NO125724B

NO125724B -

Info

Publication number: NO125724B
Application number: NO5013/68A
Authority: NO
Inventors: A Sallmann; R Pfister
Original assignee: Ciba Geigy Ag
Priority date: 1967-12-20
Filing date: 1968-12-13
Publication date: 1972-10-23
Also published as: SE366296B; YU298368A; FI49600B; ES361666A1; BE725793A; IE32591L; JPS5220469B1; DE1815802A1; JPS5526131B1; AT284823B; CS151495B2; IL31296A0; YU32986B; IE32591B1; JPS5526132B1; DK125461B; FR1595382A; JPS5635664B1; FI49600C; CS151496B2

Description

Fremgangsmåte for fremstilling av substituerte o-arylamino-fenyleddiksyrer. Process for the preparation of substituted o-arylamino-phenylacetic acids.

Nærværende oppfinnelse vedrorer en ny fremgangsmåte for fremstilling av substituerte fenyleddiksyrer med den generelle formel I, hvor betyr en lavere alkyl- eller alkoksygruppe, et fluor-, klor- eller bromatom, eller en tri-fluormetylgruppe, The present invention relates to a new process for the preparation of substituted phenylacetic acids of the general formula I, where means a lower alkyl or alkoxy group, a fluorine, chlorine or bromine atom, or a trifluoromethyl group,

R2 og R 3 hydrogen, en lavere alkylgruppe eller et fluor-, klor- eller bromatom, og R 4 hydrogen, en lavere alkyl- eller alkoksygruppe, et fluor-, klor- eller bromatom, idet minst en av substituentene R^, R2 eller R^ er plasert i ortho-stilling, og den samme ikke betyr hydrogen, R 2 and R 3 hydrogen, a lower alkyl group or a fluorine, chlorine or bromine atom, and R 4 hydrogen, a lower alkyl or alkoxy group, a fluorine, chlorine or bromine atom, at least one of the substituents R 2 , R 2 or R^ is placed in the ortho position, and the same does not mean hydrogen,

og deres salter med uorganiske og organiske baser. De substituerte fenyleddiksyrer med den generelle formel I og deres salter innehar verdifulle farmakologiske egenskaper, spesielt antiflo-gistisk (anti-inflammatorisk), analgetisk og antipyretisk virk-ning med gunstig terapeutisk indeks. De kan anvendes oralt, and their salts with inorganic and organic bases. The substituted phenylacetic acids of the general formula I and their salts have valuable pharmacological properties, especially antiphlogistic (anti-inflammatory), analgesic and antipyretic effects with a favorable therapeutic index. They can be used orally,

rektalt eller spesielt i form av vandige opplosninger av deres salter også parenteralt, spesielt intramuskulært for behandling av revmatiske, artritiske og andre inf1ammatoriske sykdommer. Dessuten innehar disse substanser evnen til å absorbere UV-stråler ved 290 - 300 mu og er derfor egnet som UV-absorbsjons-. middel for kosmetiske formål, f.eks. i solbeskyttelseskremer, fordi de absorberer de skadelige rodfargende stråler, mens de slipper gjennom de onskede brunende over 315 mu. rectally or especially in the form of aqueous solutions of their salts also parenterally, especially intramuscularly for the treatment of rheumatic, arthritic and other inflammatory diseases. Furthermore, these substances have the ability to absorb UV rays at 290 - 300 mu and are therefore suitable as UV absorbers. agent for cosmetic purposes, e.g. in sunscreens, because they absorb the harmful root-coloring rays, while letting through the desired tanning above 315 mu.

I forbindelsene med den generelle formel I og de tilsvarende, nedenfor nevnte utgangsstoffer er R^ til R^ uavhengig av hver-andre som lavere alkylgrupper f.eks. metyl- eller etylgrupper. En del av de nevnte symboler kan f.eks. også bety n-propyl-, isopropyl-, n-butyl-, sek.butyl- eller tert.butylgrupper. og R^ kan som lavere alkoksygrupper f.eks. bety metoksy-, etoksy-, n-propoksy-, isopropoksy-, n-butoksy- eller isobutoksygrupper. In the compounds with the general formula I and the corresponding starting materials mentioned below, R^ to R^ are independent of each other as lower alkyl groups, e.g. methyl or ethyl groups. Some of the mentioned symbols can e.g. also mean n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl groups. and R^ can be, as lower alkoxy groups, e.g. means methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy groups.

Fenyleddiksyrene med den generelle formel I og deres salter fremstilles ifolge oppfinnelsen på teknisk fordelaktig måte fra lett tilgjengelige utgangsstoffer, idet man omsetter et ringsubstituert difenylamin av den generelle formel II, The phenylacetic acids of the general formula I and their salts are prepared according to the invention in a technically advantageous manner from readily available starting materials, by reacting a ring-substituted diphenylamine of the general formula II,

hvor R^, R^, R^ og R^ har de under formel I angitte betydninger, med oksalylklorid til et ringsubstituert N-aryloksanilsyreklorid av den generelle formel III, hvor R^, R2, R3 og R4 har de under formel I angitte betydninger, og overforer forbindelsen av formel III i nærvær av Friedel--Crafts-kondensasjonsmidler, som aluminiumklorid, ved værelsetemperatur under ringslutning til et substituert indol-2,3-dion (isatin) av den generelle formel IV, where R^, R^, R^ and R^ have the meanings given under formula I, with oxalyl chloride to a ring-substituted N-aryloxanilic acid chloride of the general formula III, where R^, R2, R3 and R4 have the meanings given under formula I , and transfers the compound of formula III in the presence of Friedel-Crafts condensing agents, such as aluminum chloride, at room temperature under cyclization to a substituted indole-2,3-dione (isatin) of the general formula IV,

hvor R1# R2, R3 og R4 har de under formel I where R1# R2, R3 and R4 have those under formula I

angitte betydninger, stated meanings,

eventuelt omkrystalliserer den sistnevnte forbindelse, og fremstiller enten direkte ved omsetning med hydrazin eller semikar-bazider og alkalisk spaltning ifolge Wolff-Kishner den tilsvarende substituerte fenyleddiksyre av den generelle formel I, optionally recrystallizes the latter compound, and produces either directly by reaction with hydrazine or semicarbazides and alkaline cleavage according to Wolff-Kishner the corresponding substituted phenylacetic acid of the general formula I,

eller fremstiller forst ved alkalisk hydrolyse den substituerte glyoksylsyre eller et salt av denne av den generelle formel V, or first produces by alkaline hydrolysis the substituted glyoxylic acid or a salt thereof of the general formula V,

hvor R betyr hydrogen, et enverdig kation eller where R means hydrogen, a monovalent cation or

ekvivalenten av et flerverdig kation, og R^, R^, R3 og R^ har de under formel I angitte the equivalent of a polyvalent cation, and R^, R^, R3 and R^ have those indicated under formula I

betydninger, meanings,

og oppnår ved etterfolgende omsetning med hydrazin eller semi- and obtains by subsequent reaction with hydrazine or semi-

karbazider såvel som alkalimetallhydroksyd eller alkalimetallalkoholat ifolge Wolff-Kishner den substituerte fenyleddiksyre av den generelle formel I. carbazides as well as alkali metal hydroxide or alkali metal alcoholate according to Wolff-Kishner the substituted phenylacetic acid of the general formula I.

