NO147747B

NO147747B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE 1-OXO-5-INDANYLOXY ACETIC ACIDS, AND SALTS THEREOF WITH BASES

Info

Publication number: NO147747B
Application number: NO743495A
Authority: NO
Inventors: Edward Jethro Cragoe Jr; Otto William Woltersdorf Jr; Warren Kenneth Russ Jr; George Gustave Hazen; Earl Martin Chamberlin
Original assignee: Merck & Co Inc
Priority date: 1973-10-11
Filing date: 1974-09-27
Publication date: 1983-02-28
Also published as: DK506674A; NO147747C; FI278974A; NO743495L; SE423990B; SE7412046L; FI61866C; DK143553B; FI61866B; DK143553C

Description

Foreliggende oppfinnelse angår en analogifremgangsmåte The present invention relates to an analog method

ved fremstilling av nye l-oxo-5-indanyloxy-eddiksyrer og salter derav med baser, hvilke forbindelser er disubstituert i 2-stillingen. Disse forbindelser oppviser verdifulle terapeutiske egenskaper, idet de oppviser diuretisk, saluretisk og urico- in the preparation of new l-oxo-5-indanyloxy-acetic acids and their salts with bases, which compounds are disubstituted in the 2-position. These compounds exhibit valuable therapeutic properties, exhibiting diuretic, saluretic and urico-

surisk aktivitet. suric activity.

Fra tysk offentliggjørelsesskrift 1 958 918 er kjent lignende forbindelser som imidlertid er indenyloxyforbindelser som således i 2-stillingen har bare én substituent og har en dobbeltbinding i ringen, mens der fra tysk offentliggjørelses-skrift 1 958 919 er kjent indanyloxyforbindelser som imidlertid skiller seg fra foreliggende fremgangsmåteforbindelser ved at de i 2-stillingen har et dobbeltbundet substituert carbonatom. Similar compounds are known from German publication 1 958 918 which are, however, indenyloxy compounds which thus have only one substituent in the 2-position and have a double bond in the ring, while from German publication 1 958 919 indanyloxy compounds are known which, however, differ from the present method compounds in that they have a doubly bonded substituted carbon atom in the 2-position.

Disse kjente forbindelser har samme type aktivitet som These known compounds have the same type of activity as

foreliggende fremgangsmåteforbindelser, men i. svakere grad. present process compounds, but to a lesser extent.

De ved foreliggende fremgangsmåte fremstilte forbindelser har den generelle formel I som angitt i kravet. Forbindelsene har vist seg å være effektive diuretiske og saluretiske midler, som kan anvendes ved behandling av sykdommer som er led-saget av elektrolytt- og væskeretensjon. Forbindelsene er også nyttige ved behandling av hypertensjon. Dessuten er disse forbindelser i stand til å opprettholde urinsyrekonsentrasjonen i legemet på et forutbestemt nivå eller endog å bevirke en ned-settelse i urinsyrekonsentrasjonen når de administreres i terapeutiske doser i konvensjonelle bæremedier. The compounds produced by the present process have the general formula I as stated in the claim. The compounds have been shown to be effective diuretic and saluretic agents, which can be used in the treatment of diseases accompanied by electrolyte and fluid retention. The compounds are also useful in the treatment of hypertension. Moreover, these compounds are able to maintain the uric acid concentration in the body at a predetermined level or even to cause a decrease in the uric acid concentration when administered in therapeutic doses in conventional carriers.

Mange av de for tiden tilgjengelige diuretica og saluretica har en tilbøyelighet til ved administrasjon å be- Many of the currently available diuretics and saluretics have a tendency to be

virke hyperuricemia hvorved kan felles urinsyre eller natrium-urat eller begge deler i legemet, hvilket kan bevirke milde eller alvorlige tilfeller av gikt. Fremgangsmåteforbindelsene er effektive til å behandle pasienter som krever diuretisk og saluretisk behandling uten å løpe faren for å fremkalle gikt. cause hyperuricemia, whereby uric acid or sodium urate or both can accumulate in the body, which can cause mild or severe cases of gout. The method compounds are effective in treating patients who require diuretic and saluretic therapy without running the risk of inducing gout.

Når de anvendes i passende doser, virker fremgangsmåteforbindelsene endog som uricosure midler. When used in appropriate doses, the process compounds even act as uricosuric agents.

Fremgangsmåten ifølge oppfinnelsen kjennetegnes ved de The method according to the invention is characterized by the

i karakteristikken til kravet anførte trekk. features stated in the characteristics of the claim.

Særlig foretrekkes det å. fremstille l-oxo-5-indanyloxy-eddiksyrer og farmakologisk godtagbare salter derav med formelen: It is particularly preferred to prepare l-oxo-5-indanyloxy-acetic acids and pharmacologically acceptable salts thereof with the formula:

