NO132835B - - Google Patents

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NO132835B
NO132835B NO3632/71A NO363271A NO132835B NO 132835 B NO132835 B NO 132835B NO 3632/71 A NO3632/71 A NO 3632/71A NO 363271 A NO363271 A NO 363271A NO 132835 B NO132835 B NO 132835B
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general formula
meaning
compound
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formula
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NO3632/71A
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NO132835C (en
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H Koeppe
H Staehle
W Kummer
W Traunecker
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Boehringer Sohn Ingelheim
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Denne oppfinnelse angår analogifremgangsmåte for fremstilling av l-fenoksy-2-hydroksy-3-hydroksyalkylaminopropaner og deres estere og syreaddisjonssalter, som er nyttige som legemidler. De nye forbindelser har den generelle formel This invention relates to analogous processes for the preparation of 1-phenoxy-2-hydroxy-3-hydroxyalkylaminopropanes and their esters and acid addition salts, which are useful as pharmaceuticals. The new compounds have the general formula

hvor: where:

betyr cyano, etynyl, propargyl, allyl'eller alyloksy, betyr hydrogen eller metyl, og r^ betyr lineær eller forgrenet hydroksyalkylgruppe med 3-7 C-atomer. means cyano, ethynyl, propargyl, allyl' or allyloxy, means hydrogen or methyl, and r^ means linear or branched hydroxyalkyl group with 3-7 C atoms.

De nye forbindelser fremstilles i henhold til oppfinnelsen ved at The new compounds are produced according to the invention by

a) en forbindelse med den generelle formel a) a compound with the general formula

hvor R.^ og R2 har den ovenfor angitte betydning og Z betyr gruppen where R.sub.1 and R.sub.2 have the above meaning and Z means the group

eller -CHOH-CH2-Hal (Hal=halogenat6m), omsettes med or -CHOH-CH2-Hal (Hal=halogenate6m), is reacted with

et alkylamin med formelen an alkylamine of the formula

hvor R- har den ovenfor angitte betydning where R- has the meaning given above

eller or

b) i en forbindelse med den generelle formel b) in connection with the general formula

hvor R^, R^ og R^ har den ovenfor angitte betydning og G betyr en where R^, R^ and R^ have the above meaning and G means a

lett hydrolytisk avspaltbar gruppe, erstattes gruppen G hydrolytisk med hydrogen, eller easily hydrolytically cleavable group, the group G is replaced hydrolytically with hydrogen, or

c) en forbindelse med den generelle formel . c) a compound with the general formula .

hvor R^ og R^ har den ovenfor angitte betydning, omsettes med en where R^ and R^ have the meaning indicated above, is converted to a

forbindelse med formel R^-C.l hvor R^ har ovennevnte betydning, eller compound of formula R^-C.l where R^ has the above meaning, or

d) i en forbindelse med den generelle formel d) in connection with the general formula

hvor R^, R2 og R^ har den ovenfor angitte betydning'og Besk. betyr en lett hydrogenolytisk eller hydrolytisk avspaltbar beskyttelses— gruppe, erstattes, gruppen Besk. med hydrogen på hydrogenolytisk eller hydrolytisk måte, eller e) et oksazolidinon med den generelle formel where R^, R2 and R^ have the meaning stated above' and Description. means an easily hydrogenolytically or hydrolytically cleavable protecting group, is replaced, the group Besk. with hydrogen in a hydrogenolytic or hydrolytic manner, or e) an oxazolidinone of the general formula

hvor , og R^ har den ovenfor angitte betydning, hydrolyseres, where , and R^ has the meaning stated above, is hydrolyzed,

eller or

f) et urinstoffderivat med den generelle formel f) a urea derivative of the general formula

hvor R,, R„ og R har den ovenfor angitte betydning og R og R , where R,, R„ and R have the meaning given above and R and R ,

J-2 4 5 6 som kan være like eller forskjellige, betyr hydrogen eller en alkylrest, fortrinnsvis lavere alkyl, en aralkylrest, fortrinnsvis benzyl, eller en arylrest, fortrinnsvis fenyl, hydrolyseres eller pyrolyseres, eller J-2 4 5 6 which may be the same or different, means hydrogen or an alkyl residue, preferably lower alkyl, an aralkyl residue, preferably benzyl, or an aryl residue, preferably phenyl, is hydrolyzed or pyrolyzed, or

g) en forbindelse med den generelle formel g) a compound of the general formula

hvor R^ og R^ har den ovenfor angitte betydning omsettes med kobber (I) cyanid ifølge Sandmeyer, og de erholdte forbindelser overføres eventuelt til sine fysiologisk forlikelige syreaddisjonssalter eller estere. where R^ and R^ have the meaning indicated above are reacted with copper (I) cyanide according to Sandmeyer, and the compounds obtained are optionally transferred to their physiologically compatible acid addition salts or esters.

Utgangsmaterialene for fremgangsmåtene ifølge oppfinnelsen er kjent og kan fremstilles efter vanlige fremgangsmåter. Således kan epoksydene med formel II lett fremstilles ved omsetning med en tilsvarende fenol resp. fenolat med formelen The starting materials for the methods according to the invention are known and can be produced according to usual methods. Thus, the epoxides of formula II can be easily prepared by reaction with a corresponding phenol or phenolate with the formula

