NO122840B

NO122840B -

Info

Publication number: NO122840B
Application number: NO0591/69A
Authority: NO
Inventors: M Gerold; H Thoenen
Original assignee: Hoffmann La Roche
Priority date: 1968-02-14
Filing date: 1969-02-13
Publication date: 1971-08-23
Also published as: IL31513A0; SE367395B; GB1208231A; CH500163A; ES363591A1; IE32946L; DE1907247A1; BR6906186D0; AT289061B; CH500941A; NL6901894A; IE32946B1; AT289757B; BE728327A; FR2011805A1; IL31513A

Description

Analogifremgangsmåte for fremstilling av terapeutisk Analogy method for the preparation of therapeutic

virksomme fenetylaminderivater. active phenethylamine derivatives.

Nærværende oppfinnelse vedrorer en fremgangsmåte for fremstilling av terapeutisk virksomme fenetylaminderivater med den generelle formel hvor og R2 betyr hydroksy eller lavere alkoksy og The present invention relates to a method for the production of therapeutically effective phenethylamine derivatives with the general formula where and R2 means hydroxy or lower alkoxy and

R^ lavere alkyl, R^ lower alkyl,

såvel som salter av disse forbindelser. as well as salts of these compounds.

De foran nevnte alkoksyrester kan inneholde inntil 6 karbonatomer, som f.eks. metoksy- eller etoksy-resten. Også»de lavere alkylrester inneholder inntil 6 karbonatomer. Alkylrest-ene kan være forgrenet eller uforgrenet. Som eksempler på lavere alkylrester kan nevnes metyl-, etyl- eller isopropyl-resten. The above-mentioned carboxylic acid residues can contain up to 6 carbon atoms, which e.g. the methoxy or ethoxy residue. Also» the lower alkyl residues contain up to 6 carbon atoms. The alkyl radicals can be branched or unbranched. As examples of lower alkyl residues, the methyl, ethyl or isopropyl residue can be mentioned.

Som representative representanter av de ifolge oppfinnelsen fremstillbare forbindelser med formel I kan blant annet nevnes: 3,5-dihydroksy-4-metoksy-a-metyl-fenetylamin, smp. 222 - 224°C, 3.4- dihydroksy-5-metoksy-a-metyl-fenetylamin, smp. 270 - 272°C, 3 , 4, 5-trihydrolcsy-ct-metyl-f enetylamin, smeltepunkt ikke målbart, 3.5- dihydroksy-4-metoksy-a-etyl-fenetylamin, smp. 160 - 163°C. Fenetylaminderivatene med den generelle formel I og deres salter fremstilles ifolge oppfinnelsen ved at man hydrogenolyserer en forbindelse med den generelle formel hvor X ^betegner en av gruppene As representative representatives of the compounds of formula I which can be prepared according to the invention, the following can be mentioned, among others: 3,5-dihydroxy-4-methoxy-a-methyl-phenethylamine, m.p. 222 - 224°C, 3,4-dihydroxy-5-methoxy-α-methyl-phenethylamine, m.p. 270 - 272°C, 3, 4, 5-trihydrolcsy-ct-methyl-phenethylamine, melting point not measurable, 3.5-dihydroxy-4-methoxy-α-ethyl-phenethylamine, m.p. 160 - 163°C. The phenethylamine derivatives with the general formula I and their salts are prepared according to the invention by hydrogenolyzing a compound with the general formula where X ^denotes one of the groups

og , R2 og R^ har foran angitte betydning, and , R2 and R^ have the above meaning,

idet frie hydroksylgrupper er erstattet med aralk- in that free hydroxyl groups are replaced with aralk-

oksygrupper, oxygen groups,

eller at man hydrolyserer en forbindelse med den generelle formel II, or that one hydrolyzes a compound of the general formula II,

hvor X betegner gruppen where X denotes the group

og and

R^ , R£ og R^ har foran angitte betydning, idet frie R^ , R£ and R^ have the meaning given above, being free

hydroksylgrupper er erstattet med acyloksygrupper, og at man, hvis onsket, overforer den erholdte forbindelse med formel I til et salt. hydroxyl groups are replaced by acyloxy groups, and that, if desired, the obtained compound of formula I is converted to a salt.

Frie hydroksygrupper i forbindelser med formel II er beskyttet med acylrester, spesielt med lavere alkanoylrester, som f.eks. acetyl- eller aroylrester, som f.eks. benzoylrester eller med aralkylrester fortrinnsvis med aryl-laverealkylrester, som f.eks. benzylrester. Free hydroxy groups in compounds of formula II are protected with acyl residues, especially with lower alkanoyl residues, such as e.g. acetyl or aroyl residues, such as benzoyl residues or with aralkyl residues, preferably with aryl-lower alkyl residues, such as e.g. benzyl residues.

De som utgangssubstanser anvendte forbindelser med den gene- The compounds used as starting substances with the gene

relle formel II, hvor X er resten relle formula II, where X is the residue

kan fremstilles på i og for seg kjent måte f.eks. ved at man overforer et tilsvarende ringsubstituert benzaldehyd, i hvilket frie hydroksylgrupper er erstattet med acyloksy- eller aralkyloksygrupper, ved behandling med et alkylsubstituert nitrometan i nærvær av et amin, fortrinnsvis n-butylamin eller benzylamin eller et ammoniumsalt, spesielt ammoniumacetat, i et mellom ca. 20 og 120°C liggende temperaturområde til det tilsvarende ringsubstituerte (3-nitro-(3-alkyl-styrol, og reduserer dette ved hjelp av et komplekst metallhydrid, fortrinnsvis ved hjelp av litiumaluminiumhydrid i et inert opplosningsmiddel, som f.eks. eter eller tetrahydrofuran i et mellom ca. værelsetemperatur og kokepunktet for oppldsningsmidlet liggende temperaturområde. Den samme utgangsforbindelse med formel II kan videre f.eks. fremstilles ved at man overforer på i og for seg kjent måte en tilsvarende ringsubstituert benzosyreester eller en substi-tuert benzosyre, i hvilken frie hydroksygrupper er erstattet med acyloksy- eller aralkyloksygrupper, ved halogenering til det tilsvarende benzoylhalogenid, reduserer dette ved hjelp av et komplekst metallhydrid, f.eks. ved hjelp av litiumaluminiumhydrid, natriumborhydrid eller også med diboran i et inert opplosningsmiddel som eter, dioksan/vann eller dietylenglykol-dimetyleter i et mellom 0 og 40°C liggende temperaturområde, omsetter den dannede alkohol med et halogeneringsmiddel, f.eks. med fosfortriklorid eller tionylklorid i et inert opplosningsmiddel som eter, benzen eller metylenklorid, eller et alkalisalt av denne alkohol med et sulfoneringsmiddel, f.eks. med metansulfoklorid eller toluensulfoklorid i et mellom værelsetemperatur og koketemperaturen for reaksjonsblandingen liggende temperaturområde til et ringsubstituert benzylklorid eller -mesylat eller -tosylat. Deretter omsettes det erholdte halo-genid henh. sulfonat på vanlig måte med et alkalisalt av en alkylsubstituert malonsyreester i et inert opplosningsmiddel, f.eks. i en alkanol eller i benzen, spesielt i dimetylformamid i et mellom ca. 20 og 100°C liggende temperaturområde. Den erholdte ester kan f.eks. forsåpes ved behandling med alkoholisk vandig alkali, fortrinnsvis ved innvirkning, av kaliumhydroksyd i metanol/vann ved veer els etemperatur. Den dannede dikarboksyl-syre kan f.eks. selektivt dekarboksyleres ved oppvarmning, fortrinnsvis ved oppvarmning i nærvær av en fortynnet mineralsyre, f.eks. i 2-n svovelsyre. can be produced in a manner known per se, e.g. by transferring a corresponding ring-substituted benzaldehyde, in which free hydroxyl groups have been replaced by acyloxy or aralkyloxy groups, by treatment with an alkyl-substituted nitromethane in the presence of an amine, preferably n-butylamine or benzylamine or an ammonium salt, especially ammonium acetate, in a between approx. . 20 and 120°C lying temperature range to the corresponding ring-substituted (3-nitro-(3-alkyl-styrene), and reduces this with the help of a complex metal hydride, preferably with the help of lithium aluminum hydride in an inert solvent, such as ether or tetrahydrofuran in a temperature range between approx. in which free hydroxy groups are replaced by acyloxy or aralkyloxy groups, by halogenation to the corresponding benzoyl halide, this is reduced with the help of a complex metal hydride, for example with the help of lithium aluminum hydride, sodium borohydride or also with diborane in an inert solvent such as ether, dioxane/ water or diethylene glycol dimethyl ether in a temperature range between 0 and 40°C, it reacts d other alcohol with a halogenating agent, e.g. with phosphorus trichloride or thionyl chloride in an inert solvent such as ether, benzene or methylene chloride, or an alkali salt of this alcohol with a sulphonating agent, e.g. with methanesulfochloride or toluenesulfochloride in a temperature range between room temperature and the boiling temperature of the reaction mixture to a ring-substituted benzyl chloride or -mesylate or -tosylate. The resulting halogenide is then reacted according to sulphonate in the usual way with an alkali salt of an alkyl substituted malonic acid ester in an inert solvent, e.g. in an alkanol or in benzene, especially in dimethylformamide in a between approx. 20 and 100°C horizontal temperature range. The obtained ester can e.g. is saponified by treatment with alcoholic aqueous alkali, preferably by the action of potassium hydroxide in methanol/water at veer or e temperature. The formed dicarboxylic acid can e.g. is selectively decarboxylated by heating, preferably by heating in the presence of a dilute mineral acid, e.g. in 2-n sulfuric acid.