hvor R 2 'er alkyl med 1-3 carbonatomer, som methyl, ethyl, n-propyl eller isopropyl, X"<*>" er methyl eller klor? og X er hydrogen, klor eller fluor, og farmasøytisk godtagbare salter derav. ;Den ovenfor angitte gruppe av forbindelser oppviser optimal diuretisk og saluretisk aktivitet, samtidig som den ikke endrer urinsyrekonsentrasjonen eller bevirker en ned-settelse av denne. ;Oppfinnelsen angår en rekke alternative fremgangsmåter. Ifølge en slik utførelsesform utføres en 2-alkylering av en 1-oxo-5-indanoyloxy-eddiksyre eller en ester derav med formelen III med et alkyleringsmiddel med formelen R 2z, hvor Z er halogen. Denne reaksjon utføres f.eks. ved å behandle l-oxo-5-indanyloxy-eddiksyren eller esteren derav med en base, f.eks. et alkali-metallhydrid, som natriumhydrid, eller et alkalimetallalkoxyd, f.eks. kalium-t-butoxyd eller natriummethoxyd, eller alkali-metallamider, som natriumamid eller lithiumamid. Det dannede carbanion behandles derefter med alkyleringsmidlet R^Z. Et vilkårlig oppløsningsmiddel som er inert eller i det vesentlige inert overfor de anvendte reagenser, kan anvendes. Eksempler på egnede oppløsningsmidler er 1,2-dimethoxyethan, t-butanol, benzen eller dimethylformamid. Reaksjonen kan ut-føres ved en temperatur på mellom 0°C og 150°C. Reaksjonen ut-føres generelt ved en temperatur på 0-50°C. Følgende ligning illustrerer denne fremgangsmåte: ;112 3 ;hvor X , R og R er som angitt i kravet, og R er hydrogen eller alkyl. ;En annen metode for fremstilling av de omhandlede 1-oxo-5-indanyloxy-eddiksyrer består i å omsette en halogeneddik-syre eller en ester derav med formelen: ;R<3>OOC-CH2-Z ;med en tilsvarende forbindelse IV: ;;112 3 ;hvor X , R , R , R og Z er som angitt i kravet. ;Generelt kan reaksjonen utføres i nærvær av en base, som et alkalimetallcarbonat, -hydroxyd eller -alkoxyd, som kaliumcarbonat, natriumcarbonat, kaliumhydroxyd, natriumhydroxyd eller natriummethoxyd. Der kan anvendes et vilkårlig oppløsningsmiddel som er inert eller i det vesentlige inert overfor reagensene, og hvori reagensene har en passende opp-løselighet. Aceton, ethanol og dimethylformamid er eksempler på særlig fordelaktige oppløsningsmidler. Reaksjonen kan ut-føres på en temperatur på mellom 25°C og kokepunktet for reaksjonsblandingen. Hvis halogeneddiksyreesteren anvendes, hydrolyseres den dannede ester til den frie syre på i og for seg kjent vis. Hvis R 3 er t-butyl, kan den dannede ester pyrolyseres katalytisk, som ved oppvarmning i nærvær av en sterk syre, f.eks. i nærvær av p-toluensulfonsyre, svovelsyre eller gass-formig hydrogenklorid. Vanligvis skjer pyrolysen ved oppvarmning til en temperatur på 70-140°C, fortrinnsvis 80-100°C. Pyrolysen kan utføres uten oppløsningsmiddel eller i nærvær av ;et passende, ikke-vandig medium, hvori reagensene har én passende oppløselighet, f.eks. i nærvær av benzen, toluen eller xylen. ;Hvis der i 2-stillingen av de omhandlede forbindelser ;er en alkoxy-substituert fenylgruppe, kan denne på i og for seg kjent vis overføres til en hydroxyfenylgruppe. Likeledes kan en nitrofenylgruppe i 2-stillingen i de omhandlede forbindelser på ;i og for seg kjent vis omdannes til en aminofenylgruppe. ;De frie syrer med formel I kan overføres til ugiftige farmakologisk godtagbare salter av alkalimetaller, jordalkalimetaller, andre metaller og aminer, som ammoniakk, primære og sekundære aminer og kvartære ammoniumhydroxyder. Særlig fore-trukne metallkationer er avledet av alkalimetaller, f.eks. natrium, kalium eller lithium, og jordalkalimetaller, f.eks. calcium eller magnesium, og andre metaller, f.eks. aluminium, jern og zink. Disse salter fremstilles på i og for seg kjent vis. Således vil syren ved omsetning med alkalimetall- eller jordalkalxmetallhydroxyder, -carbonater, -bicarbonater, aminer eller kvartære ammoniumhydroxyder, danne de tilsvarende alkalimetall-, jordalkalimetall-, amin- eller kvartære ammonium-salter. ;Farmasøytisk godtagbare salter kan som nevnt dannes av ammoniakk, primære, sekundære eller tertiære aminer eller kvartære ammoniumhydroxyder, som methylamin, dimethylamin, trimethyl-amin, ethylamin, N-methyl-hexylamin, benzylamin, a-fenethylamin, ethylendiamin, piperidin, 1-methylpiperazin, morfolin, pyrrolidin, 1,4-dimethylpiperazin, ethanolamin, diethanolamin, triethanol-amin, tris-(hydroxymethyl)-aminomethan, N-methylglucamin, N-methylglucosamin, efedrin, procain, tetramethylammonium-hydroxyd, tetraethylammoniumhydroxyd eller benzyltrimethyl-ammonium. ;De ovennevnte salter er særlig vel egnet som parenterale oppløsninger, da de er meget oppløselige i farmasøytiske bærere, som vann eller alkohol. ;De omhandlede forbindelser inneholder et asymmetrisk carbonatom i 2-stillingen av indanylringen, og de optisk aktive antipoder kan skilles, f.eks. ved de i det efterfølgende be-skrevne metoder. Oppfinnelsen omfatter således ikke bare fremstillingen av de racemiske l-oxo-5-indanyloxy-eddiksyrer, men også fremstillingen av deres optisk aktive antipoder. ;Adskillelse av de optiske isomerer av de racemiske syrer kan utføres ved å danne et salt av den racemiske blanding med en optisk aktiv base som (+)- eller (-)-amfetimin, (-)-cinchonidin, dehydroabiethylamin, (+)- elier (-)-a-methylbenzyl-amin, (+)- eller (-)-a-(1-nafthyl)-ethylamin, brucin eller stryknin, i et passende oppløsningsmiddel som methanol, ethanol, 2-propanol, benzen, azetonitril, nitromethan, aceton, Der dannes således i oppløsningen to diastereomere salter hvorav ett vanligvis er mere oppløselig i oppløsningsmidlet enn det annet. Gjentatte omkrystallisasjoner av det krystallinske salt gir i alminnelighet en ren diastereo-mer. Den optisk rene l-oxo-5-indanyloxy-eddiksyre fåes ved sur-gjøring av saltet med en mineralsyre, ekstraksjon i ether, for-dampning av oppløsningsmidlet og omkrystallisasjon av den optisk rene antipode. ;Den annen optisk rene antipode kan i alminnelighet fåes ved å anvende en annen base for å danne det diastereomere salt. Det er fordelaktig å isolere den delvis spaltede syre fra filtratene fra rensningen av det ene diastereomere salt og videre rense dette materiale ved anvendelse av en annen optisk aktiv base. ;Fremgangsmåten ifølge oppfinnelsen illustreres nærmere av de følgende eksempler: ;Eksempel 1 ;Fremstilling av (l-oxo-2-methyl-2-fenyl-6,7-diklor-5-indanyloxy- eddiksyre ;Trinn A: 2, 3- diklor- 5- fenylacetylanisol ;Til en omrørt blanding av 62 g (0,35 mol) 2,3-dikloranisol, 54 g (0,35 mol) fenylacetylklorid og 250 ml carbondisulfid tilsettes porsjonsvis 47 g (0,35 mol) aluminiumklorid under avkjøling ved 0 - 5° C. Reaksjonsblandingen hensettes ved 25° C i 17 timer, carbondisulfidet fjernet og residuet behandles med isvann og 50 ml konsentrert saltsyre hvorved man får 68,8 g 2,3-diklor-5-fenylacetylanisol som smelter ved 126 - 129° C ved omkrystallisasjon fra benzen:cyclohexan, 2:1. ;Elementæranalyse for c]_5Hi2C^2^2 : ;Beregnet: C 61,04, H 4,10 ;Funnet : C 61,45, H 4,11 ;Trinn B: 2, 3- diklor- 4-( 2- fenylacryloyl)- anisol ;100 ml eddiksyreanhydrid tilsettes dråpevis til en suspensjon av 29,5 g (0,01 mol) 2,3-diklor-4-fenylacetylanisol i 100 ml bis-(dimethylamino)-methan under nitrogen med avkjøling for å holde reaksjonsblandingens temperatur under 60° C. Reaksjonsblandingen omrøres ved 25° C i 2 timer, og helles i 1500 ml isvann for å felle 7,4 g 2,3-diklor-4-(2-fenylacryloyl)-anisol som smelter ved 87 - 89° C. ;Elementæranalyse for C^gH^C^0^5;Beregnet: C 62,56, H 3,94 ;Funnet : C 62,67, H 4,03 ;Trinn C: 2- fenyl- 5- methoxy- 6, 7- diklor- l- indanon ;7,4 g (0,024 mol) 2,3-diklor-4-(2-fenylacryloyl)-anisol ;tilsettes prosjonsvis til 150 ml kold, konsentrert svovelsyre under omrøring. Reaksjonsblandingen omrøres i et isbad i 2 timer, og tilsettes så dråpevis til isvann for å felle 3,91 g 2-fenyl-5-methoxy- ;6,7-diklor-l-indanon som smelter ved 193 - 195° C ved krystallisasjon fra benzen:cyclohexan, 1:2. ;Elementæranalyse for C-LgH12Cl202: ;Beregnet: C 62,56, H 3,94 ;Funnet : C 62,84, H 4,00 ;Trinn D: 2- fenyl- 5- hydroxy- 6, 7- diklor- l- indanon ;En blanding av 3,91 g (0,0127 mol) 2-fenyl-5-methoxy-6,7-diklor-l-indanon og 40 g pyridin-hydroklorid oppvarmes ved 19 0° C i 1 time, og heldes så i 600 ml vann. 2,48 g 2-fenyl-5-hydroxy-6,7-diklor-l-indanon som utskilles, smelter ved 250 - 252° C etter om-krystallisas jon fra ethanol:vann, 2:1. ;Elementæranalyse for C-^H^qCI,,!^ : ;Beregnet: C 61,46, H 3,44 ;Funnet : C 60,94, H 3,66 ;Trinn E: ( l- oxo- 2- fenyl- 6, 7- diklor- 5- indanyloxy)- eddiksyre ;5,86 g (0,023 mol) 2-fenyl-5-hydroxy-6,7-diklor -1-indanon, 4,28 g (0,023 mol) jodeddiksyre, 3,04 g (0,022 mol) kaliumcarbonat og 250 ml aceton oppvarmes under tilbakeløp i 48- timer. Reaksjonsblandingen avkjøles til 25° C, og inndampes i vakuum hvorved man får et fast produkt som oppløses i vann og syres med 6N saltsyre for å felle 6,8 g av en blanding av (l-oxo-2-fenyl-6,7-diklor-5-indanyl-oxy)-eddiksyre og 2-fenyl-5-hydroxy-6,7-diklor-l-indanon. Fenolen fjernes ved omkrystallisasjon fra nitromethan. Inndampning av fil-tratet til tørrhet i vakuum og triturering med toluen gir 470 mg (l-oxo-2-fenyl-6,7-diklor-5-indanyloxy)-eddiksyre som smelter ved 181 - 185° C. ;Elementæranalyse for C^^H^Cl,,!^: ;Beregnet: C 58,14, H 3,45, Cl 20,19 ;Funnet : C 58,17, H 3,54, Cl 19,94 ;Trinn F: ( l- oxo- 2- fenyl- 2- methyl- 6, 7- diklor- 5- indanyloxy)- eddiksyre ;En omrørt•oppløsning av 0,351 g (0,001 mol) (l-oxo-2-fenyl-6,7-diklor-5-indanyloxy)-eddiksyre i 7 ml dimethylformamid avkjøles i et isbad og behamdles med 0,084 g av en 57 %-ig olje-dispersjon (0,002 mol) av natriumhydrid og omrøres i 2 timer. 1 ml methyljodid tilsettes og reaksjonsblandingen omrøres ved 25° C i 2 timer, heldes i isvann og syres med fortynnet vandig saltsyre hvilket gir (l-oxo-2-fenyl-2-methyl-6,7-diklor-5-indanyloxy)-eddiksyre som smelter ved 168 - 169°C. ;Eksempel 2 ;Når der i eksempel 1, trinn A, istedenfor 2,3-dikloranisol anvendes en ekvivalent mengde av 2-methyl-3-kloranisol, ;og trinn B - F utføres som der beskrevet, fåes (l-oxo-2-fenyl-2,6-dimethyl-7-klor-5-indanyloxy)-eddiksyre med smp. 142 - 144°C. ;Eksempel 3 ;( l- oxo- 2- methyl- 2- fenyl- 6, 7- diklor- 5- indanyloxy)- eddiksyre ;Trinn A: 2', 3'- diklor- 4'- methoxyisobutyrofenon ;En omrørt blanding av 100 g (0,565 mol) 2,3-dikloranisol (I) og 66 g (0,62 mol) isobutyrylklorid (II) i 400 ml methylenklo-rid avkjøles til 5° C og behandles med 83 g (0,62 mol) aluminiumklorid i 1 time. Reaksjonsblandingen får lov til å oppvarmes til 25° c og etter 24 timer heldes den i 400 ml isvann og 30 ml saltsyre. Den organiske fase vaskes med 5 %-ig natriumhydroxyd, vann, tørres over magnesiumsulfat og destilleres under nedsatt trykk hvilket gir 68 g 2<1>,3<1->diklor-4<1->methoxyisobutyrofenon (III) som destillerer ved 120 - 130°C/0,5 mm. ;Elementæranalyse for ciiHx2C12°2: ;Beregnet: C 53,46, H 4,89 ;Funnet : C 54,25, H 5,07 ;Trinn B: 2- brom- 2', 3'- diklor- 4'- methoxyisobutyrofenon ;En omrørt oppløsning av 45 g (0,183 mol) 2<1>,3'-diklor-4'-methoxyisobutyrofenon i 150 ml eddiksyre behandles i \ time med 30 g (0,187 mol) brom. Reaksjonsblandingen omrøres i 10 minutter heldes så i 600 ml isvann inneholdende 2 g natriumbisulfit. 2-brom-2<1>,3'-diklor-4<1->methoxyisobutyrofenon (IV) som utskilles (48 g) smelter ved 72 - 73° C etter omkrystallisasjon fra hexan. Elementæranalyse for C-QH^BrC^C^ : ;Beregnet: C 40,52, H 3,40 ;Funnet : C 40,68, H 3,38 ;Trinn C: 2- methylen- 2' , 3'- diklor- 4'- methoxypropiofenon ;En oppløsning av 32 g (0,1 mol) 2-brom-2<1>,3<1->diklor-4'-methoxyisobutyrofenon og 17,4 g (0,2 mol) vannfritt lithiumbromid i 200 ml DMF omrøres ved 95° C i en inert atmosfære i 3 timer og heldes i 500 ml isvann. 2-methylen-2',3<1->diklor-4'-methoxypropio-fenonet (V) som utskilles, smelter ved 59° C etter omkrystållisa-sjon fra petroleumether. ;Elementæranalyse for C-^H^qC^O^ : ;Beregnet: C 53,90, H 4,11 ;Funnet : C 53,72, K 4,11 ;Trinn D: 2- methyl- 5- metho. xy- 6, 7- diklor- l- indanon ;En oppløsning av 40 g (0,163 mol) 2-methylen-2',3'-diklor-4 1 -methoxypropiof enon i 75 ml konsentrert svovelsyre tilsettes ved 25° C i 24 timer og heldes så langsomt i 500 ml isvann under kraftig omrøring. 40 g 2-methyl-5-methoxy-6,7-diklor-l-indanon som utskilles, smelter ved 129° C etter omkrystallisasjon fra methyl-cyclohexan, ;Elementæranalyse for C-^H^qC^O^: ;beregnet: C 53,90, H 4,11 ;Funnet : C 53,84, H 4,00 ;Trinn E: 2- methyl- 2- fenyl- 5- methoxy- 6, 7- diklor- l- indanon ;8,42 g (0,075 mol) kalium-t-butoxyd oppløst i 300 ml t-butanol tilsettes til en under tilbakeløp kokende oppløsning av 12,26 g (0,05 mol) 2-methyl-5-methoxy-6,7-diklor-l-indanon, til-bakeløpskokingen fortsettes i 2 timer, derpå tilsettes en suspensjon av 19,0 g (0,06 mol) difenyljodoniumklorid i 1 liter t-butanol og tilbakeløpskokingen fortsettes i 2 timer. Reaksjonsblandingen avkjøles til 25° C, 300 ml vann tilsettes og blandingen inndampes til tørrhet i vakuum hvorved man får 4,97 g 2-methyl-2-fenyl-5-methoxy-6,7-diklor-l-indanon som smelter ved 161 - 163° C etter krystallisasjon fra benzen:cyclohexan, 1:2. ;Elementæranalyse for C2. 