NO772887L - PROCEDURE FOR PREPARATION OF 1-ARYLOXY-3-AMINO-PROPANE-2-OL DERIVATIVES - Google Patents

PROCEDURE FOR PREPARATION OF 1-ARYLOXY-3-AMINO-PROPANE-2-OL DERIVATIVES

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Publication number
NO772887L
NO772887L NO772887A NO772887A NO772887L NO 772887 L NO772887 L NO 772887L NO 772887 A NO772887 A NO 772887A NO 772887 A NO772887 A NO 772887A NO 772887 L NO772887 L NO 772887L
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radical
cyclopropyl
lower alkyl
formula
mol
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NO772887A
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Norwegian (no)
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Jean-Claude Cognacq
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Hexachimie
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds

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Description

Fremgangsmåte for fremstilling av l-aryloksy-3-amino-propan-2-ol-. derivater. Process for the preparation of 1-aryloxy-3-amino-propan-2-ol-. derivatives.

Oppfinnelsen vedrører en fremgangsmåte for fremstilling av nye l-arylbksy-3-amino-propanol-2-derivater. The invention relates to a process for the production of new 1-aryloxy-3-amino-propanol-2-derivatives.

Disse nye forbindelser tilsvarer den generelle formel: These new compounds correspond to the general formula:

hvor: betyr grupperingen eller where: means the grouping or

R^er et hydrogen- eller halogenatom, et lavere alkoksyradikal eller allylradikalet; R^ is a hydrogen or halogen atom, a lower alkoxy radical or the allyl radical;

1*2 er et hydrogenatom eller et lavere alkylradikal; 1*2 is a hydrogen atom or a lower alkyl radical;

R_ er et lavere alkylradikal, rettkjedet eller forgrenet eller et cyklopropylradikal; R_ is a lower alkyl radical, straight chain or branched or a cyclopropyl radical;

R er et, lavere alkylradikal med forgrenet kjede, spesielt isopropyl- eller tert.-butylradikalet, eller cyklopropylradikalet eller cyklopropylmetylradikalet, eller et/3-aryletylradikal som eventuelt er substituert, spesielt /3-(dimetoksy-3 ,4) f enyl-etylradikalet; R is a lower alkyl radical with a branched chain, especially the isopropyl or tert.-butyl radical, or the cyclopropyl radical or the cyclopropylmethyl radical, or a /3-arylethyl radical which is optionally substituted, especially the /3-(dimethoxy-3,4)phenylethyl radical ;

hvor betegnelsen "lavere alkyl" betyr et radikal med where the term "lower alkyl" means a radical with

1-4 karbonatomer.1-4 carbon atoms.

Oppfinnelsen omfatter likeledes fremstilling av ikke-toksiske, farmasøytisk akseptable syreaddisjonssalter av de nevnte forbindelser (I) . The invention also includes the preparation of non-toxic, pharmaceutically acceptable acid addition salts of the aforementioned compounds (I).

De mest interessante forbindelser er l-aryloksy-3-amino- propanol-2-derivatene av formlene: The most interesting compounds are the l-aryloxy-3-amino-propanol-2 derivatives of the formulas:

eller hvor R, , R2og R^er som angitt ovenfor, så vel som deres ikke-toksiske, farmasøytisk akseptable syreaddisjonssalter. Fremgangsmåten i henhold til oppfinnelsen for fremstilling av de ovennevnte forbindelser (I) består i omsetning av et epoksyd av.formel (II) med et amin R.NH2idet reaksjonen utføres ved anven-delse av som løsningsmiddel et overskudd av aminet R. NH 2 f.eks. en lavere alkanol, f.eks. metanol, etanol , isopropanol, or wherein R 1 , R 2 and R 3 are as defined above, as well as their non-toxic, pharmaceutically acceptable acid addition salts. The process according to the invention for the production of the above-mentioned compounds (I) consists in the reaction of an epoxide of formula (II) with an amine R.NH2 where the reaction is carried out using as solvent an excess of the amine R.NH2f .ex. a lower alkanol, e.g. methanol, ethanol, isopropanol,

Epoksydene II oppnås ved innvirkning av epiklorhydrin The epoxides II are obtained by the action of epichlorohydrin

i alkalisk miljø (natriumkarbonat eller kaliumkarbonat) på fenolene: in an alkaline environment (sodium carbonate or potassium carbonate) on the phenols:

som ikke er beskrevet i litteraturen, oppnås ved hydrogenering av kalkonene (IV) i tetrahydrofuran i nærvær av Raney-nikkel som på forhånd er behandlet med saltsyre: which is not described in the literature, is obtained by hydrogenation of the chalcones (IV) in tetrahydrofuran in the presence of Raney nickel pretreated with hydrochloric acid:

Kalkonene (IV) oppnås ved innvirkning av ketonene (V) på p-benzyloksybenzald.ehydene (VI) i alkalisk miljø (natriumkarbonat eller kaliumkarbonat): The chalcones (IV) are obtained by the action of the ketones (V) on the p-benzyloxybenzaldehidene (VI) in an alkaline environment (sodium carbonate or potassium carbonate):

oppnås ved innvirkning av hydrazinhydrat og kaliumkarbonat i etylenglykol på fenolketoneneIlla. is obtained by the action of hydrazine hydrate and potassium carbonate in ethylene glycol on the phenol ketones Illa.

Oppfinnelsen omfatter likeledes en direkte fremgangsmåte for fremstilling av de ovennevnte forbindelserIc ved reduksjon av et tilsvarende keton av formelen Ia ved hjelp av et alkalisk borhydrid (for eksempel av natrium eller kalium) i hydroalkoholisk miljø: The invention also includes a direct method for the preparation of the above-mentioned compounds Ic by reduction of a corresponding ketone of the formula Ia with the aid of an alkaline borohydride (for example of sodium or potassium) in a hydroalcoholic environment:

Forbindelsene I som fremstilles i henhold til oppfinnelsen, er i besittelse av farmakologiske egenskaper som gjør dem verdifulle som terapeutiske midler. De har. /3-adrenolytiske egenskaper og viser likeledes en selektivt inhiberende innvirkning på /3^-effektene uten å utøve noen depresjonsvirkning. The compounds I produced according to the invention possess pharmacological properties which make them valuable as therapeutic agents. They have. /3-adrenolytic properties and likewise show a selective inhibitory effect on the /3^ effects without exerting any depressant action.

Oppfinnelsen vil bedre forstås ved lesning av de føl-gende, ikke-begrensende eksempler. The invention will be better understood by reading the following, non-limiting examples.

Eksempel 1 Example 1

. ( m- klor- p- benzyloksy)- 1- fenyl- cyklopropyl- 3- propen- l- on- 3. ( m- chloro- p- benzyloxy)- 1- phenyl- cyclopropyl- 3- propen- l- one- 3

Formel IV: R1 = Cl, R2H , R3cyklopropylFormula IV: R 1 = Cl, R 2 H , R 3 cyclopropyl

Til en blanding av :For a mixture of:

0,2 mol m-klor-p-behzyloksybenzaldehyd,0.2 mol of m-chloro-p-behzyloxybenzaldehyde,

0,2 mol cyklopropylmetylketon,0.2 mol of cyclopropyl methyl ketone,

3 3

300 cm etanol,300 cm ethanol,

tilsettes dråpevis, under omrøring, en løsning av 4 g kaliumkarbonat i 10 cm^ vann. Man oppvarmer i 10 timer ved 50°C og lar . så temperaturen vende tilbake til 20°C, filtrerer, vasker med etanol og tørker. Man oppnår 55 g av det ønskede produkt, smp. 98°C. add dropwise, while stirring, a solution of 4 g of potassium carbonate in 10 cm^ of water. It is heated for 10 hours at 50°C and left. let the temperature return to 20°C, filter, wash with ethanol and dry. 55 g of the desired product is obtained, m.p. 98°C.

Eksempel 2Example 2

( m- klor- p- hydroksy)- 1- fenyl- cyklopropyl- 3- propanon- 3( m- chloro- p- hydroxy)- 1- phenyl- cyclopropyl- 3- propanone- 3

Formel III: R^ = Cl, R2= H, R^= cyklopropyl, Y 0 Man blander under røring ved 20 C, under et trykk på Formula III: R^ = Cl, R2= H, R^= cyclopropyl, Y 0 Mix while stirring at 20 C, under a pressure of

30.atmosfærer av hydrogen, i 12 timer, følgende:30.atmospheres of hydrogen, for 12 hours, the following:

0,17 mol (m-klor-p-benzyloksy)-1-fenyl-cyklopropyl-3-propen-l-on-3 som angitt i eksempel 1, 0.17 mol of (m-chloro-p-benzyloxy)-1-phenyl-cyclopropyl-3-propen-1-one-3 as indicated in Example 1,

300 cm 3tetrahydrofuran,300 cm 3 tetrahydrofuran,

3 g Raney-nikkel (på forhånd behandlet i 30 sekunder med 20 cm n/10 saltsyre, vasker to ganger med 50 cm vann og to ganger med 50 cm 3 metanol). 3 g Raney nickel (pretreated for 30 seconds with 20 cm n/10 hydrochloric acid, washed twice with 50 cm water and twice with 50 cm 3 methanol).

Man fører blandingen tilbake til vanlig trykk, fjerner katalysatoren ved filtrering og fordamper tetrahydrofuranet under vakuum. Man tar opp mndampningsresten med 200 cm 3 pentan og tri-turerer. Produktet krystalliserer ut. Man filtrerer det, vasker med pentan og tørker det. Man oppnår 34,3 g av det ønskede produkt, smp. = 100°C. The mixture is brought back to normal pressure, the catalyst is removed by filtration and the tetrahydrofuran is evaporated under vacuum. The evaporation residue is taken up with 200 cm 3 of pentane and triturated. The product crystallizes out. It is filtered, washed with pentane and dried. 34.3 g of the desired product is obtained, m.p. = 100°C.

