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NO133708B - - Google Patents

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NO133708B
NO133708B NO1615/71A NO161571A NO133708B NO 133708 B NO133708 B NO 133708B NO 1615/71 A NO1615/71 A NO 1615/71A NO 161571 A NO161571 A NO 161571A NO 133708 B NO133708 B NO 133708B
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chloro
trifluoromethylphenyl
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general formula
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NO133708C (en
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K Schromm
E-O Renth
A Mentrup
R Reichl
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Boehringer Sohn C H Chem Fab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/32—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by introduction of halogenated alkyl groups into ring compounds
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/07—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms
    • C07C205/08—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to acyclic carbon atoms
    • C07C205/09—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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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
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/562—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with nitrogen as the only hetero atom
    • C07C45/565—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with nitrogen as the only hetero atom by reaction with hexamethylene-tetramine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/55—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/64—Acyl halides
    • C07C57/76—Acyl halides containing halogen outside the carbonyl halide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline

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Description

Denne oppfinnelse angår analogifremgangsmåte for fremstilling av nye forbindelser med den generelle formel I This invention relates to analogue methods for the production of new compounds of the general formula I

hvor Cl betyr et kloratom i 4- eller 6-stilling, R^, R2 og R betyr hydrogen eller metyl, og R^ betyr hydrogen, en lavere alkylrest, en benzyl- eller en teofyllin-(7)-etyl-gruppe, eller en av restene -cnH2n_R5 ^vor n = 1 eller 2, og R^ betyr en karboksyl-, alkoksykarbonyl- eller nitrilgruppe) , ~cm~H2m-R6 e^-ler -C H_ _(CrH )-R_ (hvor m er 2, 3 eller 5, og R, betyr halogen m 2m-l 6 5 6 6 eller en hydroksylgruppe) , _cn~II2n-C0~R (hvor n = 1 eller 2, og R betyr en lavere alkyl- eller en fenylgruppe) eller -CO-R-, (hvor R? betyr en lavere alkoksy- eller alkyltiogruppe eller en alkylrest, som kan være substituert med et halogenatom eller en benzylamino- eller aminogruppe), og deres salter med fysiologisk forlikelige syreanioner. For fremstilling av de nye forbindelser anvendes følgende metoder: a) Et keton med den generelle formel II hvor restene Cl, R^ og R2 har de ovenfor angitte betydninger, kondenseres med en forbindelse med den generelle formel III where Cl means a chlorine atom in the 4- or 6-position, R^, R2 and R means hydrogen or methyl, and R^ means hydrogen, a lower alkyl residue, a benzyl or a theophylline-(7)-ethyl group, or one of the residues -cnH2n_R5 ^vor n = 1 or 2, and R^ means a carboxyl, alkoxycarbonyl or nitrile group) , ~cm~H2m-R6 e^-ler -C H_ _(CrH )-R_ (where m is 2, 3 or 5, and R, means halogen m 2m-l 6 5 6 6 or a hydroxyl group), _cn~II2n-C0~R (where n = 1 or 2, and R means a lower alkyl or a phenyl group) or -CO-R-, (where R? means a lower alkoxy or alkylthio group or an alkyl residue, which may be substituted with a halogen atom or a benzylamino or amino group), and their salts with physiologically compatible acid anions. The following methods are used for the preparation of the new compounds: a) A ketone with the general formula II where the residues Cl, R^ and R2 have the meanings given above, is condensed with a compound of the general formula III

hvor RQ betyr hydrogen, en hydroksyl-, amino-, lavere alkyl-, benzyl-, teofyllin-(7)-etyl-gruppe eller en av restene C H0 -R where RQ means hydrogen, a hydroxyl, amino, lower alkyl, benzyl, theophylline-(7)-ethyl group or one of the residues C H0 -R

(hvor n er 1 eller 2, og R betyr en karboksyl- eller alkoksykarbonylgruppe), oy -CmH2m-Rl0 eller C^^ - (CgH^ -R^ (hvor m er 2, 3 eller 4, og R^Q betyr en hydroksylgruppe, og de derved dannede mellomprodukter med formel IV (where n is 1 or 2, and R means a carboxyl or alkoxycarbonyl group), oy -CmH2m-Rl0 or C^^ - (CgH^ -R^ (where m is 2, 3 or 4, and R^Q means a hydroxyl group, and the thereby formed intermediates of formula IV

hvor Cl, Rj, R2 og Rg har de ovenfor angitte betydninger, eventuelt efter forutgående isolering, reduseres, eller kondensasjonen utføres i nærvær av et reduksjonsmiddel, where Cl, Rj, R2 and Rg have the meanings given above, optionally after prior isolation, is reduced, or the condensation is carried out in the presence of a reducing agent,

b) et nitroolefin med den generelle formel V b) a nitroolefin of the general formula V

hvor R^ betyr hydrogen eller en metylgruppe, reduseres med kom-plekse metallhydrider, f.eks. litiumalanat, hvorved det primære aminoalkan (formel I, R4=H) dannes, where R 1 means hydrogen or a methyl group, is reduced with complex metal hydrides, e.g. lithium alanate, whereby the primary aminoalkane (formula I, R4=H) is formed,

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

hvor restene Cl, R^ og R^ har de ovenfor angitte betydninger, og where the residues Cl, R^ and R^ have the meanings indicated above, and

Y betyr resten av en reaktiv ester, f.eks. et halogenatom eller en alkyl- eller aryl-sulfonsyrerest, omsettes på kjent måte med et amin med den generelle formel VII Y means the residue of a reactive ester, e.g. a halogen atom or an alkyl or aryl sulfonic acid residue is reacted in a known manner with an amine of the general formula VII

hvor R' har den for Rg angitte betydning med unntagelse av hydroksyl og amino. d) en forbindelse med den generelle formel VIII hvor Cl, R^, R2°9 R3 har de ovenfor angitte betydninger, og A betyr ftalimido- eller succinimidogruppe, en isocyansyrerest eller gruppen where R' has the meaning given for Rg with the exception of hydroxyl and amino. d) a compound of the general formula VIII where Cl, R^, R2°9 R3 have the meanings given above, and A means a phthalimido or succinimido group, an isocyanic acid residue or the group

(hvor R' har den ovenfor angitte be- (where R' has the above stated be-

tydning og Sk betyr hydrolytisk eller hydrogenolytisk, lett avspaltbare rester, f.eks. acyl eller benzyl), overføres til det ønskede amin ved hydrolyse eller hydrogenolyse. Hydrolytisk avspaltbare rester kan f.eks. være acylgrupper, særlig en formyl-eller acetylgruppe. Som hydrogenolytisk, lett avspaltbar rest kan f.eks. anvendes en benzylgruppe. tydning and Sk means hydrolytic or hydrogenolytic, easily cleavable residues, e.g. acyl or benzyl), is transferred to the desired amine by hydrolysis or hydrogenolysis. Hydrolytically cleavable residues can e.g. be acyl groups, especially a formyl or acetyl group. As a hydrogenolytic, easily cleavable residue, e.g. a benzyl group is used.

I de ved fremgangsmåten fremstilte primære aminer (formel I, R^ = H) kan man eventuelt innføre rester som har de andre betydninger angitt for R^ bortsett fra hydrogen, f.eks. ved alkylering eller acylering på kjent måte. Dessuten kan restene R^, når de inneholder funksjonelle grupper, overføres til hverandre på vanlig måte. In the primary amines produced by the method (formula I, R^ = H), one can possibly introduce residues which have the other meanings given for R^ except hydrogen, e.g. by alkylation or acylation in a known manner. Moreover, the residues R^, when they contain functional groups, can be transferred to each other in the usual way.

De fremstilte baser kan eventuelt overføres til fysiologisk, godtakbare syreaddisjonssalter. Egnete syrer er f.eks. saltsyre, svovelsyre, fosforsyre, vinsyre, askorbinsyre eller 8-klor-teofyllin. The prepared bases can optionally be transferred to physiologically acceptable acid addition salts. Suitable acids are e.g. hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, ascorbic acid or 8-chloro-theophylline.

Utgangs forbindelsene kan fremstilles ved de følgende i The output compounds can be produced by the following i

og for seg kjente metoder, eventuelt på analog måte: and known methods, possibly in an analogous way:

Ved kondensasjon av et substituert benzaldehyd (X) eller acetofenon med nitroetan får man et nitroolefin med formel V, hvorfra det ved reduksjon med jern/saltsyre dannes et keton med formel II. Sistnevnte kan ved reduksjon eller Grignardreaksjon overføres til en sekundær eller tertiær alkohol (XI), og fra den sekundære alkohol får man på kjent måte forbindelsene med formel Condensation of a substituted benzaldehyde (X) or acetophenone with nitroethane yields a nitroolefin of formula V, from which, by reduction with iron/hydrochloric acid, a ketone of formula II is formed. The latter can by reduction or Grignard reaction be transferred to a secondary or tertiary alcohol (XI), and from the secondary alcohol one obtains in a known manner the compounds of formula

VI. WE.

Reaksjonene fremgår av følgende skjema. The reactions appear in the following form.