1^ 1AC^ 2Q2: ;Beregnet: C 63,57, H 4,39 ;Funnet : C 63,24, H 4,68 ;Trinn F: 2- methyl- 2- fenyl- 5- hydroxv- 6, 7- diklor- l-indanon ;En omrørt blanding av 4,94 g (0,015 mol) 2-methyl-2-fenyl-5-methoxy-6,7-diklor-l-indanon og 50 g pyridin-hydroklorid oppvarmes ved 17 5° C i 1 time, og heldes så i 50 0 ml vann. 2,05 g 2-methyl-2-fehyl-5-hydroxy-6,7-diklor-l-indanon som utskilles, smelter ved 194 - 196° C etter omkrystallisasjon fra ethanol:vann, 2:1. ;Elementæranalyse for ci6H12C12°2<:>;Beregnet: C 62,56, H 3,94 ;Funnet : C 62,60, H 4,11 ;Trinn G: (l-oxo-2-methyl-2r-fenyl-6,7-diklor-5- iridanyloxyl- eddiksyré ;En omrørt blanding av 2,05 g (0,0067 mol) 2-methyl-2-fenyl-5-hydroxy-6,7-diklor-l-indanon, 1,85 g (0,0134 mol) kaliumcarbonat og 2,23 g (0,0134 mol) ethylbromacetat i 30 ml dimethylformamid oppvarmes ved 55 - 60° C i 3 timer, behandles med 0,97 g (0,0147 mol) kaliumhydroxyd oppløses i en minimal mengde vann i 39 ml methanol og oppvarmes på dampbad i 2,5 timer. Reaksjonsblandingen heldes i 500 ml vann, syres med 6N saltsyre og bunnfallet oppsamles etter triturering med ether-petrolether og tørres hvorved man får 1,31 g (l-oxo-2-methyl-2-fenyl-6,7-diklor-5-indanyl-oxy)-eddiksyre som smelter ved 168 - 169° C ved krystallisasjon fra eddiksyre:vann, 1:1. ;Elementæranalyse for C-^gH-^C^O^: ;Beregnet: C 59,20, H 3,86 ;Funnet : C 58,94, H 4,20 ;Eksempel 4 ;Fremstilling av [l-oxo-2-(4-klorfenyl)-2-methyl-6,7-diklor-5- indanyloxy3~ eddiksyre- hemihydrat ;Trinn A; 2-( 4- klorfenyl)- 2- nethyl- 5- methoxy- 6, 7- diklor- l- indanon ;2,81 g (0,025 mol) kalium-t-butoxyd oppløst i 150 ml t-butanol tilsettes til en under tilbakeløp kokende oppløsning av 4,90 g (0,02 mol) 2-methyl-5-methoxy-6,7-diklor-l-indanon i 100 ml t-butanol/200 ml benzen, tilbakeløpskpkningen fortsettes i 3 timer, derpå tilsettes 11,55 g (0,03 mol) 4,4'-diklor-difenyljodoniumklorid og tilbakeløpskokingen fortsettes i 2 timer. Reaksjonsblandingen avkjøles til 25° C, 100 ml vann tilsettes og blandingen inndampes til tørrhet i vakuum hvorved, man får 4,30 g 2-(4-klorfenyl)-2-methyl-5-methoxy-6,7-diklor-l-indanon som smelter ved 176 - 178° C etter krystallisasjon fra cyclohexan og benzen, 5:1. ;Trinn B: 2-( 4- klorfenyl)- 2- methyl- 5- hydroxy- 6, 7- diklor- l- indanon ;En omrørt blanding av 4,15 g (0,012 mol) 2-(4-klorfenyl)-2-methyl-5-methoxy-6,7-diklor-l-indanon og 40 g pyridin-hydroklorid oppvarmes ved 180° C i 1 time, og heldes så i 500 ml vann. 3,11 g 2-(4-klorfenyl)-2-methyl-5-hydroxy-6,7-diklor-l-indanon som utskilles smelter ved 211- 213° C etter krystallisasjon fra ethanol:vann. 1:1. ;Elementæranalyse for C-^gH^ClSC^: ;Beregnet: C 56,25, H 3,25 ;Funnet : C 55,53, H 3,23 ;Trinn C: (l-oxo-2-(4-klorfenyl)-2-methyl-6,7-diklor-5-indanyloxy^- eddiksyre- hemihydrat ;En omrørt blanding av 2,95 g (0,00863 mol) 2-(4-klor-fenyl)-2-methyl-5-hydroxy-6,7-diklor-l-indanon, 2,26 g (0,0163 mol) kaliumcarbonat og 2,72 g (0,0163 mol) ethylbromacetat i 50 ml dimethylformamid oppvarmes ved 55 - 60° C i 2 timer, behandles så med 50 ml vann og 2,5 ml (0,025 mol) 10N natriumhydroxydoppløsning, og oppvarmes ved 80° C i 1 time. Reaksjonsblandingen tilsettes langsomt til 500 ml vann og 10 ml 12N saltsyre for å felle 1,37 g (l-oxo-2-(4-klorfenyl)-2-methyl-6,7-diklor-5-indanyloxy)-eddiksyre-hemihydrat som smelter ved 141 - 142° C etter krystallisasjon fra eddiksyre:vann, 1:1. ;Elementæranalyse for C^gH^-jC^O^ • 1/2H20: ;Beregnet: C 52,90, H 3,45, Cl 26,03 ;Funnet : C 52,47, H 3,45, Cl 26,11 ;Eksempel 5 ;Fremstilling av (l-oxo-2-(4-methoxyfenyl)-2-methyl-6,7-diklor-5- indanyloxyV- eddiksyre ;Trinn A: 2- methyl- 5- hydroxy- 6, 7- diklor- l- indanon ;En omrørt blanding av 30,0 g (0,123 mol) 2-methyl-5-methoxy-6,7-diklor-l-indanon og 270 g pyridin-hydroklorid oppvarmes ved 180° C i 1 time, og heldes så i 1500 ml vann. 27,6 g 2-methyl-5-hydroxy-6,7-diklor-l-indanon som utskilles, smelter ved 224 - ;230° C og anvendes uten ytterligere rensning. ;Trinn B: 2- méthyl- 5- benzylo. xy- 6, 7- diklor- l- indanon ;Til en omrørt blanding-av 27,6 g (0,12 mol) 2-methyl-5-hydroxy-6,7-diklor-l-indanon, 24,9 g (0,18 mol) kaliumcarbonat og 21,4 ml (0,18 mol) benzylbromid i 100 ml dimethylformamid oppvarmes ved 55 - 60° C i 2 timer, og heldes så i 1 liter sann for å felle 35,5 g 2-methyl-5-benzyloxy-B,7-diklor-l-indanon som smelter ved 153 - 155° C etter krystallisasjon fra benzen:hexan. 3:2. ;Elementæranalyse for C-^H^C^C^: ;Beregnet: C 63,57, H 4,39 ;Funnet : C 6 4,28, H 4,61 ;Trinn C: 2-(4-methoxyfenyl)-2-methyl-5-benzyloxy-6,7-diklor- l- indanon ;8,42 g (0,075 mol) kalium-t-butoxyd oppløst i 450 ml t-butanol tilsettes til en under tilbakeløp kokende oppløsning av 16,1 g (0,05 mol) 2-methyl-5-benzyloxy-6,7-diklor-l-indanon i 150 ;ml t-butanol og 600 ml benzen, tilbakeløpskokingen fortsettes i 2,5 timer, derpå tilsettes 37,66 g (0,10 mol) dimethoxydifenyljodo-niumklorid, og tilbakeløpskokingen fortsettes i 3 timer. Reaksjonsblandingen avkjøles til 25° C, 500 ml vann tilsettes og blandingen inndampes i vakuum hvorved man får en brun olje som ved etherekstrak-sjon, tørring og vannfritt magnesiumsulfat, fjernelse av etheren og ;kromatografering av residuet på silicagel med kloroform gir 3,44 g 2-(4-methoxyfenyl)-2-methyl-5-benzyloxy-6,7-diklor-l-indanon som smelter ved 115 - 119° C og anvendes uten ytterligere rensning. ;Trinn D: 2-(4-methoxyfenyl)-2-methyl-5-hydroxy-6,7-diklor- l- indanon ;3,44 g (0,008 mol) 2-(4-methoxyfenyl)-2-methyl-5-benzyl-oxy-6,7-diklor-l-indanon hydrogeneres katalytisk i 300 ml absolutt eihanol over 500 mg 5 %-ig palladium-på-carbon i et Parr-apparat ved 25° C i 4 timer. Reaksjonsblandingen filtreres og inndampes i vakuum hvorved man får 2,6 g 2-(4-methoxyfenyl)-2-methyl-5-hydroxy-6,7-diklor-l-indanon som smelter ved 149 - 156° C og anvendes uten ytterligere resnning. ;Trinn E: (l-oxo-2-(4-methoxyfenyl)-2-methyl-6,7-diklor- 5- indanyloxy]- eddiksyre ;En omrørt blanding av 2,6 g (0,0077 mol) 2-(4-methoxy-fenyl) -2-methyl-5-hydroxy-6 ,7-diklor-l-indanon, 2,14 g (0,0154 mol) kaliumcarbonat og 2,58 g (0,0154 mol) ethylbromacetat i 60 ml dimethylformamid oppvarmes ved 55 - 60° Ci 2,5 timer, behandles så med 60 ml vann og 3 ml (0,93 mol) 10N natriumhydroxydoppløsning, og oppvarmes ved 100° C i 1 time. Reaksjonsblandingen tilsettes langsomt til 600 ml knust is-vann og 20 ml 12N saltsyre for å felle 1,69 g (l-oxo-2-(4-methoxyfenyl)-2-methyl-6,7-diklor-5-indanyloxy) -eddiksyre som smelter ved 173 - 175° C etter krystallisasjon fra nitromethan. ;Elementæranalyse for ci^ 2. 6C^ 2°S'' ;Beregnet: C 57,74, H 4,08 ;Funnet : C 57,35, H 4,31 ;Eksempel 6 ;Fremstilling av (l-oxo-2-(4-hydroxyfenyl)-2-methyl-6,7-diklor- 5 - indanyloxy ) - eddiksyre ;En omrørt blanding av 1,80 g (0,0046 mol) (l-oxo-2-(4-methoxyfenyl)-2-methyl-6,7-diklor-5-indanyloxy) -eddiksyre, fremstilt som i eksempel 5, trinn E, 50 ml 48%-ig hydrogenbromid og 50 ml eddiksyre oppvarmes under tilbakeløp i 1 time, heldes så på 800 ml knust is-vann for å felle 900 mg {l-oxo-2-(4-hydroxy-fenyl)-2-methyl-6,7-diklor-5-indanyloxy]-eddiksyre som smelter ved 220 - 222°C etter krystallisasjon fra eddiksyre:vann, 1:1, ;og nitromethan. ;Elementæranalyse for <C>^<gH>^d<.>^ .1/3CH3N02 :;Beregnet: C 54,84, H 3,77, N 1,16 ;Funnet : C 54,38, H 3,93, N 0,94 ;Eksempel 7 ;Fremstilling av (l-oxo-2-(4-fluorfenyl)-2-methyl-6,7-diklor- 5- indanyloxy)- eddiksyre ;Trinn A: 2-( 4- fluorfenyl)- 2- methyl- 5- methoxy- 6, 7- diklor- l- indanon ;3,38 g (0,03 mol) kalium-t-butoxyd oppløst i 150 ml t-butanol tilsettes til en under tilbakeløp kokende oppløsning av 4,90 g (0,02 mol) 2-methyl-5-methoxy-6,7-diklor-l-indanon i 50 ml t-butanol/200 ml benzen, tilbakeløpskokning fortsettes i 3 timer, derpå tilsettes 10,58 g (0,03 mol) 4,4'-difluordifenyljodonium-klorid og tilbakeløpskokningen fortsettes i 2,5 timer. Reaksjonsblandingen avkjøles til 25° C, 100 ml vann tilsettes og blandingen inndampes til tørrhet under vakuum hvorved man får 1,24 g 2-(4-fluorfenyl)-2-methyl-5-methoxy-6,7-diklor-l-indanon som smelter ved 163 - 170° C ved behandling med ether-hexan og anvendes uten ytterligere rensning. ;Trinn B: 2-( 4- fluorfenyl)- 2- methyl- 5- hydroxy- 6, 7- diklor- l- indanon ;En omrørt blanding av 1,2 g (0,00354 mol) 2-(4-fluorfenyl)-2-methyl-5-methoxy-6,7-diklor-l-indanon og 12 g pyridin-hydroklorid oppvarmes ved 180° C i 1 time og heldes så i 500 ml vann. Det erholdte 2-(4-fluorfenyl)-2-methyl-5-hydroxy-6,7-diklor-l-indanon ;smelter ved 193 - 200° C og anvendes uten ytterligere rensning. ;Trinn C: (l-oxo-2-(4-fluorfenyl)-2-methyl-6,7-diklor-5-indanyloxy)- eddiksyre ;En omrørt blanding av 1,04 g (0,0032 mol) 2-(4-fluorfenyl)-2-methyl-5-hydroxy-6,7-diklor-l-indanon, 0,885 g (0,0064 mol) kaliumcarbonat og 1,07 g (0,0064 mol) ethylbromacetat i 30 ml dimethylformamid oppvarmes ved 55 - 60° C i 3 timer, behandles så ;med 30 ml vann og 1 ml (0,01 mol) ION natriumhydroxydoppløsning, ;og oppvarmes så til 80° C i 1 time. Reaksjonsblandingen tilsettes langsomt til 500 ml vann og 10 ml 12N saltsyre for å felle 450 mg (l-oxo-2-(4-fluorfenyl)-2-methyl-6,7-diklor-5-indanyloxy)-eddiksyre ;som smelter ved 150 - 156° C etter krystallisasjon fra ethylacetat: haxan,1:3. ;Elementæranalyse for Clg<H>13Cl2F04:;Beregnet: C 56,42, H 3,42, C1118,50 ;Funnet : C 56,30, H 3,65, Cl 18,57 ;Eksempel 8 ;Fremstilling av (l-oxo-2-ethyl-2^fenyl-6,7-diklor-5-indanyloxy)- eddiksyre ;Trinn A: 2- ethyl- 2- fenyl- 5- methoxy- 6, 7- diklor- l- indanon ;1,24 g (0,023 mol) natriummethoxyd tilsettes porsjonsvis til en omrørt blanding av 4,61 g (0,015 mol) 2-fenyl-5-methoxy-6,7-diklor-l-indanon, 15,5 ml (0,15 mol) jodethan, 60 ml benzen og 60 ;ml dimethylformamid under nitrogen i et isbad. Reaksjonsblandingen får lov til å anta værelsetemperatur i løpet av 1 time, heldes så i 1 liter vann, benzenskiktet fraskilles, tørres over vannfritt magnesiumsulfat og inndampes i vakuum hvorved man får 3,23 g 2-ethyl-2-fenyl-5-methoxy-6,7-diklor-l-indanon som smelter ved 139 - 141° C etter krystallisasjon fra benzen:hexan. 1:1. ;Elementæranalyse for C^8H16C''"202 : ;Beregnet: C 64,49, H 4,81 ;Funnet : C 64,73, H 4,99 ;Trinn B: 2- ethyl- 2- fenyl- 5- hydroxy- 6, 7- diklor- l- indanon ;En omrørt blanding av 3,01 g (0,009 mol) 2-ethyl-2-fenyl-5-methoxy-6,7-diklor-l-indanon og 35 g pyridin-hydroklorid oppvarmes ved 175° C i h time, og heldes så i 350 ml vann. 2,64 g 2-ethyl-2-fenyl-5-hydroxy-6,7-diklor-l-indanon som utskilles, smelter ved 177 - 179° C. ;Elementæranalyse for C-^H-^Cl-jC^: ;Beregnet: C 63,57, H 4,39 ;Funnet : C 63,73, H 4,81 ;Trinn C: (l-oxo-2-ethyl-2-fenyl-6,7-diklor-5-indanyloxy)- eddiksyre ;En omrørt blanding av 2,6 g (0,008 mol) 2-ethyl-2-fenyl-5-hydroxy-6,7-diklor-l-indanon, 2,24 g (0,016 mol) kaliumcarbonat og 2,71 g (0,016 mol) ethylbromacetat i 40 ml dimethylformamid oppvarmes ved 55 - 60° C i 2,5 timer, behandles så med 40 ml vann og 3 ml (0,03 mol) 10N natriumhydroxydoppløsning, og oppvarmes ved ;100° C i 1 time. Reaksjonsblandingen tilsettes langsomt til 600 ml vann og 10 ml 12N saltsyre hvorved man får et gummiaktig residuum som ved etherekstråksjon, tørring og inndamping i vakuum gir 2,16 g (l-oxo-2-ethyl-2-fenyl-6,7-diklor-5-indanyloxy)-eddiksyre som smelter ved 187 - 189° C. ;Elementæranalyse for C1g<H->-L<gCl>2<0>4<:>;Beregnet: C 60,18, H 4,25 ;Funnet : C 59,76, H 4,24 ;Eksempel 9 ;Fremstilling av (l-oxo-2-methyl-2-(4-nitrofenyl)-6,7-diklor-5- indany loxy) - eddiksyre ;Trinn A: 2- methyl- 2-( 4- nitrofenyl)- 5- methoxy- 6, 7- diklor- l- indanon 40 ml amylnitrat tilsettes i 10 ml porsjoner med 2 timers mellomrom til 9,36 g (0,03 mol) 2-methyl-2-fenyl-5-methoxy-6,7-diklor-l-indanon i 150 g polyfosforsyre ved 50 - 60° C under omrør-ing. Hele oppvarmingsperioden er 8 timer. Reaksjonsblandingen behandles med knust is-vann for å felle 4,82 g 2-methyl-2-(4-nitrofenyl) -5-methoxy-6,7-diklor-l-indanon som smelter ved 179 - 180° C etter krystallisasjqn fra butylklorid. ;Elementæranalyse for C17H13C12N04: ;Beregnet: C 55,76, H 3,58, N 3,82 ;Funnet : C 55,83, H 3,66, N 3,85 ;Trinn B: 2- methyl- 2-( 4- nitrofenyl)- 5- hydroxy- 6, 7- diklor- l- indanon ;En omrørt blanding av 4,82 g (0,013 mol) 2-methyl-2-(4-nitrofehyl-5-methoxy-6,7-diklor-l-indanon og 50 g pyridin-hydroklorid oppvarmes ved 175° C i k time og heldes så i en liter knust is-vann. 4,42 g 2-methyl-2-(4-nitrofenyl)-5-hydroxy-6,7-diklor-l-indanon som utskilles, smelter ved 268 - 270° C etter krystallisasjon fra ethanol. ;Elementæranalyse for C^gH^C^NO^: ;Beregnet: C 54,57, H 3,15, N 3,98 ;Funnet : C 54,18, H 3,27, N 4,66 ;Trinn C: (l-oxo-2-methyl-2-(4-nitrofenyl)-6,7-diklor-5- indanyloxv)-- eddiksyre ;En omrørt blanding av 4,4 g (0,0126 mol) 2-methyl-2-(4-ni.trofeny])-5-hydroxy-6,7-diklor-l-indanon,. 