NO137546B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE BIPHENYLPROPIONIC ACIDS AND THEIR DERIVATIVES - Google Patents

ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE BIPHENYLPROPIONIC ACIDS AND THEIR DERIVATIVES Download PDF

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NO137546B
NO137546B NO1015/72A NO101572A NO137546B NO 137546 B NO137546 B NO 137546B NO 1015/72 A NO1015/72 A NO 1015/72A NO 101572 A NO101572 A NO 101572A NO 137546 B NO137546 B NO 137546B
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biphenylyl
acetyl
acid
compounds
trifluoro
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NO1015/72A
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Norwegian (no)
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NO137546C (en
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Stewart Sanders Adams
Bernard John Armitage
John Stuart Nicholson
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Boots Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07C205/11—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • 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
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
    • C07C45/58—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in three-membered rings
    • 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
    • C07C45/63—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 introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

Denne oppfinnelse angår fremstilling av nye substituerte propionsyrer og derivater derav som har verdifulle biologiske egenskaper, særlig anti-inflammatoriske egenskaper. This invention relates to the production of new substituted propionic acids and derivatives thereof which have valuable biological properties, particularly anti-inflammatory properties.

Det er velkjent at visse substituerte propionsyrer er It is well known that certain substituted propionic acids are

verdifulle anti-inflammatoriske midler. F.eks. anvendes 2-(4-isobutylfenyl)propionsyre i stor utstrekning som et anti-inflammatorisk middel og er også effektiv som et smertestillende og anti-pyretisk middel. I den senere tid er det foreslått å anvende 2-(substituert bifenylyl)propionsyrer for temmelig like formål. F.eks. er et stort antall slike forbindelser omtalt generelt, og noen er nevnt spesielt, valuable anti-inflammatory agents. E.g. 2-(4-isobutylphenyl)propionic acid is widely used as an anti-inflammatory agent and is also effective as an analgesic and anti-pyretic agent. In recent times, it has been proposed to use 2-(substituted biphenylyl)propionic acids for rather similar purposes. E.g. a large number of such compounds are discussed generally, and some are mentioned specifically,

i britiske patenter 1.091.403 og 1.116.432. Blant de mest effektive forbindelser i henhold til disse patenter er 2-(2-fluor-4-bifenylyl)-propionsyre. Det vil sees at de fleste av de kjente bifenylyl- in British Patents 1,091,403 and 1,116,432. Among the most effective compounds according to these patents is 2-(2-fluoro-4-biphenylyl)-propionic acid. It will be seen that most of the known biphenylyl-

forbindelser som er angitt å være anti-inflammatoriske midler, er monosubstituerte i bifenylylradikalet, selv om noen er disubstituerte. compounds reported to be anti-inflammatory agents are monosubstituted in the biphenylyl radical, although some are disubstituted.

Den kjente aktivitet for de kjente substituerte bifenylyl-propionsyrer har vært en korttidsaktivitet, i den betydning at efter administrering forblir forbindelsen i blodstrømmen, og er derfor tilgjengelig for å utøve en terapeutisk virkning, bare i meget kort tid, f.eks. noen få timer, som f.eks. maksimum 3 til 6 timer. Når forbindelsene således anvendes for behandling av kroniske lidelser, har det vært ansett nødvendig å administrere dem flere ganger daglig. The known activity of the known substituted biphenylyl-propionic acids has been a short-term activity, in the sense that after administration the compound remains in the blood stream, and is therefore available to exert a therapeutic effect, only for a very short time, e.g. a few hours, such as maximum 3 to 6 hours. When the compounds are thus used for the treatment of chronic disorders, it has been considered necessary to administer them several times a day.

Formålet med foreliggende oppfinnelse har vært å fremstille nye forbindelser med særlig ønsket langvarig anti-inflammatorisk virkning for behandling av lidelser som medfører langvarig betennelse. The purpose of the present invention has been to produce new compounds with a particularly desired long-term anti-inflammatory effect for the treatment of disorders that cause long-term inflammation.

De nye forbindelser som fremstilles i henhold til oppfinnelsen, har den generelle formel I The new compounds produced according to the invention have the general formula I

hvor , R2 og R^ hver for seg er valgt fra fluor, klor og brom, where , R2 and R^ are each selected from fluorine, chlorine and bromine,

Y er COOH, CONH2 eller CH2OH samt farmasøytisk akseptable Y is COOH, CONH 2 or CH 2 OH as well as pharmaceutically acceptable

estere (dvs. forbindelser hvor Y er COOR^ hvor R^ er et forestrende radikal), uorganiske salter og organiske salter av de forbindelser hvor Y er COOH. esters (ie compounds where Y is COOR^ where R^ is an esterifying radical), inorganic salts and organic salts of those compounds where Y is COOH.

Alle de nye forbindelser som fremstilles i henhold til oppfinnelsen, har langvarig virkning. Den grad av aktivitet som utøves av en hvilken som helst spesiell forbindelse, og aktivitetens varighet vil selvsagt variere fra forbindelse til forbindelse, avhengig av substituentene R^, R2 og R^, og kan også variere avhengig av betydningen av Y. De foretrukne forbindelser er de hvor Y er COOH. Det antas at når salter, estere, amider, All the new compounds produced according to the invention have a long-lasting effect. The degree of activity exerted by any particular compound and the duration of activity will of course vary from compound to compound depending on the substituents R 1 , R 2 and R 2 , and may also vary depending on the meaning of Y. The preferred compounds are those where Y is COOH. It is believed that when salts, esters, amides,

eller alkoholer anvendes istedenfor syrene, metaboliseres derivatene av dyrekroppen og omdannes i kroppen til de tilsvarende syrer. or alcohols are used instead of the acids, the derivatives are metabolized by the animal body and converted in the body into the corresponding acids.

Foretrukne forbindelser har minst en R^, R2 eller R^ som betyr fluor, og det foretrekkes særlig at minst to av radikalene Preferred compounds have at least one R 1 , R 2 or R 2 meaning fluorine, and it is particularly preferred that at least two of the radicals

Rl' R2°g R3 ketyr fluor, mens det tredje radikal betyr fluor eller klor. De mest foretrukne forbindelser er således difluormonoklor-forbindelsene og trifluorforbindelsen, idet sistnevnte er særlig hensiktsmessig. De foretrukne forbindelser er således 2-(2,2',4'-trifluor-4-bifenylyl)propionsyre, 2-(4'-klor-2,2<1->difluor-4-bifenylyl)propionsyre, 2-(2<1->klor-2,4'-difluor-4-bifenylyl)propion- Rl' R2°g R3 is ketyr fluorine, while the third radical means fluorine or chlorine. The most preferred compounds are thus the difluoromonochloro compounds and the trifluoro compound, the latter being particularly suitable. The preferred compounds are thus 2-(2,2',4'-trifluoro-4-biphenylyl)propionic acid, 2-(4'-chloro-2,2<1->difluoro-4-biphenylyl)propionic acid, 2-( 2<1->chloro-2,4'-difluoro-4-biphenylyl)propion-

syre og 2-(2-klor-2<1>,4'-difluor-4-bifenylyl)propionsyre, såvel som de forskjellige derivater av disse syrer hvor karboksylgruppen er erstattet med en av de andre betydninger for Y som angitt ovenfor, acid and 2-(2-chloro-2<1>,4'-difluoro-4-biphenylyl)propionic acid, as well as the various derivatives of these acids where the carboxyl group is replaced by one of the other meanings for Y as indicated above,

og saltene av disse syrer. and the salts of these acids.

I tillegg til å ha en mer langvarig virkning som anti-inflammatoriske midler, mye mer langvarig enn f.eks. 2—(4-isobutyl-fenyl)propionsyre og 2-(2-fluor-4-bifenylyl)propionsyre, har de nye forbindelser som fremstilles i henhold til oppfinnelsen, også smertestillende og anti-pyretiske egenskaper. In addition to having a more long-lasting effect as anti-inflammatory agents, much more long-lasting than e.g. 2-(4-isobutyl-phenyl)propionic acid and 2-(2-fluoro-4-biphenylyl)propionic acid, the new compounds produced according to the invention, also have analgesic and anti-pyretic properties.

Halveringstiden for de nye forbindelser i blodet til The half-life of the new compounds in the blood to

individet som de er administrert til, er et godt tegn på varigheten av deres aktivitet. Halveringstiden kan måles ved å gi orale doser av forbindelsene og bestemme innholdet i plasmaen på forskjellige tidspunkter senere. the individual to whom they are administered is a good indication of the duration of their activity. The half-life can be measured by giving oral doses of the compounds and determining the content in the plasma at various times later.

