NO148997B - PROCEDURE FOR THE PREPARATION OF PHENYLETANOLAMINES - Google Patents

PROCEDURE FOR THE PREPARATION OF PHENYLETANOLAMINES Download PDF

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NO148997B
NO148997B NO823159A NO823159A NO148997B NO 148997 B NO148997 B NO 148997B NO 823159 A NO823159 A NO 823159A NO 823159 A NO823159 A NO 823159A NO 148997 B NO148997 B NO 148997B
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general formula
amino
acid
tert
phenyl
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NO823159A
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Norwegian (no)
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NO148997C (en
NO823159L (en
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Jarkko Ruohonen
Kauko Nieminen
Johannes Keck
Gerd Krueger
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Thomae Gmbh Dr K
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Priority claimed from FI790067A external-priority patent/FI59396C/en
Priority claimed from DE19792942723 external-priority patent/DE2942723A1/en
Publication of NO823159L publication Critical patent/NO823159L/en
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Publication of NO148997B publication Critical patent/NO148997B/en
Publication of NO148997C publication Critical patent/NO148997C/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups

Description

Denne oppfinnelse angår en ny fremgangsmåte for fremstilling av fenyletanolaminer med den generelle formel This invention relates to a new process for the production of phenylethanolamines with the general formula

som er i besittelse av verdifulle, farmakologiske egenskaper, særlig bronkolytiske virkninger. which possesses valuable pharmacological properties, particularly broncholytic effects.

I den ovenstående generelle formel I betyr In the above general formula I means

et klor- eller bromatom, a chlorine or bromine atom,

1*2 en trifluormetylgruppe, et fluor- eller kloratom, og R^ en forgrenet alkylrest eller en cykloalkylgruppe med hver 1*2 a trifluoromethyl group, a fluorine or chlorine atom, and R^ a branched alkyl radical or a cycloalkyl group with each

3 til 5 karbonatomer. 3 to 5 carbon atoms.

Blant de innledningsvis angitte betydninger ved defini-sjonen av resten R^ kommer særlig i betraktning en isopropyl-, isobutyl-, tert.butyl-, isopentyl-, neopentyl-, tert.pentyl-, cyklopropyl-, cyklobutyl- eller cyklopentyl-gruppe. Among the initially stated meanings in the definition of the radical R 1 , an isopropyl, isobutyl, tert.butyl, isopentyl, neopentyl, tert.pentyl, cyclopropyl, cyclobutyl or cyclopentyl group comes into consideration in particular.

I henhold til oppfinnelsen fremstilles fenyletanolaminene med den generelle formel I ved omsetning av et 4-amino-benzaldehyd med den generelle formel According to the invention, the phenylethanolamines with the general formula I are prepared by reacting a 4-amino-benzaldehyde with the general formula

hvor R^ og R2 er som innledningsvis angitt, med et isonitril med den generelle formel hvor R^ er som innledningsvis angitt, og med en karboksylsyre med den generelle formel where R 1 and R 2 are as initially indicated, with an isonitrile of the general formula where R 2 is as initially indicated, and with a carboxylic acid of the general formula

hvor R 4 er en acylrest av en karboksylsyre, where R 4 is an acyl residue of a carboxylic acid,

og reduksjon av et således erholdt a-acyloksy-acetamid med den generelle formel and reduction of an α-acyloxy-acetamide thus obtained with the general formula

hvor R-^ til R^ er som ovenfor angitt, med et hydrid, f.eks. where R-^ to R^ are as indicated above, with a hydride, e.g.

med et metallhydrid eller et komplekst metallhydrid. with a metal hydride or a complex metal hydride.

Blant de innledningsvis angitte betydninger for resten Among the initially stated meanings for the rest

R^ kommer særlig i betraktning en acylrest av en alifatisk R 1 comes into consideration in particular an acyl residue of an aliphatic

eller aromatisk karboksylsyre så som eddiksyre, propionsyre, trimetyleddiksyre, valeriansyre, benzoesyre, nitrobenzoesyre eller naftalen-2-karboksylsyre. or aromatic carboxylic acid such as acetic acid, propionic acid, trimethylacetic acid, valerian acid, benzoic acid, nitrobenzoic acid or naphthalene-2-carboxylic acid.

