NO161548B

NO161548B - EQUIPMENT FOR REPLACEMENT, FILLING AND CLOSING OF VALVE BAGS.

Info

Publication number: NO161548B
Application number: NO860044A
Authority: NO
Inventors: Loek J Dekker
Original assignee: Bates Cepro Bv
Priority date: 1985-01-10
Filing date: 1986-01-08
Publication date: 1989-05-22
Also published as: NO161548C; JPS61164901A; JPH0536281B2; DK12786A; NL8500052A; DK158082C; ATE33234T1; DE3660110D1; DK158082B; EP0187689B1; CA1260443A; DK12786D0; EP0187689A1; NO860044L

Abstract

Equipment for erecting, filling and sealing valve bags, particularly for dangerous materials, with which no personnel has to come near the machine, having a filling device (400) which is provided with an obliquely mounted turntable carrying an even number of filling tubes diametrally to the centre line, each extending substantially horizontally in the erected position and substantially vertically in the filling position.

Description

Fremgangsmåte ved fremstilling av terapeutisk aktive (4_(2-alkylidenalkanoyl)-aryloxyj -alkansyrer. Process for the production of therapeutically active (4_(2-alkylidenealkanoyl)-aryloxyj -alkanoic acids.

Foreliggende oppfinnelse angår en ny fremgangsmåte ved fremstilling av [4-(2-alkylidenalkanoyl)-aryloxy ]-alkansyrer , som har diuretiske, natriuretiske og kloruretiske egenskaper og som derfor er nyttige ved behandling av mange lidelser som skyldes for stor til-bakeholdelse av elektrolytter. The present invention relates to a new process for the production of [4-(2-alkylidenealkanoyl)-aryloxy]-alkanoic acids, which have diuretic, natriuretic and chloruretic properties and which are therefore useful in the treatment of many disorders caused by excessive retention of electrolytes .

Det har vist seg at 2-alkylidenalkanoyl)-aryloxy ]-alkansyrer kan fremstilles ved dehydrohalogenering av 4-(halogenalkanoyl)-aryloxyalkansyrer som inneholder halogenatomer på nabocarbonatomer i en eller begge av 2- og 3-st Ulingene i alkanoylkjeden. Eliminer-ingen av hydrogenhalogenid fører til umetning av acylenheten og be-virker således en binding av olefintypen mellom carbonatomene, til hvilke de reaktive hydrogen- og halogenatomer er bundet. It has been shown that 2-alkylidenealkanoyl)-aryloxy]-alkanoic acids can be prepared by dehydrohalogenation of 4-(halogenalkanoyl)-aryloxyalkanoic acids which contain halogen atoms on neighboring carbon atoms in one or both of the 2- and 3-st Ulins in the alkanoyl chain. The elimination of the hydrogen halide leads to the unbinding of the acyl unit and thus causes a bond of the olefin type between the carbon atoms, to which the reactive hydrogen and halogen atoms are bound.

Ifølge oppfinnelsen fremstilles forbindelser av den generelle formel: According to the invention, compounds of the general formula are produced:

hvor R er hydrogen, halogen, lavere alkyl, fenyl eller benzyl, where R is hydrogen, halogen, lower alkyl, phenyl or benzyl,

R<1> er hydrogen, lavere alkyl, f.eks. methyl, ethyl, propyl, isopropyl, butyl, etc., fenyl, klor- eller hydroxy-substituert fenyl eller fenoxy, R <2>er hydrogen eller lavere alkyl, eller sammen kan R<1> is hydrogen, lower alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, etc., phenyl, chloro- or hydroxy-substituted phenyl or phenoxy, R<2>is hydrogen or lower alkyl, or together may

R 1 og R 2danne en alkylenkjede med 3 - 5 carbonatomer, X^, , X^- og X^, som kan være like eller forskjellige, er hydrogen, halogen, R 1 and R 2 form an alkylene chain with 3 - 5 carbon atoms, X^, , X^- and X^, which may be the same or different, are hydrogen, halogen,

lavere alkyl, lavere alkoxy eller sammen kan X^ og X^ eller X^ og X^ være forenet under dannelse av en hydrocarbylenkjede inneholdende 4 carbonatomer mellom sine festepunkter, f.eks. tet råmet hylen, 1,3-butadienylen (dvs. -CH=CH-CH=CH-) , etc, og n er et helt tall fra lower alkyl, lower alkoxy or together, X^ and X^ or X^ and X^ may be united to form a hydrocarbylene chain containing 4 carbon atoms between its attachment points, e.g. tet raw hylene, 1,3-butadienylene (ie -CH=CH-CH=CH-), etc, and n is an integer from