hvor Rn og R har den ovenfor angitte betydning, og Kt betyr hydrogen eller et kation (f.eks. et alkalimetallkation). Epoksydene kan på sin side anvendes til fremstilling, av andre utgangsmaterialer, f.eks. kan halogenhydrinene med formel II fremstilles ved omsetning av epoksydene med den tilsvarende halogenhydrogensyre. Aminene med formel III er kjente og er i stor utstrekning handelsprodukter. Forbindelsene med formel IV kan fremstilles ved at et halogenhydrin med formel II omsettes med en forbindelse som danner beskyttelsesgruppen G (f.eks. en vinyleter eller dihydro-pyran), og 'derefter omsettes den erholdte forbindelse med formelen hvor og , Hal og G har den ovenfor angitte betydning, med et amin med formel III. De primære aminer med formel V kan fremstilles ved at halogenhydriner med formel II omsettes med ftalimidkalium, og derefter spalter reaksjonsproduktet med. hydrazin (såkalt Gabriel-reaksjon> . De tertiære aminer, med formel VI kan fremstilles ved at én forbindelse med den generelle formel XIV omsettes med en forbindelse med den generelle formel hvor R4 og Besk. har den ovenfor angitte betydning. Oksazoli-dinonene med formel VII kan f.eks. fremstilles ved å.gå ut fra epoksydene med formel II, ved at sistnevnte omsettes med et ure-tan med formelen where Rn and R have the meaning given above, and Kt means hydrogen or a cation (e.g. an alkali metal cation). The epoxides, in turn, can be used for the production of other starting materials, e.g. the halohydrins of formula II can be prepared by reacting the epoxides with the corresponding halohydrogen acid. The amines of formula III are known and are largely commercial products. The compounds of formula IV can be prepared by reacting a halohydrin of formula II with a compound that forms the protecting group G (e.g. a vinyl ether or dihydropyran), and then reacting the obtained compound with the formula where and , Hal and G have the meaning given above, with an amine of formula III. The primary amines of formula V can be prepared by reacting halohydrins of formula II with phthalimide potassium, and then cleaving the reaction product with. hydrazine (so-called Gabriel reaction> . The tertiary amines, of formula VI can be prepared by reacting one compound of the general formula XIV with a compound of the general formula where R4 and Besk. have the meaning indicated above. The oxazolidinones of formula VII can, for example, be prepared by starting from the epoxides of formula II, by reacting the latter with a urethane of the formula

hvor har den ovenfor angitte betydning (som kan fremstilles fra klormaursyreetylester og et alkylamin med formel III). Et urinstoffderivat med formel VIII kan f.eks. fremstilles ved fremgangsmåten ifølge Chem.Abstr. 58/S.3337 c, ved at et epoksyd med formel II omsettes med det tilsvarende.substituerte urinstoff. where has the meaning given above (which can be prepared from chloroformate ethyl ester and an alkylamine of formula III). A urea derivative of formula VIII can e.g. is prepared by the method according to Chem.Abstr. 58/S.3337 c, in that an epoxide of formula II is reacted with the correspondingly substituted urea.

De nye 1-fenoksy-3-hydroksy-3-hydroksyalkylaminopropaner med den generelle formel I kan på vanlig måte overføres til sine fysiologisk forlikelige syreaddisjonssalter. Egnede syrer er f.eks. saltsyre, bromhydrogensyre, svovelsyre, metansulfonsyre, malein-syre, eddiksyre, oksansyre, melkesyre, vinsyre eller 8-klorteo-fyllin. Også overføringen til estrene kan foretaes på vanlig måte, f.eks. ved påfølgende omsetning med acylhalogenider eller acylanhydrider. Egnede estere er f.eks. 2-acetatene og 2-pro-pionatene. The new 1-phenoxy-3-hydroxy-3-hydroxyalkylaminopropanes of the general formula I can be converted in the usual way to their physiologically compatible acid addition salts. Suitable acids are e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, maleic acid, acetic acid, oxanoic acid, lactic acid, tartaric acid or 8-chlorotheophylline. The transfer to the esters can also be carried out in the usual way, e.g. by subsequent reaction with acyl halides or acyl anhydrides. Suitable esters are e.g. The 2-acetates and 2-propionates.

De nye forbindelser med den generelle formel I og The new compounds of the general formula I and

deres fysiologisk forlikelige syreaddisjonssalter har ved dyre-forsøk på marsvin vist seg å ha verdifulle terapeutiske, særlig B-adrenolytiske egenskaper, og kan derfor f.eks. anvendes til behandling eller forebyggelse av sykdommer i hjertekarene, og til behandling av hjertearytmier, særlig tachykardi, hos mennesker. Også forbindelsenes blodtrykksenkende egenskaper er av interesse. Sammenlignet med.de kjente fi-rezeptorblokkerende midler, f.eks. their physiologically compatible acid addition salts have been shown in animal experiments on guinea pigs to have valuable therapeutic, particularly B-adrenolytic properties, and can therefore e.g. used for the treatment or prevention of diseases of the heart vessels, and for the treatment of cardiac arrhythmias, especially tachycardia, in humans. The compounds' blood pressure-lowering properties are also of interest. Compared with the known four-receptor blocking agents, e.g.

l-(l-naftyloksy)-2-hydroksy-3-isopropylaminopropan (propanolol) l-(l-naphthyloxy)-2-hydroxy-3-isopropylaminopropane (propanolol)

har forbindelsene den fordel at de er vesentlig mindre giftige. the compounds have the advantage that they are significantly less toxic.

Som verdifulle har særlig vist seg å være slike forbindelser med formel I hvor betyr en forgrenet hydroksyalkylgruppe, fortrinnsvis 1, l-dimetyl-2-hydroksyetyl.-. Hvis R2 videre fortrinnsvis er hydrogen eller metyl og R^ fortrinnsvis er en umettet gruppe så som etynyl-, allyl- eller allyloksy får man forbindelser med særlig godt virkningsspektrum. Som terapeutisk særlig viktig forbindelse er funnet l-(2-etynyl-fenoksy)-2-hydroksy-3-(l,1-dimetyl-2-hydroksyetyl)-aminopropan og l-(2-cyanofenoksy)-2-hydroksy-3-(l,1-dimetyl-2-hydroksyetyl)-aminopropan, og de fysiologisk forlikelige syreaddisjonssalter og estere av disse forbindelser. Særlig virksomme er også forbindelser i hvilke fenylresten er substituert med en cyanogruppe i 2-stilling og samtidig en metylgruppe i 5-stilling, f.eks. l-(2-cyano-5-metyl-fenoksy)-2-hydroksy-3-(l,l-dimetyl-2-hydroksyetyl)-aminopropan og fysiologisk forlikelige syreaddisjonssalter og estere derav. Particularly valuable have been found to be such compounds of formula I where means a branched hydroxyalkyl group, preferably 1,1-dimethyl-2-hydroxyethyl.-. If R 2 is further preferably hydrogen or methyl and R 2 is preferably an unsaturated group such as ethynyl, allyl or allyloxy, compounds with a particularly good spectrum of action are obtained. As therapeutically particularly important compounds, l-(2-ethynyl-phenoxy)-2-hydroxy-3-(1,1-dimethyl-2-hydroxyethyl)-aminopropane and l-(2-cyanophenoxy)-2-hydroxy-3 -(1,1-dimethyl-2-hydroxyethyl)-aminopropane, and the physiologically compatible acid addition salts and esters of these compounds. Particularly effective are also compounds in which the phenyl radical is substituted with a cyano group in the 2-position and at the same time a methyl group in the 5-position, e.g. 1-(2-cyano-5-methyl-phenoxy)-2-hydroxy-3-(1,1-dimethyl-2-hydroxyethyl)-aminopropane and physiologically compatible acid addition salts and esters thereof.

