NO744352L - - Google Patents

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Publication number
NO744352L
NO744352L NO744352A NO744352A NO744352L NO 744352 L NO744352 L NO 744352L NO 744352 A NO744352 A NO 744352A NO 744352 A NO744352 A NO 744352A NO 744352 L NO744352 L NO 744352L
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Norway
Prior art keywords
compound
compound according
carbon atoms
chloro
group
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NO744352A
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Norwegian (no)
Inventor
Y Kawamatsu
T Saraie
E Imamiya
Y Hamuro
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Takeda Chemical Industries Ltd
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Priority claimed from JP13919973A external-priority patent/JPS5093935A/ja
Priority claimed from JP49044634A external-priority patent/JPS5742052B2/ja
Priority claimed from JP5811674A external-priority patent/JPS5724774B2/ja
Priority claimed from JP11655974A external-priority patent/JPS5143738A/en
Application filed by Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Publication of NO744352L publication Critical patent/NO744352L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/38—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. nitrodiphenyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/277—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring

Description

2-halogenpropionsyre og derivater derav. 2-Halopropionic acid and derivatives thereof.

Foreliggende oppfinnelse vedrører nye forbindelser med den generelle,formel: The present invention relates to new compounds with the general formula:

hvor R"*" er hydrogen, lavere alkyl med 1-5 karbonatomer, halogen, hydroksyl, lavere alkoksy med 1-4 karbonatomer eller trifluormetyl; R og R er like eller forskjellige og hver er hydrogen eller lavere alkyl med 1-5 karbonatomer; X er halogen; Y er where R"*" is hydrogen, lower alkyl of 1-5 carbon atoms, halogen, hydroxyl, lower alkoxy of 1-4 carbon atoms or trifluoromethyl; R and R are the same or different and each is hydrogen or lower alkyl of 1-5 carbon atoms; X is halogen; Y is

I IN

oksygen, alkylentio med 1-6 karbonatomer, alkylenoksy med 1-6 karbonatomer, eller alkylendioksy med 1-6 karbonatomerZ er en karboksylgruppe eller en gruppe som kan omdannes til en karboksylgruppe; og n er 1 eller 2. oxygen, alkylenethio of 1-6 carbon atoms, alkyleneoxy of 1-6 carbon atoms, or alkylenedioxy of 1-6 carbon atomsZ is a carboxyl group or a group that can be converted into a carboxyl group; and n is 1 or 2.

Det er foretatt et grundig studium av en re&ke 2-halogenpropionsyrer og derivater derav og man har kommet frem til at de ovenstående nye forbindelser med formel I har betydelige hypolipidemiske, hypoglycemiske og andre biologiske egenskaper. A thorough study of a number of 2-halopropionic acids and derivatives thereof has been carried out and it has been concluded that the above new compounds of formula I have significant hypolipidemic, hypoglycemic and other biological properties.

Formålet med oppfinnelsen er således å tilveiebringe nye forbindelser med formel I hvilke kan benyttes som legemidler for bruk i forbindelse med hyperlipemia. The purpose of the invention is thus to provide new compounds of formula I which can be used as pharmaceuticals for use in connection with hyperlipemia.

Den lavere alkylgruppe med 1-5 karbonatomer som 12 3 The lower alkyl group with 1-5 carbon atoms such as 12 3

representeres av R , R og R kan være.rett eller forgrenet og eksemplifiseres ved metyl, etyl, n-propyl, isopropyl, n-butyl, isobutyl, sek-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl is represented by R , R and R can be straight or branched and exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl

eller lignende. Halogenatomet som kan være en betydning for R"*" etc. The halogen atom which may be a meaning for R"*"

. og X kan være klor, brom, jod og fluor. Alkoksygruppen med 1-4 karbonatomer og som representeres ved R eksemplifiseres ved metoksy, etoksy, n-propoksy, isopropoksy, h-butoksy, isobutoksy, tert-butoksy. Alkylenoksygruppen med 1-6 karbonatomer representert ved Y, kan være rett eller forgrenet og eksemplifiseres ved metylenoksy (-CH^O-), etylenoksy _(-CH2CH2-0-, CH^CH-O-), propylenoksy (-CH2CH2CH2-0-, CH CHCH2-0-, CH^CH^CH-O-, . and X can be chlorine, bromine, iodine and fluorine. The alkoxy group with 1-4 carbon atoms and which is represented by R is exemplified by methoxy, ethoxy, n-propoxy, isopropoxy, h-butoxy, isobutoxy, tert-butoxy. The alkyleneoxy group with 1-6 carbon atoms represented by Y can be straight or branched and is exemplified by methyleneoxy (-CH^O-), ethyleneoxy _(-CH2CH2-0-, CH^CH-O-), propyleneoxy (-CH2CH2CH2-0 -, CH CHCH2-0-, CH^CH^CH-O-,

CH3CH2CHCH2CH2CH2-0-, CH3CHCH2CH2CH2CH20-,). Al<kylendioksygruppen>med 1-6 karbonatomer representert ved Y kan være rett eller forgrenet og eksemplifiseres ved metylendioksy (-0-CH2~0-), CH3CH2CHCH2CH2CH2-0-, CH3CHCH2CH2CH2CH20-,). Al<kylenedioxy group> with 1-6 carbon atoms represented by Y can be straight or branched and is exemplified by methylenedioxy (-0-CH2~0-),

Alkylentiogruppen med 1-6 karbonatomer representert ved Y kan være rett eller forgrenet og er eksemplifisert ved The alkylenethio group of 1-6 carbon atoms represented by Y can be straight or branched and is exemplified by

o o

Gruppen som kan .omdannes til en karboksyIgruppe, representert.ved Z, er eksempelvis formyl, cyan, aminokarbonyl, alkoksykarbonyl med 2-5 karbonatomer (f.eks. metoksykarbonyl, etoksykarbony1, n-propoksykarbonyl, i-propoksykarbony1, n-butoksykarbonyl, isobutoksykarbonyl, tert-butoksykarbonyl, sek^-butoksykarbonyl), mono- eller di-alkylaminékarbonyl med 2-9 karbonatomer (f.eks. N-metylaminokarbonyl, N,N-dimetylaminokarbonyl, N-etyl-aminokarbonyl, N,N-dietylaminokarbonyl, N-n-propylaminokarbonyl, N,N-di-n-propylaminokarbonyl, N-isopropylaminokarbonyl, N,N-diisopropylaminokarbony1, N-n-butylaminokarbonyl, N,N-di-n-butylaminokarbony1), mono- eller di-cykloalkylaminokarbonyl med 6-13 karbonatomer (f.eks. N-cyklopentylaminokarbonyl, N,N-dicyklo-pentylaminokarbony1, N-cykloheksylaminokarbony1, N,N-dicykloheksyl-aminokarbonyl), mono- eller diarylaminokarbonyl med :7~l6 karbonatomer (f. eks. N- fenylaminokarbonyl 4 N ,N-di f eny. laminokarbonyl, N-tolylaminokarbonyl, N,N-ditolylaminokarbonyl). Forbindelsene The group which can be converted into a carboxyl group, represented by Z, is for example formyl, cyano, aminocarbonyl, alkoxycarbonyl with 2-5 carbon atoms (e.g. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl , tert-butoxycarbonyl, sec^-butoxycarbonyl), mono- or di-alkylaminecarbonyl with 2-9 carbon atoms (e.g. N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-ethylaminocarbonyl, N,N-diethylaminocarbonyl, N-n -propylaminocarbonyl, N,N-di-n-propylaminocarbonyl, N-isopropylaminocarbonyl, N,N-diisopropylaminocarbonyl1, N-n-butylaminocarbonyl, N,N-di-n-butylaminocarbonyl1), mono- or di-cycloalkylaminocarbonyl with 6-13 carbon atoms ( e.g. N-cyclopentylaminocarbonyl, N,N-dicyclopentylaminocarbonyl, N-cyclohexylaminocarbonyl, N,N-dicyclohexylaminocarbonyl), mono- or diarylaminocarbonyl with :7~16 carbon atoms (e.g. N-phenylaminocarbonyl 4 N , N-diphenylaminocarbonyl, N-tolylaminocarbonyl, N,N-ditolylaminocarbonyl). The connections

med formel I hvor Z er en karboksyIgruppe omfatter farmasøytisk akseptable salter derav. Som farmasøytisk akseptable salter kan . eksempelvis nevnes et salt av karboksylsyre med ikke-toksiske kationer (f.eks. natrium, kalium, litium, kalsium, magnesium og ammonium) 'eller med organiske aminer slik som polyhydroksyalky1-aminer (f.eks. N-metylglukamin, dietanolamin, trietanolamin, tris-hydroksymetylaminometan). of formula I wherein Z is a carboxyl group includes pharmaceutically acceptable salts thereof. As pharmaceutically acceptable salts may . for example, a salt of a carboxylic acid is mentioned with non-toxic cations (e.g. sodium, potassium, lithium, calcium, magnesium and ammonium) or with organic amines such as polyhydroxyalkylamines (e.g. N-methylglucamine, diethanolamine, triethanolamine , tris-hydroxymethylaminomethane).