1 til 5, samt salter, estere og amider derav, ved at en forbindelse av formelen: 12 i hvor R, R , R , X^> ' X5» x6 °9 n er som oven^or angitt, og Z og Z , som er like eller forskjellige, er hydrogen eller halogen, idet minst én av dem er halogen, omsettes med et dehydrohalogenerings-middel, og at den erholdte syre, om ønskes, overføres til et salt, en ester eller amidet derav på i og for seg kjent vis. 1 to 5, as well as salts, esters and amides thereof, in that a compound of the formula: 12 in where R, R , R , X^> ' X5» x6 °9 n is as indicated above, and Z and Z , which are the same or different, are hydrogen or halogen, at least one of which is a halogen, is reacted with a dehydrohalogenating agent, and that the acid obtained, if desired, is transferred to a salt, an ester or the amide thereof in and of itself known way.

Generelt kan et hvilket som helst reagens som er i stand til å spalte av hydrogenhalogenid, anvendes som dehydrohalogenerings-middel ved foreliggende fremgangsmåte. Disse innbefatter f.eks. tertiære alkylaminer, pyridin, lutidin, kinolin og andre tertiære aminer, kalium-tertiært butoxyd i tertiær butanol, kaliumhydroxyd i lavere alkanoler, som methanol, ethanol eller propanol, metall- In general, any reagent capable of cleaving hydrogen halide can be used as dehydrohalogenating agent in the present process. These include e.g. tertiary alkylamines, pyridine, lutidine, quinoline and other tertiary amines, potassium tertiary butoxide in tertiary butanol, potassium hydroxide in lower alkanols, such as methanol, ethanol or propanol, metal-

halogenider, alkalimetallacetater, alkalimetallcarbonater, etc. halides, alkali metal acetates, alkali metal carbonates, etc.

Det har imidlertid vist seg at følgende dehydrohalogeneringsmidler er spesielt egnet ved foreliggende fremgangsmåte: vannfritt lithiumklorid, lithiumbromid, sølvacetat, kaliumacetat, sølvfluorid og kaliumcarbonat . However, it has been shown that the following dehydrohalogenating agents are particularly suitable in the present process: anhydrous lithium chloride, lithium bromide, silver acetate, potassium acetate, silver fluoride and potassium carbonate.

Valget av oppløsningsmiddel i hvilket fremgangsmåten kan ut-føres, er ikke kritisk, og man har anvendt slike forskjellige opp-løsningsmidler som dimethylformamid, eddiksyre, benzen og methanol til dette formål med like gode resultater. på samme måte er valget av egnet reaksjonstemperatur en smaksak og avhenger hovedsakelig av reaktiviteten av halogenforbindelsen som skal dehydrohalogeneres. The choice of solvent in which the method can be carried out is not critical, and various solvents such as dimethylformamide, acetic acid, benzene and methanol have been used for this purpose with equally good results. likewise, the choice of suitable reaction temperature is a matter of taste and depends mainly on the reactivity of the halogen compound to be dehydrohalogenated.

I alminnelighet avhenger reaksjonstemperaturen og tiden i løpet av hvilken reaksjonen utføres, av reaktiviteten av de anvendte reaktanter, og hvor reaktantene er relativt inerte eller det er ønskelig å lette avspaltningen av hydrogenhalogenidbiproduktet, bør oppvarmning anvendes inntil reaksjonen er fullstendig. In general, the reaction temperature and the time during which the reaction is carried out depend on the reactivity of the reactants used, and where the reactants are relatively inert or it is desirable to facilitate the separation of the hydrogen halide by-product, heating should be used until the reaction is complete.

