DK159262B - METHOD OF PREPARING PHENYLETHANOLAMINES - Google Patents
METHOD OF PREPARING PHENYLETHANOLAMINES Download PDFInfo
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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
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- 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
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- 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
DK 159262 BDK 159262 B
Opfindelsen angår en særlig fremgangsmåde til fremstilling af phenylethanolaminer med den almene formel I (se krav 1), der har værdifulde farmakologiske egenskaber, især broncholytiske virkninger. Fremgangsmåden 5 er ejendommelig ved det i krav 1's kendetegnende del angivne.The invention relates to a particular process for the preparation of phenylethanolamines of general formula I (see claim 1) which have valuable pharmacological properties, especially broncholytic effects. The method 5 is characterized by the characterizing part of claim 1.
I den ovenfor anførte almene formel I betyder R et chlor- eller bromatom, 2 R en trifluormethylgruppe, et fluor- eller bromatom, og 3 10 R en forgrenet alkylgruppe eller en cycloalkylgruppe hver med fra 3 til 5 carbonatomer.In the above general formula I, R is a chlorine or bromine atom, 2 R is a trifluoromethyl group, a fluorine or bromine atom, and R is a branched alkyl group or a cycloalkyl group each having from 3 to 5 carbon atoms.
33
Under de ved de ved definition af gruppen R tidligere nævnte betydninger kommer især betydningen en isopropyl-, isobutyl-, tert.butyl-, isopentyl-, 15 neopentyl-, tert.pentyl-, cyclopropyl-, cyclobutyl-eller cyclopentylgruppe i betragtning.In particular, within the meaning defined by the group R previously mentioned, the meaning is an isopropyl, isobutyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, cyclopropyl, cyclobutyl or cyclopentyl group.
Ifølge opfindelsen opnås de hidtil ukendte phenylethanolaminer med den almene formel I ved omsætning af et 4-amino-benzaldehyd med den almene for- 1 2 20 mel II (se krav 1), hvori R og R er som defineret tidligere, med et isonitril med den almene formel III (se 3 krav 1), hvori R er defineret som tidligere, og med en carboxylsyre med den almene formel IV (se krav 1), hvori 4 R er en acylgruppe af en carboxylsyre, og reduktion af 25 et således opnået a-acyloxyacetamid med den almene formel 1 4 V (se krav 1), hvori R til R er som ovenfor defineret, reduceres med et hydrid, f.eks. med et metalhydrid eller et komplekst metalhydrid.According to the invention, the novel phenylethanolamines of general formula I are obtained by reacting a 4-amino-benzaldehyde with the general formula II (see claim 1) wherein R and R are as defined previously with an isonitrile having the general formula III (see 3 claim 1) wherein R is defined as before and with a carboxylic acid of the general formula IV (see claim 1) wherein 4 R is an acyl group of a carboxylic acid and reduction of a thus obtained α-acyloxyacetamide of the general formula 14 V (see claim 1), wherein R to R are as defined above, is reduced by a hydride, e.g. with a metal hydride or a complex metal hydride.
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Blandt de ved definitionen af gruppen R givne 30 betydninger kommer især en acylgruppe af en alifatisk eller aromatisk carboxylsyre, såsom eddike-, propion-, trimethyleddike-, valeriane-, benzoe-, nitrobenzoe- og naphthalen-2-carboxylsyre, på tale.In particular, among the meanings given by the group R are an acyl group of an aliphatic or aromatic carboxylic acid, such as acetic, propionic, trimethylacetic, valeric, benzoic, nitrobenzoic and naphthalene-2-carboxylic acids.