3,49 g (0,0252 mol) kaliumcarbonat og 4,21 g (0,0252 mol) ethylbromacetat i 150 ml dimethylformamid oppvarmes ved 55 - 60° C i 3 timer, behandles så med 50 ml vann og 7,5 ml (0,075 mol) ION natriumhydroxydoppløsning, og oppvarmes ved 100° C i 1,5 timer. Reaksjonsblandingen tilsettes langsomt til 1 liter vann og 15 ml 12N saltsyre for å felle 2,44 g (l-oxo-2-methyl-2-(4-nitrofenyl)-6,7-diklor-5-indanyloxy)-eddiksyre som smelter ved 202 - 205° C etter omkrystallisasjon fra nitromethan. ;Elementæranalyse for C-^gH-^C^NOg : ;Beregnet: C 52,79, H 3,19, N 3,41 ;Funnet : C 52,72, H 3,16, N 3,30 ;Eksempel lO ;Fremstilling av {l-oxo-2-(4-aminofenyl)-2-methyl-6,7-diklor-5-indanyloxy}- eddiksyre ;6,11 g (0,015 mol) (l-oxo-2-methyl-2-(4-nitrofenyl)-6,7-diklor-5-indanyloxy)-eddiksyre i 250 ml absolutt ethanol og 2 ml ;36N svovelsyre hydrogeneres katalytisk over 500 mg 5 %-ig palladium-på-carbon i et Parr-apparat. Etter 1 time filtreres reaksjonsblandingen, og inndampes så i vakuum til 50 ml volum. 200 ml vann tilsettes for å felle ethylesteren som hydrolyseres ved tilbakeløps-kokning i 200 ml ethanol, 4,5 ml (0,045 mol) 10N natriumhydroxyd- ;oppløsning og 100 ml vann i 1,5 timer. Reaksjonsblandingen avkjø-les, Inndampes til 1/3 av sitt volum, filtreres, og nøytraliseres så med 6N saltsyre for å felle 1,09 g (l-oxo-2-(4-aminofenyl)-2-methyl-6,7-diklor-5-indanyloxy)-eddiksyre som smelter ved 235 - 236° C under spaltning. ;Elementæranalyse for C-^gH^C^NO^: ;Beregnet: C 56,86, H 3,98, N 3,68 ;Funnet : C 56,46, H 4,04, N 3,62 ;Eksempel 11 ;Fremstilling av (l-oxo-2-(4-bromfenyl)-2-methy1-6,7-diklor-5- indanyloxy}- eddiksyre ;Trinn A: 2, 3- diklor- 4-( 4- bromfenyl)- acetylanisol ;Til en omrørt blanding av 73,5 g (0,414 mol) 2,3-dikloranisol, 105 g (0,456 mol) 4-bromfenylacetylklorid og 300 ml carbondisulfid tilsettes porsjonsvis 60,9 g (0,456 mol) aluminiumklorid under avkjøling ved 0 - 5° C. Reaksjonsblandingen hensettes ved 25° C i 17 timer, spyles så med nitrogen og det faste residuum behandles med knust is og 80 ml 12N saltsyre hvorved man får 147,7 g 2,3-diklor-5-(4-bromfenyl)-acetylanisol som smelter ved 163 - 164,5° C etter krystallisasjon fra benzen:hexan, 1:1. ;Elementæranalyse for C^H^BrC^O^: ;Beregnet: C 48,16, H 2,96 ;Funnet : C 48,38, H 3,10. ;Trinn B: 2', 3 '- diklor- 4'- methoxy- 2-( 4- bromfenyl)- acrylfenon ;Til en suspensjon av 142,5 g (0,38 mol) 2,3-diklor-4-(4-bromfenyl)-acetylanisol i 325 ml bis-dimethylaminomethan under nitrogen tilsettes dråpevis 325 ml eddiksyreanhydrid under avkjø-ling for å holde reaksjonsblandingstemperaturen under 40° C. Reaksjonsblandingen omrøres ved 25° C i 1 time og heldes så i 4 liter knust is-vann for å felle 143 g 2<1>,3<1->diklor-4<1->methoxy-2-(4-bromfenyl)-acrylfenon som smelter ved 110 - 116° C etter krystallisasjon fra benzen:hexan, 1:5. ;Elementæranalyse for C^gH^BrC^C^: ;Beregnet: C 49,78, H 2,87 ;Funnet : C 49,73, H 2,88 ;Trinn G: 2-( 4- bromfenyl)- 5- methoxy- 6, 7- diklor- l- indanon ;143 g (0,37 mol) 2<1>,3'-diklor-4<1->methoxy-2-(4-bromfenyl)-acrylofenon oppløst i 2 liter diklormethan dusjes i 1 liter 36N svovelsyre og 1 liter diklormethan i et isbad i løpet av 4 timer. Etter omrøring i ytterligere \ time tilsettes reaksjonsblandingen langsomt til knust is, diklormethanskiktet fraskilles, vaskes med mettet koksaltoppløsning, og inndampes i vakuum hvorved man får 134,8 g 2-(4-bromfenyl)-5-methoxy-6,7-diklor-l-indanon som smelter ved 202 - 203° C etter triturering med vann fulgt av krystallisasjon fra benzen:hexan, 1:1. ;Elementæranalyse for C-^H^BrC^C^ : ;Beregnet: C 49,78, H 2,87 ;Funnet : C 50,46, H 3,07. ;Trinn D: 2-( 4- bromfenyl)- 2- methyl- 5- methoxy- 6, 7- diklor- l- indanon ;28,4 g (0,522 mol) natriummethoxyd tilsettes til en omrørt blanding av 134,6 h (0,348 mol) 2-(4-bromfenyl)-5-methoxy-6,7-diklor-l-indanon, 217 ml (3,46 mol) jodmethan, 1700 ml tørr benzen og 1700 ml tørt dimetylformamid under nitrogen i et is-vannbad. Reaksjonsblandingen får lov til å anta værelsetemperatur i løpet av 2 timer, og heldes så i 8 liter vann for å felle 92,2 g 2-(4-brom-fenyl) -2-methyl-5-methoxy-6 , 7-diklor-l-indanon, smeltepunkt 200 - 203° C, som ikke er oppløselig i det tilstedeværende benzen. ;Elementæranalyse for C-^H-^BrC^C^ : ;Beregnet: C 51,03, H 3,28 ;Funnet : C 50,71, H 3,24 ;Trinn E: 2-( 4- bromfenyl)- 2- methyl- 5- h. ydroxy- 6, 7- diklor- l- indanon ;En omrørt blanding av 5,0 g (0,0125 mol) 2-(4-bromfenyl)-2-methyl-5-methoxy-6,7-diklor-l-indanon og 50 g pyridin-hydroklorid oppvarmes ved 185° C i 1 time og heldes så i 500 ml knust is-vann. 4,68 g 2-(4-bromfenyl)-2-methyl-5-hydroxy-6,7-diklor-l-indanon som utskilles, smelter ved 221 - 223° C etter krystallisasjon fra ethanol . ;Elementæranalyse for C^gH-^BrC^C^: ;Beregnet: C 49,78, H 2,87 ;Funnet : C 49,18, H 2,87. ;Trinn F: (l-oxo-2-(4-bromfenyl)-2-methyl-6,7-diklor-5-indanyloxy)- eddiksyre ;En omrørt blanding av 4,48 g (0,0116 mol) 2-(4-bromfenyl)-2-methyl-5-hydroxy-6,7-diklor-l-indanon, 3,88 g (0,0232 mol) kaliumcarbonat og 3,21 g (0,0232 mol) ethylbromacetat i 100 ml dimethylformamid oppvarmes ved 55 - 60° C i 3 timer, behandles så med 100 ml vann og 5 ml (0,05 mol) 10N natriumhydroxydoppløsning og oppvarmes ved 100° C i 2 timer. Reaksjonsblandingen tilsettes langsomt til 1500 ml knust is-vann og 50 ml 12N saltsyre for å felle 3,24 g (l-oxo-2-(4-bromfenyl)-2-methyl-6,7-diklor-5-indanyl-oxy)-eddiksyre som smelter ved 171 - 172° C etter krystallisasjon fra nitromethan fulgt av eddiksyre:vann, 3:2. ;elementæranalyse for C-^gH-^BrC^C^: ;Beregnet: C 48,68, H 2,95 ;Funnet : C 48,64, H 2,93 ;Eksempel 12 ;Fremstilling av (l*-oxo-2-methyl-2-f enyl-6, 7-diklor-5- indanyloxy)_- eddiksyre where R 2 'is alkyl with 1-3 carbon atoms, such as methyl, ethyl, n-propyl or isopropyl, X"<*>" is methyl or chlorine? and X is hydrogen, chlorine or fluorine, and pharmaceutically acceptable salts thereof. The group of compounds indicated above exhibits optimal diuretic and saluretic activity, while at the same time it does not change the uric acid concentration or cause a decrease in it. The invention relates to a number of alternative methods. According to such an embodiment, a 2-alkylation of a 1-oxo-5-indanoyloxy-acetic acid or an ester thereof of the formula III is carried out with an alkylating agent of the formula R 2z, where Z is halogen. This reaction is carried out e.g. by treating the 1-oxo-5-indanyloxy-acetic acid or its ester with a base, e.g. an alkali metal hydride, such as sodium hydride, or an alkali metal alkoxide, e.g. potassium t-butoxide or sodium methoxy, or alkali metal amides, such as sodium amide or lithium amide. The carbanion formed is then treated with the alkylating agent R 2 Z . Any solvent which is inert or substantially inert to the reagents used can be used. Examples of suitable solvents are 1,2-dimethoxyethane, t-butanol, benzene or dimethylformamide. The reaction can be carried out at a temperature of between 0°C and 150°C. The reaction is generally carried out at a temperature of 0-50°C. The following equation illustrates this method: ;112 3 ;where X , R and R are as stated in the claim, and R is hydrogen or alkyl. ;Another method for producing the 1-oxo-5-indanyloxy-acetic acids in question consists in reacting a haloacetic acid or an ester thereof with the formula: ;R<3>OOC-CH2-Z ;with a corresponding compound IV: ;;112 3 ;where X , R , R , R and Z are as stated in the claim. Generally, the reaction can be carried out in the presence of a base, such as an alkali metal carbonate, hydroxide or alkoxide, such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or sodium methoxy. An arbitrary solvent can be used which is inert or essentially inert to the reagents, and in which the reagents have a suitable solubility. Acetone, ethanol and dimethylformamide are examples of particularly advantageous solvents. The reaction can be carried out at a temperature between 25°C and the boiling point of the reaction mixture. If the haloacetic acid ester is used, the formed ester is hydrolysed to the free acid in a manner known per se. If R 3 is t-butyl, the ester formed can be pyrolysed catalytically, as by heating in the presence of a strong acid, e.g. in the presence of p-toluenesulfonic acid, sulfuric acid or gaseous hydrogen chloride. Usually the pyrolysis takes place by heating to a temperature of 70-140°C, preferably 80-100°C. The pyrolysis can be carried out without a solvent or in the presence of a suitable, non-aqueous medium, in which the reagents have a suitable solubility, e.g. in the presence of benzene, toluene or xylene. If in the 2-position of the compounds in question there is an alkoxy-substituted phenyl group, this can be transferred in a manner known per se to a hydroxyphenyl group. Likewise, a nitrophenyl group in the 2-position in the compounds in question can be converted into an aminophenyl group in a manner known per se. The free acids of formula I can be converted into non-toxic pharmacologically acceptable salts of alkali metals, alkaline earth metals, other metals and amines, such as ammonia, primary and secondary amines and quaternary ammonium hydroxides. Particularly preferred metal cations are derived from alkali metals, e.g. sodium, potassium or lithium, and alkaline earth metals, e.g. calcium or magnesium, and other metals, e.g. aluminium, iron and zinc. These salts are produced in a manner known per se. Thus, upon reaction with alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates, amines or quaternary ammonium hydroxides, the acid will form the corresponding alkali metal, alkaline earth metal, amine or quaternary ammonium salts. Pharmaceutically acceptable salts can, as mentioned, be formed from ammonia, primary, secondary or tertiary amines or quaternary ammonium hydroxides, such as methylamine, dimethylamine, trimethylamine, ethylamine, N-methylhexylamine, benzylamine, α-phenethylamine, ethylenediamine, piperidine, 1- methylpiperazine, morpholine, pyrrolidine, 1,4-dimethylpiperazine, ethanolamine, diethanolamine, triethanolamine, tris-(hydroxymethyl)aminomethane, N-methylglucamine, N-methylglucosamine, ephedrine, procaine, tetramethylammonium hydroxide, tetraethylammonium hydroxide or benzyltrimethylammonium. The above-mentioned salts are particularly well suited as parenteral solutions, as they are very soluble in pharmaceutical carriers, such as water or alcohol. ;The compounds in question contain an asymmetric carbon atom in the 2-position of the indanyl ring, and the optically active antipodes can be separated, e.g. by the methods described below. The invention thus encompasses not only the preparation of the racemic 1-oxo-5-indanyloxy-acetic acids, but also the preparation of their optically active antipodes. ;Separation of the optical isomers of the racemic acids can be carried out by forming a salt of the racemic mixture with an optically active base such as (+)- or (-)-amphetamine, (-)-cinchonidine, dehydroabiethylamine, (+)- or (-)-α-methylbenzyl-amine, (+)- or (-)-α-(1-naphthyl)-ethylamine, brucine or strychnine, in a suitable solvent such as methanol, ethanol, 2-propanol, benzene, acetonitrile , nitromethane, acetone, Two diastereomeric salts are thus formed in the solution, one of which is usually more soluble in the solvent than the other. Repeated recrystallizations of the crystalline salt generally give a pure diastereomer. The optically pure 1-oxo-5-indanyloxy-acetic acid is obtained by acidifying the salt with a mineral acid, extraction in ether, evaporation of the solvent and recrystallization of the optically pure antipode. ;The other optically pure antipode can generally be obtained by using a different base to form the diastereomeric salt. It is advantageous to isolate the partially cleaved acid from the filtrates from the purification of one diastereomeric salt and further purify this material using another optically active base. ;The method according to the invention is illustrated in more detail by the following examples: ;Example 1 ;Preparation of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy-acetic acid ;Step A: 2, 3-dichloro - 5-phenylacetylanisole; To a stirred mixture of 62 g (0.35 mol) 2,3-dichloroanisole, 54 g (0.35 mol) phenylacetyl chloride and 250 ml carbon disulphide, add 47 g (0.35 mol) aluminum chloride in portions while cooling at 0 - 5° C. The reaction mixture is allowed to stand at 25° C for 17 hours, the carbon disulphide removed and the residue treated with ice water and 50 ml of concentrated hydrochloric acid, whereby 68.8 g of 2,3-dichloro-5-phenylacetylanisole is obtained which melts at 126 - 129° C by recrystallization from benzene:cyclohexane, 2: 1. ;Elementary analysis for c]_5Hi2C^2^2 : ;Calculated: C 61.04, H 4.10 ;Found : C 61.45, H 4.11 ; Step B: 2,3-dichloro-4-(2-phenylacryloyl)-anisole; 100 ml of acetic anhydride is added dropwise to a suspension of 29.5 g (0.01 mol) of 2,3-dichloro-4-phenylacetylanisole in 100 ml bis-(dimethylamino)-methane under nitrogen n with cooling to keep the temperature of the reaction mixture below 60° C. The reaction mixture is stirred at 25° C. for 2 hours, and poured into 1500 ml of ice water to precipitate 7.4 g of 2,3-dichloro-4-(2-phenylacryloyl)- anisole which melts at 87 - 89° C. ;Elementary analysis for C^gH^C^0^5;Calculated: C 62.56, H 3.94 ;Found : C 62.67, H 4.03 ;Step C: 2-phenyl-5-methoxy-6,7-dichloro-l-indanone; 7.4 g (0.024 mol) 2,3-dichloro-4-(2-phenylacryloyl)-anisole; add portionwise to 150 ml cold, concentrated sulfuric acid with stirring. The reaction mixture is stirred in an ice bath for 2 hours, and then added dropwise to ice water to precipitate 3.91 g of 2-phenyl-5-methoxy-;6,7-dichloro-1-indanone which melts at 193 - 195° C upon crystallization from benzene:cyclohexane, 1:2. ;Elementary analysis for C-LgH12Cl2O2: ;Calculated: C 62.56, H 3.94 ;Found : C 62.84, H 4.00 ;Step D: 2- phenyl- 5- hydroxy- 6, 7- dichloro- l - indanone; A mixture of 3.91 g (0.0127 mol) of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone and 40 g of pyridine hydrochloride is heated at 190° C for 1 hour, and is then poured into 600 ml of water. 