[4~(2-halogenalkanoyl)-fenoxy]-alkansyrereaktantene ved foreliggende fremgangsmåte kan fremstilles på forskjellig vis. En av disse fremgangsmåter består i Friedel Craft<*>s reaksjon av et alkanoylhalogenid med en fenoxyalkansyre under dannelse av den tilsvarende (4-alkanoylfenoxy)-alkansyre, fulgt av omsetning av denne syre med et halogeneringsmiddel, f.eks. brom, klor, etc., for å erstatte hydrogenet i 2-stillingen på alkanoylkjeden med halogen. En annen fremgangsmåte som innbefatter Friedel Craft<*>s metoden for syntese innbefatter omsetningen av et alkansyrehalogenid, som er substituert i 2-stillingen i alkylkjeden med et halogenatom, med en fenoxy-alkansyre for å danne den ønskede [4-(2-halogenalkanoyl)-fenoxy]-alkansyreforbindelse. Når R i noen av de ovenfor viste struktur-formler er halogen, f.eks. klor, brom etc, og R<1> er fenyl, fremstilles reaktantene med fordel ved omsetning av benzaldehyd, med den passende (4-alkanoylfenoxy)-alkansyre for å fremstille det tilsvarende omega-fenylmethylenderivat av (4-alkanoylfenoxy)-alkansyre, og dette derivat halogeneres så, f.eks. med brom i eddiksyre, for å danne den ønskede [4-(omega-fenyl-alfa,beta-dihalogenalkanoyl)-fenoxy]-alkansyrereaktant. På den annen side fremstilles de reaktanter hvori R er forskjellig fra halogen, f.eks. lavere alkyl, og R er fenyl, lett ved omsetning av benzaldehyd, med den passende (4-alkanoylfenoxy)-alkansyre for å danne det tilsvarende omega - fenylmethylenderivat av 4-alkanoylfenoxy-alkansyre, og dette derivat The [4~(2-haloalkanoyl)-phenoxy]-alkanoic acid reactants in the present process can be prepared in different ways. One of these methods consists in Friedel Craft<*>'s reaction of an alkanoyl halide with a phenoxyalkanoic acid to form the corresponding (4-alkanoylphenoxy)alkanoic acid, followed by reaction of this acid with a halogenating agent, e.g. bromine, chlorine, etc., to replace the hydrogen in the 2-position of the alkanoyl chain with halogen. Another method incorporating Friedel Craft<*>'s method of synthesis involves the reaction of an alkanoic acid halide, which is substituted in the 2-position of the alkyl chain with a halogen atom, with a phenoxyalkanoic acid to form the desired [4-(2-haloalkanoyl )-phenoxy]-alkanoic acid compound. When R in any of the structural formulas shown above is halogen, e.g. chlorine, bromine etc, and R<1> is phenyl, the reactants are advantageously prepared by reaction of benzaldehyde, with the appropriate (4-alkanoylphenoxy)-alkanoic acid to prepare the corresponding omega-phenylmethylene derivative of (4-alkanoylphenoxy)-alkanoic acid, and this derivative is then halogenated, e.g. with bromine in acetic acid, to form the desired [4-(omega-phenyl-alpha,beta-dihaloalkanoyl)-phenoxy]-alkanoic acid reactant. On the other hand, those reactants are prepared in which R is different from halogen, e.g. lower alkyl, and R is phenyl, readily by reaction of benzaldehyde, with the appropriate (4-alkanoylphenoxy)-alkanoic acid to form the corresponding omega - phenylmethylene derivative of 4-alkanoylphenoxy-alkanoic acid, and this derivative

hydrogeneres så for å redusere benzylidengruppen til en tilsvarende benzylgruppe, det således fremstilte mettede mellomprodukt kon-denseres med formaldehyd eller paraformaldehyd i nærvær av et sekundært amin, f.eks. dimethylamin-hydroklorid, under dannelse av det tilsvarende Mannich-amin som så dehydroamineres til den tilsvarende 4-(2-benzylidenalkanoyl)-fenoxy-alkansyre, og dette methylen-mellomprodukt hydrogeneres derpå til den tilsvarende 4"(2-benzyl-alkanoyl)-fenoxy-alkansyre og halogeneres med brom eller klor for å is then hydrogenated to reduce the benzylidene group to a corresponding benzyl group, the saturated intermediate thus produced is condensed with formaldehyde or paraformaldehyde in the presence of a secondary amine, e.g. dimethylamine hydrochloride, forming the corresponding Mannich amine which is then dehydroaminated to the corresponding 4-(2-benzylidenealkanoyl)-phenoxyalkanoic acid, and this methylene intermediate is then hydrogenated to the corresponding 4-(2-benzylidenealkanoyl)- phenoxy-alkanoic acid and halogenated with bromine or chlorine to

