NO167485B - DEVICE FOR RECORDING OF ADDITIONAL INFORMATION IN A VIEW - Google Patents

Description

Fremgangsmåte for fremstilling av hittil ukjente, Procedure for the production of hitherto unknown,

terapeutisk virksomme, substituerte fenyleddiksyreestere. therapeutically active substituted phenylacetic acid esters.

Nærværende oppfinnelse vedrører en fremgangsmåte for fremstilling av hittil The present invention relates to a method for the production of up to now

ukjente, substituerte fenyleddiksyreestere med den generelle formel I, unknown substituted phenylacetic acid esters of the general formula I,

hvor betyr en lavere alkyl- eller alkoxygruppe, et fluor-, klor- eller bromatom eller trifluormethylgruppen, where means a lower alkyl or alkoxy group, a fluorine, chlorine or bromine atom or the trifluoromethyl group,

R2 hydrogen eller en substituent tilsvarende definisjonen for R.^, R2 hydrogen or a substituent corresponding to the definition for R.^,

Rg hydrogen, en lavere alkyl- eller alkoxygruppe eller et fluor-, klor- eller bromatom, Rg is hydrogen, a lower alkyl or alkoxy group or a fluorine, chlorine or bromine atom,

R4 hydrogen, en lavere alkyl- eller alkoxygruppe, et fluor-, klor eller bromatom eller trifluormethylgruppen og R4 is hydrogen, a lower alkyl or alkoxy group, a fluorine, chlorine or bromine atom or the trifluoromethyl group and

R^ betyr en lavere alkyl- eller fenyl- (lavere alkyl) -gruppe, i særdeleshet R 1 means a lower alkyl or phenyl (lower alkyl) group, in particular

benzylgruppen. the benzyl group.

Som det nu ble funnet innehar disse estere verdifulle farmakologiske egenskaper, i særdeleshet antiflogistisk (antiinflamatorisk), analgetisk og antipyretisk virkning ved gunstig terapeutisk indeks. De kan anvendes oralt eller rektalt for behandling av revmatiske, arthritiske og andre betennende sykdommer. Den antiflogistiske virkning lar seg påvise i dyreforsøk f. eks. ved UV-erythem hos marsvin og ved Bolus alba-ødem hos rotter. As it was now found, these esters possess valuable pharmacological properties, in particular antiphlogistic (anti-inflammatory), analgesic and antipyretic action with a favorable therapeutic index. They can be used orally or rectally for the treatment of rheumatic, arthritic and other inflammatory diseases. The antiphlogistic effect can be demonstrated in animal experiments, e.g. in UV-erythema in guinea pigs and in Bolus alba edema in rats.

De ifølge oppfinnelsen fremstilte fenyleddiksyreestere er ved lav toksisitet de analogt substituerte antranilsyreestere ifølge de tyske patenter 1.163.841 og 1.149.015 overlegne. Dette kommer fremfor alt til uttrykk i Bolus alba-brøven, hvor høyere doser av antranilsyreestere er nødvendig for å oppnå den samme virkning som med de tilsvarende fenyleddiksyreestere. The phenylacetic acid esters produced according to the invention are superior in terms of low toxicity to the analogously substituted anthranilic acid esters according to the German patents 1,163,841 and 1,149,015. This is above all expressed in the Bolus alba bridge, where higher doses of anthranilic acid esters are required to achieve the same effect as with the corresponding phenylacetic acid esters.

I esterne;: med den generelle formel I og de tilsvarende nedenfor nevnte utgangsstoffer er R.^ til R4 som lavere alkylgrupper uavhengig av hverandre f. eks. methyl- eller ethylgrupper. En del av de nevnte symboler kan f.eks. også være n-propyl-, isopropyl-, n-butyl-, sek. butyl-eller tert. butyl-grupper. Lavere alkoxy-grupper eller halogenatomer Rj til R4 er f. eks. methoxy-, ethoxy-, n-propoxy-, n-butoxy- eller isobutoxygrupper henh. klor-, fluor- eller bromatomer. R^ er f. eks. methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, sek.butyl-, n-pentyl-, isopentyl-, neopentyl-, n-hexyl-, benzyl-, fenethyl- eller 3-fenylpropyl-gruppen. In the esters;: with the general formula I and the corresponding starting materials mentioned below, R 1 to R 4 are lower alkyl groups independently of each other, e.g. methyl or ethyl groups. Some of the mentioned symbols can e.g. also be n-propyl-, isopropyl-, n-butyl-, sec. butyl or tert. butyl groups. Lower alkoxy groups or halogen atoms Rj to R4 are e.g. methoxy, ethoxy, n-propoxy, n-butoxy or isobutoxy groups acc. chlorine, fluorine or bromine atoms. R^ is e.g. methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, sec.butyl-, n-pentyl-, isopentyl-, neopentyl-, n-hexyl-, benzyl-, phenethyl- or 3 -phenylpropyl group.

For fremstilling av estere med den generelle formel I overfører man syrer med den generelle formel II, For the production of esters with the general formula I, acids with the general formula II are transferred,

hvor Rj, R2> Rg og R4 har den under formel I angitte betydning, where Rj, R2 > Rg and R4 have the meaning given under formula I,

under unngåelse av økede temperaturer ved tilstedeværelsen av sure reaksjonsmedier til deres lavere alkylestere henh. fenyl- (lavere alkyl) -estere, idet man while avoiding increased temperatures in the presence of acidic reaction media to their lower alkyl esters acc. phenyl (lower alkyl) esters, whereas

a) omsetter syren med et lavere diazoalkan i et inert oppløsningsmiddel; b) omsetter syren i et inert oppløsningsmiddel med 1,1-di-(lavere alkoxy)-tri - methylamin eller et 1, l-di-(fenyl-(lavere alkoxy))-trimethylamin; c) omsetter syren med en lavere alkanol eller med benzyl-alkohol i nærvær av 1,1-dineopentyloxy-trimethylamin; d) omsetter et salt av syren med et halogenid, sulfat eller sulfonat, av en lavere alkanol eller fenyl- (lavere alkanol); eller ' e) behandler syren med en blanding bestående av en lavere alkanol eller fenyl-(lavere alkanol) og tionylklorid ved en temperatur på høyst -5°C. a) reacting the acid with a lower diazoalkane in an inert solvent; b) reacting the acid in an inert solvent with 1,1-di-(lower alkoxy)-trimethylamine or a 1,1-di-(phenyl-(lower alkoxy))-trimethylamine; c) reacting the acid with a lower alkanol or with benzyl alcohol in the presence of 1,1-dineopentyloxy-trimethylamine; d) reacts a salt of the acid with a halide, sulfate or sulfonate, of a lower alkanol or phenyl-(lower alkanol); or 'e) treating the acid with a mixture consisting of a lower alkanol or phenyl-(lower alkanol) and thionyl chloride at a temperature of at most -5°C.

Til forestring omsetter man carboxylsyrene med den generelle formel II enten med lavere diazoalkaner i inerte organiske oppløsningsmidler, som f. eks. ether, eller med acetaler av N,N-dimethylformamid med de som esterkomponenter ønskede alko-holer (med 1,1-di-(lavere alkoxy)-trimethylaminer henh. 1,l-di-(fenyl (lavere alkoxy))-trimethylaminer) i inerte oppløsningsmidler, som methylenklorid eller benzen (sml. For esterification, the carboxylic acids with the general formula II are reacted either with lower diazoalkanes in inert organic solvents, such as e.g. ether, or with acetals of N,N-dimethylformamide with the desired alcohols as ester components (with 1,1-di-(lower alkoxy)-trimethylamines according to 1,1-di-(phenyl (lower alkoxy))-trimethylamines ) in inert solvents, such as methylene chloride or benzene (cf.

H. Brechbuhler, H. Biichi, E. Hatz, J. Schreiber og A. Eschenmoser, Ang. Chemie 75, 296 (1963) såvel som H. Vorbriiggen, ibid. 296 - 297) eller med benzylalkohol eller lavere alkanoler i nærvær av N,N-dimethylformaldehyd-dineopentylacetal (1,1-dineopentyloxy-trimethylamin) (sml. H. Buchi, K. Steen og A. Eschenmoser, Ang. Chemie, 75, 1176 - 1177 (1963)). H. Brechbuhler, H. Biichi, E. Hatz, J. Schreiber and A. Eschenmoser, Ang. Chemie 75, 296 (1963) as well as H. Vorbriiggen, ibid. 296 - 297) or with benzyl alcohol or lower alkanols in the presence of N,N-dimethylformaldehyde-dineopentyl acetal (1,1-dineopentyloxy-trimethylamine) (cf. H. Buchi, K. Steen and A. Eschenmoser, Ang. Chemie, 75, 1176-1177 (1963)).

