7 C atoms, which have an olefinic double bond, such as vinyl, allyl, prop-2-en-1-yl and the like. The preferred lower alkenyl groups are -CH2-CH=CH2,

Uttrykket "cyklo-lavere alkyl" betegner mettete cykliske alifa-^tiske hydrokarbongrupper med en ring på 3-6 C-atomer. Foretrukne cyklo-lavere alkylgrupper er: cyklopropyl, cyklobutyl og cyklo-heksyl. Uttrykket "lavere alkoksy" betegner lavere alkoksygrupper med 1-7 C-atomer, som metoksy, etoksy, propoksy, isopropoksy og lignende. The term "cyclo-lower alkyl" denotes saturated cyclic aliphatic hydrocarbon groups having a ring of 3-6 carbon atoms. Preferred cyclo-lower alkyl groups are: cyclopropyl, cyclobutyl and cyclohexyl. The term "lower alkoxy" denotes lower alkoxy groups with 1-7 C atoms, such as methoxy, ethoxy, propoxy, isopropoxy and the like.

Uttrykket "hetero-aromatisk rest" betegner resten av en hydro-karbonringmed 5 eller 6 ringledd og et oksygen-, nitrogen- eller svovelatom som heteroatom. Foretrukne hetero-aromatiske ringer er tienyl, pyrolyl, furyl, pyridyl, pyranyl og lignende. The term "hetero-aromatic residue" denotes the residue of a hydrocarbon ring with 5 or 6 ring members and an oxygen, nitrogen or sulfur atom as heteroatom. Preferred heteroaromatic rings are thienyl, pyrrolyl, furyl, pyridyl, pyranyl and the like.

Uttrykket "aromatisk rest" betegner resten av et aromatisk hy-drokarbon, som fenyl eller naftyl, hvorved fenyl er foretrukket. The term "aromatic residue" denotes the residue of an aromatic hydrocarbon, such as phenyl or naphthyl, whereby phenyl is preferred.

Forbindelsene ifølge foreliggende oppfinnelsen kan erholdes idet man The compounds according to the present invention can be obtained by

a) omsetter en forbindelse med formelena) reacts a compound with the formula

hvori R-^ har ovennevnte betydning, med en forbindelse med den generelle formel wherein R-^ has the above meaning, with a compound of the general formula

hvori R og n har de ovenfor nevnte betydninger, wherein R and n have the above-mentioned meanings,

og X er halogen,and X is halogen,

elleror

b) for fremstilling av en forbindelse med formel I, hvorib) for the preparation of a compound of formula I, wherein

! R er hydroksy, spalter en eter med formelen ! R is hydroxy, cleaves an ether with the formula

hvori n og R-^har de ovenfor nevnte betydninger, wherein n and R have the above-mentioned meanings,

og R3 betyr lavere alkyl,and R 3 means lower alkyl,

elleror

c) for fremstilling av en forbindelse med formel I, hvori R^betyr -CO-(CH2)p-R2'omsetter en forbindelse med formelen c) for the preparation of a compound of formula I, in which R^ means -CO-(CH2)p-R2' reacts a compound of the formula

hvori n og R har de ovenfor angitte betydninger, med en forbindelse med en forbindelse med formelen hvor R2, p og X har de ovenfor nevnte betydninger, eller d) for fremstilling av en forbindelse med formelen I, hvori R-^betyr -CH2 (CH2) ^R.-,, reduserer en forbindelse med formelen hvori R, R2og p har de foran angitte betydninger, eller e) for fremstilling av en forbindelse med formelen I, hvori R-^ betyr hydrogen, behandler en forbindelse med formelen in which n and R have the above-mentioned meanings, with a compound with a compound of the formula where R 2 , p and X have the above-mentioned meanings, or d) for the preparation of a compound of the formula I, in which R-^ means -CH 2 ( CH2) ^R.-,, reduces a compound of the formula in which R, R2 and p have the above-mentioned meanings, or e) for the preparation of a compound of the formula I, in which R-^ represents hydrogen, treats a compound of the formula

hvori R og n har de foran angitte betydninger, wherein R and n have the above meanings,

med sink i en lavere alkankarbonsyre, ellerwith zinc in a lower alkanecarboxylic acid, or

f) for fremstilling av en forbindelse med formel I, hvori R-^ betyr -CH2(CH2)^R2, omsetter en forbindelse med formelen f) for the preparation of a compound of formula I, in which R-^ means -CH2(CH2)^R2, reacts a compound of the formula

hvori R og n har de ovenfor angitte betydninger, wherein R and n have the meanings given above,

med en forbindelse med formelenwith a connection with the formula

i i in i

hvori X, R2og p har de ovenfor angitte betydninger, wherein X, R 2 and p have the meanings given above,

elleror

g) for fremstilling av en forbindelse med formelen I, hvori'g) for the preparation of a compound of the formula I, wherein'

R-j^ betyr hydrogen, dvs. en forbindelse med formel VII, desalky-lerer en forbindelse med formelen I-C, eller R-j^ means hydrogen, i.e. a compound of formula VII, dealkylates a compound of formula I-C, or

h) for fremstilling av en forbindelse med formelen I, hvori R^betyr -CH2 (CH2) ^R,,, omsetter en forbindelse med formel VII med h) for the preparation of a compound of the formula I, in which R^ means -CH2 (CH2) ^R,,, reacts a compound of the formula VII with

en forbindelse med formel IV, ellera compound of formula IV, or

i) for fremstilling av en forbindelse med formelen I, hvori R^betyr lavere alkyl eller lavere alkenyl, omsetter en forbindelse med formel VII med en forbindelse med formelen i) for the preparation of a compound of the formula I, in which R^ is lower alkyl or lower alkenyl, react a compound of the formula VII with a compound of the formula

hvori X har ovenfor angitte betydning, og wherein X has the above meaning, and

R^betyr lavere alkyl eller lavere alkenyl, eller R 2 means lower alkyl or lower alkenyl, or

k) sykliserer en forbindelse med "formelenk) cyclizes a compound of the formula "

hvori R, R^ og n har den ovenfor nevnte betydning,- in which R, R^ and n have the above-mentioned meaning,-

og om ønsket,and if desired,

1) overfører en forbindelser méd formel I i et farmasøytisk anvendelig syreaddisjonssalt. 1) transfers a compound of formula I in a pharmaceutically usable acid addition salt.

Ifølge fremgangsmåtevariant a) fremstilles en forbindelse med According to method variant a) a compound is prepared with

I IN

i formelen I ved reaksjon av en forbindelse med formel II med in formula I by reaction of a compound of formula II with

en forbindelse med formel III.a compound of formula III.

Omsetningen av en forbindelse med formel II med en forbindelse med formelen III skjer i nærvær av en kobberkatalysator. Reaksjonen utføres i et organisk løsningsmiddel og i nærvær av en uorganisk alkalimetallbase. Prinsipielt kan ethvert konvensjonelt organisk løsningsmiddel anvendes, dog er nitrobenzen, kolli-din, diglym og tertiære aminer foretrukne. Ved de tertiære aminer kommer de cykliske tertiære aminer, som pyridin og tri-iavere alkylaminene, som trimetylamin, trietylamin og lignende i betraktning. Som allerede nevnt gjennomføres reaksjonen i nærvær av en uorganisk alkalimetallbase. Foretrukne baser er alkalime-tallhydroksyder, som kalium- og natriumhydroksyd, samt" alkalimetallkarbonater og -bikarbonater, som natriumkarbonat, kaliumkarbonat, natriumbikarbonat og kaliumbikarbonat. En foretrukken uorganisk base for denne fremgangsmåten er en sva.k base, som kaliumkarbonat. Ved denne reaksjon er temperatur og trykk ikke kritisk. Reaksjonen kan utføres ved romtemperatur og atmosfærestrykk. På den andre siden kan imidlertid om ønsket også høyere temperaturer anvendes. I alminnelighet er det foretrukket å velge temperaturer fra 100 - 250°. Som nevnt finner reaksjonen sted under nærvær av en kobberkatalysator, som kobber(II)klorid, kobber(II)bromid, kobber(II)sulfat, kobber(I)jodid eller en blanding av kobberbronse og metallisk kobber, hvorunder kornet kobber er foretrukket. The reaction of a compound of formula II with a compound of formula III takes place in the presence of a copper catalyst. The reaction is carried out in an organic solvent and in the presence of an inorganic alkali metal base. In principle, any conventional organic solvent can be used, although nitrobenzene, collidine, diglyme and tertiary amines are preferred. With the tertiary amines, the cyclic tertiary amines, such as pyridine and the tertiary alkylamines, such as trimethylamine, triethylamine and the like come into consideration. As already mentioned, the reaction is carried out in the presence of an inorganic alkali metal base. Preferred bases are alkali metal hydroxides, such as potassium and sodium hydroxide, as well as alkali metal carbonates and bicarbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. A preferred inorganic base for this process is a weak base, such as potassium carbonate. In this reaction, temperature and pressure not critical. The reaction can be carried out at room temperature and atmospheric pressure. However, on the other hand, if desired, higher temperatures can also be used. In general, it is preferred to choose temperatures from 100 - 250°. As mentioned, the reaction takes place in the presence of a copper catalyst, such as copper (II) chloride, copper (II) bromide, copper (II) sulfate, copper (I) iodide or a mixture of copper bronze and metallic copper, among which granular copper is preferred.

Forbindelser med formel I, hvori R betyr hydroksy, kan erholdes ifølge den foran nevnte reaksjon mellom en forbindelse med formelen II og en forbindelse med formel III bare i dårlige utbyt-ter. Det er derfor foretrukket å fremstille disse forbindelsene ifølge fremgangsmåtevariant b). Herved anvendes en forbindelse med formel I, hvor R betyr lavere alkoksy, altså en forbindelse med formel I-A, som utgangsmateriale. Ifølge denne fremgangsmåte erholdes en forbindelse med formelen Compounds of formula I, in which R means hydroxy, can be obtained according to the aforementioned reaction between a compound of formula II and a compound of formula III only in poor yields. It is therefore preferred to prepare these compounds according to process variant b). Hereby, a compound of formula I, where R means lower alkoxy, i.e. a compound of formula I-A, is used as starting material. According to this method, a compound with the formula is obtained

Forbindelsen med formel I-A overføres ved eterspaltning i forbindelsen med formel I-B. Enhver konvensjonell metode for eterspaltning kan herunder benyttes. Foretrukne metoder omfatter behandlingen av en forbindelse med formel I-A med kaliumhydroksyd i diglym eller behandlingen av en forbindelse med formelen I-A med pyridinhydroklorid eller vandig hydrogenbromid" i eddiksyre. Ved denne eterspaltning kan de konvensjonelle betingelser for eterspaltninger anvendes. Det skal bemerkes at denne eter-spaltningen ikke spalter fenoksygruppen og at derfor ingen pro-dukter oppstår som ville ha en vanedannende narkotisk virkning. The compound of formula I-A is transferred by ether cleavage into the compound of formula I-B. Any conventional method for ether splitting can be used below. Preferred methods include the treatment of a compound of formula I-A with potassium hydroxide in diglyme or the treatment of a compound of formula I-A with pyridine hydrochloride or aqueous hydrogen bromide" in acetic acid. In this ether cleavage the conventional conditions for ether cleavages can be used. It should be noted that this ether cleavage does not split the phenoxy group and that therefore no products arise which would have an addictive narcotic effect.

Fremgangsmåtevariant c) utføres-ved høyere temperatur, fortrinnsvis ved tilbakeløpstemperaturen, og i nærvær av et inert organisk løsningsmiddel. Ethvert konvensjonelt aromatisk løsningsmiddel kan anvendes ved denne reaksjonen. Foretrukne løsningsmidler er: aromatiske hydrokarboner, som benzen eller toluen. Process variant c) is carried out at a higher temperature, preferably at the reflux temperature, and in the presence of an inert organic solvent. Any conventional aromatic solvent can be used in this reaction. Preferred solvents are: aromatic hydrocarbons, such as benzene or toluene.

Reduksjonen ifølge fremgangsmåtevariant d) utføres med et sterkt metallhydridreduksjonsmiddel, som et alkalimetallaluminiumhy-drid, f.eks. litiumaluminiumhydrid eller et di(lavere-alkyl)-aluminiumhydrid, som diisobutylaluminiumhydrid. Ved denne re-duksjonene kan de vanlige betingelser ved anvendelsen av slike aluminiumhydridreduksjonsmidler anvendes. The reduction according to method variant d) is carried out with a strong metal hydride reducing agent, such as an alkali metal aluminum hydride, e.g. lithium aluminum hydride or a di(lower alkyl) aluminum hydride, such as diisobutylaluminum hydride. In this reduction, the usual conditions for the use of such aluminum hydride reducing agents can be used.

Ifølge fremgangsmåtevariant e) overføres forbindelser med formel VI ved behandling med sink i en lavere alkankarbonsyre i forbindelser med formelen VII. Den lavere alkankarbonsyre tje-ner ved denne reaksjonen som løsningsmiddel. Enhver vanlig lavere alkankarbonsyre, som eddiksyre, propionsyre og lignende kan anvendes. Temperatur og trykk er ved denne reaksjon ikke kritisk. Reaksjonen kan på den ene side gjennomføres ved rom- ' temperatur og atmosfærestrykk eller på den annen side ved temperaturer over 100°. According to method variant e) compounds of formula VI are transferred by treatment with zinc in a lower alkanecarboxylic acid into compounds of formula VII. The lower alkane carboxylic acid serves as a solvent in this reaction. Any common lower alkane carboxylic acid such as acetic acid, propionic acid and the like can be used. Temperature and pressure are not critical in this reaction. The reaction can on the one hand be carried out at room temperature and atmospheric pressure or on the other hand at temperatures above 100°.

Forbindelsene med formel VI er nye og kan fremstilles ved behandling av en forbindelse med formel I-C med klormaursyretriklor-etyleter. Ved denne reaksjonen kan hvilket som helst organisk, løsningsmiddel anvendes. Foretrukne løsningsmidler er aromatiske hydrokarboner, som benzen, toluen og lignende. Normalt gjennom-føres denne reaksjon i nærvær av en svak, uorganisk base. Til dette kommer enhver vanlig svak, uorganisk base i betraktning. Foretrukne svake baser er alkalimetallkarbonater og-bikarbonater, som kalium-eller natriumkarbonat. Temperatur og trykk er ikke kritiske ved denne reaksjonen. Reaksjonen kan på den ene side utføres ved romtemperatur og atmosf ærestrykk og på. den "annen si-de ved høyere temperaturer og trykk. Fortrinnsvis gjennomføres reaksjonen ved reaksjonsblandingens tilbakeløpstemperatur. The compounds of formula VI are new and can be prepared by treating a compound of formula I-C with chloroformate-trichloroethyl ether. In this reaction, any organic solvent can be used. Preferred solvents are aromatic hydrocarbons, such as benzene, toluene and the like. Normally, this reaction is carried out in the presence of a weak, inorganic base. For this, any common weak, inorganic base comes into consideration. Preferred weak bases are alkali metal carbonates and bicarbonates, such as potassium or sodium carbonate. Temperature and pressure are not critical in this reaction. On the one hand, the reaction can be carried out at room temperature and atmospheric pressure and at on the other hand, at higher temperatures and pressures. The reaction is preferably carried out at the reflux temperature of the reaction mixture.