Det er kjent at substituerte l-aryl-2-indolinoner kan hydroly-seres til de tilsvarende substituerte o-anilinofenyl-eddiksyrer. De substituerte l-aryl-2-indolinoner fremstilles f.eks. analogt det kjente 1-fenyl-2-indolinon fra de substituerte 2-klor-N-fenyl-acetanilider med etterfolgende ringslutningsreaksjon, hvilken dog bare er oppnåelig ved relativt hoye temperaturer i en aluminiumkloridsmelte ved 160°C og bare ved flere timers opp-varmning. It is known that substituted 1-aryl-2-indolinones can be hydrolysed to the corresponding substituted o-anilinophenyl acetic acids. The substituted 1-aryl-2-indolinones are prepared, e.g. analogous to the known 1-phenyl-2-indolinone from the substituted 2-chloro-N-phenyl-acetanilides with subsequent ring closure reaction, which is however only achievable at relatively high temperatures in an aluminum chloride melt at 160°C and only by several hours of heating .

Da alkylvandringer kan finne sted ved disse reaksjonsbetingelser, oppstår opparbeidelsesproblemer. Et annet uonsket etterfolgende fenomen ved anvendelse av slike reaksjonsbetingelser er spaltningen av alkoksygrupper. Overfor dette er det nå funnet at man ved fremgangsmåten ifolge oppfinnelsen på teknisk enkel måte, ved skånende reaksjonsbetingelser og med hoyt utbytte under unngåelse av uonskede bi- og etterreaksjoner (f.eks. etteralkylering av spaltede alkoksygrupper) kan oppnå de substituerte fenyleddiksyrer med den generelle formel I. As alkyl migrations can take place at these reaction conditions, work-up problems arise. Another undesired subsequent phenomenon when such reaction conditions are used is the cleavage of alkoxy groups. Faced with this, it has now been found that the method according to the invention can be obtained in a technically simple manner, under gentle reaction conditions and with high yield while avoiding unwanted side and post-reactions (e.g. post-alkylation of cleaved alkoxy groups) with the general formula I.

En ytterligere fordel ved fremgangsmåten består i at ringslut-ningsreaksjonen, ved hvilken man overforer de substituerte N-fenyl-oksaniloylklorider til de tilsvarende substituerte indol-2,3-dioner (isatiner) med den generelle formel IV, forloper usedvanlig glatt og nesten fullstendig allerede ved værelsetemperatur (95% av det teoretiske, se eksempel lb). Etter en eventuell omkrystallisering av forbindelsene av formel IV, omsetter man dem med hydrazin eller semikarbazid og med alkalimetallhydroksyd eller alkalimetallalkoholat ved forhoyet temperatur tilsvarende reduksjonsmetoden ifolge Wolff-Kishner, og overforer, hvis bnsket, det forst -jerholdte alkalisalt av en substituert fenyleddiksyre med den generelle formel I til den frie syre eller til et annet salt med en uorganisk eller organisk base. Forst omsetter man det substituerte indol-2,3-dion enten med hydrazin - som også kan anvendes i form av hydratet - eller med semikarbazid til det tilsvarende 3-(hydrazon) eller 3-(semikarbazon) og spalter dette mellomproduktet med alkalimetallhydroksyd eller alkalimetallalkoholat, eller man bringer alle tre reaksjonskomponentene sammen samtidig. A further advantage of the process is that the ring closure reaction, in which the substituted N-phenyl-oxaniloyl chlorides are transferred to the corresponding substituted indole-2,3-diones (isatins) of the general formula IV, already proceeds exceptionally smoothly and almost completely at room temperature (95% of the theoretical, see example lb). After any recrystallization of the compounds of formula IV, they are reacted with hydrazine or semicarbazide and with alkali metal hydroxide or alkali metal alcoholate at an elevated temperature corresponding to the reduction method according to Wolff-Kishner, and transfer, if desired, the preserved alkali salt of a substituted phenylacetic acid with the general formula I to the free acid or to another salt with an inorganic or organic base. First, the substituted indole-2,3-dione is reacted either with hydrazine - which can also be used in the form of the hydrate - or with semicarbazide to the corresponding 3-(hydrazone) or 3-(semicarbazone) and this intermediate product is cleaved with alkali metal hydroxide or alkali metal alcoholate , or you bring all three reaction components together at the same time.

Temperaturen for innvirkningen av alkalimetallhydroksyd henh. alkalimetallalkoholat ligger f.eks. ved 100 - 220°, fortrinnsvis ved 140 - 200°. Den eventuelt forangående dannelse av hydrazon kan gjennomfores ved vesentlig lavere temperaturer, dvs. allerede ved værelsetemperatur eller likeledes ved hoyere temperaturer, idet man eventuelt avdestillerer det med hydrazinhydrat innforte og det ved reaksjonen frisatte vann. Som reaksjonsmedium tjener f.eks. et hoytkokende organisk opplosningsmiddel, f.eks. etylenglykol eller mono- og dieter av det samme, som dietylenglykol, di etyl englykolmo nome ty leter eller trietyleti-glykol, videre hoyerekokende alkoholer, som benzylalkohol, oktyl-alkohol eller nitrilotrietanol, eller eventuelt også en lavere alkanol, såfremt reaksjonen gjennomfores i lukket kar. Man kan også avdestillere det i begynnelsen som reaksjonsmedium anvendte lavere alkanol, f.eks. etanol eller butanol, sammen med overskytende hydrazin og frisatt vann i lopet av reaksjonen, inntil den gradvis storknede reaksjonsblanding når temperaturer mellom 150 og 200°. Som alkalimetallhydroksyder anvendes spesielt kalium- eller natriumhydroksyd, mens alkalimetallalkoholatene, f.eks. natriumalkoholater enten kan avlede seg fra lavere alkanoler eller også fra de som reaksjonsmedia anvendte hoyerekokende hydroksyforbindelser. The temperature for the action of alkali metal hydroxide acc. alkali metal alcoholate lies e.g. at 100 - 220°, preferably at 140 - 200°. The possibly preceding formation of hydrazone can be carried out at significantly lower temperatures, i.e. already at room temperature or likewise at higher temperatures, with the hydrazine hydrate added and the water released during the reaction being distilled off. As a reaction medium, e.g. a high-boiling organic solvent, e.g. ethylene glycol or mono- and diethers of the same, such as diethylene glycol, di ethyl englycol mono ethylene or triethyl ethyl glycol, further high-boiling alcohols, such as benzyl alcohol, octyl alcohol or nitrilotriethanol, or possibly also a lower alkanol, provided the reaction is carried out in a closed vessel . You can also distill off the lower alkanol initially used as reaction medium, e.g. ethanol or butanol, together with excess hydrazine and liberated water during the course of the reaction, until the gradually solidified reaction mixture reaches temperatures between 150 and 200°. As alkali metal hydroxides potassium or sodium hydroxide are used in particular, while the alkali metal alcoholates, e.g. sodium alcoholates can either derive from lower alkanols or also from the high-boiling hydroxy compounds used as reaction media.