Videre kan man overføre syrene med den generelle formel II til salter, f. eks. til alkalimetallsalter og omsette disse med halogenider, sulfater eller sulfonater av lavere alkanoler eller fenyl-(lavere alkanoler), f. eks. med dimethylsulfat, diethylsulfat, methyljodid, ethyljodid, propylbromid, butylbromid, benzylklorid, benzyl-bromid eller p-toluensul-fenyl-aceto-o-toluidiner, alt etter substitusjonen av N-fenyl-gruppen. Fra a-klor-forbindelsene oppnår man ved omsetning med natrium- eller kaliumcyanid substituerte oj-cyano-N-fenyl-o-toluidiner henh. substituerte os-cyano-N-fenyl-aceto-o-toluidiner (substituerte l-(N-fenyl-acetamido)-fenylaceto-nitriler). Disse kan hydrolyseres ved hjelp av natron- eller kalilut til syrer med den generelle formel II. De substituerte of-cyano-N-fenyl-aceto-o-toluidinene lar seg også over-føre først ved behandling med alkonoliske hydrogenkloridoppløsninger til tilsvarende imidoalkylester-hydroklorider, som lar seg spalte med vann til de tilsvarende lavere alkylestere, ved hvis hydrolyse man igjen oppnår syrer med den generelle formel II. Furthermore, the acids with the general formula II can be transferred to salts, e.g. to alkali metal salts and reacting these with halides, sulfates or sulfonates of lower alkanols or phenyl-(lower alkanols), e.g. with dimethyl sulfate, diethyl sulfate, methyl iodide, ethyl iodide, propyl bromide, butyl bromide, benzyl chloride, benzyl bromide or p-toluenesul-phenyl-aceto-o-toluidines, depending on the substitution of the N-phenyl group. From the a-chloro compounds, by reaction with sodium or potassium cyanide, substituted o-cyano-N-phenyl-o-toluidines are obtained acc. substituted os-cyano-N-phenyl-aceto-o-toluidines (substituted 1-(N-phenyl-acetamido)-phenylacetonitriles). These can be hydrolysed using caustic soda or caustic soda to acids with the general formula II. The substituted o-cyano-N-phenyl-aceto-o-toluidines can also be converted first by treatment with alkanol hydrogen chloride solutions to the corresponding imidoalkyl ester hydrochlorides, which can be cleaved with water to the corresponding lower alkyl esters, on whose hydrolysis one again obtain acids of the general formula II.

De substituerte fenyleddiksyreesterne med den generelle formel I kan admini-streres oralt eller rektalt. De kan også komme til anvendelse utvortes, innarbeidet f. eks. i salvegrunnlag. The substituted phenylacetic acid esters of the general formula I can be administered orally or rectally. They can also be used externally, incorporated e.g. in an ointment base.

De daglige doser, som inntas innvortes, av estere med den generelle formel The daily doses, taken internally, of esters with the general formula

I for behandling av revmatiske, arthritiske og andre betennende sykdommer beveger seg mellom 50 og 1500 mg for voksne pasienter. Egnede doseenhetsformer, som dragéer, tabletter eller suppositorier, inneholder fortrinnsvis 25 - 300 mg av en ester med den generelle formel I. In the treatment of rheumatic, arthritic and other inflammatory diseases, the dose ranges between 50 and 1500 mg for adult patients. Suitable dosage unit forms, such as dragees, tablets or suppositories, preferably contain 25-300 mg of an ester of the general formula I.

De etterfølgende eksempler redegjør nærmere for gjennomføringen av frem-gangsmåten ifølge oppfinnelsen. Temperaturene er angitt i Celsiusgrader. The following examples explain in more detail the implementation of the method according to the invention. The temperatures are indicated in degrees Celsius.

EKSEMPEL 1 EXAMPLE 1

( o-( 2, 6- diklor- m- toluidino) - fenyl] - eddiksyre- methylester (o-(2,6-dichloro-m-toluidino)-phenyl]-acetic acid methyl ester

Til en oppløsning av 10 g Io-(2,6-diklor-m-toluidino)-f enyl]-eddiksyre (smp. 146 - 149°) i 150 ml absolutt ether lar man langsomt tildryppe 100 ml 2%'ig etherisk diazomethanoppløsning. Man lar oppløsningen stå natten over ved værelsetemperatur og inndamper den så under 11 Torr ved 40° til tørrhet. Resten oppløser man i 100 ml ether. Etheroppløsningen ekstraheres med 50 ml l-n kaliumbicarbonatoppløsning og vann, tørkes over natriumsulfat og inndampes under 11 Torr ved 40°. Resten krystalliserer fra ether-petrolether. lp-(2,6-diklor-m-toluidino)-fenyl]-eUdiksyre-methyl-esteren smelter ved 110 - 112°. Utbytte utgjør 70% av det teoretiske. To a solution of 10 g of Io-(2,6-dichloro-m-toluidino)-phenyl]-acetic acid (m.p. 146 - 149°) in 150 ml of absolute ether, slowly add 100 ml of a 2% ethereal diazomethane solution . The solution is allowed to stand overnight at room temperature and then evaporated below 11 Torr at 40° to dryness. The remainder is dissolved in 100 ml of ether. The ether solution is extracted with 50 ml 1-1 potassium bicarbonate solution and water, dried over sodium sulphate and evaporated below 11 Torr at 40°. The residue crystallizes from ether-petroleum ether. The lp-(2,6-dichloro-m-toluidino)-phenyl]-acetic acid methyl ester melts at 110-112°. Yield is 70% of the theoretical amount.

Fremstilling av den som utgangsstoff nødvendige syre kan f. eks. finne sted på Production of the acid required as starting material can e.g. take place at

den etterfølgende beskrevne måte: the following described way:

a) 2, 6- diklor- N- fenyl- m- toluidin a) 2, 6-dichloro-N-phenyl-m-toluidine

7 g N-(2,6-diklor-m-tolyl)-anthranilsyre oppvarmes i 2 timer til 280°. Den 7 g of N-(2,6-dichloro-m-tolyl)-anthranilic acid are heated for 2 hours to 280°. It

avkjølte smelte oppløses i 30 ml benzol. Den benzoliske oppløsning ekstraheres med cooled melt is dissolved in 30 ml of benzene. The benzolic solution is extracted with

5 ml 2-n natriumcarbonatoppløsning og 5 ml vann, så tørkes med natriumsulfat og inndampes. Resten destilleres under høyvakuum, hvorved 2, 6-diklor-N-fenyl-m- 5 ml of 2-n sodium carbonate solution and 5 ml of water, then dried with sodium sulphate and evaporated. The residue is distilled under high vacuum, whereby 2, 6-dichloro-N-phenyl-m-

toluidinet oppnås som gul olje, kp. 115 - 120°/0,001 Torr. the toluidine is obtained as a yellow oil, b.p. 115 - 120°/0.001 Torr.

b) N- fenyl- 2, 2', 6'- triklor- aceto- m- toluidid b) N-phenyl-2,2',6'-trichloro-aceto-m-toluidide

4 g 2,6-diklor-N-fenyl-m-toluidin kokes med 40 ml frisk destillert kloracetyl-klorid i 1 time under tilbakeløp. Den mørke oppløsning inndampes så under 11 Torr ved en badtemperatur på 50°. Resten oppløses i 70 ml ethylacetat-ether 1:1. Denne oppløsning ekstraheres med 10 ml 2-n kaliumbicarbonatoppløsning og 10 ml vann, 4 g of 2,6-dichloro-N-phenyl-m-toluidine is boiled with 40 ml of freshly distilled chloroacetyl chloride for 1 hour under reflux. The dark solution is then evaporated below 11 Torr at a bath temperature of 50°. The residue is dissolved in 70 ml of ethyl acetate-ether 1:1. This solution is extracted with 10 ml of 2-n potassium bicarbonate solution and 10 ml of water,

tørkes over natriumsulfat og inndampes under 11 Torr. N-fenyl-2, V ,6'-triklor-aceto-m-toluididet krystalliserer fra cyklohexan, smp. 117 - 118°. dried over sodium sulfate and evaporated below 11 Torr. N-phenyl-2, V ,6'-trichloro-aceto-m-toluidide crystallizes from cyclohexane, m.p. 117 - 118°.