Ifølge fremgangsmåtevariant f) omsettes en forbindelse med formel VII i nærvær av et organisk løsningsmiddel, fortrinnsvis et polart løsningsmiddel, med en forbindelse med formel X. Omsetningen skjer mellom romtemperatur og 300°C, idet et temperatur-område på 120°C - 300°C er foretrukket. Ved denne reaksjon kan ethvert polart løsningsmiddel med et kokepunkt fra 120°C - 300°C anvendes. Foretrukne løsningsmidler er høytkokende polare løs-ningsmidler, som dimetylsulfoksyd eller dimetylformamid. Reaksjonen utføres i nærvær av en base. Enhver vanlig uorganisk alkalimetallbase, som natriumbikarbonat, kaliumkarbonat, natriumkarbonat kan anvendes ved denne reaksjon. Generelt er det foretrukket å anvende en svak uorganisk base, som natrium- eller kaliumkarbonat- eller -bikarbonat. På den andre side kan også ster-ke tertiære aminer, som trietylamin eller diisopropyletylamin, anvendes som base. Temperatur og trykk er ikke kritisk ved denne reaksjonen. Reaksjonen kan utføres ved romtemperatur og atmosfærestrykk, idet man fortrinnsvis arbeider under tilbakeløpsbe-tingelser. According to method variant f) a compound of formula VII is reacted in the presence of an organic solvent, preferably a polar solvent, with a compound of formula X. The reaction takes place between room temperature and 300°C, with a temperature range of 120°C - 300° C is preferred. In this reaction, any polar solvent with a boiling point of 120°C - 300°C can be used. Preferred solvents are high-boiling polar solvents, such as dimethylsulfoxide or dimethylformamide. The reaction is carried out in the presence of a base. Any common inorganic alkali metal base such as sodium bicarbonate, potassium carbonate, sodium carbonate can be used in this reaction. In general, it is preferred to use a weak inorganic base, such as sodium or potassium carbonate or bicarbonate. On the other hand, strong tertiary amines, such as triethylamine or diisopropylethylamine, can also be used as a base. Temperature and pressure are not critical in this reaction. The reaction can be carried out at room temperature and atmospheric pressure, preferably working under reflux conditions.

Ifølge fremgangsmåtevariant g> overføres en forbindelse med formel I-C ved desalkylering i en forbindelse med formel VII. Ved dette kan ethvert konvensjonelt desalkyleringsmiddel henh. des- According to process variant g>, a compound of formula I-C is transferred by dealkylation into a compound of formula VII. In this way, any conventional dealkylation agent according to dec-

I I I I

I i alkyleringsfremgangsmåte anvendes. Fortrinnsvis utføres denne ' desalkylering ved behandling med bromcyan og etterfølgende behandling med en uorganisk mineralsyre eller ved behandling med en .klormaursyreetyl- eller -fenylester og etterfølgende behandling med et alkalimetallhydroksyd i en lavere alkanol. Ved denne desalkyleringen anvendes de for desalkyleringer vanlige betingelser. In the alkylation process is used. This dealkylation is preferably carried out by treatment with cyanogen bromide and subsequent treatment with an inorganic mineral acid or by treatment with a chloroformic ethyl or phenyl ester and subsequent treatment with an alkali metal hydroxide in a lower alkanol. In this dealkylation, the usual conditions for dealkylations are used.

Reaksjonen av en forbindelse med formel VII med en forbindelse med formel IV ifølge fremgangsmåtevariant h) utføres i et inert organisk løsningsmiddel, idet et polart løsningsmiddel er foretrukket. Ethvert polart løsningsmiddel kan anvendes hertil. Foretrukne polare løsningsmidler er benzen, toluen eller metylenklorid. Reaksjonen skjer i nærvær av en base. Herunder-er"organiske baser som trietylamin, pyridin og lignende foretrukket. Temperatur og trykk er ikke kritisk ved denne reaksjon. Reaksjonen kan utføres ved romtemperatur eller høyere temperatur. The reaction of a compound of formula VII with a compound of formula IV according to process variant h) is carried out in an inert organic solvent, a polar solvent being preferred. Any polar solvent can be used for this. Preferred polar solvents are benzene, toluene or methylene chloride. The reaction takes place in the presence of a base. Among these, organic bases such as triethylamine, pyridine and the like are preferred. Temperature and pressure are not critical in this reaction. The reaction can be carried out at room temperature or a higher temperature.

Fremgangsmåtevariant i) utføres på samme måte som fremgangsmåtevariant f) . Method variant i) is carried out in the same way as method variant f).

Cykliseringen av en forbindelse med formel XIII ifølge fremgangsmåtevariant k) skjer ved behandling av en forbindelse med formel XIII med en sterk mineralsyre. Enhver konvensjonell sterk mineralsyre, som fosforsyre, svovelsyre eller saltsyre kan anvendes til dette, idet dog fosforsyre er foretrukket. Den anvencte uorganiske syre kan tjene som et reaksjonsmedium. Temperatur og trykk er ikke kritiske ved denne reaksjon. Reaksjonen kan utfø-res ved romtemperatur og atmosfæretrykk eller ved temperaturer opp til 250°C. Generelt er det foretrukket å utføre denne reaksjon ved en temperatur på fra 100-200°C. The cyclization of a compound of formula XIII according to process variant k) takes place by treating a compound of formula XIII with a strong mineral acid. Any conventional strong mineral acid, such as phosphoric acid, sulfuric acid or hydrochloric acid can be used for this, although phosphoric acid is preferred. The inorganic acid used can serve as a reaction medium. Temperature and pressure are not critical in this reaction. The reaction can be carried out at room temperature and atmospheric pressure or at temperatures up to 250°C. In general, it is preferred to carry out this reaction at a temperature of from 100-200°C.

Utgangsforbindelsene med formel XIII er nye og kan fremstillesThe starting compounds of formula XIII are new and can be prepared

ut fra forbindelser med formelbased on compounds with formula

hvor R-^ har foran angitte betydning, og Rg betyr lavere alkyl, over et mellomprodukt med formelen where R-^ has the meaning given above, and Rg means lower alkyl, over an intermediate with the formula

hvori R, R-^og n har de ovenfor angitte betydninger. wherein R, R-^ and n have the meanings given above.

Overføringen av en forbindelse med formel XI. i en forbindelse med formel XII skjer ved eterspaltning. Til dette kan anvendes en vanlig eterspaltningsrnetode. Det er foretrukket å utføre reaksjonen av forbindelsen med formel XI med et alkalimetallhydroksyd, som natrium- eller kaliumhydroksyd i en eter, som diglym, som løsningsmiddel. Normalt utføres denne reaksjon ved reaksjonsblandingens tilbakeløpstemperatur. Forbindelsen med formel XII overføres ved omsetning med en forbindelse med formel III i forbindelsen med formel XIII. Denne reaksjon utføres på samme måte som reaksjonen av en forbindelse med II med en forbindelse med formel III. The transfer of a compound of formula XI. in a compound of formula XII occurs by ether cleavage. A common ether splitting method can be used for this. It is preferred to carry out the reaction of the compound of formula XI with an alkali metal hydroxide, such as sodium or potassium hydroxide in an ether, such as diglyme, as solvent. Normally, this reaction is carried out at the reflux temperature of the reaction mixture. The compound of formula XII is transferred by reaction with a compound of formula III into the compound of formula XIII. This reaction is carried out in the same way as the reaction of a compound of formula II with a compound of formula III.

Mellomproduktene med formlene II, IV og X er kjente eller kan fremstilles på analog måte ved fremstillingen av de kjente forbindelser . The intermediate products with the formulas II, IV and X are known or can be prepared in an analogous way in the preparation of the known compounds.

j Forbindelsene med formel I danner farmasøytisk anvendelige syre- j The compounds of formula I form pharmaceutically usable acid-

addisjonssalter med uorganiske syrer, som saltsyre, hydrogenbromid, svovelsyre og fosforsyre. Også med organiske syrer som vinsyre, oksalsyre, sitronsyre, kamfersulfonsyre, etansulfonsyre, toluensulfonsyre, salicylsyre, askorbinsyre, maleinsyre, ravsyre, maursyre, eddiksyre og lignende kan det dannes farmasøytisk anvendelige syreaddisjonssalter. addition salts with inorganic acids, such as hydrochloric acid, hydrogen bromide, sulfuric acid and phosphoric acid. Pharmaceutically applicable acid addition salts can also be formed with organic acids such as tartaric acid, oxalic acid, citric acid, camphorsulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, ascorbic acid, maleic acid, succinic acid, formic acid, acetic acid and the like.

Forbindelsene med formel I og deres farmasøytisk anvendelige syre-addis jonssalter er verdifulle som analgetika og/eller narkotika-antagonister. Forbindelsene bevirker, når administrert oralt eller peroralt, en smertelindring på samme måte som kodein. Forbindelsene ifølge foreliggende oppfinnelse kan ikke nedbrytes kjemisk til forbindelser som ville virke vanedannende, som f.eks. dromo-ran. The compounds of formula I and their pharmaceutically usable acid addition salts are valuable as analgesics and/or narcotic antagonists. The compounds, when administered orally or perorally, cause pain relief in the same way as codeine. The compounds according to the present invention cannot be broken down chemically into compounds that would have an addictive effect, such as e.g. Dromo robbery.

Forbindelsene med formel I og deres salter kan bringes i farma-søytiske standardiseringsformer. De er (anvendelige for oral eller parenteral applisering) blitt anvendt med de vanlige far-masøytiske hjelpestoffer, som f.eks. organiske eller uorganiske The compounds of formula I and their salts can be brought into pharmaceutical standardization forms. They have (usable for oral or parenteral application) been used with the usual pharmaceutical excipients, such as e.g. organic or inorganic

hjelpestoffer, som f.eks. organiske eller uorganiske bærermate-rialer, som vann, gelatin, laktose, stivelse, magnesiumstearat, kalk, vegetabilske oljer, gummi, polyalkylenglykoler og lignende: De farmasøytiske formuleringer kan anvendes i fast form, f. eks. som tabletter, suppositorier eller kapsler, eller i flytende form, f.eks. som løsninger, suspensjoner eller emulsjoner. excipients, such as organic or inorganic carrier materials, such as water, gelatin, lactose, starch, magnesium stearate, lime, vegetable oils, rubber, polyalkylene glycols and the like: The pharmaceutical formulations can be used in solid form, e.g. as tablets, suppositories or capsules, or in liquid form, e.g. as solutions, suspensions or emulsions.

Det kan tilsettes farmasøytiske hjelpestoffer, som konserve-ringsmidler, stabiliseringsmidler, fukte- eller emulgeringsmid-ler eller salter for endring av det osmotiske trykk-eller puffer. De farmasøytiske formuleringer kan også inneholde andre terapeutisk aktive stoffer. Pharmaceutical auxiliaries can be added, such as preservatives, stabilizers, wetting or emulsifying agents or salts to change the osmotic pressure or puff. The pharmaceutical formulations may also contain other therapeutically active substances.

Dæ daglige dosering for forbindelsene ifølge foreliggende oppfinnelse avhenger av virkningsgraden til den enkelte anvendte nye forbindelse, den valgte administreringsrute og pasientens størrelse. Den dosering som skal følges er ikke underlagt noen skarpe grenser, men man vil anvende en virksomt avstemt dosis for den farmakologiske funksjon av forbindelsen med formel I. The daily dosage for the compounds according to the present invention depends on the effectiveness of the individual new compound used, the chosen administration route and the size of the patient. The dosage to be followed is not subject to any sharp limits, but one will use an effectively adjusted dose for the pharmacological function of the compound with formula I.

En representativ, typisk metode for administrering av en forbin-Ldeise med formel I er den orale rute. Ved denne administrerings- A representative, typical method of administration of a compound of formula I is the oral route. At this administrative

I I I I

måten kan administreres en tablett som inneholder en forbindelse ned formel I i området 0,01 mg - 0,15 mg pr. dag og kg kropps-r vekt. the way can be administered a tablet containing a compound of formula I in the range of 0.01 mg - 0.15 mg per day and kg body weight.

Forbindelsene med formel I og deres salter er verdifulle som smertestillende midler. Den analgetiske virkning kan vises ifølge standarden "Phenylquinone Writhing test" (Sigmund et al., Proe. Soc.Exp.Biol.Med. 9_5: 729 (1957). Forbindelsene ifølge foreliggende oppfinnelse lindrer smerten betydelig og viser hos mus, hvor kjemisk-intraabdominal smerte fremkalles, analgetisk virkning. ED5Q var den dosering som reduserte det totale antall krum-ninger med 50%. De følgende forbindelser med formel I viser i sammenligning med kodein en analgetisk virkning (uttrykt som<ED>50<>>The compounds of formula I and their salts are valuable as analgesics. The analgesic effect can be shown according to the standard "Phenylquinone Writhing test" (Sigmund et al., Proe. Soc.Exp.Biol.Med. 9_5: 729 (1957). The compounds according to the present invention relieve the pain significantly and show in mice, where chemical- intra-abdominal pain is induced, analgesic effect. ED5Q was the dosage that reduced the total number of curvatures by 50%. The following compounds of formula I show, in comparison with codeine, an analgesic effect (expressed as <ED>50<>>

(-)-3-fenoksy-N-metylmorfinan-tartrat, ED5Q2,0 mg/kg (s.c.) (-)-3-(p-metyl)fenoksy-N-metylmorfinan-hydroklorid, ED^q 23 mg/ kg (s .c . ) (-)-3-(p-metoksy)fenoksy-N-metylmorfinan-hydroklorid, ED^q 2,0 mg/kg (s.c.) (-)-3-fenoksy-N-cyklobutylmetylmorfinan-hydroklorid, ED^013,0 mg/kg (s.c.) (-)-3-phenoxy-N-methylmorphinan tartrate, ED5Q2.0 mg/kg (s.c.) (-)-3-(p-methyl)phenoxy-N-methylmorphinan hydrochloride, ED^q 23 mg/ kg ( s.c. ) (-)-3-(p-methoxy)phenoxy-N-methylmorphinan hydrochloride, ED^q 2.0 mg/kg (s.c.) (-)-3-phenoxy-N-cyclobutylmethylmorphinan hydrochloride, ED^013.0 mg/kg (s.c.)

(.-)-3-f enoksy-N-fenetylmorf inan-oksalat, ED^q 0,9 mg/kg (s.c.)(.-)-3-phenoxy-N-phenethylmorphine oxalate, ED^q 0.9 mg/kg (s.c.)

(-)-3-fenoksy-N-[2-(2-furyl)etyl]morfinan-oksalat, ED5Q1,0 mg/ kg (s.c.) (-)-3-fenoksy-N-[2-(2-tienyl)etyljmorfinan-sulfat, ED5Q13,0 mg/ kg (s.c.) (-)-3-(m-fluor)fenoksy-N-metylmorfinan-d-tartrat, ED^Q6,0 mg/ kg (s . c .) (-)-3-(o-metoksy)fenoksy-N-cyklopropylmetylmorfinan-hydroklorid EDj-0 2,5 mg/kg (s.c.) (~)-3-(p-metoksy)fenoksy-N-cyklopropylmetylmorfinan-hydroklorid, EDj-0 1,3 mg/kg (s.c.) (-)-3-(m-metoksy) f enoksy-N-metylmorf inan-oksalat, EDj-Q 2,5 mg /kg (s.c.) (-)-3-(o-metoksy)fenoksy-N-metylmorfinan-oksalat, ED5Q0,49 mg/ kg (s.c.) (-)-3-phenoxy-N-[2-(2-furyl)ethyl]morphinan oxalate, ED5Q1.0 mg/ kg (s.c.) (-)-3-phenoxy-N-[2-(2-thienyl) )ethyljmorphinan sulfate, ED5Q13.0 mg/ kg (s.c.) (-)-3-(m-fluoro)phenoxy-N-methylmorphinan-d-tartrate, ED^Q6.0 mg/ kg (s.c.) ( -)-3-(o-methoxy)phenoxy-N-cyclopropylmethylmorphinan hydrochloride EDj-0 2.5 mg/kg (s.c.) (~)-3-(p-methoxy)phenoxy-N-cyclopropylmethylmorphinan hydrochloride, EDj- 0 1.3 mg/kg (s.c.) (-)-3-(m-methoxy)phenoxy-N-methylmorph inan-oxalate, EDj-Q 2.5 mg/kg (s.c.) (-)-3-( o-methoxy)phenoxy-N-methylmorphinan oxalate, ED5Q0.49 mg/ kg (s.c.)