De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere. The following examples shall serve to further illustrate the invention.

EKSEMPEL 1 EXAMPLE 1

1-(2-cyanofenoksy)-2-hydroksy-3-(1,1-dimetyl-2-hydroksyetyl)-aminopropan- hydroklorid - ifølge fremgangsmåte a) 1-(2-cyanophenoxy)-2-hydroxy-3-(1,1-dimethyl-2-hydroxyethyl)-aminopropane hydrochloride - according to method a)

17,5 g. (0,1 mol) 1-(2-cyanofenoksy)-propylenoksyd-2,3 og 17.5 g. (0.1 mol) 1-(2-cyanophenoxy)-propylene oxide-2,3 and

8,9 g (0,1 mol) 2-amiho-2-metyl-l-propano'l oppløses i 100 ml etanol og oppvarmes i 2 timer til kokning under tilbakeløpskjøling. Efter avdestillering av oppløsningsmidlet tilsettes residuet fortynnet saltsyre. De uoppløselige bestanddeler frafiltreres. Filtratet gjøres alkalisk med 20%-ig NaOH og den utskilte base opptaes i kloroform. Efter vasking, tørring og avdampning av oppløsningsmidlet er det tilbake et krystallinsk residuum.. Ved to gangers omkrystallisering fra etylacetat renses basen. Basen oppløses i etanol og felles med etrisk HCl som hydroklorid. 8.9 g (0.1 mol) of 2-amiho-2-methyl-1-propanol are dissolved in 100 ml of ethanol and heated for 2 hours to boiling under reflux. After distilling off the solvent, dilute hydrochloric acid is added to the residue. The insoluble components are filtered off. The filtrate is made alkaline with 20% NaOH and the secreted base is taken up in chloroform. After washing, drying and evaporating the solvent, a crystalline residue remains. The base is purified by recrystallization twice from ethyl acetate. The base is dissolved in ethanol and combined with etheric HCl as the hydrochloride.

Utbytte: 9,5 g, sm.p.: 132-134°C. Yield: 9.5 g, m.p.: 132-134°C.

EKSEMPEL 2 EXAMPLE 2

l-(2-cyanofenoksy)-2-hydrbksy-3-(l-ety1-2-hydroksyetyl)-aminopropan- hydroklorid, - ifølge fremgangsmåte a) 1-(2-cyanophenoxy)-2-hydroxy-3-(1-ethyl-2-hydroxyethyl)-aminopropane hydrochloride, - according to method a)

17,5 g (0,1 mol) 1-(2-cyanofenoksy)-propylenoksyd-2,3 17.5 g (0.1 mol) 1-(2-cyanophenoxy)-propylene oxide-2,3

og 13,3 g (0,15 mol) 2-amino-l-butanol oppløses i 100 ml etanol og oppvarmes i 2 timer til kokning under tilbakeløpskjøling. Efter avdestillering av oppløsningsmidlet tilsettes residuet fortynnet saltsyre. De uoppløselige bestanddeler frafiltreres. Filtratet gjøres alkalisk med 20%-ig NaOH, og den utfelte krystallinske base isoleres ved avsugning. Basen renses ved omkrystallisering fra etylacetat. Produktet oppløses i acetonitril og utfelles med etrisk HCl som hydroklorid. and 13.3 g (0.15 mol) of 2-amino-1-butanol are dissolved in 100 ml of ethanol and heated for 2 hours to boiling under reflux. After distilling off the solvent, dilute hydrochloric acid is added to the residue. The insoluble components are filtered off. The filtrate is made alkaline with 20% NaOH, and the precipitated crystalline base is isolated by suction. The base is purified by recrystallization from ethyl acetate. The product is dissolved in acetonitrile and precipitated with etheric HCl as the hydrochloride.

Utbytte: 6,1 g, sm.p.: 106-108°C. Yield: 6.1 g, m.p.: 106-108°C.

EKSEMPEL 3 EXAMPLE 3

1- (2-cyano-5-metylfenoksy) -2-hydroksy-^3-(1,1 -dimety 1-2-hydroksy-etyl)- aminopropan- hydroklorid - ifølge fremgangsmåte a) 1-(2-cyano-5-methylphenoxy)-2-hydroxy-^3-(1,1-dimethyl 1-2-hydroxy-ethyl)-aminopropane hydrochloride - according to method a)

7,55 g (0,04 mol) 1-(2-cyand-5-metylfenoksy)-propylenoksyd-2,3 og 7,lg (0,08 mol) 2-amino-2-metyl-l-propanol oppløses i 70 ml etanol og oppvarmes.i 2 timer.til kokning under tilbakeløpskjøling. Efter avdestillering åv oppløsningsmidlét tilsettes residuet eter og fortynnet saltsyre. Det-utfelte krystallinske.hydroklorid isoleres ved avsugning. Ved omkrystallisasjon fra alkohol og eter renses produktet. 7.55 g (0.04 mol) 1-(2-cyano-5-methylphenoxy)-propylene oxide-2,3 and 7.lg (0.08 mol) 2-amino-2-methyl-1-propanol are dissolved in 70 ml of ethanol and heated for 2 hours to boiling under reflux. After the solvent has been distilled off, ether and diluted hydrochloric acid are added to the residue. The precipitated crystalline hydrochloride is isolated by suction. The product is purified by recrystallization from alcohol and ether.

Utbytte: 4,5 g, sm.p.: i93-196°C. Yield: 4.5 g, m.p.: i93-196°C.