c) l-( 2, 6- diklor- m- tolyl) - 2- indolinon c) 1-(2,6-dichloro-m-tolyl)-2-indolinone

4 g N-fenyl-2,2' ,6'-triklor-aceto-m-toluidid og 4 g aluminiumklorid gjennom-blandes godt og oppvarmes i 2 timer til 160°. Smeiten avkjøles og hellesr på ca. 50 g is sålenge den ennå er varm. Den utfelte olje oppløses i 50 ml kloroform, kloroform-oppløsningen vaskes med 10 ml vann, tørkes over natriumsulfat og inndampes under 11 Torr. Resten destilleres under høyvakuum. l-(2,6-diklor-m-tolyl)-2-indolinonet koker ved 128 - 130°/0,001 Torr. Den erholdte olje krystalliserer ved henstand, krystallene smelter ved 129 - 132°. 4 g of N-phenyl-2,2',6'-trichloro-aceto-m-toluidide and 4 g of aluminum chloride are thoroughly mixed and heated for 2 hours to 160°. The mixture is cooled and poured into approx. 50 g of ice while it is still warm. The precipitated oil is dissolved in 50 ml of chloroform, the chloroform solution is washed with 10 ml of water, dried over sodium sulphate and evaporated below 11 Torr. The remainder is distilled under high vacuum. The 1-(2,6-dichloro-m-tolyl)-2-indolinone boils at 128-130°/0.001 Torr. The oil obtained crystallizes on standing, the crystals melting at 129 - 132°.

d) [ o- ( 2, 6- diklor- m- toluidino) - fenyl] - eddiksyre d) [o-(2,6-dichloro-m-toluidino)-phenyl]-acetic acid

En oppløsning av 40 g l-(2,6-diklor-m-tolyl)-2-indolinon i 280 ml l-n natron-lut og 420 ml ethanol kokes i 2 timer under tilbakeløp. Den klare oppløsning av- A solution of 40 g of 1-(2,6-dichloro-m-tolyl)-2-indolinone in 280 ml of 1-n caustic soda and 420 ml of ethanol is boiled for 2 hours under reflux. The clear resolution of-

kjøles, og ethanolen avdestilleres ved en badtemperatur på 40° under 11 Torr. Den vandige rest ekstraheres med 100 ml ether, etheren skilles fra, og den vandige opp- is cooled, and the ethanol is distilled off at a bath temperature of 40° below 11 Torr. The aqueous residue is extracted with 100 ml of ether, the ether is separated, and the aqueous

løsning avkjøles ved tilsetning av is (ca. 50 g) og ytterligere kjøling til 5°. Deretter tilsetter man under røring 2-n saltsyre, inntil pH-verdien av oppløsningen utgjør ca. solution is cooled by adding ice (approx. 50 g) and further cooling to 5°. 2-n hydrochloric acid is then added while stirring, until the pH value of the solution is approx.

6. Den utfelte syre opptas i 400 ml ether, etheroppløsningen skilles fra, og den 6. The precipitated acid is taken up in 400 ml of ether, the ether solution is separated, and the

vandige oppløsning ekstraheres ennå en gang med 200 ml ether. Etheroppløsningen aqueous solution is extracted once more with 200 ml of ether. The ether solution

vaskes med 50 ml vann, forenes, tørkes over natriumsulfat og konsentreres ved 11 washed with 50 ml of water, combined, dried over sodium sulfate and concentrated at 11

Torr uten å oppvarme. Fra den konsentrerte etheriske oppløsning utkrystalliserer Dry without heating. From the concentrated ethereal solution crystallizes out

etter tilsetning av petrolether [o-(2,6-diklor-m-toluidino)-fenyll-eddiksyren. Etter omkrystallisasjon fra ether-petrolether smelter den ved 146 - 149°. after addition of petroleum ether [o-(2,6-dichloro-m-toluidino)-phenyl-acetic acid. After recrystallization from ether-petroleum ether, it melts at 146 - 149°.

EKSEMPEL 2 EXAMPLE 2

- [ o- ( 2, 6- dikloranillno) - fenyl] - eddiksyre- methylester, - [ o - ( 2, 6- dichloroanillno) - phenyl] - acetic acid methyl ester,

smeltepunkt 101 - 102° (fra ether-petrolether); [2-(2,6-dikloranilino)-5-klorfenyl] -eddiksyre-methylester, melting point 101 - 102° (from ether-petroleum ether); [2-(2,6-dichloroanilino)-5-chlorophenyl]-acetic acid methyl ester,

smeltepunkt 87 - 88° (fra ether-petrolether); [2-(2,6-diklor-m-toluidino) - 5-klorfenyl]-eddiksyre-methylester oppnås analogt eksempel 1. melting point 87 - 88° (from ether-petroleum ether); [2-(2,6-dichloro-m-toluidino)-5-chlorophenyl]-acetic acid methyl ester is obtained analogously to example 1.

De som utgangs stoffer anvendte syrer fremstilles på følgende måte: The acids used as starting materials are produced in the following way:

a) 2, 6- diklordifenylamin a) 2, 6-dichlorodiphenylamine

15 g 2' ,6'-diklor-acetanilid oppløses i 150 ml brombenzol. Man tilsetter 5,5 Dissolve 15 g of 2',6'-dichloroacetanilide in 150 ml of bromobenzene. 5.5 is added

g glødende kaliumcarbonat og 0,5 g kobberpulver. Deretter koker man blandingen i g of glowing potassium carbonate and 0.5 g of copper powder. The mixture is then boiled in

4 dager under tilbakeløp, hvorved det dannede vann ved hjelp av en vannavskiller skilles fra. Så avkjøler man og underkaster reaksjonsblandingen en vanndampdestillasjon. Resten .ekstraherer man med 200 ml ether. Man filtrerer etheroppløsningen gjennom Hyflo og inndamper den under 11 Torr til tørrhet. Deretter oppløser man resten, det rå N-(2,6-diklorfenyl)-N-fenyl-acetamid, i 60 ml 10%'ig ethanolisk kaliumhydroxyd-oppløsning og koker oppløsningen i 3 timer under tilbakeløp. Derpå inndamper man oppløsningen under 11 Torr ved 40° til tørrhet. Resten tilsetter man 10 ml vann og ekstraherer det med 100 ml ether. Etheroppløsningen ekstraheres med 20 ml vann. Så tørker man den etheriske oppløsning med natriumsulfat og inndamper den under 11 Torr til tørrhet. Resten destillerer man under høyvakuum. 2,6-diklordifenylaminet koker ved 115°-0,01 Torr og er en gul olje. 4 days under reflux, whereby the water formed is separated using a water separator. The reaction mixture is then cooled and subjected to steam distillation. The remainder is extracted with 200 ml of ether. The ether solution is filtered through Hyflo and evaporated below 11 Torr to dryness. The residue, the crude N-(2,6-dichlorophenyl)-N-phenylacetamide, is then dissolved in 60 ml of 10% ethanolic potassium hydroxide solution and the solution is boiled for 3 hours under reflux. The solution is then evaporated below 11 Torr at 40° to dryness. The residue is added to 10 ml of water and extracted with 100 ml of ether. The ether solution is extracted with 20 ml of water. The ethereal solution is then dried with sodium sulphate and evaporated to dryness below 11 Torr. The remainder is distilled under high vacuum. The 2,6-dichlorodiphenylamine boils at 115°-0.01 Torr and is a yellow oil.