Det dannede oc-alkyl-substituerte fenylpropionsyrederivat kan f.eks. omsettes ved behandling med en klormaursyreester eller også ved behandling med tionylklorid, fosforoksyklorid eller fosforpentaklorid til det tilsvarende blandete anhydrid, deretter overfores ved behandling med natriumazid i et inert opplosningsmiddel, som f.eks. aceton mellom 0 og 30°C til azidet og ved oppvarmning omdannes til det tilsvarende isocyanat, som igjen ved innvirkning av fortynnet vandig mineralsyre gir den dnskede utgangsforbindelse med formel II, hvor X er resten The oc-alkyl-substituted phenylpropionic acid derivative formed can e.g. is converted by treatment with a chloroformic acid ester or also by treatment with thionyl chloride, phosphorus oxychloride or phosphorus pentachloride to the corresponding mixed anhydride, then transferred by treatment with sodium azide in an inert solvent, such as e.g. acetone between 0 and 30°C to the azide and on heating is converted to the corresponding isocyanate, which again under the influence of dilute aqueous mineral acid gives the desired starting compound of formula II, where X is the residue

De som utgangssubstanser anvendte forbindelser med den generelle formel II, hvor X er en 2-imino-2-alky1-etyl-gruppe, kan fremstilles på i og for seg kjent måte f.eks. ved at man til-setter et tilsvarende ringsubs tituert (3-nitro-(3-alkyl-styrol, The compounds of the general formula II used as starting substances, where X is a 2-imino-2-alkyl-ethyl group, can be prepared in a manner known per se, e.g. by adding a corresponding ring substituted (3-nitro-(3-alkyl-styrene,

i hvilket frie hydroksylgrupper er erstattet med acyloksy- eller aralkyloksygrupper, til en til koking oppvarmet blanding av in which free hydroxyl groups are replaced by acyloxy or aralkyloxy groups, to a mixture heated to boiling of

vann, metanol, iseddik og jernpulver. Oksimet som derved danner seg intermediært, forsåpes straks til det tilsvarende keton, som ved -behandling med vandig ammoniak ved værelsetemperatur lar seg omdanne til det tilsvarende imin, som ikke isoleres, men umiddelbart kan reduseres til en eventuelt ennå med beskyttelsesgrupper beskyttet forbindelse med formel I, idet eventuelt ennå tilstedeværende aralkylgrupper kan avspaltes ved hydrogenolyse, tilstedeværende acylgrupper ved hydrolyse. water, methanol, glacial acetic acid and iron powder. The oxime that is thereby formed as an intermediate is immediately saponified into the corresponding ketone, which, by treatment with aqueous ammonia at room temperature, can be converted into the corresponding imine, which is not isolated, but can be immediately reduced to a compound of formula I, possibly still protected by protective groups , since any aralkyl groups still present can be split off by hydrogenolysis, acyl groups present by hydrolysis.

De som utgangssubstanser anvendte forbindelser med den generelle formel II, hvor X er en 2-hydroksyimino-2-alkyl-etyl-gruppe, kan fremstilles på i og for seg kjent måte, f.eks. ved at man opp-varmer til koking et tilsvarende ringsubstituert benzaldehyd, i hvilket frie hydroksygrupper er erstattet med acyloksy- eller aralkyloksy-grupper, hensiktsmessig i nærvær av et amin, som n-butylamin eller benzylamin eller et ammoniumsalt, som ammoniumacetat, med et alkylsubstituert nitrometan, avkjoler reaksjonsblandingen, ihnd.amper og. reduserer det tilbakeblivende ringsubstituerte f3-nitro-(3-aIkyl-styrol. ved hjelp av nasserende hydrogen [sink/saltsyre] eller ved hjelp av katalytisk aktivert hydrogen [palladiumkull] til det tilsvarende oksim med formel II, som deretter kan reduseres til en forbindelse med formel II, hvor X The compounds of the general formula II used as starting substances, where X is a 2-hydroxyimino-2-alkyl-ethyl group, can be prepared in a manner known per se, e.g. by heating to boiling a corresponding ring-substituted benzaldehyde, in which free hydroxy groups have been replaced by acyloxy or aralkyloxy groups, suitably in the presence of an amine, such as n-butylamine or benzylamine or an ammonium salt, such as ammonium acetate, with an alkyl-substituted nitromethane, cools the reaction mixture, ihnd.amper and. reduces the remaining ring-substituted 3-nitro-(3-alkyl-styrene) by means of nascent hydrogen [zinc/hydrochloric acid] or by means of catalytically activated hydrogen [palladium charcoal] to the corresponding oxime of formula II, which can then be reduced to a compound of formula II, where X

1<3>1<3>

er en -Cb^-CH-Nh^-griippe, idet eventuelt . ennå tilstedeværende aralkylgrupper kan avspaltes ved hydrogenolyse, tilstedeværende acylgrupper ved hydrolyse. is a -Cb^-CH-Nh^-griippe, as possibly . aralkyl groups still present can be split off by hydrogenolysis, acyl groups present by hydrolysis.

En tilstedeværende 2-imino- henh.. 2-hydroksyimino-2-alkyl-etyl-gruppe X kan fordelaktig på katalytisk måte .reduseres til onsket 2-amino-2-alkyl-etylgruppe X. Reduksjonen gjennomføres hensiktsmessig ved katalytisk aktivert hydrogen i et inert opplosningsmiddel, som f.eks. metanol i et mellom værelsetemperatur og kokepunktet for oppldsningsmidlet liggende temperaturområde ved normalt eller- dket trykk. Som katalysatorer er egnet f.eks. A present 2-imino-hen.. 2-hydroxyimino-2-alkyl-ethyl group X can advantageously be catalytically reduced to the desired 2-amino-2-alkyl-ethyl group X. The reduction is suitably carried out by catalytically activated hydrogen in a inert solvent, such as e.g. methanol in a temperature range between room temperature and the boiling point of the solvent at normal pressure. Suitable catalysts are e.g.

enten Raney-nikkel eller edelmetaller, som platina eller palladium eller''Raney-kobolt. either Raney nickel or precious metals, such as platinum or palladium or ''Raney cobalt.