(-)-3-(p-hydroksy)fenoksy-N-metylmorfinan-hydroklorid, ED5Q(-)-3-(p-hydroxy)phenoxy-N-methylmorphinan hydrochloride, ED5Q

I 1 1,3 mg/kg (s.c.)<i>' I 1 1.3 mg/kg (s.c.)<i>'

(-)-3-(m-hydroksy)fenoksy-N-metylmorfinan-d-tartrat, ED^Q 9,0 i mg/kg (s.c.) (.-) -3- (o-hydroksy) f enoksy-N-metylmorf inan-d-tartrat, ED^q 1,8 mg/kg (s.c.) (-•)-3-(o-nitro) f enoksy-N-metylmorf inan-hydroklorid, ED(-Q 2,8 mg/ kg (s.c.) (-)-3-(p-fluor)fenoksy-N-metylmorfinan-hydroklorid, ED,-Q 1,0 mg/kg (s.c.) (-)-3-(o-fluor)fenoksy-N-metylmorfinan-oksalat, ED503,0 mg/kg (-)-3-(m-hydroxy)phenoxy-N-methylmorphinan-d-tartrate, ED^Q 9.0 in mg/kg (s.c.) (.-)-3-(o-hydroxy)phenoxy-N -methylmorphine d-tartrate, ED^q 1.8 mg/kg (s.c.) (-•)-3-(o-nitro) f enoxy-N-methylmorphine hydrochloride, ED(-Q 2.8 mg / kg (s.c.) (-)-3-(p-fluoro)phenoxy-N-methylmorphinan hydrochloride, ED,-Q 1.0 mg/kg (s.c.) (-)-3-(o-fluoro)phenoxy- N-methylmorphinan oxalate, ED503.0 mg/kg

(s.c.) (s.c.)

(-)-3-pentafluorfenoksy-N-metylmorfinan-oksalat, ED,-q 9,2 mg/kg (-)-3-pentafluorophenoxy-N-methylmorphinan oxalate, ED,-q 9.2 mg/kg

(s.c.) (s.c.)

(-)-3-fenoksy-N-cyklopropylmetylmorfinan-hydroklorid (17) , ED^q 1,7 mg/kg (s.c), og kodein, ED^Q 3,9 mg/kg (s.c.) (-)-3-phenoxy-N-cyclopropylmethylmorphinan hydrochloride (17) , ED^q 1.7 mg/kg (s.c), and codeine, ED^Q 3.9 mg/kg (s.c.)

Forbindelsene med formel I er virksomme mot morfinanalgese. Denne aktiviteten kan vises for morfinantagonisme ved "Mice taii flick test". Dette forsøket anvendes for å måle narkotikaantagonisme. Forbindelsene administreres 10 minutter før administrering av morfinsulfat subkutant. Den prosentuelle evaluering av reaksjons-tiden ble bestemt hver dag for 10 mg/kg sc morfinsulfat, og den aktuelle prosentøkning ble benyttet for beregning av den prosentuelle antagonisme av morfinanalgese. Den prosentuelle antagonisme ble beregnet ifølge formel til Harris og Pierson, J. Phar-makol.Exp.Ther., 143:141, 1964. Under anvendelse av (-)-3-fenoksy-N-cyklopropy lmetylmorf inanhydroklorid som representativ repre-sentant for en forbindelse ifølge oppfinnelsen kunne erholdes en morfinantagonistisk virkning, som det fremgår av ED^ på 40,28 mg/kg s.c. The compounds of formula I are effective against morphine analgesia. This activity can be shown for morphine antagonism by the "Mice taii flick test". This test is used to measure drug antagonism. The compounds are administered 10 minutes before the administration of morphine sulfate subcutaneously. The percentage evaluation of the reaction time was determined each day for 10 mg/kg sc morphine sulfate, and the relevant percentage increase was used to calculate the percentage antagonism of morphine analgesia. The percent antagonism was calculated according to the formula of Harris and Pierson, J. Pharmacol. Exp. Ther., 143:141, 1964. Using (-)-3-phenoxy-N-cyclopropylmethylmorphine hydrochloride as representative agent for a compound according to the invention, a morphine-antagonistic effect could be obtained, as is evident from the ED^ of 40.28 mg/kg s.c.

De etterfølgende eksempler illustrerer oppfinnelsen men begren-ser den dog ikke. Alle temperaturer er angitt i °C. Uttrykket eter refererer seg til dietyleter. Såfremt millimeter (mm) anvendes, betyr det mm Hg. The following examples illustrate the invention but do not limit it. All temperatures are given in °C. The term ether refers to diethyl ether. If millimeters (mm) are used, it means mm Hg.

EKSEMPEL 1 EXAMPLE 1

En blanding av 6,0 g (0,0023 mol) (-)-3-hydroksy-N-metylmorfinan, 60 ml nydestillert pyridin, 4,8 g kaliumkarbonat, 9,0 g heksa-fluorbenzen og 6,0 g kornet pulver oppvarmes i en rustfri stål-behandler i 7 dager ved 120°C. Etter avkjøling åpnes beholderen. Reaksjonsblandingen filtreres, og filtratet konsentreres under redusert trykk. Resten fordeles mellom eter (700 mi) og 5-N-vandig natriumhydroksyd. Den etter fjerning av eteren erholdte rest ekstraheres med heksan (200 ml). Den etter fjerningen av heksan erholdte rest (5,Og) kromatograferes over nøytralt aluminium-oksyd (75 g) og elueres med metylenklorid , dietyleter og eddikester. Etter forening av fraksjonene fjernes løsningsmidler ved redusert trykk, hvorved man erholder rått (-)-3-pentafluorfen-oksy-N-metylmorf inan. For analyseformål destilleres en-prøve av denne forbindelsen. Kokepunkt 150-160°/0,1 mm [a]^ -39,69° (c = 1,21 i metanol). A mixture of 6.0 g (0.0023 mol) (-)-3-hydroxy-N-methylmorphinan, 60 ml of freshly distilled pyridine, 4.8 g of potassium carbonate, 9.0 g of hexafluorobenzene and 6.0 g of granular powder heated in a stainless steel processor for 7 days at 120°C. After cooling, the container is opened. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is partitioned between ether (700 ml) and 5-N aqueous sodium hydroxide. The residue obtained after removal of the ether is extracted with hexane (200 ml). The residue (5.0 g) obtained after the removal of hexane is chromatographed over neutral aluminum oxide (75 g) and eluted with methylene chloride, diethyl ether and ethyl acetate. After combining the fractions, solvents are removed under reduced pressure, whereby crude (-)-3-pentafluorophenoxy-N-methylmorphinan is obtained. For analytical purposes, a sample of this compound is distilled. Boiling point 150-160°/0.1 mm [a]^ -39.69° (c = 1.21 in methanol).

Til 3,6 g (0,01 mol av ovenstående base i 20mi dietyleter tilsettes en løsning av 0,8 g oksalsyre i 20 ml eter. Det rå oksalat krystalliseres fra eddikester og gir (-)-3-pentafluorfenoksy-N-metylmorf inanoksalat-hemihydrat, smeltepunkt 157-160°, ta]^ To 3.6 g (0.01 mol) of the above base in 20 ml of diethyl ether is added a solution of 0.8 g of oxalic acid in 20 ml of ether. The crude oxalate is crystallized from acetic ester and gives (-)-3-pentafluorophenoxy-N-methylmorphine oxalate -hemihydrate, melting point 157-160°, ta]^

- 24,50 °(c = 1,00 i metanol).- 24.50 ° (c = 1.00 in methanol).

EKSEMPEL 2EXAMPLE 2

En løsning av 10,2 g (0,04 mol) (-)-3-hydroksy-N-metyl-morfinan i 240 ml nydestillert pyridin oppvarmes' .under Trøring -bgr-Tiitrogen^med 18,5 g brombenzen, 13,8 g kaliumkarbonat og 13,0 g kornet kobber i 8 dager under tilbakeløpskjøling. Reaksjonsblandingen filtreres, og filtratet konsentreres under redusert trykk. Resten fordeles mellom eter (500 ml) og 5-N-vandig natriumhydroksyd (200 ml). Eterløsningen vaskes med vann og tørkes. Den etter fjerning av eteren erholdte rest destilleres. Man får (-)-3-fenoksy-N-metylmorf inan med kokepunkt 180-185°/0,1 mm Hg. En prøve av denne A solution of 10.2 g (0.04 mol) (-)-3-hydroxy-N-methyl-morphinan in 240 ml of freshly distilled pyridine is heated under stirring with 18.5 g of bromobenzene, 13, 8 g potassium carbonate and 13.0 g granulated copper for 8 days under reflux. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is partitioned between ether (500 ml) and 5-N aqueous sodium hydroxide (200 ml). The ether solution is washed with water and dried. The residue obtained after removal of the ether is distilled. This gives (-)-3-phenoxy-N-methylmorphine with a boiling point of 180-185°/0.1 mm Hg. A sample of this

o 25 forbindelse omkrystalliseres fra eter, smeltepunkt 87-88 , o 25 compound is recrystallized from ether, melting point 87-88,

-60,10° (c = 0,01 i metanol).-60.10° (c = 0.01 in methanol).

10,0 g (0,03 mol) av den ovenfor nevnte base i 150 mi eter tilsettes en løsning av 3,2 g oksalsyre i 100 ml eter. Det rå oksalat.omkrystalliseres og gir (-)-3-fenoksy-N-metylmorfinanoksa-| 10.0 g (0.03 mol) of the above-mentioned base in 150 ml of ether is added to a solution of 3.2 g of oxalic acid in 100 ml of ether. The crude oxalate is recrystallized to give (-)-3-phenoxy-N-methylmorphinanoxa-|

iin

j lat med smeltepunkt 184-185° (spaltning), [a]" -35 ,47° (c = 1,00 i metanol). j lat with melting point 184-185° (decomposition), [a]" -35 .47° (c = 1.00 in methanol).