2,6,4'-triklordifenylamin med kp. 121°/0,01 Torr og N-(p-klorfenyl)-2,6-diklor-m-toluidin med kp. 135 - 145°/0,005 Torr fremstilles analogt. 2,6,4'-trichlorodiphenylamine with bp. 121°/0.01 Torr and N-(p-chlorophenyl)-2,6-dichloro-m-toluidine with b.p. 135 - 145°/0.005 Torr is produced analogously.

b) 2 - klor- N-( 2, 6- diklorfenyl) - N- fenyl- acetamid, b) 2-chloro-N-(2,6-dichlorophenyl)-N-phenylacetamide,

smeltepunkt 143 - 140° (fra methanol); 2-klor-N-(p-klorfenyl)-N-(2,6-diklorfenyl-acetamid, mp 143 - 140° (from methanol); 2-chloro-N-(p-chlorophenyl)-N-(2,6-dichlorophenyl-acetamide,

smeltepunkt 130 - 131° (fra ethanol-vann); N-(p-klorfenyl)-2,2',6,-triklor-aceto-m-toluidid, melting point 130 - 131° (from ethanol-water); N-(p-chlorophenyl)-2,2',6,-trichloro-aceto-m-toluidide,

smeltepunkt 106 - 107° (fra ethylacetat-petrolether); fremstilles analogt eksempel lb) fra forbindelsene i 2a). melting point 106 - 107° (from ethyl acetate-petroleum ether); is prepared analogously to example 1b) from the compounds in 2a).

c) l-( 2, 6- diklorfenyl)- 2- indolinon, c) 1-(2,6-dichlorophenyl)-2-indolinone,

smeltepunkt 126 - 127° (fra methanol); l-(2,6-diklorfenyl)-5-klor-2-indolinon, mp 126 - 127° (from methanol); 1-(2,6-dichlorophenyl)-5-chloro-2-indolinone,

smeltepunkt 130 - 131° (fra ethanol-vann); l-(2,6-diklor-m-tolyl)-5-klor-2-indolinon, melting point 130 - 131° (from ethanol-water); 1-(2,6-dichloro-m-tolyl)-5-chloro-2-indolinone,

smeltepunkt 152 - 154° (fra ethylacetat-petrolether); oppnås ved ringslutning analogt eksempel lc). mp 152 - 154° (from ethyl acetate-petroleum ether); achieved by looping analogously to example lc).

d) [ o- ( 2, 6- dikloranilino) - fenyl] - eddiksyre, d) [o-(2,6-dichloroanilino)-phenyl]-acetic acid,

smeltepunkt 156 - 158°; [2-(2,6-dikloranilino)-5-klorfenyl]-eddiksyre, melting point 156 - 158°; [2-(2,6-dichloroanilino)-5-chlorophenyl]-acetic acid,

smeltepunkt 152 - 156° (fra ether-petrolether); [2-(2, 6-diklor-m-toluidino) - 5-klorfenyl] -eddiksyre, mp 152 - 156° (from ether-petroleum ether); [2-(2,6-dichloro-m-toluidino)-5-chlorophenyl]-acetic acid,

smeltepunkt 152 - 156° (fra ether-petrolether)j oppnår man ved hydrolyse analogt eksempel ld). melting point 152 - 156° (from ether-petroleum ether)j obtained by hydrolysis analogously to example ld).

EKSEMPEL 3 EXAMPLE 3

[ 2- ( 2, 6- diklor- m- toluidino) - 5- methoxyf enyl] - eddiksyre- methylester [ 2-( 2, 6- dichloro- m- toluidino)- 5- methoxyphenyl] - acetic acid methyl ester

fremstilles analogt eksempel 1 og renses ved destillasjon i høyvakuum såvel som krystallisasjon fra ether-petrolether. is prepared analogously to example 1 and purified by distillation in high vacuum as well as crystallization from ether-petroleum ether.

De som utgangsstoffer nødvendige syrer fremstilles på følgende måte: The acids required as starting materials are produced in the following way:

a) 2, 6- diklor- N- ( p- methoxy- fenyl) - m- toluidin, a) 2, 6-dichloro-N-(p-methoxy-phenyl)-m-toluidine,

kp. 115 - 130°/0,001 Torr, fremstilles analogt eksempel 2a) ved å gå ut fra kp. 115 - 130°/0.001 Torr, is prepared analogously to example 2a) by starting from

2', 6'-diklor-aceto-m-toluidid og 4-brom-anisol. 2', 6'-dichloro-aceto-m-toluidide and 4-bromo-anisole.

b) N- ( p- methoxyfenyl) - 2, 2', 6'- triklor- aceto- m- toluidid (oljelignende) oppnås ved kloracetylering analogt eksempel lb). b) N-(p-Methoxyphenyl)-2,2',6'-trichloro-aceto-m-toluidide (oil-like) is obtained by chloroacetylation analogously to example lb).

c) l-( 2, 6- diklor- m- tolyl)- 5- hydroxy- 2- indolinon c) 1-(2,6-dichloro-m-tolyl)-5-hydroxy-2-indolinone

10 g N-(p-methoxyfenyl)-2,2',6'-triklor-aceto-m-toluidid blandes med 20 g 10 g of N-(p-methoxyphenyl)-2,2',6'-trichloro-aceto-m-toluidide are mixed with 20 g

finpulverisert aluminiumklorid og oppvarmes under røring i nitrogenatmosfære i 1 time til 280°. Man lar avkjøle og tilsetter den størknede smelte meget is og vann. Det danner seg derved et svart bunnfall, som filtreres fra og tørkes ved 80° og 11 Torr. Det ved kromatografi på nøytralt aluminiumoxyd rensede l-(2,6-diklor-m-tolyl)-5-hydroxy-2-indolinon smelter ved 184 - 187°. Utbytte 60% av teorien. finely powdered aluminum chloride and heated with stirring in a nitrogen atmosphere for 1 hour to 280°. Allow to cool and add a lot of ice and water to the solidified melt. A black precipitate is thereby formed, which is filtered off and dried at 80° and 11 Torr. The 1-(2,6-dichloro-m-tolyl)-5-hydroxy-2-indolinone purified by chromatography on neutral aluminum oxide melts at 184 - 187°. Yield 60% of the theory.

d) l-( 2, 6- diklor- m- tolyl)- 5- methoxy- 2- indolinon d) 1-(2,6-dichloro-m-tolyl)-5-methoxy-2-indolinone

8,1 g rå l-(2,6-diklor-m-tolyl)-5-hydroxy-2-indolinon oppløses i 26,3 ml l-n 8.1 g of crude 1-(2,6-dichloro-m-tolyl)-5-hydroxy-2-indolinone are dissolved in 26.3 ml of l-n

natronlut. Oppløsningen tilsettes 3,7 g dimethylsulfat og kokes i en 1/2 time under tilbakeløp. Etter avkjøling ekstraheres reaksjonsoppløsningen med 400 ml ethylacetat. Man filtrerer den organiske fase, vasker den en gang med vann og en gang med met-tet natriumkloridoppløsning, tørker den over natriumsulfat og inndamper den under 11 Torr til tørrhet. Resten kromatograferes for rensning over en aluminiumoxyd-kolonne og smelter etter omkrystallisasjon fra ether-petrolether ved 135 - 136°. Utbytte 20% av teorien. baking soda. 3.7 g of dimethylsulphate is added to the solution and boiled for 1/2 hour under reflux. After cooling, the reaction solution is extracted with 400 ml of ethyl acetate. The organic phase is filtered, washed once with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness below 11 Torr. The residue is chromatographed for purification over an aluminum oxide column and melts after recrystallization from ether-petroleum ether at 135 - 136°. Yield 20% of the theory.

e) [ 2-( 2, 6- diklor- m- tolyidino)- 5- methoxyfenyl1- eddiksyre e) [ 2-( 2, 6- dichloro- m-tolyidino)- 5- methoxyphenyl1- acetic acid

oppnås ved hydrolyse analogt eksempel ld), smeltepunkt 120 - 122° (fra ether-petrolether) . obtained by hydrolysis analogously to example 1d), melting point 120 - 122° (from ether-petroleum ether).

EKSEMPEL 4 EXAMPLE 4

[ 2- ( 2, 6- dikloranilino) - bromfenyl] - eddiksyre- methylester [ 2-( 2, 6- dichloroanilino) - bromophenyl] - acetic acid methyl ester

fremstilles analogt eksempel 1 og renses ved krystallisasjon fra ether-petrolether. is prepared analogously to example 1 and purified by crystallization from ether-petroleum ether.