Reduksjonen kan videre også gjennomfdres ved hjelp av komplekse metallhydrider, som natrium- eller litiumborhydrid., Anvender The reduction can also be carried out using complex metal hydrides, such as sodium or lithium borohydride., Uses

man f.eks. Raney-nikkel, platina eller palladium som katalysatorer så fjernes samtidig tilstedeværende aralkylgrupper, f.eks. benzylgrupper. Gjennomfører man derimot reduksjonen ved hjelp av Raney-kobolt eller natrium- henh. litiumborhydrid, så behol-des tilstedeværende aralkylgrupper. De kan ved hydrogenolyse f.eks. avspaltes ved hjelp av Raney-nikkel, platina eller palladium. one e.g. Raney-nickel, platinum or palladium as catalysts then simultaneously present aralkyl groups are removed, e.g. benzyl groups. On the other hand, the reduction is carried out using Raney cobalt or sodium respectively. lithium borohydride, then the aralkyl groups present are retained. They can by hydrogenolysis e.g. is cleaved using Raney nickel, platinum or palladium.

Tilstedeværende acylgrupper, f.eks. acetylgrupper kan avspaltes ved sur eller alkalisk hydrolyse, fortrinnsvis ved innvirkning av mineralsyrer, f.eks. med fortynnet saltsyre i en alkanol, Acyl groups present, e.g. acetyl groups can be split off by acid or alkaline hydrolysis, preferably by the action of mineral acids, e.g. with dilute hydrochloric acid in an alkanol,

som metanol eller ved behandling med alkali, f.eks. med natrium-hydroksyd i en vandig alkanol, som metanol, i et mellom 20 og 100°C liggende temperaturområde. as methanol or by treatment with alkali, e.g. with sodium hydroxide in an aqueous alkanol, such as methanol, in a temperature range between 20 and 100°C.

Aminene med formel I faller ut som racemater. Disse kan skilles etter kjente metoder, f.eks. ved hjelp, av optisk aktive syrer The amines of formula I precipitate as racemates. These can be separated according to known methods, e.g. by means of optically active acids

• som vinsyre. • as tartaric acid.

Aminene med formel I danner med uorganiske eller organiske syrer addisjonssalter. Som eksempler kan nevnes: salter med halogen-hydrogensyrer, spesielt med klor- eller brom-hydrogensyre, eller salter med svovelsyre eller også med organiske syrer, f.eks. med benzosyre, eddiksyre, vinsyre, sitronsyre eller melkesyre. The amines of formula I form addition salts with inorganic or organic acids. As examples can be mentioned: salts with halogen-hydrogen acids, especially with chloro- or bromo-hydrogen acid, or salts with sulfuric acid or also with organic acids, e.g. with benzoic acid, acetic acid, tartaric acid, citric acid or lactic acid.

De ifolge oppfinnelsen fremstillbare fenetylaminer er hypotensivt virksomme. Forbindelser med formel I, hvor R^ og R2 betyr en alkoksygruppe eller en hydroksygruppe og R^ en alkylgruppe, inntar en f ortrinnsstilling, er foretrukket. Som hypotensivt særlig godt vi-rksomt har 3, 5-dihydroksy- 4-metoksy-a-metyl-f enetylamin vist seg. Toksisiteten av denne forbindelse er meget lav. Hos mus ligger den letale dose [lD^0J ved oral administrasjon på mer enn 5000 mg/kg. Den blodtrykkssenkende virkning opptrer hos mus allerede ved en dose på 3 mg p.o./kg. Enkeltdosen kan okes inntil 200 mg/kg. 3,4-dihydroksy-5-metoksy-a-metyl-fenetylamin har lignende egenskaper. The phenethylamines that can be prepared according to the invention are hypotensive active. Compounds of formula I, where R 1 and R 2 mean an alkoxy group or a hydroxy group and R 1 an alkyl group, occupying a fourth position, are preferred. 3,5-dihydroxy-4-methoxy-α-methyl-phenethylamine has been shown to be particularly effective as a hypotensive agent. The toxicity of this compound is very low. In mice, the lethal dose [lD^0J by oral administration is more than 5000 mg/kg. The blood pressure-lowering effect occurs in mice already at a dose of 3 mg p.o./kg. The single dose can be increased up to 200 mg/kg. 3,4-dihydroxy-5-methoxy-α-methyl-phenethylamine has similar properties.

De nye hypotensivt virksomme fenetylaminderivater står de i det franske patent nr. 2644 M beskrevne forbindelser som har prak-tisk talt like sterke blodtrykkssenkende egenskaper. Sistnevnte forbindelser har dog, slik som det kunne påvises ved 2,4,5-trihydroksy-a-metyl-fenetylamin, bivirkninger som har en irrever-sibel beskadigelse av sympatiske nerveender til folge. Frem-gangsmåt eproduktene , f.eks. 3,4,5-trihydroksy-a-metyl-fenetylamin, forårsaker derimot ingen morfologiske forandringer i nerveendene og kan derfor uten betenkning anvendes for behandling av hypertoni. The new hypotensively active phenethylamine derivatives are the compounds described in French patent no. 2644 M, which have practically equally strong blood pressure-lowering properties. The latter compounds, however, as could be demonstrated with 2,4,5-trihydroxy-α-methyl-phenethylamine, have side effects that result in irreversible damage to sympathetic nerve endings. Procedure the e-products, e.g. 3,4,5-trihydroxy-α-methyl-phenethylamine, on the other hand, causes no morphological changes in the nerve endings and can therefore be used without hesitation for the treatment of hypertension.

Den blodtrykkssenkende effekt av fremgangsmåteproduktene er sam-menlignbare med virkningen av a-metyldopa. De ifolge oppfinnelsen fremstillbare fenetylaminer kan derfor anvendes som hypotensivt virksomt middel til bekjempelse av sykelige hoye blod-trykk, spesielt som middel mot den essensielle hypertoni. The blood pressure-lowering effect of the process products is comparable to the effect of α-methyldopa. The phenethylamines that can be prepared according to the invention can therefore be used as hypotensive agents for combating morbidly high blood pressure, especially as a remedy for essential hypertension.

Fremgangsmåteproduktene er hvite, krystalline forbindelser. De har basiske og sure egenskaper og kan anvendes som base og i form av deres syreaddisjonssalter. Saltene er karakteristiske, krystalline forbindelser, som er lett opploselige i vann. I polare opplosningsmidler, f.eks. i metanol, etanol og lignende andre alkanoler opploser de seg mindre godt. I upolare opplosningsmidler, f.eks. i benzen, eter, petroleter er saltene prak-tisk talt uoppløselige. For de fire aminer er metanol et godt opplosningsmiddel. The process products are white, crystalline compounds. They have basic and acidic properties and can be used as a base and in the form of their acid addition salts. The salts are characteristic, crystalline compounds, which are easily soluble in water. In polar solvents, e.g. in methanol, ethanol and similar other alkanols they dissolve less well. In non-polar solvents, e.g. in benzene, ether, petroleum ether the salts are practically insoluble. For the four amines, methanol is a good solvent.

Forbindelsene med formel I kan derfor finne anvendelse som legemiddel, f.eks. i form av farmasbytiske preparater, som inneholder disse forbindelser eller deres salter i blanding med en for den enterale eller parenterale administrasjon egnet farma-søytisk, organisk eller uorganisk inert bærer. The compounds of formula I can therefore find use as medicine, e.g. in the form of pharmaceutical preparations, which contain these compounds or their salts in admixture with a pharmaceutical, organic or inorganic inert carrier suitable for enteral or parenteral administration.