innføre halogen istedenfor hydrogen i 2-stillingen på alkanoylkjeden. Den således dannede forbindelse er den ønskede 4~(2-brom-2-benzylalkanoyl)-fenoxy-alkansyrereaktant. Når radikalet R er en annen gruppe enn fenyl, f.eks. hydrogen, lavere alkyl eller fenoxy, fremstilles de tilsvarende [4~(2-halogenalkanoyl)-fenoxy]-alkansyre-utgangsmaterialer ved å omsette den passende kjernesubstituerte eller kjerneusubstituerte fenoxyalkansyre med det passende alkanoylhalogenid for å danne den tilsvarende (4-alkanoylfenoxy)-alkansyre, fulgt av kondensering av denne syre med formaldehyd eller paraformaldehyd og dimethylaminhydrohalogenid for å danne det tilsvarende Mannich-aminderivat, dvs. [4-(2-dimethylaminomethylalkanoyl)-fenoxy]-alkansyre-hydrohalogenid, fulgt av desaminering av aminet ved omsetning derav med en svak base, f.eks. natriumbicarbonat, og hydrogenering av den således dannede [4-(2-methylenalkanoyl)-fenoxy]-alkansyre for å danne en [4~(2-methylalkanoyl)- fenoxy]-alkansyre som så halogeneres med et halogeneringsmiddel, f.eks. klor," brom, etc., for å danne den ønskede [4-(2-halogenalkanoyl)-fenoxy]-alkansyre. Omega-fenoxyalkanoylhalogenidet som anvendes ved foregående syntese, fremstilles ved omsetning av en passende omega-halogenalkansyre med et passende kjernesubstituert eller kjerne-usubstituert natriumfenoxyd, fulgt av omsetning av den således dannede omega-fenoxy-alkansyre med et passende halogeneringsmiddel, f.eks. thionylklorid. Når det er ønskelig å fremstille et produkt hvor radikalet R er methyl, og radikalet R1 er et av de ovenfor angitte organiske radikaler, fremstilles reaktantene i fremgangsmåten ved kondensering av de tilsvarende 2-methylsubstituerte alkanoylhalogenider med den passende fenoxyalkansyre for å danne det tilsvarende (4-alkanoylfenoxy)-alkansyre-mellomprodukt, fulgt av halogenering med brom eller klor for å danne den tilsvarende [4-(2-halogen-2-methylalkanoyl)-fenoxy]-alkansyrereaktant. Nok en annen fremgangsmåte ved fremstilling av [4-(2-halogenalkanoyl)-fenoxy]-alkansyrereaktantene består i omsetningen av et alkanoylhalogenid introduce halogen instead of hydrogen in the 2-position of the alkanoyl chain. The compound thus formed is the desired 4-(2-bromo-2-benzylalkanoyl)-phenoxy-alkanoic acid reactant. When the radical R is a group other than phenyl, e.g. hydrogen, lower alkyl or phenoxy, the corresponding [4~(2-haloalkanoyl)-phenoxy]-alkanoic acid starting materials are prepared by reacting the appropriate core-substituted or core-unsubstituted phenoxyalkanoic acid with the appropriate alkanoyl halide to form the corresponding (4-alkanoylphenoxy)-alkanoic acid , followed by condensation of this acid with formaldehyde or paraformaldehyde and dimethylamine hydrohalide to form the corresponding Mannich amine derivative, i.e. [4-(2-dimethylaminomethylalkanoyl)-phenoxy]-alkanoic acid hydrohalide, followed by deamination of the amine by reacting it with a weak base, e.g. sodium bicarbonate, and hydrogenating the thus formed [4-(2-methylenealkanoyl)-phenoxy]-alkanoic acid to form a [4-(2-methylalkanoyl)-phenoxy]-alkanoic acid which is then halogenated with a halogenating agent, e.g. chlorine," bromine, etc., to form the desired [4-(2-haloalkanoyl)-phenoxy]-alkanoic acid. The omega-phenoxyalkanoyl halide used in the preceding synthesis is prepared by reacting an appropriate omega-haloalkanoyl acid with an appropriate core substituted or core-unsubstituted sodium phenoxide, followed by reaction of the omega-phenoxy-alkanoic acid thus formed with a suitable halogenating agent, eg thionyl chloride. When it is desired to prepare a product in which the radical R is methyl, and the radical R1 is one of the above indicated organic radicals, the reactants in the process are prepared by condensation of the corresponding 2-methyl-substituted alkanoyl halides with the appropriate phenoxyalkanoic acid to form the corresponding (4-alkanoylphenoxy)-alkanoic acid intermediate, followed by halogenation with bromine or chlorine to form the corresponding [4 -(2-halo-2-methylalkanoyl)-phenoxy]-alkanoic acid reactant Yet another method in the preparation of [4-(2-haloalkanoyl)-phenoxy]-alkanoic acid reactant the ten consists in the reaction of an alkanoyl halide