Fra de forst fremkommende alkalisalter av substituerte fenyleddiksyrer med den generelle formel I frisettes, hvis onsket, syrene på vanlig måte ved hjelp av sterkere syrer, f.eks. saltsyre. De erholdte syrer overfores, hvis onsket, igjen til salter fortrinnsvis til slike med farmakologisk uskadelige uorganiske og organiske baser. Som eksempler på slike salter skal nevnes natrium-, kalium-, litium-, magnesium-, kalsium- og ammoniumsalt-ene, såvel som salter med etylamin, trietylamin, 2-aminoetanol, 2,2-iminodietanol, 2-dimetylamino-etanol, 2-dietylamino-etanol, etylendiamin, benzylamin, p-aminobenzosyre-2-dietylaminoetyl-ester, pyrrolidin, piperidin, morfolin, 1-etyl-piperidin eller 2-piperidino-etanol. Salter, som i et bestemt medium, f.eks. i vann eller i vandige lavere alkanoler, er vesentlig tyngre opp-løselige enn alkalisaltene, lar seg også direkte fremstille fra de sistnevnte ved dobbel omsetning. From the first appearing alkali salts of substituted phenylacetic acids of the general formula I, the acids are released, if desired, in the usual way by means of stronger acids, e.g. hydrochloric acid. The acids obtained are transferred, if desired, again to salts, preferably to those with pharmacologically harmless inorganic and organic bases. Examples of such salts include the sodium, potassium, lithium, magnesium, calcium and ammonium salts, as well as salts with ethylamine, triethylamine, 2-aminoethanol, 2,2-iminodiethanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, ethylenediamine, benzylamine, p-aminobenzoic acid 2-diethylaminoethyl ester, pyrrolidine, piperidine, morpholine, 1-ethylpiperidine or 2-piperidinoethanol. Salts, as in a particular medium, e.g. in water or in aqueous lower alkanols, are significantly more soluble than the alkali salts, can also be directly prepared from the latter by double reaction.

Ved overforingen av ringsubstituerte indol-2,3-dioner (isatiner) til de tilsvarende fenyleddiksyrer kan fremgangsmåten etter valg utfores via et ytterligere mellomtrinn, nemlig fremstillingen av den ringsubstituerte (o-anilinofenyl)-glyoksylsyre. Det ringsubstituerte isatin med den generelle formel IV underkastes forst en hydrolyse og den erholdte ringsubstituerte (o-anilinofenyl)-glyoksylsyre eller dens salt med den generelle formel V, In the conversion of ring-substituted indole-2,3-diones (isatins) to the corresponding phenylacetic acids, the process can be carried out, if desired, via a further intermediate step, namely the production of the ring-substituted (o-anilinophenyl)-glyoxylic acid. The ring-substituted isatin of the general formula IV is first subjected to a hydrolysis and the obtained ring-substituted (o-anilinophenyl)-glyoxylic acid or its salt of the general formula V,

ekvivalenten av et flerverdig kation og the equivalent of a polyvalent cation and

R^, R^, R^ og R^ har de under formel I angitte R^, R^, R^ and R^ have those indicated under formula I

betydninger, meanings,

reduseres etter Wolff-Kishners metode ved omsetning med hydrazin eller semikarbazid og med alkalimetallhydroksyd eller alkalimetallalkoholat ved forhbyet temperatur og, hvis onsket, overfores det forst erholdte alkalisalt av den substituerte fenyleddiksyre av den generelle formel I til den frie syre eller til et annet salt med en uorganisk eller organisk base. is reduced according to the Wolff-Kishner method by reaction with hydrazine or semicarbazide and with alkali metal hydroxide or alkali metal alcoholate at elevated temperature and, if desired, the first obtained alkali salt of the substituted phenylacetic acid of the general formula I is transferred to the free acid or to another salt with a inorganic or organic base.

Ved utfbrelsen av reduksjonen omsetter man enten forst den substituerte (o-anilinofenyl)-glyoksylsyre med den generelle formel V eller et salt av den samme med hydrazin - som også kan anvendes i form av hydratet - eller med semikarbazid til det tilsvarende hydrazon henh. semikarbazon, og spalter dette mellomproduktet med alkalimetallhydroksyd eller alkalimetallalkoholat, eller man bringer alle tre reaksjonskomponentene samtidig sammen og går frem på den samme måte som ved reduksjonen av substituerte indol-2,3-dioner. When carrying out the reduction, one either first reacts the substituted (o-anilinophenyl)-glyoxylic acid with the general formula V or a salt of the same with hydrazine - which can also be used in the form of the hydrate - or with semicarbazide to the corresponding hydrazone. semicarbazone, and cleave this intermediate with alkali metal hydroxide or alkali metal alcoholate, or you bring all three reaction components together at the same time and proceed in the same way as in the reduction of substituted indole-2,3-diones.

De etterfølgende eksempler redegjor nærmere for gjennomfbringen av fremgangsmåten ifolge oppfinnelsen såvel som fremstillingen av hittil ikke kjente mellomprodukter. Temperaturene er angitt i °C. The following examples explain in more detail the implementation of the method according to the invention as well as the production of previously unknown intermediates. The temperatures are indicated in °C.

EKSEMPEL 1 EXAMPLE 1

a) N- fenyl- 2', 6'- xylyl- oksaniloylklorid a) N-phenyl-2', 6'-xylyl-oxaniloyl chloride

Til en opplbsning av 101 g N-fenyl-2,6-xylidin i 650 ml vannfri To a solution of 101 g of N-phenyl-2,6-xylidine in 650 ml of anhydrous

benzen tildrypper man langsomt ved 5° 162 ml oksalylklorid. Deretter rbres suspensjonen i 2 timer ved værelsetemperatur og 1/2 time ved 50°, hvorved suspensjonen går i opplosning. Man avkjbler reaksjonsopplosningen og inndamper den under 11 Torr ved en badtemperatur på 40° til tbrrhet. Resten opplbses i 400 ml vannfri benzen, og opplbsningen inndampes under 11 Torr igjen til torrhet. Resten krystalliserer man fra benzen-petroleter. N-fenyl-2',6'-xylyl-oksaniloylklorid smelter ved 78 - 80°. Utbyttet utgjor 87 % av teorien. 162 ml of oxalyl chloride is slowly added dropwise at 5° to benzene. The suspension is then stirred for 2 hours at room temperature and 1/2 hour at 50°, whereby the suspension dissolves. The reaction solution is cooled and evaporated below 11 Torr at a bath temperature of 40° to dryness. The residue is dissolved in 400 ml of anhydrous benzene, and the solution is evaporated again to dryness below 11 Torr. The remainder is crystallized from benzene-petroleum ether. N-phenyl-2',6'-xylyl-oxaniloyl chloride melts at 78 - 80°. The yield makes up 87% of the theory.

Analogt fremstilles: Analogously produced:

Man oppnår 110 g N-fenyl-6'-klor-3'-trifluormetyl-oksaniloylklorid (olje) ved å gå ut fra 81 g N-f enyl-6-klor-oc ,oc ,oc-trif luor-m-toluidin, kp. 85 - 88°/0,001 Torr. 110 g of N-phenyl-6'-chloro-3'-trifluoromethyl-oxaniloyl chloride (oil) is obtained by starting from 81 g of N-phenyl-6-chloro-oc,oc,oc-trifluoro-m-toluidine, bp . 85 - 88°/0.001 Torr.

Man oppnår 65 g N-fenyl-6'-klor-2'-metyl-oksaniloylklorid (olje) ved å gå ut fra 57 g N-fenyl-6-klor-o-toluidin, kp. 88°/0,05 Torr. 65 g of N-phenyl-6'-chloro-2'-methyl-oxaniloyl chloride (oil) is obtained by starting from 57 g of N-phenyl-6-chloro-o-toluidine, b.p. 88°/0.05 Torr.

Man oppnår 62 g N-fenyl-2',6'-diklor-oksaniloylklorid, smp. 62 g of N-phenyl-2',6'-dichloro-oxaniloyl chloride are obtained, m.p.

lo7 - lo9° (fra eter-petroleter) ved å gå ut fra 50 g 2,6-diklor-difenylamin, kp. lll°/0,003 Torr. lo7 - lo9° (from ether-petroleum ether) starting from 50 g of 2,6-dichloro-diphenylamine, b.p. lll°/0.003 Torr.