Den beste metode til å påvise langvarig anti-inflammatorisk virkning for forbindelsene, er ved hjelp av en prøve ved hvilken forbindelsene administreres mot kroniske lidelser, f.eks. prøven med fremkalt artritt hos rotter. Prøver med måling av aktivitet mot akutte anti-inflammatoriske lidelser, så som prøvene på karageenin-ødem og ultra-fiolett erytem, er ikke et virkelig tegn på langvarig anti-inflammatorisk virkning, eftersom slike prøver på akutte lidelser ikke er av tilstrekkelig lang varighet til å avspeile og illustrere den langvarige virkning for forbindelsene. Prøven med fremkalt artritt hos rotter er imidlertid en prøve som omfatter en kronisk lidelse og antaes å være et godt tegn på effektiviteten av forbindelsene for behandling av kroniske lidelser hos mennesker. Ved prøven med fremkalt artritt fremkalles artritt ved at 0,1 ml The best method to demonstrate long-term anti-inflammatory activity of the compounds is by means of a test in which the compounds are administered against chronic conditions, e.g. the induced arthritis test in rats. Tests measuring activity against acute anti-inflammatory disorders, such as the carrageenan edema and ultra-violet erythema tests, are not a true indication of long-term anti-inflammatory activity, since such tests on acute disorders are not of sufficient duration to to reflect and illustrate the long-term impact of the compounds. However, the induced arthritis test in rats is a test involving a chronic condition and is believed to be a good indication of the effectiveness of the compounds for the treatment of chronic conditions in humans. In the test with induced arthritis, arthritis is induced by 0.1 ml

av en suspensjon av avlivede menneskelige tuberkelbasiller (6 mg/ml) of a suspension of killed human tubercle bacilli (6 mg/ml)

i flytende paraffin injiseres intradermalt i halen. En poly- in liquid paraffin is injected intradermally into the tail. A poly-

artritt utvikles i løpet av de neste tre uker i ubehandlede kontroll-dyr. Prøveforbindelsene (bare bæremiddel for kontrolldyrene) gies daglig'gjennom munnen i 21 dager fra den dag det artritt-fremkallende middel injiseres. På den 21. dag bedømmes graden av artritt i hvert bakben. Den grad av hemning som oppnåes ved hjelp av en forbindelse, beregnes ved sammenligning av den totale artritt-gradering med arthritis develops over the next three weeks in untreated control animals. The test compounds (only vehicle for the control animals) are given daily by mouth for 21 days from the day the arthritis-inducing agent is injected. On the 21st day, the degree of arthritis in each hind leg is assessed. The degree of inhibition achieved by a compound is calculated by comparing the total arthritis grade with

graderingen for kontrolldyrene. the grading for the control animals.

I den følgende tabell er gjengitt resultatene ved prøven med fremkalt artritt, for de fire foretrukne forbindelser samt hen-holdsvis alkoholen og amidet svarende til den første, og 2-(2-fluor-4-bifenylyl)propionsyre, idet sistnevnte forbindelse anvendes som en standard ved prøven med fremkalt artritt. The following table shows the results of the test with induced arthritis, for the four preferred compounds as well as respectively the alcohol and the amide corresponding to the first, and 2-(2-fluoro-4-biphenylyl)propionic acid, the latter compound being used as a standard in the sample with induced arthritis.

Metoder for behandling av inflammatoriske lidelser omfatter at det til den levende kropp, f.eks. en menneskelig pasient, administreres en av de nye forbindelser i en farmasøytisk akseptabel og effektiv dose, idet administreringen fortrinnsvis er oral. De nye forbindelser kan også anvendes til behandling av smertetilstander eller pyretiske tilstander hver for seg eller sam-tidig eller i en hvilken som helst kombinasjon med inflammatoriske lidelser ved tilsvarende administrering ay de nye forbindelser. Forbindelsene kan administreres på vanlig måte for andre inflammatoriske midler, f.eks. oralt, rektalt, lokalt eller parenteralt, fortrinnsvis oralt eller rektalt. Den optimale dose-mengde varierer med administreringsformen, men normalt ligger den i området 0,014-14,0 mg/kg/dag, mer vanlig mellom 0,035-7,0 mg/kg/dag. Enhetsdosen kan variere fra 0,5 til 500 mg, og for oral administrering er doseringsmengden fortrinnsvis 0,5 til 500 mg pr. individ pr. dag. Fortrinnsvis er det ikke nødvendig med mer enn én eller maksimum to doseringer daglig i den tid det er påkrevet. Methods for treating inflammatory disorders include adding to the living body, e.g. a human patient, one of the novel compounds is administered in a pharmaceutically acceptable and effective dose, the administration being preferably oral. The new compounds can also be used for the treatment of pain conditions or pyretic conditions separately or simultaneously or in any combination with inflammatory disorders by corresponding administration of the new compounds. The compounds can be administered in the usual way for other inflammatory agents, e.g. orally, rectally, topically or parenterally, preferably orally or rectally. The optimal dose amount varies with the form of administration, but normally it is in the range 0.014-14.0 mg/kg/day, more commonly between 0.035-7.0 mg/kg/day. The unit dose can vary from 0.5 to 500 mg, and for oral administration the dosage amount is preferably 0.5 to 500 mg per individual per day. Preferably, it is not necessary to take more than one or a maximum of two dosages per day during the time it is required.

For å lette administreringen tilberedes forbindelsene fortrinnsvis som terapeutiske preparater som omfatter en ny forbindelse fremstilt i henhold til oppfinnelsen, sammen med farmasøytiske hjelpemidler for fremstilling av preparater for oral, rektal, lokal eller parenteral administrering. Disse preparater inneholder fortrinnsvis 0,1-90 vekt% av en ny forbindelse fremstilt i henhold til oppf innelsen. To facilitate administration, the compounds are preferably prepared as therapeutic preparations comprising a new compound prepared according to the invention, together with pharmaceutical aids for the preparation of preparations for oral, rectal, local or parenteral administration. These preparations preferably contain 0.1-90% by weight of a new compound produced according to the invention.

De nye forbindelser kan selvsagt anvendes sammen med andre aktive anti-inflammatoriske midler, smertestillende midler og anti-pyretiske midler eller med andre legemidler. The new compounds can of course be used together with other active anti-inflammatory agents, analgesics and anti-pyretic agents or with other drugs.

Det vil fremgå at eftersom forbindelsene med den generelle formel I har et asymmetrisk karbonatom, er de vanligvis tilstede i form av en racemisk blanding. Oppspaltning av slike racemater kan utføres ved en hvilken som helst vanlig metode. It will be appreciated that since the compounds of general formula I have an asymmetric carbon atom, they are usually present in the form of a racemic mixture. Resolution of such racemates can be accomplished by any conventional method.

De nye forbindelser fremstilles i henhold til oppfinnelsen ved en rekke forskjellige metoder som er angitt nedenfor. Eftersom selve fremgangsmåtene enten allerede er kjent eller er åpenbare for fagfolk, er de beskrevet i korthet. Når de anvendte utgangsmaterialer ikke allerede er kjente forbindelser, vil fremgangsmåtene for fremstilling derav være åpenbare for fagfolk, og dessuten er typiske metoder for fremstilling av utgangsmaterialene gjengitt i noen av eksemplene. I den følgende beskrivelse for fremstilling av syrene og de forskjellige syrederivater er symbolet RQ anvendt for å betegne hvor Rlf R2 og R3 har de samme betydninger som tidligere. The new compounds are produced according to the invention by a number of different methods which are indicated below. Since the methods themselves are either already known or are obvious to those skilled in the art, they are described briefly. When the starting materials used are not already known compounds, the methods for their preparation will be obvious to those skilled in the art, and furthermore, typical methods for preparing the starting materials are reproduced in some of the examples. In the following description for the preparation of the acids and the various acid derivatives, the symbol RQ is used to denote where Rlf R2 and R3 have the same meanings as before.