Eksempel 3 Example 3

[ m- klor- p-( epoksy- 2', 3')- prpoksy]- 1- fenyl- cyklopropyl- 3- propanon- 3 [ m- chloro- p-( epoxy- 2', 3')- propoxy]- 1- phenyl- cyclopropyl- 3- propanone- 3

Formel II, 1^= Cl, R2= H, R3= cyklopropyl, Y = 0Formula II, 1^= Cl, R2= H, R3= cyclopropyl, Y = 0

Man oppløser 31,5 g (m-klor-p-hydroksy)-1-fenyl-cyklopropyl-3-propanon-3, fremstilt som i eksempel 2, i en løsning av 5,6 g natriumkarbonat i 200 cm^ vann. Til den således oppnådde løsning tilsettes under røring, alt på en gang, 15,2 g l-klor-epoksy-2 , 3-propan . Man lar blandingen omrøres i 8 timer ved omgivelsestemperatur, ekstraherer med eter, vasker ekstrakten med vann, tørker den over natriumsulfat og fordamper løsningsmidlet under vakuum, hvorved man oppnår 34,3 g av det ønskede produkt i form av en gul olje som man anvender uten ytterligere rensning for de følgende reaksjoner. 31.5 g of (m-chloro-p-hydroxy)-1-phenyl-cyclopropyl-3-propanone-3, prepared as in example 2, are dissolved in a solution of 5.6 g of sodium carbonate in 200 cm 3 of water. To the solution thus obtained, 15.2 g of 1-chloro-epoxy-2,3-propane are added, all at once, while stirring. The mixture is allowed to stir for 8 hours at ambient temperature, extracted with ether, the extract is washed with water, dried over sodium sulfate and the solvent evaporated under vacuum, thereby obtaining 34.3 g of the desired product in the form of a yellow oil which is used without further purification for the following reactions.

Eksempel 4 Example 4

[ p-( epoksy- 2', 31)- propoksy]- 1- fenyl- cyklopropyl- 3- propan[p-(epoxy-2',31)- propoxy]- 1- phenyl- cyclopropyl- 3- propane

Formel II, R^ = H, R2= H, R3= Formula II, R 1 = H, R 2 = H, R 3 =

Y=H2 Y=H2

Man arbeider som angitt i eksempel'3, men med 13,8 g p-hydroksy-l-fenyl-cyklopropyl-3-propan, 2,5, g natrxumkarbonat, 50 cm<3>vann og 6 g l-klor-epoksy-2,3-propan og oppnår 13,8 g av det ønskede produkt i form av en gul olje som anvendes uten ytterligere rensning for de følgende reaksjoner. The procedure is as indicated in example 3, but with 13.8 g of p-hydroxy-1-phenyl-cyclopropyl-3-propane, 2.5 g of sodium bicarbonate, 50 cm<3> of water and 6 g of 1-chloro-epoxy -2,3-propane and obtain 13.8 g of the desired product in the form of a yellow oil which is used without further purification for the following reactions.

Eksempel 5 Example 5

[ p-( epoksy- 2' , 3 ')- propoksy]- 1- fenyl- cyklopropyl- 3- propanon- 3 [p-(epoxy-2',3')-propoxy]-1-phenyl-cyclopropyl-3-propanone-3

Formel II, R^= H, R2= H, R3= Formula II, R 1 = H, R 2 = H, R 3 =

, Y<=>0 Man arbeider som angitt i eksempel 3, men gar ut fra 11,2 g p-hydroksyfenyl-l-cyklopropyl-3-propanon-3, 100 cm 3 vann, 2,4 g natriumkarbonat, 6,5 g l-klor-epoksy-2,3-propan og oppnår 13,7 g av tittelforbindelsen i form av en gul olje som anvendes uten ytterligere rensning for de følgende reaksjoner. Eksempel 6 [ p-( cyklopropyl- 3')- propyl]- 1- fenoksy- isopropylamino- 3- propanol- 2 . Formel I, Y = H2, R = isopropyl , R^ = H, R2■= H, , Y<=>0 Work as indicated in example 3, but start from 11.2 g p-hydroxyphenyl-1-cyclopropyl-3-propanone-3, 100 cm 3 water, 2.4 g sodium carbonate, 6.5 g of 1-chloro-epoxy-2,3-propane and obtain 13.7 g of the title compound in the form of a yellow oil which is used without further purification for the following reactions. Example 6 [p-(cyclopropyl-3')-propyl]-1-phenoxy-isopropylamino-3-propanol-2. Formula I, Y = H2, R = isopropyl, R^ = H, R2■= H,

Man lar blandingen av 13,8 g epoksyd, fremstilt som angitt i eksempel 4, og 30 cm lsopropylamm henstå i 12 timer. The mixture of 13.8 g of epoxy, prepared as indicated in example 4, and 30 cm of isopropyl alcohol is allowed to stand for 12 hours.

Man fordamper under vakuum overskuddet av isopropylamin, tar oppThe excess of isopropylamine is evaporated under vacuum, taken up

med eter, vasker med vann, tørker over magnesiumsulfat og fordamper løsningsmidlet under vakuum. with ether, wash with water, dry over magnesium sulfate and evaporate the solvent under vacuum.

Fremsti lling av oksalatProduction of oxalate

Man oppløser mndampmngsresten (14,7 g) i . 100 cm 3 eter og blander den med en løsning av 4,8 g oksalsyre i 100 cm 3eter. Dette får henstå i 3 timer, filtreres, vaskes med eter og tørkes. Man oppnår 7,2 g [p-(cyklopropyl-3')-propyl]-1-fenoksy-isopropylamino-3-propanol-2-oksalat som smelter ved 133°C. The evaporation residue (14.7 g) is dissolved in . 100 cm 3 of ether and mixes it with a solution of 4.8 g of oxalic acid in 100 cm 3 of ether. This is allowed to stand for 3 hours, filtered, washed with ether and dried. 7.2 g of [p-(cyclopropyl-3')-propyl]-1-phenoxy-isopropylamino-3-propanol-2-oxalate is obtained, which melts at 133°C.

Eksempel 7 Example 7

[ p-( cyklopropyl- 3')- propyl]- 1- fenoksy- tert.- butylamino- 3- propanol- 2 [ p-( cyclopropyl- 3')- propyl]- 1- phenoxy- tert.- butylamino- 3- propanol- 2

Formel I, Y = H2, R = tert.-butyl, R^ = H, R2= H,Formula I, Y = H 2 , R = tert-butyl, R 2 = H, R 2 = H,

Man arbeider som angitt i eksempel 5, men med 14,5 g epoksyd fremstilt som angitt i eksempel 4 og med 30 cm 3 tert.-butylamin. One works as indicated in example 5, but with 14.5 g of epoxide prepared as indicated in example 4 and with 30 cm 3 of tert-butylamine.

Fremstilling av maleatetPreparation of the maleate

Man oppløser mndampmngsresten (14,9 g) i 50 cm • 3 etylacetat og blander den med' en løsning av 6 g maléinsyre i 100 cm<3>etylacetat. Man lar dette henstå i 3 timer, filtrerer, vasker med etylacetat og tørker. Man .oppnår 8,1 g [p-(cyklopropyl-3')-propyl]-fenoksy-tert.-butylamino-3-propanol-3-maleat som smelter ved 147°C. The evaporation residue (14.9 g) is dissolved in 50 cm3 ethyl acetate and mixed with a solution of 6 g maleic acid in 100 cm3 ethyl acetate. This is allowed to stand for 3 hours, filtered, washed with ethyl acetate and dried. 8.1 g of [p-(cyclopropyl-3')-propyl]-phenoxy-tert-butylamino-3-propanol-3-maleate is obtained which melts at 147°C.

Eksempel 8 Example 8

[ p-( cyklopropyl- 3'- 3'- okso)- propyl]- 1- fenoksy- isopropylamino- 3-rwnnanr\1 O [p-(cyclopropyl-3'-3'-oxo)-propyl]-1-phenoxy-isopropylamino-3-rwnnanr\1 O

Formel I, Y = 0, R = isopropyl, R.^ = H, R2= H, Formula I, Y = 0, R = isopropyl, R 1 = H, R 2 = H,

Man lar blandingen av 13,7 g epoksyd, fremstilt som an-3 . 3 The mixture of 13.7 g of epoxide, prepared as an-3, is left. 3

gitt i eksempel 5, 50 cm isopropanol og 10 cm isopropylamin, given in example 5, 50 cm isopropanol and 10 cm isopropylamine,

henstå i 12 timer, fordamper under vakuum isopropanolen og overskudd av isopropylamin, tar resten opp med eter, vasker med vann, tørker over magnesiumsulfat og fordamper løsningsmidlet under vakuum. stand for 12 hours, evaporate the isopropanol and excess isopropylamine under vacuum, take up the residue with ether, wash with water, dry over magnesium sulfate and evaporate the solvent under vacuum.

Man oppløser i et minimum av eter inndampningsresten, avkjøler den til -30°C, filtrerer, vasker ved -30°C med litt eter og tørker, hvorved man oppnår 9,8 g av det ønskede produkt,'smp. 88°C. The evaporation residue is dissolved in a minimum of ether, cooled to -30°C, filtered, washed at -30°C with a little ether and dried, thereby obtaining 9.8 g of the desired product, m.p. 88°C.

F remstilling av maleatetPreparation of the maleate

Man oppløser 7,5 g av den oppnådde base, angitt ovenfor,. i 50 cm 3 etylacetat og blander med en løsning av 3 g malemsyre i 100 cm 3' etylacetat. Man lar blandingen henstå i 3. timer, filtrerer, vasker med etylacetat og tørker. Man oppnår 9 g maleat-salt av det ønskede produkt. Smp. = 132°C. 7.5 g of the base obtained, specified above, is dissolved. in 50 cm 3 of ethyl acetate and mix with a solution of 3 g of maleic acid in 100 cm 3 of ethyl acetate. The mixture is allowed to stand for 3 hours, filtered, washed with ethyl acetate and dried. 9 g of the maleate salt of the desired product is obtained. Temp. = 132°C.

Eksempel 9 Example 9

[ p-( cyklopropyl- 3'- 3'- okso)- propyl]- 1- fenoksy- tert.- butylamind- 3-DroDanol-2 [ p-( cyclopropyl- 3'- 3'- oxo)- propyl]- 1- phenoxy- tert.- butylamine- 3-DroDanol-2

Formel I, Y = 0, R = tert.-butyl, R^ = H, R2 = H, Formula I, Y = 0, R = tert-butyl, R^ = H, R2 = H,

Man gjentar fremgangsmåten fra eksempel 8, men med 14 g epooksyd, fremstilt som i eksempel 5, 50 cm 3 isopropanol og 10 cm 3 tert.-butylamin. The procedure from example 8 is repeated, but with 14 g of epoxide, prepared as in example 5, 50 cm 3 of isopropanol and 10 cm 3 of tert-butylamine.