Forbindelsene med formel I har betydelig hypolipidemisk og.hypoglycemisk aktivitet og viser lav toksisitet og små bivirkninger. Forbindelsene kan derfor med stor sikkerhet anvendes som legemidler for hypérlipemia og sukkersyke hos pattedyr inkludert mennesket.. Når en forbindelse med formel I anvendes som et slikt legemiddel kan den administreres, enten som sådan eller blandet The compounds of formula I have significant hypolipidemic and hypoglycemic activity and show low toxicity and little side effects. The compounds can therefore be used with great certainty as drugs for hyperlipemia and diabetes in mammals including humans. When a compound of formula I is used as such a drug it can be administered, either as such or mixed

med en farmasøytisk akseptabel bærer, hjelpemiddel eller/og for-tynningsmiddel, oralt eller parenteralt i forskjellige doserings-former slik som pulvere, granulater, tabletter, kapsler, supposi-torier og injeksjoner. Når en av forbindelsene anvendes for behandling av hypérlipemia, kan' den administreres oralt eller ikke-oralt i mengder på 0,03-1,0 g pr. dag for et voksent menneske. with a pharmaceutically acceptable carrier, aid and/or diluent, orally or parenterally in various dosage forms such as powders, granules, tablets, capsules, suppositories and injections. When one of the compounds is used for the treatment of hyperlipemia, it can be administered orally or non-orally in amounts of 0.03-1.0 g per day for an adult.

Når én av forbindelsene anvendes for behandling av sukkersyke,When one of the compounds is used for the treatment of diabetes,

kan den administreres oralt eller ikke-oralt i mengder på 0,1-it can be administered orally or non-orally in amounts of 0.1-

3,0 g pr. dag for et voksent menneske.3.0 g per day for an adult.

/ /

i in

Forbindelsene med formel I kan fremstilles ved .omsetning av et diazoniumsalt med formelen: The compounds of formula I can be prepared by reacting a diazonium salt with the formula:

4 1 hvor R har den for R ovenfor angitte betydning eller er en gruppe med formelen -N2 + X ; og hvor X, Y og n har den ovenfor angitte betydning, med en etylenforbindelse med formelen: 4 1 where R has the meaning given for R above or is a group with the formula -N2 + X; and where X, Y and n have the meaning given above, with an ethylene compound of the formula:

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

Denne reaksjon utføres med fordel i et svakt molekylart overskudd av etylenforbindelsen i forhold til diazoniumsaltet. Reaksjonen utføres vanligvis i et oppløsningsmiddel. Som opp-løsningsmiddel kan anvendes vann, metanol, etanol, n-propanol, aceton, metyletylketon, dietylketon, etylpropylketon, acetonitril, N-metylpyrrolidon, dimetylsulfoksyd ,og sulfolan, samt blandinger This reaction is advantageously carried out in a slight molecular excess of the ethylene compound in relation to the diazonium salt. The reaction is usually carried out in a solvent. As a solvent, water, methanol, ethanol, n-propanol, acetone, methyl ethyl ketone, diethyl ketone, ethyl propyl ketone, acetonitrile, N-methylpyrrolidone, dimethyl sulfoxide, and sulfolane, as well as mixtures can be used

av slike oppløsningsmidler. Reaksjonen utføres fordelaktig ved tilsetning av en hydrohalogensyre slik som saltsyre eller hydro-bromsyre til reaksjonssystemet. Når et oppløsningsmiddel inneholdende en hydrohalogensyre anvendes, kan diazoniumsalter med formel II hvor X er et anion forskjellig fra et halogenatom, anvendes som utgangsmateriale i foreliggende oppfinnelse. Reaksjonen kan dessuten akselereres ved benyttelse av en katalysator. Som of such solvents. The reaction is advantageously carried out by adding a hydrohalic acid such as hydrochloric acid or hydrobromic acid to the reaction system. When a solvent containing a hydrohalic acid is used, diazonium salts of formula II where X is an anion different from a halogen atom can be used as starting material in the present invention. The reaction can also be accelerated by using a catalyst. As

katalysator kan f.eks. kobberforbindelser benyttes. Det er således vanlig å benytte kuprooksyd, kuprioksyd, kuproklorid, kupriklorid, kuprobromid, kupribromid, kobbernitrat, kobbersulfat osv., idet kuprooksyd foretrekkes.'Mengden av katalysatoren er vanligvis 0,02-0,2, fortrinnsvis 0,05~0,1•mol pr. mol diazoniumsalt. For å regulere reaksjonshastigheten kan ovennevnte katalysator anvendes i forøket mengde eller forminsket mengde. Temperatur, tid, trykk catalyst can e.g. copper connections are used. It is thus common to use cupric oxide, cupric oxide, cupric chloride, cupric chloride, cupric bromide, cupric bromide, copper nitrate, copper sulfate, etc., cupric oxide being preferred. The amount of the catalyst is usually 0.02-0.2, preferably 0.05~0.1 • moles per moles of diazonium salt. In order to regulate the reaction rate, the above-mentioned catalyst can be used in an increased amount or a reduced amount. Temperature, time, pressure

og andre betingelser ved reaksjonen velges under hensyntagen til utgangsmaterialer, oppløsningsmiddel og katalysator. Reaksjonen forløper vanligvis godt ved en temperatur under avkj:ølihg.'med is til romtemperatur. Når det anvendes -et diazoniumsalt hvor R^ ér en gruppe med formelen -N2+X , som utgangsmateriale, oppnås en and other conditions of the reaction are chosen taking into account starting materials, solvent and catalyst. The reaction usually proceeds well at a temperature below cooling with ice to room temperature. When a diazonium salt where R^ is a group with the formula -N2+X is used as starting material, a

ønsket forbindelse med formel I hvor R1 har betydningen halogen representert ved X. the desired compound of formula I where R1 has the meaning halogen represented by X.

Når Z i den således oppnådde forbindelse er en karboksy1-gruppe, kan den omdannes på i og for seg kjent måte til et farmasøytisk akseptabelt salt med et ikke-toksisk kation eller med et organisk amin som nevnt ovenfor eller til en ester slik som metylester, etylester, n-propylester og isopropylester. Når Z i forbindelsen med formel I er en gruppe som kan omdannes til karboksyl, kan gruppen omdannes til denne gruppe på i og for seg kjent måte. Når Z er en cyangruppe, en alkoksykarbonyIgruppe eller en aminokarbonyIgruppe som er substituert eller usubstituert, kan den omdannes til karboksyIgruppen ved hjelp av hydrolyse, mens når Z er formyl kan den oksyderes til en karboksyIgruppe. Når Z When Z in the compound thus obtained is a carboxyl group, it can be converted in a manner known per se to a pharmaceutically acceptable salt with a non-toxic cation or with an organic amine as mentioned above or to an ester such as methyl ester, ethyl ester, n-propyl ester and isopropyl ester. When Z in the compound of formula I is a group that can be converted to carboxyl, the group can be converted to this group in a manner known per se. When Z is a cyano group, an alkoxycarbonyl group or an aminocarbonyl group which is substituted or unsubstituted, it can be converted to the carboxyl group by means of hydrolysis, while when Z is formyl it can be oxidized to a carboxyl group. When Z

er en cyanogruppe, kan den også omdannes til en aminokarbonylgruppe. Hydrolysen kan f.eks. bevirkes ved å behandle forbindelsen 'med formel I med en syre slik som saltsyre, svovelsyre, salpetersyre, fosforsyre eller karbonsyre eller med en base slik som natriumhydroksyd, kaliumhydroksyd, natriumkarbonat eller kaliumkarbonat. is a cyano group, it can also be converted to an aminocarbonyl group. The hydrolysis can e.g. is effected by treating the compound of formula I with an acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or carbonic acid or with a base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

I denne reaksjon kan også en alkohol slik som metanol eller etanol være tilstede. Oksydasjonen av formyIgruppen kan foretas ved at et egnet oksydasjonsmiddel anvendes sammen med forbindelsen med formel I i et egnet oppløsningsmiddel. Eksempler på oksydasjonsmiddel er kaliumdikromat, kaliumkromat, kaliumpermanganat, hydrogenperoksyd, bariumperoksyd, pereddiksyre, perbenzosyre, hypoklorsyre og ozon. Temperatur, tid og andre reaksjonsbetingelser i ovennevnte hydrolyse og oksydasjon velges under hensyntagen til den ønskede forbindelse med formel I, oppløsningsmiddel og metode. In this reaction, an alcohol such as methanol or ethanol can also be present. The oxidation of the formyl group can be carried out by using a suitable oxidizing agent together with the compound of formula I in a suitable solvent. Examples of oxidizing agents are potassium dichromate, potassium chromate, potassium permanganate, hydrogen peroxide, barium peroxide, peracetic acid, perbenzoic acid, hypochlorous acid and ozone. Temperature, time and other reaction conditions in the above-mentioned hydrolysis and oxidation are chosen taking into account the desired compound of formula I, solvent and method.