Syrer Acids

1. Hydrolyse av 1. Hydrolysis of

hvor Z er cyano, karbamoyl, where Z is cyano, carbamoyl,

N,N-disubstituert tiokarbamoyl eller COOR^ hvor R^ er en esterdannende gruppe, særlig lavere alkyl. Den N,N-disubstituerte tiokarbamoyl-gruppe er fortrinnsvis avledet fra morfolin. N,N-disubstituted thiocarbamoyl or COOR^ where R^ is an ester-forming group, especially lower alkyl. The N,N-disubstituted thiocarbamoyl group is preferably derived from morpholine.

Hydrolysen kan utføres i henhold til metoder som er velkjente innen teknikken, f.eks. ved anvendelse av syre eller alkali i vann, The hydrolysis can be carried out according to methods well known in the art, e.g. when using acid or alkali in water,

i et organisk, flytende reaksjonsmedium eller i en blanding derav, in an organic, liquid reaction medium or in a mixture thereof,

og en behandlingstemperatur på 15-150°C er hensiktsmessig. Fortrinnsvis utføres hydrolysen ved tilbakeløpsbehandling i nærvær and a treatment temperature of 15-150°C is appropriate. Preferably, the hydrolysis is carried out by reflux treatment in the presence

av et alkalimetallhydroksyd eller av en mineralsyre, og det organiske, flytende reaksjonsmedium er fortrinnsvis en lavere alkanol. of an alkali metal hydroxide or of a mineral acid, and the organic liquid reaction medium is preferably a lower alkanol.

Utgangsmaterialene kan f.eks. fremstilles fra de substituerte acetofenoner RQ-CO-CH3 på vanlig måte, og andre metoder omfatter de som er beskrevet nedenfor under overskriftene "estere" og "amider". The starting materials can e.g. are prepared from the substituted acetophenones RQ-CO-CH3 in the usual manner, and other methods include those described below under the headings "esters" and "amides".

2. Dekarboksylering av 2. Decarboxylation of

Dette kan utføres ved oppvarming av forbindelsen ved ca. 200°C. This can be done by heating the compound at approx. 200°C.

Utgangsmaterialene kan hensiktsmessig fremstilles på vanlig måte, f.eks. ved omsetning av en alkylester av en syre RQ-CH2-COOH med et alkylkarbonat og et alkalimetallalkoksyd for å danne et alkalimetallderivat av en forbindelse med formelen Rq-CH-(COOalkyl)2, metylering av denne og hydrolyse av produktet. The starting materials can conveniently be produced in the usual way, e.g. by reacting an alkyl ester of an acid RQ-CH2-COOH with an alkyl carbonate and an alkali metal alkoxide to form an alkali metal derivative of a compound of the formula Rq-CH-(COOalkyl)2, methylation thereof and hydrolysis of the product.

3. Oksydasjon av 3. Oxidation of

Oksydasjonen kan utføres under anvendelse av et hvilket som helst egnet oksydasjonsmiddel så som permanganater, kromsyre, dikromater, persyrer, hydrogenperoksyd, salpetersyre, hypokloritter, sølvoksyd eller oksygen. En meget hensiktsmessig fremgangsmåte omfatter oksydasjon i vandig etanol med alkali (f.eks. et alkalimetall- The oxidation can be carried out using any suitable oxidizing agent such as permanganates, chromic acid, dichromates, peracids, hydrogen peroxide, nitric acid, hypochlorites, silver oxide or oxygen. A very convenient method comprises oxidation in aqueous ethanol with alkali (e.g. an alkali metal

hydroksyd) og sølvoksyd. hydroxide) and silver oxide.

Utgangsmaterialene kan fremstilles ved de fremgangsmåter som er beskrevet for beslektede forbindelser i vårt britiske patent 1.160.725. The starting materials can be prepared by the methods described for related compounds in our British patent 1,160,725.

4> Hydrolyse av 4> Hydrolysis of

hvor "alkyl" fortrinnsvis er metyl. Typiske hydrolysebetingelser er beskrevet under fremgangsmåte (1). where "alkyl" is preferably methyl. Typical hydrolysis conditions are described under procedure (1).

Utgangsmaterialene kan fremstilles under anvendelse av fremgangsmåter lik de som er beskrevet av Meyers og Temple, J. Amer. chem. Soc. 1970, 92_, 6644. The starting materials can be prepared using methods similar to those described by Meyers and Temple, J. Amer. chem. Soc. 1970, 92_, 6644.

Estere Esters

Forestring av syrene på vanlig måte: f.eks. Esterification of the acids in the usual way: e.g.

Amider Amides

Fremstilling av amidene på vanlig måte, f0eks.: Preparation of the amides in the usual way, e.g.:

Salter Salts

1. Omsetning av syrene med organiske eller uorganiske baser. 2. Alkalisk hydrolyse av 1. Reaction of the acids with organic or inorganic bases. 2. Alkaline hydrolysis of

Typiske uorganiske salter som kan dannes, er natrium- og kaliumsaltene. Typiske organiske salter som kan dannes, er amin-salter, innbefattet hydroksyaminsalter. F.eks. kan det dannes salter med trietylamin eller dietylaminoetanol eller benzylamin. Typical inorganic salts that can be formed are the sodium and potassium salts. Typical organic salts that can be formed are amine salts, including hydroxyamine salts. E.g. salts can be formed with triethylamine or diethylaminoethanol or benzylamine.

Alkoholer Alcohols

1. Reduksjon av syrene eller, fortrinnsvis, estrene (særlig alkylestrene). Anvendelse av litiumaluminiumhydrid i et egnet oppløsningsmiddel, f„eks. eter, fulgt av surgjøring er et eksempel. Alterrativt kan hydrogenering i nærvær av en kobber/kromoksyd-katalysator anvendes. Estere kan reduseres med natrium i en lavere alkanol. 1. Reduction of the acids or, preferably, the esters (especially the alkyl esters). Use of lithium aluminum hydride in a suitable solvent, e.g. ether, followed by acidification is an example. Alternatively, hydrogenation in the presence of a copper/chromium oxide catalyst can be used. Esters can be reduced with sodium in a lower alkanol.

Eksempel 1 (Fremstilling av utgangsmateriale) Example 1 (Manufacturing starting material)

2,4-difluorjodbenzen og 4-brom-3-nitroacetofenon ble omsatt under Ullmann betingelser for å danne 4-acetyl-2',4'-difluor-2-nitrobifenyl, k.p. 150-158°C/0,2 mm Hg, og denne forbindelse ble redusert med tinn(ll)klorid for å danne 4-acetyl-2-amino-2',4<1->difluorbifenyl, sm.p. 93-95°C. Ved tilsvarende fremgangsmåter fikk man 2,4-difluoroiodobenzene and 4-bromo-3-nitroacetophenone were reacted under Ullmann conditions to form 4-acetyl-2',4'-difluoro-2-nitrobiphenyl, b.p. 150-158°C/0.2 mm Hg, and this compound was reduced with stannous chloride to form 4-acetyl-2-amino-2',4<1->difluorobiphenyl, m.p. 93-95°C. By similar procedures, one got

4-acetyl-2'-klor-4'-fluor-2-nitrobifenyl, k.p. 178-190/0,2 mm Hg, sm.p. 62-64°C og 4-acetyl-2-amino-2<1->klor-4'-fluorbifenyl, 4-acetyl-2'-chloro-4'-fluoro-2-nitrobiphenyl, m.p. 178-190/0.2 mm Hg, m.p. 62-64°C and 4-acetyl-2-amino-2<1->chloro-4'-fluorobiphenyl,

sm.p. 84-86°C; sm.p. 84-86°C;

4-acetyl-4'-klor-2'-fluor-2-nitrobifenyl, k.p. 174-180/0,2 mm Hg, sm.p. 85-86°C og 4-acetyl-4'-chloro-2'-fluoro-2-nitrobiphenyl, m.p. 174-180/0.2 mm Hg, m.p. 85-86°C and