Fra ketonene med den generelle formel II får man. med aminer med den generelle formel VII i nærvær av.maursyre, formid-ater eller eventuelt med formamidene av nevnte aminer først form-ylderivatene (VIII a, hvor "Acyl" betyr en formylgruppe og hydrogen) av de nye forbindelser med formel I, som kan forsepes ved fremgangsmåte d). From the ketones of the general formula II one obtains. with amines of the general formula VII in the presence of formic acid, formamides or optionally with the formamides of said amines first the formyl derivatives (VIII a, where "Acyl" means a formyl group and hydrogen) of the new compounds of formula I, which can be saponified by method d).

Alkoholene med formel XI eller de tilsvarende alken-derivater kan omsettes med nitriler eller hydrogencyanid i.svovelsyre for å danne N-acylderivatene med formel VIII a, som like-ledes kan overføres til de nye aminer med formel I ved fremgangsmåte d) . The alcohols of formula XI or the corresponding alkene derivatives can be reacted with nitriles or hydrogen cyanide in sulfuric acid to form the N-acyl derivatives of formula VIII a, which can likewise be transferred to the new amines of formula I by method d).

Karboksylsyrene (XII) får man f.eks. ved omsetning av trifluormetyl-klor-benzylklorid med metylmalonsyreester og deretter partiell dekarboksylering. Ved karboksylsyre-avbygnings-reaksjoner dannes derav på kjent måte, f.eks. ifølge Hoffmann over syreamidene, ifølge Curtius eller Schmidt over syreazidene eller ifølge Lossen over hydroksamsyrene, isocyansyreestere med formel VIII b, som for det meste straks overføres til de primære aminer under reaksjonsbetingelsene ved hydrolyse ifølge fremgangsmåte d). Isocyansyreestrene (VIII b) lar seg ofte ikke iso-lere i det hele tatt under de anvendte reaksjonsbetingelser. The carboxylic acids (XII) are obtained e.g. by reaction of trifluoromethyl-chloro-benzyl chloride with methylmalonic acid ester and then partial decarboxylation. In carboxylic acid decomposition reactions, it is formed in a known manner, e.g. according to Hoffmann over the acid amides, according to Curtius or Schmidt over the acid azides or according to Lossen over the hydroxamic acids, isocyanic acid esters of formula VIII b, which are mostly immediately transferred to the primary amines under the reaction conditions by hydrolysis according to method d). The isocyanic acid esters (VIII b) often cannot be isolated at all under the reaction conditions used.

De nye forbindelser med formel I er stoffer som virker appetittreduserende og som i motsetning til de kjente appetittreduserende midler bare forårsaker en meget liten sentralstimulering og oppviser en særlig lav toksisitet. En særlig god virkning oppviser forbindelser med den generelle formel I hvor R^ betyr hydrogen, en alkoksykarbonylgruppe eller en alkylgruppe, som kan være substituert med en hydroksylgruppe eller en alkoksykarbonyl-eller aminokarbonylrest. Særlig godt virker slike forbindelser med formel I hvor R. er hydrogen, en alkylgruppe med 1 eller 2 C-atomer eller en /3-hydroksyetylgruppe, og restene R1, R^ og R^ betyr hydrogen. De sistnevnte forbindelser oppviser den beste virkning med minimal sentralstimulering og toksisitet, når klor-atomet står i 4-stilling. For anvendelse av de nye forbindelser er enkeltdosen ca. 1 til 50 mg, fortrinnsvis 2,5 til 10 mg. The new compounds of formula I are substances which have an appetite-reducing effect and which, in contrast to the known appetite-reducing agents, only cause a very small central stimulation and exhibit a particularly low toxicity. A particularly good effect is shown by compounds of the general formula I where R 1 means hydrogen, an alkoxycarbonyl group or an alkyl group, which may be substituted with a hydroxyl group or an alkoxycarbonyl or aminocarbonyl residue. Such compounds of formula I work particularly well where R. is hydrogen, an alkyl group with 1 or 2 C atoms or a β-hydroxyethyl group, and the residues R 1 , R 1 and R 2 mean hydrogen. The latter compounds show the best effect with minimal central stimulation and toxicity, when the chlorine atom is in the 4-position. For the use of the new compounds, the single dose is approx. 1 to 50 mg, preferably 2.5 to 10 mg.

I den følgende tabell er gjengitt resultatene av sam-menlignings forsøk hvor de særlig gode egenskaper ved de nye forbindelser^ fremstilt ifølge oppfinnelsen er illustrert, sammen-lignet med kjente forbindelser. I tabellen representerer ED^q den hemning av foropptaket som ble funnet etter subkutan administrering på rotter, og den dødelige dose (LD^q) ble funnet på samme måte. Sentralstimuleringen (ZD5q) ble bestemt etter subkutan administrering på mus. Alle doser er uttrykt i milligram pr. kilo. The following table shows the results of comparison tests where the particularly good properties of the new compounds produced according to the invention are illustrated, compared with known compounds. In the table, ED^q represents the inhibition of pre-uptake found after subcutaneous administration in rats, and the lethal dose (LD^q) was found in the same way. The central stimulation (ZD5q) was determined after subcutaneous administration to mice. All doses are expressed in milligrams per kilo.

Som det vil sees av sammenligningsforsøkene, mangler As will be seen from the comparison tests, lacks

hos forbindelsene fremstilt ifølge oppfinnelsen den uønskede sen-tralstimulerende virkning, og for noen forbindelser viser den ned-satte motilitet at det til og med er oppnådd en motsatt virkning. ED5_ o verdiene for hemningen.av forinntaket er omtrentliq 3 av samme størrelsesorden, mens det av den terapeutiske indeks LD5Q fremgår at de nye forbindelser fremstilt ifølge oppfinnelsen er bedre enn de kjente forbindelser. with the compounds produced according to the invention the unwanted central stimulating effect, and for some compounds the reduced motility shows that an opposite effect has even been achieved. The ED5_ o values for the inhibition of pre-uptake are approximately 3 of the same order of magnitude, while it is clear from the therapeutic index LD5Q that the new compounds produced according to the invention are better than the known compounds.

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

Eksempel 1 (Fremgangsmåte a) Example 1 (Procedure a)

1- ( 4- klor- 3- trifluormetylfenyl)- 2-( 2- hydroksyetylamino)- propan 1-( 4- chloro- 3- trifluoromethylphenyl)- 2-( 2- hydroxyethylamino)- propane

Ved 5 timers omrøring av en blanding av o-klorbenzotri-fluorid, konsentrert svovelsyre og symmetrisk diklordimetyleter ved 55°C får man 4-klor-3-trifluormetylbenzylklorid (k.p.15: 100-103°C), hvorfra det med urotropin i kloroform og påfølgende behandling med saltsyre dannes 4-klor-3-trifluormetylbenzalde-hyd (k.p.^^:100°C). Ved kondensasjon med nitroetan i nærvær av piperidinbenzoat i toluen får man 1-(4-klor-3-trifluormetylfenyl 2- nitropropan (k.p.g ^:120-130°C), som ved hjelp av jern og saltsyre overføres til 1-(4-klor-3-trifluormetylfenyl)-2-propanon (k.p.15:135-138°C). 10 g 1-(4-klor-3-trifluormetylfenyl)-2-propanon og 2,6 g etanolamin hydrogeneres i 100 ml metanol i nærvær av 1 g Pt02 ved 60°C og 5 atmosfærer. Deretter befris reaksjonsblandingen for katalysator og oppløsningsmiddel, tilsettes fortynnet ammoniakk, ekstraheres med eter, inndampes og destilleres fraksjonert. Det dannede 1-(4-klor-3-trifluormetylfenyl)-2-hydroksyetyl-amino ) -propan (k.p.Q 2:140-145°C) i etylacetat med eterisk saltsyre og eter til hydrokloridet (sm.p.:118-120°C). By stirring a mixture of o-chlorobenzotrifluoride, concentrated sulfuric acid and symmetrical dichlorodimethyl ether at 55°C for 5 hours, 4-chloro-3-trifluoromethylbenzyl chloride is obtained (b.p.15: 100-103°C), from which with urotropin in chloroform and subsequent treatment with hydrochloric acid forms 4-chloro-3-trifluoromethylbenzaldehyde (b.p.^^:100°C). Condensation with nitroethane in the presence of piperidine benzoate in toluene gives 1-(4-chloro-3-trifluoromethylphenyl 2-nitropropane (b.p.g.: 120-130°C), which with the help of iron and hydrochloric acid is transferred to 1-(4- chloro-3-trifluoromethylphenyl)-2-propanone (b.p. 15:135-138°C). 10 g of 1-(4-chloro-3-trifluoromethylphenyl)-2-propanone and 2.6 g of ethanolamine are hydrogenated in 100 ml of methanol in presence of 1 g of Pt02 at 60°C and 5 atmospheres. The reaction mixture is then freed of catalyst and solvent, dilute ammonia is added, extracted with ether, evaporated and fractionally distilled. The formed 1-(4-chloro-3-trifluoromethylphenyl)-2- hydroxyethyl-amino)-propane (b.p.Q 2: 140-145°C) in ethyl acetate with ethereal hydrochloric acid and ether to the hydrochloride (m.p.: 118-120°C).