med en fenylalkylether, f.eks. en anisol, for å danne den tilsvarende 4-alkanoylsubstituerte fenylalkylether, som så enten overføres til den tilsvarende fenol ved behandling med aluminiumklorid, fulgt av omsetning av fenolen med en passende omega-halogenalkansyre, eller en ester derav, for å danne den ønskede 4-alkanoylsubstituerte fenoxyalkansyre, eller hvis den anvendte omega-halogenalkansyre er esterderivatet, hydrolyseres den således dannede 4-alkanoylsubstituerte fenoxyalkansyreester til den tilsvarende syre. Dessuten når begge Z-grupper i utgangsmaterialene angitt ovenfor er halogen, og R er lavere alkyl, og R 1 og R 2 begge er hydrogen, fremstilles reaktantene ved omsetning av et alfa-halogen-alfa-(halogenmethyl)-alkanoylhalogenid med en passende fenoxyalkansyre for å danne den tilsvarende |4_[2-halogen-2-(halogenmethyl)-alkanoyl]-fenoxy|-alkansyrereaktant. Av den foregående beskrivelse vil fremgangs-måtene ved fremstilling av utgangsmaterialene ved foreliggende fremgangsmåte være åpenbare for en fagmann. Også andre fremgangsmåter kan imidlertid anvendes ved fremstilling av disse reaktanter. with a phenyl alkyl ether, e.g. an anisole, to form the corresponding 4-alkanoyl substituted phenyl alkyl ether, which is then either converted to the corresponding phenol by treatment with aluminum chloride, followed by reaction of the phenol with an appropriate omega-haloalkanoic acid, or an ester thereof, to form the desired 4- alkanoyl-substituted phenoxyalkanoic acid, or if the omega-haloalkanoic acid used is the ester derivative, the 4-alkanoyl-substituted phenoxyalkanoic acid ester thus formed is hydrolysed to the corresponding acid. Also, when both Z groups in the starting materials listed above are halogen, and R is lower alkyl, and R 1 and R 2 are both hydrogen, the reactants are prepared by reacting an alpha-halo-alpha-(halomethyl)-alkanoyl halide with an appropriate phenoxyalkanoic acid to form the corresponding |4_[2-halo-2-(halomethyl)-alkanoyl]-phenoxy|-alkanoic acid reactant. From the preceding description, the procedures for producing the starting materials in the present method will be obvious to a person skilled in the art. However, other methods can also be used in the preparation of these reactants.