4-acetyl-2-amino-2'-fluor-4'-klorbifenyl, sm.p. 115°C; 4-acetyl-2',4<1->diklor-2-nitrobifenyl, sm.p. 72-74°C og 4-acetyl-2-amino-2<1>,4<1->diklorbifenyl, sm.p. 75-76°C; 4-acetyl-2',4'-dibrom-2-nitrobifenyl, k.p. 210°C/0,3 mm Hg og 4-acetyl-2-amino-2<1>,4'-dibrombifenyl, sm.p. 107-109°C; 4-acetyl-4<*->brom-2'-fluor-2-nitrobifenyl, sm.p. 116-117°C og 4-acetyl-2-amino-4<1->brom-2<1->fluorbifenyl, sm.p. 120-121°C; 4-acetyl-2<1->brom-4'-fluor-2-nitrobifenyl, k.p. 188-200°C/0,3 mm Hg, sm.p. 75-77°C og 4-acetyl-2-amino-2'-fluoro-4'-chlorobiphenyl, m.p. 115°C; 4-acetyl-2',4<1->dichloro-2-nitrobiphenyl, m.p. 72-74°C and 4-acetyl-2-amino-2<1>,4<1->dichlorobiphenyl, m.p. 75-76°C; 4-acetyl-2',4'-dibromo-2-nitrobiphenyl, b.p. 210°C/0.3 mm Hg and 4-acetyl-2-amino-2<1>,4'-dibromobiphenyl, m.p. 107-109°C; 4-acetyl-4<*->bromo-2'-fluoro-2-nitrobiphenyl, m.p. 116-117°C and 4-acetyl-2-amino-4<1->bromo-2<1->fluorobiphenyl, m.p. 120-121°C; 4-acetyl-2<1->bromo-4'-fluoro-2-nitrobiphenyl, b.p. 188-200°C/0.3 mm Hg, m.p. 75-77°C and

4-acetyl-2-amino-2'-brom-4<*->fluorbifenyl, sm.p. 98-100°C; 4-acetyl-4'-brom-2'-klor-2-nitrobifenyl, k.p. 185-190°C/0,2 mm Hg og 4-acetyl-2-amino-4<1->brom-2<1->klorbifenyl, sm.p. 93-95°C; og 4-acetyl-2-amino-2'-bromo-4<*->fluorobiphenyl, m.p. 98-100°C; 4-acetyl-4'-bromo-2'-chloro-2-nitrobiphenyl, m.p. 185-190°C/0.2 mm Hg and 4-acetyl-2-amino-4<1->bromo-2<1->chlorobiphenyl, m.p. 93-95°C; and

4-acetyl-2'-brom-4'-klor-2-nitrobifenyl, sm.p. 84-86°C; og 4-acetyl-2-amino-2'-brom-4'-klorbifenyl, sm.p. 98-100°C. 4-acetyl-2'-bromo-4'-chloro-2-nitrobiphenyl, m.p. 84-86°C; and 4-acetyl-2-amino-2'-bromo-4'-chlorobiphenyl, m.p. 98-100°C.

Eksempel 2 (Fremstilling av utgangsmateriale) Example 2 (Production of starting material)

4-acetyl-2-amino-2',4'-difluorbifenyl fremstilt som beskrevet i eksempel 1, ble underkastet Schiemann reaksjonen under anvendelse åv fluorborsyre, for å danne 4-acetyl-2,2',4'-trifluorbifenyl, 4-acetyl-2-amino-2',4'-difluorobiphenyl prepared as described in Example 1 was subjected to the Schiemann reaction using hydrofluoric acid to form 4-acetyl-2,2',4'-trifluorobiphenyl,

sm.p. 92-94°C. Ved en tilsvarende fremgangsmåte med de passende produkter fra eksempel 1 som utgangsmaterialer fikk man 4-acetyl-4'-klor-2,2'-difluor-bifenyl, sm.p. 69-70°C og 4-acetyl-4'-brom-2,2'-difluorbifenyl, sm.p. 75-76°C. sm.p. 92-94°C. By a similar procedure with the appropriate products from example 1 as starting materials, 4-acetyl-4'-chloro-2,2'-difluoro-biphenyl was obtained, m.p. 69-70°C and 4-acetyl-4'-bromo-2,2'-difluorobiphenyl, m.p. 75-76°C.

Eksempel 3 (Fremstilling av utgangsmateriale) Example 3 (Manufacturing starting material)

4-acetyl-2-amino-2',4'-difluorbifenyl fra eksempel 1 ble underkastet Sandmeyer reaksjonen under anvendelse av kobber(I)klorid for å danne 4-acetyl-2-klor-2',4'-difluorbifenyl, k.p. 132-134°C/-0,3 mm Hg. Ved en lik fremgangsmåte fikk man fra det passende utgangsmateriale 4-acetyl-2,2'-diklor-4-fluorbifenyl, 4-acetyl-2,4'-diklor-2'-fluorbifenyl, k.p. 134-138°C/0,05 mm Hg, 4-acetyl-2,2',4'-triklorbifenyl, k.p. 154-155°C/0,2 mm Hg, 4-acetyl-2<1>,4'-dibrom-2-klorbifenyl, k.p. 174-178°C/0,5 mm Hg, 4-acetyl-4'-brom-2-klor-2'-fluorbifenyl, k.p. 165-170°C/0,1 mm Hg 4-acetyl-2'-brom-2-klor-4<1->fluorbifenyl, k.p. 168-170°C/1,0 mm Hg og under anvendelse av kobber(I)bromid istedenfor kobber(I)klorid i Sandmeyer reaksjonen, 4-acetyl-2,2<1->4'-tribrombifenyl, sm.p. 73-75,5°C, 4-acetyl-2,4'-dibrom-2'-fluorbifenyl, sm.p. 63-64°C, 4-acetyl-2,2'-dibrom-4<:->fluorbifenyl, k.p. 166-168°c/0,8 mm Hg, 4-acetyl-2,4'-dibrom-2<*->klorbifenyl, sm.p. 53-54°C og 4-acetyl-2,2'-dibrom-4<1->klorbifenyl, sm.p. 75-77°c. 4-acetyl-2-amino-2',4'-difluorobiphenyl from Example 1 was subjected to the Sandmeyer reaction using copper(I) chloride to form 4-acetyl-2-chloro-2',4'-difluorobiphenyl, m.p. 132-134°C/-0.3 mm Hg. By a similar procedure, 4-acetyl-2,2'-dichloro-4-fluorobiphenyl, 4-acetyl-2,4'-dichloro-2'-fluorobiphenyl, b.p. 134-138°C/0.05 mm Hg, 4-acetyl-2,2',4'-trichlorobiphenyl, b.p. 154-155°C/0.2 mm Hg, 4-acetyl-2<1>,4'-dibromo-2-chlorobiphenyl, b.p. 174-178°C/0.5 mm Hg, 4-acetyl-4'-bromo-2-chloro-2'-fluorobiphenyl, b.p. 165-170°C/0.1 mm Hg 4-acetyl-2'-bromo-2-chloro-4<1->fluorobiphenyl, b.p. 168-170°C/1.0 mm Hg and using copper (I) bromide instead of copper (I) chloride in the Sandmeyer reaction, 4-acetyl-2,2<1->4'-tribromobiphenyl, m.p. 73-75.5°C, 4-acetyl-2,4'-dibromo-2'-fluorobiphenyl, m.p. 63-64°C, 4-acetyl-2,2'-dibromo-4<:->fluorobiphenyl, b.p. 166-168°c/0.8 mm Hg, 4-acetyl-2,4'-dibromo-2<*->chlorobiphenyl, m.p. 53-54°C and 4-acetyl-2,2'-dibromo-4<1->chlorobiphenyl, m.p. 75-77°c.

Eksempel 4 (Fremstilling av utgangsmateriale) Example 4 (Production of starting material)

2,4-diklorjodbenzen og 2,5-dibromnitrobenzen ble omsatt under Ullmann betingelser for å danne 4-brom-2',4<1->diklor-2-nitro-bifenyl, sm.p. 112-115°C. Denne forbindelse ble redusert med tinn(II)klorid for å danne 2-amino-4-brom-2',4'-diklorbifenyl, k.p. 170-175°C/0,2 mm Hg. Denne forbindelse ble underkastet Schiemann reaksjonen under anvendelse av fluorborsyre, for å danne 4-brom-2<1>,4'-diklor-2-fluorbifenyl, sm.p. 63-65°C. Denne forbindelse ble omsatt med kobber(I)cyanid i dimetylformamid for å danne 2,4-dichloroiodobenzene and 2,5-dibromonitrobenzene were reacted under Ullmann conditions to form 4-bromo-2',4<1->dichloro-2-nitro-biphenyl, m.p. 112-115°C. This compound was reduced with stannous chloride to give 2-amino-4-bromo-2',4'-dichlorobiphenyl, m.p. 170-175°C/0.2 mm Hg. This compound was subjected to the Schiemann reaction using fluoroboric acid to form 4-bromo-2<1>,4'-dichloro-2-fluorobiphenyl, m.p. 63-65°C. This compound was reacted with copper(I) cyanide in dimethylformamide to form

2<1>,4'-diklor-4-cyano-2-fluorbifenyl, sm.p. 98-103°C som deretter ble omsatt med metylmagnesiumjodid fulgt av hydrolyse med fortynnet saltsyre for å danne 4-acetyl-2<1>,4'-diklor-2-fluorbifenyl, sm.p. 65-67°C. 2<1>,4'-dichloro-4-cyano-2-fluorobiphenyl, m.p. 98-103°C which was then reacted with methylmagnesium iodide followed by hydrolysis with dilute hydrochloric acid to form 4-acetyl-2<1>,4'-dichloro-2-fluorobiphenyl, m.p. 65-67°C.