Omsætningen af et 4-amino-benzaldehyd med den al-35 mene formel II med et isonitril med den almene formel III og med en carboxylsyre med den almene formel IV gennemføres hensigtsmæssigt i et egnet opløsningsmiddel, såsom methylenchlorid, chloroform, benzen, ether, tetra-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, tetra -
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2 hydrofuran eller dioxan ved lave temperaturer, f.eks. ved temperaturer mellem -20 og 75°C, hensigtsmæssigt dog stuetemperatur. Omsætningen gennemføres dog for-5 trinsvis på den måde, at der enten samtidigt fra hver sin tildrypningstragt tildryppes en forbindelse med den almene formel III og en carboxylsyre med den almene formel IV til en opløsning af et aldehyd med den almene formel 11' eller til en opløsning af et isonitril med 10 den almene formel III og et aldehyd med den almene formel II tildryppes en carboxylsyre med den almene formel iv inden for flere timer, f.eks. 5-10 timer, alt dette under omrøring og ved stuetemperatur, og derpå omrøres i yderligere 10 til 165 timer.2 hydrofuran or dioxane at low temperatures, e.g. at temperatures between -20 and 75 ° C, however, conveniently at room temperature. However, the reaction is preferably carried out in that either a compound of the general formula III and a carboxylic acid of the general formula IV are added simultaneously to each solution of an aldehyde of the general formula 11 'or to a solution of an isonitrile of general formula III and an aldehyde of general formula II a carboxylic acid of general formula iv is added dropwise within several hours, e.g. 5-10 hours, all this while stirring and at room temperature, and then stirring for an additional 10 to 165 hours.
15 Reduktionen af et opnået α-acyloxy-acetamid med den almene formel V med et hydrid gennemføres fortrinsvis i et egnet opløsningsmiddel, såsom ether, tetrahy-drofuran eller dioxan ved lave eller let forhøjede temperaturer, f.eks. ved temperaturer mellem 0 og 100°C, 20 hensigtsmæssigt dog ved reaktionsblandingens kogetemperatur. Særlig fordelagtig gennemføres reduktionen dog med boran/tetrahydrofuran ved kogetemperaturen af det som opløsningsmiddel anvendte tetrahydrofuran.The reduction of an obtained α-acyloxyacetamide of the general formula V with a hydride is preferably carried out in a suitable solvent such as ether, tetrahydrofuran or dioxane at low or slightly elevated temperatures, e.g. however, at temperatures between 0 and 100 ° C, conveniently at the boiling temperature of the reaction mixture. However, the reduction in borane / tetrahydrofuran is particularly advantageous at the boiling temperature of the tetrahydrofuran used as the solvent.
Isoleringen af det ønskede slutprodukt med den 25 almene formel I sker hensigtsmæssigt med vandige baser, f.eks. med vand/ammoniak, hvorved en eventuelt stadig tilstedeværende a-acyloxygruppe fraspaltes.The isolation of the desired final product of the general formula I is conveniently carried out with aqueous bases, e.g. with water / ammonia, thereby cleaving off any possibly a-acyloxy group.
En således opnået phenylethanolamin med den almene formel I lader sig om ønsket derpå med en uorganisk 30 eller organisk syre overføre i dens fysiologisk forligelige syreadditionssalt med den pågældende syre. Som syre kommer hertil f.eks. saltsyre, hydrogenbromid, svovlsyre, phosphorsyre, mælkesyre, vinsyre, citronsyre, fumar-syre eller maleinsyre i betragtning.A phenylethanolamine thus obtained of the general formula I can, if desired, be transferred with an inorganic or organic acid into its physiologically compatible acid addition salt with the acid in question. As an acid addition, e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, lactic acid, tartaric acid, citric acid, fumaric acid or maleic acid under consideration.
35 De som udgangsmaterialer anvendte forbindelser med de almene formler IV og mer kendte fra litteratu- 3The compounds used as starting materials of general formulas IV and more known in the literature 3
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ren.clean.
Et som udgangsprodukt anvendt aldehyd med den almene formel II opnås f.eks. ved reduktion af et tilsvarende 4-amino-benzoesyrehalogenid eller -ester og påføl-5 gende oxidation af den i påkommende tilfælde opnåede benzylalkohol med brunsten.An aldehyde of the general formula II used as a starting product is obtained e.g. by reduction of a corresponding 4-amino-benzoic acid halide or ester and subsequent oxidation of the benzyl alcohol obtained with brownstone as appropriate.