Fremstilling av maleatetPreparation of the maleate

inndampningsresten (17,8 g) oppløses i 80 cm 3 etylacetat. Den således oppnådde løsning blandes med en løsning av 3 the evaporation residue (17.8 g) is dissolved in 80 cm 3 of ethyl acetate. The solution thus obtained is mixed with a solution of 3

7 g maleinsyre i 120 cm etylacetat.7 g maleic acid in 120 cm ethyl acetate.

Man lar dette henstå i 3 timer, filtrerer, vasker med etylacetat og tørker for oppnåelse av 13,3 g [p-(cyklopropyl-3'-3'-okso)-propyl]-1-fenoksy-tert.-butylamino-3-propanol-3-maleat som smelter ved 142°C. This is allowed to stand for 3 hours, filtered, washed with ethyl acetate and dried to obtain 13.3 g of [p-(cyclopropyl-3'-3'-oxo)-propyl]-1-phenoxy-tert-butylamino-3 -propanol-3-maleate which melts at 142°C.

Eksempel 10 Example 10

[ o- klor- p- ( cyklopropyl- 3 '- 3 '- okso)- pr. opyl)- 1- f enoksy- isopropylamino- 3- pr opanol- 2 [o-chloro-p-(cyclopropyl-3'-3'-oxo)- pr. opyl)- 1- f enoxy- isopropylamino- 3- pr opanol- 2

Formel I, Y = 0, R = isopropyl, R^^= Cl , R2= H,Formula I, Y = 0, R = isopropyl, R^^= Cl , R 2 = H,

Man gjentar fremgangsmåten fra eksempel 8, men med: The procedure from example 8 is repeated, but with:

14 g epoksyd,fremst ilt som angitt i eksempel 3,14 g epoxide, mainly oxygen as indicated in example 3,

50 cm isopropanol og50 cm isopropanol and

9 cm isopropylamin.9 cm isopropylamine.

Inndampningsresten tas opp med 100 cm 3 petroleter, tritureres, får henstå i 3 timer, filtreres, vaskes med petroleter og tørkes for oppnåelse av 12 g av det ønskede produkt, The evaporation residue is taken up with 100 cm 3 of petroleum ether, triturated, allowed to stand for 3 hours, filtered, washed with petroleum ether and dried to obtain 12 g of the desired product,

smp. 74°C.m.p. 74°C.

Fremstilling av klorhydratetPreparation of the chloral hydrate

Man oppløser 10 g av den base som er oppnådd som angitt ovenfor, i 100 cm 3 etylacetat. Man tilsetter under røring saltsur eter til pH = 1, lar henstå i 3 timer, filtrerer, vasker med etylacetat og tørker for oppnåelse av 8 g av klorhydratet av [o-klor-p-(cyklopropyl-3'-3'-okso)-propyl]-1-fenoksy-isopropylamino-3-propanol-2 som smelter ved 118°C. 10 g of the base obtained as stated above is dissolved in 100 cm 3 of ethyl acetate. Hydrochloric ether is added while stirring to pH = 1, allowed to stand for 3 hours, filtered, washed with ethyl acetate and dried to obtain 8 g of the hydrochloride of [o-chloro-p-(cyclopropyl-3'-3'-oxo) -propyl]-1-phenoxy-isopropylamino-3-propanol-2 which melts at 118°C.

Eksempel 11 Example 11

[ o- klor- p- ( cyklopropyl- 3 ' - 3 ' - okso) - propyl] - 1- f enoksy- l- tert. - butylamino- 3- propanol- 2 [o-chloro-p-(cyclopropyl-3'-3'-oxo)-propyl]-1-f enoxy-l- tert. - butylamino- 3- propanol- 2

Formel I, Y = 0, R = tert.-butyl, R^ = Cl, R2= H, Formula I, Y = 0, R = tert-butyl, R^ = Cl, R2 = H,

Man går frem på samme måte som angitt i eksempel 14, men med 14 g epoksyd , fremstilt som angitt i eksempel 3, 50 cm isopropanol og 9 cm 3 tert.-butylamin. One proceeds in the same way as indicated in example 14, but with 14 g of epoxide, prepared as indicated in example 3, 50 cm3 of isopropanol and 9 cm3 of tert-butylamine.

Fremstilling av klorhydratetPreparation of the chloral hydrate

Inndampningsresten (15,8 g) tas opp med 100cm 3 etylacetat. Man tilsetter saltsur eter til pH = 1, fortynner med en volumdel eter, lar henstå i 3 timer, filtrerer, vasker med en blanding av etylacetat og eter (40/60) og tørker, hvorved man oppnår 10,5 g av klorhydratet av [o-klor-p-(cyklopropyl-3'-3'-okso)-propyl]-1-fénoksy-tert.-butylamino-3-propanol-2 som smelter ved 141°C. The evaporation residue (15.8 g) is taken up with 100 cm 3 of ethyl acetate. Hydrochloric ether is added to pH = 1, diluted with one part by volume of ether, allowed to stand for 3 hours, filtered, washed with a mixture of ethyl acetate and ether (40/60) and dried, whereby 10.5 g of the hydrochloride of [ o-chloro-p-(cyclopropyl-3'-3'-oxo)-propyl]-1-phenoxy-tert-butylamino-3-propanol-2 melting at 141°C.

Eksempel 12 Example 12

[ o- klor- p-( cyklopropyl- 3'- 3'- okso)- propyl]- 1- fenoksy- cyklopropyl-metylamino- 3- propanol- 2 [ o- chloro- p-( cyclopropyl- 3'- 3'- oxo)- propyl]- 1- phenoxy- cyclopropyl- methylamino- 3- propanol- 2

Formel I, Y = 0, Formula I, Y = 0,

, R^ — Cl, R2— H, , R 2 — Cl, R 2 — H,

Man gjentar fremgangsmåten fra eksempel 8, men med 14 g . The procedure from example 8 is repeated, but with 14 g.

epoksyd, fremstilt som angitt i . eksempel 3, 50 cm 3 isopropanol og 5 g cyklopropylmetylamin. epoxy, prepared as indicated in . example 3, 50 cm 3 of isopropanol and 5 g of cyclopropylmethylamine.

Fremstilling av oksalatetPreparation of the oxalate

Inndampningsresten (16,8 g) tas opp med 60cm 3etylacetat. Til den således oppnådde løsning tilsetter man en løsning. The evaporation residue (16.8 g) is taken up with 60 cm 3 ethyl acetate. A solution is added to the solution thus obtained.

3 3

av 4,5 g oksalsyre i 90cm etylacetat. Man fortynner med 100cm 3eter, lar henstå i 3 timer, filtrerer, vasker med en 50/50 etylacétat/eter-blanding og tørker for oppnåelse av 7,5 g av oksalatet av [ o-klor-p-(cyklopropyl-3 '-3 ' okso)-propyl]-1-f enoksy-cyklopropylmetylamino-3-propanol-2 som smelter ved 135°c. of 4.5 g of oxalic acid in 90 cm ethyl acetate. It is diluted with 100 cm 3 of ether, allowed to stand for 3 hours, filtered, washed with a 50/50 ethyl acetate/ether mixture and dried to obtain 7.5 g of the oxalate of [o-chloro-p-(cyclopropyl-3'- 3' oxo)-propyl]-1-phenoxy-cyclopropylmethylamino-3-propanol-2 which melts at 135°c.

Eksempel 13 Example 13

[ p-( cyklopropyl- 3'- 3'- okso)- propyl]- 1- fenoksy- cyklopropylmetyl-3- propanol- 2 [ p-( cyclopropyl- 3'- 3'- oxo)- propyl]- 1- phenoxy- cyclopropylmethyl-3- propanol- 2

Formel I, Y = 0, Formula I, Y = 0,

, Ri — H , R2— H , , Ri — H , R2 — H ,

Man går frem på samme måte som angitt i eksempel 8, men med 12,3 g epoksyd, fremstilt som angitt 1 eksempel 5, 50 cm isopropanol og 5 g cyklopropylmetylamin. One proceeds in the same way as indicated in example 8, but with 12.3 g of epoxide, prepared as indicated in example 1 5, 50 cm of isopropanol and 5 g of cyclopropylmethylamine.

Fremstilling av oksalatet Preparation of the oxalate

Inndampningsresten (14 g) tas opp med 60 cm^ etylacetat. The evaporation residue (14 g) is taken up with 60 cc of ethyl acetate.

Til den således oppnådde løsning tilsetter man en løsning av 4,5 g 3 3 oksalsyre 1 90 cm etylacetat. Man fortynner med 100cm eter, lar henstå i 3 timer, filtrerer, vasker med en 50/50 etylacetat/ eterblanding og tørker for oppnåelse av 9,1 g av oksalatet av [p-(cyklopropyl-3'-3'-okso)-propyl]-1-fenoksy-cyklopropylmetyl-amino-3-propanol-2 som smelter ved 165°C. A solution of 4.5 g 3 3 oxalic acid and 1 90 cm ethyl acetate is added to the solution thus obtained. It is diluted with 100 cm of ether, allowed to stand for 3 hours, filtered, washed with a 50/50 ethyl acetate/ether mixture and dried to obtain 9.1 g of the oxalate of [p-(cyclopropyl-3'-3'-oxo)- propyl]-1-phenoxy-cyclopropylmethyl-amino-3-propanol-2 which melts at 165°C.

Eksempel 14 Example 14

p-( cyklopropyl- 3'- 3'- okso- propyl)- 1- fenoksy- dimetoksy- 3", 4"-p-( cyclopropyl- 3'- 3'- oxo- propyl)- 1- phenoxy- dimethoxy- 3", 4"-

fenyletylamino- 3- propanol- 2 phenylethylamino- 3- propanol- 2

Formel I , Y = 0„ R = CH2CH2- Formula I , Y = 0„ R = CH2CH2-

R1= H R2~H' R1=H R2~H'

Man går frem som angitt i eksempel 8, men med 14 g epoksyd, fremstilt som angitt i eksempel 5, 50 cm 3isopropanol og 9 g homoveratrylamin. Proceed as indicated in example 8, but with 14 g of epoxide, prepared as indicated in example 5, 50 cm3 of isopropanol and 9 g of homoveratrylamine.