Til 7,0 g (0,02 mol) av den tidligere nevnte base i 25 ml aceton tilsettes under omrøring en løsning av 3,5 g D-vinsyre i 75 ml aceton. Reaksjonsblandingen røres i 1/2 time ved romtemperatur og i 4 timer ved 0-5°. Tartratsaltet fjernes ved filtrering og omkrystalliseres fra etanol (40 ml). Man får (-)-3-fenoksy-N-metylmorf inan d-tartrat med smeltepunkt 131-133°, [<*]j^ -20,08° ;(c = 0,99 i metanol).. ;EKSEMPEL 3;En løsning av 5,0 g (0,01 mol) (-)-3-hydroksy-N-metylmorfinan;i 20 ml nydestillert pyridin oppvarmes under røring og nitrogen med 6,4 g p-bromtoluen, 4,0 g kaliumkarbonat og 0,2 g kornet kobber i 9 dager til tilbakeløpskjøling. Reaksjonsblandingen filtreres, og filtratet konsentreres under redusert trykk. Resten ekstraheres med eter (200 ml). Eteriøsningen vaskes først med 2-N-natriumhydroksyd (100 ml) og deretter med vann og tørkes deretter. Den etter fjerning av eteren erholdte rest destilleres og gir (-)-3-(p-metyl)-fenoksy-N-metylmorfinan med kokepunkt 125-140°/0,15 mm Hg. En prøve av denne forbindelse krystalliseres ;o 25 ;fra eter, smeltepunkt 94-96 , [a]D -55,98 (c = 1,00 i metanol). ;Ved behandling av 3,3 g (0,01 mol) av den ovennevnte base med vannfritt hydrogenklorid i eddikester (5 ml) får man 3,3 g rått hydroklorid. Omkrystallisasjon fra eddikester gir (-)-3-(p-metyl) -fenoksy-N-metylmorfinan-hydroklorid, smeltepunkt 223-224°, [a]^ (c = 0,59 i metanol). ;EKSEMPEL 4;En løsning av 5,1 g (0,02 mol (-)-3-hydroksy-N-metylmorfinan i 20 ml nydestillert pyridin oppvarmes under røring og nitrogen ;med 7,5 g p-bromanisol, 4,01 g kaliumkarbonat og 0,2 g kornet kobber i 7 dager til tilbakeløpskjøling. Reaksjonsblandingen filtreres, og filtratet konsentreres under redusert trykk. Resten fordeles mellom eter (400 ml) og 10-N-natriumhydroksyd (100 ;ml). Eteriøsningen vaskes med vann og tørkes. Den etter fjer-j ning av eteren erholdte rest destilleres og gir (-)-3-(p-met- ;i oksy)fenoksy-N-metylmorfinan med kokepunkt 139-155°/0,15 mm Hg. Denne forbindelse krystalliseres fra eter og gir et rent produkt med smeltepunkt 130-132°, [a]J<5>-51,59° (c = 0,99 i metanol). ;2,0 g (0,006 mol) av det ovenfor nevnte produkt gir etter behandling med vannfritt hydrogenklorid i eddikester rått hydroklorid, som etter krystallisasjon fra eddikester gir (-)-3-(p-metoksy ) f enoksy-N-metylmorf inanhydroklorid med smeltepunkt 170-172°. ;[a]p<5>-34,22° (c = 0,99 i metanol).;EKSEMPEL 5;En .løsning av 5,1 g (0,02 mol) (-)-3-hydroksy-N-metylmorfinan i 20 ml nydestillert pyridin oppvarmes under røring og nitrogen med ;7,5 g N-bromanisol, 4,1 g kaliumkarbonat og 0,2 g kornet kobber i 10 dager ved tilbakeløpskjøling. Til reaksjonsblandingen tilsettes det dobbelte volum eter, hvorpå man filtrerer. Resten fordeles mellom eter og 5-N-natriumhydroksyd. Eteriøsningen vaskes med vann og tørkes. Den etter fjerning av eteren erholdte rest destilleres og gir (-)-3-(N-metoksy)fenoksy-N-metylmorfi-nan med kokepunkt 14 5-160°/0,1 mm Hg. For analyseformål krystalliseres en prøve av denne forbindelse fra eter, smeltepunkt 88-90°, [a]^<5>-61,81° (c = 1,00 i metanol) . ;Til 1,5 g (0,04) mol av produktet foran i eter'tilsettes en løs-ning av 0,4 g oksalsyre i eter. Det rå oksalat krystalliseres fra etanol/eter og gir (-)-3-(N-metoksy)fenoksy-N-metylmorfinan-oksalat med smeltepjnkt 148-150°, [a].^<5>-39,60 (c = 1,00 i metanol) . ;EKSEMPEL 6;En løsning av 5,1 g (0,02 mol (-)-3-hydroksy-N-metylmorfinan i 20 ml nydestillert pyridin oppvarmes under røring og nitrogen ;med 7,5 g o-bromanisol, 4,1 g kaliumkarbonat og 5,0 g kornet kobber i 3 dager til tilbakeløpskjøling. Reaksjonsblandingen filtreres, og filtratet konsentreres under redusert trykk. Resten fordeles mellom eter og 5-N-natriumhydroksyd. Eteriøsningen vaskes med vann og tørkes. Den etter fjerning av eteren erholdte rest destilleres og gir (-)-3-(o-metoksy)fenoksy-N-metylmorfi-nan med kokepunkt 165°/0,2 mm Hg. For analyseformål krystalli-j ;i seres en prøve av denne forbindelse fra eddikeste" r, smeltep' unktI 87-89°, [a]<25>-59,32° (c = 1,16 i metanol). ;Til 2,7 g (0,01 mol av produktet ovenfor i eter tilsettes en løs-ning av 0,7 g oksalsyre i eter. Det rå oksalat omkrystalliseres fra etanol)eter og gir (-)-3-(o-metoksy)fenoksy-N-metylmorfinan-oksalat, smeltepunkt 185-187° (spatlning), U]<25>-37,19° (c = 0,9 9 i metanol). ;EKSEMPEL 7;En blanding av 2,0 g (0,005 mol) (-)-3-(p-metoksy)fenoksy-N-metyl-morfinan og 20 g pyridinhydroklorid oppvarmes under røring og nitrogen i■ 25 minutter ved 220°, kjøles deretter i isbad og fortynnes til slutt med vann (50 ml). Reaks jonsblandingen"gjøres basisk med konsentrert ammoniumhydroksyd og ekstraheres med kloroform (100 ml). Kloroformløsningen vaskes med vann (50 ml) og tørkes. Ved fjerning av løsningsmidlet i vakuum får man en rest, som behandles med eter og filtreres og gir (-)-3-(p-hydroksy)-fenoksy-N-metylmorfinan. For analyseformål krystalliseres en prøve av denne forbindelse fra etanol/eter, smeltepunkt 188-190°, [a]<25>-51,6° (c 0,86 i metanol). ;D ;Ved behandling av 1,4 g (0,004 mol) av forannevnte produkt med vannfritt hydrogenklorid i eddikester (10 ml) får man det rå hydroklorid. Ved krystallisasjon av denne • forbindelse fra etanol/eddikester får.man (-)-3-(p-hydroksy)fenoksy-N-metylmorfi-nanhydroklorid med smeltepunkt 160-163° (spaltning), -34,55° ;(c = 0,99 i metanol).;EKSEMPEL 8;En blanding av 3,8 g (0,01 mol) (-)-3-(m-metoksy)fenoksy-N-metylmorf inan og 30 g pyridinhydroklorid oppvarmes under røring og nitrogen i 25 minutter til 220°, kjøles i et isbad og fortynnes deretter med vann. Reaksjonsblandingen gjøres basisk med konsentrert ammoniumhydroksyd og ekstraheres med eter. Etereks-traktene vaskes med vann og tørkes. Den etter fjerning av løs-ningsmidlet erholdte rest gir - (-)-(m-hydroksy)fenoksy-N-metyl-morfinan. For analyseformål omkrystalliseres en prøve av denne [.forbindelse fra etanol, smeltepunkt 212-214°, [a]^<5>-53,13° j ;(c = 1,00 i metanol). j ;Til 2,2 g (0,01 mol) av forannevnte produkt i etanol tilsettes en løsning av 1,0 g d-vinsyre i etanol (20 ml). Løsningen fortynnes med eter, og de utfelte krystaller samles. Det rå salt krystalliseres fra etanol/eddikester og gir (-)-3-(m-hydroksy)fenoksy-N-metylmorf inan-d-tartrat-etanolat , smeltepunkt 135-138°, [a]2<5>-19,21° (c = 1,26 i metanol). ;EKSEMPEL 9;En blanding av 2,5 g (0,007 mol) (-)-3-(o-metoksy)-fenoksy-N-metylmorf inan og 2 5,0 g pyridinhydroklorid oppvarmes under røring og nitrogen i 25 minutter til 220°, kjøles i isbad og fortynnes med vann (50 ml). Reaksjonsblandingen gjøres basisk med konsentrert vandig ammoniumhydroksyd og ekstraheres med kloroform (80 ml). Kloroformløsningen vaskes med vann og tørkes. Etter fjerning av løsningsmidlet i vakuum får man en rå base, som etter krystallisasjon fra eddikester/heksan gir rent (-)-3-(o-hydroksy-fenoksy-N-metylmorfinan, smeltepunkt 167-168°, [a]^ -52,91° ;(c = 1,07 i metanol).;0,152 g (0,001 mol) av det forannevnte produkt og 0,07 g d-vinsyre løses i 1 ml varm etanol, hvorpå man lar krystalliserer ved romtemperatur. Det rå salt omrkrystalliseres fra etanol og gir (-)-3-(o-hydroksy)fenoksy-N-metylmorfinan-d-tartrat-etano-lat ., smeltepunkt 111-112°, [a]<25>-15,96° (c = 1,07 i metanol). ;EKSEMPEL 10;En løsning av 6,4 g (0,02 mol (-)-3-hydroksy-N-metylmorfinan i 30 ml nydestillert pyridin oppvarmes under røring og nitrogen ;med 10,0 g l-brom-2-nitrobenzen, 6,0 g kaliumkarbonat og 0,3 g kornet kobber i 3 dager til tilbakeløpskjøling. Reaksjonsblan-dignen filtreres, og filtratet konsentreres under redusert trykk. Resten fordeles mellom eter og 5-N-natriumhydroksyd. Eteriøs-ningen vaskes med vann og tørkes. Den etter fjerning av eteren erholdte rest fordeles igjen mellom kloroform og 5-N-natriumhydroksyd. Den etter fjerning av kloroformen i vakuum erholdte rest krystalliseres fra eter og gir (-)-3-(o-nitro)fenoksy-N-metylmorfinan, smetelpunkt 158-160°, [a]^<5>-53,16° (c = 0,99 j i metanol). ;Ved behandling av 2,0 g (0,005 mol) av forannevnte produkt med vannfritt hydrogenklorid får man rått hydroklorid, som etter krystallisasjon fra eddikester gir (-)-3-(o-nitro)fenoksy-N-metylmorf inan-hydroklorid-hemihydrat,' smeltepunkt 155-157° ;(spatlning), [a]25 -32,62° (c = 0,99 i metanol).;EKSEMPEL 11;En løsning av 5,1 g (0,02 mol) (-)-3-hydroksy-N-metylmorfinan;i 20 ml nydestillert pyridin oppvarmes under røring og nitrogen med 17,0 g p-fluorbrombenzen, 4,1 g kaliumkarbonat og 0,2 g kornet kobber.i 5 dager til tilbakeløpskjøling. Reaksjonsblandingen tilsettes den dobbelte mengde eter og filtreres. Filtratet konsentreres i vakuum. Resten suspenderes i 150 ml varmt heksan og filtreres. Filtratet vaskes med 5-N-natriumhydroksyd og deretter med vann og tørkes. Den etter fjerning av løsningsmidlet erholdte rest krystalliseres fra heksan og gir (-)-3-(p-fluor)fenoksy-N-metylmorf inan, smeltepunkt 102-104°C, [a]25 -53,36° (c = 1,00 i metanol). ;4,0 g (0,01 mol) av forannevnte produkt gir etter behandling med vannfritt hydrogenklorid rått hydroklorid. Omkrystallisasjon fra eddikester gir (-)-3-(p-fluor)fenoksy-N-metylmorfinanhydro-klorid-hemihydrat med smeltepunkt 162-164°, [ci]^ -34 ,83° (c<=>0,9 8 i metanol). ;EKSEMPEL 12;En løsning av 2,0 g (0,007 mol) (-)-3-hydroksy-N-metylmorfinan;i 10 ml nydestillert pyridin oppvarmes under røring og nitrogen med 3,5 g o-fluorbrombenzen, 2,0 g kaliumkarbonat og 2,0 g kornet kobber i 2 dager til tilbakeløpskjøling. Reaksjonsblandingen tilsettes den dobbelte mengde eter og filtreres. Filtratet konsentreres i vakuum. Resten tas opp i eter (200 ml) og vaskes med 5-N-natriumhydroksyd. Eteriøsningen vaskes med vann og tørkes. Ved fjerning av eteren får man rått (-)-3-(o-fluor)-fenoksy-N-metylmorf inan.. For analyseformål krystalliseres en prøve av denne forbindelse fra eter, smeltepunkt 113-115° [a]<2>^ -48,67° (c<=>0,9 5 i metanol). ;I ;Til 2,5 g (0,007 mol) av det forannevnte produkt i eter til-<I>j settes en løsning av 0,7 g oksalsyre i eter (25 ml). Det rå oksalat omkrystalliseres fra etanol og gir (-)-3-(o-fluor)fenoksy-N-metylmorf inanoksalat med smeltepunkt 180-182°, t*]^ -30,98° (c = 1,00 i metanol). To 7.0 g (0.02 mol) of the previously mentioned base in 25 ml of acetone, a solution of 3.5 g of D-tartaric acid in 75 ml of acetone is added while stirring. The reaction mixture is stirred for 1/2 hour at room temperature and for 4 hours at 0-5°. The tartrate salt is removed by filtration and recrystallized from ethanol (40 ml). One obtains (-)-3-phenoxy-N-methylmorphine d-tartrate with melting point 131-133°, [<*]j^ -20.08°; (c = 0.99 in methanol).. ;EXAMPLE 3 ;A solution of 5.0 g (0.01 mol) (-)-3-hydroxy-N-methylmorphinan;in 20 ml of freshly distilled pyridine is heated under stirring and nitrogen with 6.4 g of p-bromotoluene, 4.0 g of potassium carbonate and 0.2 g of granulated copper for 9 days to reflux. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is extracted with ether (200 ml). The ethereal solution is washed first with 2-N sodium hydroxide (100 ml) and then with water and then dried. The residue obtained after removal of the ether is distilled and gives (-)-3-(p-methyl)-phenoxy-N-methylmorphinan with a boiling point of 125-140°/0.15 mm Hg. A sample of this compound is crystallized ;o 25 ;from ether, melting point 94-96 , [a]D -55.98 (c = 1.00 in methanol). ;By treating 3.3 g (0.01 mol) of the above-mentioned base with anhydrous hydrogen chloride in acetic ester (5 ml), 3.3 g of crude hydrochloride is obtained. Recrystallization from acetic ester gives (-)-3-(p-methyl)-phenoxy-N-methylmorphinan hydrochloride, m.p. 223-224°, [a]^ (c = 0.59 in methanol). ;EXAMPLE 4;A solution of 5.1 g (0.02 mol (-)-3-hydroxy-N-methylmorphinan in 20 ml of freshly distilled pyridine is heated with stirring and nitrogen ;with 7.5 g of p-bromoanisole, 4.01 g of potassium carbonate and 0.2 g of granulated copper for 7 days under reflux. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is partitioned between ether (400 ml) and 10-N sodium hydroxide (100 ml). The ether solution is washed with water and The residue obtained after removal of the ether is distilled and gives (-)-3-(p-meth- ioxy)phenoxy-N-methylmorphinan with a boiling point of 139-155°/0.15 mm Hg. This compound crystallized from ether and gives a pure product with melting point 130-132°, [α]J<5>-51.59° (c = 0.99 in methanol).;2.0 g (0.006 mol) of the above product gives, after treatment with anhydrous hydrogen chloride in ethyl acetate, crude hydrochloride, which after crystallization from ethyl acetate gives (-)-3-(p-methoxy)phenoxy-N-methylmorphine hydrochloride with a melting point of 170-172°. ;[a]p<5 >-34.22° (c = 0.99 in methanol EXAMPLE 5 A solution of 5.1 g (0.02 mol) (-)-3-hydroxy-N-methylmorphinan in 20 ml of freshly distilled pyridine is heated under stirring and nitrogen with 7.5 g of N-bromoanisole , 4.1 g of potassium carbonate and 0.2 g of granulated copper for 10 days under reflux. Double the volume of ether is added to the reaction mixture, after which it is filtered. The residue is distributed between ether and 5-N-sodium hydroxide. The ethereal solution is washed with water and dried. The residue obtained after removal of the ether is distilled and gives (-)-3-(N-methoxy)phenoxy-N-methylmorphinan with boiling point 14 5-160°/0.1 mm Hg. For analytical purposes, a sample of this compound is crystallized from ether, melting point 88-90°, [α]^<5>-61.81° (c = 1.00 in methanol). A solution of 0.4 g of oxalic acid in ether is added to 1.5 g (0.04) mol of the product above in ether. The crude oxalate is crystallized from ethanol/ether and gives (-)-3-(N-methoxy)phenoxy-N-methylmorphinan oxalate with melting point 148-150°, [a].^<5>-39.60 (c = 1.00 in methanol). ;EXAMPLE 6;A solution of 5.1 g (0.02 mol (-)-3-hydroxy-N-methylmorphinan in 20 ml of freshly distilled pyridine is heated with stirring and nitrogen ;with 7.5 g of o-bromoanisole, 4.1 g of potassium carbonate and 5.0 g of granulated copper for 3 days under reflux. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is partitioned between ether and 5-N sodium hydroxide. The ether solution is washed with water and dried. The residue obtained after removal of the ether is distilled and gives (-)-3-(o-methoxy)phenoxy-N-methylmorphinan with a boiling point of 165°/0.2 mm Hg. For analytical purposes, a sample of this compound is crystallized from vinegar, melting point 87-89°, [α]<25>-59.32° (c = 1.16 in methanol). To 2.7 g (0.01 mol of the above product in ether is added a solution of 0.7 g of oxalic acid in ether. The crude oxalate is recrystallized from ethanol) ether to give (-)-3-(o-methoxy)phenoxy-N-methylmorphinan oxalate, melting point 185-187° (spatling), U]< 25>-37.19° (c = 0.99 in methanol). ;EXAMPLE 7;A mixture of 2.0 g (0.005 mol) (-)-3-(p-methoxy)phenoxy-N-methyl-morphinan and 20 g of pyridine hydrochloride are heated with stirring and nitrogen for 25 minutes at 220°, then cooled in an ice bath and finally diluted with water ( 50 ml). The reaction mixture is made basic with concentrated ammonium hydroxide and extracted with chloroform (100 ml). The chloroform solution is washed with water (50 ml) and dried. Removal of the solvent in vacuo gives a residue, which is treated with ether and filtered to give (-) -3-(p-hydroxy)-phenoxy-N-methylmorphinan For analytical purposes a sample of this compound is crystallized from ethanol/ether, mp 188-190°, [α]<25>-51.6° (c 0.86 in methanol). ;D ;By treating 1.4 g (0.004 mol) of the above-mentioned product with anhydrous hydrogen chloride in ethyl acetate (10 ml), the crude hydrochloride is obtained. By crystallization of this • compound from ethanol/acetic ester, one obtains ( -)-3-(p-hydroxy)phenoxy-N-methylmorphinane hydrochloride with melting point 160-163° (decomposition), -34.55°; (c = 0.99 in methanol).; EXAMPLE 8; A mixture of 3.8 g (0.01 mol) (-)-3-(m-methoxy)phenoxy-N-methylmorphine and 30 g pyridine hydrochloride are heated with stirring and nitrogen for 25 minutes to 220°, cooled in an ice bath and then diluted with water. The reaction mixture is made basic with concentrated ammonium hydroxide and extracted with ether. The Eterex funnels are washed with water and dried. The residue obtained after removal of the solvent gives - (-)-(m-hydroxy)phenoxy-N-methyl-morphinan. For analytical purposes, a sample of this [.compound is recrystallized from ethanol, melting point 212-214°, [a]^<5>-53.13° j ; (c = 1.00 in methanol). j ;To 2.2 g (0.01 mol) of the above-mentioned product in ethanol is added a solution of 1.0 g of d-tartaric acid in ethanol (20 ml). The solution is diluted with ether, and the precipitated crystals are collected. The crude salt is crystallized from ethanol/acetic ester and gives (-)-3-(m-hydroxy)phenoxy-N-methylmorphinan-d-tartrate-ethanolate, melting point 135-138°, [a]2<5>-19, 21° (c = 1.26 in methanol). ;EXAMPLE 9;A mixture of 2.5 g (0.007 mol) (-)-3-(o-methoxy)-phenoxy-N-methylmorphine and 2 5.0 g of pyridine hydrochloride is heated with stirring and nitrogen for 25 minutes at 220 °, cool in an ice bath and dilute with water (50 ml). The reaction mixture is basified with concentrated aqueous ammonium hydroxide and extracted with chloroform (80 mL). The chloroform solution is washed with water and dried. After removal of the solvent in vacuo, a crude base is obtained, which after crystallization from ethyl acetate/hexane gives pure (-)-3-(o-hydroxy-phenoxy-N-methylmorphinan, melting point 167-168°, [a]^ -52 .91° ;(c = 1.07 in methanol).;0.152 g (0.001 mol) of the above-mentioned product and 0.07 g of d-tartaric acid are dissolved in 1 ml of hot ethanol, after which it is allowed to crystallize at room temperature. The crude salt recrystallized from ethanol to give (-)-3-(o-hydroxy)phenoxy-N-methylmorphinan-d-tartrate-ethanolate ., melting point 111-112°, [a]<25>-15.96° (c = 1.07 in methanol). ;EXAMPLE 10;A solution of 6.4 g (0.02 mol (-)-3-hydroxy-N-methylmorphinan in 30 ml of freshly distilled pyridine is heated with stirring and nitrogen ;with 10.0 g of 1-bromo-2-nitrobenzene, 6.0 g of potassium carbonate and 0.3 g of granulated copper for 3 days under reflux. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is partitioned between ether and 5-N-sodium hydroxide. The ethereal solution is washed with water and dried t is distributed again between chloroform and 5-N-sodium hydroxide. The residue obtained after removal of the chloroform in vacuo is crystallized from ether and gives (-)-3-(o-nitro)phenoxy-N-methylmorphinan, melting point 158-160°, [a]^<5>-53.16° ( c = 0.99 j in methanol). ;By treating 2.0 g (0.005 mol) of the above-mentioned product with anhydrous hydrogen chloride, crude hydrochloride is obtained, which after crystallization from acetic ester gives (-)-3-(o-nitro)phenoxy-N-methylmorphine hydrochloride hemihydrate ,' melting point 155-157° ;(spatling), [a]25 -32.62° (c = 0.99 in methanol).;EXAMPLE 11;A solution of 5.1 g (0.02 mol) (- )-3-hydroxy-N-methylmorphinan; in 20 ml of freshly distilled pyridine is heated under stirring and nitrogen with 17.0 g of p-fluorobromobenzene, 4.1 g of potassium carbonate and 0.2 g of granulated copper. for 5 days to reflux. Double the amount of ether is added to the reaction mixture and filtered. The filtrate is concentrated in vacuo. The residue is suspended in 150 ml of hot hexane and filtered. The filtrate is washed with 5-N sodium hydroxide and then with water and dried. The residue obtained after removal of the solvent is crystallized from hexane to give (-)-3-(p-fluoro)phenoxy-N-methylmorphine, melting point 102-104°C, [α]25 -53.36° (c = 1 .00 in methanol). ; 4.0 g (0.01 mol) of the above-mentioned product gives crude hydrochloride after treatment with anhydrous hydrogen chloride. Recrystallization from acetic ester gives (-)-3-(p-fluoro)phenoxy-N-methylmorphinan hydrochloride hemihydrate with melting point 162-164°, [ci]^ -34 .83° (c<=>0.9 8 i methanol). ;EXAMPLE 12;A solution of 2.0 g (0.007 mol) (-)-3-hydroxy-N-methylmorphinan;in 10 ml of freshly distilled pyridine is heated with stirring and nitrogen with 3.5 g of o-fluorobromobenzene, 2.0 g potassium carbonate and 2.0 g of granulated copper for 2 days to reflux. Double the amount of ether is added to the reaction mixture and filtered. The filtrate is concentrated in vacuo. The residue is taken up in ether (200 ml) and washed with 5-N sodium hydroxide. The ethereal solution is washed with water and dried. On removal of the ether, crude (-)-3-(o-fluoro)-phenoxy-N-methylmorphine is obtained. For analytical purposes, a sample of this compound is crystallized from ether, melting point 113-115° [a]<2>^ -48.67° (c<=>0.95 in methanol). A solution of 0.7 g of oxalic acid in ether (25 ml) is added to 2.5 g (0.007 mol) of the above-mentioned product in ether. The crude oxalate is recrystallized from ethanol and gives (-)-3-(o-fluoro)phenoxy-N-methylmorph inoxalate with melting point 180-182°, t*]^ -30.98° (c = 1.00 in methanol) .