Omsetningen av et 4-amino-benzaldehyd med den generelle formel II med et isonitril med den generelle formel III og med en karboksylsyre med den generelle formel IV fo"retas hensiktsmessig i et egnet oppløsningsmiddel så som metylenklorid, kloroform, benzen, eter, tetrahydrofuran eller dioksan, ved lavere temperaturer, f.eks. ved temperaturer mellom -20 og 7 5°C, hensiktsmessig ved romtemperatur. Omsetningen utføres fortrinnsvis slik at under omrøring og ved romtemperatur tilsettes dråpevis enten samtidig fra hver sin dråpetrakt, en forbindelse med den generelle formel III og en karboksylsyre med den generelle formel IV til en oppløsning av et aldehyd med den generelle formel II, eller en karboksylsyre med den generelle formel IV til en oppløsning av et isonitril med den generelle formel III og et aldehyd med den generelle formel II, The reaction of a 4-amino-benzaldehyde of the general formula II with an isonitrile of the general formula III and with a carboxylic acid of the general formula IV is conveniently carried out in a suitable solvent such as methylene chloride, chloroform, benzene, ether, tetrahydrofuran or dioxane, at lower temperatures, e.g. at temperatures between -20 and 75°C, suitably at room temperature. The reaction is preferably carried out so that while stirring and at room temperature, a compound with the general formula is added dropwise or simultaneously from each drop funnel III and a carboxylic acid of the general formula IV to a solution of an aldehyde of the general formula II, or a carboxylic acid of the general formula IV to a solution of an isonitrile of the general formula III and an aldehyde of the general formula II,

i løpet av flere timer, f.eks. 5-10 timer, og derefter omrøres i 10 til 165 timer. during several hours, e.g. 5-10 hours, and then stirred for 10 to 165 hours.

Reduksjonen av et erholdt a-acyloksy-acetamid med den. generelle formel V med et hydrid foretas fortrinnsvis i et egnet oppløsningsmiddel så som eter, tetrahydrofuran eller dioksan ved lavere eller svakt forhøyede temperaturer, f.eks. ved temperaturer mellom 0 og 100°C, hensiktsmessig ved reaksjons-blandingens koketemperatur. Særlig fordelaktig utføres imidlertid denne reduksjon med boran/tetrahydrofuran ved koke-temperaturen for det som oppløsningsmiddel anvendte tetrahydrofuran. The reduction of an obtained α-acyloxy-acetamide with it. general formula V with a hydride is preferably carried out in a suitable solvent such as ether, tetrahydrofuran or dioxane at lower or slightly elevated temperatures, e.g. at temperatures between 0 and 100°C, suitably at the boiling temperature of the reaction mixture. Particularly advantageously, however, this reduction is carried out with borane/tetrahydrofuran at the boiling temperature of the tetrahydrofuran used as solvent.

Isoleringen av det ønskede sluttprodukt med den generelle formel I foretas hensiktsmessig over vandige baser, f.eks. over vann/ammoniakk, hvorved en eventuelt ennu tilstedeværende a-acyloksygruppe avspaltes. The isolation of the desired end product with the general formula I is conveniently carried out over aqueous bases, e.g. over water/ammonia, whereby a possibly still present α-acyloxy group is split off.

Et således erholdt fenyletanolamin med den generelle formel I kan eventuelt derefter overføres med en uorganisk eller organisk syre til sitt fysiologisk forlikelige syreaddisjonssalt med vedkommende syre. Som syrer kan f.eks. anvendes saltsyre, bromhydrogensyre, svovelsyre, fosforsyre, melkesyre, vinsyre, sitronsyre , f umarsyre. eller, maleinsyre . A phenylethanolamine of the general formula I thus obtained can optionally then be transferred with an inorganic or organic acid to its physiologically compatible acid addition salt with the acid in question. As acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, tartaric acid, citric acid, fumaric acid are used. or, maleic acid.