Fremstilling av klorhydratetPreparation of the chloral hydrate

Inndampningsresten (21 g) tas opp med 150 cm 3 aceton. The evaporation residue (21 g) is taken up with 150 cm 3 of acetone.

Til den således oppnådde løsning tilsetter man saltsur eter til pH = 1, lar henstå i 3 timer ved omgivelsestemperatur, filtrerer, vasker med aceton og tørker for oppnåelse av 11 g klorhydrat av det ønskede produkt, smp. = 149°c. To the solution thus obtained, hydrochloric acid ether is added to pH = 1, allowed to stand for 3 hours at ambient temperature, filtered, washed with acetone and dried to obtain 11 g of chlorohydrate of the desired product, m.p. = 149°c.

Eksempel 15 Example 15

( m- metoksy- p- benzyloksy)- 1- fenyl- cyklopropyl- 3- propen- l- on- 3 ( m- methoxy- p- benzyloxy)- 1- phenyl- cyclopropyl- 3- propen- l- one- 3

Formel IV, R- L = OCH3, R2 = H, Formula IV, R- L = OCH3, R2 = H,

Til en blanding av: For a mixture of:

0,2 mol m-metoksy-p-benzyloksybenzaldehyd,0.2 mol m-methoxy-p-benzyloxybenzaldehyde,

0,2 mol cyklopropylmetylketon og0.2 mol cyclopropyl methyl ketone and

3 3

300 cm etanol,300 cm ethanol,

tilsettes dråpevis, under røring, en løsning av 4 g kaliumkarbonat i 10 cm^ vann. Deretter oppvarmer man i 10 timer ved 50°C , lar temperaturen innstille seg til 20°C, tilsetter langsomt 150 cm vann, lar blandingen henstå i 3 timer, filtrerer, vasker med en etanol/vannblanding 50/50 og tørker. Man oppnår 52 g av det ønskede produkt, smp. = 124°c. add dropwise, while stirring, a solution of 4 g of potassium carbonate in 10 cm^ of water. Then heat for 10 hours at 50°C, allow the temperature to settle to 20°C, add slowly 150 cm of water, let the mixture stand for 3 hours, filter, wash with an ethanol/water mixture 50/50 and dry. 52 g of the desired product is obtained, m.p. = 124°c.

Eksempel 16 Example 16

( m- metoksy- p- hydroksy)- 1- fenyl- cyklopropyl- 3- propanon- 3( m- methoxy- p- hydroxy)- 1- phenyl- cyclopropyl- 3- propanone- 3

Formel III, R1= 0CH3, R2 = H, Formula III, R1 = 0CH3, R2 = H,

, Y = 0 , Y = 0

En blanding av 0,4 mol (m-metoksy-p-benzyloksy)-1-fenyl-cyklopropyl-3-propen-l-on-3,fremstilt som angitt i eksempel 15, 500 cm 3 tetrahydrofuran og 5 g Raney-nikkel (på forhånd behandlet i 30 sekunder med 30cm n/10 saltsyre, vasket to ganger med 50 cm 3 vann og to ganger med 50 cm 3 metanol) bringes under røring til 20°C , under et hydrogentrykk på 30 atm., i 12 timer. Man fører trykket tilbake til det. vanlige, fjerner katalysatoren ved filtrering og fjerner tetrahydrofuranet under vakuum. A mixture of 0.4 mol of (m-methoxy-p-benzyloxy)-1-phenyl-cyclopropyl-3-propen-1-one-3, prepared as indicated in Example 15, 500 cm 3 of tetrahydrofuran and 5 g of Raney nickel (pre-treated for 30 seconds with 30 cm n/10 hydrochloric acid, washed twice with 50 cm 3 of water and twice with 50 cm 3 of methanol) is brought under stirring to 20°C, under a hydrogen pressure of 30 atm., for 12 hours . The pressure is brought back to it. common, remove the catalyst by filtration and remove the tetrahydrofuran under vacuum.

Inndampningsresten tas opp med 420 cm 3 av en normal-natriumkarbonatløsning. Den således oppnådde vandige løsning behandles med 2 g animalsk kull, filtreres, surgjøres til pH 1 med saltsyre. Man ekstraherer med eter, tørker over magnesiumsulfat og fordamper løsningsmidlet under vakuum så at man oppnår 85 g av det ønskede produkt i form av en gul olje som man anvender uten ytterligere rensning for de følgende reaksjoner. The evaporation residue is taken up with 420 cm 3 of a normal sodium carbonate solution. The aqueous solution thus obtained is treated with 2 g of animal charcoal, filtered, acidified to pH 1 with hydrochloric acid. Extract with ether, dry over magnesium sulphate and evaporate the solvent under vacuum so that 85 g of the desired product is obtained in the form of a yellow oil which is used without further purification for the following reactions.

Eksempel 17 Example 17

J_ m- metoksy- p-( eppksy- 2', 3')- propoksy]- 1- fenyl- cyklopropyl- 3-propanon- 3 J_ m- methoxy- p-( eppoxy- 2', 3')- propoxy]- 1- phenyl- cyclopropyl- 3-propanone- 3

Formel II, R± = OCH3, R2= H, Formula II, R± = OCH3, R2= H,

, Y = 0 , Y = 0

Man oppløser 0,2 mol fenol, fremstilt som angitt i eksempel 16, i 200 cm 3 normalnatriumkarbonatløsning. Til den således oppnådde løsning tilsettes, alt på én gang, 23 g l-klor-epoksy-2 , 3-propan . Man lar blandingen henstå under røring i 8 timer ved omgivelsestemperatur, ekstraherer med eter, vasker med vann, tørker over magnesiumsulfat og fordamper løsningsmidlet under vakuum for oppnåelse av 47,8 g av det ønskede.produkt i form av en gul olje som.anvendes uten ytterligere rensning for de føl-gende reaksjoner. 0.2 mol of phenol, prepared as indicated in example 16, is dissolved in 200 cm 3 of normal sodium carbonate solution. To the solution thus obtained, 23 g of 1-chloro-epoxy-2,3-propane are added all at once. The mixture is allowed to stand with stirring for 8 hours at ambient temperature, extracted with ether, washed with water, dried over magnesium sulfate and the solvent evaporated under vacuum to obtain 47.8 g of the desired product in the form of a yellow oil which is used without further purification for the following reactions.

Eksempel 18Example 18

[ p-( epoksy- 2' , 3 ' )- propoksy]- 1- fenyl- butanon- 3[p-(epoxy-2',3')-propoxy]-1-phenyl-butanone-3

Formel II, R± ■ H, R2H, R3 ■ = CH3, Y = 0Formula II, R± ■ H, R2H, R3 ■ = CH3, Y = 0

Man går frem på samme måte som angitt i eksempel 17, You proceed in the same way as indicated in example 17,

men med:but with:

0,2 mol p-hydroksyfenyl-l-butanon-3,0.2 mol p-hydroxyphenyl-1-butanone-3,

200 cm 3 normal natriumkarbonatløsning og 23 g l-klor-epoksy-2 , 3-propan. 200 cm 3 of normal sodium carbonate solution and 23 g of 1-chloro-epoxy-2,3-propane.

Etter fordampning av løsningsmidlet i vakuum oppnår man After evaporation of the solvent in a vacuum, one obtains

37 g av tittelforbindelsen i form av en gul olje som man anvender uten ytterligere rensning for de følgende reaksjoner. Eksempel 19 [ p- ( epoksy- 2', 3')- propoksy]- 1- fenyl- 4- metyl- pentanon- 3 Formel II, R1= H, R2= H, R3 = 37 g of the title compound in the form of a yellow oil which is used without further purification for the following reactions. Example 19 [p-(epoxy-2',3')-propoxy]-1-phenyl-4-methyl-pentanone-3 Formula II, R1= H, R2= H, R3 =

, Y = 0 , Y = 0

Man anvender samme fremgangsmåte som angitt i eksempel 17, men med: The same procedure as stated in example 17 is used, but with:

0,2 mol p-hydroksyfenyl-l-4-métyl-pentanon-3 ,0.2 mol p-hydroxyphenyl-1-4-methyl-pentanone-3,

200 cm 3 normal natriumkarbonatløsning og 23 g l-klor-epoksy-2,3-propan. 200 cm 3 of normal sodium carbonate solution and 23 g of 1-chloro-epoxy-2,3-propane.

Etter fordampning av løsningsmidlet under vakuum oppnår man 36,5 g av tittelforbindelsen i form av en gul olje som man anvender uten ytterligere rensning for de følgende reaksjoner. After evaporation of the solvent under vacuum, 36.5 g of the title compound is obtained in the form of a yellow oil which is used without further purification for the following reactions.

Eksempel. 20 Example. 20

[ p- ( epoksy- 2' , 3')- propoksy]- 1- fenyl- 2- metyl- butanon- 3[p-(epoxy-2',3')-propoxy]-1-phenyl-2-methyl-butanone-3

Man anvender samme fremgangsmåte som angitt i eksempel 17, men med: The same procedure as stated in example 17 is used, but with:

0,2 mol p-hydroksyfenyl-l-2-métyl-butanon-3,0.2 mol p-hydroxyphenyl-1-2-methyl-butanone-3,

200 cm 3: normal natriumkarbonatløsning og 23 g l-klor-epoksy-2,3-propan. 200 cm 3: normal sodium carbonate solution and 23 g of 1-chloro-epoxy-2,3-propane.

Etter fordampning av løsningsmidlet under vakuum, oppnår man 38 g av tittelforbindelsen. After evaporation of the solvent under vacuum, 38 g of the title compound are obtained.