EKSEMPEL 13EXAMPLE 13

Til en blanding av 2,3 g (0,007 mol) (-)-3-fenoksy-N-metylmorfi-nan, 150 ml benzen og 0,35 kaliumkarbonat tilsettes dråpevis 3,3 g klormaursyre-2,2,2-trikloretylester. Reaksjonsblandingen oppvarmes i 6 dager under røring til tilbakeløpskjøling. Reaksjonsblandingen fortynnes med eter og ekstraheres med 4-N-saltsyre. Den organiske fase vaskes med fortynnet ammoniumhydroksyd og med vann og tørkes deretter. Ved fjerning av løsningsmidlet får man (-)-3-fenoksy-N-triklorkarbetoksymorfinan. For analyseformål destilleres en prøve av denne forbindelse, kokepunkt 230-240°/0,05 mm Kg, [cx]<25>-119,65° (c = 0,95 i metanol). To a mixture of 2.3 g (0.007 mol) (-)-3-phenoxy-N-methylmorphinan, 150 ml of benzene and 0.35 of potassium carbonate, 3.3 g of chloroformate-2,2,2-trichloroethyl ester is added dropwise. The reaction mixture is heated for 6 days with stirring to reflux. The reaction mixture is diluted with ether and extracted with 4-N-hydrochloric acid. The organic phase is washed with dilute ammonium hydroxide and with water and then dried. Removal of the solvent gives (-)-3-phenoxy-N-trichlorocarbethoxymorphinan. For analytical purposes, a sample of this compound is distilled, boiling point 230-240°/0.05 mm Kg, [cx]<25>-119.65° (c = 0.95 in methanol).

EKSEMPEL 14EXAMPLE 14

Til en løsning av 3,4 g (0,007 mol) (-)-3-fenoksy-N-triklorkarb-etoksymorf inan i 40 ml 90%ig eddiksyre tilsettes porsjonsvis 2,0 g sinkstøv. Reaksjonsblandingen røres ved romtemperatur i 16 timer og filtreres. Filtratet konsentreres i vakuum. Resten fordeles mellom eter og fortynnet ammoniumhydroksyd. Eteriøsningen ekstraheres med 4-N-saltsyre. Den sure løsning ekstraheres med kloroform. Etter fjerning av kloroformen krystalliseres det rå hydroklorid fra etanol og gir (-)-3-fenoksymorfinan-hydroklorid med smeltepunkt•322-324°, [a]<25>-33,88° (c = 1,00 i metanol). To a solution of 3.4 g (0.007 mol) (-)-3-phenoxy-N-trichlorocarb-ethoxymorphine in 40 ml of 90% acetic acid, 2.0 g of zinc dust is added in portions. The reaction mixture is stirred at room temperature for 16 hours and filtered. The filtrate is concentrated in vacuo. The remainder is distributed between ether and dilute ammonium hydroxide. The ethereal solution is extracted with 4-N-hydrochloric acid. The acidic solution is extracted with chloroform. After removal of the chloroform, the crude hydrochloride is crystallized from ethanol and gives (-)-3-phenoxymorphinan hydrochloride with melting point•322-324°, [a]<25>-33.88° (c = 1.00 in methanol).

EKSEMPEL. 15EXAMPLE. 15

Til en løsning av 3,7 g (0,011 mol) (-)-3-fenoksy-N-metylmorfi-nan i 50 ml toluen tilsettes ved 5° dråpevis en løsning av 5,8 g cyklopropankarboksylsyreklorid i 2 5 ml toluen. Man lar reaksjonsblandingen oppvarmes først til romtemperatur og oppvarmer den deretter i 15 timer til tilbakeløpskjøling. Den etter fjerning av løsningsmidlet erholdte rest fordeles mellom eter og fortynnet saltsyre. Eteriøsningen vaskes med vann og tørkes. Ved fjerning av løsningsmidlet i vakuum får. man (-)-3-fenoksy-N-cyklo- To a solution of 3.7 g (0.011 mol) (-)-3-phenoxy-N-methylmorphinan in 50 ml of toluene, a solution of 5.8 g of cyclopropanecarboxylic acid chloride in 25 ml of toluene is added dropwise at 5°. The reaction mixture is first allowed to warm to room temperature and then heated for 15 hours to reflux. The residue obtained after removal of the solvent is distributed between ether and dilute hydrochloric acid. The ethereal solution is washed with water and dried. Removal of the solvent in vacuo gives man (-)-3-phenoxy-N-cyclo-

! propylkarbonylmorfinan. For analyseformål destilleres en prøve! ! propylcarbonylmorphinan. For analysis purposes, a sample is distilled!

o 25 o 25

av denne forbindelse, kokepunkt 230-240 /0,05 mm Hg, [a]D of this compound, boiling point 230-240 /0.05 mm Hg, [a]D

-173,45° (c = 0,99 i metanol).-173.45° (c = 0.99 in methanol).

EKSEMPEL 16EXAMPLE 16

Til en suspensjon av 0,4 g litiumaluminiumhydrid i 20 ml vannfritt tetrahydrofuran tilsettes i løpet av 15 minutter en løs-ning av 4,6 g (0,011 mol) (-)-3-fenoksy-N-cyklopropyl-karbonyl-morfinan i 30 ml vannfritt tetrahydrofuran. Reaksjonsblandingen oppvarmes under nitrogen i 16 timer .til tilbakeløpskjøling og kjøles deretter til romtemperatur. Derpå tilsettes vann dråpevis. Den erholdte suspensjon filtreres, og filtratet konsentreres. Resten fordeles mellom eter og 4-N-saltsyre. Den sure fase gjø-res basisk med konsentrert ammoniumhydroksyd. Den vandige løs-ning ekstraheres med eter. Eteriøsningen vaskes med vann og tør-kes. Ved fjerning av eteren under redusert trykk får man (-)-3-fenoksy-N-cyklopropylmetylmorfinan. For analyseformål destilleres en prøve av denne forbindelse, kokepunkt 190-200°/0,l mm Hg, [a]<25>-89,07° (c = 0,99 i metanol). To a suspension of 0.4 g of lithium aluminum hydride in 20 ml of anhydrous tetrahydrofuran, a solution of 4.6 g (0.011 mol) (-)-3-phenoxy-N-cyclopropyl-carbonyl-morphinan in 30 ml anhydrous tetrahydrofuran. The reaction mixture is heated under nitrogen for 16 hours to reflux and then cooled to room temperature. Water is then added drop by drop. The resulting suspension is filtered, and the filtrate is concentrated. The residue is distributed between ether and 4-N-hydrochloric acid. The acidic phase is made basic with concentrated ammonium hydroxide. The aqueous solution is extracted with ether. The ethereal solution is washed with water and dried. Removal of the ether under reduced pressure yields (-)-3-phenoxy-N-cyclopropylmethylmorphinan. For analytical purposes, a sample of this compound is distilled, boiling point 190-200°/0.1 mm Hg, [a]<25>-89.07° (c = 0.99 in methanol).

Ved behandling av 2,6 g (0,007 mol) av forannevnte produkt med vannfritt hydrogenklorid i eter får man det rå hydroklorid, som gir, etter krystallisasjon fra eddiketer,(-)-3-fenoksy-N-cyklopropylmetylmorfinan-hydroklorid, smeltepunkt 186-188°, [a]^ -67,16° By treating 2.6 g (0.007 mol) of the above-mentioned product with anhydrous hydrogen chloride in ether, the crude hydrochloride is obtained, which gives, after crystallization from acetic ether, (-)-3-phenoxy-N-cyclopropylmethylmorphinan hydrochloride, melting point 186- 188°, [α]^ -67.16°

(c = 1,00 i metanol).(c = 1.00 in methanol).

EKSEMPEL 17EXAMPLE 17

En blanding av 253,9 g (0,935 mol) (-)-1-(p-metoksybenzyl)-2-metyl-1,2,3,4,5,6,7,8-oktahydroisokinolin og 1,2 1 dietylengly-kol oppvarmes til 80-100°, hvorpå kaliumhydroksyd tilsettes. Reaksjonsblandingen oppvarmes til 210° og holdes under røring og en konstant nitrogenstrøm i 3 6 timer ved denne temperatur. Herunder åpnes fra tid til annen sperrekranen for å la damp unnvike. Hvis dette ikke gjøres kan den ønskete indre temperatur ikke holdes på 210°. Den svartbrune løsning kjøles til romtemperatur, fortynnes med vann (600 ml) og ekstraheres med eter (400 ml). Den vandige løsning surgjøres med konsentrert saltsyre og derpå gjøres den alkalisk med konsentrert ammoniumhydroksyd. Den vandige suspensjon ekstraheres med eddikester (4 ganger 250 ml). A mixture of 253.9 g (0.935 mol) (-)-1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline and 1,2 1 diethylenegly -coal is heated to 80-100°, whereupon potassium hydroxide is added. The reaction mixture is heated to 210° and kept under stirring and a constant stream of nitrogen for 36 hours at this temperature. Below this, the shut-off valve is opened from time to time to allow steam to escape. If this is not done, the desired internal temperature cannot be maintained at 210°. The black-brown solution is cooled to room temperature, diluted with water (600 ml) and extracted with ether (400 ml). The aqueous solution is acidified with concentrated hydrochloric acid and then made alkaline with concentrated ammonium hydroxide. The aqueous suspension is extracted with acetic acid (4 times 250 ml).

! I Eddikesterløsningen vakses med vann og tørkes. Ved fjerning avi ! In the Acetic ester solution, wax with water and dry. When removing avi

I IN

i løsningsmidlet får man (-)-1-(p-hydroksybenzyl)-2-metyl-1,2,3,4,5,6,7,8-oktahydroisokinolin. For analyseformål krystalliseres en prøve av denne forbindelse fra tetrahydrofuran/heptan smeltepunt 119-120°, [a]<25>-36,01° (c = 0,98 i metanol). in the solvent gives (-)-1-(p-hydroxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. For analytical purposes, a sample of this compound is crystallized from tetrahydrofuran/heptane melting point 119-120°, [a]<25>-36.01° (c = 0.98 in methanol).

EKSEMPEL 18EXAMPLE 18

En løsning av 2,4 g (0,009 mol) (-)-1-(p-hydroksybenzyl)-2-metyl-1,2,3,4,5,6,7,8-oktahydroisokinolin og 10 ml nydestillert pyridin oppvarmes under røring og nitrogen med 3,1 g brombenzen,- 2,0 g kaliumkarbonat og 0,1 g kornet kobber i 9 dager til tilbakeløps-kjøling. Reaksjonsblandingen filtreres, hvoretter filtratet konsentrert under redusert trykk. Resten tilsettes eter (150 ml), hvorpå av eter uløselig materiale filtreres fra. Filtratet ekstraheres med 2-N-natriumhydroksyd, vaskes med vann og tørkes. Ved fjerning av løsningsmidlet får man (-)-(p-fenoksy-benzyl)-2-metyl-l,2,3,4,5,6,7,8-oktahydroisokinolin. For analyseformål destilleres en prøve av denne forbindelse. Kokepunkt 120°/0,15 mm Hg, [alD 25 -18,53 o (c = 1,14 i metanol). A solution of 2.4 g (0.009 mol) (-)-1-(p-hydroxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline and 10 ml of freshly distilled pyridine is heated under stirring and nitrogen with 3.1 g of bromobenzene, - 2.0 g of potassium carbonate and 0.1 g of granulated copper for 9 days to reflux. The reaction mixture is filtered, after which the filtrate is concentrated under reduced pressure. Ether (150 ml) is added to the residue, after which material insoluble in ether is filtered off. The filtrate is extracted with 2-N sodium hydroxide, washed with water and dried. Removal of the solvent gives (-)-(p-phenoxy-benzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. For analytical purposes, a sample of this compound is distilled. Boiling point 120°/0.15 mm Hg, [alD 25 -18.53 o (c = 1.14 in methanol).