EKSEMPEL 1 EXAMPLE 1

13,5 g 3',5'-dibenzyloksy-4'-metoksy-2-imino-propyl-benzen - fremstilt fra 13,9 g (3,5-dibenzyloksy-4-metoksy-fenyl)-aceton og 81 ml 25 %' ig vandig ammoniakki 250 ml absolutt metanol - hydreres ved hjelp av 3 g Raney-nikkel under normalbetinqelser. Hydreringsprosessen avbrytes etter opptagelse av 1100 ml hydrogen. Katalysatoren filtreres fra og vaskes med 50 ml metanol. Det med vaskemetanolen forente filtrat inndampes under forminsket trykk. Den mdrkebruntfargede rest opptas i 200 ml eter, vaskes to ganger hver gang med 50 ml 2-n saltsyre og en gang med 150 ml vann. Den vandige faseskilles fra, ekstraheres med 200 ml eter. Ekstraktet konsentreres under forminsket trykk til 100 ml og fordeles deretter mellom 100 ml av en mettet, vandig kaliumkarbonat-oppldsning og 200 ml eter. Den vandige fase ekstraheres ennå en gang med 200 ml eter. Ekstraktene forenes, tdrkes over natriumsulfat og inndampes under forminsket trykk. Det tilbakeblivende 3,5-dibenzyloksy-4-metoksy-oc-metyl-f enetylamin opploses i 130 ml absolutt metanol og 26 ml 2-n vandig saltsyre og hydreres etter tilsetning av 1,3 g 5 %'ig palladiumkull under normalbetingelser. Hydreringen kommer til stillstand etter opptagelse av 570 ml hydrogen. Katalysatoren filtreres fra. og vaskes med 50 ml metanol. Det med vaskemetanolen forente filtrat inndampes under forminsket trykk. Det tilbakeblivende 3,5-dihydroksy-4-metoksy-a-metyl-fenetylamin-hydroklorid smelter etter to gangers omkrystallisasjon fra acetonitril/metanol ved 222 - 224°C. 13.5 g of 3',5'-dibenzyloxy-4'-methoxy-2-imino-propyl-benzene - prepared from 13.9 g of (3,5-dibenzyloxy-4-methoxy-phenyl)-acetone and 81 ml 25 % aqueous ammonia 250 ml absolute methanol - is hydrated with the aid of 3 g Raney nickel under normal conditions. The hydration process is interrupted after absorption of 1100 ml of hydrogen. The catalyst is filtered off and washed with 50 ml of methanol. The filtrate combined with the washing methanol is evaporated under reduced pressure. The dark brown residue is taken up in 200 ml of ether, washed twice each time with 50 ml of 2-N hydrochloric acid and once with 150 ml of water. The aqueous phase is separated from, extracted with 200 ml of ether. The extract is concentrated under reduced pressure to 100 ml and then distributed between 100 ml of a saturated aqueous potassium carbonate solution and 200 ml of ether. The aqueous phase is extracted once more with 200 ml of ether. The extracts are combined, dried over sodium sulphate and evaporated under reduced pressure. The remaining 3,5-dibenzyloxy-4-methoxy-oc-methyl-phenethylamine is dissolved in 130 ml of absolute methanol and 26 ml of 2-N aqueous hydrochloric acid and hydrated after adding 1.3 g of 5% palladium charcoal under normal conditions. The hydrogenation stops after absorption of 570 ml of hydrogen. The catalyst is filtered off. and washed with 50 ml of methanol. The filtrate combined with the washing methanol is evaporated under reduced pressure. The remaining 3,5-dihydroxy-4-methoxy-α-methyl-phenethylamine hydrochloride melts after two recrystallizations from acetonitrile/methanol at 222 - 224°C.

Det for fremstillingen av utgangsforbindelsen nddvendige (3,5-dibenzyloksy-4-metoksy-fenyl)-aceton kan fremstilles som folger: 30 g 3,5-dibenzyloksy-4-metoksy-benzaldehyd oppvarmes sammen med 150 ml nitroetan og 5,06 g •ammoniumacetat i en argonatmosfære i 20 timer til koking. Etter avkjdling inndampes reaksjonsblandingen under forminsket trykk. Resten opptas i 500 ml metylenklorid.. Oppløsningen vaskes i rekkefolge med hver 200 ml vann, 200 ml "2-n vandig svovelsyre, 200 ml vann, 200 ml av . en mettet, vandig natriumbikarbonatoppldsning og tilslutt med 200 ml vann, tdrkes over natriumsulfat og inndampes under forminsket trykk. Det til-bak ebli.vendé 3 '■ ,51 -dibenzyloksy-4 ' -metoksy-2-nitro-prope-nyl-benzen smelter ved 100 - 103°C. The (3,5-dibenzyloxy-4-methoxy-phenyl)-acetone required for the preparation of the starting compound can be prepared as follows: 30 g of 3,5-dibenzyloxy-4-methoxy-benzaldehyde are heated together with 150 ml of nitroethane and 5.06 g •ammonium acetate in an argon atmosphere for 20 hours until boiling. After cooling, the reaction mixture is evaporated under reduced pressure. The residue is taken up in 500 ml of methylene chloride. The solution is washed successively with each 200 ml of water, 200 ml of 2-n aqueous sulfuric acid, 200 ml of water, 200 ml of a saturated, aqueous sodium bicarbonate solution and finally with 200 ml of water, dried over sodium sulphate and evaporated under reduced pressure. The resulting 3'■,51-dibenzyloxy-4'-methoxy-2-nitro-propenyl-benzene melts at 100 - 103°C.

39.8 g av denne forbindelse innfores i ldpet av 8 timer i en kokende blanding av 140 ml vann, 190 ml etanol, 9,1 ml iseddik og 33,6 g jernpulver. Reaksjonsblandingen vidererdres deretter ytterligere i 8 timer under tilbakeldpsbetingelser, avkjdles deretter og ved en temperatur mellom 10 og 20°C tilsettes dråpevis 72 ml 3-n vandig saltsyre og 23 ml konsentrert saltsyre (37 %). Blandingen ekstraheres med 500 ml benzen/eddiksyreetylester (1:1). Ekstraktet vaskes to ganger hver gang med 200 ml 2-n vandig saltsyre, to ganger hver gang med 200 ml vann og en gang med 200 ml av en mettet, vandig natriumbikarbonatopp-losning, tdrkes over natriumsulfat, renses ved rystning med aktivkull, filtreres og inndampes under forminsket trykk. Det tilbakeblivende (3,5-dibenzyloksy-4-metoksy-fenyl)-aceton smelter etter tre gangers omkrystallisasjon fra metanol ved 67 - 69°C. 39.8 g of this compound are introduced over a period of 8 hours into a boiling mixture of 140 ml of water, 190 ml of ethanol, 9.1 ml of glacial acetic acid and 33.6 g of iron powder. The reaction mixture is then further stirred for 8 hours under reflux conditions, then cooled and at a temperature between 10 and 20°C, 72 ml of 3-n aqueous hydrochloric acid and 23 ml of concentrated hydrochloric acid (37%) are added dropwise. The mixture is extracted with 500 ml of benzene/ethyl acetate (1:1). The extract is washed twice each time with 200 ml of 2-N aqueous hydrochloric acid, twice each time with 200 ml of water and once with 200 ml of a saturated, aqueous sodium bicarbonate solution, dried over sodium sulfate, purified by shaking with activated carbon, filtered and evaporated under reduced pressure. The remaining (3,5-dibenzyloxy-4-methoxy-phenyl)-acetone melts after three recrystallizations from methanol at 67 - 69°C.

EKSEMPEL 2 EXAMPLE 2

7,8 g 3 ,5-dibenzyloksy-4-metoksy-cc-metyl-f enetylamin-hydroklorid opploses i 400 ml absolutt metanol og hydreres ved hjelp av 1,5 g 5 %' ig palladiumkull under normalbetingelser. Hydreringen kommer til stillstand etter opptagelse av ca. 860 ml hydrogen. Katalysatoren filtreres fra. Filtratet inndampes under forminsket trykk. Det tilbakeblivende 3,5-dihydroksy-4-metoksy-a-metyl-fenetylamin-hydroklorid smelter etter to gangers omkrystallisasjon fra acetonitril/metanol ved 223 - 224°C. 7.8 g of 3,5-dibenzyloxy-4-methoxy-cc-methyl-phenethylamine hydrochloride is dissolved in 400 ml of absolute methanol and hydrated with the aid of 1.5 g of 5% palladium charcoal under normal conditions. The hydration comes to a standstill after absorption of approx. 860 ml of hydrogen. The catalyst is filtered off. The filtrate is evaporated under reduced pressure. The remaining 3,5-dihydroxy-4-methoxy-α-methyl-phenethylamine hydrochloride melts after two recrystallizations from acetonitrile/methanol at 223 - 224°C.