Den tilsvarende syre oppnås på følgende måte: The corresponding acid is obtained in the following way:

~a) l-( 2, 6- diklorfenyl)- 5- brom- 2- indolinon ~a) 1-(2,6-dichlorophenyl)-5-bromo-2-indolinone

En oppløsning av 11,2 g l-(2,6-diklorfenyl)-2-indolinon (sml. eksempel 2a) - 2c)) i 700 ml ethanol tilsettes til en oppløsning av 8 g kaliumbromid og 2,08 g brom i 160 ml vann. Blandingen gjennomrystes kraftig og står deretter til henstand i 3 timer ved 0°. Ethanolen avdampes og det uoppløselige bunnfall frafiltreres fra den overskytende vandige oppløsning. Dette opptas i methylenklorid. Man tørker methylen-kloridoppløsningen over natriumsulfat og inndamper under 11 Torr til tørrhet. Resten består av en blanding, som inneholder 60% 1-(2, 6-diklorfenyl)-5-brom-2-indolinon. Dette renses ved gjentatt kromatografi på en silicagelkolonne og smelter, etter at A solution of 11.2 g of 1-(2,6-dichlorophenyl)-2-indolinone (cf. examples 2a) - 2c)) in 700 ml of ethanol is added to a solution of 8 g of potassium bromide and 2.08 g of bromine in 160 ml of water. The mixture is shaken vigorously and then allowed to stand for 3 hours at 0°. The ethanol is evaporated and the insoluble precipitate is filtered off from the excess aqueous solution. This is taken up in methylene chloride. The methylene chloride solution is dried over sodium sulphate and evaporated below 11 Torr to dryness. The remainder consists of a mixture containing 60% 1-(2,6-dichlorophenyl)-5-bromo-2-indolinone. This is purified by repeated chromatography on a silica gel column and melts, after which

det ble krystallisert flere ganger fra ether eller ether-petrolether, ved 188 - 190°. it was crystallized several times from ether or ether-petroleum ether, at 188 - 190°.

b) [ 2- ( 2, 6- dikloranilino) - 5- bromf enyl] - eddiksyre b) [ 2- ( 2, 6- dichloroanilino) - 5- bromophenyl] - acetic acid

oppnås fra forbindelsen i a) ved hydrolyse analogt eksempel ld) og renses ved obtained from the compound in a) by hydrolysis analogous to example ld) and purified by

krystallisasjon fra ether-petrolether. Den spalter seg ved 161°. crystallization from ether-petroleum ether. It splits at 161°.

EKSEMPEL 5 EXAMPLE 5

[o-( a , a , a- trif luor- m- toluidino) - fenyl] - eddiksyre- methylester [o-(a,a,a-trifluoro-m-toluidino)-phenyl]-acetic acid methyl ester

oppnås analogt eksempel 1 og renses ved destillasjon i stedet for ved krystallisasjon i høyvakuum, kp. 120°/0,01 Torr. is obtained analogously to example 1 and is purified by distillation instead of by crystallization in high vacuum, b.p. 120°/0.01 Torr.

Likeledes oppnår man analogt eksempel 1 [o-(6-methoxy-m-toluidino)-fenyl] - eddiksyre-methylester en. Likewise, one obtains analogously to example 1 [o-(6-methoxy-m-toluidino)-phenyl]-acetic acid methyl ester one.

De som utgangsstoffer nødvendige syrer fremstilles f. eks. på følgende måte: The acids required as starting materials are produced, e.g. in the following way:

a) o- ( a , a , o- trifluor- m- toluidino) - benzylalkohol a) o-(a,a,o-trifluoro-m-toluidino)-benzyl alcohol

Til en oppløsning av 3,8 natriumborhydrid i 160 ml vannfri diglyme (diethyl-englykol-dimethylether) tilsettes 8,7 g lithiumbromid. Man rører blandingen i en 1/2 time ved værelsetemperatur. Deretter tilsettes dråpevis en oppløsning av 14,8 g N-(a,a,a-trifluor-m-tolyl)-anthranilsyre-methylester i 40 ml vannfri diglyme. Så oppvarmer man i 3 timer ved 100°, avkjøler og heller på en blanding av 300 g is og 30 ml konsentrert saltsyre. Etter kort røring ekstraherer man den utskilte olje med 300 ml ethylacetat. Ethylacetatoppløsningen vaskes med 2-n kaliumbicarbonat-oppløsning og vann, tørkes over natriumsulfat og inndampes under 11 Torr ved 40°. Resten destilleres fraksjonert over en kort Vigreuxkolonne. o-fa.a.a-trifluor-m-toluidino)-benzylalkoholen koker ved 127 - 129°/0,001 Torr. Utbytte utgjør 75% av teorien. 8.7 g lithium bromide is added to a solution of 3.8 sodium borohydride in 160 ml anhydrous diglyme (diethyl-englycol-dimethylether). The mixture is stirred for 1/2 hour at room temperature. A solution of 14.8 g of N-(α,α,α-trifluoro-m-tolyl)-anthranilic acid methyl ester in 40 ml of anhydrous diglyme is then added dropwise. It is then heated for 3 hours at 100°, cooled and poured onto a mixture of 300 g of ice and 30 ml of concentrated hydrochloric acid. After brief stirring, the separated oil is extracted with 300 ml of ethyl acetate. The ethyl acetate solution is washed with 2-n potassium bicarbonate solution and water, dried over sodium sulphate and evaporated below 11 Torr at 40°. The remainder is fractionally distilled over a short Vigreux column. The o-fa.a.a-trifluoro-m-toluidino)-benzyl alcohol boils at 127-129°/0.001 Torr. Yield makes up 75% of the theory.

Analogt oppnås o-(6-methoxy-m-toluidino)-benzylalkoholen med smeltepunkt 138 - 139° (fra methanol). Analogously, the o-(6-methoxy-m-toluidino)-benzyl alcohol with melting point 138 - 139° (from methanol) is obtained.

b) q- klor- N- ( a , a , q- trifluor- m- tolyl) - aceto- o- toluidid b) q-chloro-N-(a,a,q-trifluoro-m-tolyl)-aceto-o-toluidide

En oppløsning av 23 g o-( a, a,a-trifluor-m-toluidino) -benzylalkohol i 70 ml A solution of 23 g o-(α,α,α-trifluoro-m-toluidino)-benzyl alcohol in 70 ml

acetylklorid oppvarmes under nitrogen i 1 time ved koking under tilbakeløp. Den orangefargede oppløsning konsentreres derpå under 11 Torr og en badetemperatur påj acetyl chloride is heated under nitrogen for 1 hour by refluxing. The orange-coloured solution is then concentrated below 11 Torr and a bath temperature of

40°. Resten oppløses i 150 ml ethylacetat-ether 1:1. Den organiske fase vaskes med 20 ml 2-n kaliumbicarbonatoppløsning og 20 ml vann, tørkes over natriumsulfat og inndampes under vakuum. Tilbake blir en lys olje, som krystalliserer fra ether-petrolether. Det erholdte a-klor-N-(a,a,a-trifluor-m-tolyl) -aceto-o-toluidid smelter ved 83 - 85°. 40°. The residue is dissolved in 150 ml of ethyl acetate-ether 1:1. The organic phase is washed with 20 ml of 2-n potassium bicarbonate solution and 20 ml of water, dried over sodium sulphate and evaporated under vacuum. A light oil is left behind, which crystallizes from ether-petroleum ether. The α-chloro-N-(α,α,α-trifluoro-m-tolyl)-aceto-o-toluidide obtained melts at 83-85°.