Fra litteraturen er der allerede kendt en fremgangsmåde til fremstilling af phenylethanolaminer med den almene formel I , der er kendetegnet ved, at et 10 glycolsyreamid med den almene formel VIFrom the literature, a process for the preparation of phenylethanolamines of the general formula I is already known, characterized in that a glycolic acid amide of the general formula VI
0H w 1 * 'co' 15 H2N""S; ir 12 3 hvori R , R og R er defineret som tidligere,reduceres med et kompleks metalhydrid.0H w 1 * 'co' 15 H2N "" S; ir 12 3 wherein R, R and R are defined as before are reduced by a complex metal hydride.
Denne fremgangsmåde har dog den ulempe, at det 20 hertil som udgangsprodukt nødvendige glycolsyreamid kun vanskeligt lader sig fremstille.However, this process has the disadvantage that the glycolic acid amide necessary for this is only difficult to produce.
De med den omhandlede nye fremgangsmåde opnåede gode udbytter kan ikke forudses af en fagmand, da det fra litteraturen er kendt (se J.Amer. chem. Soc. 6_7 25 1499-1500 (1945)), at Passerini-reaktionen ikke lader sig gennemføre med sterisk blokerede og med α,β-umættede carbonylforbindelser. Her forklares a,3-umættede carbonylforbindelsers, f.eks. crotonaldehyds, ureaktivitet over for Passerini-reaktionen ved neutralisationen 30 af carbonylfunktionens elektroniske centrum på grund af de mesomere grænsestrukturer o © yeThe good yields obtained by the present process cannot be predicted by one skilled in the art, as it is known from the literature (see J. Ammer. Chem. Soc. 6_7 25 1499-1500 (1945)) that the Passerini reaction is not feasible. with sterically blocked and with α, β-unsaturated carbonyl compounds. Herein, α, 3-unsaturated carbonyl compounds, e.g. crotonaldehydes, unreactivity to the Passerini reaction by the neutralization 30 of the carbonyl function's electronic center due to the so-called boundary structures and
R-CH=CH-C-R <-> R-CH-CH=C-RR-CH = CH-C-R <-> R-CH-CH = C-R
35 altså på grund af den elektronleverende virkning fra en nabogruppe.35, because of the electron-delivery effect of a neighboring group.
Yderligere er det kendt, at aminogruppen i o- eller p-positionen af en phenylkerne har en stærk elektronle- 4Further, it is known that the amino group at the o or p position of a phenyl nucleus has a strong electron reading.
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verende virkning.lasting effect.
Fagmanden måtte derfor forvente, at det elektroniske centrum i carbonyl funktionen af et 4-aminobenzaldéhyd 5 med den almene formel II på grund af den mesomere graensestruktur med den almene formel IlaTherefore, one skilled in the art would expect that the electronic center in the carbonyl function of a 4-aminobenzaldehyde 5 of the general formula II due to the mesomer boundary structure of the general formula IIa
R1 CR1 C
'Ύ*ίΚγ^<\0© yjyf'Ύ * ίΚγ ^ <\ 0 © yjyf
Er R^ deaktiveres, og at Passerinireaktionen dermed ikke er 15 tilgængelig. Dette er overraskende ikke tilfældet.Is R ^ deactivated and thus the Passerini reaction is not available. This is surprisingly not the case.
De efterfølgende eksempler belyser opfindelsen nærmere: 20The following examples further illustrate the invention:
Eksempel 1 a-Acetoxy-α-(4-amino-3,5-dichlor-phenyl)-N-tert.buty1-25 ace tamid.Example 1 α-Acetoxy-α- (4-amino-3,5-dichloro-phenyl) -N-tert-butyl-acetamide.