Eksempel la Example la

Analogt med eksempel 1 fremstilles en l-(6-klor-3-tri-fluormetylfenyl)-2-metylaminopropan fra 1-(6-klor-3-trifluor-metylfenyl)-2-propanon og metylamin. Smeltepunkt 146 - 148°C Analogously to example 1, a 1-(6-chloro-3-trifluoromethylphenyl)-2-methylaminopropane is prepared from 1-(6-chloro-3-trifluoromethylphenyl)-2-propanone and methylamine. Melting point 146 - 148°C

(hydroklorid). (hydrochloride).

Eksempel lb Example lb

Analogt med eksempel 1 fremstilles l-(4-klor-3-tri-fluormetylfenyl)-2-metylaminopropan fra l-(4-klor-3-trifluormetyl-fenyl-2-propanon og metylamin. Smeltepunkt 195 - 198DC (hydroklorid) Analogously to example 1, l-(4-chloro-3-trifluoromethylphenyl)-2-methylaminopropane is prepared from l-(4-chloro-3-trifluoromethyl-phenyl-2-propanone and methylamine. Melting point 195 - 198DC (hydrochloride)

Eksempel lc Example lc

Analogt med eksempel 1 fremstilles 1-(4-klor-3-tri-f luormetylf enyl) -2-benzylaminopropan fra l-(4-klor-3-trifluormetyl-feny])-2-propanon og benzylamin. Smeltepunkt 158 - 162°C (hydroklorid) Analogous to example 1, 1-(4-chloro-3-trifluoromethylphenyl)-2-benzylaminopropane is prepared from 1-(4-chloro-3-trifluoromethylphenyl])-2-propanone and benzylamine. Melting point 158 - 162°C (hydrochloride)

Eksempel ld Example ld

Analogt med eksempel 1 fremstilles 1-(4-klor—3-tri-fluormetylfenyl)-2-etylaminopropan fra l-(4-klor-3-trifluormetyl-fenyl)-2-propanon og etylamin. Smeltepunkt 199 - 200°C (hydroklorid). Analogous to example 1, 1-(4-chloro-3-trifluoromethylphenyl)-2-ethylaminopropane is prepared from 1-(4-chloro-3-trifluoromethyl-phenyl)-2-propanone and ethylamine. Melting point 199 - 200°C (hydrochloride).

Eksempel le Example le

Analogt med eksempel 1 fremstilles l-(4-klor-3-tri-f luormetylf enyl) -2-.( 2-hydroksy-2-f enyletylamino) -propan fra 1-(4-klor-3-trifluormetylfenyl)-2-propanon og 2-hydroksy-2-fenyl— etylamin. Smeltepunkt 165 - 167°C (hydroklorid). Analogous to example 1, 1-(4-chloro-3-trifluoromethylphenyl)-2-(2-hydroxy-2-phenylethylamino)-propane is prepared from 1-(4-chloro-3-trifluoromethylphenyl)-2 -propanone and 2-hydroxy-2-phenyl- ethylamine. Melting point 165 - 167°C (hydrochloride).

Eksempel lf Example lf

Analogt med eksempel 1 fremstilles l-(4-klor-3-trifluor-metylfenyl)-2-[2-(7-teofyllinyl)-etylamino]-propan fra l-(4-klor-3-trifluormetylfemyl)-2-propanon og 6-(2-aminoe^yl)-teofyllin. Smeltepunkt 244 - 248°C (hydroklorid). Analogously to example 1, 1-(4-chloro-3-trifluoromethylphenyl)-2-[2-(7-theophyllinyl)-ethylamino]-propane is prepared from 1-(4-chloro-3-trifluoromethylphenyl)-2-propanone and 6-(2-aminoethyl)-theophylline. Melting point 244 - 248°C (hydrochloride).

Eksempel 2 (Fremgangsmåte a) Example 2 (Procedure a)

N-( 4- klor- 3- trifluormetyl- g- metyl- fenetyl)- glycinetylester N-(4-Chloro-3-trifluoromethyl-g-methyl-phenethyl)- glycine ethyl ester

En blanding av 10 g 1-(4-klor-3-trifluormetylfenyl)-2-propanon, 6,3 5 g glycinetylester-hydroklorid, 2,45 g natrium-metylat og 100 ml metanol hydrogeneres i nærvær av 1 g Pt02 ved 60°C og 5 atmosfærer. Etter avsugning av katalysatoren og av-destillering av metanolen tilsettes kaliumkarbonatoppløsning, blandingen ekstraheres med eter, inndampes og destilleres fraksjonert. Den dannede N-(4-klor-3-trifluormetyl-a-metylfenetyl)-glycinetylester, som koker ved 13o°C ved 0,25 torr, overføres til hydrokloridet (sm.p. :165-167°C). med eterisk saltsyre. A mixture of 10 g of 1-(4-chloro-3-trifluoromethylphenyl)-2-propanone, 6.35 g of glycine ethyl ester hydrochloride, 2.45 g of sodium methylate and 100 ml of methanol is hydrogenated in the presence of 1 g of PtO 2 at 60 °C and 5 atmospheres. After suctioning off the catalyst and distilling off the methanol, potassium carbonate solution is added, the mixture is extracted with ether, evaporated and fractionally distilled. The formed N-(4-chloro-3-trifluoromethyl-α-methylphenethyl)-glycine ethyl ester, which boils at 13o°C at 0.25 torr, is transferred to the hydrochloride (m.p.: 165-167°C). with ethereal hydrochloric acid.

Eksempel 2a Example 2a

Analogt med eksempel 2 fremstilles l-(4-klor-3-trifluormetyl-a-metylfenetyl)-glycin fra l-(4~klor-3-trifluormetylfenyl)-2-propanon og glycin. Smeltepunkt 208 - 210°C(hydroklorid) Eksempel 3 (Fremgangsmåte a) Analogous to example 2, 1-(4-chloro-3-trifluoromethyl-α-methylphenethyl)-glycine is prepared from 1-(4-chloro-3-trifluoromethylphenyl)-2-propanone and glycine. Melting point 208 - 210°C (hydrochloride) Example 3 (Procedure a)

1-( 4- klor- 3- trifluormetylfenyl)- 2- aminopropan 1-(4-chloro-3-trifluoromethylphenyl)-2-aminopropane

Fra det i eksempel 1 beskrevne 1-(4-klor-3-trifluor-metylf enyl)-2-propanon fremstilles i pyridin med hydroksylamin 1-(4-klor-3-trifluormetylfenyl)-2-propanon-oksim (sm.p.: 94-96°C). 7,5 g av denne forbindelse hydrogeneres i 50 ml metanol med Raney-nikkel som katalysator under normalbetingelser, befris for katalysator og oppløsningsmiddel og destilleres fraksjonert. Det dannede 1-(4-klor-3-trifluormetylfenyl)-2-amino-propan (k.p.:^,.: 120-124°c) gir i acetonitril med eterisk saltsyre hydrokloridet (sm.p.:196-198°C). From the 1-(4-chloro-3-trifluoromethylphenyl)-2-propanone described in example 1 is prepared in pyridine with hydroxylamine 1-(4-chloro-3-trifluoromethylphenyl)-2-propanone oxime (m.p. .: 94-96°C). 7.5 g of this compound are hydrogenated in 50 ml of methanol with Raney nickel as catalyst under normal conditions, freed from catalyst and solvent and fractionally distilled. The formed 1-(4-chloro-3-trifluoromethylphenyl)-2-amino-propane (b.p.:^,.: 120-124°C) gives in acetonitrile with ethereal hydrochloric acid the hydrochloride (m.p.: 196-198°C ).

på analog måte med eksempelene på fremgangsmåte a fremstilles : 1-(4-klor-3-trifluormetylfenyl)-2-(3-hydroksypropyl-amino)-propan-hydroklorid (Sm 421), sm.p.:141-143°C. in an analogous manner to the examples of method a, the following is prepared: 1-(4-chloro-3-trifluoromethylphenyl)-2-(3-hydroxypropyl-amino)-propane hydrochloride (Sm 421), m.p.: 141-143°C .