Analogt oppnår man a-klor-N-(6-methoxy-m-tolyl)-aceto-o-toluidid med smeltepunkt 121 - 123° (fra ether-petrolether). Analogously, α-chloro-N-(6-methoxy-m-tolyl)-aceto-o-toluidide is obtained with melting point 121 - 123° (from ether-petroleum ether).

c) a- cyano- N-( a, a, q- trifluor- m- tolyl)- aceto- o- toluidid c) a-cyano-N-(a,a,q-trifluoro-m-tolyl)-aceto-o-toluidide

Til en suspensjon av 2,2 g natriumcyanid i 20 ml dimethylsulfoxyd tilsettes To a suspension of 2.2 g of sodium cyanide in 20 ml of dimethylsulfoxide is added

ved 40° under røring en oppløsning av 11,6 g a-klor-N-( a, a, a-trifluor-m-tolyl)-aceto-o-toluidid i 60 ml dimethylsulfoxyd i løpet av 10 minutter. Temperaturen bør derved ikke overstige 40°. Deretter røres blandingen i 3 timer ved 40°, avkjøles til 10° og fortynnes med 200 ml vann. Oppløsningen ekstraheres fire ganger med 150 ml ethylacetat. De forente ethylacetatoppløsninger rystes med 200 ml 6-n saltsyre og tilslutt med 30 ml vann, tørkes så med natriumsulfat og inndampes under 11 Torr ved 40°. Det som gul olje tilbakeblivende a-cyano-N-(a, a, a-trifluor-m-tolyl)-aceto-o-toluidid kan arbeides direkte videre. at 40° with stirring a solution of 11.6 g of α-chloro-N-(α,α,α-trifluoro-m-tolyl)-aceto-o-toluidide in 60 ml of dimethylsulfoxide during 10 minutes. The temperature should therefore not exceed 40°. The mixture is then stirred for 3 hours at 40°, cooled to 10° and diluted with 200 ml of water. The solution is extracted four times with 150 ml of ethyl acetate. The combined ethyl acetate solutions are shaken with 200 ml of 6-n hydrochloric acid and finally with 30 ml of water, then dried with sodium sulphate and evaporated below 11 Torr at 40°. The α-cyano-N-(α,α,α-trifluoro-m-tolyl)-aceto-o-toluidide remaining as a yellow oil can be worked up directly.

Det analogt fremstilte a-cyano-N-(6-methoxy-m-tolyl)-aceto-o-toluidid smelter ved 108 - 109° (fra cyklohexan). The analogously prepared α-cyano-N-(6-methoxy-m-tolyl)-aceto-o-toluidide melts at 108 - 109° (from cyclohexane).

d) [ o- ( a, a , q- trif luor- m- toluidino) - fenyl] - eddiksyre d) [o-(a,a,q-trifluoro-m-toluidino)-phenyl]-acetic acid

9,5 g a-cyano-N-(a, a,a-trifluor-m-tolyl)-aceto-o-toluidid oppløses i 100 ml Dissolve 9.5 g of α-cyano-N-(α,α,α-trifluoro-m-tolyl)-aceto-o-toluidide in 100 ml

ethanol og 90 ml l-n natronlut. Oppløsningen kokes i 14 timer under tilbakeløp. Deretter avkjøler man og konsentrerer under 11 Torr ved 40° til ca. 70 ml. Den vandige, alkaliske oppløsning ekstraheres med 50 ml ether, denne etheroppløsning skilles fra, og den vandige fase ansyres med 2-n saltsyre. Man ekstraherer den sure oppløsning med ether, vasker etherekstraktet med vann, tørker det over natriumsulfat og konsentrerer det under 11 Torr uten oppvarmning. Resten krystalliserer fra ether-petrolether. Etter omkrystallisasjon fra ether-petrolether smelter [o-a, a, a-trif luor-m-toluidino) -fenyl]-eddiksyren ved 112 - 114°. Utbytte utgjør 35% av teorien. ethanol and 90 ml l-n caustic soda. The solution is boiled for 14 hours under reflux. It is then cooled and concentrated below 11 Torr at 40° to approx. 70 ml. The aqueous, alkaline solution is extracted with 50 ml of ether, this ether solution is separated, and the aqueous phase is acidified with 2-N hydrochloric acid. The acidic solution is extracted with ether, the ether extract is washed with water, dried over sodium sulfate and concentrated below 11 Torr without heating. The residue crystallizes from ether-petroleum ether. After recrystallization from ether-petroleum ether, the [o-a,a,a-trifluoro-m-toluidino)-phenyl]-acetic acid melts at 112 - 114°. Yield makes up 35% of the theory.

På analog måte oppnår man [o-(6-methoxy-m-toluidino)-fenyl]-eddiksyren, smeltepunkt 105 - 107° (fra ether). [o-(6-methoxy-m-toluidino)-phenyl]-acetic acid is obtained in an analogous manner, melting point 105 - 107° (from ether).

EKSEMPEL 6 EXAMPLE 6

[ o-( a, q, a- trifluor- 6- klor- m- toluidino)- fenyl]- eddiksyre- methylester, smp. 45 - 47°, [o-(a,q,a-trifluoro-6-chloro-m-toluidino)-phenyl]-acetic acid methyl ester, m.p. 45 - 47°,

oppnås analogt eksempel 1 fra den tilsvarende syre. For fremstilling av syren kan nedenstående reaksjonsrekkefølge brukes: is obtained analogously to example 1 from the corresponding acid. For the production of the acid, the following reaction sequence can be used:

a) o-( q, a, a- trilfuor- 6- klor- m- toluidino)- benzylalkohol a) o-(q,a,a-trifluoro-6-chloro-m-toluidino)-benzyl alcohol

fremstilles ved å gå ut fra N-(a,a,a-trifluor-6-klor-m-tolyl)-anthranilsyre- is prepared by starting from N-(α,α,α-trifluoro-6-chloro-m-tolyl)-anthranilic acid-

methylester analogt eksempel 5a), smeltepunkt 100 - 101° fra petrolether. methyl ester analogous to example 5a), melting point 100 - 101° from petroleum ether.

b) q- klor- N- ( a , q, q- trif luor- 6- klor- m- tolyl) - o- toluidin b) q-chloro-N-(a,q,q-trifluoro-6-chloro-m-tolyl)-o-toluidine

En oppløsning av 20g o-(a,a,a-trifluor-6-klor-m-toluidino)-benzylalkohol i A solution of 20 g of o-(α,α,α-trifluoro-6-chloro-m-toluidino)-benzyl alcohol in

70~ml acetylklorid kokes i nitrogenatmosfære i 16 timer under tilbakeløp. Deretter inndampes oppløsningen ved ca. 40° under forminsket trykk. Resten opptas i 40 ml benzol og inndampes ennå en gang. Så opptar man resten med 200 ml ether, vasker den etheriske oppløsning med 2-n natriumcarbonatoppløsning og vann, tørker den over natriumsulfat og avdamper oppløsningsmidlet under forminsket trykk. Den overskytende olje destilleres i høyvakuum, kp. 120°/0,001 Torr. a-klor-N-(a,a,a-trifluor-6-klor-m-tolyl)-o-toluidinet lar seg krystallisere fra petrolether, smeltepunkt 50 - 51°. Utbyttet utgjør 32% av teorien. 70~ml of acetyl chloride is boiled in a nitrogen atmosphere for 16 hours under reflux. The solution is then evaporated at approx. 40° under reduced pressure. The residue is taken up in 40 ml of benzene and evaporated once more. The residue is then taken up with 200 ml of ether, the ethereal solution is washed with 2-n sodium carbonate solution and water, dried over sodium sulphate and the solvent is evaporated under reduced pressure. The excess oil is distilled in high vacuum, bp. 120°/0.001 Torr. The a-chloro-N-(a,a,a-trifluoro-6-chloro-m-tolyl)-o-toluidine can be crystallized from petroleum ether, melting point 50 - 51°. The yield is 32% of the theory.

c) a- cyano- N- ( a, a, a- trif luor- 6- klor- m- tolyl) - o- toluidin c) a-cyano-N-(a,a,a-trifluoro-6-chloro-m-tolyl)-o-toluidine

En suspensjon av 6 g natriumcyanid i 120 ml dimethylsulfoxyd oppvarmes ved A suspension of 6 g of sodium cyanide in 120 ml of dimethylsulfoxide is heated at

40°. Så tilsettes under røring en oppløsning av 33 g a-klor-N-(a,a,a-trifluor-6-klor-m-tolyl)-o-toluidin i 150 ml dimethylsulfoxyd, hvorved temperaturen ikke skal overstige 40°. Man rører blandingen i 3 timer ved 40° og fortynner den deretter med 600 ml vann. Oppløsningen ekstraheres derpå, tre ganger hver gang med 1000 ml ethylacetat. Så vasker man de forente uttrekk med 100 ml 6-n saltsyre og 100 ml vann, tørker dem over natriumsulfat og destillerer oppløsningsmidlet av under forminsket trykk. Resten destilleres under høyvakuum. a-cyano-N-(a,a,a-trifluor-6-klor-m-tolyl)-o-toluidinet koker ved 122 - 126°/0,01 Torr og kan krystalliseres fra petrolether. Etter omkrystallisasjon ligger smeltepunktet ved 58 - 59°. Utbyttet utgjør 74% av teorien. 40°. A solution of 33 g of α-chloro-N-(α,α,α-trifluoro-6-chloro-m-tolyl)-o-toluidine in 150 ml of dimethylsulfoxide is then added while stirring, whereby the temperature should not exceed 40°. The mixture is stirred for 3 hours at 40° and then diluted with 600 ml of water. The solution is then extracted three times each time with 1000 ml of ethyl acetate. The combined extracts are then washed with 100 ml of 6-n hydrochloric acid and 100 ml of water, dried over sodium sulphate and the solvent is distilled off under reduced pressure. The remainder is distilled under high vacuum. The α-cyano-N-(α,α,α-trifluoro-6-chloro-m-tolyl)-o-toluidine boils at 122 - 126°/0.01 Torr and can be crystallized from petroleum ether. After recrystallization, the melting point is 58 - 59°. The yield is 74% of the theory.