Den således erholdte forbindelse.med formel I kan separeres og renses ved hjelp av kjente separerings-rensemetoder slik som krystallisering, omkrystallisering, konsentrasjon, destillasjon, kromatografi osv. The compound of formula I thus obtained can be separated and purified using known separation-purification methods such as crystallization, recrystallization, concentration, distillation, chromatography, etc.

Diazoniumsalt-utgangsmaterialet med formel II kan fremstilles ved diazotering av tilsvarende aminoforbindelse i nærvær av en hydrohalogensyre på konvensjonell' måte eller ved å bringe et diazoniumsalt med formel II, hvor X er et anion annet enn halogen, The diazonium salt starting material of formula II can be prepared by diazotization of the corresponding amino compound in the presence of a hydrohalic acid in a conventional manner or by bringing a diazonium salt of formula II, where X is an anion other than halogen,

i kontakt med en hydrohalogensyre.in contact with a hydrohalic acid.

Referanseeksempel Reference example

I 120 ml etanol oppløses 31,2 g fenol hvortil det tilsettes 24 g av en metanoloppløsning inneholdende 28% natriummetoksyd og 0,3 g kaliumjodid. Deretter tilsettes 20 g 4-(2-brom-ety1)acetanilid til blandingen og blandingen tilbakeløpskokes i 3,5 timer. Etter avdestillering av oppløsningsmidlet tilsettes en vandig oppløsning av natriumhydroksyd i 200 ml vann til den oppnådde rest og dannede krystaller oppsamles ved filtrering. Omkrystallisering fra etylacetat gir 12 g 4-(2-fenoksyetyl)-acetanilid, 31.2 g of phenol are dissolved in 120 ml of ethanol, to which is added 24 g of a methanol solution containing 28% sodium methoxide and 0.3 g of potassium iodide. Then 20 g of 4-(2-bromo-ethyl)acetanilide are added to the mixture and the mixture is refluxed for 3.5 hours. After distilling off the solvent, an aqueous solution of sodium hydroxide in 200 ml of water is added to the obtained residue and the crystals formed are collected by filtration. Recrystallization from ethyl acetate gives 12 g of 4-(2-phenoxyethyl)-acetanilide,

smp. 121-123°C. m.p. 121-123°C.

Til en blandet oppløsning av 30 ml saltsyre og 20 ml vann tilsettes 10 g 4-(2-fenoksyetyl)-acetanilid og blandingen tilbakeløpskokes i 2 timer. Etter avkjøling oppsamles dannede krystaller ved filtrering. Omkrystallisering fra vann gir 7,5 g 4-(2-fenoksyetyl)anilinhydroklorid, smp. 189-191°C To a mixed solution of 30 ml of hydrochloric acid and 20 ml of water, 10 g of 4-(2-phenoxyethyl)-acetanilide are added and the mixture is refluxed for 2 hours. After cooling, formed crystals are collected by filtration. Recrystallization from water gives 7.5 g of 4-(2-phenoxyethyl)aniline hydrochloride, m.p. 189-191°C

Referanseeksempel 2Reference example 2

En blanding av 37,8 g 1-feny1-1-brom-2-metylpropan,A mixture of 37.8 g of 1-phenyl-1-bromo-2-methylpropane,

23,6 g p-nitrofenol, 150 ml etanol og 9,5 g natriummetoksyd kokes under tilbakeløp i 5 timer. Etter at reaksjonen er ferddg avdestilleres etanol og resten underkastes -ekstraksjon med eter. Ekstraktet vasket med 5% vandig oppløsning av natriumhydroksyd 23.6 g of p-nitrophenol, 150 ml of ethanol and 9.5 g of sodium methoxide are refluxed for 5 hours. After the reaction is complete, ethanol is distilled off and the residue is subjected to -extraction with ether. The extract was washed with 5% aqueous solution of sodium hydroxide

og deretter med vann. Etter tørking med magnesiumsulfat fradestilleres oppløsningsmidlet. Det således oppnådde røde oljeaktige stoff av uren 1-feny1-1-(4-nitrofenoksy-2-metylpropan oppløses i 100 ml metanol og underkastes katalytisk reduksjon under anvendelse av palladium-karbon. Etter at reduksjonen er ferdig fjernes katalysatoren ved filtrering. Det oljeaktige stoff som oppnås ved fjerning av oppløsningsmidlet oppløses i 50 ml eter og konsentrert saltsyre tilsettes til oppløsningen og dette gir 4-(1-feny1-2-metylpropoksy)anilinhydroklorid, and then with water. After drying with magnesium sulphate, the solvent is distilled off. The thus obtained red oily substance of impure 1-phenyl-1-(4-nitrophenoxy-2-methylpropane) is dissolved in 100 ml of methanol and subjected to catalytic reduction using palladium carbon. After the reduction is complete, the catalyst is removed by filtration. The oily substance obtained by removal of the solvent is dissolved in 50 ml of ether and concentrated hydrochloric acid is added to the solution and this gives 4-(1-phenyl-2-methylpropoxy)aniline hydrochloride,

smp. 165-168°C m.p. 165-168°C

Referanseeksempel 3Reference example 3

En blanding av 240 g p-klorbenzylklorid, 240 g p-acetaminofenol, 850 ml etanol og 290 g av en 28% metanolisk opp-løsning av natriummetoksyd omrøres under oppvarming over en mantel-ioppvarmingsinhretning. Reaksjonen begynner plutselig i nærheten av 65°C og blaildingen begynner å koke kraftig under tilbakeløp. (Mantel-oppvarmingsinnretningen fjernes). Reaksjonsblandingen kokes under tilbakeløp i 2,5 timer hvoretter ca. 700. ml av oppløsningsmidlet avdestilleres. Resten helles i 1 liter av en 4% vandig oppløsning av NaOH (inneholdende is) og det resulterende bunnfall av 4-acetaminofenoksy-4-klorfenylmetan (hvite^krystaller) oppsamles ved filtrering. A mixture of 240 g of p-chlorobenzyl chloride, 240 g of p-acetaminophenol, 850 ml of ethanol and 290 g of a 28% methanolic solution of sodium methoxide is stirred while heating over a mantle heating device. The reaction starts suddenly near 65°C and the blailding begins to boil vigorously under reflux. (The mantle heater is removed). The reaction mixture is boiled under reflux for 2.5 hours, after which approx. 700 ml of the solvent is distilled off. The residue is poured into 1 liter of a 4% aqueous solution of NaOH (containing ice) and the resulting precipitate of 4-acetaminophenoxy-4-chlorophenylmethane (white crystals) is collected by filtration.

De således oppnådde hvite krystaller tørkes ikke, men oppløses direkte i 1,5 kg n-propanol og etter tilsetning av 120 g NaOH-granulater, kokes oppløsningen under tilbakeløp under omrøring i 5 timer. Etter at reaksjonen er ferdig konsentreres blandingen under redusert trykk for å fjerne ca. 600 ml av oppløsningsmidlet og 2 kg isvann tilsettes under omrøring. Det resulterende bunnfall av 4-(4-klorbenzyloksy)anilin ; (brune granulater) oppsamles ved filtrering og vaskes med vann, utbytte 324 g, smp. 102°C. The white crystals thus obtained are not dried, but are dissolved directly in 1.5 kg of n-propanol and, after adding 120 g of NaOH granules, the solution is boiled under reflux with stirring for 5 hours. After the reaction is complete, the mixture is concentrated under reduced pressure to remove approx. 600 ml of the solvent and 2 kg of ice water are added while stirring. The resulting precipitate of 4-(4-chlorobenzyloxy)aniline; (brown granules) are collected by filtration and washed with water, yield 324 g, m.p. 102°C.