De som utgangsstoffer anvendte forbindelser med de generelle formler III og IV er kj.ent fra litteraturen. The compounds with the general formulas III and IV used as starting materials are known from the literature.

Et som utgangsstoff anvendt aldehyd med den generelle formel II får man f.eks. ved reduksjon av et tilsvarende 4-amino-benzo.esyrehalogenid eller -ester og påfølgende oksydasjon av den eventuelt erholdte benzylalkohol med brunsten. An aldehyde with the general formula II used as a starting material gives, for example, by reduction of a corresponding 4-amino-benzoic acid halide or ester and subsequent oxidation of the possibly obtained benzyl alcohol with the tan.

Fra litteraturen er det tidligere kjent en fremgangsmåte for fremstilling av fenyletanolaminene méd den generelle formel I, som kjennetegnes ved at et glykolsyreamid med den generelle formel A method for the preparation of the phenylethanolamines with the general formula I is previously known from the literature, which is characterized by the fact that a glycolic acid amide with the general formula

hvor R^, R2 og R^ er som ovenfor angitt, reduseres med et komplekst metallhydrid. where R 1 , R 2 and R 2 are as indicated above, is reduced with a complex metal hydride.

Denne fremgangsmåte oppviser imidlertid den ulempe at However, this method has the disadvantage that

de som utgangsstoffer nødvendige glykolsyreamider er vanskelige å fremstille. the glycolic acid amides required as starting materials are difficult to produce.

De gode utbytter som oppnås ved fremgangsmåten ifølge oppfinnelsen, kunne ikke forutsees av en fagmann, eftersom det er kjent fra litteraturen (se J. Amer. Chem. Soc. 67, 1499-1500 (1945)), at Passerini-reaksjonen ikke kan gjennom-føres med sterisk hindrede og med a, |3-umettede karbonyl-forbindelser. Her forklares den manglende reaktivitet hos a, (3-umettede karbonylf orbindelser , f.eks. av krotonaldehyd , The good yields obtained by the process according to the invention could not be predicted by a person skilled in the art, since it is known from the literature (see J. Amer. Chem. Soc. 67, 1499-1500 (1945)) that the Passerini reaction cannot go through - is carried out with sterically hindered and with a, |3-unsaturated carbonyl compounds. Here is explained the lack of reactivity of a, (3-unsaturated carbonyl compounds, e.g. of crotonaldehyde,

i forhold til Passerini-reaksjonen ved nøytralisering av det elektroniske sentrum av karbonylfunksjonen på grunn av de mesomere grensestrukturer in relation to the Passerini reaction by neutralization of the electronic center of the carbonyl function due to the mesomeric boundary structures

altså på grunn av den elektronavgivende virkning hos en nabo-gruppe. that is, due to the electron-donating effect of a neighboring group.

Videre er det kjent at aminogruppen i o- eller p-stilling i en fenylkjerne har en sterk elektronavgivende virkning. Furthermore, it is known that the amino group in the o- or p-position in a phenyl nucleus has a strong electron-donating effect.

En fagmann måtte således vente at det elektroniske sentrum i karbonylfunksjonen i et 4-amino-benzaldehyd med den generelle formel II, på grunn av den mesomere grensestruktur med den generelle formel A person skilled in the art would thus have to expect that the electronic center in the carbonyl function of a 4-amino-benzaldehyde of the general formula II, due to the mesomeric boundary structure of the general formula

deaktiveres og at Passerini-reaksjonen således ikke er til-gjengelig. Overraskende er det funnet at dette ikke er tilfelle. is deactivated and that the Passerini reaction is thus not available. Surprisingly, it has been found that this is not the case.

De følgende eksempler skal illustrere oppfinnelsen ytterligere. The following examples shall further illustrate the invention.