Eksempel 21Example 21

[ p-( cyklopropyl- 3 , 3'- okso- propyl]- 1- fenoksy- cyklopropylamino- 3-propanol- 2 [p-(cyclopropyl-3,3'-oxo-propyl]-1-phenoxy-cyclopropylamino-3-propanol-2

.. Formel I, i — H, R2 — H, .. Formula I, i — H, R2 — H,

, Y = 0 , Y = 0

En blanding bestående av:A mixture consisting of:

0,1 mol [p-(epoksy-2',3')propoksy]-1-fenyl-cyklopropyl-3-propanon-3, 50 cm isopropanol, 0.1 mol [p-(epoxy-2',3')propoxy]-1-phenyl-cyclopropyl-3-propanone-3, 50 cm isopropanol,

0,11 mol cyklopropylamin0.11 mol cyclopropylamine

får hvile i 12 timer. Deretter fordamper man isopropanolen og overskuddet av cyklopropylamin under vakuum, tar opp resten méd eter, vasker med vann, tørker over magnesiumsulfat og fordamper løsningsmidlet under vakuum. allowed to rest for 12 hours. The isopropanol and excess cyclopropylamine are then evaporated under vacuum, the residue taken up with ether, washed with water, dried over magnesium sulfate and the solvent evaporated under vacuum.

(fremstilt som angitt i eksempel 17, men ut fra p-hydroksyfenyl-l-3-cyklopropyl-p£opanon-3) (prepared as indicated in example 17, but from p-hydroxyphenyl-1-3-cyclopropyl-p£opanon-3)

Fremstilling av klorhydratetPreparation of the chloral hydrate

3Inndampningsresten (28 g) tas opp med 100 cm isopropanol. Til den således oppnådde løsning tilsettes saltsur eter til pH 1. Man lar blandingen henstå natten over, filtrerer vasker med aceton og deretter med eter og tørker for oppnåelse av 10,2 g av klorhydratet av [p-(cyklopropyl-3'-3'-okso)propyl]-1-fenoksy-cyklopropylamino-3-propanol-2, smp. = 122°C. 3 The evaporation residue (28 g) is taken up with 100 cm isopropanol. To the solution thus obtained, hydrochloric acid ether is added to pH 1. The mixture is allowed to stand overnight, the washings are filtered with acetone and then with ether and dried to obtain 10.2 g of the hydrochloride of [p-(cyclopropyl-3'-3' -oxo)propyl]-1-phenoxy-cyclopropylamino-3-propanol-2, m.p. = 122°C.

Eksempel 22 Example 22

[ o- metoksy- p-( cyklopropyl- 3'- 3'- okso) propyl]- 1- fenoksy- isopropylamino- 3- propanol- 2 [ o- methoxy- p-( cyclopropyl- 3'- 3'- oxo) propyl]- 1- phenoxy- isopropylamino- 3- propanol- 2

Formel. I , R^ — OCH2 1 ~~ ^' ^3' — Formula. I , R^ — OCH2 1 ~~ ^' ^3' —

Y 0 Y 0

Man går frem som angitt i eksempel 21, men med:Proceed as indicated in example 21, but with:

0,1 mol epoksyd, fremstilt som angitt i eksempel 17, 50 cm isopropanol 0.1 mol epoxide, prepared as indicated in example 17, 50 cm isopropanol

0,11 mol isopropylamin.0.11 mol of isopropylamine.

Inndampningsresten tritureres i pentan, de oppnådde krystaller avsuges, vaskes med pentan og tørkes for oppnåelse av 26 g av det ønskede produkt, smp. 79°c. The evaporation residue is triturated in pentane, the crystals obtained are filtered off with suction, washed with pentane and dried to obtain 26 g of the desired product, m.p. 79°c.

Eksempel 2 3 Example 2 3

[ o- metoksy- p- ( cyklopropyl- 3 ' - 3 1 - okso) propyl] - 1- f enoksy- tert .,-butylamino- 3- propanol- 2 [o-Methoxy-p-(cyclopropyl-3'-31-oxo)propyl]-1-phenoxy- tert.,-butylamino-3-propanol-2

Formel I, R = Formula I, R =

R^ — OCH^;R2— H, R 2 — OCH 2 ; R 2 — H,

Y = 0 Y = 0

Man går frem på samme måte som angitt i eksempel 21, men. me d: You proceed in the same way as stated in example 21, but. with d:

0,1 mol epoksyd, fremstilt som angitt i eksempel 17,0.1 mol of epoxide, prepared as indicated in Example 17,

50 cm isopropanol50 cm isopropanol

0,11 mol tert.-butylamin.0.11 mol tert-butylamine.

Fremstilling av nøytralt suksinatPreparation of neutral succinate

3 Inndampningsresten (33 g) tas opp méd 100 cm aceton. Den således oppnådde løsning tømmes ned på en varm løsning av 3 The evaporation residue (33 g) is taken up with 100 cm acetone. The solution thus obtained is poured onto a warm solution of

.5 g ravsyre i 100 cm 3 isopropanol. Man lar blandingen henståo natten over, filtrerer, vasker med aceton og tørker for oppnåelse .5 g succinic acid in 100 cm 3 isopropanol. The mixture is allowed to stand overnight, filtered, washed with acetone and dried to obtain

av 20 g nøytralt suksinat av det ønskéde produkt, smp. = 162°C. of 20 g of neutral succinate of the desired product, m.p. = 162°C.

Eksempel 24 Example 24

[ p-( 4 '- metyl- 3- okso) fenyl]- 1- fenoksy- isopropylamino- 3- propanol- 2 [ p-(4 '- methyl- 3- oxo) phenyl]- 1- phenoxy- isopropylamino- 3- propanol- 2

Formel I, Formula I,

Rx = H., Rx = H.,

Y = 0 Y = 0

Man går frem på samme måte som angitt i eksempel 21, men med: 0,1 mol epoksyd, fremstilt som angitt i eksempel 19, 3 .. ■ Proceed in the same way as stated in example 21, but with: 0.1 mol of epoxide, prepared as stated in example 19, 3 .. ■

50 cm isopropanol50 cm isopropanol

0,11 mol isopropylamin0.11 mol of isopropylamine

Fremstilling av oksalatet Preparation of the oxalate

Inndampningsresten (26 g) tas opp med 100 cm 3 etylacetat. Til den således oppnådde løsning tilsettes en løsning av 9 g oksalsyre i 80 cm<3>etylacetat. Man lar blandingen henstå i 6 timer, filtrerer, vasker med etylacetat.og tørker for oppnåelse av 21 g oksalat av det ønskede produkt, smp. = 92°C. The evaporation residue (26 g) is taken up with 100 cm 3 of ethyl acetate. A solution of 9 g of oxalic acid in 80 cm<3>ethyl acetate is added to the solution thus obtained. The mixture is allowed to stand for 6 hours, filtered, washed with ethyl acetate and dried to obtain 21 g of oxalate of the desired product, m.p. = 92°C.

Eksempel 25 Example 25

[ p-( 4'- metyl- 3'- okso) pentyl]- 1- fenoksy- tert.- butyjamino- 3-propanol- 2 [ p-(4'- methyl- 3'- oxo) pentyl]- 1- phenoxy- tert.- butyamino- 3-propanol- 2

Formel I, Formula I,

R^H, R_ — H / R^H, R_ — H /

Y = 0 Y = 0

Man går frem på samme måte som angitt i eksempel 21, man med: You proceed in the same way as stated in example 21, with:

0,1 mol epoksyd, fremstilt som angitt i eksempel 18, 3 . 0.1 mol of epoxide, prepared as indicated in example 18, 3 .

50 cm isopropanol50 cm isopropanol

0,11 mol tert.-butylamin0.11 mol tert-butylamine

Fremstilling av fumaratetPreparation of the fumarate

Inndampningsresten (29 g) tas opp med 100 cm 3 aceton i varme. Til den således oppnådde løsning tilsettes 0,09 mol fumarsyre i 200 cm 3 varm aceton. Man lar blandingen henstå i 6 timer, separerer de oppnådde krystaller ved filtrering, vasker dem med aceton, tørker og rekrystalliserer ut fra etanol for oppnåelse av 17 g av fumaratet av. det ønskede produkt, smp. = 186°c. The evaporation residue (29 g) is taken up with 100 cm 3 of acetone in heat. To the solution thus obtained, 0.09 mol of fumaric acid in 200 cm 3 of hot acetone is added. The mixture is allowed to stand for 6 hours, the crystals obtained are separated by filtration, washed with acetone, dried and recrystallized from ethanol to obtain 17 g of the fumarate. the desired product, m.p. = 186°c.

Eksempel 26 Example 26

[ p- ( 3 '- okso)- butyl) - 1- f enoksy- isopropylamiho- 3- propanol- 2 [p-(3'-oxo)-butyl)-1-phenoxy-isopropylamiho-3-propanol-2

Formel I, Formula I,

R^ — H; R 2 — H, R ^ — CH^/Y — 0 R^—H; R 2 — H, R ^ — CH^/Y — 0

Man går frem på samme måte som angitt i eksempel 21, men med0,1 mol epoksyd, fremstilt som angitt i eksempel 18, 50 cm 3 i.sopropanol og0,11 mol isopropylamin. One proceeds in the same way as indicated in example 21, but with 0.1 mol of epoxide, prepared as indicated in example 18, 50 cm 3 of isopropanol and 0.11 mol of isopropylamine.

Fremstilling av fumaratetPreparation of the fumarate

Inndampningsresten (25 g) tas opp med 80 cm 3 isopropanol. Til den således oppnådde, løsning tilsettes en varm løsning av 0,09 mol fumarsyre i 150 cm 3 isopropanol. Man lar blandingen henstå natten over, filtrerer, vasker med isopropanol og tørker for oppnåelse av 15 g fumarat av det ønskede produkt, smp. = 138°C. The evaporation residue (25 g) is taken up with 80 cm 3 of isopropanol. A hot solution of 0.09 mol of fumaric acid in 150 cm 3 of isopropanol is added to the solution thus obtained. The mixture is allowed to stand overnight, filtered, washed with isopropanol and dried to obtain 15 g of fumarate of the desired product, m.p. = 138°C.

Eksempel 27 Example 27

[ p-( 3'- okso) butyl]- 1- fenoksy- tert.- butylamino- 3- propanol- 2 [ p-(3'-oxo)butyl]- 1- phenoxy- tert.- butylamino- 3- propanol- 2

Formel I, Formula I,

R-^= H, R2 - H , R3= CH3, Y = 0 R-^= H, R 2 - H , R 3 = CH 3 , Y = 0

Man går frem på samme måte som angitt i eksempel 21, men med: You proceed in the same way as stated in example 21, but with:

0,1 mol epoksyd, fremstilt som angitt i eksempel 18,0.1 mol of epoxide, prepared as indicated in Example 18,

50 cm isopropanol50 cm isopropanol

0,11 mol tert.-butylamin.0.11 mol tert-butylamine.