Ref eranseeksempel 4.Reference example 4.

I 500 ml metanol oppløses 25 g 4-(4-klorfenoksymety1) nitrobenzen og med tilsetning av Raney-nikkel, rystes oppløsningen i hydrogenatmosfære. Dette gir en total absorbsjon av 2,5 liter hydrogen. Raney-nikkelet frafiltreres og filtratet konsentreres til ca. 4Q.ml. De resulterende krystaller oppsamles ved filtrering, og dette gir 3,5 g 4-(4-klorfenoksymetyl)-anilin, smp. 125-126°C. In 500 ml of methanol, 25 g of 4-(4-chlorophenoxymethyl)nitrobenzene are dissolved and, with the addition of Raney nickel, the solution is shaken in a hydrogen atmosphere. This gives a total absorption of 2.5 liters of hydrogen. The Raney nickel is filtered off and the filtrate is concentrated to approx. 4Q.ml. The resulting crystals are collected by filtration, and this gives 3.5 g of 4-(4-chlorophenoxymethyl)-aniline, m.p. 125-126°C.

, Referanseeksempel 5, Reference example 5

I 50 ml dimetylformamid oppløses 58,8 g m-trifluor-metylfenol og.24 g kaliumhydroksyd, fulgt av tilsetning av 57,2 g p-nitroklorbenzen og 200 mg kobberpulver. In 50 ml of dimethylformamide, 58.8 g of m-trifluoromethylphenol and 24 g of potassium hydroxide are dissolved, followed by the addition of 57.2 g of p-nitrochlorobenzene and 200 mg of copper powder.

Blandingen kokes under tilbakeløp i 7 timer hvoretter den helles i 1 liter av en kald fortynnet oppløsning av natriumhydroksyd. De resulterende krystaller innvinnes ved filtrering og underkastes destillasjon ved'redusert trykk. Dette gir 76,7 g 4-( 3-trif luormetylf enoksy)-nitrobenzen, kokepunkt l40-l45°C/l mm Hg'. The mixture is refluxed for 7 hours, after which it is poured into 1 liter of a cold dilute solution of sodium hydroxide. The resulting crystals are recovered by filtration and subjected to distillation at reduced pressure. This gives 76.7 g of 4-(3-trifluoromethylphenoxy)-nitrobenzene, boiling point 140-145°C/l mm Hg'.

I 300 ml benzen oppløses 76,6 g av den ovenfor oppnådde 4-(3-trifluormetylfenoksy)nitrobenzen og med tilsetning av^300 mg 10% palladium-på-karbon (fuktig), utføres reduksjon ved atmosfære-trykk. In 300 ml of benzene, 76.6 g of the 4-(3-trifluoromethylphenoxy)nitrobenzene obtained above are dissolved and with the addition of ^300 mg of 10% palladium-on-carbon (moist), reduction is carried out at atmospheric pressure.

Katalysatoren frafiltreres og oppløsningsmidlet avdestilleres hvilket gir 67,7 g 4-(3-trifluormetylfenoksy)-anilin i form av et oljeaktig produkt. The catalyst is filtered off and the solvent is distilled off, which gives 67.7 g of 4-(3-trifluoromethylphenoxy)-aniline in the form of an oily product.

Referanseeksempel 6Reference example 6

En.blanding av 37,8 g 1-fenyl-l-brom-2-metylpropan,A mixture of 37.8 g of 1-phenyl-1-bromo-2-methylpropane,

23,6 g p-nitrofenol, 150 ml etanol og 9,5 g natriummetylat, til--bakeløpskokes under omrøring i 5 timer. Etter at reaksjonen er ferdig fradestilleres etanol og resten ekstraheres medveter. Ekstraktet vaskes med 5% vandig oppløsning av natriumhydroksyd og med vann, og tørkes over magnesiumsulfat. Oppløsningsmidlet fradestilleres hvilket'gir uren 1-feny1-1-(4-nitrofenoksy)-2-metylpropan i form av et rødt oljeaktig stoff. Dette stoff underkastes katalytisk reduksjon ved benyttelse av palladium-karbon som katalysator. Etter at reduksjonen er ferdig frafiltreres katalysatoren og oppløsningsmidlet avdestilleres. Det resulterende oljeaktige stoff oppløses i 50 ml eter. Til oppløsningen tilsettes' konsentrert saltsyre og dette gir 4-(1-feny1-2-metyIpropyloksy) anilihhydroklorid. Smp. 165-168°C. 23.6 g of p-nitrophenol, 150 ml of ethanol and 9.5 g of sodium methylate are refluxed with stirring for 5 hours. After the reaction is finished, ethanol is distilled off and the residue is extracted deliberately. The extract is washed with 5% aqueous solution of sodium hydroxide and with water, and dried over magnesium sulfate. The solvent is distilled off, which gives impure 1-phenyl-1-(4-nitrophenoxy)-2-methylpropane in the form of a red oily substance. This substance is subjected to catalytic reduction using palladium-carbon as a catalyst. After the reduction is complete, the catalyst is filtered off and the solvent is distilled off. The resulting oily substance is dissolved in 50 ml of ether. Concentrated hydrochloric acid is added to the solution and this gives 4-(1-phenyl-2-methylpropyloxy)aniline hydrochloride. Temp. 165-168°C.

Følgende eksempler illustrerer oppfinnelsen.The following examples illustrate the invention.

Eksempel 1-( 1)Example 1-( 1)

I 500 ml aceton-oppløses 94 g 4-(4-klorbenzyloksy)anilin og en blanding av 200 g saltsyre og 100 g vann ved romtemperatur tilsettes» Oppløsningen avkjøles godt méd is. Mens oppløsningen omrøres tilsettes en oppløsning av 30,8 g natriumnitrit i 100 ml vann, deretter 100 g etylakrylat og til slutt 5,8 g kuprooksyd-pulver. Nitrogengass utvikles i økende mengder. Isbadet fjernes etter 10 minutter og ved 12°G tilsettes ytterligere .5,8 g kuprooksyd. Med utvikling av nitrogengass i moderate mengder, øker temperaturen gradvis. Blandingen omrøres ved romtemperatur i 7 timer. Etter at reaksjonen er ferdig konsentreres reaksjcns-blandingen under redusert trykk og, ekstraheres med etylacetat. Etylacetatet fradestilleres og den resterende rødfargede olje renses ved kromatografi på silisiumdioksydgel. Dette gir 70 g ety1-2-klor-3-/4-(4-klorbenzyloksy)fenyl7propionat som et gult oljeaktig produkt. Cykloheksan/benzen anvendes som eluerings-middel (først 1:1 og deretter 1:4). Dissolve 94 g of 4-(4-chlorobenzyloxy)aniline in 500 ml of acetone and add a mixture of 200 g of hydrochloric acid and 100 g of water at room temperature. The solution is cooled well with ice. While the solution is being stirred, a solution of 30.8 g of sodium nitrite in 100 ml of water is added, then 100 g of ethyl acrylate and finally 5.8 g of cupric oxide powder. Nitrogen gas is developed in increasing quantities. The ice bath is removed after 10 minutes and at 12°C a further .5.8 g of cuprous oxide is added. With the evolution of nitrogen gas in moderate amounts, the temperature gradually increases. The mixture is stirred at room temperature for 7 hours. After the reaction is finished, the reaction mixture is concentrated under reduced pressure and extracted with ethyl acetate. The ethyl acetate is distilled off and the remaining red colored oil is purified by chromatography on silica gel. This gives 70 g of ethyl 1-2-chloro-3-[4-(4-chlorobenzyloxy)phenyl]propionate as a yellow oily product. Cyclohexane/benzene is used as eluent (first 1:1 and then 1:4).

NMR spektrum ( 6 ppm, CCl^):NMR spectrum (6 ppm, CCl^):

1,17(3H, t), 3,01 - 3,21(2H,.m), 4,08(2H, q), 4,23.1.17(3H, t), 3.01 - 3.21(2H,.m), 4.08(2H, q), 4.23.

(1H, t), 4,89(2H, s), 6,74(2H, d), 7,02(2H, d), (1H, t), 4.89(2H, s), 6.74(2H, d), 7.02(2H, d),

7,22(4H, s) 7.22(4H, s)

, Eksempler 1-(2) - 1-( 57) ■ , Examples 1-(2) - 1-( 57) ■

På lignende måte som i eksempel 1-.(1), fremstilles . følgende forbindelser. In a similar way as in example 1-.(1), is produced. the following compounds.