2.48 g of 2-phenyl-5-hydroxy-6,7-dichloro-1-indanone which is separated, melts at 250 - 252° C after recrystallization from ethanol:water, 2:1. ;Elementary analysis for C-^H^qCI,,! ^ : ;Calculated: C 61.46, H 3.44 ;Found : C 60.94, H 3.66 ;Step E: ( l- oxo- 2- phenyl- 6, 7- dichloro- 5- indanyloxy)- acetic acid; 5.86 g (0.023 mol) 2-phenyl-5-hydroxy-6,7-dichloro-1-indanone, 4.28 g (0.023 mol) iodoacetic acid, 3.04 g (0.022 mol) potassium carbonate and 250 ml acetone is heated under reflux for 48 hours. The reaction mixture is cooled to 25° C, and evaporated in vacuo, whereby a solid product is obtained which is dissolved in water and acidified with 6N hydrochloric acid to precipitate 6.8 g of a mixture of (l-oxo-2-phenyl-6,7- dichloro-5-indanyl-oxy)-acetic acid and 2-phenyl-5-hydroxy-6,7-dichloro-1-indanone. The phenol is removed by recrystallization from nitromethane. Evaporation of the filtrate to dryness in vacuo and trituration with toluene gives 470 mg of (1-oxo-2-phenyl-6,7-dichloro-5-indanyloxy)-acetic acid which melts at 181 - 185° C. ;Elementary analysis for C ^^H^Cl,,! ^: ;Calculated: C 58.14, H 3.45, Cl 20.19 ;Found : C 58.17, H 3.54, Cl 19.94 ;Step F: ( l- oxo- 2- phenyl- 2 - methyl- 6, 7- dichloro- 5-indanyloxy)- acetic acid; A stirred solution of 0.351 g (0.001 mol) (1-oxo-2-phenyl-6,7-dichloro-5-indanyloxy)-acetic acid in 7 ml dimethylformamide is cooled in an ice bath and treated with 0.084 g of a 57% oil dispersion (0.002 mol) of sodium hydride and stirred for 2 hours. 1 ml of methyl iodide is added and the reaction mixture is stirred at 25° C for 2 hours, poured into ice water and acidified with dilute aqueous hydrochloric acid which gives (1-oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)- acetic acid which melts at 168 - 169°C. ;Example 2 ;When in example 1, step A, an equivalent amount of 2-methyl-3-chloroanisole is used instead of 2,3-dichloroanisole, ;and steps B - F are carried out as described there, (l-oxo-2 -phenyl-2,6-dimethyl-7-chloro-5-indanyloxy)-acetic acid with m.p. 142 - 144°C. ;Example 3 ;( l- oxo- 2- methyl- 2- phenyl- 6, 7- dichloro- 5- indanyloxy)- acetic acid ; Step A: 2', 3'- dichloro- 4'- methoxyisobutyrophenone ; A stirred mixture of 100 g (0.565 mol) 2,3-dichloroanisole (I) and 66 g (0.62 mol) isobutyryl chloride (II) in 400 ml methylene chloride are cooled to 5° C and treated with 83 g (0.62 mol) aluminum chloride for 1 hour. The reaction mixture is allowed to warm to 25° C and after 24 hours it is poured into 400 ml of ice water and 30 ml of hydrochloric acid. The organic phase is washed with 5% sodium hydroxide, water, dried over magnesium sulfate and distilled under reduced pressure, which gives 68 g of 2<1>,3<1->dichloro-4<1->methoxyisobutyrophenone (III) which distills at 120 - 130°C/0.5 mm. ;Elementary analysis for ciiHx2C12°2: ;Calculated: C 53.46, H 4.89 ;Found : C 54.25, H 5.07 ;Step B: 2- bromo- 2', 3'- dichloro- 4'- methoxyisobutyrophenone ;A stirred solution of 45 g (0.183 mol) of 2<1>,3'-dichloro-4'-methoxyisobutyrophenone in 150 ml of acetic acid is treated for \ hour with 30 g (0.187 mol) of bromine. The reaction mixture is stirred for 10 minutes, then poured into 600 ml of ice water containing 2 g of sodium bisulphite. 2-bromo-2<1>,3'-dichloro-4<1->methoxyisobutyrophenone (IV) which separates (48 g) melts at 72 - 73° C after recrystallization from hexane. Elemental analysis for C-QH^BrC^C^ : ;Calculated: C 40.52, H 3.40 ;Found : C 40.68, H 3.38 ;Step C: 2- methylene- 2' , 3'- dichloro - 4'- methoxypropiophenone; A solution of 32 g (0.1 mol) 2-bromo-2<1>,3<1->dichloro-4'-methoxyisobutyrophenone and 17.4 g (0.2 mol) anhydrous lithium bromide in 200 ml of DMF is stirred at 95° C in an inert atmosphere for 3 hours and poured into 500 ml of ice water. The 2-methylene-2',3<1->dichloro-4'-methoxypropio-phenone (V) which is separated, melts at 59° C after recrystallization from petroleum ether. ;Elementary analysis for C-^H^qC^O^ : ;Calculated: C 53.90, H 4.11 ;Found : C 53.72, K 4.11 ;Step D: 2- methyl- 5- metho. xy- 6, 7-dichloro-l-indanone; A solution of 40 g (0.163 mol) 2-methylene-2',3'-dichloro-4 1 -methoxypropiophenone in 75 ml of concentrated sulfuric acid is added at 25° C for 24 hours and then poured slowly into 500 ml of ice water with vigorous stirring. 40 g of 2-methyl-5-methoxy-6,7-dichloro-1-indanone which is separated, melts at 129° C after recrystallization from methyl-cyclohexane, ;Elementary analysis for C-^H^qC^O^: ;calculated: C 53.90, H 4.11 ; Found : C 53.84, H 4.00 ; Step E: 2- methyl- 2- phenyl- 5- methoxy- 6, 7- dichloro-l- indanone ; 8.42 g (0.075 mol) potassium t-butoxide dissolved in 300 ml t-butanol is added to a refluxing boiling solution of 12.26 g (0.05 mol) 2-methyl-5-methoxy-6,7-dichloro-l -indanone, refluxing is continued for 2 hours, then a suspension of 19.0 g (0.06 mol) of diphenyliodonium chloride in 1 liter of t-butanol is added and refluxing is continued for 2 hours. The reaction mixture is cooled to 25° C, 300 ml of water is added and the mixture is evaporated to dryness in vacuo, whereby 4.97 g of 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone is obtained which melts at 161 - 163° C after crystallization from benzene:cyclohexane, 1:2. ;Elementary analysis for C2. 1^ 1AC^ 2Q2: ;Calculated: C 63.57, H 4.39 ;Found : C 63.24, H 4.68 ;Step F: 2- methyl- 2- phenyl- 5- hydroxyv- 6, 7- dichloro-l-indanone; A stirred mixture of 4.94 g (0.015 mol) 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone and 50 g pyridine hydrochloride is heated at 175° C for 1 hour, and then poured into 500 ml of water. 2.05 g of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone which separates, melts at 194 - 196° C after recrystallization from ethanol:water, 2:1. ;Elementary analysis for ci6H12C12°2<:>;Calculated: C 62.56, H 3.94 ;Found : C 62.60, H 4.11 ;Step G: (l-oxo-2-methyl-2r-phenyl- 6,7-dichloro-5-iridanyloxyl-acetic acid;A stirred mixture of 2.05 g (0.0067 mol) 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone, 1, 85 g (0.0134 mol) potassium carbonate and 2.23 g (0.0134 mol) ethyl bromoacetate in 30 ml dimethylformamide are heated at 55 - 60° C for 3 hours, treated with 0.97 g (0.0147 mol) potassium hydroxide dissolve in a minimal amount of water in 39 ml of methanol and heated on a steam bath for 2.5 hours. The reaction mixture is poured into 500 ml of water, acidified with 6N hydrochloric acid and the precipitate collected after trituration with ether-petroleum ether and dried to obtain 1.31 g (l -oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyl-oxy)-acetic acid which melts at 168 - 169° C on crystallization from acetic acid:water, 1:1. ;Elementary analysis for C-^ gH-^C^O^: ;Calculated: C 59.20, H 3.86 ;Found : C 58.94, H 4.20 ;Example 4 ;Preparation of [l-oxo-2-(4-chlorophenyl) -2-methyl-6,7-dichloro-5-indanyloxy3~ edd ic acid hemihydrate; Stage A; 2-(4-chlorophenyl)-2-nethyl-5-methoxy-6,7-dichloro-l-indanone; 2.81 g (0.025 mol) of potassium t-butoxide dissolved in 150 ml of t-butanol are added to a reflux boiling solution of 4.90 g (0.02 mol) 2-methyl-5-methoxy-6,7-dichloro-1-indanone in 100 ml t-butanol/200 ml benzene, the reflux reaction is continued for 3 hours, then add 11.55 g (0.03 mol) of 4,4'-dichlorodiphenyliodonium chloride and the reflux is continued for 2 hours. The reaction mixture is cooled to 25° C, 100 ml of water is added and the mixture is evaporated to dryness in vacuo, whereby 4.30 g of 2-(4-chlorophenyl)-2-methyl-5-methoxy-6,7-dichloro-l- indanone melting at 176 - 178° C after crystallization from cyclohexane and benzene, 5:1. ;Step B: 2-( 4- chlorophenyl)- 2- methyl- 5- hydroxy- 6, 7- dichloro- l- indanone ; A stirred mixture of 4.15 g (0.012 mol) 2-(4-chlorophenyl)- 2-methyl-5-methoxy-6,7-dichloro-1-indanone and 40 g of pyridine hydrochloride are heated at 180° C. for 1 hour, and then poured into 500 ml of water. 3.11 g of 2-(4-chlorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone which is separated melts at 211-213° C after crystallization from ethanol:water. 1:1. ;Elementary analysis for C-^gH^ClSC^: ;Calculated: C 56.25, H 3.25 ;Found : C 55.53, H 3.23 ;Step C: (l-oxo-2-(4-chlorophenyl )-2-methyl-6,7-dichloro-5-indanyloxy^- acetic acid hemihydrate ;A stirred mixture of 2.95 g (0.00863 mol) 2-(4-chloro-phenyl)-2-methyl-5 -hydroxy-6,7-dichloro-1-indanone, 2.26 g (0.0163 mol) potassium carbonate and 2.72 g (0.0163 mol) ethyl bromoacetate in 50 ml dimethylformamide are heated at 55 - 60° C for 2 hours , then treated with 50 ml of water and 2.5 ml (0.025 mol) of 10N sodium hydroxide solution, and heated at 80° C. for 1 hour. The reaction mixture was added slowly to 500 ml of water and 10 ml of 12N hydrochloric acid to precipitate 1.37 g (l -oxo-2-(4-chlorophenyl)-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid hemihydrate which melts at 141 - 142° C after crystallization from acetic acid:water, 1:1. ;Elementary analysis for C^gH^-jC^O^ 1/2H20: ;Calculated: C 52.90, H 3.45, Cl 26.03 ;Found : C 52.47, H 3.45, Cl 26.11 ;Example 5; Preparation of (1-oxo-2-(4-methoxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxyV-acetic acid; Step n A: 2-methyl-5-hydroxy-6,7-dichloro-l-indanone; A stirred mixture of 30.0 g (0.123 mol) 2-methyl-5-methoxy-6,7-dichloro-l-indanone and 270 g of pyridine hydrochloride are heated at 180° C. for 1 hour, and then poured into 1500 ml of water. 27.6 g of 2-methyl-5-hydroxy-6,7-dichloro-1-indanone which is separated, melts at 224 - 230° C and is used without further purification. ;Step B: 2- methyl- 5- benzyl. xy- 6, 7-dichloro-l-indanone; To a stirred mixture-of 27.6 g (0.12 mol) 2-methyl-5-hydroxy-6,7-dichloro-l-indanone, 24.9 g (0.18 mol) of potassium carbonate and 21.4 ml (0.18 mol) of benzyl bromide in 100 ml of dimethylformamide are heated at 55 - 60° C. for 2 hours, and then poured into 1 liter true to precipitate 35.5 g of 2- methyl-5-benzyloxy-B,7-dichloro-1-indanone which melts at 153 - 155° C after crystallization from benzene:hexane. 3:2. ;Elementary analysis for C-^H^C^C^: ;Calculated: C 63.57, H 4.39 ;Found : C 6 4.28, H 4.61 ;Step C: 2-(4-methoxyphenyl)- 2-methyl-5-benzyloxy-6,7-dichloro-1-indanone; 8.42 g (0.075 mol) of potassium t-butoxide dissolved in 450 ml of t-butanol is added to a refluxing boiling solution of 16.1 g (0.05 mol) 2-methyl-5-benzyloxy-6,7-dichloro-1-indanone in 150 ml of t-butanol and 600 ml of benzene, the reflux is continued for 2.5 hours, then 37.66 g ( 0.10 mol) of dimethoxydiphenyliodonium chloride, and refluxing is continued for 3 hours. The reaction mixture is cooled to 25° C, 500 ml of water is added and the mixture is evaporated in vacuo, whereby a brown oil is obtained which, by ether extraction, drying and anhydrous magnesium sulfate, removal of the ether and chromatography of the residue on silica gel with chloroform gives 3.44 g 2-(4-methoxyphenyl)-2-methyl-5-benzyloxy-6,7-dichloro-1-indanone which melts at 115 - 119° C and is used without further purification. ;Step D: 2-(4-methoxyphenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone ;3.44 g (0.008 mol) 2-(4-methoxyphenyl)-2-methyl- 5-Benzyl-oxy-6,7-dichloro-1-indanone is catalytically hydrogenated in 300 ml of absolute ethanol over 500 mg of 5% palladium-on-carbon in a Parr apparatus at 25° C. for 4 hours. The reaction mixture is filtered and evaporated in vacuo, whereby 2.6 g of 2-(4-methoxyphenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone is obtained, which melts at 149 - 156° C and is used without further resolution. ;Step E: (1-oxo-2-(4-methoxyphenyl)-2-methyl-6,7-dichloro-5- indanyloxy]-acetic acid ;A stirred mixture of 2.6 g (0.0077 mol) of 2- (4-methoxy-phenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone, 2.14 g (0.0154 mol) potassium carbonate and 2.58 g (0.0154 mol) ethyl bromoacetate in 60 ml of dimethylformamide is heated at 55 - 60° C for 2.5 hours, then treated with 60 ml of water and 3 ml (0.93 mol) of 10N sodium hydroxide solution, and heated at 100° C for 1 hour. The reaction mixture is added slowly to 600 ml of crushed ice-water and 20 ml of 12N hydrochloric acid to precipitate 1.69 g of (1-oxo-2-(4-methoxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid melting at 173 - 175 ° C after crystallization from nitromethane. ;Elementary analysis for ci^ 2. 