Fremstilling av maleatetPreparation of the maleate

3 Inndampningsresten (25 g) tas opp med 100 cm isopropanol. Til den således oppnådde løsning tilsettes en løsning av 0,1 mol malemsyre i 100 cm 3 isopropanol. Man lar blandingen henstå i 6 timer, filtrerer, vasker med isopropanol,• tørker, og rekrystalliserer fra aceton for oppnåelse av 19 g av maleatet av det ønskede produkt, smp. = 140°C. 3 The evaporation residue (25 g) is taken up with 100 cm isopropanol. A solution of 0.1 mol of maleic acid in 100 cm 3 of isopropanol is added to the solution thus obtained. The mixture is allowed to stand for 6 hours, filtered, washed with isopropanol, • dried and recrystallized from acetone to obtain 19 g of the maleate of the desired product, m.p. = 140°C.

Eksempel 28 Example 28

[ p- ( 2 ' - metyl- 3 ' - okso)- butyl] - 1- f enoksy- tert. - butylamino- 3-propanol- 2 [p-(2'-methyl-3'-oxo)-butyl]-1-phenoxy- tert. - butylamino-3-propanol-2

Formel I, Formula I,

= H, R2= CH3, R3= CH3, Y = 0 = H, R 2 = CH 3 , R 3 = CH 3 , Y = 0

Man går frem på samme måte som angitt i eksempel 21, men med: You proceed in the same way as stated in example 21, but with:

0,1 mol epoksyd, fremstilt som i eksempel 200.1 mol of epoxide, prepared as in example 20

50 cm isopropanol50 cm isopropanol

0,11 mol tert ..-but<y>lamin. 0.11 mol tert ..-but<y>lamine.

Fremstilling av oksalatetPreparation of the oxalate

Inndampningsresten (25 g) tas opp med 75 cm<3>aceton; til den således oppnådde løsning tilsettes en løsning av 0,1 mol oksalsyre i 75 cm 3 aceton. Man lar blandingen henstå natten over, filtrerer, vasker med aceton og tørker for oppnåelse av 13,8 g av oksalatet av. det ønskede produkt, smp.= 140°C. The evaporation residue (25 g) is taken up with 75 cm<3>acetone; a solution of 0.1 mol of oxalic acid in 75 cm 3 of acetone is added to the solution thus obtained. The mixture is allowed to stand overnight, filtered, washed with acetone and dried to obtain 13.8 g of the oxalate. the desired product, m.p.= 140°C.

Eksempel 29Example 29

( m- allyl- p- hydroksy) - rl- f enyl- cyklopropyl- 3- propanon- 3( m- allyl- p- hydroxy) - rl- phenyl- cyclopropyl- 3- propanone- 3

Formel III, R1= -CH2~CH=CH2, R2 = H, Formula III, R1= -CH2~CH=CH2, R2 = H,

., Y = 0 ., Y = 0

a) ( p- allyloksy)- 1- fenyl- cyklopropyl- 3- propanon- 3a) ( p- allyloxy)- 1- phenyl- cyclopropyl- 3- propanone- 3

Til en løsning av 0,1 mol n.atrium-etylat i 100 cm<3>To a solution of 0.1 mol n.atrium ethylate in 100 cm<3>

etanol tilsettes, alt på en gang, 0,1 mol p-hydroksyfenyl-1-cyklopropyl-3-propanon^3 ethanol is added, all at once, 0.1 mol of p-hydroxyphenyl-1-cyclopropyl-3-propanone^3

(III R-j^= R2= H, (III R-j^= R2= H,

, Y = 0) og.deretter rører man i 15 min. ved omgivelsestemperatur. Man tilsetter 0,1 mol allylbromid, alt på én gang, og bringer etanolen .... 3 til t llbakeløpsk jølmg i 5 timer. Man tilsetter 300 cm vann, ekstraherer med eter, tørker den organiske fase over magnesiumsulfat og fordamper løsningsmidlet under.vakuum for oppnåelse av 19,5 g av det ønskede produkt i form av en klar, gul olje. b) ( m- allyl- p- hydroksy)- 1- fenyl- cyklopropyl- 3- propanon- 3 Allyletéren (19,5 g) som ble fremstilt under a), bringes i løpet av 4 timer til 200-220°C under en lett nitrogen-strøm. , Man avkjøler og foretar omrøring i 2 timer med 200 cm<3>av en 0,05 n natriumkarbonat løsning. Mari fjerner det uløselige materiale ved ekstraksjon med eter, surgjør den vandige fase med saltsyre (pH = 2), ekstraherer med eter, tørker den organiske fase over magnesiumsulfat og fordamper eteren under vakuum for oppnåelse av 16 g av det ønskede produkt i form av en gul, klar olje. Eksempel 30 [ m- allyl- p-( epoksy- 2', 3'- propoksy)]- 1- fenyl- cyklopropyl- 3- propanon- 3 Formel II, R, =-CH„^CH= CH„, R» = H, 1 2 2 2 , Y = 0) and then stir for 15 min. at ambient temperature. 0.1 mol of allyl bromide is added, all at once, and the ethanol .... 3 is refluxed for 5 hours. 300 cm of water are added, extracted with ether, the organic phase is dried over magnesium sulfate and the solvent is evaporated under vacuum to obtain 19.5 g of the desired product in the form of a clear, yellow oil. b) (m-allyl-p-hydroxy)-1-phenyl-cyclopropyl-3-propanone-3 The allyl ether (19.5 g) which was prepared under a), brought within 4 hours to 200-220°C under a light stream of nitrogen. , It is cooled and stirred for 2 hours with 200 cm<3> of a 0.05 n sodium carbonate solution. Mari removes the insoluble material by extraction with ether, acidifies the aqueous phase with hydrochloric acid (pH = 2), extracts with ether, dries the organic phase over magnesium sulfate and evaporates the ether under vacuum to obtain 16 g of the desired product in the form of a yellow, clear oil. Example 30 [m-allyl-p-(epoxy-2',3'-propoxy)]-1-phenyl-cyclopropyl-3-propanone-3 Formula II, R, =-CH„^CH= CH„, R» = H, 1 2 2 2

, Y = 0 , Y = 0

Man oppløser 0,1 mol (m-allyl-p-hydroksy)-1-fenyl-cyklopropyl-3-propanon-3, fremst ilt som angitt i eksempel 29, One dissolves 0.1 mol of (m-allyl-p-hydroxy)-1-phenyl-cyclopropyl-3-propanone-3, primarily oxygen as indicated in example 29,

i 100 cm 3 ln-natriumkarbonatløsning. Til den således oppnåodde løsning tilsetter man, alt på én gang, 11,5 g l-klor-epoksy-2,3- in 100 cm 3 ln sodium carbonate solution. To the solution thus obtained, 11.5 g of l-chloro-epoxy-2,3-

propan. Man lar blandingen bli omrørt i 8 timer ved omgivelses- , temperatur, ekstraherer med eter, tørker den organiske fase over magnesiumsulfat og fordamper løsningsmidlet under vakuum for oppnåelse av 25,2 g av det ønskede produkt i form av en klar, gul olje. propane. The mixture is allowed to stir for 8 hours at ambient temperature, extracted with ether, the organic phase is dried over magnesium sulfate and the solvent is evaporated under vacuum to obtain 25.2 g of the desired product in the form of a clear, yellow oil.

Eksempel 31 Example 31

[ o- allyl- p- ( cyklopropyl- 3 .' - 3 ' - okso- propyl) ] - 1- f enoksy- isoprbpyl-amino- 3- propanol- 2 [o-allyl-p-(cyclopropyl-3.'-3'-oxo-propyl)]-1-phenoxy- isoprbpyl-amino-3-propanol-2

Formel I, R = isopropyl, R^ = -CH2-CH=CH2, R2 = H, Formula I, R = isopropyl, R^ = -CH2-CH=CH2, R2 = H,

Y. = 0 Y. = 0

Man lar blandingen av 0,05 mol epoksyd, fremstilt som The mixture of 0.05 mol of epoxide, prepared as

.... 3 .... 3

angitt i eksempel 30, 0,06 mol isopropylamin. og 50 cm isopropanol henstå i 12 timer, fordamper isopropanolen og overskuddet av isopropylamin under vakuum. stated in Example 30, 0.06 mol of isopropylamine. and 50 cm of isopropanol to stand for 12 hours, evaporate the isopropanol and the excess of isopropylamine under vacuum.

Fremstilling av oksalatet:Preparation of the oxalate:

3Inndampningsresten (16,1 g) tas opp med 100 cm aceton. Til den således oppnådde løsning tilsetter man en løsning av 3 The evaporation residue (16.1 g) is taken up with 100 cm acetone. A solution of is added to the solution thus obtained

0,05 mol oksalsyre i 50 cm 3 aceton, blandingén fåor henstå i 2 timer, filtreres, vaskes med aceton og rekrystalliseres ut fra etanol slik at man oppnår 9,2 g oksalat av det ønskede produkt, smp..= 132-134°C. 0.05 mol of oxalic acid in 50 cm 3 of acetone, the mixture is allowed to stand for 2 hours, filtered, washed with acetone and recrystallized from ethanol so that 9.2 g of oxalate of the desired product is obtained, m.p.= 132-134° C.

Eksempel 32 Example 32

[ m- brom- p-( epoksy- 2' , 3 '- propoksy)]- 1- fenyl- 3- metyl- butanon- 3[m-bromo-p-(epoxy-2',3'-propoxy)]-1-phenyl-3-methyl-butanone-3

Formel II, R^= Br, R2= R 3 = CH3, Y = 0Formula II, R^= Br, R 2= R 3 = CH 3 , Y = 0

Man går frem på samme måte som i eksempel 30, men medYou proceed in the same way as in example 30, but with

0,1 mol (m-brom-p-hydroksy)-1-fenyl-2-metyl-butanon-3, for oppnåelse av 2 3,7 g av det ønskede produkt i form av en klar, gul ol je . 0.1 mol of (m-bromo-p-hydroxy)-1-phenyl-2-methyl-butanone-3, to obtain 2 3.7 g of the desired product in the form of a clear, yellow oil.