Eksempel 2-( l) Example 2-(l)

I 60 ml aceton oppløses 6 g 4,4 *-diaminobifenyleter og under avkjøling med is og under omrøring tilsettes videre 15 ml saltsyre, en oppløsning av 4,8 g natriumnitrit i 9 ml vann, 15 ml etylakrylat og 0,2 g findelt kuprooksyd, og tilsetningen foretas i den nevnte rekkefølge. Blandingen omrøres ved 10°C i 20 minutter og ved romtemperatur i l time hvoretter den é.kstraheres med eter. Det urene produkt som således oppnås destilleres under redusert trykk. Dette gir 8,3 g etyl-2-klor-3"/4-(4-klorfenoksy)fenyl7-propionat som et oljeaktig produkt som koker ved 200-210°C/0,1-0,2 mm Hg. Dissolve 6 g of 4,4*-diaminobiphenyl ether in 60 ml of acetone and, while cooling with ice and stirring, add 15 ml of hydrochloric acid, a solution of 4.8 g of sodium nitrite in 9 ml of water, 15 ml of ethyl acrylate and 0.2 g of finely divided cuprous oxide , and the addition is made in the aforementioned order. The mixture is stirred at 10°C for 20 minutes and at room temperature for 1 hour, after which it is extracted with ether. The impure product thus obtained is distilled under reduced pressure. This gives 8.3 g of ethyl 2-chloro-3"/4-(4-chlorophenoxy)phenyl-7-propionate as an oily product boiling at 200-210°C/0.1-0.2 mm Hg.

Eksempler 2-( 2) - 2-( 7)Examples 2-( 2) - 2-( 7)

På lignende måte som i eksempel 2-(l), fremstilles følgende forbindelser. In a similar manner to example 2-(1), the following compounds are prepared.

Eksempel 3~( 1) Example 3~( 1)

I 40 ml metanol oppløses 5,0 g etyl-2-klor-3-/4-(4-klorbenzyloksy)fenyl7propionat og 6,0 g av en 20% vandig oppløsning av natriumhydroksyd tilsettes. Blandingen omrøres ved romtemperatur i 3 timer og de resulterende hvite krystaller oppsamles ved filtrering og vaskes med eter. ' Dette gir 3,9 g natrium-2-klor-,3_ /4-(4-klorbenzyloksy)fenyl/propionat, monohydrat i form av hvite krystaller som smelter ved 2l8-221°C. 5.0 g of ethyl-2-chloro-3-[4-(4-chlorobenzyloxy)phenyl-7-propionate are dissolved in 40 ml of methanol and 6.0 g of a 20% aqueous solution of sodium hydroxide are added. The mixture is stirred at room temperature for 3 hours and the resulting white crystals are collected by filtration and washed with ether. This gives 3.9 g of sodium 2-chloro-,3_/4-(4-chlorobenzyloxy)phenyl/propionate, monohydrate in the form of white crystals melting at 218-221°C.

Eksempler 3~( 2) - 3~( 12)Examples 3~( 2) - 3~( 12)

På lignende måte som i eksempel 3-(D, fremstilles følgende salter fra de tilsvarende estere. In a similar manner to example 3-(D), the following salts are prepared from the corresponding esters.

E ksempel 4-( l) E xample 4-(l)

I 60 ml aceton oppløses 7,5 g 4-(2-fenoksyety1) anilinhydroklorid, fulgt av tilsetning av 7,5 ml saltsyre, In 60 ml of acetone, 7.5 g of 4-(2-phenoxyethyl)aniline hydrochloride are dissolved, followed by the addition of 7.5 ml of hydrochloric acid,

og blandingen holdes ved en temperatur på ikke høyere enn 10°C. Under omrøring tilsettes en oppløsning av 2,3 g natriumnitrit and the mixture is kept at a temperature not higher than 10°C. While stirring, a solution of 2.3 g of sodium nitrite is added

i 4,5 ml vann og blandingen holdes ved samme temperatur i 30 -minutter. Til blandingen tilsettes 25 ml etylakrylat og under omrøring tilsettes kuprooksyd i små mengder inntil utvikling av gass har stoppet. Blandingen underkastes ekstraksjon med eter og ekstraktet vaskes tre ganger med vann og deretter avdestilleres oppløsningsmidlet. Resten Oppløses i 70 ml etanol og under omrøring og isavkjøling tilsettes en oppløsning in 4.5 ml of water and the mixture is kept at the same temperature for 30 minutes. 25 ml of ethyl acrylate is added to the mixture and, while stirring, cuprous oxide is added in small quantities until the evolution of gas has stopped. The mixture is subjected to extraction with ether and the extract is washed three times with water and then the solvent is distilled off. The residue is dissolved in 70 ml of ethanol and a solution is added while stirring and ice-cooling

av 1,2 g natriumhydroksyd i 4 ml vann. Etter 1 time oppsamles de resulterende krystaller ved filtrering og tørkes. Omkrystallisering fra ligroin gir 4,5 g 2-klor-3_(2-fenoksy-etyl)fenyl/propionsyre, smp. 97-99°C. of 1.2 g of sodium hydroxide in 4 ml of water. After 1 hour, the resulting crystals are collected by filtration and dried. Recrystallization from ligroin yields 4.5 g of 2-chloro-3_(2-phenoxy-ethyl)phenyl/propionic acid, m.p. 97-99°C.

v Eksempel 4-( 2) v Example 4-( 2)

På lignende måte som i eksempel 4-(l) fremstilles følgende forbindelse. In a similar way as in example 4-(1), the following compound is prepared.

E ksempel 5~( 1) E xample 5~( 1)

Til 30 ml saltsyre tilsettes 1,70 g etyl-2-klor-3~1.70 g of ethyl-2-chloro-3~ is added to 30 ml of hydrochloric acid

(4-klorfenoksy)fenyl7propionat og blandingen tilbakeløpskokes (4-Chlorophenoxy)phenyl7propionate and the mixture is refluxed

■i 6 timer hvoretter den ekstraheres med eter. Ekstraktet renses med kolonnekromatografi på'silisiumdioksydgel hvilket.gir 1,15 g 2-k'lor-3-/4-( 4-klorf enoksy )fenyl7propionsyre i form av et oljeaktig produkt. ■for 6 hours after which it is extracted with ether. The extract is purified by column chromatography on silica gel, which gives 1.15 g of 2-chloro-3-[4-(4-chlorophenoxy)phenyl]propionic acid in the form of an oily product.

NMR spektrum (6 ppm, CDCl^)NMR spectrum (6 ppm, CDCl^)

2,82-3,63(2H,m), 4,48(IH,t), 6,94(4H,d), 7,42(2H,d), ,7,45(2H,d) 2.82-3.63(2H,m), 4.48(1H,t), 6.94(4H,d), 7.42(2H,d), .7.45(2H,d)

Eksempel 5-( 2)Example 5-( 2)

I 40 ml metanol oppløses 6,6 g etyl-2-klor-3-/4-(2-fenoksyetoksy)fenyl7propionat og under avkjøling med isbg om-røring tilsettes en oppløsning av 0,8 g natriumhydroksyd i 1,2 ml vann. Blandingen holdes under de samme betingelser i 3 timer In 40 ml of methanol, 6.6 g of ethyl-2-chloro-3-(4-(2-phenoxyethoxy)phenyl-7-propionate are dissolved and, while cooling with ice-cold stirring, a solution of 0.8 g of sodium hydroxide in 1.2 ml of water is added. The mixture is kept under the same conditions for 3 hours

hvoretter oppløsningen nøytraliser.es med eddiksyre. Oppløsningen blir deretter konsentrert til tørrhet. Resten vaskes godt med cykloheksan og. oppløses i vann. Etter behandling med aktivert karbon surgjøres oppløsningen med' saltsyre. Det resulterende oljeaktige stoff ekstraheres med kloroform og kloroformen avdestilleres og dette gir 4 g 2-klor-3-/5-(l~fenyletyloksy)fenyl7 propionsyre som et fargeløst oljeaktig stoff. after which the solution is neutralized with acetic acid. The solution is then concentrated to dryness. The residue is washed well with cyclohexane and. dissolves in water. After treatment with activated carbon, the solution is acidified with hydrochloric acid. The resulting oily substance is extracted with chloroform and the chloroform is distilled off and this gives 4 g of 2-chloro-3-[5-(l~phenylethyloxy)phenyl7-propionic acid as a colorless oily substance.

NMR spektrum (6 ppm, CCl^)NMR spectrum (6 ppm, CCl^)

l,57(3H,d), 3,10(2H,m), 4,27(lH,t), 5,17(lH,q), 6,70(2H,d), 6,97(2H,d), 7,20(5H,s), ll,53(lH,s). 1.57(3H,d), 3.10(2H,m), 4.27(1H,t), 5.17(1H,q), 6.70(2H,d), 6.97(2H ,d), 7.20(5H,s), 11.53(1H,s).