Eksempel 4 (Fremgangsmåte b) Example 4 (Procedure b)

. 1-( 4- klor- 3- trifluormetylfenyl)- 2- aminopropan . 1-(4-chloro-3-trifluoromethylphenyl)-2-aminopropane

Til 16 g litiumalanat i 400 ml eter settes dråpevis ved 25°C en oppløsning i 100 ml eter av 1-(4-klor-3-trifluormetyl-fenyl)-2-nitropropan, hvis fremstilling er beskrevet i eksempel 1, og blandingen kokes i 2 timer under tilbakeløpskjøling. Deretter helles blandingen i isvann, eterfasen tørres, inndampes og destilleres fraksjonert. Fra det dannede 1-(4-klor-3-trifluormetyl-fenyl)-2-aminopropan (k.p. : 124°C ) fremstilles i acetonitril med eterisk saltsyre hydrokloridet som smelter ved 196-198 C, etter omkrystallisering i litt acetonitril. To 16 g of lithium alanate in 400 ml of ether is added dropwise at 25°C a solution in 100 ml of ether of 1-(4-chloro-3-trifluoromethyl-phenyl)-2-nitropropane, the preparation of which is described in example 1, and the mixture is boiled for 2 hours under reflux. The mixture is then poured into ice water, the ether phase is dried, evaporated and fractionally distilled. From the formed 1-(4-chloro-3-trifluoromethyl-phenyl)-2-aminopropane (b.p.: 124°C), the hydrochloride is prepared in acetonitrile with ethereal hydrochloric acid, which melts at 196-198 C, after recrystallization in a little acetonitrile.

på tilsvarende måte fremstilles: 1-(6-klor-3-trifluormetylfenyl)-2-aminopropan-hydroklorid, sm.p.:226-230°C. prepared in a similar way: 1-(6-chloro-3-trifluoromethylphenyl)-2-aminopropane hydrochloride, m.p.: 226-230°C.

Eksempel 5 (Fremgangsmåte c) Example 5 (Procedure c)

1-( 4- klor- 3- trifluormetylfenyl)- 2- benzylaminopropan Det i eksempel 1 beskrevne 1-(4-klor-3-trifluormetyl-fenyl)-2-propanon reduseres med natriumboranat til den tilsvarende 2-propanol (k.p.^2:134°C) og overføres med- metansulfonsyre-klorid til 1-(4-klor-3-trifluormetylfenyl)-2-propanolmetansul-fonat (sm.p.:70°C). 15 g av denne forbindelse, 5,5 g benzylamin og 7 g I^CO-j kokes i 50 ml xylen i 8 timer under tilbakeløps-kjøling, bunnfallet avsuges deretter, og xylen avdestilleres. Residuet oppløses i acetonitril, og 1-(4-klor-3-trifluormetyl-fenyl)-benzylaminopropan-metansulfonat (sm.p.:158-162°C) ut-krystalliseres. 1-(4-chloro-3-trifluoromethylphenyl)-2-benzylaminopropane The 1-(4-chloro-3-trifluoromethyl-phenyl)-2-propanone described in example 1 is reduced with sodium boranate to the corresponding 2-propanol (b.p.^2 :134°C) and transferred with methanesulfonic acid chloride to 1-(4-chloro-3-trifluoromethylphenyl)-2-propanol methanesulfonate (m.p.: 70°C). 15 g of this compound, 5.5 g of benzylamine and 7 g of I^CO-j are boiled in 50 ml of xylene for 8 hours under reflux cooling, the precipitate is then suctioned off, and the xylene is distilled off. The residue is dissolved in acetonitrile, and 1-(4-chloro-3-trifluoromethyl-phenyl)-benzylaminopropane-methanesulfonate (m.p.: 158-162°C) is crystallized out.

Eksempel 5a Example 5a

Analogt med eksempel 5 får man 1-(4-klor-3-trifluor-metylf enyl) -2-hydroksyetylaminopropan fra 1-(4-klor-3-trifluor-metylfenyl)-2-propylklorid og 2-hydroksyetylamin. Smelte- Analogous to example 5, 1-(4-chloro-3-trifluoromethylphenyl)-2-hydroxyethylaminopropane is obtained from 1-(4-chloro-3-trifluoromethylphenyl)-2-propyl chloride and 2-hydroxyethylamine. Melt-

punkt 118 - 120°C (hydroklorid). point 118 - 120°C (hydrochloride).

Eksempel 5b Example 5b

Analogt med eksempel 5 får man 1-(4-klor-3-trifluor-metylfenyl)-2-etylaminopropan fra l-(4-klor-3-trifluormetyl-fenyl)-2-propyltosylat og etylamin. Smeltepunkt 199 - 200°c (hydroklorid). Analogous to example 5, 1-(4-chloro-3-trifluoromethylphenyl)-2-ethylaminopropane is obtained from 1-(4-chloro-3-trifluoromethyl-phenyl)-2-propyltosylate and ethylamine. Melting point 199 - 200°c (hydrochloride).

Eksempel 5c Example 5c

Analogt med eksempel 5 får man N-(4-klor-3-trifluormetyl-a-metyl-fenetyl)-glycin fra 1-(4-klor-3-trifluormetylfenyl)-2-propylbromid og glycinetylester. Smeltepunkt 165 - 7 oC (hydroklorid). Analogous to example 5, N-(4-chloro-3-trifluoromethyl-α-methyl-phenethyl)-glycine is obtained from 1-(4-chloro-3-trifluoromethylphenyl)-2-propyl bromide and glycine ethyl ester. Melting point 165 - 7 oC (hydrochloride).

Eksempel 5d Example 5d

Analogt med eksempel 5 får man N-(4-klor-3-trifluormetyl-a-metyl-fenetyl)-glycin fra 1-(4-klor-3-trifluormetylfenyl)-2-propylbromid og glycin. Smeltepunkt 208 - 10°C (hydroklorid; spaltning). Analogous to example 5, N-(4-chloro-3-trifluoromethyl-α-methyl-phenethyl)-glycine is obtained from 1-(4-chloro-3-trifluoromethylphenyl)-2-propyl bromide and glycine. Melting point 208 - 10°C (hydrochloride; decomposition).

Eksempel 6 (Fremgangsmåte d) Example 6 (Procedure d)

1-( 6- klor- 3- trifluormetylfenyl)- 2- metylaminopropan 1-(6-chloro-3-trifluoromethylphenyl)-2-methylaminopropane

10 g 1-(6-klor-3-trifluormetylfenyl)-2-propanon, som fremstilles på tilsvarende måte som det i eksempel 1 angitte 1-(4-klor-3-trifluormetylfenyl)-2-propanon, 8,5 g metylformamid og 2 ml maursyre kokes i 2 timer under tilbakeløpskjøling, der- 10 g of 1-(6-chloro-3-trifluoromethylphenyl)-2-propanone, which is prepared in a similar way to the 1-(4-chloro-3-trifluoromethylphenyl)-2-propanone specified in example 1, 8.5 g of methylformamide and 2 ml of formic acid are boiled for 2 hours under reflux, where-

etter tilsettes ytterligere 2 ml maursyre, og oppvarming fort- then a further 2 ml of formic acid is added, and heating continues

settes i 3 timer. Deretter helles blandingen på is, ekstraheres med eter og inndampes. Residuet består av det urensede N-formyl-1-(6-klor-3-trifluormetylfenyl)-2-metylaminopropan. For hydro- set for 3 hours. The mixture is then poured onto ice, extracted with ether and evaporated. The residue consists of the crude N-formyl-1-(6-chloro-3-trifluoromethylphenyl)-2-methylaminopropane. For hydro-

lyse kokes dette i 100 ml 20%-ig saltsyre i 7 timer under til-bakeløpskjøling, blandingen inndampes, residuet oppløses i vann, ekstraheres med eter, den vandige fase gjøres alkalisk med natron- light, this is boiled in 100 ml of 20% hydrochloric acid for 7 hours under reflux, the mixture is evaporated, the residue is dissolved in water, extracted with ether, the aqueous phase is made alkaline with sodium

lut og utetres. Etter avdamping av eteren oppløses residuet i acetonitril, og med eterisk saltsyre og eter utfelles l-(6-klor-3-trifluormetylfenyl)-2-metylaminopropan-hydroklorid, som etter omkrystallisering fra acetonitril smelter ved 146-148°C. lye and uteres. After evaporation of the ether, the residue is dissolved in acetonitrile, and with ethereal hydrochloric acid and ether, 1-(6-chloro-3-trifluoromethylphenyl)-2-methylaminopropane hydrochloride is precipitated, which after recrystallization from acetonitrile melts at 146-148°C.