Til en løsning av 1,0 g (0,003 mol) av forannevnte produkt i 5 ml eter tilsettes en løsning av 0,3 g oksalsyre i eter. Det rå oksalat omkrystalliseres fra etanol og gir (-)-1-(p-fenoksybenzyl)-2-metyl-l,2,3,4,5,6,7,8-oktahydroisokinolinoksalat med smeltepunkt160-162°. [a]<25>-37,17° (c = 1,00 i metanol). A solution of 0.3 g of oxalic acid in ether is added to a solution of 1.0 g (0.003 mol) of the above-mentioned product in 5 ml of ether. The crude oxalate is recrystallized from ethanol and gives (-)-1-(p-phenoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline oxalate with melting point 160-162°. [α]<25>-37.17° (c = 1.00 in methanol).

EKSEMPEL 19EXAMPLE 19

En blanding av 0,5 g (0,002 mol) (-)-1-(p-fenoksybenzyl)-2-metyl-1,2,3,4,5,6,7,8-oktahydroisokinolin og 5 ml 99 % 1ig fosforsyre oppvarmes under røring og nitrogen i 3 dager til 135°. Reaksjonsblandingen helles på isvann og innstilles basisk med konsentrert ammoniumhydroksyd. Den vandige suspensjon ekstraheres med kloroform. De forenete kloroformekstrakter vaskes med vann og tørkes. Fjerning av løsnningsmidlet gir rått (-)-3-fenoksy-N-metylmorf inan . A mixture of 0.5 g (0.002 mol) (-)-1-(p-phenoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline and 5 ml of 99% 1ig phosphoric acid is heated with stirring and nitrogen for 3 days to 135°. The reaction mixture is poured onto ice water and made basic with concentrated ammonium hydroxide. The aqueous suspension is extracted with chloroform. The combined chloroform extracts are washed with water and dried. Removal of the solvent gives crude (-)-3-phenoxy-N-methylmorph inan.

EKSEMPEL 20EXAMPLE 20

Til en løsning av'3,9 g (0,01 mol) (-)-3-fenoksy-N-metylmorfinan i 50 ml toluen tilsettes dråpevis ved romtemperatur en løsning To a solution of 3.9 g (0.01 mol) (-)-3-phenoxy-N-methylmorphinan in 50 ml toluene is added dropwise at room temperature a solution

; av 6,9 g cyklobutankarboksylsyreklorid i 30 ml toluen. Reak- ; of 6.9 g of cyclobutanecarboxylic acid chloride in 30 ml of toluene. Reac-

sjonsblandingen kjøles til romtemperatur og vaskes suksessivt med 4-N-saltsyre, vann og 5-N-natriumyydroksyd. Den organiske fase tørkes og filtreres. Ved fjerning av løsningsmidlet i vakuum får man (-)-3-fenoksy-N-cyklobutylkarbonyl-morfinan. For analyseformål destilleres en prøve av denne forbindelse. Kokepunkt 220° (0,1 mm Hg), [a]<25>-163,25° (c = 0,98 i metanol).. the reaction mixture is cooled to room temperature and washed successively with 4-N-hydrochloric acid, water and 5-N-sodium hydroxide. The organic phase is dried and filtered. Removal of the solvent in vacuo gives (-)-3-phenoxy-N-cyclobutylcarbonyl-morphinan. For analytical purposes, a sample of this compound is distilled. Boiling point 220° (0.1 mm Hg), [a]<25>-163.25° (c = 0.98 in methanol)..

EKSEMPEL 21EXAMPLE 21

Til en suspensjon av 0,4 g litiumaluminiumhydrid i 40 ml vannfritt tetrahydrofuran tilsettes dråpevis en løsning av 2,1 g (0,005 mol) (-)-3-fenoksy-N-cyklobutylkarbonyl-morfinan i 20 ml vannfritt tetrahydrofuran. Reaksjonsblandingen oppvarmes under nitrogen i 3 timer til tilbakeløpskjøling, kjøles deretter til romtemperatur og tilsettes til slutt dråpevis vann. Den erholdte suspensjon filtreres. Filtratet konsentreres<p>g resten løses i eter (50 ml). Løsningen ekstraheres med 4-N-saltsyre (75 ml). Den vandige løsning gjøres alkalisk med 10-N-natriumhydroksyd og ekstraheres med eter (75 ml). Den eteriske løsning vaskes A solution of 2.1 g (0.005 mol) (-)-3-phenoxy-N-cyclobutylcarbonyl-morphinan in 20 ml of anhydrous tetrahydrofuran is added dropwise to a suspension of 0.4 g of lithium aluminum hydride in 40 ml of anhydrous tetrahydrofuran. The reaction mixture is heated under nitrogen for 3 hours to reflux, then cooled to room temperature and finally water is added dropwise. The suspension obtained is filtered. The filtrate is concentrated and the residue is dissolved in ether (50 ml). The solution is extracted with 4-N-hydrochloric acid (75 ml). The aqueous solution is made alkaline with 10-N sodium hydroxide and extracted with ether (75 mL). The ethereal solution is washed

med vann og tørkes. Ved fjerning av løsningsmidlet i vakuum får man rått (-)-3-fenoksy-N-cyklobutylmetylmorfinan. For analyseformål destilleres en prøve av denne forbindelse. Kokepunkt 215-225° (0,5 mm Hg), [cx]<2>)<5>-73,25° (c = 0,99 i metanol). with water and dried. By removing the solvent in vacuo, crude (-)-3-phenoxy-N-cyclobutylmethylmorphinan is obtained. For analytical purposes, a sample of this compound is distilled. Boiling point 215-225° (0.5 mm Hg), [cx]<2>)<5>-73.25° (c = 0.99 in methanol).

Ved behandling av 1,1 g (0,003 mol) av forannevnte base med vannfritt hydrogenklorid i eddikester får man det rå hydroklorid, som etter krystallisasjon fra eddikester gir rent (-)-3-fénoksy-N-cyklobutylmetylmorfinan-hydroklo'rid med smeltepunkt 17 5-17 7°. By treating 1.1 g (0.003 mol) of the aforementioned base with anhydrous hydrogen chloride in ethyl acetate, the crude hydrochloride is obtained, which after crystallization from ethyl acetate gives pure (-)-3-phenoxy-N-cyclobutylmethylmorphinan hydrochloride with a melting point of 17 5-17 7°.

[a]D^ -66,59° (c = 1,03 i metanol).[α]D^ -66.59° (c = 1.03 in methanol).

EKSEMPEL 2 2EXAMPLE 2 2

Til en blanding av 4,0 g (0,012 mol) (-)-3-fenoksymorfinan,To a mixture of 4.0 g (0.012 mol) (-)-3-phenoxymorphinan,

2,5 g trietylamin og 15 ml metylenklorid tilsettes dråpevis en løsning av '2,9 g fenylacetylklorid i 15 ml metylenklorid. Reaksjonsblandingen oppvarmes i 14 timer til tilbakeløpskjøling, derpå kjøles og vaskes deretter suksessivt med vann, 4-N-saltsyre, 2-N-ntriumhydroksyd og vann. Den organiske løsning tørkes, hvorpå løsningsmidlet dampes av. For analyseformål destilleres 2.5 g of triethylamine and 15 ml of methylene chloride are added dropwise to a solution of 2.9 g of phenylacetyl chloride in 15 ml of methylene chloride. The reaction mixture is heated for 14 hours to reflux, then cooled and then washed successively with water, 4-N-hydrochloric acid, 2-N-sodium hydroxide and water. The organic solution is dried, after which the solvent is evaporated. Distilled for analysis purposes

en prøve av denne forbindelse. Kokepunkt 240-250° (0,05 mm Hg) a sample of this compound. Boiling point 240-250° (0.05 mm Hg)

[cx]<2>/"133,27° ( c 1,11 i metanol). 1[cx]<2>/"133.27° ( c 1.11 in methanol). 1

I I I I

' EKSEMPEL 23 Til en suspensjon av 0,8 g litiumaluminiumhydrid i 40 ml vannfritt tetrahydrofuran tilsettes i løpet av 4 5 minutter en løs-ning av 4,2 g (0,01 mol) (-)-3-fenoksy-N-fenylacetylmorfinan i 40 ml vannfritt tetrahydrofuran. Reaksjonsblandingen oppvarmes EXAMPLE 23 A solution of 4.2 g (0.01 mol) (-)-3-phenoxy-N-phenylacetylmorphinan is added over 45 minutes to a suspension of 0.8 g of lithium aluminum hydride in 40 ml of anhydrous tetrahydrofuran in 40 ml anhydrous tetrahydrofuran. The reaction mixture is heated

under nitrogen i 3 timer til tilbakeløpskjøling, kjøles derpå, til romtemperatur og tilsettes vann dråpevis. Den erholdte suspensjon filtreres, og filtratet konsentreres. Resten fordeles mellom eter og vann. Den eteriske løsning tørkes. Ved avdamp - ning av løsningsmidlet får man rått (-)-3-fenoksy-N-fenetyl-morfinan. For analyseformål destilleres en prøve av denne forbindelse. Kokepunkt 160-165° (0,1 mm Hg), [a]25 -100,27° (c = 0,55 i metanol). under nitrogen for 3 hours to reflux, then cool to room temperature and add water dropwise. The resulting suspension is filtered, and the filtrate is concentrated. The remainder is distributed between ether and water. The ethereal solution is dried. By evaporating the solvent, crude (-)-3-phenoxy-N-phenethyl-morphinan is obtained. For analytical purposes, a sample of this compound is distilled. Boiling point 160-165° (0.1 mm Hg), [a]25 -100.27° (c = 0.55 in methanol).

Til en løsning av 3,2 g (0,007 mol) av den forannevnte base i eter tilsettes en løsning av 0,8 g oksalsyre i eter. Det rå oksalat omkrystalliseres to ganger fra etanol og. gir rent (-)-3-fenoksy-N-fenetylmorfinan-oksalat med smeltepunkt 217-219°. A solution of 0.8 g of oxalic acid in ether is added to a solution of 3.2 g (0.007 mol) of the aforementioned base in ether. The crude oxalate is recrystallized twice from ethanol and. gives pure (-)-3-phenoxy-N-phenethylmorphinan oxalate with melting point 217-219°.

[a]<25>-72,17° (c = 1,06 i metanol).[α]<25>-72.17° (c = 1.06 in methanol).

EKSEMPEL 24EXAMPLE 24

Til en blanding av 4,0 g (0,012 mol) (-)-3-fenoksymorfinan, 2,5 g trietylamin og 15 ml metylenklorid tilsettes dråpevis en løs-ning av 2,7 g 2-furylacetylklorid. Reaksjonsblandingen oppvarmes i 14 timer til tilbakeløpskjøling, kjøles deretter til romtemperatur og vaskes suksessivt med vann, 4-N-saltsyre, 5-N-natriumhydroksyd og vann. Den organiske løsning tørkes og dampes inn og gir rått (-)-3-.f enoksy-N- [(2-f ur ylme tyl) karbonyl] morf inan. For A solution of 2.7 g of 2-furylacetyl chloride is added dropwise to a mixture of 4.0 g (0.012 mol) (-)-3-phenoxymorphinan, 2.5 g of triethylamine and 15 ml of methylene chloride. The reaction mixture is heated for 14 hours to reflux, then cooled to room temperature and washed successively with water, 4-N-hydrochloric acid, 5-N-sodium hydroxide and water. The organic solution is dried and evaporated to give crude (-)-3-.phenoxy-N-[(2-furylmethyl)carbonyl]morphine. For

analyseformål destilleres en prøve av denne forbindelse. Kokepunkt 215-225° (0,1 mm Hg), [cx]<25>-135,36° (c = 1,06 i metanol). For analytical purposes, a sample of this compound is distilled. Boiling point 215-225° (0.1 mm Hg), [cx]<25>-135.36° (c = 1.06 in methanol).

EKSEMPEL 25EXAMPLE 25

Til en suspensjon av 0,8 g litiumaluminiumhydrid i 40 ml vannfritt tetrahydrofuran tilsettes dråpevis en løsning av 5,1 g (0,012 mol) (-)-3-fenoksy-N-[(2-furylmetyl)karbonyl]morfinan i 40 ml vannfritt tetrahydrofuran. Reaksjonsblandingen oppvarmes To a suspension of 0.8 g of lithium aluminum hydride in 40 ml of anhydrous tetrahydrofuran, a solution of 5.1 g (0.012 mol) (-)-3-phenoxy-N-[(2-furylmethyl)carbonyl]morphinan in 40 ml of anhydrous is added dropwise tetrahydrofuran. The reaction mixture is heated

under nitrogen i 3 timer til tilbakeløpskjøling, deretter kjø-les den til romtemperatur og tilsettes dråpevis vann. Den erhold-i ■ j ' te suspensjon filtreres. Filtratet konsentreres. Resten forde-! under nitrogen for 3 hours to reflux, then it is cooled to room temperature and water is added dropwise. The obtained suspension is filtered. The filtrate is concentrated. The rest for-!

les mellom eter og vann. Den eteriske løsning vaskes med 5-N-natriumhydroksyd og tørkes. Ved fjerning av løsningsmidlet i vakuum får man en oljeaktig rest. Resten renses ved kromatografi over silika-gel (50 g) og eluering med eter og gir (-)-3-fenoksy-N-[-2-(2-furyl)etyl]morfinan. For analyseformål destilleres en read between ether and water. The ethereal solution is washed with 5-N sodium hydroxide and dried. When the solvent is removed in vacuo, an oily residue is obtained. The residue is purified by chromatography over silica gel (50 g) and elution with ether to give (-)-3-phenoxy-N-[-2-(2-furyl)ethyl]morphinan. For analysis purposes, one is distilled

o 25 prøve av denne forbindelse. Kokepunkt 145-150 (0,1 mm Hg), [a]^ o 25 samples of this compound. Boiling point 145-150 (0.1 mm Hg), [a]^

-94,15° (c = 1,06 i metanol).-94.15° (c = 1.06 in methanol).

Til en løsning av 1,2 g (0,003 mol av denne base i eter tilsettes en løsning av 0,3 g oksalsyre i eter. Det rå oksalat omkrystalliseres to ganger fra etanol og gir (-)-3-fenoksy-N-[2-(2-furyl)-etyl]morfinanoksalat med smeltepunkt 195-197° (spaltning), [ot]D2 5 To a solution of 1.2 g (0.003 mol) of this base in ether is added a solution of 0.3 g of oxalic acid in ether. The crude oxalate is recrystallized twice from ethanol to give (-)-3-phenoxy-N-[2 -(2-furyl)-ethyl]morphinoxalate with melting point 195-197° (decomposition), [ot]D2 5

-64,52° (c = 1,03 i metanol).-64.52° (c = 1.03 in methanol).