Eksempel 1 Example 1

g- acetoksy- g-( 4- amino- 3, 5- diklor- fenyl)- N- tert. butyl- acetamid g- acetoxy- g-(4- amino- 3, 5- dichloro- phenyl)- N- tert. butyl acetamide

Til en oppløsning av 3,8 g (0,02 mol) 4-amino-3,5-diklor-benzaldehyd i 50 ml absolutt metylenklorid setter man dråpevis under omrøring ved romtemperatur 3,32 g (0,04 mol) tert.butyl-isonitril og 4,8 g (0,08 mol) iseddik fra to adskilte dråpe-trakter med samme hastighet i løpet av 8 timer. Derefter inndampes den erholdte oppløsning til halvt volum og avkjøles. Det herved utfelte, uomsatte 4-amino-3,5-diklorbenzaldehyd avsuges, og filtratet inndampes påny til h"alvt volum. Til den erholdte blanding setter man det samme volum diisopropyleter, hvorved det ønskede produkt utkrystalliserer, avsuges og vaskes med diisopropyleter. To a solution of 3.8 g (0.02 mol) 4-amino-3,5-dichloro-benzaldehyde in 50 ml absolute methylene chloride, 3.32 g (0.04 mol) tert-butyl is added dropwise while stirring at room temperature -isonitrile and 4.8 g (0.08 mol) glacial acetic acid from two separate dropping funnels at the same rate during 8 hours. The resulting solution is then evaporated to half volume and cooled. The thus precipitated, unreacted 4-amino-3,5-dichlorobenzaldehyde is filtered off with suction, and the filtrate is evaporated again to half the volume. To the resulting mixture is added the same volume of diisopropyl ether, whereby the desired product crystallizes out, is filtered off and washed with diisopropyl ether.

Smeltepunkta 175-176°C. Melting point 175-176°C.

Eksempel 2 Example 2

g- acetoksy- g-( 4- amino- 3, 5- diklor- fenyl)- N- tert. butyl- acetamid g- acetoxy- g-(4- amino- 3, 5- dichloro- phenyl)- N- tert. butyl acetamide

Til en oppløsning av 30 g (0,16 mol) 4-amino-3,5-diklor-benzaldehyd i 280 ml metylenklorid settes 45 ml tert.butyl-isocyanid og derefter dråpevis under omrøring og ved romtemperatur ca. 40 ml iseddik i løpet av 16 timer. Derefter omrører man i ytterligere 4 timer og inndamper i vakuum inntil de første krystaller faller ut. - Efter avkjøling- til 0°C avsuges det utfelte, uomsatte 4-amino-3,5-diklorbenzaldehyd. Dette kan omsettes direkte påny. Filtratet tilsettes n-heksan, hvorved det ønskede produkt utfelles. Bunnfallet avsuges, vaskes med n-heksan og tørres. To a solution of 30 g (0.16 mol) 4-amino-3,5-dichloro-benzaldehyde in 280 ml of methylene chloride is added 45 ml of tert-butyl isocyanide and then dropwise with stirring and at room temperature approx. 40 ml of glacial acetic acid within 16 hours. The mixture is then stirred for a further 4 hours and evaporated in vacuo until the first crystals fall out. - After cooling to 0°C, the precipitated, unreacted 4-amino-3,5-dichlorobenzaldehyde is suctioned off. This can be traded directly again. n-hexane is added to the filtrate, whereby the desired product is precipitated. The precipitate is filtered off, washed with n-hexane and dried.

Smeltepunkt: 175-176°C. Melting point: 175-176°C.

Eksempel 3 Example 3

1-( 4- amino- 3, 5- diklor- fenyl)- 2- tert. butylamino- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-tert. butylamino-ethanol

Til en oppløsning av 4,01 g g<->acetoksy-g<->(4~amino-3,5-diklorfenyl)-N-tert.butyl-acetamid i 50 ml absolutt tetrahydrofuran settes 100 ml av en 1 molar oppløsning av boran i tetrahydrofuran. Efter 2 timers omrøring under tilbakeløpskjøling foretas inndampning, 100 ml vann tilsettes, og blandingen sur-gjøres med saltsyre til pH 2. Den vandige fase vaskes med etyl-acetat, gjøres derefter alkalisk med ammoniakk og ekstraheres med metylenklorid. Efter inndampning av den^organiske fase får man hydrokloridet fra isopropanol ved tilsetning av eterisk saltsyre. 100 ml of a 1 molar solution of borane in tetrahydrofuran. After stirring for 2 hours under reflux, evaporation is carried out, 100 ml of water is added, and the mixture is acidified with hydrochloric acid to pH 2. The aqueous phase is washed with ethyl acetate, then made alkaline with ammonia and extracted with methylene chloride. After evaporation of the organic phase, the hydrochloride is obtained from isopropanol by adding ethereal hydrochloric acid.