På analog måte fremstilles: In an analogous way, the following is produced:

Eksempel 7 (Fremgangsmåte d) Example 7 (Procedure d)

1-( 4, klor- 3- trifluormetylfenyl)- 2- amino- 2- metyl- propan 1-( 4, Chloro- 3- trifluoromethylphenyl)- 2- amino- 2- methyl- propane

Fra det i eksempel 1 beskrevne 1-(4-klor-3-trifluor-metylf enyl)-2-propanon fremstilles med metylmagnesiumjodid l-(4-klor-3-trifluormetylfenyl)-2-metyl-2-propanol (k.p.^^:132°C).Til en avkjølt blanding av 5,6 g natriumcyanid i 11,2 ml iseddik settes dråpevis under 20°C en oppløsning av 21,5 ml konsentrert svovelsyre og 11,2 ml iseddik. Deretter tilsettes 24 g 1-(4-klor-3-trifluormetylfenyl)-2-metyl-2-propanol, og blandingen etter-røres i 1 time ved 70°C. Den helles deretter i isvann, nøytraliseres med konsentrert natronlut og utetres. Etter inn-xlamping foretas destillert fraksjon. 10 g 4-klor-3-trifluormetyl-jx,a-dimetylfenetylformamid (k.p.Q6:160-164°C) kokes i 6 timer med 100 ml 20%-ig saltsyre. Deretter avkjøles, og 1-(4-klor-3-trifluormetylfenyl)-2-amino-2-metyl-propan-hydroklorid avsuges, ettervaskes med eter og omkrystalliseres fra acetonitril (sm.p.: 226-228°C). From the 1-(4-chloro-3-trifluoromethylphenyl)-2-propanone described in example 1 is prepared with methylmagnesium iodide 1-(4-chloro-3-trifluoromethylphenyl)-2-methyl-2-propanol (b.p.^^ :132°C).A solution of 21.5 ml of concentrated sulfuric acid and 11.2 ml of glacial acetic acid is added dropwise below 20°C to a cooled mixture of 5.6 g of sodium cyanide in 11.2 ml of glacial acetic acid. Then 24 g of 1-(4-chloro-3-trifluoromethylphenyl)-2-methyl-2-propanol are added, and the mixture is then stirred for 1 hour at 70°C. It is then poured into ice water, neutralized with concentrated caustic soda and strained. After in-xamping, a distilled fraction is made. 10 g of 4-chloro-3-trifluoromethyl-x,a-dimethylphenethylformamide (b.p. Q6: 160-164°C) is boiled for 6 hours with 100 ml of 20% hydrochloric acid. It is then cooled, and 1-(4-chloro-3-trifluoromethylphenyl)-2-amino-2-methyl-propane hydrochloride is filtered off with suction, washed with ether and recrystallized from acetonitrile (m.p.: 226-228°C).

på analog måte fremstilles: 1-(4-klor-3-trifluormetylfenyl)-2-amino-l,1,2-trimetylpropan-hydroklorid, sm.p.: 205°C (spaltning). prepared in an analogous manner: 1-(4-chloro-3-trifluoromethylphenyl)-2-amino-1,1,2-trimethylpropane hydrochloride, m.p.: 205°C (decomposition).

Eksempel 8 (Fremgangsmåte e) Example 8 (Procedure e)

4- klor- 3- trifluormetyl- g- metylfenetyl- karbamidsyreetylester 4- chloro- 3- trifluoromethyl- g- methylphenethyl- carbamic acid ethyl ester

Til en blanding av 7 g av det i eksempel 4 beskrevne 1- (4-klor-3-trifluormetylfenyl)-2-aminopropan, 4 g natriumkarbon-at og 50 ml acetonitril settes dråpevis 3,3 g klormaursyreetyl-ester, og blandingen oppvarmes i 15 minutter til 40°C. Deretter omrøres i 12 timer, blandingen avsuges og inndampes. Den gjenværende olje oppløses i eter, ristes med fortynnet saltsyre, og eterfasen inndampes. Etter fraksjonert destillasjon får man 4-klor-3-trifluormetyl-a-metylfenetylkarbamidsyreetylester (k.p.Q 35# som krystalliserer fra petroleter (sm.p.:56-58°C). To a mixture of 7 g of the 1-(4-chloro-3-trifluoromethylphenyl)-2-aminopropane described in example 4, 4 g of sodium carbonate and 50 ml of acetonitrile, 3.3 g of chloroformic acid ethyl ester are added dropwise, and the mixture is heated for 15 minutes at 40°C. It is then stirred for 12 hours, the mixture is filtered off and evaporated. The remaining oil is dissolved in ether, shaken with dilute hydrochloric acid, and the ether phase is evaporated. After fractional distillation, 4-chloro-3-trifluoromethyl-a-methylphenethylcarbamic acid ethyl ester (b.p.Q 35#) is obtained which crystallizes from petroleum ether (m.p.: 56-58°C).

Eksempel 8a Example 8a

Analogt med eksempel 8 får man 4-klor-3-trifluormetyl-fenetyl-karbamidisyreetyl-tioester fra l-(4-klor-3-trifluormetyl-fenyl)-2-aminopropan og klormaursyremetyltioester. Smeltepunkt 67°C (base) . Analogous to example 8, 4-chloro-3-trifluoromethyl-phenethyl-carbamic acid ethyl thioester is obtained from 1-(4-chloro-3-trifluoromethyl-phenyl)-2-aminopropane and chloroformic acid methyl thioester. Melting point 67°C (base).

Eksempel 9 Example 9

2- ( 4- klor- 3- trifluormetyl- a- metylfenetylamino)- acetonitril 2-( 4- chloro- 3- trifluoromethyl- a- methylphenethylamino)- acetonitrile

Til 13,7 g av en 38%-ig, vandig natriumhydrogensulfit-oppløsning settes 5 g av en 30%-ig formalinoppløsning, og_ etter-røring foretas i 10 minutter. Deretter tilsettes dråpevis 12 g av det i eksempel 4 beskrevne 1-(4-klor-3-trifluormetylfenyl)-2-aminopropan, hvorved temperaturen stiger til 60°C. Etter dråpevis tilsetning av en oppløsning av 3,75 g kaliumcyanid i7,5 ml vann, etter-røres i 1 time, deretter tilsettes vann, og blandingen utetres. Eterfasen tørres og inndampes, og den gjenværende olje destilleres fraksjonert. 2-(4-klor-3-trifluormetyl-a-metyl-fenetylamino)-acetonitril som destillerer over ved 0,02 torr ved 130-150°C, oppløses i litt etylacetat, surgjøres med metansulfonsyre, og metansulfonatet som utkrystalliserer etter etertilset-ning, omkrystalliseres fra alkohol (sm.p.:181°C, spaltning). 5 g of a 30% formalin solution are added to 13.7 g of a 38% aqueous sodium hydrogen sulphite solution, and stirring is carried out for 10 minutes. 12 g of the 1-(4-chloro-3-trifluoromethylphenyl)-2-aminopropane described in example 4 are then added dropwise, whereby the temperature rises to 60°C. After the dropwise addition of a solution of 3.75 g of potassium cyanide in 7.5 ml of water, the mixture is stirred for 1 hour, then water is added, and the mixture is strained. The ether phase is dried and evaporated, and the remaining oil is fractionally distilled. 2-(4-chloro-3-trifluoromethyl-a-methyl-phenethylamino)-acetonitrile which distills over at 0.02 torr at 130-150°C, is dissolved in a little ethyl acetate, acidified with methanesulfonic acid, and the methanesulfonate which crystallizes after the addition of ether- ning, recrystallized from alcohol (m.p.: 181°C, cleavage).

Eksempel 10 (Fremgangsmåte d) Example 10 (Procedure d)

1-( 4- klor- 3- trifluormetylfenyl)- 2- aminopropan 1-(4-chloro-3-trifluoromethylphenyl)-2-aminopropane

Ved koking av det i eksempel 1 fremstilte 4-klor-3-trifluormetylbenzylklorid med natriumetylat og monometylmalon-syredietylester i absolutt metanol får man 4-klor-3-trifluormetyl-benzyl-metylmalonsyredietylester( k.p. O , ^OnD:118-120°C), som ved hjelp av kaliumhydroksyd i metanol/vann (2 : 1) forsepes til 4-klor-3-trifluorrnetylbenzylmetylraalonsyre. Ved oppvarming til 250°C dannes 1-(4-klor-3-trifluormetylfenyl)-isosmørsyre, som ved hjelp av tionylklorid overføres til 1-(4-klor-3-trifluor-metylf enyl)-isobutyryklorid (k.p.Q Q^:90-92OC). By boiling the 4-chloro-3-trifluoromethylbenzyl chloride prepared in example 1 with sodium ethylate and monomethylmalonic acid diethyl ester in absolute methanol, 4-chloro-3-trifluoromethylbenzylmethylmalonic acid diethyl ester is obtained (b.p. O , ^OnD: 118-120°C) , which is saponified with the help of potassium hydroxide in methanol/water (2:1) to 4-chloro-3-trifluoromethylbenzylmethylraalonic acid. When heated to 250°C, 1-(4-chloro-3-trifluoromethylphenyl)-isobutyric acid is formed, which with the help of thionyl chloride is transferred to 1-(4-chloro-3-trifluoromethylphenyl)-isobutyric chloride (b.p.Q Q^:90 -92°C).