Man oppnår 42 g N-fenyl-2',6'-diklor-3'-metyl-oksaniloylklorid, smp. 102 - 103° (fra eter-petroleter) ved å gå ut fra 34 g N-f enyl-2,6-diklor-m-toluidin, smp. 76 - 79°., 42 g of N-phenyl-2',6'-dichloro-3'-methyl-oxaniloyl chloride are obtained, m.p. 102 - 103° (from ether-petroleum ether) starting from 34 g of N-phenyl-2,6-dichloro-m-toluidine, m.p. 76 - 79°.,

Man oppnår 82 g N-fenyl-6'-metoksy-3'-metyl-oksaniloylklorid (olje), ved å gå ut fra 76 g N-fenyl-6-metoksy-m-toluidin, 82 g of N-phenyl-6'-methoxy-3'-methyl-oxaniloyl chloride (oil) is obtained, starting from 76 g of N-phenyl-6-methoxy-m-toluidine,

kp. 122°/0,001 Torr. kp. 122°/0.001 Torr.

Man oppnår 34 g N-(p-tolyl)-2',6'-dimetyl-oksaniloylklorid (olje) ved å gå ut fra 22 g N-(p-tolyl)-2,6-xylidin, kp. 115 - 120°/ 0,001 Torr. 34 g of N-(p-tolyl)-2',6'-dimethyl-oxaniloyl chloride (oil) is obtained by starting from 22 g of N-(p-tolyl)-2,6-xylidine, b.p. 115 - 120°/ 0.001 Torr.

Utgangsstoffene -som anvendes ifolge eksempel la) fremstilles som folger: The starting materials - which are used according to example la) are prepared as follows:

al) N-( 2, 6- xylyl)- antranilsyre al) N-(2,6-xylyl)-anthranilic acid

En blanding av 525 g o-klorbenzosyre og 195 g 85 %'ig kaliumhydroksyd i 1500 ml n-pentanol oppvarmes under roring til 160°. A mixture of 525 g of o-chlorobenzoic acid and 195 g of 85% potassium hydroxide in 1500 ml of n-pentanol is heated with stirring to 160°.

I lbpet av 30 minutter avdestilleres ca. 400 ml n-pentanol. Deretter tilsetter man 1000 g 2,6-xylidin og 12,5 g kobberpulver og koker blandingen i 15 timer under tilbakelop. Deretter av-kjoler man, heller blandingen i en opplosning av 180 g natrium-karbonat i 600 ml vann og destillerer opplbsningen med vann-damp. Etter at det overskytende 2,6-xylidin er avdestillert, filtrerer man fra den vandige rest over Hyflo og"Surgjor fil-tratet med konsentrert saltsyre. De utskilte krystaller filtreres fra og krystalliseres fra etanol-vann. Man oppnår 460 g N-(2,6-xylyl)-antranilsyre med smp. 205 - 208°. Utbyttet utgjor 57 %. In the course of 30 minutes, approx. 400 ml of n-pentanol. 1000 g of 2,6-xylidine and 12.5 g of copper powder are then added and the mixture is refluxed for 15 hours. The mixture is then cooled, poured into a solution of 180 g of sodium carbonate in 600 ml of water and the solution is distilled with steam. After the excess 2,6-xylidine has been distilled off, the aqueous residue is filtered over Hyflo and "Surgjor" the filtrate with concentrated hydrochloric acid. The separated crystals are filtered off and crystallized from ethanol-water. 460 g of N-(2 ,6-xylyl)-anthranilic acid with mp 205 - 208° The yield is 57%.

Analogt fremstilles: Analogously produced:

Man oppnår 180 g N- (6-klor-oc ,oc ,oc-trif luor-m-tolyl)-antranilsyre, smp. 183 - 185° (fra etanol), ved å gå ut fra 450 g o-klorbenzosyre. 180 g of N-(6-chloro-oc,oc,oc-trifluoro-m-tolyl)-anthranilic acid is obtained, m.p. 183 - 185° (from ethanol), starting from 450 g of o-chlorobenzoic acid.

Man oppnår 376 g N-(6-klor-o-tolyl)-antranilsyre, smp. 216 - 217° (fra etanol), ved å gå ut fra 580 g o-klorbenzosyre. 376 g of N-(6-chloro-o-tolyl)-anthranilic acid is obtained, m.p. 216 - 217° (from ethanol), starting from 580 g of o-chlorobenzoic acid.

Man oppnår 310 g N-(2,6-diklor-fenyl)-antranilsyre, smp. 212 - 213° (fra etanol), ved å gå ut fra 960 g o-klorbenzosyre. 310 g of N-(2,6-dichloro-phenyl)-anthranilic acid is obtained, m.p. 212 - 213° (from ethanol), starting from 960 g of o-chlorobenzoic acid.

Man oppnår 93 g N-(2,6-diklor-m-tolyl)-antranilsyre, smp. 247 - 249° (fra etanol), ved å gå ut fra 168 g o-klorbenzosyre. 93 g of N-(2,6-dichloro-m-tolyl)-anthranilic acid is obtained, m.p. 247 - 249° (from ethanol), starting from 168 g of o-chlorobenzoic acid.

Man oppnår 140 g N-(6-metoksy-m-tolyl)-antranilsyre, smp. 141 - 142° (fra eter-petroleter), ved å gå ut fra 168 g o-klorbenzosyre. 140 g of N-(6-methoxy-m-tolyl)-anthranilic acid is obtained, m.p. 141 - 142° (from ether-petroleum ether), starting from 168 g of o-chlorobenzoic acid.

Man oppnår 65 g N-(2,6-xylyl)-5-metyl-antranilsyre, smp. 220 - 225° (fra etanol), ved å gå ut fra 110 g o-klorbenzpsyre. 65 g of N-(2,6-xylyl)-5-methyl-anthranilic acid is obtained, m.p. 220 - 225° (from ethanol), starting from 110 g of o-chlorobenzoic acid.

a2) N- f enyl- 2, 6- xylidin a2) N-phenyl-2,6-xylidine

370 g N-(2,6-xylyl)-antranilsyre oppvarmes i 2 1/2 time til 280°. Den avkjblte smelte opploses i 1500 ml. eter. Oppløs-ningen vaskes to ganger med 300 ml 2 N natriumkarbonatopplbs-ning og 300 ml vann. Deretter skiller man eteropplosningen fra, torker den over natriumsulfat og konsentrerer den under 11 Torr ved 40° til torrhet. Resten destilleres, idet N-fenyl-2,6-xylidin oppnås som gul olje, kp. 125°/0,01 Torr. Destillatet krystalliseres fra petroleter. Man oppnår 230 g N-fenyl-2,6-xylidin, smp. 52 - 54°. 370 g of N-(2,6-xylyl)-anthranilic acid are heated for 2 1/2 hours to 280°. The cooled melt is dissolved in 1500 ml. ether. The solution is washed twice with 300 ml of 2 N sodium carbonate solution and 300 ml of water. The ether solution is then separated, dried over sodium sulphate and concentrated to dryness below 11 Torr at 40°. The residue is distilled, whereby N-phenyl-2,6-xylidine is obtained as a yellow oil, b.p. 125°/0.01 Torr. The distillate is crystallized from petroleum ether. 230 g of N-phenyl-2,6-xylidine is obtained, m.p. 52 - 54°.