EKSEMPEL 4 EXAMPLE 4

1-(2-allyloksyfenoksy)-2-hydroksy-3-(1,1-dimety1-2-hydroksyetyl)-aminopropan- hydroklorid - ifølge fremgangsmåte a) 1-(2-allyloxyphenoxy)-2-hydroxy-3-(1,1-dimethyl-2-hydroxyethyl)-aminopropane hydrochloride - according to method a)

12,4 g (0,06 mol) 1-(2-allyloksyfenoksy)-propylenoksyd- 12.4 g (0.06 mol) 1-(2-allyloxyphenoxy)-propylene oxide-

2,3 og 10,7 g (0,12 mol) 2-amino-2-metyl-l-propanol oppløses i 80 ml.etanol og oppvarmes i 2 timer til kokning under tilbakeløps-kjøling. Efter avdestillering av oppløsningsmidlet tilsettes residuet fortynnet HCl og utetres en gang. HCl-fasen gjøres alkalisk med 20%-ig NaOH, og den utskilte base opptaes i eter. 2.3 and 10.7 g (0.12 mol) of 2-amino-2-methyl-1-propanol are dissolved in 80 ml of ethanol and heated for 2 hours to boiling under reflux cooling. After distilling off the solvent, dilute HCl is added to the residue and filtered once. The HCl phase is made alkaline with 20% NaOH, and the separated base is taken up in ether.

Efter vasking, tørring og avdampning av eteren, blir det tilbake After washing, drying and evaporation of the ether, it remains

et krystallinsk residuum. Ved omkrystallisasjon fra etylacetat og petroleter renses dette stoff. Basen oppløses i etanol og utfelles med etrisk HCl som hydroklorid. Utbytte: 12 g, sm.p. 76-79°C. a crystalline residue. This substance is purified by recrystallization from ethyl acetate and petroleum ether. The base is dissolved in ethanol and precipitated with etheric HCl as the hydrochloride. Yield: 12 g, m.p. 76-79°C.

EKSEMPEL 5 EXAMPLE 5

l-(2-ety.nylfenoksy)-2-hydroksy-3-(l,l-dimetyl-2-hydroksyetyl)-aminopropan- hydroklorid - ifølge fremgangsmåte a) 1-(2-ethynylphenoxy)-2-hydroxy-3-(1,1-dimethyl-2-hydroxyethyl)-aminopropane hydrochloride - according to method a)

8,65 g (0,05 mol) 1-(2-ety.nylfenoksy) -propylenoksyd-2, 3 8.65 g (0.05 mol) 1-(2-ethynylphenoxy)-propylene oxide-2,3

og 8,9 g (0,1 mol) 2-amino-2-metyl-l-propanol oppløses i-100 ml etanol og oppvarmes i to timer til kokning under tilbakeløpskjøling. Efter avdestillering av oppløsningsmidlet tilsettes residuet fortynnet saltsyre og^ utetres to ganger. HCl-fasen gjøres alkalisk and 8.9 g (0.1 mol) of 2-amino-2-methyl-1-propanol are dissolved in 100 ml of ethanol and heated for two hours to boiling under reflux. After distilling off the solvent, dilute hydrochloric acid is added to the residue and filtered twice. The HCl phase is made alkaline

med 20%-ig NaOH, og den utskilte olje opptaes i eter. Efter vasking, tørring og avdampning av eteren blir det tilbake en olje som residuum. Ved oppløsning i etanol og tilsetning av etrisk HCl krystalliseres produktet som hydroklorid. Rensningen foretaes ved omkrystallisasjon fra etanol og eter. Utbytte: 6,5 g, sm.p. 139-141°C. with 20% NaOH, and the separated oil is taken up in ether. After washing, drying and evaporation of the ether, an oil remains as a residue. Upon dissolution in ethanol and addition of etheric HCl, the product crystallizes as hydrochloride. The purification is carried out by recrystallization from ethanol and ether. Yield: 6.5 g, m.p. 139-141°C.

EKSEMPEL 6 EXAMPLE 6

1-(2-allyloksyfenoksy)-2-hydroksy-3-(2-mety1-2-hydroksyetyl)-aminopropan- hydroklorid- ifølge fremgangsmåte a) 1-(2-allyloxyphenoxy)-2-hydroxy-3-(2-methyl-2-hydroxyethyl)-aminopropane hydrochloride - according to method a)

10,4 g (0,05 mol) 1-(.2-ally loksyf enoksy) -propylenoksyd- 10.4 g (0.05 mol) 1-(.2-allyloxyphenoxy)-propylene oxide-

2,3 og 11,3 g (0,15 mol) l-aminopropanol-2 oppløses i 80 ml etanol og oppvarmes i 2 timer til kokning under tilbakeløpskjøling. Efter-avdestillering av oppløsningsmidlet blir det tilbake et- fast residuum. Ved to gangers omkrystallisasjon fra etylacetat og petroleter (40°C) renses produktet. Basen oppløses i acetonitril og utfelles som hydroklorid med etrisk HCl. 2.3 and 11.3 g (0.15 mol) of 1-aminopropanol-2 are dissolved in 80 ml of ethanol and heated for 2 hours to boiling under reflux. After distilling off the solvent, a solid residue remains. The product is purified by recrystallization twice from ethyl acetate and petroleum ether (40°C). The base is dissolved in acetonitrile and precipitated as hydrochloride with etheric HCl.

Utbytte: 8,2 g, sm.p. 82-85°C. Yield: 8.2 g, m.p. 82-85°C.

EKSEMPEL 7 EXAMPLE 7

1-C2 -ally loksyf enoksy) -2-hydroksy-3-(l-metyl-2-hydroksyetyl) - aminopropan - ifølge fremgangsmåte a) 1-C2 -allyloxy enoxy)-2-hydroxy-3-(1-methyl-2-hydroxyethyl)-aminopropane - according to method a)

Analogt med eksempel 4 fremstilles det i tittelen ^angitte forbindelse fra 1-(2-allyloksyfenoksy)-2,3-propylénoksyd ved aminolyse med l-metyl-2-hydroksyetylamin. Sm.p. lo5-106°C. (Base). Analogous to example 4, the compound indicated in the title is prepared from 1-(2-allyloxyphenoxy)-2,3-propylene oxide by aminolysis with 1-methyl-2-hydroxyethylamine. Sm.p. lo5-106°C. (Base).

EKSEMPEL 8 EXAMPLE 8

1-(2-propargyloksyfenoksy)-2-hydroksy-3-(1,1-dimety1-2-hydroksy-etyl)- aminopropan- hydroklorid - ifølge fremgangsmåte a) 1-(2-propargyloxyphenoxy)-2-hydroxy-3-(1,1-dimethyl-2-hydroxy-ethyl)- aminopropane hydrochloride - according to procedure a)

Som i eksempel 1 omsettes l-(2-propargyloksyfenoksy)-2,3-propylenoksyd med 1,1-dimetyl-2-hydroksy-etylamin til aminoalkoholen. Sm.p. 63-66°C. As in example 1, 1-(2-propargyloxyphenoxy)-2,3-propylene oxide is reacted with 1,1-dimethyl-2-hydroxyethylamine to the amino alcohol. Sm.p. 63-66°C.