Eksempel 6-( l)Example 6-(l)

I 40 ml etanol oppløses 1,46 g 2-klor-3"4-klor-benzyloksy )feny1/propionsyre fulgt av tilsetning av 0,25 g kaliumhydroksyd. Blandingen omrøres ved romtemperatur 1 time og de resulterende krystaller oppsamles under filtrering.'Disse krystaller omkrystalliseres fra vann hvilket gir 1,2 g kalium-2-klor-3-/4-(4-klorbenzyloksy)fenyl/propionat, smp.. 161-162°C. In 40 ml of ethanol, 1.46 g of 2-chloro-3'4-chloro-benzyloxy)phenyl/propionic acid is dissolved followed by the addition of 0.25 g of potassium hydroxide. The mixture is stirred at room temperature for 1 hour and the resulting crystals are collected by filtration.'These crystals are recrystallized from water which gives 1.2 g of potassium 2-chloro-3-(4-(4-chlorobenzyloxy)phenyl/propionate, m.p. 161-162°C).

Eksempler 6-( 2) - 6-( 4)Examples 6-( 2) - 6-( 4)

På lignende måte som i eksempel 6-(l) fremstilles følgende salte.r. In a similar way as in example 6-(l), the following salts are prepared.r.

Eksempel 7~( 1) Example 7~( 1)

I 40 ml aceton oppløses 5,3 g 4-(3-fenoksypropyl) anilinhydroklorid, fulgt av tilsetning av 5 ml saltsyre og blandingen holdes,ved én temperatur på ikke høyere enn 10°C. 5.3 g of 4-(3-phenoxypropyl) aniline hydrochloride are dissolved in 40 ml of acetone, followed by the addition of 5 ml of hydrochloric acid and the mixture is kept at a temperature not higher than 10°C.

Under omrøring tilsettes en oppløsning av 1,52 g natriumnitritWhile stirring, a solution of 1.52 g of sodium nitrite is added

i 3 .ml vann og blandingen holdes ved den samme temperatur i 30 minutter. Til blandingen tilsettes 16 ml akrylsyre og kuprooksyd tilsettes i små porsjoner under omrøring og ved 0^5°C inntil gassutviklingen har stoppet. Reaksjonsblandingen konsentreres til tørrhet under redusert trykk. Til resten tilsettes fortynnet saltsyre og blåndingen underkastes ekstraksjon. in 3.ml of water and the mixture is kept at the same temperature for 30 minutes. 16 ml of acrylic acid is added to the mixture and cuprous oxide is added in small portions while stirring and at 0^5°C until gas evolution has stopped. The reaction mixture is concentrated to dryness under reduced pressure. Dilute hydrochloric acid is added to the residue and the mixture is subjected to extraction.

med benzen. Benzenlaget vaskes med vann og en vandig oppløsning av 2 g vannfritt natriumkarbonat i 100 ml vann tilsettes. De resulterende krystaller oppvarmes for-å oppløses og-blir deretter avkjølt.. Krystallene som dannes oppsamles ved filtrering og vaskes med litt vann og etanol og tørkes under reduser* trykk. Dette gir 4 g natrium-2-klor-3_(3-fenoksypropyl)fenyl/propionat, smp. 195-196°C. with benzene. The benzene layer is washed with water and an aqueous solution of 2 g of anhydrous sodium carbonate in 100 ml of water is added. The resulting crystals are heated to dissolve and then cooled. The crystals formed are collected by filtration and washed with a little water and ethanol and dried under reduced pressure. This gives 4 g of sodium 2-chloro-3_(3-phenoxypropyl)phenyl/propionate, m.p. 195-196°C.

Eksempel 8-( l)Example 8-(l)

I 30 ml aceton oppløses 3,3 g 4-klor-4'-aminobifenyleter og etter tilsetning av 4 ml saltsyre avkjøles 'oppløsningen med is. Under omrøring tilsettes" en oppløsning av 1,15 g natriumnitrit i ml vann.samt 10 ml etylakrylat og 0,1 g findelt kuprooksyd i nevnte rekkefølge. Temperaturen holdes under 20°C og det foregår en utvikling av nitrogengass. Isbadet fjernes etter 30 minutter og reaksjonsblandingen omrøres ved romtemperatur i 1 time, hvoretter den konsentreres under redusert trykk og ekstraheres med eter. Eteren fradestilleres og den resulterende rødfargede olje oppløses i 30 ml metanol. Mens oppløsningen avkjøles med is tilsettes 10 g 18% vandig natriumhydroksyd. Blandingen omrøres på et isbad i 25 minutter hvoretter den konsentreres under redusert trykk.. Resten vaskes godt med cykloheksan, og uoppløselige stoffer oppsamles ved filtrering, vaskes med et lite volum vann og tørkes. Dette gir 3 g natrium-2-klor-3_/4~-(4-klorfenoksy)fenyl7propionat In 30 ml of acetone, 3.3 g of 4-chloro-4'-aminobiphenyl ether are dissolved and after the addition of 4 ml of hydrochloric acid, the solution is cooled with ice. While stirring, a solution of 1.15 g of sodium nitrite in ml of water is added, as well as 10 ml of ethyl acrylate and 0.1 g of finely divided cuprous oxide in the order mentioned. The temperature is kept below 20°C and nitrogen gas is evolved. The ice bath is removed after 30 minutes and the reaction mixture is stirred at room temperature for 1 hour, after which it is concentrated under reduced pressure and extracted with ether. The ether is distilled off and the resulting red-colored oil is dissolved in 30 ml of methanol. While the solution is cooled with ice, 10 g of 18% aqueous sodium hydroxide is added. The mixture is stirred on a ice bath for 25 minutes, after which it is concentrated under reduced pressure. The residue is washed well with cyclohexane, and insolubles are collected by filtration, washed with a small volume of water, and dried. This gives 3 g of sodium 2-chloro-3_/4~-( 4-Chlorophenoxy)phenyl7propionate

som smelter ved l82-l83°C.which melts at l82-l83°C.

Eksempel 8-( 2) - 8-(5)Example 8-(2) - 8-(5)

På lignende måte som i eksempel 8-(l) fremstilles-følgende forbindelser. The following compounds are prepared in a similar manner as in example 8-(1).

Eksempel 9~( D Example 9~( D

I 600 ml aceton oppløses 70 g 4-(3-klorbenzyloksy)anilin fulgt av tilsetning av 100 ml saltsyre. Under omrøring og av-kjøling med is tilsettes en oppløsning av 22,8 g natriumnitrit i et tilstrekkelig, volum vann til 45 ml. Blandingen omrøres under de'samme betingelser i 30 minutter hvoretter 250 ml etylakrylat tilsettes. Mens reaksjonsblandingen holdes ved 24-26°C tilsettes kuprooksyd i små mengder inntil gassutviklingen er stoppet. Deretter tilsettes 200 ml eter og det organiske lag vaskes tre ganger med vann. Oppløsningsmidlet avdestilleres grundig og resten oppløses i 900 ml etanol. Under avkjøling med is og omrøring tilsettes langsomt en oppløsning av 15 g natriumhydroksyd i en tilstrekkelig mengde vann til et ovlum på 40 ml. Deretter omrøres blandingen, under de samme betingelser i 1,5 timer og de resulterende krystaller oppsamles, ved filtrering. Omkrystallisering f ra ■ fortynnet etanol gir 55 g natrium-2-klor-3-/4"-(3_ klorbenzyloksy)fenyl/propionat, smp. 205_208°C. 70 g of 4-(3-chlorobenzyloxy)aniline are dissolved in 600 ml of acetone, followed by the addition of 100 ml of hydrochloric acid. While stirring and cooling with ice, a solution of 22.8 g of sodium nitrite in a sufficient volume of water to 45 ml is added. The mixture is stirred under the same conditions for 30 minutes, after which 250 ml of ethyl acrylate is added. While the reaction mixture is kept at 24-26°C, cuprous oxide is added in small amounts until gas evolution has stopped. 200 ml of ether are then added and the organic layer is washed three times with water. The solvent is thoroughly distilled off and the residue is dissolved in 900 ml of ethanol. While cooling with ice and stirring, a solution of 15 g of sodium hydroxide in a sufficient amount of water is slowly added to a volume of 40 ml. The mixture is then stirred under the same conditions for 1.5 hours and the resulting crystals are collected by filtration. Recrystallization from ■ dilute ethanol yields 55 g of sodium 2-chloro-3-[4''-(3-chlorobenzyloxy)phenyl/propionate, m.p. 205-208°C.