Til 48,5 g 1-(4-klor-3-trifluormetylfenyl)-isobutyry-klorid i 250 ml dioksan settes dråpevis 35 ml konsentrert ammoniakk under omrøring, etter 10 minutter helles blandingen i isvann og surgjøres med fortynnet saltsyre. 16 g av det utkrystal-liserte 1-(4-klor-3-trifluormetylfenyl)-isosmørsyreamid (sm.p.: 86-88°C) settes til en blanding av fortynnet natronlut (14,5 g etznatron i 120 ml vann) og 3,7 ml brom ved 0°C, deretter omrøres i 1 1/2 time ved 20-25°C og 4 1/2 time ved 60°C. Ved utrysting med eter og surgjøring med eterisk saltsyre får- man l-(4-klor-3-trifluormetylfenyl)-2-aminopropan-hydroklorid, som smelter ved 195-197°C. To 48.5 g of 1-(4-chloro-3-trifluoromethylphenyl)-isobutyry chloride in 250 ml of dioxane, 35 ml of concentrated ammonia is added dropwise while stirring, after 10 minutes the mixture is poured into ice water and acidified with dilute hydrochloric acid. 16 g of the crystallized 1-(4-chloro-3-trifluoromethylphenyl)-isobutyric acid amide (m.p.: 86-88°C) is added to a mixture of diluted caustic soda (14.5 g caustic soda in 120 ml water) and 3.7 ml of bromine at 0°C, then stirred for 1 1/2 hours at 20-25°C and 4 1/2 hours at 60°C. By shaking out with ether and acidifying with ethereal hydrochloric acid, 1-(4-chloro-3-trifluoromethylphenyl)-2-aminopropane hydrochloride is obtained, which melts at 195-197°C.

Eksempel 11 Example 11

1-( 4- klor- 3- trifluormetylfenyl)- 2-( 3- klorpropylamino)- propan 1-( 4- chloro- 3- trifluoromethylphenyl)- 2-( 3- chloropropylamino)- propane

3 g 1-(4-klor-3-trifluormetylfenyl)-2-(3-hydroksypro-pylamino)-propan-hydroklorid fremstilt analogt med eksempel 3, kokes i 50 ml acetonitril med 1 ml tionylklorid i 30 minutter under tilbakeløpskjøling, reaksjonsblandingen inndampes, og residuet oppslemmes i eter. Det krystallinske 1-(4-klor-3-trifluor-metylf enyl ) -2- (3-klorpropylamino ) -propan-hydroklorid avsuges og smelter etter omkrystallisering fra vann. ved 15o^.l52°C3 g of 1-(4-chloro-3-trifluoromethylphenyl)-2-(3-hydroxypropylamino)-propane hydrochloride, prepared analogously to example 3, are boiled in 50 ml of acetonitrile with 1 ml of thionyl chloride for 30 minutes under reflux, the reaction mixture is evaporated , and the residue is slurried in ether. The crystalline 1-(4-chloro-3-trifluoromethylphenyl)-2-(3-chloropropylamino)-propane hydrochloride is filtered off with suction and melts after recrystallization from water. at 15o^.l52°C

På tilsvarende måte får man fra 1-(4-klor-3-trifluor-metylf enyl)-2-(2-hydroksyetylamino)-pr opan med tionylklorid 1-(4-klor-3-trifluor-metylfenyl)-2-(2-kloretylamino)-propan-hydroklorid, som smelter ved 154-156°C. In a similar way, one obtains from 1-(4-chloro-3-trifluoromethylphenyl)-2-(2-hydroxyethylamino)-propane with thionyl chloride 1-(4-chloro-3-trifluoromethylphenyl)-2-( 2-chloroethylamino)-propane hydrochloride, which melts at 154-156°C.

Eksempel 12a Example 12a

1-( 4- klor- 3- trifluormetylfenyl)- 2 -( 2- kloracetyl- aminopropan) 1-( 4- chloro- 3- trifluoromethylphenyl)- 2-( 2- chloroacetyl- aminopropane)

Man lar en blanding av 62,8 g (0,2 mol) l-(4-klor-3-trifluormetylfenyl)-2-aminopropan, fremstilt ved en av frem-gangsmåtene a), b), c) eller d) og 10,2 ml 2-kloracetylklorid i 250 ml acetonitril reagere i 1 time ved romtemperatur. Der-efter frafiltreres utfelt salt, filtratet inndampes, og tittel-forbindelsen utfelles med petroleter. Smeltepunkt: 59 - 63°C (base). A mixture of 62.8 g (0.2 mol) of 1-(4-chloro-3-trifluoromethylphenyl)-2-aminopropane, prepared by one of the methods a), b), c) or d) and 10.2 ml of 2-chloroacetyl chloride in 250 ml of acetonitrile react for 1 hour at room temperature. The precipitated salt is then filtered off, the filtrate is evaporated, and the title compound is precipitated with petroleum ether. Melting point: 59 - 63°C (base).

Eksempel 12b Example 12b

1- ( 4- klor- 3- trifluormetylfenyl)- 2 -( 2- benzyl- aminoacetylamino)-propan 1-(4-chloro-3-trifluoromethylphenyl)-2-(2-benzylaminoacetylamino)-propane

12,6 g l-(4-klor-3-trifluormetylfenyl)-2-(2-kloracetyl-amino)-propan kokes i 100 ml acetonitril med 9,4 g benzylamin 12.6 g of 1-(4-chloro-3-trifluoromethylphenyl)-2-(2-chloroacetyl-amino)-propane are boiled in 100 ml of acetonitrile with 9.4 g of benzylamine

i 2 timer under tilbakeløpskjøling, og etter fjernelse av benzylamin -hydrokloridet og oppløsningsmidlet i iseddik vaskes med vann, og med eterisk saltsyre utfelles 1-(4-klor-3-trifluormetyl-fenyl) -2-(2-benzylaminoacetylamino)-propan-hydroklorid, som efter omkrystallisering fra vann smelter ved 161 - 164°c. for 2 hours under reflux, and after removing the benzylamine hydrochloride and the solvent in glacial acetic acid, wash with water, and with ethereal hydrochloric acid precipitate 1-(4-chloro-3-trifluoromethyl-phenyl)-2-(2-benzylaminoacetylamino)-propane- hydrochloride, which after recrystallization from water melts at 161 - 164°c.

Eksempel 13 Example 13

1-( 4- klor- 3- trifluormetylfenyl)- 2-( 2- amino- acetylamino- propan 1-( 4- chloro- 3- trifluoromethylphenyl)- 2-( 2- amino- acetylamino- propane

Ved omsetning av 1-(4-klor-3-trifluormetylfenyl)-2-(2-kloracetylamino)-propan i dimetylformamid med ftalimid- By reacting 1-(4-chloro-3-trifluoromethylphenyl)-2-(2-chloroacetylamino)-propane in dimethylformamide with phthalimide-

kalium ved 100°C får man 1-(4-klor-3-trifluormetylfenyl)-2-(2-ftalimidoacetylamino)-propan. 16 g av denne forbindelse tilbake-løpsbehandles i 250 ml etanol med 3,8 g hydrazinhydrat i 1 time, surgjøres deretter med iseddik, avkjøles, avsuges og inndampes. Residuet oppløses i vann, avsuges over aktivt kull, gjøres alkalisk med ammoniakk, ekstraheres med etylacetat, vaskes med vann, tørres og inndampes. Residuet oppløses i acetonitril og surgjøres med metansulfonsyre. 1-(4-klor-3-trifluormetylfenyl)-2-(2-amino-acetylamino)-propanmetansulfonat utkrystalliserer. Det smelter etter omkrystalliserinq fra alkohol ved 193-196°C. potassium at 100°C gives 1-(4-chloro-3-trifluoromethylphenyl)-2-(2-phthalimidoacetylamino)-propane. 16 g of this compound are refluxed in 250 ml of ethanol with 3.8 g of hydrazine hydrate for 1 hour, then acidified with glacial acetic acid, cooled, suction filtered and evaporated. The residue is dissolved in water, filtered off over activated carbon, made alkaline with ammonia, extracted with ethyl acetate, washed with water, dried and evaporated. The residue is dissolved in acetonitrile and acidified with methanesulfonic acid. 1-(4-Chloro-3-trifluoromethylphenyl)-2-(2-amino-acetylamino)-propanemethanesulfonate crystallizes out. It melts after recrystallization from alcohol at 193-196°C.

Eksempel 13a Example 13a

På analog måte får man l-(4-klor-3-trifluormetylfenyl)-2- aminopropan fra 1-(4-klor-3-trifluormetylfenyl)-2-(ftalimido)-propan. Smeltepunkt 168 - 169°C (hydroklorid). In an analogous manner, 1-(4-chloro-3-trifluoromethylphenyl)-2-aminopropane is obtained from 1-(4-chloro-3-trifluoromethylphenyl)-2-(phthalimido)-propane. Melting point 168 - 169°C (hydrochloride).

Eksempel 14 Example 14

1-( 4- klor- 3- trifluormetylfenyl)- 2-( 2- hydroksy- 2- fenyletylamino)-propan 1-( 4- chloro- 3- trifluoromethylphenyl)- 2-( 2- hydroxy- 2- phenylethylamino)- propane

Den fra 7 g 1-(4-klor-3-trifluormetylfenyl)-2-(fenacyl-amino)-propanhydroklorid fremstilte base reduseres i 50 ml etanol med 0,7 g natriumborhydrid ved romtemperatur, og etter fjernelse The base prepared from 7 g of 1-(4-chloro-3-trifluoromethylphenyl)-2-(phenacyl-amino)-propane hydrochloride is reduced in 50 ml of ethanol with 0.7 g of sodium borohydride at room temperature, and after removal

av oppløsningsmidlet og spaltning av overskudd av natriumborhyd- of the solvent and cleavage of excess sodium borohydride

rid i eter, tilsettes den beregnete mengde eterisk saltsyre. 1-(4-klor-3-trifluormetylfenyl) -2-(2-hydroksy-2-fenylétylamino)-propan-hydroklorid utkrystalliserer. Det smelter ved 165-167°C etter omkrystallisering fra litt acetonitril. rid in ether, the calculated amount of ethereal hydrochloric acid is added. 1-(4-chloro-3-trifluoromethylphenyl)-2-(2-hydroxy-2-phenylethylamino)-propane hydrochloride crystallizes out. It melts at 165-167°C after recrystallization from a little acetonitrile.