Analogt fremstilles: Analogously produced:

Man oppnår 57 g 6-klor-oc ,a ,a-trif luor-N-f enyl-m-toluidin , 57 g of 6-chloro-oc,a,a-trifluoro-N-phenyl-m-toluidine are obtained,

kp. 85 - 88°/0,00l Torr, ved å gå ut fra 100 g N- (6-klor-oc ,<x ,a-trifluor-m-tolyl)-antranilsyre, smp. 183 - 185 . kp. 85 - 88°/0.00l Dry, starting from 100 g of N-(6-chloro-oc,<x,a-trifluoro-m-tolyl)-anthranilic acid, m.p. 183 - 185 .

Man oppnår 125 g N-fenyl-6-klor-o-toluidin, kp. 88°/0,005 Torr, ved å gå ut fra 180 g N-(6-klor-o-tolyl)-antranilsyre, smp. 125 g of N-phenyl-6-chloro-o-toluidine, b.p. 88°/0.005 Torr, starting from 180 g of N-(6-chloro-o-tolyl)-anthranilic acid, m.p.

216 - 217°. 216 - 217°.

Man oppnår 97 g 2,6-diklor-difenylamin, kp. lll°/0,003 Torr, ved å gå ut fra 141 g N-(2,6-diklor-fenyl)-antranilsyre, 97 g of 2,6-dichlorodiphenylamine is obtained, b.p. lll°/0.003 Torr, starting from 141 g of N-(2,6-dichloro-phenyl)-anthranilic acid,

smp. 212 - 2r3°. m.p. 212 - 2r3°.

Man oppnår 55 g N-fenyl-2,6-diklor-m-toluidin, smp. 76 - 79° 55 g of N-phenyl-2,6-dichloro-m-toluidine is obtained, m.p. 76 - 79°

(fra petroleter), ved å gå ut fra 70 g N-(2,6-diklor-m-tolyl)-antranilsyre, smp. 247 - 249°. (from petroleum ether), starting from 70 g of N-(2,6-dichloro-m-tolyl)-anthranilic acid, m.p. 247 - 249°.

Man oppnår 120 g N-fenyl-6-metoksy-m-toluidin , kp. 122°/0,001 Torr, ved å gå ut fra 145 g N-(6-metoksy-m-tolyl)-antranilsyre, smp. 141 - 142°. 120 g of N-phenyl-6-methoxy-m-toluidine is obtained, b.p. 122°/0.001 Torr, starting from 145 g of N-(6-methoxy-m-tolyl)-anthranilic acid, m.p. 141 - 142°.

Man oppnår 67 g N-(p-tolyl)-2,6-xylidin, kp. 115 - 120°/0,001 Torr, ved å gå ut fra 82 g N-(2,6-xylyl)-5-metyl-antranilsyre, smp. 195 - 200°. 67 g of N-(p-tolyl)-2,6-xylidine are obtained, b.p. 115 - 120°/0.001 Torr, starting from 82 g of N-(2,6-xylyl)-5-methyl-anthranilic acid, m.p. 195 - 200°.

b) l-( 2, 6- xylyl)- indol- 2, 3- dion b) 1-(2,6-xylyl)-indole-2,3-dione

Til en opplosning av 124 g N-fenyl-2',6'-dimetyl-oksaniloylklorid i 900 ml tetrakloretan tilsetter man porsjonsvis 58,6 g pulverisert aluminiumklorid. Blandingen rores i 48 timer ved værelsetemperatur. Deretter heller man den på en blanding av 1000 g is og 200 ml 2 W saltsyre. Man tilsetter 500 ml kloro-form og gjennomryster godt. Tetrakloretan-kloroformopplosningen skilles fra, vaskes med 300 ml 2 N natriumkarbonatopplosning og deretter med 300 ml vann, torkes over natriumsulfat og inndampes under 0,1 Torr til torrhet. Resten krystalliseres fra eter-petroleter. 1-(2,6-xylyl)-indol-2,3-dion smelter ved 157 - 159°. Utbyttet utgjor 95 % av teorien. To a solution of 124 g of N-phenyl-2',6'-dimethyl-oxaniloyl chloride in 900 ml of tetrachloroethane, 58.6 g of powdered aluminum chloride is added in portions. The mixture is stirred for 48 hours at room temperature. It is then poured onto a mixture of 1000 g of ice and 200 ml of 2 W hydrochloric acid. Add 500 ml of chloroform and shake well. The tetrachloroethane-chloroform solution is separated, washed with 300 ml of 2 N sodium carbonate solution and then with 300 ml of water, dried over sodium sulfate and evaporated to dryness under 0.1 Torr. The residue is crystallized from ether-petroleum ether. 1-(2,6-xylyl)-indole-2,3-dione melts at 157 - 159°. The yield makes up 95% of the theory.

Analogt fremstilles: Analogously produced:

Man oppnår 76,5 g 1-(6-klor-oc,o,a-trifluor-m-tolyl)-indol-2,3-dion, smp. 134 - 136° (fra eter), ved å gå ut fra 110,0 g N-fenyl-6'-klor-3'-trifluormetyl-oksaniloylklorid (olje). 76.5 g of 1-(6-chloro-oc,o,a-trifluoro-m-tolyl)-indole-2,3-dione are obtained, m.p. 134 - 136° (from ether), starting from 110.0 g of N-phenyl-6'-chloro-3'-trifluoromethyl-oxaniloyl chloride (oil).

Man oppnår 48,7 g l-(6-klor-o-tolyl)-indol-2,3-dion, smp. 163 - 165° (fra eter), ved å gå ut fra 65,0 g N-fenyl-6'-klor-2'-metyl-oksaniloylklorid (olje). 48.7 g of 1-(6-chloro-o-tolyl)-indole-2,3-dione are obtained, m.p. 163 - 165° (from ether), starting from 65.0 g of N-phenyl-6'-chloro-2'-methyl-oxaniloyl chloride (oil).

Man oppnår 42,3 g 1-(2,6-diklorfenyl)-indol-2,3-dion, smp. 175 - 176° (fra etanol), ved å gå ut fra 85,0 g N-fenyl-2',6'-diklor-oksaniloylklorid, smp. 107 - 109°. 42.3 g of 1-(2,6-dichlorophenyl)-indole-2,3-dione are obtained, m.p. 175 - 176° (from ethanol), starting from 85.0 g of N-phenyl-2',6'-dichloro-oxaniloyl chloride, m.p. 107 - 109°.

Man oppnår 38,8 g 1-(2,6-diklor-m-tolyl)-indol-2,3-dion, smp. 38.8 g of 1-(2,6-dichloro-m-tolyl)-indole-2,3-dione are obtained, m.p.

162 - 165° (fra etanol), ved å gå ut fra 57,0 g N-fenyl-2',6'-diklor-3'-metyl-oksaniloylklorid, smp. 102 - 103°. 162 - 165° (from ethanol), starting from 57.0 g of N-phenyl-2',6'-dichloro-3'-methyl-oxaniloyl chloride, m.p. 102 - 103°.

Man oppnår 16,2 g 1-(6-metoksy-m-tolyl)-indol-2,3-dion, smp. 16.2 g of 1-(6-methoxy-m-tolyl)-indole-2,3-dione are obtained, m.p.

168 - 169° (fra etylacetat), ved å gå ut fra 31,0 g N-fenyl-6'-metoksy-3'-metyl-oksaniloyl-klorid (olje). 168 - 169° (from ethyl acetate), starting from 31.0 g of N-phenyl-6'-methoxy-3'-methyl-oxaniloyl chloride (oil).