EKSEMPEL 2 6EXAMPLE 2 6

Til en blanding av 4,0 g (0,012 mol) (-)- 3- fenoksymorfinan, 2,5 g trietylamin og 15 ml metylenklorid tilsettes dråpevis en løs-ning av 3,3 g 2-tienylacetylklorid i 15 ml metylenklorid. Reaksjonsblandingen oppvarmes i 15 timer til tilbakeløpskjøling, kjøles til romtemperatur, fortynnes metylenklorid og vaskes suksessivt med vann, 4-N-saltsyre, 5-N-natriumhydroksyd og vann. Den organiske fase tørkes og inndampes. Man erholder rått (-)-3-fenoksy-N-[(2-tienylmetyl)karbonyl]morfinan. For analyseformål destilleres en prøve av denne forbindelse. Kokepunkt 235-240° A solution of 3.3 g of 2-thienylacetyl chloride in 15 ml of methylene chloride is added dropwise to a mixture of 4.0 g (0.012 mol) (-)-3-phenoxymorphinan, 2.5 g of triethylamine and 15 ml of methylene chloride. The reaction mixture is heated for 15 hours to reflux, cooled to room temperature, methylene chloride is diluted and washed successively with water, 4-N-hydrochloric acid, 5-N-sodium hydroxide and water. The organic phase is dried and evaporated. Crude (-)-3-phenoxy-N-[(2-thienylmethyl)carbonyl]morphinan is obtained. For analytical purposes, a sample of this compound is distilled. Boiling point 235-240°

(0,05 mm Hg), [a]<25>-134,17° (c = 1,03 i metanol).(0.05 mm Hg), [α]<25>-134.17° (c = 1.03 in methanol).

EKSEMPEL 27EXAMPLE 27

Til en suspensjon av 0,8 g litiumaluminiumhydrid i 40 ml vannfritt tetrahydrofuran tilsettes dråpevis en løsning av 6,2 g (0,014 mol) (-)-3-fenoksy-N-[(2-tienylmetyl)karbonyl]morfinan i 40 ml vannfritt tetrahydrofuran. Reaksjonsblandingen oppvarmes i 3 timer til tilbakeløpskjøling, kjøles deretter til romtemperatur og vann tilsettes dråpevis. Den erholdte suspensjon filtreres. Filtratet inndampes. Resten løses i eter. Den eteriske løs-ning ekstraheres med 4-N-saltsyre. Den vandige fase innstilles alkalisk med 10-N-hatriumhydroksyd og ekstraheres med eter. Den organiske fase tørkes. Etter f-jerning av løsningsmidlet får man rått (-')-3-f enoksyJSI-[2-(2-tienyl) etyl]morf inan. For analysefor- To a suspension of 0.8 g lithium aluminum hydride in 40 ml anhydrous tetrahydrofuran, a solution of 6.2 g (0.014 mol) (-)-3-phenoxy-N-[(2-thienylmethyl)carbonyl]morphinan in 40 ml anhydrous is added dropwise tetrahydrofuran. The reaction mixture is heated for 3 hours to reflux, then cooled to room temperature and water is added dropwise. The suspension obtained is filtered. The filtrate is evaporated. The remainder is dissolved in ether. The ethereal solution is extracted with 4-N-hydrochloric acid. The aqueous phase is made alkaline with 10-N sodium hydroxide and extracted with ether. The organic phase is dried. After removal of the solvent, crude (-')-3-phenoxyJS1-[2-(2-thienyl)ethyl]morphinan is obtained. For analysis

i ol' I mål destilleres en prøve av denne forbindelse. Kokepunkt 150 i i ol' I measure a sample of this compound is distilled. Boiling point 150 i

i (0,05 mm Hg), [a]£ -96,45° (c = 1,23 i metanol). in (0.05 mm Hg), [α]£ -96.45° (c = 1.23 in methanol).

En løsning av 3,0 g (0,007 mol) av den forannevnte base i eter behandles med svovelsyre. Det rå sulfat krystalliseres fra metanol/eter og gir rent (-)-3-fenoksy-N-[2-(2-tienyl)etyl]morfinan-sulfat med smeltepunkt 135-138°. [a]<25>-67,28 (c = 1,00 i metanol) . A solution of 3.0 g (0.007 mol) of the aforementioned base in ether is treated with sulfuric acid. The crude sulfate is crystallized from methanol/ether and gives pure (-)-3-phenoxy-N-[2-(2-thienyl)ethyl]morphinan sulfate with a melting point of 135-138°. [α]<25>-67.28 (c = 1.00 in methanol).

- EKSEMPEL 28- EXAMPLE 28

En blanding av 3,0 g (0,011 mol) (-)-3-hydroksy-N-metylmorfinan, 50 ml nydestillert pyridin, 2,2 g 3-bromfluorbenzen, 2,4 g kaliumkarbonat og 3 g kornet kobber oppvarmes i en rustfri stålbe-holder i 8 dager til 120°. Etter avkjøling åpnes beholderen og reaksjonsblandingen filtreres. Filtratet konsentreres under redusert trykk. Resten fordeles mellom eter og 10-N-natriumhydroksyd. Eteriøsningen vaskes med vann og tørkes. Ved fjerning av løsningsmidlet i vakuum får man en svart rest, som ved 131-140° (0,15 mm Hg) destilleres og gir (-)-3-(m-fluor)fenoksy-N-metylmorf inan . [4Jy5 -56,79° (c = 1,04 i metanol). A mixture of 3.0 g (0.011 mol) (-)-3-hydroxy-N-methylmorphinan, 50 ml of freshly distilled pyridine, 2.2 g of 3-bromofluorobenzene, 2.4 g of potassium carbonate and 3 g of granulated copper is heated in a stainless steel container for 8 days at 120°. After cooling, the container is opened and the reaction mixture is filtered. The filtrate is concentrated under reduced pressure. The residue is distributed between ether and 10-N sodium hydroxide. The ethereal solution is washed with water and dried. When the solvent is removed in vacuo, a black residue is obtained, which is distilled at 131-140° (0.15 mm Hg) and gives (-)-3-(m-fluoro)phenoxy-N-methylmorphine. [4Jy5 -56.79° (c = 1.04 in methanol).

En løsning på 0,4 g (0,001 mol) av forannevnte base i 2 ml aceton tilsettes en løsning av 0,2 g d-vinsyre i 10 ml aceton. Det rå tartrat omkrystalliseres fra aceton og gir (-)-3-(m-fluor)fenoksy-N-metylmorf inan-d-tartrat-hemihydrat med smeltepunkt 121-123° [a]^<5>-18,61° ( c = 1,03 i metanol). A solution of 0.4 g (0.001 mol) of the aforementioned base in 2 ml of acetone is added to a solution of 0.2 g of d-tartaric acid in 10 ml of acetone. The crude tartrate is recrystallized from acetone and gives (-)-3-(m-fluoro)phenoxy-N-methylmorphinan-d-tartrate hemihydrate with melting point 121-123° [a]^<5>-18.61° ( c = 1.03 in methanol).

EKSEMPEL 29EXAMPLE 29

Til en løsning av 1,7 g (0,005 mol) (-)-3-(o-metoksy)fenoksy-N-metylmorf inan i 25 ml toluen tilsettes ved romtemperatur under røring og nitrogen dråpevis en løsning av 2,5 g cyklopropankarboksylsyreklorid i 15 ml toluen.Reaksjonsblandingen oppvarmes i 13 dager til tilbakeløpskjøling. Den etter fjerning av løsningsmidlet i vakuum erholdte rest fordeles mellom eter (500 ml) og 4-N-saltsyre (200 ml). Den eteriske løsning vaskes med fortynnet ammoniumhydroksyd og vann og tørkes derpå. Ved fjerning av løsningsmidlet får man rått (-)-3-(o-metoksy)-fenoksy-N-eyklopropylkarbonylmorfinan, som reduseres uten ytterligere rensing. To a solution of 1.7 g (0.005 mol) (-)-3-(o-methoxy)phenoxy-N-methylmorphine in 25 ml of toluene, a solution of 2.5 g of cyclopropanecarboxylic acid chloride in 15 ml toluene. The reaction mixture is heated for 13 days to reflux. The residue obtained after removal of the solvent in vacuo is distributed between ether (500 ml) and 4-N-hydrochloric acid (200 ml). The ethereal solution is washed with dilute ammonium hydroxide and water and then dried. Removal of the solvent gives crude (-)-3-(o-methoxy)-phenoxy-N-cyclopropylcarbonylmorphinan, which is reduced without further purification.

i . ■ i in . ■ i

Ti• l en suspensjon av 0,2 g litiumaluminiumhydrid i 20 ml vann-I'1 Ti• l a suspension of 0.2 g of lithium aluminum hydride in 20 ml of water-I'1

fritt tetrahydrofuran tilsettes dråpevis en løsning av 1,0 g (0,002 mol) (-)-3-(o-metoksy)fenoksy-N-cyklopropylkarbonylmorfi-nan i 10 ml vannfritt tetrahydrofuran. Reaksjonsblandingen oppvarmes under nitrogen i 15 timer til tilbakeløpskjøling, kjøles til romtemperatur og tilsettes deretter vann dråpevis.. Den erholdte suspensjon filtreres. Den etter konsentrering av filtratet erholdte rest fordeles mellom eter og 4-N-saltsyre. Den vandige løsning innstilles alkalisk med 10-N-natriumhydroksyd og ekstraheres med eter. Eteriøsningen vaskes med vann og tørkes. Ved fjerning av løsningsmidlet i vakuum får man rått (-)-3-(o-metoksy )fenoksy-N-cyklopropylmetylmorfinan. For analyseformål destilleres en prøve av denne forbindelse. Kokepunkt 210-220° (0,1 mmHg), [a]<25>-57,34 (c = 0,52 i metanol). of free tetrahydrofuran is added dropwise to a solution of 1.0 g (0.002 mol) (-)-3-(o-methoxy)phenoxy-N-cyclopropylcarbonylmorphinan in 10 ml of anhydrous tetrahydrofuran. The reaction mixture is heated under nitrogen for 15 hours to reflux, cooled to room temperature and then water is added dropwise. The resulting suspension is filtered. The residue obtained after concentration of the filtrate is distributed between ether and 4-N-hydrochloric acid. The aqueous solution is made alkaline with 10-N sodium hydroxide and extracted with ether. The ethereal solution is washed with water and dried. By removing the solvent in vacuo, crude (-)-3-(o-methoxy)phenoxy-N-cyclopropylmethylmorphinan is obtained. For analytical purposes, a sample of this compound is distilled. Boiling point 210-220° (0.1 mmHg), [a]<25>-57.34 (c = 0.52 in methanol).

Ved behandling av 0,5 g (0,001 mol) av forannevnte base med vannfritt hydrogenklorid i eddikester får man rått hydroklorid, som etter krystallisasjon fra etanol/eter gir (-)-3-(o-metoksy)-fenoksy-N-cyklopropyImety1-morfinan-hydroklorid med smeltepunkt 226-227° (spaltning), [a]<25>-71,-18° (c = 1,00 i metanol). By treating 0.5 g (0.001 mol) of the above-mentioned base with anhydrous hydrogen chloride in acetic acid, crude hydrochloride is obtained, which after crystallization from ethanol/ether gives (-)-3-(o-methoxy)-phenoxy-N-cyclopropylmethyl- morphinan hydrochloride m.p. 226-227° (dec.), [α]<25>-71.-18° (c = 1.00 in methanol).

EKSEMPEL 30EXAMPLE 30

Til en løsning av 1,9 g (0,005 mol) (-)-3-(p-metoksyfenoksy-N-metylmorf inan i 25 ml toluen tilsettes ved romtemperatur under nitrogen dråpevis en løsning av 2,9 g cyklopropankarboksylsyreklorid i 12 ml toluen. Reaksjonsblandingen oppvarmes under rø-ring i 13 dager til tilbakeløpskjøling. Den etter fjerning av løsningsmidlet under redusert trykk erholdte rest fordeles mellom eter og 4-N-saltsyre. Den eteriske løsning vaskes med fortynnet ammoniumhydroksyd og vann og tørkes deretter. Ved fjerning av løsningsmidlet får man en oljeaktig rest, som etter de-stillasjon gir (-)-3-(p-metoksy)fenoksy-N-cyklopropylkarbonyl-morfinan med kokepunkt 170° (0,05 mm Hg). Denne forbindelse anvendes uten ytterligere rensning for reduksjonen. To a solution of 1.9 g (0.005 mol) (-)-3-(p-methoxyphenoxy-N-methylmorphine) in 25 ml of toluene, a solution of 2.9 g of cyclopropanecarboxylic acid chloride in 12 ml of toluene is added dropwise at room temperature under nitrogen. The reaction mixture is heated with stirring for 13 days to reflux. The residue obtained after removal of the solvent under reduced pressure is distributed between ether and 4-N-hydrochloric acid. The ethereal solution is washed with dilute ammonium hydroxide and water and then dried. Upon removal of the solvent, an oily residue, which after distillation yields (-)-3-(p-methoxy)phenoxy-N-cyclopropylcarbonyl-morphinan with a boiling point of 170° (0.05 mm Hg). This compound is used without further purification for the reduction.

Til en suspensjon av 0,4 g litiumaluminiumhydrid i 20 ml vannfritt tetrahydrofuran tilsettes dråpevis en løsning av 2,2 g > A solution of 2.2 g > is added dropwise to a suspension of 0.4 g of lithium aluminum hydride in 20 ml of anhydrous tetrahydrofuran

(0,005 mol) (-)-3-(p-metoksy)fenoksy-N-cyklopropylkarbonylmorfi-! I nan i 10 ml vannfr- itt tetrahydrofuran.Reaksjonsblandingen opp-Ii (0.005 mol) (-)-3-(p-methoxy)phenoxy-N-cyclopropylcarbonylmorphi-! I nan in 10 ml anhydrous tetrahydrofuran. The reaction mixture up-Ii

' I 'I

varmes under nitrogen i 15 timer til tilbakeløpskjøling, kjø-les til romtemperatur og tilsettes deretter vann dråpevis. Den erholdte suspensjon filtreres. Den etter konsentrasjon av filtratet erholdte rest fordeles mellom eter' og 4-N-saltsyre. Den vandige løsning gjøres alkalisk med 10-N-natriumhydroksyd og ekstraheres med eter. Eteriøsningen vaskes med vann og tørkes. Ved fjerning av løsningsmidlet i vakuum får man rått (-)-3-(p-metoksy)-fenoksy-N-cyklopropylmetylmorfinan. For analyseformål destilleres en prøve av denne forbindelse. Kokepunkt 215-220° is heated under nitrogen for 15 hours to reflux, cooled to room temperature and then water is added dropwise. The suspension obtained is filtered. The residue obtained after concentration of the filtrate is distributed between ether and 4-N-hydrochloric acid. The aqueous solution is made alkaline with 10-N sodium hydroxide and extracted with ether. The ethereal solution is washed with water and dried. By removing the solvent in vacuo, crude (-)-3-(p-methoxy)-phenoxy-N-cyclopropylmethylmorphinan is obtained. For analytical purposes, a sample of this compound is distilled. Boiling point 215-220°

(0,25 mm Hg), [a]2<5>-77,78° (c =0,45 i metanol).(0.25 mm Hg), [α]2<5>-77.78° (c =0.45 in methanol).