Det som utgangsforbindelse anvendte 3,5-dibenzyloksy-4-metoksy-a-metyl-fenetylamin-hydroklorid kan f.eks. fremstilles på fol-gende måte: 20.9 g litiumaluminiumhydrid suspenderes i 400 ml absolutt eter og tilsettes 200 ml tetrahydrofuran. Til denne blanding innfores dråpevis under roring og gassing med argon 27 g 3',5'-dibenzyloksy-4 1-meto.ksy-2-nitropropenyl-benzen i 400 ml tetrahydrofuran på den- måte at temperaturen for reaksjonsblandingen holdes mellom 35 pg 40°C. Blandingen rdres etter avsluttet inn-føring i ytterligere 4 timer under tilbakeldpsbetingelser, spaltes under avkjoling med is/metanol ved forsiktig tilsetning av 82 ml vann og oppvarmes kort til koking. Aluminiumoksydet, som faller ut som flak, filtreres fra og kokes ut to ganger hver gang med 200 ml tetrahydrofuran. Tetrahydrofuranfiltratene forenes med hovedfiltratet og inndampes under forminsket trykk. Resten opptas i 500 ml benzen, vaskes med 100 ml av en mettet, vandig natriumkarbonatoppldsning, tdrkes over kaliumkarbonat, filtreres og inndampes under forminsket 'trykk. Det tilbakeblivende olje-■aktige 3,5-dibenzyloksy-4-metoksy-a-metyl-fenetylamin oppldses i 150 ml l-n etanolisk saltsyre. Oppldsningen inndampes under forminsket trykk. Det tilbakeblivende 3,5-dibenzyloksy-4-metol<-sy-a-metyl-fenetylamin-hydroklorid smelter etter to gangers omkrystallisas jon fra eddiksyreetylester og metanol ved 135 - The 3,5-dibenzyloxy-4-methoxy-α-methyl-phenethylamine hydrochloride used as starting compound can e.g. is prepared in the following way: 20.9 g of lithium aluminum hydride is suspended in 400 ml of absolute ether and 200 ml of tetrahydrofuran is added. To this mixture, 27 g of 3',5'-dibenzyloxy-4-1-methoxy-2-nitropropenyl-benzene in 400 ml of tetrahydrofuran are added dropwise while stirring and gassing with argon in such a way that the temperature of the reaction mixture is kept between 35 and 40 °C. After completion of the introduction, the mixture is stirred for a further 4 hours under reflux conditions, split while cooling with ice/methanol by the careful addition of 82 ml of water and briefly heated to boiling. The aluminum oxide, which falls out as flakes, is filtered off and boiled out twice each time with 200 ml of tetrahydrofuran. The tetrahydrofuran filtrates are combined with the main filtrate and evaporated under reduced pressure. The residue is taken up in 500 ml of benzene, washed with 100 ml of a saturated, aqueous sodium carbonate solution, dried over potassium carbonate, filtered and evaporated under reduced pressure. The remaining oily 3,5-dibenzyloxy-4-methoxy-α-methyl-phenethylamine is dissolved in 150 ml of 1-1 ethanolic hydrochloric acid. The solution is evaporated under reduced pressure. The remaining 3,5-dibenzyloxy-4-methol<-sy-a-methyl-phenethylamine hydrochloride melts after two recrystallizations from acetic acid ethyl ester and methanol at 135 -

EKSEMPEL 3 EXAMPLE 3

16 g 3,5-dibenzyloksy-4-metoksy-a-etyl-fenetylamin-hydroklorid 16 g 3,5-dibenzyloxy-4-methoxy-α-ethyl-phenethylamine hydrochloride

innfores i 200 ml absolutt metanol og hydreres ved hjelp av 3 g introduced into 200 ml of absolute methanol and hydrated with the help of 3 g

5 %' ig palladiurnkull under normalbetingelser. Hydreringen kommer 5% palladium coal under normal conditions. The hydration is coming

til stillstand etter ca. 1 time. Katalysatoren filtreres fra. Filtratet inndampes under forminsket trykk. Det tilbakeblivende 3,5-dihydroksy-4-metoksy-a-etyl-fenetylamin krystalliserer etter digerering med acetonitril. Den sterkt hygroskopiske forbindelse smelter etter to gangers omkrystallisasjon fra acetonitril/metanol ved 160 - 163°C. to a standstill after approx. 1 hour. The catalyst is filtered off. The filtrate is evaporated under reduced pressure. The remaining 3,5-dihydroxy-4-methoxy-α-ethyl-phenethylamine crystallizes after digestion with acetonitrile. The highly hygroscopic compound melts after two recrystallizations from acetonitrile/methanol at 160 - 163°C.

Det som utgangsforbindelse anvendte 3,5-dibenzyloksy-4-metoksy-a-etyl-fenetylamin-hydroklorid kan fremstilles på fdlgende måte: 50 g 3,5-dibenzyloksy-4-metoksy-benzaldehyd oppvarmes sammen med 8,3 g ammonijacetat og 287 ml 1-nitropropan i 20 timer i en inert gassatmosfære under tilbakeldpsbetingelser. Reaksjonsblandingen avkjdles så og inndampes under forminsket trykk. Resten opptas i 600 benzen. Oppldsningen vaskes i rekkefolge med hver 200 ml vann, 200 ml vandig 2-n svovelsyre, 200 ml vann, 200 ml av en mettet, vandig natfiumbikarbonatoppldsning og 200 ml vann, torkes over natriumsulfat under tilsetning av aktivkull, filtreres og inndampes under forminsket trykk. Det tilbakeblivende 3',5'-dibenzyloksy-4'-metoksy-(2-nitro-1-butenyl)-benzen omkrystalli-seres fra metanol og deretter fra eter. -Forbindelsen smelter ved 68 - 69°C. 22 g litiumalurniniumhydrid suspenderes i 400 ml absolutt eter og tilsettes 200 ml absolutt tetrahydrofuran. Til denne blanding innfores dråpevis under rdring og gassing med argon 29 g 3',5'-dibenzyloksy-4'-metoksy-(2-nitro-l-butenyl)-benzen i 400 ml absolutt tetrahydrofuran på den måte at temperaturen for reaksjonsblandingen holdes mellom 3b og 40°C. Blandingen rdres etter avsluttet innfdring ytterligere i 4 timer under tilbakeldpsbetingelser, spaltes så under avkjdling med is/metanol ved forsiktig tilsetning av 88 ml vann og oppvarmes kort til koking. Aluminiumoksydet, som faller ut som flak, filtreres fra og kokes ut to ganger hver gang med 1000 ml tetrahydrofuran. Tetrahydrofuranfiltratene forenes med hovedfiltratet og inndampes under forminsket trykk. Resten opptas i 500 ml benzen. Oppldsningen rystes med 200 ml av en mettet, vandig natriumkarbonatoppldsning, tdrkes over kaliumkarbonat, filtreres og inndampes under forminsket trykk. Det. tilbakeblivende 3 ,5-dibenzyloks y-4 - metoksy-a-etyl-fenetylamin oppldses i 100 ml l-n etanolisk saltsyre. Oppldsningen inndampes under forminsket trykk. Det tilbakeblivende 3,5-dibenzyloksy-4-metoks y-a-etyl-fenetylamin-hydroklorid smelter etter to gangers omkrystallisas jon fra tneta-noi/eter ved 148 - 150°C. The 3,5-dibenzyloxy-4-methoxy-α-ethyl-phenethylamine hydrochloride used as starting compound can be prepared in the following way: 50 g of 3,5-dibenzyloxy-4-methoxy-benzaldehyde is heated together with 8.3 g of ammonium acetate and 287 ml of 1-nitropropane for 20 hours in an inert gas atmosphere under reflux conditions. The reaction mixture is then cooled and evaporated under reduced pressure. The rest is taken up in 600 benzene. The solution is washed successively with 200 ml of water, 200 ml of aqueous 2-n sulfuric acid, 200 ml of water, 200 ml of a saturated, aqueous sodium bicarbonate solution and 200 ml of water, dried over sodium sulphate while adding activated carbon, filtered and evaporated under reduced pressure. The remaining 3',5'-dibenzyloxy-4'-methoxy-(2-nitro-1-butenyl)-benzene is recrystallized from methanol and then from ether. -The compound melts at 68 - 69°C. 22 g of lithium alurninium hydride are suspended in 400 ml of absolute ether and 200 ml of absolute tetrahydrofuran are added. To this mixture, 29 g of 3',5'-dibenzyloxy-4'-methoxy-(2-nitro-1-butenyl)-benzene in 400 ml of absolute tetrahydrofuran are introduced dropwise under stirring and gassing with argon in such a way that the temperature of the reaction mixture is maintained between 3b and 40°C. After completion of the introduction, the mixture is stirred for a further 4 hours under reflux conditions, then split while cooling with ice/methanol by the careful addition of 88 ml of water and heated briefly to boiling. The aluminum oxide, which falls out as flakes, is filtered off and boiled twice each time with 1000 ml of tetrahydrofuran. The tetrahydrofuran filtrates are combined with the main filtrate and evaporated under reduced pressure. The residue is taken up in 500 ml of benzene. The solution is shaken with 200 ml of a saturated, aqueous sodium carbonate solution, dried over potassium carbonate, filtered and evaporated under reduced pressure. The. residual 3,5-dibenzyloxy y-4-methoxy-α-ethyl-phenethylamine is dissolved in 100 ml 1-1 ethanolic hydrochloric acid. The solution is evaporated under reduced pressure. The remaining 3,5-dibenzyloxy-4-methoxy γ-α-ethyl-phenethylamine hydrochloride melts after two recrystallizations from ether at 148-150°C.