Til en opløsning af 3,8 g (0,02 mol) 4-amino-3,5-dichlor-benzaldehyd i 50 ml absolut methylenchlorid dryppes under omrøring ved stuetemperatur 3,32 g (0,04 mol) tert.butylisonitril og 4,8 g (0,08 mol) 30 iseddike med samme hastighed fra to adskilte tildryp-ningstragte i løbet af 8 timer. Derpå inddampes den opnåede opløsning til halvdelen og afkøles. Det herved udfældede,ikke-omsatte 4-amino-3,5-dichlor-benzaldehyd suges af, og filtratet inddampes påny til halvdelen.To a solution of 3.8 g (0.02 mol) of 4-amino-3,5-dichlorobenzaldehyde in 50 ml of absolute methylene chloride is added dropwise with stirring at room temperature 3.32 g (0.04 mol) of tert.butyl isonitrile and 4 8 g (0.08 mole) of glacial acetic acid at the same rate from two separate dropping funnels over 8 hours. Then the resulting solution is evaporated to half and cooled. The precipitated, unreacted 4-amino-3,5-dichlorobenzaldehyde is thereby suctioned off and the filtrate is again evaporated to half.
35 ' 535 '5
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Til den opnåede blanding sættes det samme rumfang diisopropylether, hvorved det ønskede produkt udkrystalliserer, suges af, og vaskes med diisopropylether.To the resulting mixture is added the same volume of diisopropyl ether, whereby the desired product crystallizes, is suctioned off and washed with diisopropyl ether.
5 Sxnp.: 175-176°C.M.p .: 175-176 ° C.
Eksempel 2 a-Acetoxy-α-(4-amino-3,5-dichlor-phenyl)-N-tert.buty1-acetamid.Example 2 α-Acetoxy-α- (4-amino-3,5-dichloro-phenyl) -N-tert-butyl-acetamide.
10 Til en opløsning af 30 g (0,16 mol) 4-amino-3,5- dichlor-benzaldehyd i 280 ml methylenchlorid sættes 45 ml tert.butylisocyanic^ og derpå tildryppes under omrøring og ved stuetemperatur ca.40 ml. iseddike i løbet af 16 timer. Derefter omrøres i yderligere 4 timer og 15 inddampes så længe i vakuum, at de første krystaller udfældes. Efter afkøling til 0°C afsuges det udfældede ikke-omsatte 4-amino-3,5-dichlor-benzaldehyd. Dette kan direkte omsættes påny. Filtratet tilsættes n-hexan, hvorved det ønskede produkt udfældes. Bundfaldet afsuges, 20 vaskes med n-hexan og tørres.To a solution of 30 g (0.16 mol) of 4-amino-3,5-dichlorobenzaldehyde in 280 ml of methylene chloride is added 45 ml of tert-butyl isocyanic acid and then added dropwise with stirring and at room temperature about 40 ml. glacial vinegar over 16 hours. Then stir for a further 4 hours and evaporate for a long time in vacuo to precipitate the first crystals. After cooling to 0 ° C, the precipitated unreacted 4-amino-3,5-dichloro-benzaldehyde is aspirated. This can be directly reacted again. The filtrate is added to n-hexane to precipitate the desired product. The precipitate is aspirated, washed with n-hexane and dried.
Smp.: 175-176°C.Mp: 175-176 ° C.
Eksempel 3 1- (4-Amino-3,5-dichlor-phenyl)-2-tert.butylamino-ethanoL 25 Til en opløsning af 4,01 g a-acetoxy-a-(4-amino- 3,5-dichlor-phenyl)-N-tert.butylacetamid i 50 ml absolut tetrahydrofuran sættes 100 ml af en 1-molær opløsning af koran i tetøh^drafuran. Efter 2 tiners cp^ntning inter tilbageswaling inddampes fe, 100 ml· vand tilsættes, og bLandingai geres sur ned saltsyre til pH 2. D=n 30 vandige fase vaskes med ethylacetat, gøres derpå alkalisk med ammoniak og ekstraheres med methylenchlorid. Efter inddampningen af den organiske fase opnås hydrochloridet fra isopropanol ved tilsætning af etherholdig saltsyre. Hydrochloridets smp.: 174-175°C.Example 3 1- (4-Amino-3,5-dichloro-phenyl) -2-tert-butylamino-ethanol To a solution of 4.01 g of α-acetoxy-α- (4-amino-3,5-dichloro) -phenyl) -N-tert-butylacetamide in 50 ml of absolute tetrahydrofuran is added 100 ml of a 1-molar solution of Quran in tetrahydrofuran. After 2 tins of refluxing, inter reflux is evaporated, 100 ml of water is added, and the mixture is acidified with hydrochloric acid to pH 2. D = n 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 the addition of ethereal hydrochloric acid. The hydrochloride mp: 174-175 ° C.