EKSEMPEL 9 EXAMPLE 9

1-(2-propargyloksyfenoksy)-2-hydroksy-3-(l-metyl-2-hydroksyetyl)-aminopropan - ifølge fremgangsmåte a) 1-(2-propargyloxyphenoxy)-2-hydroxy-3-(1-methyl-2-hydroxyethyl)-aminopropane - according to method a)

Syntesen av den i tittelen angitte forbindelse foretaes analogt med eksempel 8 ved omsetning av 1-(2-propargyloksyfenoksy)-2,3-propylénoksyd med l-metyl-2-hydroksy-etylamin. The synthesis of the compound indicated in the title is carried out analogously to example 8 by reacting 1-(2-propargyloxyphenoxy)-2,3-propylene oxide with 1-methyl-2-hydroxyethylamine.

Sm.p. 81-84°C. (Base). Sm.p. 81-84°C. (Base).

EKSEMPEL 10 EXAMPLE 10

1-(2-etynylfeno3csy-2-hydroksy-3 -(l-metyl-2-hydroksyetyl) - aminopropan- hydroklorid - ifølge fremgangsmåte a) 1-(2-ethynylphenoxy-2-hydroxy-3-(1-methyl-2-hydroxyethyl)-aminopropane hydrochloride - according to method a)

Den i tittelen angitte forbindelse fremstilles ved The compound indicated in the title is produced by

aminolyse av 1-(2-etynylfenoksy) -2 , 3-propylénoksyd med l«métyl-2-hydroksyetylamin analogt med eksempel 5. Sm.p. 89-91°C. aminolysis of 1-(2-ethynylphenoxy)-2,3-propylene oxide with 1-methyl-2-hydroxyethylamine analogously to example 5. M.p. 89-91°C.

EKSEMPEL 11 EXAMPLE 11

l-(2-cyanofenoksy)~2-hydroksy-3-(2-hydroksypropyl)-aminopropan-hydroklorid - ifølge fremgangsmåte a) 1-(2-cyanophenoxy)~2-hydroxy-3-(2-hydroxypropyl)-aminopropane hydrochloride - according to method a)

Analogt med eksempel 1 omsettes 1-(2-cyanofenoksy)-2,3-propylénoksyd med 2-hydroksy-propylamin. Analogous to example 1, 1-(2-cyanophenoxy)-2,3-propylene oxide is reacted with 2-hydroxypropylamine.

Sm.p. 112-116°C. Sm.p. 112-116°C.

EKSEMPEL 12 EXAMPLE 12

l-(2-cyano-5-metylfenoksy)-2-hydroksy-3-(2-hydroksypropylJ-aminopropan- hydroklorid - ifølge fremgangsmåte a) 1-(2-cyano-5-methylphenoxy)-2-hydroxy-3-(2-hydroxypropyl J-aminopropane hydrochloride - according to method a)

1_ (2 .-cyanO'"5-metyl f enoksy)' - 2, 3 -propylénoksyd omsettes med 1_ (2.-cyanO'"5-methylphenoxy)'-2,3-propylene oxide is reacted with

2-hydroksy-propylamin under de i eksempel 1 angitte betingelser. Sm.p. 143-147°C. 2-hydroxypropylamine under the conditions stated in example 1. Sm.p. 143-147°C.

EKSEMPEL 13 EXAMPLE 13

l-(2-cyanofenoksy)-2-hydroksy-3-(2-mety1-2-hydroksyetyl)-aminopropan-hydroklorid - ifølge fremgangsmåte a) 1-(2-cyanophenoxy)-2-hydroxy-3-(2-methyl-2-hydroxyethyl)-aminopropane hydrochloride - according to method a)

En blanding bestående av .0,3 g (ca. 0,0015 mol) l-(2-cyanofenoksy-2-hydroksy-3-aminopropan, 5 ml absolutt alkohol, 0,21 A mixture consisting of .0.3 g (about 0.0015 mol) of 1-(2-cyanophenoxy-2-hydroxy-3-aminopropane), 5 ml of absolute alcohol, 0.21

g (0,002 mol) soda, 30 mg KJ og 0,189 g (0,002 mol) propylenklor-hydrin kokes under omrøring i 20 timer ved tilbakeløpskjøling. Allerede efter kort tid viser tynnskiktkromatogrammet den ønskede forbindelse, og dannelsen av denne er avsluttet efter-20 timer. g (0.002 mol) soda ash, 30 mg KJ and 0.189 g (0.002 mol) propylene chlorohydrin are boiled with stirring for 20 hours under reflux cooling. Already after a short time, the thin-layer chromatogram shows the desired compound, and the formation of this is completed after 20 hours.

Den kan renutvinnes efter vanlig bearbeidelse av produktblandingen ved rensning over en silikagelkolonne. Hydrokloridet utfelles fra den alkoholiske oppløsning ved tilsetning av etrisk HCl. It can be purified after normal processing of the product mixture by purification over a silica gel column. The hydrochloride is precipitated from the alcoholic solution by the addition of etheric HCl.

Sm.p. 108/109-111°C. Sm.p. 108/109-111°C.

EKSEMPEL 14 EXAMPLE 14

l-(2-cyanofenoksy)-2-hydroksy-3-(2-hydroksypropyl)-aminopropanhydroklorid - ifølge fremgangsmåte b) 1-(2-cyanophenoxy)-2-hydroxy-3-(2-hydroxypropyl)-aminopropane hydrochloride - according to method b)

0,848 g (0,002 mol) 1-(2-cyanofenoksy)-3-(2-hydroksy-propyl) -aminopropan-tetrahydropyranyleter-oksalat oppløses i 10 0.848 g (0.002 mol) of 1-(2-cyanophenoxy)-3-(2-hydroxy-propyl)-aminopropane tetrahydropyranyl ether oxalate is dissolved in 10

ml IN HCl og omrøres i 10 minutter i kokende vannbad, avkjøles og utetres 2 ganger. Derefter gjøres den vandige fase alkalisk med NaOH. Den utskilte olje opptaes i kloroform. Efter vasking, tørring og avdampning av kloroformen er det tilbake 430 mg residuum. Residuet oppløses i acetonitril, og hydrokloridet felles med etrisk HCl. ml IN HCl and stirred for 10 minutes in a boiling water bath, cooled and filtered twice. The aqueous phase is then made alkaline with NaOH. The separated oil is taken up in chloroform. After washing, drying and evaporation of the chloroform, 430 mg of residue remains. The residue is dissolved in acetonitrile, and the hydrochloride is combined with etheric HCl.