6C^ 2°S'' ;Calculated: C 57.74, H 4.08 ;Found : C 57.35, H 4.31 ;Example 6 ;Preparation of (l-oxo-2-(4-hydroxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid; A stirred mixture of 1.80 g (0.0046 mol) (l-oxo- 2-(4-Methoxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid, preparation t as in example 5, step E, 50 ml of 48% hydrogen bromide and 50 ml of acetic acid are heated under reflux for 1 hour, then poured into 800 ml of crushed ice-water to precipitate 900 mg of {l-oxo-2-(4 -hydroxy-phenyl)-2-methyl-6,7-dichloro-5-indanyloxy]-acetic acid which melts at 220 - 222°C after crystallization from acetic acid:water, 1:1, and nitromethane. ;Elementary analysis for <C>^<gH>^d<. >^ .1/3CH3N02 :;Calculated: C 54.84, H 3.77, N 1.16 ;Found : C 54.38, H 3.93, N 0.94 ;Example 7 ;Preparation of (l- oxo-2-(4-fluorophenyl)-2-methyl-6,7-dichloro- 5- indanyloxy)- acetic acid; Step A: 2-( 4- fluorophenyl)- 2- methyl- 5- methoxy- 6, 7- dichloro-l-indanone; 3.38 g (0.03 mol) potassium t-butoxide dissolved in 150 ml t-butanol is added to a refluxing boiling solution of 4.90 g (0.02 mol) 2-methyl- 5-methoxy-6,7-dichloro-1-indanone in 50 ml t-butanol/200 ml benzene, reflux is continued for 3 hours, then 10.58 g (0.03 mol) of 4,4'-difluorodiphenyliodonium chloride are added and the reflux is continued for 2.5 hours. The reaction mixture is cooled to 25° C, 100 ml of water is added and the mixture is evaporated to dryness under vacuum, whereby 1.24 g of 2-(4-fluorophenyl)-2-methyl-5-methoxy-6,7-dichloro-1-indanone is obtained which melts at 163 - 170° C when treated with ether-hexane and is used without further purification. ;Step B: 2-( 4- fluorophenyl)- 2- methyl- 5- hydroxy- 6, 7- dichloro-l- indanone ; A stirred mixture of 1.2 g (0.00354 mol) 2-(4- fluorophenyl )-2-methyl-5-methoxy-6,7-dichloro-1-indanone and 12 g of pyridine hydrochloride are heated at 180° C. for 1 hour and then poured into 500 ml of water. The 2-(4-fluorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone obtained melts at 193 - 200° C. and is used without further purification. ;Step C: (1-oxo-2-(4-fluorophenyl)-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid ;A stirred mixture of 1.04 g (0.0032 mol) of 2- (4-fluorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone, 0.885 g (0.0064 mol) potassium carbonate and 1.07 g (0.0064 mol) ethyl bromoacetate in 30 ml dimethylformamide are heated at 55 - 60° C for 3 hours, then treated with 30 ml of water and 1 ml (0.01 mol) ION sodium hydroxide solution, and then heated to 80° C for 1 hour. The reaction mixture is added slowly to 500 ml of water and 10 ml of 12N hydrochloric acid to precipitate 450 mg of (1-oxo-2-(4-fluorophenyl)-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid, which melts at 150 - 156° C after crystallization from ethyl acetate: hexane, 1:3. ;Elementary analysis for Clg<H>13Cl2F04:;Calculated: C 56.42, H 3.42, C1118.50 ;Found : C 56.30, H 3.65, Cl 18.57 ;Example 8 ;Preparation of (l -oxo-2-ethyl-2^phenyl-6,7-dichloro-5-indanyloxy)-acetic acid; Step A: 2-ethyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone;1 .24 g (0.023 mol) of sodium methoxide is added portionwise to a stirred mixture of 4.61 g (0.015 mol) of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone, 15.5 ml (0.15 mol ) iodoethane, 60 ml benzene and 60 ml dimethylformamide under nitrogen in an ice bath. The reaction mixture is allowed to reach room temperature over the course of 1 hour, then poured into 1 liter of water, the benzene layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo, whereby 3.23 g of 2-ethyl-2-phenyl-5-methoxy- 6,7-dichloro-1-indanone which melts at 139 - 141° C after crystallization from benzene:hexane. 1:1. ;Elementary analysis for C^8H16C''"202 : ;Calculated: C 64.49, H 4.81 ;Found : C 64.73, H 4.99 ;Step B: 2- ethyl- 2- phenyl- 5- hydroxy - 6, 7-dichloro-l-indanone; A stirred mixture of 3.01 g (0.009 mol) 2-ethyl-2-phenyl-5-methoxy-6,7-dichloro-l-indanone and 35 g pyridine hydrochloride heated at 175° C for h hour, and then poured into 350 ml of water. 2.64 g of 2-ethyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone which separates out, melts at 177 - 179° C. ;Elementary analysis for C-^H-^Cl-jC^: ;Calculated: C 63.57, H 4.39 ;Found : C 63.73, H 4.81 ;Step C: (l-oxo-2 -ethyl-2-phenyl-6,7-dichloro-5-indanyloxy)-acetic acid; A stirred mixture of 2.6 g (0.008 mol) 2-ethyl-2-phenyl-5-hydroxy-6,7-dichloro- l-indanone, 2.24 g (0.016 mol) potassium carbonate and 2.71 g (0.016 mol) ethyl bromoacetate in 40 ml dimethylformamide are heated at 55 - 60° C. for 2.5 hours, then treated with 40 ml water and 3 ml ( 0.03 mol) 10N sodium hydroxide solution, and heated at ;100° C for 1 hour. The reaction mixture is added slowly to 600 ml of water and 10 ml of 12N hydrochloric acid whereby a gummy residue is obtained which, by ether extraction, drying and evaporation in vacuum, gives 2.16 g of (1-oxo-2-ethyl-2-phenyl-6,7-dichloro-5-indanyloxy)-acetic acid which melts at 187 - 189° C. ;Elementary analysis for C1g<H->-L<gCl>2<0>4<:>;Calculated: C 60.18, H 4.25 ;Found : C 59.76, H 4.24 ; Example 9: Preparation of (1-oxo-2-methyl-2-(4-nitrophenyl)-6,7-dichloro-5-indanyloxy)-acetic acid; Step A: 2-methyl-2-(4-nitrophenyl) - 5- methoxy- 6, 7- dichloro-l- indanone 40 ml amyl nitrate is added in 10 ml portions at 2 hour intervals to 9.36 g (0.03 mol) 2-methyl-2-phenyl-5-methoxy-6 ,7-dichloro-1-indanone in 150 g of polyphosphoric acid at 50 - 60° C with stirring. The entire heating period is 8 hours. The reaction mixture is treated with crushed ice-water to precipitate 4.82 g of 2-methyl-2-(4-nitrophenyl)-5-methoxy-6,7-dichloro-1-indanone which melts at 179-180°C after crystallization from butyl chloride. ;Elementary analysis for C17H13C12N04: ;Calculated: C 55.76, H 3.58, N 3.82 ;Found : C 55.83, H 3.66, N 3.85 ;Step B: 2- methyl- 2-( 4- nitrophenyl)- 5- hydroxy- 6, 7- dichloro-l- indanone; A stirred mixture of 4.82 g (0.013 mol) 2-methyl-2-(4-nitrophenyl-5-methoxy-6,7- Dichloro-1-indanone and 50 g of pyridine hydrochloride are heated at 175° C for k hours and then poured into one liter of crushed ice water. 4.42 g of 2-methyl-2-(4-nitrophenyl)-5-hydroxy-6 ,7-dichloro-l-indanone which is separated, melts at 268 - 270° C after crystallization from ethanol. ;Elementary analysis for C^gH^C^NO^: ;Calculated: C 54.57, H 3.15, N 3 .98 ;Found : C 54.18, H 3.27, N 4.66 ;Step C: (1-oxo-2-methyl-2-(4-nitrophenyl)-6,7-dichloro-5-indanyloxy) -- acetic acid ;A stirred mixture of 4.4 g (0.0126 mol) 2-methyl-2-(4-nitrophenyl])-5-hydroxy-6,7-dichloro-1-indanone,. 3, 49 g (0.0252 mol) of potassium carbonate and 4.21 g (0.0252 mol) of ethyl bromoacetate in 150 ml of dimethylformamide are heated at 55 - 60° C. for 3 hours, then treated with 50 ml of water and 7.5 ml (0.075 mol ) ION sodium hydroxide solution, and heated at 100° C. for 1.5 hours. The reaction mixture is slowly added to 1 liter of water and 15 ml of 12N hydrochloric acid to precipitate 2.44 g of (1-oxo-2-methyl-2-(4-nitrophenyl)-6,7-dichloro-5-indanyloxy)-acetic acid which melts at 202 - 205° C after recrystallization from nitromethane. ;Elementary analysis for C-^gH-^C^NOg : ;Calculated: C 52.79, H 3.19, N 3.41 ;Found : C 52.72, H 3.16, N 3.30 ;Example 10 ;Preparation of {l-oxo-2-(4-aminophenyl)-2-methyl-6,7-dichloro-5-indanyloxy}-acetic acid ;6.11 g (0.015 mol) (l-oxo-2-methyl- 2-(4-nitrophenyl)-6,7-dichloro-5-indanyloxy)-acetic acid in 250 ml of absolute ethanol and 2 ml of ;36N sulfuric acid is catalytically hydrogenated over 500 mg of 5% palladium-on-carbon in a Parr apparatus . After 1 hour, the reaction mixture is filtered, and then evaporated in vacuo to a volume of 50 ml. 200 ml of water is added to precipitate the ethyl ester which is hydrolysed by refluxing in 200 ml of ethanol, 4.5 ml (0.045 mol) of 10N sodium hydroxide solution and 100 ml of water for 1.5 hours. The reaction mixture is cooled, evaporated to 1/3 of its volume, filtered, and then neutralized with 6N hydrochloric acid to precipitate 1.09 g of (1-oxo-2-(4-aminophenyl)-2-methyl-6,7- dichloro-5-indanyloxy)-acetic acid which melts at 235 - 236° C during decomposition. ;Elementary analysis for C-^gH^C^NO^: ;Calculated: C 56.86, H 3.98, N 3.68 ;Found : C 56.46, H 4.04, N 3.62 ;Example 11 ;Preparation of (1-oxo-2-(4-bromophenyl)-2-methyl-6,7-dichloro-5-indanyloxy}-acetic acid ;Step A: 2, 3-dichloro-4-(4-bromophenyl)- acetylanisole ; To a stirred mixture of 73.5 g (0.414 mol) 2,3-dichloroanisole, 105 g (0.456 mol) 4-bromophenylacetyl chloride and 300 ml carbon disulphide, 60.9 g (0.456 mol) aluminum chloride is added in portions while cooling at 0 - 5° C. The reaction mixture is left at 25° C for 17 hours, then flushed with nitrogen and the solid residue is treated with crushed ice and 80 ml of 12N hydrochloric acid, whereby 147.7 g of 2,3-dichloro-5-(4-bromophenyl) are obtained )-acetylanisole melting at 163 - 164.5° C after crystallization from benzene:hexane, 1:1. ;Elementary analysis for C^H^BrC^O^: ;Calculated: C 48.16, H 2.96 ;Found : C 48.38, H 3.10. ;Step B: 2',3'-dichloro-4'-methoxy-2-(4-bromophenyl)-acrylphenone ;To a suspension of 142.5 g (0.38 mol) 2,3-dichloro-4-(4-bromophenyl)-acetylanisole i 325 ml of bis-dimethylaminomethane under nitrogen is added dropwise to 325 ml of acetic anhydride while cooling to keep the reaction mixture temperature below 40° C. The reaction mixture is stirred at 25° C for 1 hour and then poured into 4 liters of crushed ice-water to precipitate 143 g 2 <1>,3<1->dichloro-4<1->methoxy-2-(4-bromophenyl)-acrylphenone which melts at 110 - 116° C after crystallization from benzene:hexane, 1:5. ;Elementary analysis for C^gH^BrC^C^: ;Calculated: C 49.78, H 2.87 ;Found : C 49.73, H 2.88 ;Step G: 2-( 4- bromophenyl)- 5- methoxy-6,7-dichloro-1-indanone; 143 g (0.37 mol) 2<1>,3'-dichloro-4<1->methoxy-2-(4-bromophenyl)-acrylophenone dissolved in 2 liters dichloromethane is showered in 1 liter of 36N sulfuric acid and 1 liter of dichloromethane in an ice bath over the course of 4 hours. After stirring for a further \ hour, the reaction mixture is slowly added to crushed ice, the dichloromethane layer is separated, washed with saturated sodium chloride solution, and evaporated in vacuo, whereby 134.8 g of 2-(4-bromophenyl)-5-methoxy-6,7-dichloro- l-indanone which melts at 202 - 203° C after trituration with water followed by crystallization from benzene:hexane, 1:1. ;Elementary analysis for C-^H^BrC^C^ : ;Calculated: C 49.78, H 2.87 ;Found : C 50.46, H 3.07. Step D: 2-(4-bromophenyl)-2-methyl-5-methoxy-6,7-dichloro-1-indanone; 28.4 g (0.522 mol) of sodium methoxide are added to a stirred mixture of 134.6 h ( 0.348 mol) 2-(4-bromophenyl)-5-methoxy-6,7-dichloro-1-indanone, 217 ml (3.46 mol) iodomethane, 1700 ml dry benzene and 1700 ml dry dimethylformamide under nitrogen in an ice- water bath. The reaction mixture is allowed to warm to room temperature over 2 hours and then poured into 8 liters of water to precipitate 92.2 g of 2-(4-bromo-phenyl)-2-methyl-5-methoxy-6,7-dichloro -1-indanone, melting point 200 - 203° C, which is not soluble in the benzene present. ;Elementary analysis for C-^H-^BrC^C^ : ;Calculated: C 51.03, H 3.28 ;Found : C 50.71, H 3.24 ;Step E: 2-( 4-bromophenyl)- 2- methyl- 5- h. ydroxy- 6, 7- dichloro-l- indanone; A stirred mixture of 5.0 g (0.0125 mol) 2-(4-bromophenyl)-2-methyl-5-methoxy- 6,7-dichloro-1-indanone and 50 g of pyridine hydrochloride are heated at 185° C. for 1 hour and then poured into 500 ml of crushed ice water. 4.68 g of 2-(4-bromophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone which is separated, melts at 221 - 223° C after crystallization from ethanol. ;Elementary analysis for C^gH-^BrC^C^: ;Calculated: C 49.78, H 2.87 ;Found : C 49.18, H 2.87. ;Step F: (1-oxo-2-(4-bromophenyl)-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid ;A stirred mixture of 4.48 g (0.0116 mol) of 2- (4-bromophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone, 3.88 g (0.0232 mol) potassium carbonate and 3.21 g (0.0232 mol) ethyl bromoacetate in 100 ml dimethylformamide is heated at 55 - 60° C for 3 hours, then treated with 100 ml of water and 5 ml (0.05 mol) 10N sodium hydroxide solution and heated at 100° C for 2 hours. The reaction mixture is added slowly to 1500 ml of crushed ice-water and 50 ml of 12N hydrochloric acid to precipitate 3.24 g of (1-oxo-2-(4-bromophenyl)-2-methyl-6,7-dichloro-5-indanyl-oxy)-acetic acid melting at 171 - 172°C after crystallization from nitromethane followed by acetic acid:water, 3:2. ;elemental analysis for C-^gH-^BrC^C^: ;Calculated: C 48.68, H 2.95 ;Found : C 48.64, H 2.93 ;Example 12 ;Preparation of (l*-oxo- 2-methyl-2-phenyl-6, 7-dichloro-5-indanyloxy)_-acetic acid