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Eksempel 4 a-Acetoxy-α-(4-amino-3-chlor-5-trifluormethyl-phenyl)-eddikesyre-tert.butylamid.Example 4 α-Acetoxy-α- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -acetic acid tert-butylamide.
Til en opløsning af 4,47 g (20 mmol) 4-amino-3-chlor-5-trifluormethyl-benzaldehyd i 50 ml methylenchlo- 6 rid tildryppes ved stuetemperatur under omrøring 3,32 g (40 mmol) tert.butylisonitril og 4,8 g (80 mmol) iseddike samtidigt i løbet af 5 timer,og derpå omrøres blandingen 5 i 65 timer ved stuetemperatur. Efter fjernelse af opløsningsmidlet i vakuum opløses resten i ether, vaskes efter hinanden med vand og en mættet natriumhydrogen-carbonatopløsning, tørres over magnesiumsulfat og inddampes i vakuum til tørhed. Resten chromatograferes på 10 en kiselgelsøjle med methylenchlorid som elueringsmiddel. De fraktioner, der indeholder den ønskede forbindelse, samles og inddampes, og resten krystalliseres i ether. Smp.: 155-156°C.To a solution of 4.47 g (20 mmol) of 4-amino-3-chloro-5-trifluoromethyl-benzaldehyde in 50 ml of methylene chloride is added dropwise at room temperature with stirring 3.32 g (40 mmol) of tert.butylisonitrile and 4 8 g (80 mmol) glacial acetic acid simultaneously over 5 hours, and then the mixture is stirred 5 for 65 hours at room temperature. After removing the solvent in vacuo, the residue is dissolved in ether, washed successively with water and a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo to dryness. The residue is chromatographed on a silica gel column with methylene chloride as the eluent. The fractions containing the desired compound are collected and evaporated and the residue is crystallized in ether. Mp: 155-156 ° C.
15 Eksempel 5 1- (4-Amino-3-chlor-5-trifluormethyl-phenyl) -2-tert.-butylamino-ethanol-hydrochlorid.Example 5 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride.
2 g (5,4 mmol) a-acetoxy-α-(4-amino-3-chlor-5-trifluormethyl-phenyl)-eddikesyre-tert.butylamid oplø-20 ses i 15 ml absolut tetrahydrofuran og sættes under nitrogen på én gang til 27 ml af en 1-molær opløsning af boran i tetrahydrofuran. Efter 4 timers kogning under tilbagesvaling sættes der yderligere 15 ml l-molær boranopløsning til og opvarmes yderligere i 2 timer 25 under tilbagesvaling. Derefter nedbrydes overskuddet af boran med acetone. Borkomplekset opløses med vand, og derpå afdampes opløsningsmidlet i vakuum. Den vandige destillationsrest gøres sur med 2n-saltsyre, gøres atter alkalisk med ammoniak og ekstraheres med ether.2 g (5.4 mmol) of α-acetoxy-α- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -acetic acid tert-butylamide are dissolved in 15 ml of absolute tetrahydrofuran and placed under nitrogen on one to 27 ml of a 1-molar solution of borane in tetrahydrofuran. After 4 hours of reflux, an additional 15 ml of 1-molar borane solution is added and further heated for 2 hours under reflux. Then the excess of borane is degraded with acetone. The boron complex is dissolved with water and then the solvent is evaporated in vacuo. The aqueous distillation residue is acidified with 2N hydrochloric acid, again made alkaline with ammonia and extracted with ether.