Utbytte: 240 mg, sm.p.: 108-111°C. Yield: 240 mg, m.p.: 108-111°C.

EKSEMPEL 15 EXAMPLE 15

l-(2-propargylfenoksy)-2-hydroksy-3-(l-etyl-2-hydroksyetyl)-aminopropan - ifølge fremgangsmåte d) 1-(2-propargylphenoxy)-2-hydroxy-3-(1-ethyl-2-hydroxyethyl)-aminopropane - according to procedure d)

En oppløsning bestående av 3,6 g (ca. 0,01 mol)l-(2-propargylfenoksy)-3-[N-acetyl-(l-etyl-2-hydroksyetyl)]-aminopropan, 30 ml etylalkohol og 1 g KOH kokes under omrøring i 2 timer med tilbakeløpskjøling. Oppløsningsmidlet avdestilleres, og residuet oppløses i 25 ml IN HCl. HCl-fasen utetres 2 ganger, gjøres alkalisk med 20%-ig NaOH, og den utskilte olje opptaes i eter. A solution consisting of 3.6 g (approx. 0.01 mol) 1-(2-propargylphenoxy)-3-[N-acetyl-(1-ethyl-2-hydroxyethyl)]-aminopropane, 30 ml ethyl alcohol and 1 g KOH is boiled with stirring for 2 hours with reflux. The solvent is distilled off, and the residue is dissolved in 25 ml of 1N HCl. The HCl phase is extracted twice, made alkaline with 20% NaOH, and the separated oil is taken up in ether.

Efter vasking, tørring og avdampning av eteren, ble tilbake et krystallinsk residuum. Rensningen foretas ved omkrystallisasjon fra etylacetat og petroleter. Utbytte: 21,1 g, sm.p. 78-81°C. After washing, drying and evaporation of the ether, a crystalline residue remained. The purification is carried out by recrystallization from ethyl acetate and petroleum ether. Yield: 21.1 g, m.p. 78-81°C.

EKSEMPEL 16 EXAMPLE 16

l-(l-allylfenoksy)-2-hydroksy-3-(1,1-dimetyl-2-hydroksyetyl)-aminopropan - rfølge fremgangsmåte f) 1-(1-allylphenoxy)-2-hydroxy-3-(1,1-dimethyl-2-hydroxyethyl)-aminopropane - follow procedure f)

En oppløsning bestående av 3,8 g (0,01 mol) N-[3-(2-allylfenoksy)-2-hydroksypropyl]-N-(l,1-dimetyl-2-hydroksyetyl)-N1 - isopropyl-urinstoff, 20 ml tetralin og 100 ml LiCl oppvarmes i oljebad i 1 1/2 time ved 200°C. A solution consisting of 3.8 g (0.01 mol) of N-[3-(2-allylphenoxy)-2-hydroxypropyl]-N-(1,1-dimethyl-2-hydroxyethyl)-N1 - isopropyl urea, 20 ml tetralin and 100 ml LiCl are heated in an oil bath for 1 1/2 hours at 200°C.

Efter avkjøling av blandingen fortynnes oppløsningen med After cooling the mixture, the solution is diluted with

eter og utristes 2 ganger med 10 ml IN HCl pr. gang. Derefter vaskes HCl-fasen o gang med eter og gjøres alkalisk med NaOH. Den utskilte olje opptaes i eter. Efter vasking, tørring og avdampning av eteren blir det tilbake et fast residuum. Ved omkrystallisasjon fra etylacetat og tilsetning av petroleter renses produktet. ether and shake out 2 times with 10 ml IN HCl per time. The HCl phase is then washed once with ether and made alkaline with NaOH. The separated oil is taken up in ether. After washing, drying and evaporation of the ether, a solid residue remains. The product is purified by recrystallization from ethyl acetate and addition of petroleum ether.

Utbytte: 1,3 g, sm.p. 63-64°C. Yield: 1.3 g, m.p. 63-64°C.

EKSEMPEL 17 EXAMPLE 17

1-(2-cyanofenoksy)-2-hydroksy-3- (1,1-dimetyl-2-hydroksyetyl)-aminopropan- hydroklorid - i følge fremgangsmåte g 1-(2-cyanophenoxy)-2-hydroxy-3-(1,1-dimethyl-2-hydroxyethyl)-aminopropane hydrochloride - according to procedure g

1.92 g (0,0075 mol) l-(2-aminofenoksy)-2-hydroksy-3-(1,1-dimetyl-2-hydroksyetyl)-aminopropan (fremstilt ved reduksjon av l-( 2-nitrofenoksy) -2-hydroksy-3 - (1,1-dimety 1.-2-hydroksyetyl) - aminopropan, som på sin side er fremstilt av o-nitrofenol ved omsetning med epiklorhydrin til o-nitrofenoksypropylenoksyd-2,3 og aminolyse av dette med 1, l - dimet'yl-2-hydroksyetylamin) oppløses 1.92 g (0.0075 mol) 1-(2-aminophenoxy)-2-hydroxy-3-(1,1-dimethyl-2-hydroxyethyl)-aminopropane (prepared by reduction of 1-(2-nitrophenoxy)-2- hydroxy-3-(1,1-dimethyl 1.-2-hydroxyethyl)-aminopropane, which in turn is produced from o-nitrophenol by reaction with epichlorohydrin to o-nitrophenoxypropylene oxide-2,3 and aminolysis of this with 1, l - dimethyl-2-hydroxyethylamine) is dissolved

i 4 ml konsentrert HCl og 10 ml H2:0. Under avkjøling til -5 til ~~ -io°C tilsettes dråpe vis 1,035 -g ' (0,0.15 mol) NaN0„ oppløst i 2,5 ml H20. Derefter røres ytterligere 10 minutter ved -5c. in 4 ml of concentrated HCl and 10 ml of H2:0. While cooling to -5 to ~~ -io°C, 1.035 g (0.0.15 mol) NaN0„ dissolved in 2.5 ml H20 are added dropwise. Then stir for a further 10 minutes at -5c.