Eksempel 5 (Fremstilling av utgangsmateriale) Example 5 (Production of starting material)

4-acetyl-2-amino-2'-klor-4'-fluorbifényl erholdt fra eksempel 1 ble underkastet diazotering i flussyre med natriumnitrit for å danne 4-acetyl-2'-klor-2,4'-difluorbifenyl, k.p. 140-160°C/4-acetyl-2-amino-2'-chloro-4'-fluorobiphenyl obtained from Example 1 was subjected to diazotization in hydrofluoric acid with sodium nitrite to form 4-acetyl-2'-chloro-2,4'-difluorobiphenyl, m.p. 140-160°C/

1 mm Hg. Ved en lik fremgangsmåte under anvendelse av de passende .utgangsmaterialer fra eksempel 1 fikk man 4-acetyl-2<1>,4<1->dibrom-2-fluorbifenyl, 4-acetyl-2'-brom-2,4'-difluorbifenyl, 4-acetyl-4'-brom-2'-klor-2-fluorbifenyl og 4-acetyl-2'-brom-4<1->klor-2-fluor-bifenyl. 1 mm Hg. By a similar procedure using the appropriate starting materials from example 1, 4-acetyl-2<1>,4<1->dibromo-2-fluorobiphenyl, 4-acetyl-2'-bromo-2,4'- difluorobiphenyl, 4-acetyl-4'-bromo-2'-chloro-2-fluorobiphenyl and 4-acetyl-2'-bromo-4<1->chloro-2-fluoro-biphenyl.

Eksempel 6 (Fremstilling av utgangsmateriale) Example 6 (Production of starting material)

4-acetyl-2,2',4'-trifluorbifenyl fra eksempel 2 ble behandlet med natriumisopropoksyd og etylkloråcetat i henhold til Darzens reaksjon for å danne en blanding av estere inneholdende den urensede isopropylester av 3-(2,2',4'-trifluorbifenylyl)2,3-epoksysmørsyre, som ble hydrolysert med natriumhydroksyd/vandig alkohol for å danne et urenset natriumsalt av nevnte smørsyre. Denne ble dekarboksylert ved oppvarming ved 90°C for å gi 2-(2,2<1>,4'-trifluor-4-bifenylyl)-propionaldehyd, k.p. 132-134°c/l mm Hg. Hver av de andre 4-acetyl-trihalogen-bifenylforbindelsene fremstilt i eksemplene 2 til 5 ble underkastet den samme reaksjon for å danne de tilsvarende trihalogenaldehyder. Slike aldehyder omfatter blant annet 2-(4'-klor-2,2'-difluor-4-bifenylyl)propionaldehyd, k.p. 174-180°C/ 0,1 mm Hg, 2-(2,4'-diklor-2'-fluor-4-bifenylyl)propionaldehyd, 4-Acetyl-2,2',4'-trifluorobiphenyl from Example 2 was treated with sodium isopropoxide and ethyl chloroacetate according to Darzen's reaction to form a mixture of esters containing the crude isopropyl ester of 3-(2,2',4'- trifluorobiphenylyl)2,3-epoxybutyric acid, which was hydrolyzed with sodium hydroxide/aqueous alcohol to form an impure sodium salt of said butyric acid. This was decarboxylated by heating at 90°C to give 2-(2,2<1>,4'-trifluoro-4-biphenylyl)-propionaldehyde, m.p. 132-134°c/l mm Hg. Each of the other 4-acetyl-trihalo-biphenyl compounds prepared in Examples 2 to 5 was subjected to the same reaction to form the corresponding trihaloaldehydes. Such aldehydes include, among others, 2-(4'-chloro-2,2'-difluoro-4-biphenylyl)propionaldehyde, b.p. 174-180°C/ 0.1 mm Hg, 2-(2,4'-dichloro-2'-fluoro-4-biphenylyl)propionaldehyde,

k.p. 152-156°C/0,1 mm Hg, 2-(2',4'-diklor-2-fluor-4-bifenylyl)-propionaldehyd, k.p. 160-162°C/0,3 mm Hg, 2-(2,2',4'-triklor-4-bifenylyDpropionaldehyd, k.p. 190-192°C/1, 0 mm Hg, 2-(2 , 4'-dibrom-2<1->fluor-4-bifenylyl)propionaldehyd, k.p. 167-170°C/0,1 mm Hg, 2-(4'-brom-2,2'-difluor-4-bifenylyl)propionaldehyd, k.p. 145-146°c/ 0,07 mm Hg, 2-(4'-brom-2-klor-2'-fluor-4-bifenylyl)propionaldehyd, k.p. 155-160°C/0,07 mm Hg og 2-(2-brom-4'-klor-2'-fluor-4-bifenylyl)-propionaldehyd, k.p. 158-160°C/0,07 mm Hg. k.p. 152-156°C/0.1 mm Hg, 2-(2',4'-dichloro-2-fluoro-4-biphenylyl)-propionaldehyde, b.p. 160-162°C/0.3 mm Hg, 2-(2,2',4'-trichloro-4-biphenylylDpropionaldehyde, b.p. 190-192°C/1.0 mm Hg, 2-(2 , 4'- dibromo-2<1->fluoro-4-biphenylyl)propionaldehyde, b.p. 167-170°C/0.1 mm Hg, 2-(4'-bromo-2,2'-difluoro-4-biphenylyl)propionaldehyde, b.p. 145-146°c/ 0.07 mm Hg, 2-(4'-bromo-2-chloro-2'-fluoro-4-biphenylyl)propionaldehyde, bp 155-160°C/0.07 mm Hg and 2- (2-bromo-4'-chloro-2'-fluoro-4-biphenylyl)-propionaldehyde, mp 158-160°C/0.07 mm Hg.

Eksempel 7 Example 7

Hydroksylaminsulfat (3,02 g) ble satt til en vandig opp-løsning av natriumacetat [fremstilt fra iseddik (2,4 ml), 18N vandig natriumhydroksyd (2,34 ml) og vann (23 ml)]. 2-(2,2',4<1->trifluor-4-bifenylyl)propionaldehyd (8,26 g) i etanol (23 ml) ble tilsatt, Hydroxylamine sulfate (3.02 g) was added to an aqueous solution of sodium acetate [prepared from glacial acetic acid (2.4 mL), 18N aqueous sodium hydroxide (2.34 mL) and water (23 mL)]. 2-(2,2',4<1->trifluoro-4-biphenylyl)propionaldehyde (8.26 g) in ethanol (23 mL) was added,

og blandingen ble omrørt ved romtemperatur i 2,5 timer og deretter ved 90°C i 1 minutt. Efter avkjøling ble det utfelte oksim suspendert i vann inneholdende nikkelsulfat (0,2 g) og oppvarmet til tilbakeløpstemperatur for å danne en vandig suspensjon av and the mixture was stirred at room temperature for 2.5 hours and then at 90°C for 1 minute. After cooling, the precipitated oxime was suspended in water containing nickel sulfate (0.2 g) and heated to reflux temperature to form an aqueous suspension of

2-(2,2',4'-trifluor-4-bifenylyl)propionamid. Vandig natriumhydroksyd (18N, 6,75 ml) ble deretter tilsatt, og tilbakeløps-behandling ble fortsatt i 24 timer. Den resulterende oppløsning ble avkjølt til 40°C, surgjort med konsentrert saltsyre, og produktet ble isolert i eter. Efter en viss rensning ved hjelp av en vanlig tilbake-ekstraheringsteknikk med vandig kaliumkarbonat, ble den endelige eterekstrakt inndampet til tørrhet. Denne urensede syre i metylenklorid ble kromatografert på en kolonne av et syntetisk magnesiumoksyd/silikagél adsorbsjonsmiddel. Inndampning av eluatet og omkrystallisering av residuet fra petroleter (k.p. 80-100°C) ga 2-(2,2',4'-trifluor-4-bifenylyl)propionsyre, sm.p. 105-108°C. 2-(2,2',4'-trifluoro-4-biphenylyl)propionamide. Aqueous sodium hydroxide (18N, 6.75 mL) was then added and refluxing was continued for 24 hours. The resulting solution was cooled to 40°C, acidified with concentrated hydrochloric acid, and the product was isolated in ether. After some purification using a conventional back-extraction technique with aqueous potassium carbonate, the final ether extract was evaporated to dryness. This crude acid in methylene chloride was chromatographed on a column of a synthetic magnesium oxide/silica gel adsorbent. Evaporation of the eluate and recrystallization of the residue from petroleum ether (b.p. 80-100°C) gave 2-(2,2',4'-trifluoro-4-biphenylyl)propionic acid, m.p. 105-108°C.