Foreliggende oppfinnelse angår også fremstilling av syreaddi-sjonssaltene av de ifølge oppfinnelsen fremstilte fenoxy-alkansyrer, som fremstilles ved omsetning av disse syrer med en base med én ikke-toksisk farmasøytisk godtagbar kation. Generelt betraktes en hvilken som helst base som vil danne et syreaddisjonssalt med en carboxylsyre og hvis farmakologiske egenskaper ikke vil bevirke noen uheldig fysiologisk virkning når det opptaes i legemssystemet, som kommende innen rammen av foreliggende oppfinnelse, og egnede baser innbefatter således f.eks. alkalimetall- og jordalkalimetall-hydroxydene, -carbonatene, etc; ammoniakk; primære, sekundære og tertiære aminer, som monoalkylaminer, dialkylaminer og trialkyl-aminer; og heterocycliske aminer, f.eks. piperidin, etc De således fremstilte syreaddisjonssalter er de funksjonelle ekvivalenter av de tilsvarende fenoxyalkansyrer og i den utstrekning fenoxyalkansyrene fremstilt ifølge oppfinnelsen er nyttige i terapi, er syreaddisjons-saltene som omfattes av oppfinnelsen, bare begrenset av det kriterium at basene som anvendes ved dannelse av saltene, er både ikke-toksiske og fysiologisk godtagbare. The present invention also relates to the production of the acid addition salts of the phenoxyalkanoic acids produced according to the invention, which are produced by reacting these acids with a base with one non-toxic pharmaceutically acceptable cation. In general, any base which will form an acid addition salt with a carboxylic acid and whose pharmacological properties will not cause any adverse physiological effect when absorbed into the body system is considered to be within the scope of the present invention, and suitable bases thus include e.g. the alkali metal and alkaline earth metal hydroxides, carbonates, etc; ammonia; primary, secondary and tertiary amines, such as monoalkylamines, dialkylamines and trialkylamines; and heterocyclic amines, e.g. piperidine, etc. The acid addition salts thus prepared are the functional equivalents of the corresponding phenoxyalkanoic acids and to the extent that the phenoxyalkanoic acids prepared according to the invention are useful in therapy, the acid addition salts covered by the invention are only limited by the criterion that the bases used in forming the salts , are both non-toxic and physiologically acceptable.

Farmakologiske studier av produktene fremstilt ved foreliggende fremgangsmåte viser at de er effektive diuretiske og saluretiske midler, og at de således er nyttige ved behandling av tilstander som skyldes en for høy konsentrasjon av elektrolytt i legemet, som ved behandling av vatersott-tUstander som skyldes f.eks. hjertesvikt. Pharmacological studies of the products produced by the present method show that they are effective diuretic and saluretic agents, and that they are thus useful in the treatment of conditions caused by an excessively high concentration of electrolyte in the body, such as in the treatment of dropsy conditions caused by e.g. e.g. heart failure.

Eksempel 1 Example 1

[ 3- klor-4-(2- methylcrotonoyl)- f enoxy]- eddiksyre [3-chloro-4-(2-methylcrotonoyl)-phenoxy]-acetic acid

Trinn A: ( 3- klor- 4- butyrylfenoxy)- eddiksyre Step A: (3-chloro-4-butyrylphenoxy)-acetic acid

217 9 (1,625 mol) pulverisert aluminiumklorid og 4oO ml carbondisulfid anbringes i en 1-liters, 4-halset kolbe forsynt med rører, dråpet rakt, tilbakeløpskjøler og innvendig termometer. 93,3 g (0,5 mol) (3-klorfenoxy)-eddiksyre tilsettes i porsjoner under omrøring og derpå tilsettes 66,6 g (0,625 mol) n-butyrylklorid i porsjoner under omrøring i løpet av en halv time ved en temperatur på ca. 22 - 26°C. Efter omrøring i en time ved værelsetemperatur anbringes reaksjonskolben i et vannbad, og temperaturen holdes på 50°C i 3 timer. Carbondisulfidet dekanteres så fra, og aluminium-komplekset som er tilbake, tilsettes til en blanding av 1 kg is og 100 ml konsentrert saltsyre. Et fast stoff utskilles og oppløses i 1,5 1 mettet natriumbicarbonatoppløsning. Oppløsningen filtreres, og det klare, gule filtrat syres med saltsyre. Den gule olje som utskilles, størkner langsomt under dannelse av. et fast stoff som smelter ved 76 - 85°C. Efter omkrystallisasjon fra benzen fikk man 66,7 g (51%) (3-klor-4-butyrylfenoxy)-eddiksyre med smeltepunkt 89 - 90°C. 217 9 (1.625 mol) of powdered aluminum chloride and 4o0 ml of carbon disulfide are placed in a 1-liter, 4-necked flask equipped with a stirrer, dropper, reflux condenser, and internal thermometer. 93.3 g (0.5 mol) of (3-chlorophenoxy)-acetic acid is added in portions while stirring and then 66.6 g (0.625 mol) of n-butyryl chloride is added in portions while stirring over the course of half an hour at a temperature of about. 22 - 26°C. After stirring for one hour at room temperature, the reaction flask is placed in a water bath, and the temperature is maintained at 50°C for 3 hours. The carbon disulphide is then decanted off, and the remaining aluminum complex is added to a mixture of 1 kg of ice and 100 ml of concentrated hydrochloric acid. A solid is separated and dissolved in 1.5 l of saturated sodium bicarbonate solution. The solution is filtered, and the clear, yellow filtrate is acidified with hydrochloric acid. The yellow oil that is secreted slowly solidifies to form. a solid that melts at 76 - 85°C. After recrystallization from benzene, 66.7 g (51%) of (3-chloro-4-butyrylphenoxy)-acetic acid with a melting point of 89 - 90°C was obtained.