d) [ o-( a, q, a- trifluor- 6- klor- m- tolyl)- fenyl]- eddiksyre d) [o-(a,q,a-trifluoro-6-chloro-m-tolyl)-phenyl]-acetic acid

En oppløsning av 18,4 g a-cyano-N-(<q>,<q>,a-trifluor-6-klor-m-tolyl)-o-toluidin A solution of 18.4 g of α-cyano-N-(<q>,<q>,α-trifluoro-6-chloro-m-tolyl)-o-toluidine

i 120 ml l-n natronlut og 120 ml ethanol kokes i 10 timer under tilbakeløp. Deretter konsentreres reaksjonsoppløsningen ved 40° under forminsket trykk til et volum på ca. 80 ml, og den vandige oppløsning ekstraheres med 100 ml ether. Den vandig, alkaliske fase ansyres så ved 5° med 2-n saltsyre, og den utfelte olje opptas i ether. Ether-oppløsningen skilles fra, vaskes med vann, tørkes over natriumsulfat og konsentreres uten oppvarmning ved forminsket trykk. Ved tilsetning av petrolether krystalliserer [o-(<q>,<q>,Q(-trifluor-6-klor-m-toluidino)-fenyl]-eddiksyren ut, smeltepunkt 94 - 96°. Utbytte 55% av teorien. in 120 ml 1-n caustic soda and 120 ml ethanol are boiled for 10 hours under reflux. The reaction solution is then concentrated at 40° under reduced pressure to a volume of approx. 80 ml, and the aqueous solution is extracted with 100 ml of ether. The aqueous, alkaline phase is then acidified at 5° with 2-n hydrochloric acid, and the precipitated oil is taken up in ether. The ether solution is separated, washed with water, dried over sodium sulfate and concentrated without heating under reduced pressure. On addition of petroleum ether, the [o-(<q>,<q>,Q(-trifluoro-6-chloro-m-toluidino)-phenyl]-acetic acid crystallizes out, melting point 94 - 96°. Yield 55% of theory.

EKSEMPEL 7 EXAMPLE 7

[ o- ( 2, 6- dikloranilino) - fenyl] - eddiksyre- ethylester [o-(2,6-dichloroanilino)-phenyl]-acetic acid ethyl ester

En oppløsning av 16 g [o-(2,6-dikloranilino)-fenyl]-eddiksyre (sml. eksempel 2d) i 1600 ml vann og 40 ml 2-n natron-lut avkjøles til 5°. Man tilsetter under røring 10 ml diethylsulfat, hvorved oppløsningen avkjøles med et isbad. Man rører i 2 timer ved 5 - 10° og tilsetter så ennå en gang 20 ml 2-n natronlut og 10 ml diethylsulfat. Deretter røres reaksjonsblandingen i 15 timer ved værelsetemperatur. De utfelte krystallene filtreres fra, vaskes godt med vann og oppløses i 100 ml ether. Man ekstraherer den etheriske oppløsning med 30 ml vann, tørker den over natriumsulfat og inndamper den under forminsket trykk ved 40°. [o-(2, 6-dikloranilino)-fenyl]-eddiksyre-ethylesteren krystalliserer fra ether-petrolether, smp. 50 - 52°. Utbyttet ut-gjør 15% av teorien. A solution of 16 g of [o-(2,6-dichloroanilino)-phenyl]-acetic acid (cf. example 2d) in 1600 ml of water and 40 ml of 2-n sodium hydroxide solution is cooled to 5°. 10 ml of diethyl sulphate is added while stirring, whereby the solution is cooled with an ice bath. The mixture is stirred for 2 hours at 5 - 10° and then 20 ml of 2-N caustic soda and 10 ml of diethyl sulphate are added once more. The reaction mixture is then stirred for 15 hours at room temperature. The precipitated crystals are filtered off, washed well with water and dissolved in 100 ml of ether. The ethereal solution is extracted with 30 ml of water, dried over sodium sulphate and evaporated under reduced pressure at 40°. The [o-(2,6-dichloroanilino)-phenyl]-acetic acid ethyl ester crystallizes from ether-petroleum ether, m.p. 50 - 52°. The yield makes up 15% of the theory.

På analog måte kan, ved å gå ut fra de i eksemplene 1 og 3 til 6 som utgangsstoffer anvendte syrer, de følgende estere fremstilles: In an analogous way, by proceeding from the acids used as starting materials in examples 1 and 3 to 6, the following esters can be prepared:

[o- (2, 6-diklor-m-toluidino) -fenyl] -eddiksyre-ethylester, [o-(2,6-dichloro-m-toluidino)-phenyl]-acetic acid ethyl ester,

[2- (2,6-diklor-m-toluidino) -5-methoxyfenyl] -eddiksyre-ethylester, [2-(2,6-dichloro-m-toluidino)-5-methoxyphenyl]-acetic acid ethyl ester,

[2- (2,6-dikloranilino) -5-klorfenyl]-eddiksyre-ethylester, [2-(2,6-dichloroanilino)-5-chlorophenyl]-acetic acid ethyl ester,

[2- (2,6-diklor-m-toluidino) -5-klorfenyl] -eddiksyre-ethylester, [2-(2,6-dichloro-m-toluidino)-5-chlorophenyl]-acetic acid ethyl ester,

[2- (2,6-dikloranilino) -5-bromf enyl] -eddiksyre-ethylester, [2-(2,6-dichloroanilino)-5-bromophenyl]-acetic acid ethyl ester,

[o-( a, a, o-trifluor-m-toluidino) -fenyl]-eddiksyre-ethylester, [o-(a,a,o-trifluoro-m-toluidino)-phenyl]-acetic acid ethyl ester,

[o- ( a, a, a-trifluor-6-klor-m-toluidino) -fenyl] -eddiksyre-ethylester, o-(2,6-xylidino)-fenyleddiksyre-ethylester, smp. 56 - 57°. [o-(α,α,α-trifluoro-6-chloro-m-toluidino)-phenyl]-acetic acid ethyl ester, o-(2,6-xylidino)-phenylacetic acid ethyl ester, m.p. 56 - 57°.

EKSEMPEL 8 EXAMPLE 8

[ o- ( 2, 6- dikloranilino) - fenyl] - eddiksyre- benzylester [o-(2,6-dichloroanilino)-phenyl]-acetic acid benzyl ester

En oppløsning av 2,96 g [o-(2,6-dikloranilino)-fenyl]-eddiksyre (sml. eksempel 2d), 1,2 g absolutt benzylalkohol og 3 g dimethylformamid-dineopentylacetal (1,1-dineopentyloxy-trimethylamin) i 40 ml methylenklorid røres under nitrogen i 55 timer. Deretter avdestilleres under 12 Torr methylenkloridet. Man fortynner med 50 ml ethylacetat, ekstraherer oppløsningen med vann og tørker den over natriumsulfat. A solution of 2.96 g of [o-(2,6-dichloroanilino)-phenyl]-acetic acid (cf. example 2d), 1.2 g of absolute benzyl alcohol and 3 g of dimethylformamide-dineopentyl acetal (1,1-dineopentyloxy-trimethylamine) in 40 ml of methylene chloride is stirred under nitrogen for 55 hours. The methylene chloride is then distilled off under 12 Torr. Dilute with 50 ml of ethyl acetate, extract the solution with water and dry it over sodium sulphate.