Eksempel 15 Example 15

1-( 4- klor- 3- trifluormetylfenyl)- 2- [ 2-( 7- teofyllinyl)- etylamino]-Pr°Pan 1-( 4- Chloro- 3- trifluoromethylphenyl)- 2- [ 2-( 7- theophyllinyl)- ethylamino]-Pr°Pan

En blanding av 15 g 1-(4-klor-3-trifluormetylfenyl)-2-amino-propan og 7,6 g 6-(2-kloretyl)-teofyllin oppvarmes til 190°C. Derved inntrer en eksoterm reaksjon. Deretter omrøres blandingen i 1 time ved 170°C, avkjøles, tilsettes etylacetat, avsuges og filtratet surgjøres med eterisk saltsyre. Det ut-krystalliserende 1-(4-klor-3-trifluormetylfenyl)-2-[2-(7-teo-fyllinyl)-etylamino]-propan-hydroklorid har etter omkrystallisering fra metanol et smeltepunkt på 244-248°C. A mixture of 15 g of 1-(4-chloro-3-trifluoromethylphenyl)-2-amino-propane and 7.6 g of 6-(2-chloroethyl)-theophylline is heated to 190°C. Thereby an exothermic reaction occurs. The mixture is then stirred for 1 hour at 170°C, cooled, ethyl acetate is added, filtered off and the filtrate acidified with ethereal hydrochloric acid. The crystallising 1-(4-chloro-3-trifluoromethylphenyl)-2-[2-(7-theo-phyllinyl)-ethylamino]-propane hydrochloride has, after recrystallization from methanol, a melting point of 244-248°C.

Eksempel 16 Example 16

1-( 4- klor- 3- trifluormetylfenyl)- 2- acetonylamino)- propan 1-(4-chloro-3-trifluoromethylphenyl)-2-acetonylamino)-propane

Til den kokende blanding av 6,45 g 1-(4-klor-3-tri-fluormetylfenyl)-2-aminopropan, 50 ml acetonitril og 2,93 g na-triumkarbonat settes dråpevis 2,53 ml kloraceton, og blandingen kokes i 1 time under tilbakeløpskjøling. Etter avsugning og inn-damping oppløses residuet i etylacetat, og ved hjelp av eterisk saltsyre og eter utfelles 1-(4-klor-3-trifluormetylfenyl)-2-(acetonylamino)-propan-hydroklorid, som etter omkrystallisering fra isopropanol smelter ved 191-194°C. To the boiling mixture of 6.45 g of 1-(4-chloro-3-trifluoromethylphenyl)-2-aminopropane, 50 ml of acetonitrile and 2.93 g of sodium carbonate, 2.53 ml of chloroacetone are added dropwise, and the mixture is boiled in 1 hour under reflux cooling. After suction and evaporation, the residue is dissolved in ethyl acetate, and with the help of ethereal hydrochloric acid and ether, 1-(4-chloro-3-trifluoromethylphenyl)-2-(acetonylamino)-propane hydrochloride is precipitated, which after recrystallization from isopropanol melts at 191 -194°C.

Eksempel 17 Example 17

1-( 4- klor- 3- trifluormetylfenyl)- 2-( 2- cyanoetylamino)- propan 1-( 4- chloro- 3- trifluoromethylphenyl)- 2-( 2- cyanoethylamino)- propane

En blanding av 5 g 1-(4-klor-3-trifluormetylfenyl)-2-amino—propan og 1,2 g akrylnitril omrøres i 5 timer ved 90°C, deretter avdestilleres uomsatt amin (k.p.^j. = 124°c), og fra det i etylacetat oppløste residum utfelles ved hjelp av eterisk saltsyre og eter 1-(4-klor-3-trifluormetylfenyl)-2-(2-cyanoetyl-amino ) -propan-hydroklorid , som etter omkrystallisering-fra litt vann smelter ved 170-173°C. A mixture of 5 g of 1-(4-chloro-3-trifluoromethylphenyl)-2-amino-propane and 1.2 g of acrylonitrile is stirred for 5 hours at 90°C, then unreacted amine is distilled off (b.p.^j. = 124°c ), and from the residue dissolved in ethyl acetate is precipitated with the help of ethereal hydrochloric acid and ether 1-(4-chloro-3-trifluoromethylphenyl)-2-(2-cyanoethyl-amino)-propane hydrochloride, which after recrystallization-from a little water melts at 170-173°C.

Eksempel 18 Example 18

1—( 4- klor- 3- trifluormetylfenyl)- 2-( 2- hydroksyetylamino)- propan En blanding av 23,7 g 1-(4-klor-3-trifluormetylfenyl)- 1-(4-chloro-3-trifluoromethylphenyl)-2-(2-hydroxyethylamino)-propane A mixture of 23.7 g of 1-(4-chloro-3-trifluoromethylphenyl)-

2-amino-propan, 3,6 g etylenoksyd, 120 ml metanol og 1,2 5 ml vann ristes i trykkar i 48 timer ved romtemperatur. Etter av-destillering av oppløsningsmidlet destilleres residuet fraksjonert. Det erholdte 1-(4-klor-3-trifluormetylfenyl)-2-(2-hydroksyetylamino)-propan (k.p.Q 2 = 140-145°C) overføres til hydrokloridet (sm.p.: 127-128°C) i etylacetat med eterisk saltsyre og eter. 2-amino-propane, 3.6 g of ethylene oxide, 120 ml of methanol and 1.25 ml of water are shaken in a pressure vessel for 48 hours at room temperature. After distilling off the solvent, the residue is fractionally distilled. The obtained 1-(4-chloro-3-trifluoromethylphenyl)-2-(2-hydroxyethylamino)-propane (b.p. Q 2 = 140-145°C) is transferred to the hydrochloride (m.p.: 127-128°C) in ethyl acetate with ethereal hydrochloric acid and ether.

Eksempel 19 Example 19

1- ( 4- klor- 3- trifluormetylfenyl)- 2-( fenacylamino)- propan 1-( 4- chloro- 3- trifluoromethylphenyl)- 2-( phenacylamino)- propane

En blanding av 23,8 g 1-(4-klor-3-trifluormetylfenyl)-2- amino-propan, 9,3 g a-bromacetofenon og 100 ml acetonitril om-røres i 30 minutter og inndampes. Etter tilsetning av eter foretas avsugning, og filtratet inndampes. Fra residuet som er opp-løst i acetonitril, utfelles ved hjelp av eterisk saltsyre l-(4-klor-3-trifluormetylfenyl)-2-(fenacylamino)-propan-hydroklorid, som etter omkrystallisering fra metanol/vann smelter ved 210-213°C. A mixture of 23.8 g of 1-(4-chloro-3-trifluoromethylphenyl)-2-amino-propane, 9.3 g of α-bromoacetophenone and 100 ml of acetonitrile is stirred for 30 minutes and evaporated. After adding ether, suction is carried out, and the filtrate is evaporated. From the residue dissolved in acetonitrile, 1-(4-chloro-3-trifluoromethylphenyl)-2-(phenacylamino)-propane hydrochloride is precipitated with ethereal hydrochloric acid, which after recrystallization from methanol/water melts at 210-213 °C.

Eksempel 20 Example 20

1-( 4- klor- 3- trifluormetylfenyl)- 2 -( 2- hydroksyetylamino)- propan 1-( 4- Chloro- 3- Trifluoromethylphenyl)- 2-( 2- Hydroxyethylamino)- propane

1,6 g l-(4-klor-3-trifluormetylfenyl) -2-(2-hydroksyetyl-benzylamino)-propanhydroklorid (smeltepunkt 122 - 124 c), fremstilt analogt med eksempel 5 fra 1-(4-klor-3-trifluormetyl-fenyl)-2-propanolmetansulfonat og benzylaminoetanol, hydrogeneres i 50 ml metanol med palladium/kull som katalysator ved romtemperatur og normaltrykk. Efter avsugning og inndampning får man 0,9 g (72,5 % utbytte) l-(4-klor-3-trifluormetylfenyl)-2-(2-hydroksyetylamino)-propanhydroklorid, som efter omkrystallisering fra etylacetat/eter smelter ved 127 - 128°C. 1.6 g of 1-(4-chloro-3-trifluoromethylphenyl)-2-(2-hydroxyethyl-benzylamino)-propane hydrochloride (melting point 122 - 124 c), prepared analogously to example 5 from 1-(4-chloro-3- trifluoromethyl-phenyl)-2-propanol methanesulfonate and benzylaminoethanol, are hydrogenated in 50 ml of methanol with palladium/charcoal as catalyst at room temperature and normal pressure. After suction and evaporation, 0.9 g (72.5% yield) of 1-(4-chloro-3-trifluoromethylphenyl)-2-(2-hydroxyethylamino)-propane hydrochloride is obtained, which after recrystallization from ethyl acetate/ether melts at 127 - 128°C.