Eksempel 33 Example 33

[ o- brom- p-( 2'- metyl- 3'- oksobutyl)]- 1- fenoksy- isopropylamino- 3-propanol- 2. [ o- bromo- p-(2'- methyl- 3'- oxobutyl)]- 1- phenoxy- isopropylamino- 3-propanol- 2.

Formel I, R = isopropyl, R^^ = Br, R2= R^CH3, Y = 0 Formula I, R = isopropyl, R^^ = Br, R 2 = R^CH 3 , Y = 0

Man følger fremgangsmåten fra eksempel 31, men medThe procedure from example 31 is followed, but with

0,05 mol epoksyd, fremstilt som angitt i eksempel 32.0.05 mol of epoxide, prepared as indicated in Example 32.

Fremstilling av klorhydratet Preparation of the chloral hydrate

Inndampningsresten (16,3 g) tas opp med 100 cm<3>aceton. Til den således oppnådde løsning tilsettes under røring saltsur eter til pH = 1, blandingen får henstå i 5 timer, filtreres, vaskes med aceton og tørkes for oppnåelse av 10,2 g av klorhydratet av det ønskede produkt, smp. = 144-146°c. The evaporation residue (16.3 g) is taken up with 100 cm<3>acetone. To the solution thus obtained, hydrochloric acid ether is added while stirring to pH = 1, the mixture is allowed to stand for 5 hours, filtered, washed with acetone and dried to obtain 10.2 g of the hydrochloride of the desired product, m.p. = 144-146°c.

Eksempel 34 Example 34

[ p-( cyklopropyl- 3'- 3'- hydroksy) propyl]- 1- fenoksy- isopropylamino-j- propanol- 2 [ p-( cyclopropyl- 3'- 3'- hydroxy) propyl]- 1- phenoxy- isopropylamino-j- propanol- 2

Formel I, Formula I,

R-^ — H, R2 - H, R^— R-^ — H, R2 - H, R^—

Man oppløser 0,05[p-(cyklopropyl-3'-3'-okso)propyl]-1-fenoksy-isopropylamino-3-propanol-2: 0.05[p-(cyclopropyl-3'-3'-oxo)propyl]-1-phenoxy-isopropylamino-3-propanol-2 is dissolved:

Formel I, R-j^ — H, R2— H, R^— Y = 0 3 3 ' i 100 cm metanol. Man tilsetter 10 cm vann og deretter, under røring, i små porsjoner, 0,06 mol kaiiumborhydrid, og man lar blandingen bli omrørt i 6 timer. Man fordamper metanolen under vakuum, tar opp blandingen med 100 cm vann og 4 cm konsentrert natriumkarbonatløsning. Man ekstraherer med eter, vasker med vann, tørker den organiske fase og fordamper eteren under vakuum. Formula I, R-j^ — H, R 2 — H, R^ — Y = 0 3 3 ' in 100 cm of methanol. 10 cm of water is added and then, while stirring, in small portions, 0.06 mol of calcium borohydride, and the mixture is allowed to stir for 6 hours. The methanol is evaporated under vacuum, the mixture is taken up with 100 cm of water and 4 cm of concentrated sodium carbonate solution. Extract with ether, wash with water, dry the organic phase and evaporate the ether under vacuum.

Fremstilling av oksalatetPreparation of the oxalate

Inndampni. ngsresten (13,9 g)tas opp med 150 cm<3>etylacetat. Den således oppnådde løsning tilsettes til en løsning, av 0,05 mol oksalsyre i 75 cm 3aceton. Man lar blandingen henstå natten over, filtrerer den, vasker med etylacetat.og tørker for oppnåelse av 15,3 g oksalat av det ønskede produkt, smp. 121°C. Evaporation rate. The residue (13.9 g) is taken up with 150 cm<3>ethyl acetate. The solution thus obtained is added to a solution of 0.05 mol of oxalic acid in 75 cm 3 of acetone. The mixture is allowed to stand overnight, filtered, washed with ethyl acetate and dried to obtain 15.3 g of oxalate of the desired product, m.p. 121°C.

Eksempel 35 Example 35

[ p-( cyklopropyl- 3'- 3'- hydroksy) propyl]- 1- fenoksy- tert.- butylamino-3- propanol- 2 [ p-( cyclopropyl- 3'- 3'- hydroxy) propyl]- 1- phenoxy- tert.- butylamino-3- propanol- 2

Formel I, Formula I,

R-^ — H', R2— H , R^ R-^ — H', R2 — H , R^

Man går frem.på samme måte som i eksempel 34, men You proceed in the same way as in example 34, but

med 0,05 mol [p-(cyklopropyl-3'-3'-okso)propyl]-1-fenoksy-tert.-butylamino-3-propanol-2 with 0.05 mol [p-(cyclopropyl-3'-3'-oxo)propyl]-1-phenoxy-tert-butylamino-3-propanol-2

Formel I, Formula I,

R^ — H, R2— H, R^—H, R2—H,

, Y = 0 , Y = 0

og.0,06 mol kaliumborhydrid.and.0.06 mole of potassium borohydride.

Fremstilling av maleatetPreparation of the maleate

3 Inndampningsresten (15,2 g) tas opp i 80 cm etylacetat. Til den således oppnådde løsning tilsetter man en løsning av 0,05 mol malemsyre i 120 cm 3 etylacetat. Man lar blandingen henstå natten over, avsuger den, vasker med etylacetat og tørker, for oppnåelse av 14,8 g av maleatet av det ønskede produkt, smp. = 139°C. 3 The evaporation residue (15.2 g) is taken up in 80 cm ethyl acetate. A solution of 0.05 mol of maleic acid in 120 cm 3 of ethyl acetate is added to the solution thus obtained. The mixture is allowed to stand overnight, filtered off with suction, washed with ethyl acetate and dried to obtain 14.8 g of the maleate of the desired product, m.p. = 139°C.

Eksempel 36 Example 36

[ p-( cyklopropyl- 3'- 3'- hydroksy) propyl- o- metoksy]- 1- fenoksy-tert .- butylamino- 3- propanol- 2 [ p-( cyclopropyl- 3'- 3'- hydroxy) propyl- o- methoxy]- 1- phenoxy-tert.- butylamino- 3- propanol- 2

Formel I, Formula I,

Rj^ — OCHj , R2 — H, R^ — Man går frem på samme måte som i eksempel 34, mén med"0,05 mol [p-(cyklopropyl-3'-3'-okso)propyl-o-metoksy]fenoksy-1-tert,-butylamino-3-propanol-2 Formel I, R-^— OCH3 , R2 — H, ^3— Rj^ — OCHj , R2 — H, R^ — One proceeds in the same way as in example 34, except with "0.05 mol [p-(cyclopropyl-3'-3'-oxo)propyl-o-methoxy] phenoxy-1-tert,-butylamino-3-propanol-2 Formula I, R-^— OCH3 , R2 — H, ^3—

, Y - 0 , Y - 0

og 0,06 mol kaliumborhydrid.and 0.06 mole of potassium borohydride.

Fremstilling av nøytralt suksinat Preparation of neutral succinate

Inndampni. ngsresten (16,1 g) tas opp med 50 cm 3isopropanol. Den således oppnådde løsning tilsettes en varm løsning av 0,025 mol ravsyre i llo cm 3 isopropanol. Man lar blandingen henstå natten over, filtrerer den, vasker med isopropanol og tørker for oppnåelse av 13 g nøytralt suksinat av det ønskede produkt, smp. - 166°C. Evaporation rate. The residue (16.1 g) is taken up with 50 cm 3 of isopropanol. A hot solution of 0.025 mol of succinic acid in 10 cm 3 of isopropanol is added to the solution thus obtained. The mixture is allowed to stand overnight, filtered, washed with isopropanol and dried to obtain 13 g of neutral succinate of the desired product, m.p. - 166°C.

Eksempel 37 Example 37

.[ p-( hydroksy- 3') butyl]- 1- fenoksy- tert.- butylamino- 3- propanol- 2 .[ p-(hydroxy- 3') butyl]- 1- phenoxy- tert.- butylamino- 3- propanol- 2

Formel I, Formula I,

Y H OH " \ / Rx = H, R2 = H, R3 = CH3, -C- er -C Man går frem på samme måte som i eksempel 34, men med 0,05 mol [p-(okso-3']butyl]-1-fenoksy-tert.-butylåmino-3-propanol-2 Formel I, Y H OH " \ / Rx = H, R2 = H, R3 = CH3, -C- is -C Proceed in the same way as in example 34, but with 0.05 mol [p-(oxo-3']butyl ]-1-phenoxy-tert-butylamino-3-propanol-2 Formula I,

R-j^ — H, R2— H, R3 — ' ^ — ^ R-j^ — H, R2— H, R3 — ' ^ — ^

og 0 ,06 mol kaliumborhydrat.and 0.06 mole of potassium borohydrate.

Fremstilling av maleatetPreparation of the maleate

Inndampningsresten (14,1 g) tas opp i 80 cm<3>etylacetat. The evaporation residue (14.1 g) is taken up in 80 cm<3>ethyl acetate.

Til den således oppnådde løsning tilsetter man en løsning av 0,05 mol maleinsyre i 120 cm' 3 etylacetat. Man lar blandingen henståo natten over, avsuger den, vasker med etylacetat og tørker for oppnåelse av 13,4 g av maleatet av det ønskede produkt, smp. = 133°C. A solution of 0.05 mol of maleic acid in 120 cm' 3 of ethyl acetate is added to the solution thus obtained. The mixture is allowed to stand overnight, filtered off with suction, washed with ethyl acetate and dried to obtain 13.4 g of the maleate of the desired product, m.p. = 133°C.

De farmakologiske egenskaper for forbindelsene som fremstilles i henhold til oppfinnelsen, er vist ved følgende forsøk. The pharmacological properties of the compounds produced according to the invention are shown by the following experiments.