Eksempel 10-( 1)Example 10-( 1)

I 10 ml vann oppløses 300 mg natrium-2-klor-3_.Z4"-(1-fenylpropyloksy)fenyl7propionat, fulgt av tilsetning av et- overskudd av en vandig oppløsning av kalsiumklorid. Det oljeaktige stoff som utsepareres ekstraheres med en blanding av eter og.etylacetat (1:1). Ekstraktet vaskes med vann og det dannede bunnfall frafiltreres. Oppløsningsmidlet avdestilleres og resten underkastes omkrystallisering fra 4-ml 50% vandig etanol. Dette gir 150 mg kalsium-2-klor-3-/4-(1-fenylpropyloksy)fenyl7propionat, smp. l45°C. In 10 ml of water dissolve 300 mg of sodium 2-chloro-3_.Z4"-(1-phenylpropyloxy)phenyl7propionate, followed by the addition of an excess of an aqueous solution of calcium chloride. The oily substance which separates out is extracted with a mixture of ether and ethyl acetate (1:1). The extract is washed with water and the precipitate formed is filtered off. The solvent is distilled off and the residue is subjected to recrystallization from 4 ml of 50% aqueous ethanol. This gives 150 mg of calcium-2-chloro-3-/4-( 1-phenylpropyloxy)phenyl7propionate, mp 145°C.

Eksempel ll-( l)Example ll-(l)

I 20 ml tetrahydrofuran oppløses 1,0 g 2-klor-3~/4-(1-fenyletyloksy)fenyl7propionsyre. Under avkjøling og omrøring tilsettes dråpevis 0,33 g trietylamin og deretter 0,34 g etyl-klorkarbonat. Det resulterende hvite bunnfall frafiltreres. Til 1.0 g of 2-chloro-3-[4-(1-phenylethyloxy)phenyl-7-propionic acid is dissolved in 20 ml of tetrahydrofuran. During cooling and stirring, 0.33 g of triethylamine and then 0.34 g of ethyl chlorocarbonate are added dropwise. The resulting white precipitate is filtered off. To

.filtratet tilsettes 0,31 g anilin dråpevis under avkjøling med is 0.31 g of aniline is added dropwise to the filtrate while cooling with ice

og omrøring. Blandingen omrøres i ca. 2 timer. Etter at tetrahydrofuran er avdestillert tilsettes kloroform. Kloroformlaget vaskes med fortynnet saltsyre og tørkes over magnesiumsulfat. and stirring. The mixture is stirred for approx. 2 hours. After tetrahydrofuran has been distilled off, chloroform is added. The chloroform layer is washed with dilute hydrochloric acid and dried over magnesium sulfate.

Etter at kloroformen -er avdestillert renses den resulterende oljeAfter the chloroform is distilled off, the resulting oil is purified

ved kolonnekromatografi og dette gir 580 mg olje. Tilvdenne olje tilsettes en blanding av petroleumeter og metanol og de resulterende krystaller oppsamles ved filtrering. Omkrystallisering fra petroleumeter gir N-fenyl-2-klor-3-/5-(1-fenyletyloksy)fényl7 propionamid, smp. 90-.91°C. by column chromatography and this gives 580 mg of oil. A mixture of petroleum ether and methanol is added to the melted oil and the resulting crystals are collected by filtration. Recrystallization from petroleum ether gives N-phenyl-2-chloro-3-(5-(1-phenylethyloxy)phenyl7-propionamide, m.p. 90-.91°C.

Eksempler ll-( 2) - ll-(3)Examples ll-(2) - ll-(3)

På lignende måte som i eksempel 11-(1) fremstilles følgende forbindelser. In a similar manner to example 11-(1), the following compounds are prepared.

Claims (32)