Ved en lik fremgangsmåte fikk man fra de tilsvarende aldehyder ifølge eksempel 6 de tilsvarende propionsyrer. De fysikalske data for de forskjellige forbindelser som ble fremstilt, er angitt i den følgende tabell hvor symbolene , R2 og R^ betegner substituentene i formel I, og tallet i høyre spalte er smeltepunktet for den resulterende syre. By a similar procedure, the corresponding propionic acids were obtained from the corresponding aldehydes according to example 6. The physical data for the various compounds that were prepared are given in the following table where the symbols , R 2 and R 1 denote the substituents in formula I, and the number in the right column is the melting point of the resulting acid.

Eksempel 8 Example 8

Benzylamin (0,15 ml) ble satt til en eteroppløsning av 2-(2,2',4'-trifluor-4-bifenylyl)propionsyre (280 mg i 20 ml). Blandingen ble omrørt ved romtemperatur i 15 minutter, og saltet ble derefter oppsamlet, vasket med eter og omkrystallisert fra en blanding av aceton og lett bensin (k.p. 40-60°C). Produktet var benzylammonium-2-(2,2',4'-trifluor-4-bifenylyl)propionat, Benzylamine (0.15 mL) was added to an ether solution of 2-(2,2',4'-trifluoro-4-biphenylyl)propionic acid (280 mg in 20 mL). The mixture was stirred at room temperature for 15 minutes, and the salt was then collected, washed with ether and recrystallized from a mixture of acetone and light gasoline (b.p. 40-60°C). The product was benzylammonium 2-(2,2',4'-trifluoro-4-biphenylyl)propionate,

sm.p. 133-134°C. sm.p. 133-134°C.

Ved den samme metode med den passende syre som utgangsmateriale ble det fremstilt benzylammonium-2-(2<1>,4<1->diklor-2-fluor-4-bifenylyl)propionat, sm.p. 111-113°C. Ved den samme metode får man andre organiske salter. By the same method with the appropriate acid as starting material, benzylammonium 2-(2<1>,4<1->dichloro-2-fluoro-4-biphenylyl)propionate was prepared, m.p. 111-113°C. Other organic salts are obtained by the same method.

Eksempel 9 Example 9

En oppløsning av natriumhydroksyd (0,1 g) i vann (1,0 ml) ble satt til en oppløsning av 2-(2,2',4<1->trifluor-4-bifenylyl)-propionsyre (0,5 g) i aceton (5 ml). Efter omrøring i 15 minutter ble det resulterende salt filtrert, vasket med aceton og omkrystallisert fra vann. Det resulterende natrium-2-(2,2',4'-tri-fluor-4-bifenylyl)propionat hadde sm.p. 222-224°C. Ved den samme metode får man andre uorganiske salter, særlig natriumsalter. A solution of sodium hydroxide (0.1 g) in water (1.0 ml) was added to a solution of 2-(2,2',4<1->trifluoro-4-biphenylyl)-propionic acid (0.5 g ) in acetone (5 mL). After stirring for 15 minutes, the resulting salt was filtered, washed with acetone and recrystallized from water. The resulting sodium 2-(2,2',4'-trifluoro-4-biphenylyl)propionate had m.p. 222-224°C. By the same method, other inorganic salts are obtained, especially sodium salts.

Eksempel 10 Example 10

En blanding av 2-(2,2<1>,4'-trifluor-4-bifenylyl)propionsyre (2,0 g), absolutt etanol (25 ml) og konsentrert H2S0^ (1 ml) ble tilbakeløpsbehandlet natten over. Oppløsningen ble avkjølt, fortynnet med vann, og esteren ble isolert i eter. Destillasjon ga en farveløs olje med k.p. 124-126°c/0,3 mm Hg, som stivnet og deretter ble krystallisert fra lettbensin (k.p. 40-60°C) for å gi farveløse nåler av etyl-<2-(2 , 2', 4'-trifluor-4-bif enylyl)propionat, sm.p. 3 6-38°C. A mixture of 2-(2,2<1>,4'-trifluoro-4-biphenylyl)propionic acid (2.0 g), absolute ethanol (25 mL) and concentrated H 2 SO 4 (1 mL) was refluxed overnight. The solution was cooled, diluted with water, and the ester isolated in ether. Distillation gave a colorless oil with b.p. 124-126°c/0.3 mm Hg, which solidified and then crystallized from light naphtha (b.p. 40-60°C) to give colorless needles of ethyl-<2-(2 , 2', 4'-trifluoro- 4-bienyl)propionate, m.p. 3 6-38°C.

På samme måte fikk man etyl-2-(4'-brom-2,2'-difluor-4-bifenylyl)propionat, k.p. 152-153°C/0,1 mm Hg. På samme.måte får man andre lavere alkanoatestere, særlig de hvor alkylgruppen inneholder l.til 4 karbonatomer, fra syrene fremstilt i eksempel 7. In the same way, ethyl 2-(4'-bromo-2,2'-difluoro-4-biphenylyl)propionate was obtained, b.p. 152-153°C/0.1 mm Hg. In the same way, other lower alkanoate esters, especially those where the alkyl group contains 1 to 4 carbon atoms, are obtained from the acids prepared in example 7.

Eksempel 11 Example 11

Etyl-2-(2,2',4'-trifluor-4-bifenylyl)propionat (708 mg) , (eksempel 10) i etanol (5 ml) og vann (5 ml) inneholdende natriumhydroksyd5 (0,4 ml av 18N) ble tilbakeløpsbehandlet i 1 time. Etanolen ble avdestillert, og den gjenværende blanding ble avkjølt og surgjort. Den faste syre ble oppsamlet, vasket, tørret og omkrystallisert fra .lettbensin (k.p. 80-100°C) for å danne farveløse nåler, sm.p. 107-108,5°C. Ethyl 2-(2,2',4'-trifluoro-4-biphenylyl)propionate (708 mg), (Example 10) in ethanol (5 ml) and water (5 ml) containing sodium hydroxide5 (0.4 ml of 18N ) was refluxed for 1 hour. The ethanol was distilled off, and the remaining mixture was cooled and acidified. The solid acid was collected, washed, dried and recrystallized from naphtha (b.p. 80-100°C) to form colorless needles, m.p. 107-108.5°C.

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Eksempel 12 Example 12

En oppløsning av etyl-2-(2,2',4'-trifluor-4-bifenylyl)-propionat (0,5 g) i tørr eter (10 ml) ble i løpet av 5 minutter satt til en omrørt suspensjon av litiumaluminiumhydrid (0,1 g) i tørr eter (10 ml). Efter tilbakeløpsbehandling i 90 minutter ble overskudd av hydrid spaltet ved suksessiv tilsetning av fuktig eter, vann og tilslutt fortynnet svovelsyre. A solution of ethyl 2-(2,2',4'-trifluoro-4-biphenylyl)-propionate (0.5 g) in dry ether (10 ml) was added over 5 minutes to a stirred suspension of lithium aluminum hydride (0.1 g) in dry ether (10 ml). After reflux treatment for 90 minutes, excess hydride was split by successive addition of moist ether, water and finally dilute sulfuric acid.

Propanolen ble isolert i eter, vasket, tørret, inndampet og destillert for å gi en farveløs uklar olje, k.p. 140-142°C/0,7 mm Hg, som stivnet og deretter ble krystallisert fra lettbensin (k.p. 62-68°C) for å gi farveløse nåler av 2-(2,2',4'-trifluor-4-bifenylyl)propan-l-ol, sm.p. 58-59°C. The propanol was isolated in ether, washed, dried, evaporated and distilled to give a colorless cloudy oil, m.p. 140-142°C/0.7 mm Hg, which solidified and then crystallized from naphtha (b.p. 62-68°C) to give colorless needles of 2-(2,2',4'-trifluoro-4-biphenylyl )propan-l-ol, m.p. 58-59°C.