I - KARDIOVASKULÆR HEMODYNAMIKK HOS HUNDERI - CARDIOVASCULAR HEMODYNAMICS IN DOGS

A) RIKTIG OPPTREDENA) PROPER CONDUCT

MetodeMethod

Hunder av blandingskull, hanner eller hunner, bedøves med natrium-mebubarbital (30 mg/kg I.V.) og ventileres kunstig med en Pesty-pumpe RPP. De suppleres med oksygen. Man måler: det systoliske (P.A. syst.) . og diastoliske (P.A.Diast.) trykk i halspulsåren; - hjertefrekvensen (F.C.) ; Mixed litter dogs, male or female, are anesthetized with sodium mebubarbital (30 mg/kg I.V.) and artificially ventilated with a Pesty pump RPP. They are supplemented with oxygen. One measures: the systolic (P.A. syst.) . and diastolic (P.A.Diast.) pressure in the carotid artery; - the heart rate (F.C.);

den sammentrekkbare kraft i hjertemuskelen.(F.Co). the contractile force in the heart muscle. (F.Co).

Signalene forsterkes og registreres på Beckman Dynograph. The signals are amplified and recorded on the Beckman Dynograph.

Man beregner: det gjennomsnittlige arterietrykk (<p>.A. gj.sn.) = diastolisk trykk + 0,43 (systolisk trykk - diastolisk trykk). One calculates: the average arterial pressure (<p>.A. average) = diastolic pressure + 0.43 (systolic pressure - diastolic Print).

Produktene fra eksemplene injiseres i modervenen,The products from the examples are injected into the parent vein,

i doser på 0,125. 0,50, 2 og 4 mg/kg, oppløst.i en 9 °/oo vandig løsning av natriumklorid. in doses of 0.125. 0.50, 2 and 4 mg/kg, dissolved in a 9 °/oo aqueous solution of sodium chloride.

ResultaterResults

Tabell I nedenunder viser gjennomsnittet av de oppnådde resultater i prosent variasjon i forhold til den opprinnelige ver-di for de forskjellige hjerteparametere som er studert, for hvert eksempel. Table I below shows the average of the results obtained in percent variation in relation to the original value for the various heart parameters that have been studied, for each example.

B) / ?- BLOKKERENDE VIRKNINGB) / ?- BLOCKING EFFECT

Metode.Method.

Den/J-blokkerende adrenergiske aktivitet for produktene fra de forskjellige eksempler er studert hos de samme hunder, i forhold til effektene/31 og ( 32 av isoprenalin. The /J-blocking adrenergic activity of the products of the various examples has been studied in the same dogs, in relation to the effects /31 and (32) of isoprenaline.

Man beregner prosent inhibering av effektene /3 1 og 2 av isoprenalin. The percent inhibition of the effects /3 1 and 2 of isoprenaline is calculated.

Man beregner prosent inhibering av effektene 1 (for-sterkning av den myokardiske sammentrekkbare kraft) og effektene/3 2 (nedsettelse av det diastoliske arterietrykk) for isoprenalin, i funksjon av doser (mg/kg I.V.) av produkter fra de forskjellige eksempler. One calculates the percent inhibition of the effects 1 (strengthening of the myocardial contractile force) and the effects /3 2 (reduction of the diastolic arterial pressure) for isoprenaline, as a function of doses (mg/kg I.V.) of products from the various examples.

ResultaterResults

Tabellene II og III viser gjennomsnittet av prosent inhibering av effektene/3 1 og/? 2 av isoprenalin for produktene fra de forskjellige eksempler. Tables II and III show the average percentage inhibition of the effects /3 1 and/? 2 of isoprenaline for the products from the various examples.

II - . TOKSISITET II - . TOXICITY

Den dødelige dose 50 for rotter, av produkter fra de forskjellige eksempler, ligger på mellom 64 og 256 mg/kg. Disse produkter er administrert.ad intraperitoneal vei. The lethal dose 50 for rats, of products from the various examples, is between 64 and 256 mg/kg. These products are administered intraperitoneally.

Som konklusjon kan sies at produktene fra eksemplene viser en/31-blokkerende aktivitet , og kan administreres som tera-peutikum for bryst-angina og forhøyet blodtrykk i daglige orale doser av 100 til 400 mg, eller intravenøst med 25 til 100 mg. In conclusion, it can be said that the products of the examples show a/31-blocking activity, and can be administered as a therapeutic for angina pectoris and elevated blood pressure in daily oral doses of 100 to 400 mg, or intravenously with 25 to 100 mg.

Claims (2)

1. Fremgangsmåte for fremstilling av l-aryloksy-3-amino- . propanol-2-derivater av den generelle formel: 1. Process for the production of 1-aryloxy-3-amino-. propanol-2 derivatives of the general formula: hvor: Y ■i-C- betyr grupperinger where: Y ■i-C- means groupings er et hydrogen- eller halogenatom, et lavere alkoksyradikal eller allylradikalet> 1*2 er et hydrogenatom eller et lavere alkylradikal; R- er et lavere alkylradikal, rettkjedet eller forgrenet, eller et cyklopropylradikal; R er et lavere alkylradikal med forgrenet kjede, eller cyklopropyl- eller cyklopropylmetylradikalet , eller et/ 3-aryl-etylradikal som eventuelt er substituert; idet betegnelsen"lavere alkyl",betyr et radikal med 1-4 karbonatomer; samt de ikke-toksiske, farmasøytisk akseptable syreaddisjbnssalter av de nevnte forbindelser, karakterisert ved at man omsetter et epoksyd med formelen: is a hydrogen or halogen atom, a lower alkoxy radical or the allyl radical> 1*2 is a hydrogen atom or a lower alkyl radical; R- is a lower alkyl radical, straight chain or branched, or a cyclopropyl radical; R is a lower alkyl radical with a branched chain, or the cyclopropyl or cyclopropylmethyl radical, or an optionally substituted et/3-aryl-ethyl radical; wherein the term "lower alkyl" means a radical with 1-4 carbon atoms; as well as the non-toxic, pharmaceutically acceptable acid addition salts of the aforementioned compounds, characterized by reacting an epoxide with the formula: med et amin RNI^, hvor R, R^ , R2 , R3 og Y er som definert ovenfor, idet reaksjonen utføres ved at man som løsningsmiddel anvender et overskudd av aminet RNH., eller en lavere alkanol, hvoretter man isolerer det ønskede produkt og eventuelt omdan-ner .det til et ikke-toksisk syreaddisjonssalt på i og for seg kjent måte.with an amine RNI^, where R, R^, R2, R3 and Y are as defined above, the reaction being carried out by using as solvent uses an excess of the amine RNH., or a lower alkanol, after which the desired product is isolated and optionally converted into a non-toxic acid addition salt in a manner known per se. 2. Fremgangsmåte for fremstilling av l-aryloksy-3-amino-propanol-2-derivatér med den generelle formel: 2. Process for the production of 1-aryloxy-3-amino-propanol-2-derivatives with the general formula: hvor er et hydrogen- eller halogenatom eller et lavere alkoksyradikal, eller allylradikalet; R^ er et hydrogenatom eller et lavere alkylradikal; R3 er et lavere alkylradikal, rettkjedet eller forgrenet, eller et cyklopropylradikal; R er et lavere alkylradikal med forgrenet kjede eller cyklopropylradikalet eller cyklopropylmetylradikalet eller et/ 3-aryletylradikal som eventuelt er substituert; idet betegnelsen "lavere alkyl" betyr et radikal med 1-4 karbonatomer, så vel som de ikke-toksiske, farmasøytisk akseptable syreaddisjonssalter av disse forbindelser, karakterisert ved at man reduserer et tilsvarende keton: where is a hydrogen or halogen atom or a lower alkoxy radical, or the allyl radical; R 1 is a hydrogen atom or a lower alkyl radical; R 3 is a lower alkyl radical, straight chain or branched, or a cyclopropyl radical; R is a lower alkyl radical with a branched chain or the cyclopropyl radical or the cyclopropylmethyl radical or an optionally substituted et/3-arylethyl radical; wherein the term "lower alkyl" means a radical of 1-4 carbon atoms, as well as the non-toxic, pharmaceutically acceptable acid addition salts of these compounds, characterized by reducing a corresponding ketone: ved hjelp av et alkalisk borhydrid i hydroalkoholisk miljø.using an alkaline borohydride in a hydroalcoholic environment.
NO772887A 1976-08-21 1977-08-19 PROCEDURE FOR PREPARATION OF 1-ARYLOXY-3-AMINO-PROPANE-2-OL DERIVATIVES NO772887L (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK154208B (en) * 1980-06-02 1988-10-24 Du Pont METHOD OF ANALOGUE FOR PREPARING P-SUBSTITUTED 3-PHENOXY-1-ALKYLAMINOPROPANOLS OR THERAPEUTIC ACCEPTABLE SALTS THEREOF

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* Cited by examiner, † Cited by third party
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SE8004088L (en) * 1980-06-02 1981-12-03 Haessle Ab NEW SUBSTITUTED 3-PHENOXI-L-ALCOXICARBONYLALKYLAMINO-PROPANOL-2 WITH BETA-RECEPTOR BLOCKING PROPERTIES AND PROCEDURE FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS OF THE METHOD
ATE72562T1 (en) * 1987-06-23 1992-02-15 Helopharm Petrik Co Kg AMINOPROPANOL DERIVATIVES OF 3-(2-HYDROXYPHENYL)-1-PROPANONE COMPOUNDS, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICALS CONTAINING THESE COMPOUNDS.
EP0296264A1 (en) * 1987-06-23 1988-12-28 Helopharm W. Petrik GmbH &amp; Co.KG. Aminopropanol derivatives of 3-(2-hydroxyphenyl)-1-propanone, process for their preparation and medicines containing these compounds
EP0296265A1 (en) * 1987-06-23 1988-12-28 Helopharm W. Petrik GmbH &amp; Co.KG. Aminopropanol derivatives of 3-(3-hydroxyphenyl)-1-propanone, process for their preparation and medicines containing these compounds

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK154208B (en) * 1980-06-02 1988-10-24 Du Pont METHOD OF ANALOGUE FOR PREPARING P-SUBSTITUTED 3-PHENOXY-1-ALKYLAMINOPROPANOLS OR THERAPEUTIC ACCEPTABLE SALTS THEREOF

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DE2736106A1 (en) 1978-02-23
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PT66890A (en) 1977-09-01
PT66890B (en) 1979-01-25
DK368877A (en) 1978-02-22
FR2362115A1 (en) 1978-03-17
NL7708845A (en) 1978-02-23
DD132431A5 (en) 1978-09-27
ES461779A1 (en) 1978-12-16

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