Trinn A: t-butyl-(l-oxo-2-methyl-2-fenyl-6,7-diklor- 5- indanyloxyj- acetat Step A: t-butyl-(1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy-acetate

En blanding av 9,2 g (0,03 mol) 2-methyl-2-fenyl-5-hydroxy-6,7-diklor-l-indanon, 8,29 g (0,06 mol) kaliumcarbonat og 6,44 g (0,033 mol) t-butyl-bromacetat i 30 ml dimethylformamid om-røres ved 25° C i 2 timer. Reaksjonsblandingen heldes i 150 ml koldt vann og t-butyl-(l-oxo-2-methyl-2-fenyl-6,7-diklor-5-indanyl-oxy)-acetat som utskilles, frafiltreres, skyldes med vann og tørres. A mixture of 9.2 g (0.03 mol) of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone, 8.29 g (0.06 mol) of potassium carbonate and 6.44 g (0.033 mol) of t-butyl bromoacetate in 30 ml of dimethylformamide is stirred at 25° C. for 2 hours. The reaction mixture is poured into 150 ml of cold water and t-butyl-(1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyl-oxy)-acetate which is separated, filtered off, washed with water and dried.

Trinn B: ( 1- oxo- 2- methyl- 2- fenyl- 6, 7- diklor- 5- indanyloxy)- eddiksyre Step B: ( 1- oxo- 2- methyl- 2- phenyl- 6, 7- dichloro- 5- indanyloxy)- acetic acid