Man oppnår 18,0 g l-(2,6-xylyl)-5-metyl-indol-2,3-dion, smp. 158° 18.0 g of 1-(2,6-xylyl)-5-methyl-indole-2,3-dione are obtained, m.p. 158°

(fra eter), ved å gå ut fra 34,0 g N-(p-tolyl)-2',6'-dimetyl-oksaniloylklorid (olje). (from ether), starting from 34.0 g of N-(p-tolyl)-2',6'-dimethyl-oxaniloyl chloride (oil).

c) [ o-( 2, 6- xylidino)- f enyl]- eddiksyre c) [o-(2,6-xylidino)-phenyl]-acetic acid

Til en opplosning av 3 g 1-(2,6-xylyl)-indol-2,3-dion i 20 ml To a solution of 3 g of 1-(2,6-xylyl)-indole-2,3-dione in 20 ml

dietylenglykol-monometyleter tilsetter man 1,56 g hydrazinhydrat. Derved oppvarmer oppløsningen seg. Etter 15 minutter tilsetter man.1,34 g pulverisert kaliumhydroksyd. Oppløsnin-gen oppvarmes i oljebad langsomt til 150° og oppvarmes så i 1 time ved denne temperatur. Deretter avkjbler man oppløsnin-gen og heller den på is. Den dannede blanding surgjoreS' med konsentrert saltsyre og ekstraheres med eter. Eteropplbsningen skilles fra og ekstraheres to ganger med 2 W natriumkarbonat-opplbsning. Natriumkarbonatopplbsningene forenes og surgjores med 2 N saltsyre. Den utskilte olje ekstraheres med eter. Eteropplbsningen vaskes med vann, tbrkes over natriumsulfat og inndampes under 11 Torr ved 40°. Resten krystalliserer man to ganger fra eter-petroleter. [o-(2,6-xylidino)-fenyl]-eddiksyre smelter ved 120 - 127° under spaltning. diethylene glycol monomethyl ether, 1.56 g of hydrazine hydrate is added. The solution thereby heats up. After 15 minutes, 1.34 g of powdered potassium hydroxide is added. The solution is heated in an oil bath slowly to 150° and then heated for 1 hour at this temperature. The solution is then cooled and poured onto ice. The resulting mixture is acidified with concentrated hydrochloric acid and extracted with ether. The ether solution is separated and extracted twice with 2 W sodium carbonate solution. The sodium carbonate solutions are combined and acidified with 2 N hydrochloric acid. The separated oil is extracted with ether. The ether solution is washed with water, dried over sodium sulphate and evaporated below 11 Torr at 40°. The residue is crystallized twice from ether-petroleum ether. [o-(2,6-xylidino)-phenyl]-acetic acid melts at 120 - 127° during decomposition.

Analogt fremstilles: Analogously produced:

Man oppnår 6,5 g [6-(2,6-xylidino)-m-tolyl]-eddiksyre, smp. 6.5 g of [6-(2,6-xylidino)-m-tolyl]-acetic acid is obtained, m.p.

88 - 89° (fra etylacetat-petroleter), ved å gå ut fra 9,2 g l-(2,6-xylyl)-5-metyl-indol-2,3-dion, smp. 158°. 88 - 89° (from ethyl acetate-petroleum ether), starting from 9.2 g of 1-(2,6-xylyl)-5-methyl-indole-2,3-dione, m.p. 158°.

Man oppnår 12,0 g [o-(2,6-diklor-anilino)-fenyl]-eddiksyre, smp. 156 - 158° (fra eter-petroleter), ved å gå ut fra 20,5 g l-(2,6-diklorfenyl)-indol-2,3-dion, smp. 175 - 176°. 12.0 g of [o-(2,6-dichloro-anilino)-phenyl]-acetic acid is obtained, m.p. 156 - 158° (from ether-petroleum ether), starting from 20.5 g of 1-(2,6-dichlorophenyl)-indole-2,3-dione, m.p. 175 - 176°.

Man oppnår 2,5 g [o-(6-metoksy-m-toluidino)-fenyl]-eddiksyre, smp. 98 - 99° (fra eter-petroleter), ved å gå ut fra 5,4 g 1-(6-metoksy-m-tolyl)-indol-2,3-dion, smp. 168 - 169°. 2.5 g of [o-(6-methoxy-m-toluidino)-phenyl]-acetic acid is obtained, m.p. 98 - 99° (from ether-petroleum ether), starting from 5.4 g of 1-(6-methoxy-m-tolyl)-indole-2,3-dione, m.p. 168 - 169°.

EKSEMPEL 2 EXAMPLE 2

a) [ o-( 2, 6- xylidino)- fenyl]- glyoksylsyre a) [o-(2,6-xylidino)-phenyl]-glyoxylic acid

En opplosning av 7,3 g 1-(2,6-xylyl)-indol-2,3-dion, 15 ml 2 N A solution of 7.3 g of 1-(2,6-xylyl)-indole-2,3-dione, 15 ml of 2 N

natronlut og 100 ml etanol kokes i 15 timer under tilbakelbp. Deretter avkjbles oppløsningen og inndampes under 11 Torr ved 40 til tbrrhet. Resten opplbser man i 200 ml vann. Den vandige oppløsning ekstraheres med eter, skilles fra og surgjbres caustic soda and 100 ml of ethanol are boiled for 15 hours under reflux. The solution is then cooled and evaporated below 11 Torr at 40 to dryness. The rest is dissolved in 200 ml of water. The aqueous solution is extracted with ether, separated and acidified

ved tilsetning av 2 N saltsyre. De utskilte gule krystaller opploses i eter. Eteroppldsningen skilles fra, ekstraheres med vann, torkes over natriumsulfat og inndampes under 11 Torr ved 40°. Resten krystalliserer man fra eter-petroleter. by adding 2 N hydrochloric acid. The separated yellow crystals are dissolved in ether. The ether solution is separated, extracted with water, dried over sodium sulphate and evaporated below 11 Torr at 40°. The remainder is crystallized from ether-petroleum ether.

[o-(2,6-xylidino)-fenyl]-glyoksylsyre smelter ved 135 - 137°. [o-(2,6-xylidino)-phenyl]-glyoxylic acid melts at 135 - 137°.

b) [ o-( 2, 6- xylidino)- fenyl]- eddiksyre b) [o-(2,6-xylidino)-phenyl]-acetic acid

Til en opplosning av 1,5 g [o-(2,6-xylidino)-fenyl]-glyoksylsyre i 10 ml absolutt etanol tilsetter man 2,25 g hydrazinhydrat. Etter at opplosningen igjen er avkjblt til værelsetemperatur, tilsetter man en opplosning av 2,25 g natrium i 55 ml absolutt etanol. Blandingen oppvarmes langsomt til 200°, idet etanol, vann og hydrazin avdampes og en krystallinsk rost hensettes i 15 minutter ved 200°. Deretter avkjbler man og opplbser resten i 20 ml vann, filtrerer opplosningen gjennom Hyflo og gjor den sur med 2 N saltsyre. Den utskilte olje opploses i eter. Man vasker eteropplbsningen med 2 N kaliumbikarbonatopplbsning og vann, skiller den vandig-alkaliske opplosning fra og innstiller den sur med 2 N saltsyre. Den utskilte olje ekstraheres med eter. To a solution of 1.5 g of [o-(2,6-xylidino)-phenyl]-glyoxylic acid in 10 ml of absolute ethanol, 2.25 g of hydrazine hydrate is added. After the solution has again cooled to room temperature, a solution of 2.25 g of sodium in 55 ml of absolute ethanol is added. The mixture is slowly heated to 200°, as ethanol, water and hydrazine evaporate and a crystalline rust is left for 15 minutes at 200°. Then cool and dissolve the residue in 20 ml of water, filter the solution through Hyflo and make it acidic with 2 N hydrochloric acid. The separated oil is dissolved in ether. The ether solution is washed with 2 N potassium bicarbonate solution and water, the aqueous-alkaline solution is separated and made acidic with 2 N hydrochloric acid. The separated oil is extracted with ether.