EKSEMPEL 4 EXAMPLE 4

3,9 g 3',5<1->dibenzyloksy-4'-metoksy-2-hydroksyiminopropylbenzen innfores i 80 ml absolutt metanol og hydreres etter tilsetning av 2 ml konsentrert vandig saltsyre ved hjelp av 0,5 g platinaoksyd under normalbetingelser. Etter opptagelse av 1785 ml hydrogen filtreres katalysatoren fra og vaskes med 20 ml metanol. Filtratet inndampes under forminsket trykk. Det tilbakeblivende 3,5-dihydroksy-4-metoksy-a-metyl-f enetylamin-hydroklorid smelter etter to gangers omkrystallisasjon fra metanol ved 222 - 224°C. 3.9 g of 3',5<1->dibenzyloxy-4'-methoxy-2-hydroxyiminopropylbenzene are introduced into 80 ml of absolute methanol and hydrated after the addition of 2 ml of concentrated aqueous hydrochloric acid using 0.5 g of platinum oxide under normal conditions. After absorption of 1785 ml of hydrogen, the catalyst is filtered off and washed with 20 ml of methanol. The filtrate is evaporated under reduced pressure. The remaining 3,5-dihydroxy-4-methoxy-α-methyl-phenethylamine hydrochloride melts after two recrystallizations from methanol at 222 - 224°C.

Det som utgangsforbindelse anvendte 3',5'-bis-benzyloksy-4'-metoksy-2-hydroksyiminopropyl-benzen kan f.eks. fremstilles som folger: 7,52 g [ 3,5-dibenzyloksy-4-metoksy-fenyl]-aceton, 1,34 g hydrok-sylaminhydroklorid, 1,4 ml absolutt pyridin og 20 ml absolutt etanol oppvarmes sammen i 2 timer under tilbakeldpsbetingelser. Reaksjonsblandingen inndampes deretter under forminsket trykk. Resten deles mellom 100 ml iddiksyreetylester og 50 ml vann. The 3',5'-bis-benzyloxy-4'-methoxy-2-hydroxyiminopropyl benzene used as starting compound can e.g. is prepared as follows: 7.52 g [3,5-dibenzyloxy-4-methoxy-phenyl]-acetone, 1.34 g hydroxylamine hydrochloride, 1.4 ml absolute pyridine and 20 ml absolute ethanol is heated together for 2 hours under reflux conditions. The reaction mixture is then evaporated under reduced pressure. The residue is divided between 100 ml of acetic acid ethyl ester and 50 ml of water.

Den organiske fase vaskes i rekkefolge med to ganger hver gang 50 ml 2-n vandig svovelsyre, to ganger hver gang med 50 ml vann, The organic phase is washed in sequence with twice each time 50 ml of 2-n aqueous sulfuric acid, twice each time with 50 ml of water,

en gang med 100 ml av en mettet, vandig natriumbikarbonatoppldsning, tdrkes over natriumsulfat og inndampes under forminsket trykk. Det tilbakeblivende 3', 51-dibenzyloksy-41-metoksy-2-hydroksyiminopropyl-benzen smelter etter omkrystallisasjon fra toluen/petroleter ved 105 - 113°C. once with 100 ml of a saturated, aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure. The remaining 3', 51-dibenzyloxy-41-methoxy-2-hydroxyiminopropylbenzene melts after recrystallization from toluene/petroleum ether at 105-113°C.

EKSEMPEL 5 EXAMPLE 5

3,9 g 3' ,5'-dibenzyloksy-4'-metoksy-2-hydroksyiminopropyl-benzen innfores i 100 ml absolutt metanol og hydreres ved hjelp av 1 g 5 %'ig palladiumkull under normalbetingelser. Hydreringen kommer til stillstand etter opptagelse av 500 ml hydrogen. Katalysatoren filtreres fra. Filtratet inndampes under forminsket trykk. Det tilbakeblivende 3',5<1->dihydroksy-4'-metoksy-2-hydrok-syiminopropyl-benzen smelter etter to gangers omkrystallisasjon fra vann ved 137°C. 3.9 g of 3',5'-dibenzyloxy-4'-methoxy-2-hydroxyiminopropylbenzene are introduced into 100 ml of absolute methanol and hydrated with the aid of 1 g of 5% palladium charcoal under normal conditions. The hydrogenation comes to a standstill after 500 ml of hydrogen has been absorbed. The catalyst is filtered off. The filtrate is evaporated under reduced pressure. The remaining 3',5<1->dihydroxy-4'-methoxy-2-hydroxy-cyiminopropyl-benzene melts after two recrystallizations from water at 137°C.

2 g 3',5'-dihydroksy-4'-metoksy-2-hydroksyiminopropyl-benzen 2 g 3',5'-dihydroxy-4'-methoxy-2-hydroxyiminopropyl-benzene

innfores i 50 ml metanol og hydreres etter tilsetning av 10 ml vandig konsentrert saltsyre over 0,2 g platinaoksyd under normalbetingelser. Etter opptagelse av den beregnede mengde hydrogen filtreres katalysatoren fra. Filtratet inndampes under forminsket trykk. Det tilbakeblivende 3 ,5-dihydroksy-4-metoksy-oc-metyl-fenetylamin-hydroklorid smelter etter to gangers omkrystallisasjon fra metanol/acetonitril ved 222 - 224°C. introduced into 50 ml of methanol and hydrated after adding 10 ml of aqueous concentrated hydrochloric acid over 0.2 g of platinum oxide under normal conditions. After absorption of the calculated amount of hydrogen, the catalyst is filtered off. The filtrate is evaporated under reduced pressure. The remaining 3,5-dihydroxy-4-methoxy-oc-methyl-phenethylamine hydrochloride melts after two recrystallizations from methanol/acetonitrile at 222 - 224°C.