En oppløsning av 1,0 g (0,00237 mol) t-butyl-(l-oxo-2-methyl-2-fenyl-6,7-diklor-5-indanyloxy)-acetat i 25 ml benzen behandles med 2 dråper methansulfonsyre og kokes under tilbakeløp i h time. Reaksjonsblandingen behandles med 20 ml cyclohexan og avkjøles hvilket gir (l-oxo-2-methyl-2-fenyl-6,7-diklor-5-indanyloxy)-eddiksyre som frafUtreres og tørres. Produktet smelter ved 168 - 169°C efter omkrystallisasjon fra eddiksyre:vann 1:1. A solution of 1.0 g (0.00237 mol) of t-butyl-(1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)-acetate in 25 ml of benzene is treated with 2 drops methanesulfonic acid and boil under reflux for h hour. The reaction mixture is treated with 20 ml of cyclohexane and cooled, which gives (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)-acetic acid which is filtered off and dried. The product melts at 168 - 169°C after recrystallization from acetic acid:water 1:1.

Elementæranalyse for C, 0H., .C1_0 . : Elemental analysis for C, 0H., .C1_0 . :

18 14 2 4 18 14 2 4

Beregnet: C 59,20, H 3,8 6 Calculated: C 59.20, H 3.8 6

Funnet: C 58,94, H 4,20 Found: C 58.94, H 4.20

Eksempel 13 Example 13

Fremstilling av (l-oxo-2-methyl-2-fenyl-6,7-diklor-5-indanyloxy)- eddiksyre Preparation of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)-acetic acid

Til en suspensjon av 0,24 g (0,01 mol) natriumhydrid i To a suspension of 0.24 g (0.01 mol) sodium hydride i

10 ml 1,2-dimethoxyethan tilsettes en oppløsning av 3,07 g (0,01 mol) 2-methyl-2-fenyl-5-hydroxy-6,7-diklor-l-indanon i 10 ml 1,2-dimethoxyethan i løpet av 15 minutter. Når utviklingen av hydrogen' opphører tilsettes 2,39 g (0,01 mol) diethyl-2-brommalonat og blandingen kokes under tilbakeløp i 1 time. Oppløsningsmidlet avdestilleres under nedsatt trykk. Det gjenværende diethyl-2-(l-oxo-2-methyl-2-fenyl-6,7-diklor-5-indanyloxy)-malonat oppløses i 50 ml ethanol og derpå tilsettes 50 ml vann og 2,5 g natriumbicar-bonat, og blandingen kokes under tilbakeløp i 4 timer, avkjøles, syres, ekstraheres med ether, vaskes med vann og tørres over magnesiumsulfat. 10 ml of 1,2-dimethoxyethane is added to a solution of 3.07 g (0.01 mol) 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone in 10 ml of 1,2-dimethoxyethane within 15 minutes. When the evolution of hydrogen ceases, 2.39 g (0.01 mol) of diethyl-2-bromomalonate are added and the mixture is refluxed for 1 hour. The solvent is distilled off under reduced pressure. The remaining diethyl-2-(1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)-malonate is dissolved in 50 ml of ethanol and then 50 ml of water and 2.5 g of sodium bicarbonate are added , and the mixture is refluxed for 4 hours, cooled, acidified, extracted with ether, washed with water and dried over magnesium sulfate.

Etheren fordampes under nedsatt trykk hvorved man får The ether is evaporated under reduced pressure, which gives

rå 2- (1 -oxo-2-methyl-2-f enyl-6 , 7-diklor-5-indanyloxy) -malonsy.re som oppvarmes ved 150° C inntil utviklingen av carbondioxyd opphører hvilket gir (l-oxo-2-methyl-2-fenyl-6,7-diklor-5-indanyloxy)-eddiksyre som smelter ved 168 - 169° C etter omkrystallisasjon fra nitromethan. crude 2-(1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)-malonic acid which is heated at 150° C until the evolution of carbon dioxide ceases giving (1-oxo-2 -methyl-2-phenyl-6,7-dichloro-5-indanyloxy)-acetic acid which melts at 168 - 169° C after recrystallization from nitromethane.

Eksempel 14 Example 14

Spaltning av de optiske isomerer ay (l^oxo-2-methyl-2-fenyl-6, 7- dik. lor- 5- i. ndanyloxy l- eddiksyre Cleavage of the optical isomers ay (l^oxo-2-methyl-2-phenyl-6, 7- dik. lor- 5- i. ndanyloxy l- acetic acid

Trinn A: (+')_- isomeren Step A: The (+')_- isomer

En blanding av 26 g (0,071 mol) racemisk (l-oxo-2-methyl-2-fenyl-6,7-diklor-5-indanyloxy)-eddiksyre og 8,6 g (0,0 71 mol) L- (-) -c>G-methylbenzylamin oppvarmes i 250 ml varm acetonitril og eldes ved 25° C i 18 timer. A mixture of 26 g (0.071 mol) racemic (l-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)-acetic acid and 8.6 g (0.0 71 mol) L-( -) -c>G-methylbenzylamine is heated in 250 ml of hot acetonitrile and aged at 25° C. for 18 hours.

Acetonitrilet dekanteres fra det dannede salt (13,2 g) som omkrystalliseres tre ganger fra et minimalt volum av 2-propanol hvilket gir 1,9 g av saltet av den rene (+)-enantiomer som over-føres til syren ved behandling av saltet med fortynnet saltsyre og ether. Etherfasen vaskes med vann, tørres over magnesiumsulfat og etheren avdestilleres under nedsatt trykk. (+)-isomeren smelter ved 16 3° C etter krystallisasjon fra toluen. The acetonitrile is decanted from the salt formed (13.2 g) which is recrystallized three times from a minimal volume of 2-propanol which gives 1.9 g of the salt of the pure (+)-enantiomer which is transferred to the acid on treatment of the salt with dilute hydrochloric acid and ether. The ether phase is washed with water, dried over magnesium sulphate and the ether is distilled off under reduced pressure. The (+)-isomer melts at 16 3° C after crystallization from toluene.

Trinn B: (-)- isomeren Step B: The (-)- isomer

Ved å følge i det vesentlige fremgangsmåten beskrevet i trinn A idet der som reaktanter anvendes 15,5 g (0,042 mol) (1-oxo-2-methyl-2-fenyl-6,7-diklor-5-indanyloxy)-eddiksyre (erholdt fra acetonitril-morluten i trinn A) og 5,15 g (0,042 mol) D-( + )-"C-methylbenzylamin i 150 ml acetonitril og tre gangers omkrystallisasjon av det erholdte salt fra et minimalt volum av 2-{>ropanol, fåes 2,2 g av saltet av den rene (-)-enantiomere. By essentially following the procedure described in step A, using 15.5 g (0.042 mol) (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)-acetic acid ( obtained from the acetonitrile mother liquor in step A) and 5.15 g (0.042 mol) D-( + )-"C-methylbenzylamine in 150 ml of acetonitrile and three times recrystallization of the salt obtained from a minimal volume of 2-{>ropanol , 2.2 g of the salt of the pure (-)-enantiomer are obtained.

(-)-isomeren smelter ved 164° C etter krystallisasjon fra toluen. The (-)-isomer melts at 164° C after crystallization from toluene.

Noen typiske forbindelser fremstilt ifølge oppfinnelsen, ble undersøkt på diuretisk og uricosurisk aktivitet ved følgende metode: Fastende han-sjimpanser med en vekt på 21-77 kg ble immobilisert med fencyclidin (hvilket viste seg å være uten virkning på resultatene) (1,0-1,5 mg/kg im pluss 2,5 mg/kg iv om nødvendig) og ble forberedt til kateterisering for standard renal uttømningsundersøkelse ved den vanlige kliniske aseptiske metode. Pyrogenfritt inulin (iv) ble anvendt til å måle glomerulær filtreringshastighet (GFR). Uttømning av inulin, urat og utskillelseshastighet for Na+, K+ og Cl ble bestemt ved standard autoanalyse (inulin og urat i sjimpanseplasma er lett filtrerbart). Gjennomsnittlig kontrolluttømning ble beregnet fra tre efter hverandre følgende 20 minutters perioder. Verdier for legemiddelrespons ble bestemt som gjennomsnitt av åtte 15-20 min. uttømningsperioder efter oral inngivelse av en vandig oppløsning av forbindelsen gjennom et nasalkateter. Alle data ble bestemt som forskjellen mellom (middel)verdier for behandling og kontroll, oppnådd fra enkelte forsøk. Some typical compounds prepared according to the invention were investigated for diuretic and uricosuric activity by the following method: Fasting male chimpanzees weighing 21-77 kg were immobilized with phencyclidine (which proved to have no effect on the results) (1.0- 1.5 mg/kg im plus 2.5 mg/kg iv if necessary) and were prepared for catheterization for standard renal emptying examination by the usual clinical aseptic method. Pyrogen-free inulin (iv) was used to measure glomerular filtration rate (GFR). Depletion of inulin, urate and excretion rate of Na + , K + and Cl were determined by standard autoassay (inulin and urate in chimpanzee plasma are easily filterable). Average control depletion was calculated from three consecutive 20 minute periods. Values for drug response were determined as the average of eight 15-20 min. washout periods following oral administration of an aqueous solution of the compound through a nasal catheter. All data were determined as the difference between (mean) values for treatment and control, obtained from individual trials.

De diuretiske (D) og uricosuriske (U) data for sjimpanser er angitt ved et poengsystem på følgende måte: Data for diuretisk test på sjimpansen ble opprinnelig beregnet som en &, u ekv./lin., og urat-data er målt som The diuretic (D) and uricosuric (U) data for chimpanzees are given by a scoring system as follows: Data for the diuretic test on the chimpanzee were originally calculated as a &, u eq./lin., and urate data are measured as

CC CC

A urat/ inulin. De oppnådde poengverdier er følgende: A urate/ inulin. The obtained point values are the following:

Alle doser var på 5 mg/kg po (oralt). All doses were 5 mg/kg po (oral).

Furosemid = 4-Cl-N-furfuryl-5-sulfamoyl-antranilsyre. Furosemide = 4-Cl-N-furfuryl-5-sulfamoyl-anthranilic acid.

De opnådde resultater fremgår av følgende tabel: The results obtained appear in the following table:

Sammenlignings! orsøk Comparative! cause

Det ble foretatt sammenligningsforsøk for sammenligning av noen typiske forbindelser fremstilt ved fremgangsmåten ifølge oppfinnelsen og en fra DOS 1 958 918 kjent forbindelse. Forsøkene ble utført ved å undersøke forskjellige forbindelser for diuretisk og saluretisk aktivitet på hunrotter ved måling av utskilt salt i urinen i et tidsrom på 24 timer efter administrasjon. Virkningen av den ved fremgangsmåten ifølge oppfinnelsen erholdte forbindelse (l-oxo-2-methyl-2-fenyl-6,7-diklor-5-indanyloxy)-eddiksyre ble satt til 1,0, og de øvrige forbindelser ble bedømt i forhold.til denne. De erholdte resultater fremgår av den efterfølgende tabell. Comparison tests were carried out to compare some typical compounds produced by the method according to the invention and a compound known from DOS 1 958 918. The experiments were carried out by examining different compounds for diuretic and saluretic activity on female rats by measuring excreted salt in the urine over a period of 24 hours after administration. The effect of the compound obtained by the method according to the invention (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)-acetic acid was set to 1.0, and the other compounds were judged in proportion. to this one. The results obtained appear in the following table.

Claims

Analogous procedure for the production of therapeutically active 1-oxo-5-indanyloxy-acetic acids with the formula:

where X" is chlorine or methyl; R"*" is phenyl which is optionally p-substituted with hydroxy, nitro, alkoxy with 1-6 carbon atoms, halogen or amino;

R 2 is alkyl of 1-6 carbon atoms;

and pharmaceutically acceptable salts thereof with bases;

characterized in that a) a compound with the formula: 11 2

where X , R and R are as indicated above, react with a compound of the formula: 3

where R is hydrogen or alkyl and Z is halogen, after which the reaction product, if R 3 is alkyl, is hydrolyzed, or if R 3 is t-butyl, pyrolyzed, or b) a compound of the formula: 11 3

where R and X are as above, and R is hydrogen or alkyl, is reacted with an alkylating agent to introduce an alkyl group of 1-6 carbon atoms, after which the reaction product, if R 3 is alkyl, is hydrolyzed or, if R 3 is t -butyl, is pyrolysed, or c) a compound of the formula: 12 1 5 where R , R and X are as indicated above, and R is alkyl, is hydrolyzed to form the free acid, or d) a compound of the formula: 112

where X , R and R are as above, decarboxylated,

and that a compound obtained where R<1> is nitrophenyl is optionally reduced to the corresponding compound where R<1> is aminophenyl, or that a compound obtained where R<1> is alkoxyphenyl is optionally subjected to an ether cleavage to form a corresponding compound where R<1> is p-phenoxyphenyl,

after which a racemate possibly formed in the preceding steps is split into the optically active isomers, and/or a free acid formed is possibly transferred to a corresponding pharmaceutically acceptable salt with a base in a manner known per se, before or after a racemate split.