Eteropplbsningen vaskes med vann, torkes over natriumsulfat og inndamper under 11 Torr ved 40°. Resten krystalliserer man to ganger fra eter-petroleter. [o-(2,6-xylidino)-fenyl]-eddiksyre smelter ved 120 - 127° under spaltning. The ether solution is washed with water, dried over sodium sulphate and evaporated below 11 Torr at 40°. The residue is crystallized twice from ether-petroleum ether. [o-(2,6-xylidino)-phenyl]-acetic acid melts at 120 - 127° during decomposition.

Analogt fremstilles: Analogously produced:

Man oppnår 42 g [o-(2,6-diklor-m-toluidino)-fenyl]-eddiksyre, smp. 147 - 149° (fra eter-petroleter), ved å gå ut fra 7 g [o-(2,6-diklor-m-toluidino)-fenyl]-glyoksylsyre, smp. 153-158°. 42 g of [o-(2,6-dichloro-m-toluidino)-phenyl]-acetic acid is obtained, m.p. 147 - 149° (from ether-petroleum ether), starting from 7 g of [o-(2,6-dichloro-m-toluidino)-phenyl]-glyoxylic acid, m.p. 153-158°.

EKSEMPEL 3 EXAMPLE 3

a) Natriumsalt av [ o-( 6- klor- oc , oc , oc- trif luor- m- toluidino) - fenyl]- glyoksylsyre a) Sodium salt of [o-(6-chloro-oc,oc,oc-trifluoro-m-toluidino)-phenyl]-glyoxylic acid

En opplosning av 32,5 g 1-( 6-klor-oc ,oc ,oc-trif luor-m-tolyl)-indol-2,3-dion i 100 ml etanol og 100 ml 1 N natronlut kokes i 1 time under tilbakelbp. Deretter avkjbler man opplosningen og inndamper den under 11 Torr ved 50° til tbrrhet. Til resten tilsetter man to ganger hver gang 50 ml absolutt benzen og inndamper hver gang blandingen under 11 Torr ved 40° til tbrrhet, A solution of 32.5 g of 1-(6-chloro-oc,oc,oc-trifluoro-m-tolyl)-indole-2,3-dione in 100 ml of ethanol and 100 ml of 1 N caustic soda is boiled for 1 hour under return lbp. The solution is then cooled and evaporated below 11 Torr at 50° to dryness. To the residue, 50 ml of absolute benzene are added twice each time and each time the mixture is evaporated below 11 Torr at 40° to dryness,

idet man oppnår rent natriumsalt av [o-(6-klor-oc ,<x ,oc-trif luor-m-toluidinoH"enyl]-glyoksylsyre. Natriumsaltet av [o-(6-klor-o-toluidino)-fenyl]-glyoksylsyre oppnås helt analogt. b) [ o - ( 6- klor- oc , oc, a- tri f luor- m- toluidino) - f enyl] - eddik syre Til en opplosning av 36,6 g natriumsalt av [o-(6-klor-a ,oc ,a-trifluor-m-toluidino)-fenyl]-glyoksylsyre i 200 ml absolutt etanol tilsetter man 37 g hydrazinhydrat. Man oppvarmer opplosningen i 15 minutter til 40° og tilsetter så en opplosning av 36,5 g natrium i 1500 ml absolutt etanol. Man oppvarmer opplosningen på kokende vannbad og avdestillerer derved ca. obtaining pure sodium salt of [o-(6-chloro-oc ,<x ,oc-trifluoro-m-toluidinoH"enyl]-glyoxylic acid. The sodium salt of [o-(6-chloro-o-toluidino)-phenyl] -glyoxylic acid is obtained completely analogously. b) [ o - ( 6- chloro- oc , oc, a- tri fluor- m- toluidino) - phenyl] - acetic acid To a solution of 36.6 g of the sodium salt of [o- (6-chloro-α,oc,α-trifluoro-m-toluidino)-phenyl]-glyoxylic acid in 200 ml of absolute ethanol is added 37 g of hydrazine hydrate. The solution is heated for 15 minutes to 40° and then a solution of 36, 5 g of sodium in 1500 ml of absolute ethanol.The solution is heated in a boiling water bath and thereby distilled off approx.

1000 ml etanol. Deretter oppvarmer man resten i oljebad ved en badtemperatur på 170°, hvorved den resterende etanol såvel som vann og hydrazin damper av. Den krystalliserte rest opploser man i 2000 ml vann. Den vandige opplosning ekstraheres med eter, skilles fra og filtreres gjennom et skikt Hyflo. Deretter surgjor man den vandige opplosning ved tilsetning av 2 W saltsyre. Den utfelte olje ekstraherer man med eter. Eterfasen vaskes med vann, torkes over natriumsulfat og inndampes under 11 Torr ved 40°. Resten krystalliserer man fra eter-petroleter. [o-(6-klor-a ,oc ,a-trif luor-m-toluidino)-f enyl]-eddiksyre smelter- ved 94 - 96°. 1000 ml of ethanol. The residue is then heated in an oil bath at a bath temperature of 170°, whereby the remaining ethanol as well as water and hydrazine evaporates. The crystallized residue is dissolved in 2000 ml of water. The aqueous solution is extracted with ether, separated and filtered through a pad of Hyflo. The aqueous solution is then acidified by adding 2 W hydrochloric acid. The precipitated oil is extracted with ether. The ether phase is washed with water, dried over sodium sulphate and evaporated below 11 Torr at 40°. The remainder is crystallized from ether-petroleum ether. [o-(6-chloro-α,oc,α-trifluoro-m-toluidino)-phenyl]-acetic acid melts at 94 - 96°.

Analogt fremstilles: Analogously produced:

Man oppnår 8,5 g [o-(6-klor-o-toluidino)-fenyl]-eddiksyre, smp. 140 - 147° (fra eter), ved å gå ut fra 14,2 g [o-(6-klor-o-toluidino)-fenyl]-glyoksylsyre-natriumsalt. 8.5 g of [o-(6-chloro-o-toluidino)-phenyl]-acetic acid is obtained, m.p. 140 - 147° (from ether), starting from 14.2 g of [o-(6-chloro-o-toluidino)-phenyl]-glyoxylic acid sodium salt.

Man oppnår 11,0 g [o-(2,6-diklor-fenyl)-5-klorfenyl)-eddiksyre, smp. 181 - 183° (fra metanol), ved å gå ut fra 18,5 g [o-(2,6-diklor-fenyl)-5-klor-fenyl]-glyoksylsyre-natriumsalt. 11.0 g of [o-(2,6-dichloro-phenyl)-5-chlorophenyl)-acetic acid is obtained, m.p. 181 - 183° (from methanol), starting from 18.5 g of [o-(2,6-dichloro-phenyl)-5-chloro-phenyl]-glyoxylic acid sodium salt.