1. Forbindelse, karakterisert ved formelen: 1. Compound, characterized by the formula: hvor R"*" er hydrogen, lavere alkyl med 1~5 karbonatomer, halogen, hydroksyl, lavere alkoksy med 1-4 karbonatomer eller 2 3 r • trifluormetyl; R og R er like eller forskjellige og hver er hydrogen eller lavere alkyl med 1-5 karbonatomer, X er halogen, Y er et oksygenatom, alkylentio med 1-6 karbonatomer,. alkylenoksy med 1-6 karbonatomer, alkyldioksy med 1-6 karbonatomer; Z er en karboksylgruppe eller en gruppe som kan omdannes til en karboksylgruppe; og n er 1 eller 2.where R"*" is hydrogen, lower alkyl with 1~5 carbon atoms, halogen, hydroxyl, lower alkoxy with 1-4 carbon atoms or 2 3 r • trifluoromethyl; R and R are the same or different and each is hydrogen or lower alkyl of 1-5 carbon atoms, X is halogen, Y is an oxygen atom, alkylenethio with 1-6 carbon atoms. alkyleneoxy of 1-6 carbon atoms, alkyldioxy of 1-6 carbon atoms; Z is a carboxyl group or a group that can be converted into a carboxyl group; and n is 1 or 2. 2. Forbindelse ifølge krav 1, karakterisert ved at Y er et oksygenatom.2. Compound according to claim 1, characterized in that Y is an oxygen atom. 3. Forbindelse ifølge krav 1, karakterisert ved at Y er en alkylentiogruppe med 1-6 karbonatomes.3. Compound according to claim 1, characterized in that Y is an alkylenethio group with 1-6 carbon atoms. 4. Forbindelse ifølge krav 1, karakterisert ved at Y er en alkylenoksygruppe med 1-6 karbonatomer.4. Compound according to claim 1, characterized in that Y is an alkyleneoxy group with 1-6 carbon atoms. 5. Forbindelse ifølge krav 1, karakterisert ved at Y er an alkylendioksygruppe med 1-6 karbonatomer.5. Compound according to claim 1, characterized in that Y is an alkylenedioxy group with 1-6 carbon atoms. 6. Forbindelse ifølge krav 1, karakterisert ved at R 2 er et hydrogenatom.6. Compound according to claim 1, characterized in that R 2 is a hydrogen atom. 7. Forbindelse ifølge krav 1, karakterisert 2 . ved at R er en alkylgruppe med 1-5 karbonatomer.7. Compound according to claim 1, characterized 2. in that R is an alkyl group with 1-5 carbon atoms. 8. Forbindelse ifølge krav 1, karakterisert ved at R er et hydrogenatom.8. Compound according to claim 1, characterized in that R is a hydrogen atom. 9. Forbindelse ifølge krav 1, karakterisert ved at R^ er en alkylgruppe med 1-5 karbonatomer.9. Compound according to claim 1, characterized in that R 1 is an alkyl group with 1-5 carbon atoms. 10. Forbindelse ifølge krav 1, karakterisert ved at X er et kloratom.10. Compound according to claim 1, characterized in that X is a chlorine atom. 11. Forbindelse ifølge-' krav 1, karakterisert ved at-R er et hydrogenatom.11. Compound according to claim 1, characterized in that R is a hydrogen atom. 12. Forbindelse ifølge krav 1, karakterisert ved' at R1 er en lavere alkylgruppe med 1-5 karbonatomer.12. Compound according to claim 1, characterized in that R1 is a lower alkyl group with 1-5 carbon atoms. 13. Forbindelse ifølge krav 1, karakterisert ved at R1 er et halogenatom.13. Compound according to claim 1, characterized in that R1 is a halogen atom. 14 . Forbindelse ifølge krav 1, karakterisert , ved at R1 er en alkoksygruppe med 1-5 karbonatomer.14 . Compound according to claim 1, characterized in that R1 is an alkoxy group with 1-5 carbon atoms. 15. Forbindelse ifølge krav 1, karakterisert ved at Z er en karboksylgruppe.15. Compound according to claim 1, characterized in that Z is a carboxyl group. 16. Forbindelse ifølge krav 1, karakterisert ved at gruppen som kan omdannes til karboksyl og representert ved Z er formyl, cyan, aminokarbonyl, alkoksykarbonyl med 2-5 karbonatomer, mono- eller di-alkylaminokarbonyl med 2-9 karbonatomer, mono- eller di-cykliskalkylaminokarbonyl med 6^ -13 karbonatomer, mono- eller di-arylaminokarbonyl med 7~ l6 karbonatomer, et salt av karboksylgruppen med et ikke-toksisk kation eller med et organisk amin.16. Compound according to claim 1, characterized in that the group which can be converted to carboxyl and represented by Z is formyl, cyan, aminocarbonyl, alkoxycarbonyl with 2-5 carbon atoms, mono- or di-alkylaminocarbonyl with 2-9 carbon atoms, mono- or di -cyclicalkylaminocarbonyl with 6^-13 carbon atoms, mono- or diarylaminocarbonyl with 7-16 carbon atoms, a salt of the carboxyl group with a non-toxic cation or with an organic amine. 17. Forbindelse ifølge krav 1, karakterisert ved at forbindelsen er 2-klor-3_(4-benzyloksyfenyl)propionsyre.17. Compound according to claim 1, characterized in that the compound is 2-chloro-3-(4-benzyloxyphenyl)propionic acid. 18. " Forbindelse ifølge krav 1, karakterisert v ed at forbindelsen er 2-klor-3~ (4-benzyloksyfenyl)propionamid.18. "Compound according to claim 1, characterized in that the compound is 2-chloro-3-(4-benzyloxyphenyl)propionamide. 19. Forbindelse ifølge krav 1, karakterisert ved at forbindelsen er etyl-2-klor~3_(4-benzyloksyfenyl)propionat.19. Compound according to claim 1, characterized in that the compound is ethyl-2-chloro-3-(4-benzyloxyphenyl)propionate. 20. Forbindelse ifølge krav 1, karakterisert ved at forbindelsen er 2-klor-3_/5-(4-klorbenzyloksy)fenyl7 propionsyre.20. Compound according to claim 1, characterized in that the compound is 2-chloro-3-[5-(4-chlorobenzyloxy)phenyl]propionic acid. 21. Forbindelse ifølge krav 15karakterisert ved at forbindelsen er etyl-2-klor-3-/^-(4-klorbenzyloksy)fenyl? propionat.21. Compound according to claim 15, characterized in that the compound is ethyl-2-chloro-3-(4-chlorobenzyloxy)phenyl? propionate. 22. Forbindelse ifølge krav 1., karakterisert ved at forbindelsen er 2-klor-3-/^-(3~klorbenzyloksy)fenyl7 propionsyre.22. A compound according to claim 1, characterized in that the compound is 2-chloro-3-β-(3-chlorobenzyloxy)phenyl-7-propionic acid. 23. Forbindelse ifølge krav 1, karakterisert ved at forbindelsen er etyl-2-klor-3~/4-( 2-klorbenzylo.ksy) fenyl/propionat. v23. Compound according to claim 1, characterized in that the compound is ethyl-2-chloro-3~/4-(2-chlorobenzyloxy)phenyl/propionate. v 24. Forbindelse ifølge krav 1, karakterisert ved at forbindelsen er etyl-2-klor-3_/5-(4-fluorbenzyloksy) fenyl7propionat.24. Compound according to claim 1, characterized in that the compound is ethyl-2-chloro-3-[5-(4-fluorobenzyloxy) phenyl7propionate. 25- - Forbindelse ifølge krav 13karakterisert ved at forbindelsen ér 2-klor-3-/^-(1-fenyletyloksy)fenyl7 propionsyre.25- - Compound according to claim 13, characterized in that the compound is 2-chloro-3-β-(1-phenylethyloxy)phenyl7-propionic acid. 26. Forbindelse ifølge krav 1, karakterisert ved at forbindelsen er etyl-2-klor-3"/4~-(1-fenyletyloksy)fenyl7 propionat.26. Compound according to claim 1, characterized in that the compound is ethyl-2-chloro-3'/4~-(1-phenylethyloxy)phenyl7 propionate. 27. Forbindelse ifølge krav 1, karakterisert ved at forbindelsen er 2-klor-3-/4"-(1-fenylpropyloksy)fenyl7 propionsyre.27. Compound according to claim 1, characterized in that the compound is 2-chloro-3-[4''-(1-phenylpropyloxy)phenyl-7-propionic acid. 28. Forbindelse ifølge krav 1, karakterisert ved at forbindelsen er etyl-2-klor-3-/Ii-(l~f enylpropyloksy) fenyl7propionat.28. Compound according to claim 1, characterized in that the compound is ethyl-2-chloro-3-(1-phenylpropyloxy)phenylpropionate. '29. Forbindelse ifølge krav 1, karakterisert ved at forbindelsen er etyl-2-klor-3_/^-(l-metyl-2-fenyl- .. ety loksy) f eny l7-propionat.'29. Compound according to claim 1, characterized in that the compound is ethyl-2-chloro-3-H-(1-methyl-2-phenyl- .. ety loxy) f eny l7-propionate. 30. Forbindelse ifølge krav 1,' karakterisert ved at forbindelsen er ety1-2-klor-3_(4-fenoksymetylfenyl) propionat.30. Compound according to claim 1, characterized in that the compound is ethyl 1-2-chloro-3-(4-phenoxymethylphenyl)propionate. 31. Forbindelse ifølge krav 1, karakteris" ert ved at forbindelsen er ety1-2-klor-3~ /5-(1-fenoksyetyl)fenyl7 propionat.31. Compound according to claim 1, characterized in that the compound is ethyl 1-2-chloro-3-(5-(1-phenoxyethyl)phenyl)propionate. 32. Forbindelse ifølge krav 1, karakterisert ved at forbindelsen er 2-klor-3" (4-fenoksyfenyl)propionsyre. 33- Forbindelse ifølge krav 1, karakterisert y e d at forbindelsen er 2-klor~3~/5-(4-klorfenoksy)fenyl? propionsyre. 34. Fremgangsmåte til fremstilling av en-forbindelse med den generelle formel: 32. Compound according to claim 1, characterized in that the compound is 2-chloro-3" (4-phenoxyphenyl)propionic acid. 33- Compound according to claim 1, characterized in that the compound is 2-chloro~3~/5-(4-chlorophenoxy)phenyl? propionic acid. 34. Method for the preparation of a compound of the general formula: hvor R"^ er hydrogen, lavere alkyl med 1-5 karbonatomer, halogen, hydroksyl, lavere alkoksy med 1-4 karbonatomer eller.trifluor-2 3 metyl; R og R er like eller forskjellige og hver er hydrogen eller lavere alkyl med 1-5 karbonatomer; X er halogen; Y er et oksygenatom, alkylentio med 1-6 karbonatomer, alkylenoksy med 1-6 karbonatomer, alkylendioks-y med 1-6 karbonatomer; Z er en karboksyIgruppe.eller en gruppe som kån omdannes til en karboksylgruppe; n er 1 eller 2, samt farmasøytisk akseptable salter derav, karakterisert ved at en forbindelse med formelen: where R"^ is hydrogen, lower alkyl with 1-5 carbon atoms, halogen, hydroxyl, lower alkoxy with 1-4 carbon atoms or.trifluoro-2 3 methyl; R and R are the same or different and each is hydrogen or lower alkyl of 1-5 carbon atoms; X is halogen; Y is an oxygen atom, alkylenthio with 1-6 carbon atoms, alkyleneoxy with 1-6 carbon atoms, alkylenedioxy-y with 1-6 carbon atoms; Z is a carboxyl group or a group which can be converted into a carboxyl group; n is 1 or 2, as well as pharmaceutically acceptable salts thereof, characterized in that a compound with the formula: hvor R 4 er en gruppe representert ved R 1 som angitt ovenfor eller en gruppe med formelen -N2+X ; og hvor X, Y og n har den ovenfor angitte betydning, omsettes med en forbindelse med den generelle formel: where R 4 is a group represented by R 1 as indicated above or a group of the formula -N 2 +X ; and where X, Y and n have the meaning stated above, are reacted with a compound of the general formula: hvor R , R og Z har den ovenfor angitte betydning, og,, om ønsket, omdannelse av et således erholdt produkt til et farmasøytisk akseptabelt salt derav. 25. Fremgangsmåte ifølge krav 34, karakter, i sert ved at reaksjonen utføres i nærvær av■en kobberforbindelse. 36.. Fremgangsmåte ifølge krav 3^, karakterisert ved at reaksjonen utføres i nærvær av et materiale valgt fra gruppen bestående av kuprooksyd, kuprioksyd, kuproklorid, kupriklorid, kuprobromid, kupribromid, kobbernitrat og kobbersulfat.where R , R and Z have the above meaning, and, if desired, converting a product thus obtained into a pharmaceutically acceptable salt thereof. 25. Method according to claim 34, character, in that the reaction is carried out in the presence of a copper compound. 36.. Method according to claim 3^, characterized in that the reaction is carried out in the presence of a material selected from the group consisting of cuprous oxide, cupric oxide, cupric chloride, cupric chloride, cupric bromide, cupric bromide, copper nitrate and copper sulphate.
NO744352A 1973-12-12 1974-12-03 NO744352L (en)

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