30 Etherekstrakten ekstraheres med 0,5n saltsyre, syreopløsningen vaskes med ether, gøres alkalisk med ammoniak og ekstraheres påny med ether. Etherekstrakten vaskes med vand, tørres med magnesiumsulfat og inddampes i vakuum. Den olieagtige inddampningsrest opløses i 35 ether og gøres sur med etherholdig saltsyre. De udfældede krystaller suges af og vaskes med ether.The ether extract is extracted with 0.5n hydrochloric acid, the acid solution is washed with ether, made alkaline with ammonia and extracted again with ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated in vacuo. The oily residue is dissolved in 35 ether and acidified with ethereal hydrochloric acid. The precipitated crystals are sucked off and washed with ether.
Smp.: 192-193°C.Mp: 192-193 ° C.
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Eksempel 6 a-Acetoxy-α-(4-amino-3,5-dichlor-phenyl)-N-tert.buty1-acetamid.Example 6 α-Acetoxy-α- (4-amino-3,5-dichloro-phenyl) -N-tert-butyl-acetamide.
5 Til en opløsning af 14,1 g (0,08 mol) 4-amino-3,5- dichlor-benzaldehyd i 60 ml methylenchlorid tilsættes ved stuetemperatur og under omrøring 3,6 g (0,06 mol) eddikesyre og 2,5 g (0,03 mol) tert.butylisonitril.To a solution of 14.1 g (0.08 mol) of 4-amino-3,5-dichlorobenzaldehyde in 60 ml of methylene chloride is added at room temperature and with stirring 3.6 g (0.06 mol) of acetic acid and 2, 5 g (0.03 mole) of tert.butylisonitrile.
Derpå opvarmes reaktionsblandingen i 3 timer under til-10 bagesvaling. Efter at den ovennævnte operation (tilsætning af eddikesyre, tert.butylisonitril og opvarmning under tilbagesvaling) er gentaget fire gange, hældes reaktionsblandingen over i kold 2N natronlud,, og den organiske fase isoleres. Efter vask med vand og tørring 15 af den organiske fase over natriumsulfat inddampes der i vakuum, og resten krystalliseres af methylenchlorid/hexan.Then, the reaction mixture is heated for 3 hours under reflux. After the above operation (addition of acetic acid, tert.butylisonitrile and reflux heating) is repeated four times, the reaction mixture is poured into cold 2N sodium hydroxide solution, and the organic phase is isolated. After washing with water and drying the organic phase over sodium sulfate, evaporate in vacuo and the residue is crystallized by methylene chloride / hexane.
Smp. 175-176°C.Mp. 175-176 ° C.
Eksempel 7 20 a-(4-Amino-3,5-dichlor-phenyl)-a-benzoyloxy-N-tert.-butylacetamid.Example 7 α- (4-Amino-3,5-dichloro-phenyl) -α-benzoyloxy-N-tert.-butylacetamide.
Fremstillet analogt med eksempel 4 af 4-amino- 3.5- dichlor-benzaldehyd, tert.butylisonitril og benzoesyre i chloroform og ved tilbagesvalingstempera- 25 tur.Prepared analogously to Example 4 of 4-amino-3,5-dichloro-benzaldehyde, tert-butylisonitrile and benzoic acid in chloroform and at reflux temperature.
Smp.: 189-192°C (sintrer fra 185°C).Mp: 189-192 ° C (sintering from 185 ° C).
Eksempel 8 a-(4-Amino-3,5-dichlor-phenyl)-a-valeroyloxy-N-tert.-30 butylacetamid.Example 8 α- (4-Amino-3,5-dichloro-phenyl) -α-valeroyloxy-N-tert-butylacetamide.
Fremstillet analogt med eksempel 4 af 4-amino-3,5-dichlor-benzaldehyd, tert.butylisonitril og valerian-syre.Prepared analogously to Example 4 of 4-amino-3,5-dichloro-benzaldehyde, tert-butylisonitrile and valeric acid.
Smp.: 95-98°C.Mp: 95-98 ° C.