Smeltepunkt for hydrokloridet: 174-175°C. Melting point for the hydrochloride: 174-175°C.

Eksempel 4 Example 4

g- acetoksy- g- ( 4- amino- 3- klor- 5- trifluormety1- fenyl)- eddiksyre-tert. butylamid g-acetoxy-g-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-acetic acid-tert. butylamide

Til en oppløsning av 4,47 g (20 mmol) 4-amirio-3-klor-5-trifluormetyl-benzaldehyd i 50 ml metylenklorid settes dråpevis ved romtemperatur under omrøring 3,32 g (40 mmol) tert.butyl-isonitril og 4,8 g (80 mmol) iseddik samtidig i løpet av 5 timer, og derefter omrøres blandingen i 65 timer ved romtemperatur. Efter fjernelse av oppløsningsmidlet i vakuum, oppløses residuet i eter, vaskes med vann og derefter med en mettet natriumbikarbonatoppløsning, tørres over magnesiumsulfat og inndampes til tørrhet i vakuum. Residuet kromatograferer man over en silikagelkolonne med metylenklorid som eluerings-middel. Fraksjonene som inneholder den ønskede forbindelse, samles, inndampes, og residuet krystalliseres fra eter. Smeltepunkt: 155-156°C. To a solution of 4.47 g (20 mmol) 4-amirio-3-chloro-5-trifluoromethyl-benzaldehyde in 50 ml methylene chloride is added dropwise at room temperature with stirring 3.32 g (40 mmol) tert-butyl isonitrile and 4 .8 g (80 mmol) of glacial acetic acid at the same time during 5 hours, and then the mixture is stirred for 65 hours at room temperature. After removal of the solvent in vacuo, the residue is dissolved in ether, washed with water and then with a saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed over a silica gel column with methylene chloride as eluent. The fractions containing the desired compound are collected, evaporated, and the residue crystallized from ether. Melting point: 155-156°C.

Eksempel 5 Example 5

1-( 4- amino- 3- klor- 5- trifluormety1- fenyl)- 2- tert. butylamino-etanol- hydroklorid 1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2- tert. butylaminoethanol hydrochloride

2 g (5,4 mmol) g<->acetoksy-g<->(4-amino-3-klor-5-trifluor-metylfenyl)-eddiksyre-tert.butylamid oppløses i 15 ml absolutt tetrahydrof.uran og settes i én porsjon under nitrogen til 27 ml av en 1 molar oppløsning av boran i tetrahydrofuran. Efter 4 timers kokning under tilbakeløpskjøling tilsetter man ytterligere 15 ml 1 molar boranoppløsning og oppvarmer videre i 2 timer under tilbakeløpskjøling. Derefter ødelegges over-skuddet av boran med aceton, borkomplekset spaltes med vann, og derefter.avdampes oppløsningsmidlet i vakuum. Den vandige destillasjonsrest surgjøres med 2N saltsyre til pH 1, gjøres igjen alkalisk med ammoniakk og ekstraheres med eter. Eter-ekstraktén ekstraheres med 0,5N saltsyre-, den sure oppløsning vaskes med eter, gjøres alkalisk med ammoniakk og' ekstraheres påny med eter. Eterekstrakten vaskes med vann", tørres med magnesiumsulfat og inndampes i vakuum. Det oljeaktige inn-dampningsresiduum oppløses i eter og surgjøres med eterisk saltsyre. De utfelte krystaller avsuges og vaskes med eter. Smeltepunkt: 192-19 3°C. 2 g (5.4 mmol) g<->acetoxy-g<->(4-amino-3-chloro-5-trifluoromethylphenyl)-acetic acid tert-butylamide are dissolved in 15 ml of absolute tetrahydrofuran and placed in one portion under nitrogen to 27 ml of a 1 molar solution of borane in tetrahydrofuran. After 4 hours of boiling under reflux cooling, a further 15 ml of 1 molar borane solution is added and further heated for 2 hours under reflux cooling. The excess of borane is then destroyed with acetone, the boron complex is cleaved with water, and then the solvent is evaporated in vacuo. The aqueous distillation residue is acidified with 2N hydrochloric acid to pH 1, made alkaline again with ammonia and extracted with ether. The ether extract is extracted with 0.5N hydrochloric acid, the acidic solution is washed with ether, made alkaline with ammonia and extracted again with ether. The ether extract is washed with water", dried with magnesium sulfate and evaporated in vacuo. The oily evaporation residue is dissolved in ether and acidified with ethereal hydrochloric acid. The precipitated crystals are filtered off with suction and washed with ether. Melting point: 192-19 3°C.