Claims (3)

1. Analogifremgangsmåte for fremstilling av fysiologisk aktive forbindelser med den generelle formel hvor Cl betyr et kloratom i 4- eller 6-stilling, R^, R2 og R^ betyr hydrogen eller metyl, og R4 betyr hydrogen, en lavere alkylrest, en benzyl- eller en teofyllin-(7)-etyl-gruppe, eller en av restene -C H„ -R_ (hvor n = 1 eller 2, og Rr betyr en kar- n 2n 5 ^5 boksyl-, alkoksykarbonyl- eller nitrilgruppe) , -cm~H2m~R6 eHer -C H. ,(C_H_)-R (hvor m er 2, 3 eller 5, og Rr betyr halogen m 2m-l 6 5 6 b eller en hydroksylgruppe), -Cn-H2n~CO-R (hvor n = 1 eller 2, og R betyr en lavere alkyl- eller en fenylgruppe) eller -CO-R-, (hvor R7 betyr en lavere alkoksy- eller alkyltiogruppe eller en alkylrest, som kan være substituert med et halogenatom eller en benzylamino- eller aminogruppe), og deres salter med fysiologisk forlikelige syreanioner, karakterisert ved at a) et keton med den generelle formel II hvor restene Cl, R^ og R2 har de ovenfor angitte betydninger, kondenseres med en forbindelse med den generelle formel III hvor R8_ betyr hydrogen, en hydroksyl-, amino-, lavere alkyl-, benzyl-, teofyllin-(7)-etyl-gruppe eller en av restene cnH2n-Ry' (hvor n er 1 eller 2, og betyr en karboksyl- eller alkoksykarbonylgruppe), og ^m<H>2m"<R>l0 eller C^^ C^)- R±Q (hvor m er 2, 3 eller 4, og R^Q betyr en hydroksylgruppe, og de derved dannede mellomprodukter med formel IV hvor Cl, R, ,; R„ og R_ har de ovenfor angitte betydninger, eventuelt 1 • 2 o efter forutgående isolering, reduseres, eller kondensasjonen utføres i nærvær av et reduksjonsmiddel, eller b) et nitroolefin med den generelle formel V hvor R^ betyr hydrogen eller en metylgruppe, reduseres med kom-plekse metallhydrider, f.eks. litiumalanat, hvorved det primære aminoalkan (formel I, R4=H) dannes, eller c) en forbindelse med den generelle formel VI hvor restene cl, R^ og R^ har de ovenfor angitte betydninger, og Y betyr resten av en reaktiv ester, f.eks. et halogenatom eller en alkyl- eller aryl-sulfonsyrerest, omsettes på kjent måte med et amin med den generelle formel VII hvor R' har de for Rg angitte betydninger med unntagelse av hydroksyl og amino, eller d) en forbindelse med den generelle formel VIII hvor Cl, R^, R~°9 R3 har de ovenfor angitte betydninger, og A betyr ftalimido- eller succinimidogruppe, en isocyansyrerest eller gruppen (hvor R' har de ovenfor angitte be tydninger og Sk betyr hydrolytisk eller hydrogenolytisk, lett avspaltbare rester, f.eks. acyl eller benzyl), overføres til det ønskede amin ved hydrolyse eller hydrogenolyse, og i de fremstilte, primære aminer.(formel I, R^=H) innføres eventuelt de andre rester med de for R 4 angitte betyd ninger bortsett fra hydrogen, ved alkylering eller acylering på kjent måte, og/eller disse rester R^ kan, når de inneholder funksjonelle grupper, omdannes ved vanlige metoder til hverandre, og/eller de fremstilte baser kan overføres til fysiologisk godtagbare syreaddisjonssalter.1. Analogy method for the production of physiological active compounds of the general formula where Cl means a chlorine atom in the 4- or 6-position, R^, R2 and R^ means hydrogen or methyl, and R4 means hydrogen, a lower alkyl residue, a benzyl or a theophylline-(7)-ethyl group, or one of the residues -C H„ -R_ (where n = 1 or 2, and Rr means a car- n 2n 5 ^5 boxyl, alkoxycarbonyl or nitrile group) , -cm~H2m~R6 eHer -C H. ,(C_H_)-R (where m is 2, 3 or 5, and Rr means halogen m 2m-l 6 5 6 b or a hydroxyl group), -Cn-H2n~CO-R (where n = 1 or 2, and R means a lower alkyl or a phenyl group) or -CO-R-, (where R7 means a lower alkoxy or alkylthio group or a alkyl residue, which may be substituted with a halogen atom or a benzylamino or amino group), and their salts with physiologically compatible acid anions, characterized in that a) a ketone of the general formula II where the radicals Cl, R 1 and R 2 have the meanings given above, are condensed with a compound of the general formula III where R8_ means hydrogen, a hydroxyl-, amino-, lower alkyl-, benzyl-, theophylline-(7)-ethyl group or one of the residues cnH2n-Ry' (where n is 1 or 2, and means a carboxyl or alkoxycarbonyl group), and ^m<H>2m"<R>l0 or C^^ C^)- R±Q (where m is 2, 3 or 4, and R^Q means a hydroxyl group, and the thereby formed intermediates with formula IV where Cl, R, ,; R„ and R_ have the meanings given above, possibly 1 • 2 o after prior isolation, is reduced, or the condensation is carried out in the presence of a reducing agent, or b) a nitroolefin of the general formula V where R 1 means hydrogen or a methyl group, is reduced with complex metal hydrides, e.g. lithium alanate, whereby the primary aminoalkane (formula I, R4=H) is formed, or c) a compound of the general formula VI where the residues cl, R^ and R^ have the meanings given above, and Y means the residue of a reactive ester, e.g. a halogen atom or an alkyl or aryl sulfonic acid residue is reacted in a known manner with an amine of the general formula VII where R' has the meanings given for Rg with the exception of hydroxyl and amino, or d) a compound of the general formula VIII where Cl, R^, R~°9 R3 have the meanings given above, and A means a phthalimido or succinimido group, an isocyanic acid residue or the group (where R' has the above specified be interpretations and Sk means hydrolytic or hydrogenolytic, easily cleavable residues, e.g. acyl or benzyl), is transferred to the desired amine by hydrolysis or hydrogenolysis, and in the primary amines produced (formula I, R^=H) optionally introduce the other residues with the meanings given for R 4 nings except hydrogen, by alkylation or acylation in a known manner, and/or these residues R^ can, when they contain functional groups, be converted by usual methods into each other, and/or the prepared bases can be transferred to physiologically acceptable acid addition salts. 2. Fremgangsmåte som angitt i krav 1 for fremstilling av l-(3-trifluormetyl-4-klorfenyl)-2-aminopropan, karakteri sert ved at det anvendes utgangsmateriale hvor Cl er i 4-stilling, og R^ R2, R3 og R^ respektive Rg respektive R' betyr hydrogen.2. Process as stated in claim 1 for the production of 1-(3-trifluoromethyl-4-chlorophenyl)-2-aminopropane, characterized in that starting material is used where Cl is in the 4-position, and R^ R2, R3 and R ^ respective Rg respectively R' means hydrogen. 3. Fremgangsmåte som angitt i krav 1 for fremstilling av 1-(3-trifluormetyl-4-klorfenyl)-2-(B-hydroksyetyl)-aminopropan karakterisert ved at det anvendes utgangsmat-erialer hvor Cl er i 4-stilling og R^, R2 og F^ er hydrogen, og R4 respektive Rg respektive R" er B-hydroksyetyl eller omdannes dertil.3. Process as set forth in claim 1 for the production of 1-(3-trifluoromethyl-4-chlorophenyl)-2-(B-hydroxyethyl)-aminopropane, characterized in that starting materials are used where Cl is in the 4-position and R , R 2 and F 4 are hydrogen, and R 4 and R 8 and R 1 respectively are B-hydroxyethyl or converted thereto.
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BG21016A3 (en) 1976-01-20
SU439963A3 (en) 1974-08-15
YU36285B (en) 1982-06-18
JPS5750773B1 (en) 1982-10-28
AT317175B (en) 1974-08-12
CH561169A5 (en) 1975-04-30
FR2092123A1 (en) 1972-01-21
CH570968A5 (en) 1975-12-31
ZA712788B (en) 1973-01-31
GB1354451A (en) 1974-06-05
ES402636A1 (en) 1976-01-01
CH579022A5 (en) 1976-08-31
PL85189B1 (en) 1976-04-30
RO62296A (en) 1978-01-15
NL169462C (en) 1982-07-16

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