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Eksempel 9 1-(4-Amino-3,5-dichlor-phenyl)-2-tert.butylamino-ethanoL Fremstillet analogt med eksempel 3 af a-(4-amino- 3.5- dichlor-phenyl)-a-benzoyloxy-N-tert.butylacetamid 8Example 9 1- (4-Amino-3,5-dichloro-phenyl) -2-tert-butylamino-ethanol Prepared analogously to Example 3 of α- (4-amino-3,5-dichloro-phenyl) -α-benzoyloxy-N -butyl acetamide 8
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og lithiumaluminiumhydrid i tetrahydrofuran.and lithium aluminum hydride in tetrahydrofuran.
Hydrochloridets smp.: 174-175°C.The hydrochloride mp: 174-175 ° C.
5 Eksempel 10 1- U-Amino-S, 5-dichlor-phenyl) -2-tert.butylamino-ethanol.Example 10 1- U-Amino-5,5-dichloro-phenyl) -2-tert-butylamino-ethanol.
Fremstillet af 4-amino-3,5-dichlor-benzaldehyd, tert.butylisonitril og valeriansyre analogt med eksemplerne 2 og 5 uden isolering af det dannede a-(4-amino- 10 3,5-dichlorphenyl)-N-tert.butyl-a-valeroyloxy-acetamid.Prepared from 4-amino-3,5-dichloro-benzaldehyde, tert-butylisonitrile and valeric acid analogous to Examples 2 and 5 without isolation of the resulting α- (4-amino-3,5-dichlorophenyl) -N-tert.butyl -A-valeroyloxy-acetamide.
Hydrochloridets smp.: 174-175°C.The hydrochloride mp: 174-175 ° C.
Analogt med de foregående eksempler blev de følgende forbindelser fremstillet:By analogy to the preceding examples, the following compounds were prepared:
1-(4-amino-3-brom-5-fluor-phenyl)-2-tert.butylamino-15 ethanol-hydrochlorid, smp.: 207-208°C1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride, mp: 207-208 ° C
1-(4-amino-3-chlor-5-fluor-phenyl)-2-cyclopropylamino- ! ethanol-hydrochlorid, smp.: 175-177°C1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylaminoyl ethanol hydrochloride, mp: 175-177 ° C
20 1-(4-amino-3-chlor-5-fluor-phenyl)-2-tert.butylamino-1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino
ethanol-hydrochlorid, smp.: 206-208°Cethanol hydrochloride, mp: 206-208 ° C
1-(4-amino-3-chlor-5-trifluormethyl-phenyl)-2-cyclo-butylamino-ethanol-hydrochlorid,1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclo-butylamino-ethanol hydrochloride,
25 smp.: 177-178°CMp: 177-178 ° C
1-(4-amino-3-brom-5-fluor-phenyl)-2-cyclobutylamino-ethanol-hydrochlorid, smp.: 164-166°C1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride, mp: 164-166 ° C
1- (4-amino-3-chlor-5-trifluormethyl-phenyl) -2-tert.-3 0 pentylamino-ethanol-hydrochlorid, smp.: 176-178°C (sønderdeling) 1-(4-amino-3-chlor-5-fluor-phenyl)-2-isopropylamino- ethanol-hydrochlorid, smp.: 152-154°C (sønderdeling) 35 l-(4-amino-3-brom-5-trifluormethyl-phenyl)-2-cyclopen-tylamino-ethanol, smp.: 100-102,5°C (sønderdeling).1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol hydrochloride, mp: 176-178 ° C (dec.) 1- (4-amino-3 -chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride, mp: 152-154 ° C (dec.) 35- (4-amino-3-bromo-5-trifluoromethyl-phenyl) -2- cyclopentylamino-ethanol, mp: 100-102.5 ° C (dec.).