5 g CuS0„ . 5H„0, 5>8 g KCN og 30 ml H„0 blandes og 5 g CuS0„ . 5H„0, 5>8 g KCN and 30 ml H„0 are mixed and

oppvarmes til 90 o C^ . Til denne varme oppløsning settes drå•pevis diazoniumoppløsnirigen. Under sterk oppskumning utskilles en seig ol j-e..1 1/2. time røres videre ved 85 - 90 C Blandingen avkjøles is heated to 90 o C^ . The diazonium solvent is added dropwise to this hot solution. During vigorous foaming, a tenacious ol j-e..1 1/2 is secreted. hour is further stirred at 85 - 90 C. The mixture is cooled

i isbad, gjøres alkalisk med 20%-ig-NaOH og tilsettes kloroform. Harpiksdanneride bestanddeler av suges,- og kloroformen fraskilles. in an ice bath, made alkaline with 20% NaOH and chloroform added. Resin-forming components of the extract are sucked and the chloroform is separated.

Den. vandige fase utristes ytterligere 2" ganger med kloroform. It. aqueous phase is decanted a further 2 times with chloroform.

Efter vasking, tørring og avdampning av kloroformen blir det til- After washing, drying and evaporating the chloroform, there is

bake et brunt residuum. Residuet oppløses i acetonitril, og hydro- bake a brown residue. The residue is dissolved in acetonitrile, and hydro-

kloridet felles med etrisk HCl. the chloride is combined with etheric HCl.

Utbytte: 700 mg, sm.p .129-132°C. Yield: 700 mg, mp 129-132°C.

EKSEMPEL 18 (fremgangsmåte e) l-(2-cyanofenoksy)-2-hydroksy-3-(l,1-dimetyl-2-hydroksyetyl)-aminopropan- hydroklorid EXAMPLE 18 (Procedure e) 1-(2-Cyanophenoxy)-2-hydroxy-3-(1,1-dimethyl-2-hydroxyethyl)-aminopropane hydrochloride

5,8 g (0,02 mol) 3~(1,1-dimetyl-2-hydroksyetyl) -5-(2-cyano-fenoksymetyl)-oksazolidin-2-on kokes i 2 timer under tilbake-løpskjøling i en blanding av 12 ml IIog 30 ml etanol efter tilsetning av 5,6 g (0,1 mol) KOH. Derefter avdestilleres oppløsnings-midlet, residuet kokes med °9 surgjøres med HCl. Den sure, vandige oppløsning utrystes med kloroform og gjøres derefter alkalisk med NaOH. De utfelte, basiske bestanddeler opptaes i CHCl-j, den organiske fase vaskes med vann og tørres over Na2S04- Efter avdestillering av oppløsningsmidlet oppløses det gjenværende residuum i litt etylacetat, og petroleter (Kp 4o°C) tilsettes. Basen utkrystalliserer farveløs og er kromatografisk ren. 5.8 g (0.02 mol) of 3~(1,1-dimethyl-2-hydroxyethyl)-5-(2-cyano-phenoxymethyl)-oxazolidin-2-one are boiled for 2 hours under reflux in a mixture of 12 ml of II and 30 ml of ethanol after the addition of 5.6 g (0.1 mol) of KOH. The solvent is then distilled off, the residue is boiled at °9 and acidified with HCl. The acidic aqueous solution is shaken with chloroform and then made alkaline with NaOH. The precipitated basic components are taken up in CHCl-j, the organic phase is washed with water and dried over Na2S04- After distilling off the solvent, the remaining residue is dissolved in a little ethyl acetate, and petroleum ether (Kp 4o°C) is added. The base crystallizes colorless and is chromatographically pure.

Sm.p. 100-102°C. Sm.p. 100-102°C.

• EKSEMPEL 19 (fremgangsmåte g) - 1-(2-cyanofenoksy-2-hydroksy-3-(1,1-dimetyl-2-hydroksyetyl)-aminopropan- hydroklorid • EXAMPLE 19 (method g) - 1-(2-cyanophenoxy-2-hydroxy-3-(1,1-dimethyl-2-hydroxyethyl)-aminopropane hydrochloride

2,3 g (0,01 mol) l-(2-aminofenoksy)-2-hydroksy-3-1,l-dimetyl-2-hydroksyetyl) -aminopropan oppløses i 20 ml ^0 under tilsetning av 4 ml konsentrert HCl. Under omrøring og avkjøling tilsettes dråpevis ved 5 til 10°C 1,4 g (0,02 mol) NaNO oppløst i 10 ml HO. Derefter omrøres 1 ytterligere 30 minutter ved 10 oC. 2.3 g (0.01 mol) of 1-(2-aminophenoxy)-2-hydroxy-3-1,1-dimethyl-2-hydroxyethyl)-aminopropane is dissolved in 20 ml of NaO while adding 4 ml of concentrated HCl. While stirring and cooling, 1.4 g (0.02 mol) of NaNO dissolved in 10 ml of HO are added dropwise at 5 to 10°C. Then 1 is stirred for a further 30 minutes at 10 oC.

Denne diazbniumsaltoppløsning settes i løpet av 20 minutter dråpevis til en varm oppløsning av 5 g CuS04-5 H20 og 5,6 g KCN i 30 ml ^0 > idet temperaturen holdes ved 80 til 90°C. Det om-røres derefter i ytterligere 1/2 time ved denne temperatur. De derved dannede, harpiksaktige bestanddeler avsuges og utrystes med CHC13- Også den vandige fase ekstraheres med.CHCl3, kloro-formekstraktene samles, vaskes med og tørres over Na^SO^. This diazbnium salt solution is added dropwise over the course of 20 minutes to a hot solution of 5 g of CuSO 4 -5 H 2 O and 5.6 g of KCN in 30 ml of ^0>, keeping the temperature at 80 to 90°C. It is then stirred for a further 1/2 hour at this temperature. The resulting resinous components are filtered off with suction and shaken out with CHCl3. The aqueous phase is also extracted with CHCl3, the chloroform extracts are collected, washed with and dried over Na^SO^.