Eksempel 6 Example 6

g- acetoksy- g-( 4- amino- 3, 5- diklor- fenyl)- N- tert- butyl- acetamid g- acetoxy- g-(4- amino- 3, 5- dichloro- phenyl)- N- tert- butyl- acetamide

Til en oppløsning av 14,1 g (0,08 mol) 4-amino-3,5-diklor-benzaldehyd i 60 ml metylenklorid settes ved romtemperatur og under omrøring 3,6 g (0,06 mol) eddiksyre og 2,5 g (0,03 mol) tert.butyl-isonitril. Derefter oppvarmes reaksjonsblandingen i 3 timer under tilbakeløpskjøling. Efter at den ovenstående operasjon (tilsetning av eddiksyre, tert.butyl-isonitril og oppvarmning under tilbakeløpskjøling) er gjentatt 4 ganger, heller man reaksjonsblandingen i kald 2N natronlut og fra-skiller den organiske fase. Efter vasking med vann og tørring av den organiske fase over natriumsulfat foretas inndampning i vakuum, og residuet krystalliseres fra metylenklorid/heksan. Smeltepunkt: 175-176°C. 3.6 g (0.06 mol) of acetic acid and 2.5 g (0.03 mol) tert-butyl isonitrile. The reaction mixture is then heated for 3 hours under reflux. After the above operation (addition of acetic acid, tert-butyl isonitrile and heating under reflux) is repeated 4 times, the reaction mixture is poured into cold 2N caustic soda and the organic phase is separated. After washing with water and drying the organic phase over sodium sulphate, evaporation is carried out in vacuo, and the residue is crystallized from methylene chloride/hexane. Melting point: 175-176°C.

Eksempel 7 Example 7

g- ( 4- amino- 3, 5- diklor- feny1)- g- benzoyloksy- N- tert. butyl- acetamid Fremstilles fra 4-amino-3,5-diklor-benzaldehyd, tert.butyl-isonitril og benzoesyre i kloroform og ved tilbakeløpstempératur analogt med eksempel 4. g-( 4- amino- 3, 5- dichloro- phenyl)- g- benzoyloxy- N- tert. butyl acetamide Prepared from 4-amino-3,5-dichloro-benzaldehyde, tert-butyl-isonitrile and benzoic acid in chloroform and at reflux temperature analogously to example 4.

Smeltepunkt: 189-192°C (sintring fra 185°C). Melting point: 189-192°C (sintering from 185°C).

Eksempel 8 Example 8

g-( 4- amino- 3, 5- diklor- feny1)- g- valeroyloksy- N- tert. butyl- acetamid g-(4-amino-3,5-dichloro-phenyl)-g-valeroyloxy-N-tert. butyl acetamide

Fremstilles fra 4-amino-3,5-diklor-benzaldehyd, tert.butyl-isonitril og valeriansyre analogt med eksempel 4. Prepared from 4-amino-3,5-dichloro-benzaldehyde, tert-butyl isonitrile and valeric acid analogously to example 4.

Smeltepunkt: 95-9 8°C. Melting point: 95-98°C.