Claims (5)
Applications Claiming Priority (4)
| 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 |
| FI790067 | 1979-01-10 | ||
| DE2942723 | 1979-10-23 | ||
| DE19792942723 DE2942723A1 (en) | 1979-10-23 | 1979-10-23 | Prepn. of broncholytic phenyl-ethanolamine derivs. - via new 2-acyloxy-2-phenyl-acetamide derivs. |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK517289A DK517289A (en) | 1989-10-18 |
| DK517289D0 DK517289D0 (en) | 1989-10-18 |
| DK159262B true DK159262B (en) | 1990-09-24 |
| DK159262C DK159262C (en) | 1991-02-18 |
Family
ID=25781629
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK008480A DK159263C (en) | 1979-01-10 | 1980-01-08 | PROCEDURE FOR THE PREPARATION OF ALFA ACYLOXYACETAMIDES |
| DK517289A DK159262C (en) | 1979-01-10 | 1989-10-18 | METHOD OF PREPARING PHENYLETHANOLAMINES |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK008480A DK159263C (en) | 1979-01-10 | 1980-01-08 | PROCEDURE FOR THE PREPARATION OF ALFA ACYLOXYACETAMIDES |
Country Status (18)
| Country | Link |
|---|---|
| AT (1) | AT367398B (en) |
| BG (1) | BG33584A3 (en) |
| CA (1) | CA1146958A (en) |
| CH (1) | CH645611A5 (en) |
| CS (1) | CS214689B2 (en) |
| DD (2) | DD150198A5 (en) |
| DK (2) | DK159263C (en) |
| ES (1) | ES487548A0 (en) |
| GR (1) | GR74391B (en) |
| HU (2) | HU188207B (en) |
| NL (1) | NL8000126A (en) |
| NO (2) | NO148522C (en) |
| PL (2) | PL126046B1 (en) |
| PT (1) | PT70661A (en) |
| RO (1) | RO78779A (en) |
| SE (2) | SE447102B (en) |
| SU (1) | SU884563A3 (en) |
| YU (1) | YU4880A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR102020008433A2 (en) | 2020-04-28 | 2021-11-03 | Universidade Federal Do Parana | ARTHROPOD REPELLENTS OBTAINED FROM THE CHEMICAL TRANSFORMATION OF LACTIC ACID, LACTATES OR OTHER LACTIC ACID DERIVATIVES |
-
1979
- 1979-12-24 BG BG7946027A patent/BG33584A3/en unknown
- 1979-12-28 NO NO794314A patent/NO148522C/en unknown
-
1980
- 1980-01-04 GR GR60893A patent/GR74391B/el unknown
- 1980-01-04 AT AT0003380A patent/AT367398B/en not_active IP Right Cessation
- 1980-01-04 SU SU802863255A patent/SU884563A3/en active
- 1980-01-07 PT PT70661A patent/PT70661A/en not_active IP Right Cessation
- 1980-01-07 CS CS80164A patent/CS214689B2/en unknown
- 1980-01-07 CH CH6680A patent/CH645611A5/en not_active IP Right Cessation
- 1980-01-08 CA CA000343261A patent/CA1146958A/en not_active Expired
- 1980-01-08 YU YU00048/80A patent/YU4880A/en unknown
- 1980-01-08 DD DD80218350A patent/DD150198A5/en unknown
- 1980-01-08 DK DK008480A patent/DK159263C/en not_active IP Right Cessation
- 1980-01-08 DD DD80227454A patent/DD156179A5/en unknown
- 1980-01-09 NL NL8000126A patent/NL8000126A/en not_active Application Discontinuation
- 1980-01-09 PL PL1980234384A patent/PL126046B1/en unknown
- 1980-01-09 HU HU8330A patent/HU188207B/en unknown
- 1980-01-09 ES ES487548A patent/ES487548A0/en active Granted
- 1980-01-09 SE SE8000175A patent/SE447102B/en not_active IP Right Cessation
- 1980-01-09 PL PL1980221288A patent/PL126876B1/en unknown
- 1980-01-09 HU HU8041A patent/HU181681B/en unknown
- 1980-01-09 RO RO8099824A patent/RO78779A/en unknown
-
1982
- 1982-09-17 NO NO823159A patent/NO148997C/en unknown
-
1984
- 1984-11-09 SE SE8405631A patent/SE452979B/en not_active IP Right Cessation
-
1989
- 1989-10-18 DK DK517289A patent/DK159262C/en not_active IP Right Cessation
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| Date | Code | Title | Description |
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| PBP | Patent lapsed |