På samme måte, men under anvendelse av de passende utgangsmaterialer fikk man 2-(4'-brom-2,2'-difluor-4-bifenylyl)propan-l-ol, k.p. 139-140°C/0,05 mm Hg og 2-(2',4'-diklor-2-fluor-4-bifenylyl)-propan-l-ol, k.p. 174-176°C/2 mm Hg, og andre alkoholer kan fremstilles på samme måte fra syrene fremstilt i eksempel 7. In the same way, but using the appropriate starting materials, 2-(4'-bromo-2,2'-difluoro-4-biphenylyl)propan-1-ol was obtained, m.p. 139-140°C/0.05 mm Hg and 2-(2',4'-dichloro-2-fluoro-4-biphenylyl)-propan-1-ol, b.p. 174-176°C/2 mm Hg, and other alcohols can be prepared in the same way from the acids prepared in Example 7.

Eksempel 13 Example 13

2-(2',4'-diklor-2-fluor-4-bifenylyl)propionsyre (1,2 g) 2-(2',4'-dichloro-2-fluoro-4-biphenylyl)propionic acid (1.2 g)

ble oppløst i metanol (10 ml) og konsentrert H2S04 (0,3 ml) og tilbakeløpsbehandlet i 5 timer. Metanolen ble fjernet, og residuet ble fortynnet med vann, ekstrahert med eter, vasket med vandig kaliumkarbonat, vann og tørret over vannfritt natriumsulfat. Eteren ble fjernet, og residuet ble destillert i vakuum. Produktet var metyl-2-(2',4'-diklor-2-fluor-4-bifenylyl)propionat, k.p. 167-168°C/ 1 mm Hg. was dissolved in methanol (10 mL) and concentrated H 2 SO 4 (0.3 mL) and refluxed for 5 h. The methanol was removed and the residue was diluted with water, extracted with ether, washed with aqueous potassium carbonate, water and dried over anhydrous sodium sulfate. The ether was removed and the residue was distilled in vacuo. The product was methyl 2-(2',4'-dichloro-2-fluoro-4-biphenylyl)propionate, m.p. 167-168°C/ 1 mm Hg.

Eksempel i4 Example i4

2-(2,2',4'-trifluor-4-bifenylyl)propionsyre (1,0 g) i tionylklorid (10 ml) ble tilbakeløpsbehandlet i 1 time. Overskudd av tionylklorid ble avdestillert, og det gjenværende syreklorid i eter (10 ml) ble satt dråpevis til ammoniakk (10 ml, egenvekt 0,880), omrørt og avkjølt i is. Efter 15 minutter ble én ytterligere mengde (250 ml) eter tilsatt for å oppløse amidet, eterlaget ble vasket med fortynnet ammoniakk og vann, tørret og inndampet. 2-(2,2',4'-trifluoro-4-biphenylyl)propionic acid (1.0 g) in thionyl chloride (10 ml) was refluxed for 1 hour. Excess thionyl chloride was distilled off, and the remaining acid chloride in ether (10 ml) was added dropwise to ammonia (10 ml, specific gravity 0.880), stirred and cooled in ice. After 15 minutes, one additional amount (250 ml) of ether was added to dissolve the amide, the ether layer was washed with dilute ammonia and water, dried and evaporated.

Omkrystållisering fra metylenklorid/lettbensin (k.p. 40-60°C) ga farveløse nåler av 2-(2,2',41-trifluor-4-bifenylyl)propionamid, sm.p. 136-137°C. Andre amider kan fremstilles ved den samme metode fra syrene fremstilt i eksempel 7. Recrystallization from methylene chloride/light naphtha (b.p. 40-60°C) gave colorless needles of 2-(2,2',41-trifluoro-4-biphenylyl)propionamide, m.p. 136-137°C. Other amides can be prepared by the same method from the acids prepared in example 7.

Eksempel 15 Example 15

4-acetyl-2,2',4'-trifluorbifenyl (eksempel 2) ga ved tilbakeløpsbehandling med svovel og morfolin i henhold til Willgerodt reaksjonen, fulgt av syrehydrolyse, 2,2',4'-trifluor-4-bifenylyleddiksyre, sm.p. 145-147°C. For.estring ved tilbakeløps-behandling med etanol og svovelsyre ga etyl-2,2<1>,4<1->trifluor-4-bifenylylacetat, k.p. 130-136°/0,4 mm Hg, sm.p. 50-52°C, som efter omsetning med etylkarbonat og natriumetoksyd fulgt av metylsulfat ga etyl-2-metyl-2-(2,2',4'-trifluor-4-bifenylyl)malonat og efter hydrolyse med vandig natriumhydroksyd og etanol, 2-metyl-2-(2,2<1>,4'-trifluor-4-bifenylyl)malonsyre. 4-Acetyl-2,2',4'-trifluorobiphenyl (Example 2) gave, by refluxing with sulfur and morpholine according to the Willgerodt reaction, followed by acid hydrolysis, 2,2',4'-trifluoro-4-biphenylylacetic acid, sm. p. 145-147°C. Esterification by reflux treatment with ethanol and sulfuric acid gave ethyl 2,2<1>,4<1->trifluoro-4-biphenylyl acetate, b.p. 130-136°/0.4 mm Hg, m.p. 50-52°C, which after reaction with ethyl carbonate and sodium ethoxide followed by methyl sulfate gave ethyl 2-methyl-2-(2,2',4'-trifluoro-4-biphenylyl)malonate and after hydrolysis with aqueous sodium hydroxide and ethanol, 2-Methyl-2-(2,2<1>,4'-trifluoro-4-biphenylyl)malonic acid.

2-metyl-2-(2,2',4'-trifluor-4-bifenylyl)malonsyre (1,9 g) ble dekarboksylert ved oppvarming ved 180-200°C i 30 minutter. 2-Methyl-2-(2,2',4'-trifluoro-4-biphenylyl)malonic acid (1.9 g) was decarboxylated by heating at 180-200°C for 30 minutes.

Det gjenværende materiale ble renset ved preparativ tynnskikt-kromatografi på "Kieselgel PF254" un(^er anvendelse av oppløsnings-middelblandingen 5% eddiksyre/lettbensin (k.p. 60-80°C) og eluering med etylacetat. Det krystallinske residuum ble efter fjernelse av etylacetat omkrystallisert fra lettbensin (k.p. 80-100°C) for å gi 2-(2,2',4'-trifluor-4-bifenylyl)propionsyre, sm.p. 105-107°C. The remaining material was purified by preparative thin-layer chromatography on "Kieselgel PF254" using the solvent mixture 5% acetic acid/light petrol (b.p. 60-80°C) and elution with ethyl acetate. The crystalline residue after removal of ethyl acetate was recrystallized from light naphtha (b.p. 80-100°C) to give 2-(2,2',4'-trifluoro-4-biphenylyl)propionic acid, mp 105-107°C.