Eksempel 9 Example 9

1-( 4- amino- 3, 5- diklor- fenyl)- 2- tert. butylamino- etanol 1-(4-amino-3,5-dichloro-phenyl)-2- tert. butylamino-ethanol

Fremstilles fra g<->(4-amino-3,5-diklor-fenyl)-g<->benzoyloksy-N-tert .butyl-acetamid og litiumaluminiumhydrid i tetrahydrofuran analogt med eksempel 3. Smeltepunkt for hydrokloridet: 174-175°C. Prepared from g<->(4-amino-3,5-dichloro-phenyl)-g<->benzoyloxy-N-tert.butyl-acetamide and lithium aluminum hydride in tetrahydrofuran analogously to example 3. Melting point for the hydrochloride: 174-175° C.

Eksempel 10 Example 10

1-( 4- amino- 3, 5- diklor- fenyl)- 2- tert. butylamirio- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-tert. butylamirio-ethanol

Fremstilles fra 4-amino-3,5-diklor-benzaldehyd, tert.butyl-isonitril og valeriansyre analogt med eksempel 2 og 5 uten isolering av det dannede a-(4-amino-3,5-diklorfenyl)-N-tert.-butyl-a-valeroyloksy-acetamid. Prepared from 4-amino-3,5-dichloro-benzaldehyde, tert.butyl-isonitrile and valeric acid analogously to examples 2 and 5 without isolation of the formed a-(4-amino-3,5-dichlorophenyl)-N-tert. -butyl-α-valeroyloxy-acetamide.

Smeltepunkt for hydrokloridet: 174-175°C. Melting point for the hydrochloride: 174-175°C.

Analogt med de ovenstående eksempler ble følgende forbindelser fremstilt: 1-(4-amino-3-brom-5-fluor-fenyl)-2-tert.butylamino-etanol-hydroklorid, Smeltepunkt: 207-208°C, Analogous to the above examples, the following compounds were prepared: 1-(4-amino-3-bromo-5-fluoro-phenyl)-2-tert.butylamino-ethanol hydrochloride, Melting point: 207-208°C,

1-(4-amino-3-klor-5-fluor-fenyl)-2-cyklopropylamino-etanol-vhydroklorid, 1-(4-amino-3-chloro-5-fluoro-phenyl)-2-cyclopropylamino-ethanol vhydrochloride,

Smeltepunkt: 175-177°C, Melting point: 175-177°C,

1-(4-amino~3-klor-5-fluor-fenyl)-2-tert.butylamino-etanol-hydroklorid, 1-(4-amino~3-chloro-5-fluoro-phenyl)-2-tert-butylamino-ethanol hydrochloride,

Smeltepunkt: 206-208°C, Melting point: 206-208°C,

1-(4-amino-3-klor-5-trifluormety1-fenyl)-2-cyklobutylamino-etanol-hydroklorid, 1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-cyclobutylamino-ethanol hydrochloride,

Smeltepunkt: 177-178°C, Melting point: 177-178°C,

1-(4-amino-3-brom-5-fluor-fenyl)-2-cyklobutylamino-etanol-hydroklorid, 1-(4-amino-3-bromo-5-fluoro-phenyl)-2-cyclobutylamino-ethanol hydrochloride,

Smeltepunkt: 16 4-16 6°C, Melting point: 16 4-16 6°C,

1-(4-amino-3-klor-5-trifluormetyl-fenyl)-2-tert.<p>entylamino-etanol-hydroklorid, 1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.<p>entylamino-ethanol hydrochloride,

Smeltepunkt: 176-178°C (spaltn.) Melting point: 176-178°C (dec.)

1-(4-amino-3-klor-5-fluor-fenyl)-2-isopropylamino-etanol-hydroklorid, 1-(4-amino-3-chloro-5-fluoro-phenyl)-2-isopropylamino-ethanol hydrochloride,

Smeltepunkt: 152-154°C (spaltn.) Melting point: 152-154°C (dec.)

1-(4-amino-3-brom-5-trifluormetyl-fenyl)-2-cyklopentylamino-etanol, Smeltepunkt: 100-102., 5°C (spaltn.) 1-(4-amino-3-bromo-5-trifluoromethyl-phenyl)-2-cyclopentylamino-ethanol, Melting point: 100-102., 5°C (dec.)