EKSEMPEL 6 EXAMPLE 6

12 g 3,5-dibenzoyloksy-4-metoksy-a-metyl-fenetylamin-hydroklorid oppvarmes med 120 ml vandig 4-n saltsyre i en inert gassatmosfære i 14 timer til. koking. Reaksjonsblandingen avkjdles så til 0°. Den utfelte benzosyre filtreres fra og vaskes med 50 ml vann. Det med vaskevannet forente filtrat inndampes under forminsket trykk. Det tilbakeblivende 3,5-dihydroksy-4-metoksy-a-metyl-fenetylamin-hydroklorid smelter etter to gangers omkrystallisasjon fra metanol ved 221 - 224°C. 12 g of 3,5-dibenzoyloxy-4-methoxy-α-methyl-phenethylamine hydrochloride are heated with 120 ml of aqueous 4-n hydrochloric acid in an inert gas atmosphere for a further 14 hours. cooking. The reaction mixture is then cooled to 0°. The precipitated benzoic acid is filtered off and washed with 50 ml of water. The filtrate combined with the washing water is evaporated under reduced pressure. The remaining 3,5-dihydroxy-4-methoxy-α-methyl-phenethylamine hydrochloride melts after two recrystallizations from methanol at 221 - 224°C.

Det som utgangsforbindelse anvendte 3,5-dibenzoyloksy-4-metoksy-oc-metyl-f enetylamin-hydrok lorid kan f.eks. fremstilles som folger: 19,6 g 3,5-dibenzoyloksy-p-anissyre, 20 ml friskt destillert tionylklorid og 50 ml absolutt kloroform oppvarmes i en inert. gassatmosfære i 1 time under tilbakeldpsbetingelser. Reaksjonsblandingen konsentreres så. Konsentratet opptas i 100 ml absolutt benzen og filtreres over aluminiumoksyd. Det etter inndampning av eluatet tilbakeblivende gule, halvfaste 3,5-dibenzoyloksy-p-anissyreklorid kan umiddelbart anvendes videre som folger. The 3,5-dibenzoyloxy-4-methoxy-oc-methyl-phenethylamine hydrochloride used as starting compound can e.g. is prepared as follows: 19.6 g of 3,5-dibenzoyloxy-p-anisic acid, 20 ml of freshly distilled thionyl chloride and 50 ml of absolute chloroform are heated in an inert. gas atmosphere for 1 hour under reflux conditions. The reaction mixture is then concentrated. The concentrate is taken up in 100 ml of absolute benzene and filtered over aluminum oxide. The yellow, semi-solid 3,5-dibenzoyloxy-p-anisic acid chloride remaining after evaporation of the eluate can be immediately used further as a follow-on.

40 g 3,5-dibenzoyloksy-p-anissyreklorid hydreres i nærvær av 40 g of 3,5-dibenzoyloxy-p-anisic acid chloride are hydrated in the presence of

11 g av en partiell med kinolin desaktivert. palladium/barium-sulfat-katalysator i 250 ml kokende absolutt xylen. Reaksjons-oppldsningen filtreres varm etter avslutning av saltsyregassut-viklingen [ca. etter 2,5 timer]. Filtratet konsentreres under forminsket trykk. Det tilbakeblivende oljelignende 3,5-dibenzoyloksy-p-anisaldehyd bringes til krystallisasjon etter tilsetning av petroleter. Aldehydet smelter etter omkrystallisasjon fra eter/petroleter ved 101 - 102°C. 12 g 3,5-dib_enzoyloksy-p-anissyrealdehyd og 4 g nitroetan oppvarmes sammen med 0,6 g eddiksyre og 0,23 g n-butylamin i 20 ml absolutt toluen i 15 timer under tilbakeldpsbetingelser. Det frittblivende vann oppfanges på en vannavskiller. Reaksjonsblandingen inndampes deretter under forminsket trykk. Det tilbakeblivende oljeaktige 3-' ,5 '-dibenzoyloksy-4 ' -metoksy-2-nitroprope-nyl-benzen krystalliserer fra isopropanol/diisopropyleter og smelter ved 102°C. 11 g of a partial with quinoline deactivated. palladium/barium sulfate catalyst in 250 ml of boiling absolute xylene. The reaction solution is filtered hot after completion of the evolution of hydrochloric acid gas [approx. after 2.5 hours]. The filtrate is concentrated under reduced pressure. The remaining oil-like 3,5-dibenzoyloxy-p-anisaldehyde is crystallized after the addition of petroleum ether. The aldehyde melts after recrystallization from ether/petroleum ether at 101 - 102°C. 12 g of 3,5-dibenzoyloxy-p-anisic acid aldehyde and 4 g of nitroethane are heated together with 0.6 g of acetic acid and 0.23 g of n-butylamine in 20 ml of absolute toluene for 15 hours under reflux conditions. The free water is collected on a water separator. The reaction mixture is then evaporated under reduced pressure. The residual oily 3-',5'-dibenzoyloxy-4'-methoxy-2-nitropropenyl-benzene crystallizes from isopropanol/diisopropyl ether and melts at 102°C.

I en til koketemperatur oppvarmet blanding av 25 g jernpulver, 105 ml vann, 140 ml metanol og 6,9 ml iseddik innfores under roring-i ldpet av 10 timer 29 g 31 ,5.'-diberizoyloksy-4 '-metoksy-2-nitropropenyl-benzen. Reaksjonsblandingen rdres deretter i ytterligere 14 timer under tilbakeldpsbetingelser, deretter tilsettes under isavkjdling 71 ml vandig 3-n saltsyre og 23 ml konsentrert vandig saltsyre og ekstraheres to ganger hver gang med 500 ml eddiksyreetylester. Eddik esteruttrekkene vaskes i rekkefolge to ganger med 200 ml 2-n saltsyre, to ganger med 200 nil vann og to ganger med 200 ml av en mettet, vandig natriumbikarbonatoppldsning, forenes så, tdrkes over natrium-sulf.at og inndampes under forminsket trykk. Det tilbakeblivende [3,5-dibenzoyloksy-4-metoksy-fenyl]-aceton smelter etter to gangers omkrystallisasjon fra eter ved 88 - 89°C. 10 g L3,5-dibenzoyloksy-4-metoksy-fenylj-aceton oppldses i 100 ml dioksan og hydreres etter tilsetning av 20 ml av en mettet, vandig ammoniakoppldsning ved hjelp av Raney-nikkel under normalbetingelser. Katalysatoren filtreres fra etter avsluttet hydrogen-opptagelse. Filtratet konsentreres ved 30°C under forminsket trykk til ca. 50 ml, fortynnes med 50 ml vann og ekstraheres deretter to ganger hver gang med 100 ml eddiksyreetylester. Eddikesteruttrekkene vaskes med 100 ml vann, forenes,'tdrkes over natriumsulfat og inndampes under forminsket trykk. Resten opptas i 10 ml vann. De uoppløselige deler filtreres fra. Filtratet tilsettes 50 ml eterisk saltsyre. Det utfelte oljelignende 3,5-dibenzoyloksy-4-metoks<y>-oc-metyl-fenetylamin-hydroklorid krystalliserer etter digerering med acetonitril og smelter etter og gangers omkrystallisasjon fra aceton/eter ved 127 - 128°C. Into a mixture heated to boiling temperature of 25 g of iron powder, 105 ml of water, 140 ml of methanol and 6.9 ml of glacial acetic acid, 29 g of 31,5.'-diberizoyloxy-4'-methoxy-2- nitropropenyl-benzene. The reaction mixture is then stirred for a further 14 hours under reflux conditions, then 71 ml of aqueous 3-n hydrochloric acid and 23 ml of concentrated aqueous hydrochloric acid are added under ice-cooling and extracted twice each time with 500 ml of acetic acid ethyl ester. The acetic ester extracts are washed in sequence twice with 200 ml of 2-n hydrochloric acid, twice with 200 ml of water and twice with 200 ml of a saturated, aqueous sodium bicarbonate solution, then combined, dried over sodium sulfate and evaporated under reduced pressure. The remaining [3,5-dibenzoyloxy-4-methoxy-phenyl]-acetone melts after two recrystallizations from ether at 88 - 89°C. 10 g of L3,5-dibenzoyloxy-4-methoxy-phenylj-acetone are dissolved in 100 ml of dioxane and hydrated after the addition of 20 ml of a saturated, aqueous ammonia solution using Raney nickel under normal conditions. The catalyst is filtered off after completion of hydrogen uptake. The filtrate is concentrated at 30°C under reduced pressure to approx. 50 ml, dilute with 50 ml of water and then extract twice each time with 100 ml of ethyl acetate. The acetic ester extracts are washed with 100 ml of water, combined, dried over sodium sulphate and evaporated under reduced pressure. The remainder is taken up in 10 ml of water. The insoluble parts are filtered off. 50 ml of ethereal hydrochloric acid is added to the filtrate. The precipitated oil-like 3,5-dibenzoyloxy-4-methoxy<y>-oc-methyl-phenethylamine hydrochloride crystallizes after digestion with acetonitrile and melts after repeated recrystallization from acetone/ether at 127 - 128°C.