Man konsentrerer oppløsningen under 11 Torr ved 40° til tørrhet. Resten kromatograferer man på 60 g nøytralt aluminiumoxyd. Fraksjonene 2 og 3, eluert med ether-petrolether 7:3, inneholder den rene [o-(2,6-dikloranilino)-fenyl]-eddiksyre-benzylester. Utbyttet utgjør 30% av teorien. The solution is concentrated below 11 Torr at 40° to dryness. The residue is chromatographed on 60 g of neutral aluminum oxide. Fractions 2 and 3, eluted with ether-petroleum ether 7:3, contain the pure [o-(2,6-dichloroanilino)-phenyl]-acetic acid benzyl ester. The yield is 30% of the theory.

EKSEMPEL 9 EXAMPLE 9

[ o- ( 2, 6- dikloranilino) - fenyl] - eddiksyre- benzylester [o-(2,6-dichloroanilino)-phenyl]-acetic acid benzyl ester

Til 40 ml absolutt benzylalkohol lar man ved -10° under god røring og innled-ning av nitrogen tildryppe 6 ml thionylklorid. Etter 5 minutter tildryppes ved -10° 6 ml of thionyl chloride is added dropwise to 40 ml of absolute benzyl alcohol at -10° with good stirring and the introduction of nitrogen. After 5 minutes, add dropwise at -10°

en oppløsning av 2,96 g [o-(2,6-dikloranilino)-fenyl]-eddiksyre (sml. eksempel 2d) i 10 ml absolutt benzylalkohol. Deretter rører man reaksjonsblandingen i 15 timer ved værelsetemperatur og heller på is. Man ekstraherer den utfelte olje med 100 ml ether. a solution of 2.96 g of [o-(2,6-dichloroanilino)-phenyl]-acetic acid (cf. example 2d) in 10 ml of absolute benzyl alcohol. The reaction mixture is then stirred for 15 hours at room temperature and poured onto ice. The precipitated oil is extracted with 100 ml of ether.

Etheruttrekket vasker man med 10 ml 2-n kaliumbicarbonatoppløsning og vann, tørker The ether extract is washed with 10 ml of 2-n potassium bicarbonate solution and water, dried

det over natriumsulfat og inndamper etheroppløsningen under 11 Torr ved 40° til tørr- over sodium sulfate and evaporate the ether solution below 11 Torr at 40° to dryness

het. Resten kromatograferer man på 90 g nøytralt aluminiumoxyd. Fraksjonene 1 og 2, eluert med ether-petrolether 1:1, inneholder den rene [o-(2,6-dikloranilino) -fenyl] - hot. The residue is chromatographed on 90 g of neutral aluminum oxide. Fractions 1 and 2, eluted with ether-petroleum ether 1:1, contain the pure [o-(2,6-dichloroanilino)-phenyl]-

eddiksyre-benzylester. Utbyttet utgjør 48% av teorien. acetic acid benzyl ester. The yield is 48% of the theory.

EKSEMPEL 10 EXAMPLE 10

Analogt eksempel 1 oppnår man: Analogous to example 1, one achieves:

o-(6-klor-o-toluidino)-fenyleddiksyre-methylester, smp. 97 - 99°, ved å gå ut fra o-(6-klor-o-toluidino)-fenyleddiksyre, smp. 140 - 147°. o-(6-chloro-o-toluidino)-phenylacetic acid methyl ester, m.p. 97 - 99°, starting from o-(6-chloro-o-toluidino)-phenylacetic acid, m.p. 140 - 147°.

o-(2, 6-x<y>lidino)-fen<y>leddiks<y>re-meth<yl>ester, smp. 79 - 81°, ved å gå ut fra o-(2,6-xylidino)-fenyleddiksyre, smp. 120 - 127°. o-(2, 6-x<y>lidino)-phen<y>leddix<y>re-meth<yl>ester, m.p. 79 - 81°, starting from o-(2,6-xylidino)-phenylacetic acid, m.p. 120 - 127°.

o-(2-methyl-3-klor-anilino)-fenyleddiksyre-methylester, smp. 47 - 48°, ved å gå ut fra o-(2-methyl-3-klor-anilino)-fenyleddiksyre, smp. 124 - 125°. o-(2,3-xylidino)-fenyleddiksyre-methylester, smp. 52 - 54°, ved å gå ut fra o-(2,3-xylidino)-fenyleddiksyre, smp. 112 - 113°. o-(2-methyl-3-chloro-anilino)-phenylacetic acid methyl ester, m.p. 47 - 48°, starting from o-(2-methyl-3-chloro-anilino)-phenylacetic acid, m.p. 124 - 125°. o-(2,3-xylidino)-phenylacetic acid methyl ester, m.p. 52 - 54°, starting from o-(2,3-xylidino)-phenylacetic acid, m.p. 112 - 113°.

[o-(2,6-xylidino)-fenyl]-eddiksyre-ethylester, smp. 56 - 57°, ved å gå ut fra 7,4 g [o-(2,6-xylidino)-fenyl]-eddiksyre, smp. 120 - 127°. [o-(2,6-xylidino)-phenyl]-acetic acid ethyl ester, m.p. 56 - 57°, starting from 7.4 g of [o-(2,6-xylidino)-phenyl]-acetic acid, m.p. 120 - 127°.

Claims (1)

Fremgangsmåte for fremstilling av hittil ukjente, terapeutisk virksomme fenyleddiksyreestere med den generelle formel (I),Process for the production of hitherto unknown, therapeutically effective phenylacetic acid esters with the general formula (I), hvor R., betyr en lavere alkyl- eller alkoxygruppe, et fluor-, klor- eller bromatom eller trifluormethylgruppen, Rg hydrogen eller en substituent tilsvarende definisjonen for R^, Rg hydrogen, en lavere alkyl- eller alkoxygruppe eller et fluor-, klor- eller bromatom, R^ hydrogen, en lavere alkyl- eller alkoxygruppe, et fluor-, klor- eller bromatom eller trif luormethylgruppen, og R^ betyr en lavere alkyl- eller fenyl-(lavere alkyl)-gruppe, karakterisert ved at en syre med den generelle formel (II), hvor R^, Rg, Rg, og R^ har den under formel (D angitte betydning, eller et funksjonelt derivat derav forestres med en alkohol med den generelle formel hvor R^ har den under formel®angitte betydning, eller et funksjonelt derivat derav, idet man a) omsetter syren med et lavere diazoalkan i et inert oppløsningsmiddel; b) omsetter syren i et inert oppløsningsmiddel med et 1 ,l-di-(lavere-alkoxy)-trimethylamin eller et 1,1-di[fenyl-(lavere alkoxy)[-trimethylamin; c) omsetter syren med en lavere alkanol eller med benzyl-alkohol i nærvær av 1,1-dineopentyloxy-trimethylamin; d) omsetter et salt av syren med et halogenid, sulfat eller sulfonat, av en lavere -alkanol eller fenyl-(lavere alkanol); eller e) behandler syren med en blanding bestående av en lavere alkanol eller fenyl-(lavere alkanol) og tionylklorid ved en temperatur på høyst -5°C.where R., means a lower alkyl or alkoxy group, a fluorine, chlorine or bromine atom or the trifluoromethyl group, Rg hydrogen or a substituent corresponding to the definition for R^, Rg hydrogen, a lower alkyl or alkoxy group or a fluorine, chlorine- or bromine atom, R^ is hydrogen, a lower alkyl or alkoxy group, a fluorine, chlorine or bromine atom or the trifluoromethyl group, and R^ means a lower alkyl or phenyl-(lower alkyl) group, characterized in that an acid with the general formula (II), where R^, Rg, Rg, and R^ has the meaning given under formula (D, or a functional derivative thereof is esterified with an alcohol of the general formula where R^ has the meaning given under formula®, or a functional derivative thereof, by a) reacting the acid with a lower diazoalkane in an inert solvent; b) reacting the acid in an inert solvent with a 1,1-di-(lower alkoxy)-trimethylamine or a 1,1-di[phenyl-(lower alkoxy)[-trimethylamine; c) reacting the acid with a lower alkanol or with benzyl alcohol in the presence of 1,1-dineopentyloxy-trimethylamine; d) reacts a salt of the acid with a halide, sulfate or sulfonate, of a lower -alkanol or phenyl-(lower alkanol); or e) treating the acid with a mixture consisting of a lower alkanol or phenyl-(lower alkanol) and thionyl chloride at a temperature of at most -5°C.