Claims (1)

1. Fremgangsmåte for fremstilling av fenyletanolaminer med den generelle formel1. Process for the production of phenylethanolamines with the general formula hvor R-^ betyr et klor- eller bromatom,where R-^ means a chlorine or bromine atom, R2 betyr en trifluormetylgruppe, et fluor- eller kloratom og R., betyr en forgrenet alkylrest eller en cykloalkylrest medR2 means a trifluoromethyl group, a fluorine or chlorine atom and R., means a branched alkyl residue or a cycloalkyl residue with hver 3 til 5 karbonatomer,every 3 to 5 carbon atoms, og fysiologisk forlikelige syreaddisjonssalter derav med uorganiske eller organiske syrer, karakterisert ved at et 4-amino-benzaldehyd med den generelle formeland physiologically compatible acid addition salts thereof with inorganic or organic acids, characterized in that a 4-amino-benzaldehyde of the general formula hvor R^ og R2 er som innledningsvis angitt, omsettes med et isonitril med den generelle formelwhere R 1 and R 2 are as indicated at the outset, is reacted with an isonitrile of the general formula hvor R^ er som innledningsvis angitt, og med en karboksylsyre med den generelle formelwhere R^ is as stated at the outset, and with a carboxylic acid of the general formula hvor R^ betyr en acylrest av en karboksylsyre, og et således erholdt a-acyloksy-acetamid med den generelle formelwhere R^ means an acyl residue of a carboxylic acid, and a thus obtained α-acyloxy-acetamide of the general formula hvor til R^ er som innledningsvis angitt, reduseres med et hydrid, f.eks. et metallhydrid eller et komplekst metallhydrid, og derefter overføres eventuelt et erholdt fenyletanolamin med den generell formel I med en uorganisk eller organisk syre til et fysiologisk godtagbart syreaddisjonssalt.where to R^ is as indicated at the beginning, is reduced by a hydride, e.g. a metal hydride or a complex metal hydride, and then an optionally obtained phenylethanolamine of the general formula I is transferred with an inorganic or organic acid to a physiologically acceptable acid addition salt.
NO823159A 1979-01-10 1982-09-17 PROCEDURE FOR THE PREPARATION OF PHENYLETANOLAMINES NO148997C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI790067A FI59396C (en) 1979-01-10 1979-01-10 PROCEDURE FOR THE FRAMSTATION OF AV 2- (4-AMINO-3,5-DICHLOROPHENYL) -2-CARBOXY-N-TERT-BUTYL ACETAMIDER
DE19792942723 DE2942723A1 (en) 1979-10-23 1979-10-23 Prepn. of broncholytic phenyl-ethanolamine derivs. - via new 2-acyloxy-2-phenyl-acetamide derivs.

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NO823159L NO823159L (en) 1980-07-11
NO148997B true NO148997B (en) 1983-10-17
NO148997C NO148997C (en) 1984-01-25

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HU188207B (en) 1986-03-28
ES8102547A1 (en) 1981-01-16
DK159263C (en) 1991-02-18
ES487548A0 (en) 1981-01-16
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ATA3380A (en) 1981-11-15
NO148522B (en) 1983-07-18
DD156179A5 (en) 1982-08-04
DD150198A5 (en) 1981-08-19
CS214689B2 (en) 1982-05-28
SE447102B (en) 1986-10-27
NO148997C (en) 1984-01-25
NL8000126A (en) 1980-07-14
DK159263B (en) 1990-09-24
PT70661A (en) 1980-02-01
HU181681B (en) 1983-11-28
AT367398B (en) 1982-06-25
SU884563A3 (en) 1981-11-23
DK517289A (en) 1989-10-18
CH645611A5 (en) 1984-10-15
PL221288A1 (en) 1980-12-15
NO823159L (en) 1980-07-11
DK517289D0 (en) 1989-10-18
RO78779A (en) 1982-04-12
SE8000175L (en) 1980-07-11

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