EKSEMPEL 7 EXAMPLE 7

3,89 g 3,4-dibenzyloksy-5-metoksy-a-metyl-fenetylamin-hydroklorid innfores i 200 ml absolutt metanol og hydreres ved hjelp av 0,5 g palladiumkull [5 %\ under normalbetingelser. Hydreringen kommer til stil-lstand etter opptagelsen .av ca. 430 ml hydrogen. Katalysatoren filtreres fra. Filtratet inndampes. Det tilbakeblivende 3 ,4-dlhydroksy-5 -metok s y-oc-metyl - f enetylamin-hydrok lorid krystalliserer etter digerering med diisopropyleter. Forbindelsen smelter etter omkrystallisasjon fra metanol ved 270°C [spaltning]. 3.89 g of 3,4-dibenzyloxy-5-methoxy-a-methyl-phenethylamine hydrochloride are introduced into 200 ml of absolute methanol and hydrated with the aid of 0.5 g of palladium charcoal [5%] under normal conditions. The hydration comes to a standstill after the absorption of approx. 430 ml of hydrogen. The catalyst is filtered off. The filtrate is evaporated. The remaining 3,4-dlhydroxy-5-methoxy-oc-methyl-phenethylamine hydrochloride crystallizes after digestion with diisopropyl ether. The compound melts after recrystallization from methanol at 270°C [decomposition].

Det som utgangsforbindelse anvendte 3,4-dibenzyIoksy-5-metoksy-oc-metyl-f enetylamin-hydroklorid kan f. eks. fremstilles som folger: The 3,4-dibenzyloxy-5-methoxy-oc-methyl-phenethylamine hydrochloride used as starting compound can e.g. produced as follows:

E KSEMPEL 8 EXAMPLE 8

4,79 g 3,4,5-tribenzyloksy-a-metyl-fenetylamin-hydrobromid innfores i 200 ml absolutt metanol og hydreres ved hjelp av 0,5 g palladiumkull [5 %] under normalbetingelser. Hydreringen stopper etter opptagelsen av ca. 700 ml hydrogen. Katalysatoren filtreres fra. Filtratet inndampes. Det gjenværende 3,4,5-trihydroksy-a-metyl-fenetylamin-hydrobromid stiv-ner, som meget hygroskopisk skum som i luft straks flyter ut. 4.79 g of 3,4,5-tribenzyloxy-a-methyl-phenethylamine hydrobromide are introduced into 200 ml of absolute methanol and hydrated with the aid of 0.5 g of palladium charcoal [5%] under normal conditions. The hydration stops after the absorption of approx. 700 ml of hydrogen. The catalyst is filtered off. The filtrate is evaporated. The remaining 3,4,5-trihydroxy-a-methyl-phenethylamine hydrobromide solidifies as a very hygroscopic foam which immediately floats out in air.

Det som utgangsforbindelse anvendte 3,4,5-tribenzyloksy-a-metyl-fenetylamin-hydrobromid kan f.eks. fremstilles som folger: 42,4 g 3,4,5-tribenzyloksy-benzaldehyd og 15,0 g nitroetan oppvarmes sammen med en blanding av 2,6 ml n-butylamin og 4,5 ml iseddik i 120 ml vannfri toluen 12 timer under tilbake-lopsbetingelser. Det frigjorte vann oppfanges i en vannfra-skiller. Reaksjonsblandingen inndampes derpå under redusert trykk. Den tilbakeblivende olje renses ved adsorpsjon på silisiumgel. The 3,4,5-tribenzyloxy-α-methyl-phenethylamine hydrobromide used as starting compound can, for example, is prepared as follows: 42.4 g of 3,4,5-tribenzyloxy-benzaldehyde and 15.0 g of nitroethane are heated together with a mixture of 2.6 ml of n-butylamine and 4.5 ml of glacial acetic acid in 120 ml of anhydrous toluene for 12 hours under return-run conditions. The released water is collected in a water separator. The reaction mixture is then evaporated under reduced pressure. The remaining oil is purified by adsorption on silicon gel.

<c>,2 g litiumaluminiumhydrid innfores i 200 ml absolutt tetrahydrofuran og tilsettes i en argon-atmosfære dråpevis en opp-losning av 27,4 g 31,41,5'-tribenzyloksy-2-nitropropenyl-benzen i 200 ml absolutt tetrahydrofuran. Temperaturen for reaksjonsblandingen steg da til 55°C. Reaksjonsblandingen rores om ytterligere 7 timer ved 80°C, spaltes derpå etter 12 timers henstand ved værelsetemperatur forsiktig etter tilsetning av eddiksyreetylester med vann og oppvarmes kort til koking. Aluminiumoksydet som flokker seg ut, filtreres fra. Filtratet konsentreres og fordeles mellom eter og vann. Eter-fasen vaskes med vann, torkes og inndampes. Den gjenværende olje tilsettes 20 %'ig metanolisk bromhydrogensyre. Etter inndampning får man en svakt brun olje som straks viderefor-arbeides. <c>.2 g of lithium aluminum hydride is introduced into 200 ml of absolute tetrahydrofuran and a solution of 27.4 g of 31,41,5'-tribenzyloxy-2-nitropropenyl-benzene in 200 ml of absolute tetrahydrofuran is added dropwise in an argon atmosphere. The temperature of the reaction mixture then rose to 55°C. The reaction mixture is stirred for a further 7 hours at 80°C, then, after a 12-hour standstill at room temperature, is carefully decomposed after the addition of ethyl acetate with water and briefly heated to boiling. The aluminum oxide that flocculates is filtered off. The filtrate is concentrated and distributed between ether and water. The ether phase is washed with water, dried and evaporated. 20% methanolic hydrobromic acid is added to the remaining oil. After evaporation, a light brown oil is obtained, which is immediately further processed.

Claims

■ 1. Analogy method for the production of therapy

tically active phenethylamine derivatives of the general formula

where and R 2 means hydroxy or lower alkoxy and R 2 lower alkyl,

as well as salts of these compounds, characterized by hydrogenolyzing a compound with

the general formula

where X denotes one of the groups

and R^, R2 and have the above meaning,

in that free hydroxyl groups are replaced by aralk-poxy groups,

or that one hydrolyzes a compound of the general formula II,

where X denotes the group

and Rl' R2 °^ R3 ^ar ^oran stated meaning,

in that free hydroxyl groups are replaced by acyloxy groups,

and that, if desired, the obtained compound of formula I is transferred to a salt.

2. Method according to claim 1, characterized in that a compound of formula II is used as starting compound, where X denotes the 1-amino-1-methyl-ethyl group, the 1-imino-1-methyl-ethyl group or 1-hydroxy -imino-1-methyl-ethyl group and means methoxy and aralkyl according to acyloxy, or R^ aralkoxy henh,acyloxy and R ? methoxy (and the free hydroxyl group is replaced by aralkyloxy or acyloxy.