EKSEMPEL 4 EXAMPLE 4

[ o-( 2, 6- xylidino)- m- tolyl]- eddiksyre- natriumsalt 26,9 g [o-(2,6-xylidino)-m-tolyl]-eddiksyre (se eksempel 2) [o-(2,6-xylidino)-m-tolyl]-acetic acid sodium salt 26.9 g [o-(2,6-xylidino)-m-tolyl]-acetic acid (see example 2)

opploses i 100 ml 1 N natronlut. Opplosningen inndampes under 11 Torr ved en badtemperatur på 50° til tbrrhet. Resten tilsetter man 40 ml absolutt benzen, inndamper ennå en gang til tbrrhet og krystalliserer resten fra dioksan. Natriumsaltet av [o-(2,6-xylidino)-m-tolyl]-eddiksyre smelter ved 341 - 343°. dissolve in 100 ml 1 N caustic soda. The solution is evaporated below 11 Torr at a bath temperature of 50° to dryness. 40 ml of absolute benzene is added to the residue, evaporated once more to dryness and the residue crystallized from dioxane. The sodium salt of [o-(2,6-xylidino)-m-tolyl]-acetic acid melts at 341 - 343°.

Analogt fremstilles: Analogously produced:

Man oppnår [o-(6-klor-o-toluidino)-fenyl]-eddiksyre-kaliumsalt, smp. 287 - 295°, under spaltning (fra etanol-eter). One obtains [o-(6-chloro-o-toluidino)-phenyl]-acetic acid potassium salt, m.p. 287 - 295°, with decomposition (from ethanol-ether).

Man oppnår [o-(2,6-diklor-anilino)-fenyl]-eddiksyre-natriumsalt, smp. 281 - 283° (fra etanol-vann). One obtains [o-(2,6-dichloro-anilino)-phenyl]-acetic acid sodium salt, m.p. 281 - 283° (from ethanol-water).

Man oppnår [o-(2,6-diklor-m-toluidino}-fenyl]-eddiksyre-natriumsalt, smp. 287 - 289° (fra vann). One obtains [o-(2,6-dichloro-m-toluidino}-phenyl]-acetic acid sodium salt, mp 287 - 289° (from water).

Man oppnår [o-(2,6-xylidino)-fenyl]-eddiksyre-natriumsalt, One obtains [o-(2,6-xylidino)-phenyl]-acetic acid sodium salt,

smp. 298 - 305° (fra etylacetat). m.p. 298 - 305° (from ethyl acetate).

Man oppnår [o-(2,6-diklor-fenyl)-5-klor-fenyl]-eddiksyre-natriumsalt, smp. 295° spaltning (fra vann). One obtains [o-(2,6-dichloro-phenyl)-5-chloro-phenyl]-acetic acid sodium salt, m.p. 295° cleavage (from water).

EKSEMPEL 5 EXAMPLE 5

2, 6- diklor- 4'- klor- difenylamin 2, 6-dichloro-4'-chloro-diphenylamine

2,6-diklor-4<1->klor-difenylamin, som tjener som utgangsstoff for den under eksempel 3 analogt fremstilte [o-(2,6-diklor-fenyl)-5-klor-fenyl]-eddiksyre, fremstilles som folger: 220 g 2,6-diklor-acetanilid opploses i 1000 ml 4-brom-klor-benzen. Man tilsetter 100 g glbdet kaliumkarbonat og 10 g kobberpulver. Derpå oppvarmer man blandingen i 4 dager med tilbakelbp, idet det dannede vann skilles fra ved hjelp av en vannutskiller. Deretter avkjbler man og blandingen underkastes en vanndampdestillasjon. Resten ekstraherer man med 2500 ml eter. Man filtrerer eteropplbsningen gjennom Hyflo og konsentrerer under 11 Torr til tbrrhet. Deretter opplbser man resten i 1400 ml 10 36* ig etanolisk kaliumhydroksydoppldsning og opp- 2,6-dichloro-4<1->chloro-diphenylamine, which serves as starting material for the [o-(2,6-dichloro-phenyl)-5-chloro-phenyl]-acetic acid prepared analogously under example 3, is prepared as follows: 220 g of 2,6-dichloro-acetanilide is dissolved in 1000 ml of 4-bromo-chloro-benzene. Add 100 g of powdered potassium carbonate and 10 g of copper powder. The mixture is then heated for 4 days under reflux, the water formed being separated by means of a water separator. It is then cooled and the mixture subjected to steam distillation. The residue is extracted with 2500 ml of ether. The ether solution is filtered through Hyflo and concentrated below 11 Torr to dryness. The residue is then dissolved in 1400 ml of 10 36% ethanolic potassium hydroxide solution and

varmer opplosningen i 16 timer med tilbakelop. Deretter konsentrerer man opplosningen under 11 Torr ved 50° til tbrrhet. Resten tilsetter man 150 ml vann og ekstraherer med 1500 ml etylacetat. Etylacetatopplbsningen skilles fra, torkes med natriumsulfat og inndampes under 11 Torr til tbrrhet. Resten destillerer man i hbyvakuum. 2,6-diklor-4'-klor-difenylamin koker ved 121°/0,01 Torr. Utbyttet utgjor 45 % (beregnet på 2,6-diklor-acetanilid). heating the solution for 16 hours at reflux. The solution is then concentrated below 11 Torr at 50° to dryness. 150 ml of water is added to the residue and extracted with 1500 ml of ethyl acetate. The ethyl acetate solution is separated, dried with sodium sulfate and evaporated below 11 Torr to dryness. The rest is distilled in high vacuum. 2,6-dichloro-4'-chloro-diphenylamine boils at 121°/0.01 Torr. The yield is 45% (calculated on 2,6-dichloroacetanilide).

Analogt fremstilles: Analogously produced:

Man oppnår 13 g N-(p-anisyl)-2,6-diklor-p-anisidin, smp. 127 - 129° (fra etanol), ved å gå ut fra 27 g N-acetyl-2,6-diklor-p-anisidin. 13 g of N-(p-anisyl)-2,6-dichloro-p-anisidine are obtained, m.p. 127 - 129° (from ethanol), starting from 27 g of N-acetyl-2,6-dichloro-p-anisidine.

Claims

Process for the preparation of substituted o-arylamino-phenylacetic acids of the general formula I,

where means a lower alkyl or alkoxy group, a fluorine, chlorine or bromine atom, or a trifluoromethyl group, 1*2 and R 3 hydrogen, a lower alkyl group or a fluorine, chlorine or bromine atom, and R^ hydrogen, a lower alkyl or alkoxy group, a fluorine, chlorine or bromine atom, in that at least one of the substituents R^, R2 or R^ is placed in the ortho position, and the same does not mean hydrogen, and their salts with inorganic and organic bases, characterized by reacting a ring-substituted diphenylamine of the general formula II, where R.sub.2, R.sub.2, R.sub.4 and R.sub.4 have the meanings given under formula I, with oxalyl chloride in a suitable solvent to a ring-substituted N-aryl-oxanilic acid chloride of the general formula III, where R 1 , R 2 , R 3 and R 4 have the meanings given under formula I, and transfers the compound of formula III in the presence of Friedel-Crafts condensing agents at room temperature under ring closure to a substituted indole-2,3-dione of the general formula IV, where R^, R^, R^ and R^ have those of formula I stated meanings, optionally recrystallizes the latter compound, and either a) reacts it with hydrazine or semicarbazide and alkali metal hydroxide or alkali metal alcoholate at elevated temperature to a salt of an acid of formula I, or b) hydrolyzes it to an (o-anilinophenyl)-glyoxylic acid or a salt thereof with the formula where R means hydrogen, a monovalent cation or the equivalent of a polyvalent cation, and R^, R2# R3 and R^ have the meanings given under formula I, and reacts the compound of formula V with hydrazine or semicarbazide and alkali metal hydroxide or alkali metal alcoholate at elevated temperature to a salt of the acid of formula I, and optionally converts the obtained salt into the free acid or into another salt with an inorganic or organic base.