Eksempel 16 Example 16

Kaliumhydroksyd (3,04 ml av 13,2N) fortynnet med vann (7,3 ml) ble satt dråpevis til en omrørt oppløsning av sølvnitrat (6,8 g) Potassium hydroxide (3.04 mL of 13.2N) diluted with water (7.3 mL) was added dropwise to a stirred solution of silver nitrate (6.8 g)

i vann (8 ml). Oppslemningen av sølvoksyd ble fortynnet med etanol (9 ml) fulgt av langsom tilsetning av en oppløsning av 2-(2,2',4'-trifluor-4-bifenylyl)propionaldehyd (5,1 g) (eksempel 6) i etanol in water (8 ml). The slurry of silver oxide was diluted with ethanol (9 ml) followed by the slow addition of a solution of 2-(2,2',4'-trifluoro-4-biphenylyl)propionaldehyde (5.1 g) (Example 6) in ethanol

(17 ml). Efter omrøring i 15 minutter ble kaliumhydroksyd (1,8 ml av 13,2N) og vann (1,8 ml) tilsatt i løpet av 1 time, mens temperaturen ble holdt ved 43-45°C. Efter omrøring ved 40°C i 30 minutter ble sølvet oppsamlet og vasket med vann. Etanol ble fjernet fra filtratet ved destillasjon under redusert trykk, residuet ble surgjort med fortynnet saltsyre, og syren ble isolert i eter og ekstrahert inn i kaliumkarbonatoppløsning (2,5%). De vandige ekstrakter ble surgjort, og den frigjorte syre ble isolert i eter, vasket med vann, tørret og inndampet. Den gjenværende 2-(2,2',4'-trifluor-4-bifenylyl)propionsyre hadde efter omkrystallisasjon fra lettbensin (k.p. 80-100°C) sm.p. 105-108°C. (17ml). After stirring for 15 minutes, potassium hydroxide (1.8 ml of 13.2N) and water (1.8 ml) were added over 1 hour while maintaining the temperature at 43-45°C. After stirring at 40°C for 30 minutes, the silver was collected and washed with water. Ethanol was removed from the filtrate by distillation under reduced pressure, the residue was acidified with dilute hydrochloric acid, and the acid was isolated in ether and extracted into potassium carbonate solution (2.5%). The aqueous extracts were acidified, and the liberated acid was isolated in ether, washed with water, dried and evaporated. The remaining 2-(2,2',4'-trifluoro-4-biphenylyl)propionic acid had after recrystallization from light petrol (b.p. 80-100°C) m.p. 105-108°C.

Eksempel 17 Example 17

2-[l-(2,2',4'-trifluor-4-bifenylyl)etyl]-4,4-dimetyl-2-oksazolin (0,53 g) ble omrørt og tilbakeløpsbehandlet med saltsyre 2-[1-(2,2',4'-trifluoro-4-biphenylyl)ethyl]-4,4-dimethyl-2-oxazoline (0.53 g) was stirred and refluxed with hydrochloric acid

(5 ml av 2N) i 5 timer. Blandingen ble fortynnet med vann, ekstrahert med eter, og sistnevnte ble ekstrahert med 2,5% kalium-karbonatoppløsning. De vandige ekstrakter ble surgjort med fortynnet saltsyre, og bunnfallet ble isolert i eter, vasket med vann, tørret og inndampet. Residuet ble omkrystallisert fra lettbensin (k.p. 80-100°C) for å gi 2- (2 ,2 ' ,4'-trifluor-4-bifenylyl)propion-syre , sm.p. 107-108,5°C. (5 ml of 2N) for 5 hours. The mixture was diluted with water, extracted with ether, and the latter was extracted with 2.5% potassium carbonate solution. The aqueous extracts were acidified with dilute hydrochloric acid, and the precipitate was isolated in ether, washed with water, dried and evaporated. The residue was recrystallized from light naphtha (b.p. 80-100°C) to give 2-(2,2',4'-trifluoro-4-biphenylyl)propionic acid, m.p. 107-108.5°C.

Eksempel 18 Example 18

En blanding av 2-(2,2 ' ,4'-trifluor-4-bifenylyl)propion-amid (2,44 g) , fremstilt som beskrevet i eksempel 7, med fosfor-oksyklorid (15 ml) ble omrørt og oppvarmet under tilbakeløpskjø-ling i 4 timer. Blandingen ble avkjølt, hellet på is, og råproduktet ble isolert i eter. Ekstraktene ble inndampet, og produktet ble omkrystallisert fra petroleter (k.p. 62-68°C) for å gi 1,5 og 2- (2 ,2 ' ,4'-trifluor-4-bifenylyl)propionitril, sm.p. 83-85°C. 0,5 g av dette nitril ble blandet med 18N kaustisk soda (1,5 ml) A mixture of 2-(2,2',4'-trifluoro-4-biphenylyl)propionamide (2.44 g), prepared as described in Example 7, with phosphorus oxychloride (15 ml) was stirred and heated under reflux cooling for 4 hours. The mixture was cooled, poured onto ice, and the crude product was isolated in ether. The extracts were evaporated and the product recrystallized from petroleum ether (b.p. 62-68°C) to give 1,5 and 2-(2,2',4'-trifluoro-4-biphenylyl)propionitrile, m.p. 83-85°C. 0.5 g of this nitrile was mixed with 18N caustic soda (1.5 ml)

og vann (10 ml) og omrørt og oppvarmet under tilbakeløpskjøling i 24 timer. Blandingen ble avkjølt, surgjort, og produktet ble isolert i eter. Ekstraktene ble tilbakeekstrahert i vandig kaliumkarbonat og surgjort påny for å gi råproduktet. Dette ble omkrystallisert fra petroleter (k.p. 80-100°C) for å gi 2-(2,21,41-trifluor-4-bifenylyl)propionsyre, sm.p. 104-107°C. and water (10 mL) and stirred and heated under reflux for 24 hours. The mixture was cooled, acidified, and the product was isolated in ether. The extracts were back-extracted into aqueous potassium carbonate and acidified again to give the crude product. This was recrystallized from petroleum ether (b.p. 80-100°C) to give 2-(2,21,41-trifluoro-4-biphenylyl)propionic acid, m.p. 104-107°C.

Eksempel 19 Example 19

2- (2,2 1 ,4'-trifluor-4-bifenylyl)-N,N-3-oksapenta-metylen-tiopropionamid (350 mg) i iseddik (5 ml), konsentrert svovelsyre (1 ml) og vann (1 ml) ble oppvarmet under tilbakeløps-kjøling i 24 timer. Blandingen ble fortynnet med vann, og bunnfallet ble ekstrahert i eter. 2-(2,2 1 ,4'-trifluoro-4-biphenylyl)-N,N-3-oxapenta-methylene-thiopropionamide (350 mg) in glacial acetic acid (5 ml), concentrated sulfuric acid (1 ml) and water (1 ml) was heated under reflux for 24 hours. The mixture was diluted with water and the precipitate was extracted into ether.

Ekstraktene ble derefter renset som beskrevet i The extracts were then purified as described in

eksempel 18 for å gi 2- (2 ,2 ' ,4'-trifluor-4-bifenylyl)propionsyre, sm.p. 104-107°C. Example 18 to give 2-(2,2',4'-trifluoro-4-biphenylyl)propionic acid, m.p. 104-107°C.

Claims (1)

Analogifremgangsmåte for fremstilling av terapeutisk aktive forbindelser med den generelle formel I:Analogous process for the preparation of therapeutically active compounds of the general formula I: hvorwhere Rl' R2°^ R3 ^ver ^or se<3 er valgt fra fluor, klor og brom;R1' R2°^ R3 ^ver ^or se<3 is selected from fluorine, chlorine and bromine; Y er COOH, C0NH2 eller CH2OH,-Y is COOH, C0NH2 or CH2OH,- og farmasøytisk akseptable estere, uorganiske salter og organiske salter av de forbindelser hvor Y er-COOH, karakterisert ved at (1) en forbindelse med den generelle formel IIand pharmaceutically acceptable esters, inorganic salts and organic salts of the compounds where Y is -COOH, characterized in that (1) a compound of the general formula II hvor Z er cyano, karbamoyl, N,N-disubstituert tiokarbamoyl eller COOR^ hvor R^ er en esterdannende gruppe, hydrolyseres, eller (2) en forbindelse med den generelle formel III dekarboksyleres, eller (3) en forbindelse med den generelle formel Vwhere Z is cyano, carbamoyl, N,N-disubstituted thiocarbamoyl or COOR^ where R^ is an ester-forming group, is hydrolyzed, or (2) a compound of the general formula III is decarboxylated, or (3) a compound of the general formula V oksyderes, eller (4) en forbindelse med den generelle formel XIis oxidized, or (4) a compound of the general formula XI underkastes hydrolyse eller alkoholyse, og eventuelt: a) en således erholdt fri syre forestres for å danne en ester, b) en således erholdt fri syre amideres for å gi et amid c) en således erholdt fri syre eller ester behandles for å gi en alkohol, eller d) en således erholdt fri syre omdannes til et farmasøytisk godtagbart organisk eller uorganisk salt. -subjected to hydrolysis or alcoholysis, and optionally: a) a free acid thus obtained is esterified to form an ester, b) a free acid thus obtained is amidated to give an amide c) a free acid or ester thus obtained is treated to give an alcohol , or d) a thus obtained free acid is converted into a pharmaceutically acceptable organic or inorganic salt. -
NO1015/72A 1971-03-26 1972-03-24 ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE BIPHENYLPROPIONIC ACIDS AND DERIVATIVES THEREOF NO137546C (en)

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