Efter avdestillering av CHCI3 oppløses residuet i etylacetat, og noe petroleter (k.p. 40°C) tilsettes. Aminet utkrystalliserer f arveløst.' Man får 480 -mg rent produkt som smelter ved 100-102°. After the CHCl3 has been distilled off, the residue is dissolved in ethyl acetate, and some petroleum ether (b.p. 40°C) is added. The amine crystallizes without inheritance.' 480 mg of pure product is obtained which melts at 100-102°.

Sammenligningsforsøk Comparison experiment

Forsøket ble utført på levende marsvinunger. Som sammenligning s-forbindelse tjente 3,4-diklorisoproterenol (DCI) , hvis virkning ble satt lik 1. The experiment was carried out on live guinea pigs. As a comparison s-compound, 3,4-dichloroisoproterenol (DCI) served, whose effect was set equal to 1.

Claims (1)

Analogifremgangsmåte for fremstilling av terapeutisk aktive forbindelser med den generelle formelAnalogous method for the preparation of therapeutically active compounds of the general formula hvor betyr cyano, etynyl, propargyl, allyl eller allyloksy, r2 betyr hydrogen eller metyl og r^ betyr en lineær eller forgrenet hydroksyalkylgruppe med 3-7 C-atomer, og salter og estere derav,karakterisert ved at a) en forbindelse med den generelle formel hvor R^ og R^ har den ovenfor angitte betydning og Z bétyr gruppen eller -CHOH-CH2-Hal (Hal = halogenatom), omsettes med et alkylamin med formelen hvor R. har den ovenfor angitte betydning eller b) i en forbindelse med den generelle formel hvor R^, R2 og R^ har den ovenfor angitte betydning og G betyr en lett hydrolytisk avspaltbar gruppe, erstattes gruppen G hydrolytisk med hydrogen, eller c) en forbindelse med den generelle'formel hvor R-^ og R,, har den ovenfor angitte betydning, omsettes med en forbindelse med formel R^-Cl hvor R^ har ovennevnte betydning, eller d) i en forbindelse med den generelle formel hvor Rj_, R2 0<3 R ^ar ^en ovenfor angitte betydning og Besk. betyr en lett hydrogenolytisk eller hydrolytisk avspaltbar beskyttelses- gruppe, erstattes gruppen Besk. med hydrogen på hydrogenolytisk eller hydrolytisk måte, eller e) et oksazolidinon med den generelle formel hvor R^, R2°g R4 har den ovenfor angitte betydning, hydrolyseres, eller f) et urinstoff med den generelle fon-oi hvor R^, R2 og R^ har den ovenfor angitte betydning og R,, og Rg, som kan være like eller forskjellige, betyr hydrogen eller en alkylrest, fortrinnsvis lavere alkyl, en aralkylrest,'fortrinnsvis benzyl, eller en arylrest, fortrinnsvis fenyl, hydrolyseres eller pyrolyseres, eller g) en forbindelse med den generelle formel hvor R^°g R4 har den ovenfor angitte betydning omsettes med kobber (X) cyanid ifølge Sandmeyer, > og de erholdte forbindelser overføres eventuelt til sine fysiologisk forlikelige syreaddisjonssalter eller estere.where means cyano, ethynyl, propargyl, allyl or allyloxy, r2 means hydrogen or methyl and r^ means a linear or branched hydroxyalkyl group with 3-7 C atoms, and salts and esters thereof, characterized in that a) a compound with the general formula where R^ and R^ have the meaning indicated above and Z denotes the group or -CHOH-CH2-Hal (Hal = halogen atom), is reacted with an alkylamine with the formula where R. has the above meaning or b) in a connection with the general formula where R^, R2 and R^ have the above meaning and G means an easily hydrolytically cleavable group, the group G is hydrolytically replaced by hydrogen, or c) a compound with the general formula where R-^ and R,, have the above-mentioned meaning, are reacted with a compound of formula R^-Cl where R^ has the above-mentioned meaning, or d) in a compound of the general formula where Rj_, R2 0<3 R ^ar ^an above stated meaning and Besk. means an easily hydrogenolytically or hydrolytically cleavable protecting group, the group Besk is replaced. with hydrogen in a hydrogenolytic or hydrolytic manner, or e) an oxazolidinone of the general formula where R^, R 2 and R 4 have the meaning indicated above, is hydrolyzed, or f) a urea of the general formula where R^, R 2 and R^ has the meaning given above and R,, and Rg, which may be the same or different, means hydrogen or an alkyl residue, preferably lower alkyl, an aralkyl residue, preferably benzyl, or an aryl residue, preferably phenyl, is hydrolyzed or pyrolyzed, or g) a compound with the general formula where R^°g R4 has the above meaning is reacted with copper (X) cyanide according to Sandmeyer, > and the compounds obtained are optionally transferred to their physiologically compatible acid addition salts or esters.
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AT318571B (en) 1974-10-25
AT318566B (en) 1974-10-25
ES395671A1 (en) 1974-10-16
CH584185A5 (en) 1977-01-31
BG18857A3 (en) 1975-03-20
PL84223B1 (en) 1976-03-31
FR2110230A1 (en) 1972-06-02
FR2110230B1 (en) 1975-03-14
ES399873A1 (en) 1975-07-01
AT318565B (en) 1974-10-25
BG18858A3 (en) 1975-03-20
CH564507A5 (en) 1975-07-31
IE35693B1 (en) 1976-04-28
AT318568B (en) 1974-10-25
CH563342A5 (en) 1975-06-30
RO62267A (en) 1978-01-15
YU23679A (en) 1980-10-31
CS172950B2 (en) 1977-01-28
ES399868A1 (en) 1975-06-16
BG19134A3 (en) 1975-04-30
CH587227A5 (en) 1977-04-29
PH9959A (en) 1976-06-14
YU35577B (en) 1981-04-30
RO62358A (en) 1978-04-15
AU3418271A (en) 1973-04-12
AT318561B (en) 1974-10-25
CS172932B2 (en) 1977-01-28
CH564516A5 (en) 1975-07-31
SU419024A3 (en) 1974-03-05
JPS5710097B1 (en) 1982-02-24
BE773472A (en) 1972-04-04
NL174249C (en) 1984-05-16
RO62356A (en) 1977-08-15
ES399869A1 (en) 1975-06-16
AT318567B (en) 1974-10-25
RO62313A (en) 1977-08-15
RO62359A (en) 1977-11-15

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