Ved behandling av 1,5 g (0,004 mol) av forannevnte base med vannfritt hydrogenklorid i eddikester får man rått hydroklorid. Ved omkrystallisasjon. fra etanol/eter får man (-)-3-(p-metoksy) fenoksy-N-cyklopropylmetylmorfinan-hydroklorid med smeltepunkt 204-206°. [cx]2<5>-60,50° ( c = 0,99 i metanol). By treating 1.5 g (0.004 mol) of the aforementioned base with anhydrous hydrogen chloride in acetic acid, crude hydrochloride is obtained. Upon recrystallization. from ethanol/ether one obtains (-)-3-(p-methoxy)phenoxy-N-cyclopropylmethylmorphinan hydrochloride with a melting point of 204-206°. [cx]2<5>-60.50° ( c = 0.99 in methanol).

EKSEMPEL 31EXAMPLE 31

En tablett fremstilles som følger:A tablet is prepared as follows:

Fremgangsmåte Approach

1. Bestanddelene 1,2,3,4 og 5 blandes i en egnet blandeanord ning og granuleres med vann. Man tørker i ovn over natten og maler deretter i en mølle. 2. Bestandel 6 tilsettes, hvorpå, tabletter utpresses på en egnet presse. EKSEMPEL 32 En tablett fremstilles som følger: 1. The components 1,2,3,4 and 5 are mixed in a suitable mixing device ning and granulated with water. It is dried in an oven overnight and then ground in a mill. 2. Component 6 is added, after which, tablets are squeezed out on a suitable press. EXAMPLE 32 A tablet is prepared as follows:

Fremgangsmåte Approach

1. Bestanddelene 1,2,3,4 og 5 blandes i 10-15 minutter"i et egnet blandeapparat. 2. Magnesiumstearatet (bestanddel 6) tilblandes, hvoretter det blandes ytterligere 4 minutter. Tablettene presses på en egnet presse. 1. Components 1,2,3,4 and 5 are mixed for 10-15 minutes in a suitable mixing device. 2. The magnesium stearate (component 6) is mixed, after which it is mixed for a further 4 minutes. The tablets are pressed on a suitable press.

EKSEMPEL 33EXAMPLE 33

En kapsel fremstilles som følger:A capsule is prepared as follows:

Fremgangsmåte Approach

1. Bestanddelene 1,2 og 3 blandes i en egnet blandeanordning og males deretter i en egnet mølle, 2. Bestanddelene 4 og 5 tilblandes, hvoretter man maskinelt fyl-ler blandingen i kapsler. 1. Components 1,2 and 3 are mixed in a suitable mixing device and then ground in a suitable mill, 2. Components 4 and 5 are mixed, after which the mixture is mechanically filled into capsules.

EKSEMPEL 34EXAMPLE 34

En kapsel fremstilles som følger:A capsule is prepared as follows:

I i i . i I i i . in

Fremgangsmåte Approach

1. Bestanddelene 1, 2 og 3 blandes i en egnet blandeanordning og males deretter i en egnet mølle. 2. Bestanddelene 4 og 5 tilblandes, hvoretter man maskinelt fyl-ler blandingen i kapsler. 1. Components 1, 2 and 3 are mixed in a suitable mixing device and then ground in a suitable mill. 2. Components 4 and 5 are mixed, after which the mixture is mechanically filled into capsules.

EKSEMPEL 35EXAMPLE 35

En kapsel fremstilles på samme måte som i eksempel 14, hvorved det dog som virksomt stoff anvendes (-)-(p-metyl)fenoksy-N-metylmorf inan. A capsule is prepared in the same way as in example 14, whereby (-)-(p-methyl)phenoxy-N-methylmorphine is used as active substance.

EKSEMPEL 3 6EXAMPLE 3 6

En tablett, (våtgranulering) fremstilles som følger:A tablet, (wet granulation) is prepared as follows:

Fremgangsmåte Approach

1. Bestanddelene 1-4 blandes i en egnet blandeanordning.1. The components 1-4 are mixed in a suitable mixing device.

2. Granulatet blandes med tilstrekkelig vann til at en ren konsistens erholdes. Deretter males. 3. Det tørkes i en egnet ovn. Det blandes i 3 minutter med magnesiumstearat 4. Det presses til tabletter på en egnet tablettpresse. 2. The granules are mixed with sufficient water to obtain a clean consistency. Then painted. 3. It is dried in a suitable oven. It is mixed for 3 minutes with magnesium stearate 4. It is pressed into tablets on a suitable tablet press.

I I I I

EKSEMPEL 37i|EXAMPLE 37i|

En tablett (vatgranulering) fremstilles som følger:A tablet (cotton granulation) is prepared as follows:

Fremgangsmåte: Approach:

2. Granulatet tilsettes tilstrekkelig destillert vann for å2. Sufficient distilled water is added to the granulate to

oppnå en ren konsistens. Derpå males.achieve a clean consistency. Then paint.

3. Det tørkes i en egnet ovn. Det blandes i 3 minutter med magnesiumstearat. 3. It is dried in a suitable oven. It is mixed for 3 minutes with magnesium stearate.

4. Tablettene presses på en egnet tablettpresse. 4. The tablets are pressed on a suitable tablet press.

Claims

1. Process for the preparation of levorotatory 3-phenoxy-N-substituted morphinan derivatives with the general formula

where R means halogen, nitro, lower alkyl, lower alkoxy, hydroxy or hydrogen, R^ hydrogen, lower alkyl, lower alkenyl, the group -CH2 (CH2 )pR2 or -CO-(CH2)p R2, R2 a hetero-aromatic or aromatic residue or cyclo-lower alkyl, P an integer from 0 to 3, and n means an integer from 1 to 5, as well as pharmaceutically usable salts thereof, characterized in that mana) reacts with a compound of the formula

in which R-^ has the above meaning, with a compound of the general formula

wherein R and n have the above meanings, and X means halogen, or b) for the preparation of a compound of formula I, wherein R. is hydroxy, cleaves an ether with the formula li IN

where i n and R-^ have the above meanings, and <R>3 means lower alkyl, or c) for the preparation of a compound of formula I, in which R^ means -CO-(CH2)p-R2' reacts a compound with the formula

wherein n and R have the above meanings, with a connection with the formula X—CO—(CH2 )p—R2 IV in which R 2 , p and X have the above meanings, ord) for the preparation of a compound of the formula I, in which ' R^ means -CH 2 (CH 2 ) ^R 2 , reduces a compound of the formula

in which R, R2 and p have the above meanings, or N e) for the preparation of a compound of formula I, wherein R-j^ means hydrogen, treats a compound of the formula

wherein R and n have the above meanings, with zinc in a lower alkane carboxylic acid, or f) for the preparation of a compound of formula I, wherein R-^ means -CH 2 (CH 2 ) R 2 , reacts a compound of formula

wherein R and n have the above meanings, with a connection of the formula

wherein X, R 2 and p have the above meanings, or g) for the preparation of a compound of formula I, in which R-^ means hydrogen, i.e. a compound of formula VII, dealkylates a compound of formula I-C, or II In h) for the preparation of a' compound of formula I, wherein ~" R-^ means -CH2 (CH2) ^R2, reacts a compound of formula VII - with a compound of formula IV, or ii) for the preparation of a compound of formula I, wherein R is lower alkyl or lower alkenyl, reacts a compound of formula VII with a compound of formula

wherein X has the above meaning, and Ry means lower alkyl or lower alkenyl, ork) cyclizes a compound of formula

in which R, R-l and n have the above meanings, and if desired,

1) transfers a compound of formula I in a pharmaceutically usable acid addition salt.

2. Method according to claim 1, characterized in that R means cyclo-lower alkyl.

3. Process according to claim 1, characterized in that R1 means lower alkyl.

4. Process according to claim 3, characterized in that Rj means methyl. II

5 . Method according to claim 1, character i-I is characterized in that R1 means -CO-(CH2 )p-R2 . IN

6. Method according to claim 5, characterized in that p is 0.

7. Process according to claim 6, characterized in that is cyclopropyl.

8. Procedure. according to claim 5, characterized in that p is 1.

9. Process according to claim 8, characterized in that R2 means phenyl.

10. Method according to claim 8, characterized in that R means 2-furyl.

11. Method according to claim 1, characterized in that R-j- means -CH2(CH2)R2.

12. Method according to claim 11, characterized in that p is 0.

13. Process according to claim 12, characterized in that Rj is cyclopropyl. .

14. Method according to claim 1, characterized in that R means hydrogen.

15. Method according to claim 1, characterized in that R means lower alkyl.

16. Method according to claim 14, characterized in that R means methyl,

17. Method according to claim 16, characterized in that n is 1.

18. Process according to claim 1, characterized in that R means lower alkoxy. in i

19. Method according to claim 18, characterized in that R means methoxy.

20. Method according to claim 19, characterized in that n is 1.

21. Method according to claim 1, characterized in that R means hydroxy.

22. Method according to claim 21, characterized in that n is 1.

23. Method according to claim 1, characterized in that R means nitro.

24. Method according to claim 23, characterized in that n is 1.

25. Method according to claim 1, characterized in that R means halogen.

26. Method according to claim 25, characterized in that R means fluorine.

27. Method according to claim 26, characterized in that n is 1 or 5.

28. Process according to claim 1, characterized in that (-)-3-phenoxy-N-methylmorphinan is produced.

29. Process according to claim 1, characterized in that (-)-3-(p-methyl)phenoxy-N-methylmorphinan is produced.

30. Method according to claim 1, characterized in that (-)-3-phenoxy-N-phenethylmorphinan is produced.

31. Process according to claim 1, characterized in that one prepares (-)-3-phenoxy-N-[2-(2-furyl)ethyl]- in morphinan.

32. Method according to claim 1, characterized in that (-)-3-(o-methoxy)phenoxy-N-cyclopropyl methylmorphinan is produced.

33. Method according to claim 1, characterized in that (-)-3-(p-methoxy)phenoxy-N-cyclopropylmethylmorphine is produced.

34. Process according to claim 1, characterized in that (-)-3-(m-methoxy)phenoxy-N-methylmorphinan is produced.

35. Process according to claim 1, characterized in that (-)-3-(o-methoxy)phenoxy-N-methylmorphinan is produced.

36. Process according to claim 1, characterized in that (-)-3-(p-hydroxy)phenoxy-N-methylmorphine is produced.

37. Process according to claim 1, characterized in that (-)-3-(o-hydroxy)phenoxy-N-methylmorphine is produced.

38. Process according to claim 1, characterized in that (-)-3-(o-nitro)phenoxy-N-methylmorphinan is produced.

39. Process according to claim 1, characterized in that (-)-3-(p-fluoro)phenoxy-N-rhethylmorphinan is produced.

40. Method according to claim 1, characterized in that (-)-3-(o-fluoro)phenoxy-N-methylmorphinan is produced.

41. Method according to claim 1, characterized in that (-)-3-pentafluorophenoxy-N-methylmorphinan is produced.

42. Method according to claim 1, characterized by preparing (-)-3-phenoxy-N-cyclopropylmethylmorphine nan. in

43. Process according to claim 1, characterized in that (-)-3-phenoxy-17-cyclopropylcarbonyl-morphinan is produced.

44. Process for the production of preparations with analgesic and/or drug-antagonistic properties, characterized by mixing a morphinan derivative according to the general formula I in claim 1 or a pharmaceutically usable acid addition salt thereof as active ingredient for therapeutic administration suitable, non-toxic, inert, in and of themselves in such preparations common solid and liquid carriers and/or excipients.

45. Preparations with analgesic and/or drug-antagonistic properties, characterized in that they contain a compound of the general formula I according to claim 1 or a pharmaceutically usable acid addition salt thereof together with a suitable carrier material.

46. Compounds, characterized by the formula

wherein R means halogen, nitro, lower alkyl, lower alkoxy, hydroxy or hydrogen, and n means an integer from 1 to 5.

47. (-)-3-phenoxy-N-trichlorocarbethoxymorphinan.

48. Compounds, characterized by the formula in

wherein R means halogen, nitro, lower alkyl, lower alkoxy, hydroxy or hydrogen, R-^ means hydrogen, lower alkyl, lower alkenyl, -CO-(CH2 ) -R2 or -CH2(CH2), R2 a heteroaromatic residue, an aromatic residue or cyclo-lower alkyl, p an integer from 0 - 3, and n an integer from 1-5, as well as pharmaceutically usable salts thereof.

49. (-)-1-(p-phenoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octa-hydroisoquinoline.

5 0. Levorotatory 3-phenoxy-N-substituted morphinan derivatives, characterized by the general formula

wherein R means halogen, nitro, lower alkyl, lower alkoxy, hydroxy or hydrogen, R-L hydrogen, lower alkyl, lower alkenyl, -CO-(CH2) p-R2 or -CH9(CH9) R,, R2 a heteroaromatic or aromatic residue or ! cyclo-lower alkyl, p means an integer from 0-3, and n an integer from 1-5, as well as pharmaceutically usable acid addition salts thereof.

51. Compound according to claim 50, characterized in that R 2 means cyclo-lower alkyl.

52. Compound according to claim 50, characterized in that R-^ means lower alkyl.

53. Compound according to claim 52, characterized in that means methyl.

54. Compound according to claim 50, characterized in that R1 means -CO-(CH2)p-R7.

55. Compound according to claim 54, characterized in that p is 0.

56. Compound according to claim 55, characterized in that R2 is cyclopropyl.

57. Compound according to claim 54, characterized in that p is 1.

58. Compound according to claim 57, characterized in that Rj means phenyl.

59. Compound according to claim 58, characterized in that R 2 means 2-furyl.

60. Compound according to claim 50, characterized in that R1 means -CO-(CH2)p-R2.

61. Compound according to claim 60, characterized in that p is 0. ! I i ;

62. Compound according to claim 61, characterized in that is cyclopropyl.

63. Compound according to claim 50, characterized in that R is hydrogen.

64. Connection according to claim 50. characterized in that R means lower alkyl.

65. Compound according to claim 64, characterized in that R means methyl.

66. Compound according to claim 65; ., characterized by n being 1.

67. Compound according to claim 50, characterized in that R means lower alkoxy.

68. Compound according to claim 67, characterized in that R means methoxy.

69. Compound according to claim 68, characterized in that n is 1. ,,,

70. Compound according to claim 50, characterized in that R means hydroxy.

71. Compound according to claim 70, characterized in that n is 1.

72. Compound according to claim 50, characterized in that R means nitro.

73. Compound according to claim 72, characterized in that n is 1.

74. Compound according to claim 50, characterized in that R means halogen. i i i i IN IN <!>

75. Compound according to claim 74, characterized in that R means fluorine.

76. Compound according to claim 75, characterized in that n is 1 or 5.

77. (-)-3-phenoxy-N-methylmorphinan.

78. (-)-3-(p-methyl)phenoxy-N-methylmorphinan.

79 . (-)-3-phenoxy-N-phenethylmorphinan.

80. (-)-3-phenoxy-N-[2-(2-furyl)ethyl]morphinan.

81. (-)-3-(o-Methoxy)phenoxy-N-cyclopropylmethylmorphinan.

82. (-)-3-(p-Methoxy)phenoxy-N-cyclopropylmethylmorphinan.

83. (-)-3-(m-Methoxy)phenoxy-N-methylmorphinan.

84. (-)-3-(o-Methoxy)phenoxy-N-methylmorphinan.

85. (-)-3-(p-hydroxy)phenoxy-N-methylmorphinan.

86. (-)-3-(o-hydroxy)phenoxy-N-methylmorphinan.

87. (-)-3-(o-nitro)phenoxy-N-methylmorphinan.

88. (-)-3-(p-fluoro)phenoxy-N-methylmorphinan.

89. (-)-3-(o-fluoro)phenoxy-N-methylmorphinan.

90. (-)-3-pentafluorophenoxy-N-methylmorphinan.

91. (-)-3-phenoxy-N-cyclopropylmethylmorphinan.

92. (-)-3-phenoxy-17-cyclopropylcarbonylmorphinan. • in I