Trinn B: [3-klor-4-(2-dimethylaminomethylbutyryi)-fenoxy]-eddiksyre-hyd roklorid Step B: [3-chloro-4-(2-dimethylaminomethylbutyryi)-phenoxy]-acetic acid hydrochloride

I en lOO ml rundkolbe forsynt med utløpsrør egnet for påføring av leilighetsvis sug, oppvarmes en intim blanding av 5,12 g (0,02 mol) (3-klor-4-butyrylfenoxy)-eddiksyre, 0,7 g (0,022 mol) paraformaldehyd, 1,78 g (0,02 mol) dimethylamid-hydroklorid og 4 dråper eddiksyre på dampbad i ca. 1,5 timer, hvorunder der påføres sug av et minutts varighet 5 eller 6 ganger. Ved avkjøling dannes et fast stoff som krystalliseres fra acetonitril og fra isopropanol, hvorved man får [3-klor-4-(2-dimethylaminomethylbutyryl)-fenoxy]-eddiksyre-hydroklorid med smeltepunkt 127 - 129°C. In a lOO ml round-bottomed flask fitted with an outlet tube suitable for the application of occasional suction, heat an intimate mixture of 5.12 g (0.02 mol) of (3-chloro-4-butyrylphenoxy)-acetic acid, 0.7 g (0.022 mol) paraformaldehyde, 1.78 g (0.02 mol) dimethylamide hydrochloride and 4 drops of acetic acid on a steam bath for approx. 1.5 hours, during which a minute's worth of suction is applied 5 or 6 times. On cooling, a solid is formed which is crystallized from acetonitrile and from isopropanol, whereby one obtains [3-chloro-4-(2-dimethylaminomethylbutyryl)-phenoxy]-acetic acid hydrochloride with a melting point of 127 - 129°C.

Trinn C: [ 3- klor- 4-( 2- methylenbutyryl)- fenoxy]- eddiksyre Step C: [ 3- chloro- 4-( 2- methylenebutyryl)- phenoxy]- acetic acid

Mannich-forbindelsen erholdt som beskrevet i trinn B, oppløses i 25 ml vann, og oppløsningen gjøres svakt basisk ved tilsetning av 10%-ig natriumbicarbonatoppløsning. Den dannede oppløsning oppvarmes i 25 minutter på dampbad, avkjøles og syres med 6 N saltsyre, hvorved man får 3,7 g (69%) råprodukt med smeltepunkt I08 - 109,5°C. Efter omkrystallisasjon fra en blanding av cyclohexan og benzen fåes [3-klor-4-{2-methylenbutyry1)-fenoxy]-eddiksyre i form av en farve-las krystall med smeltepunkt lo9 - 111°C. The Mannich compound obtained as described in step B is dissolved in 25 ml of water, and the solution is made weakly basic by the addition of 10% sodium bicarbonate solution. The resulting solution is heated for 25 minutes on a steam bath, cooled and acidified with 6 N hydrochloric acid, whereby 3.7 g (69%) of crude product with melting point I08 - 109.5°C is obtained. After recrystallization from a mixture of cyclohexane and benzene, [3-chloro-4-{2-methylenebutyryl)-phenoxy]-acetic acid is obtained in the form of a colored crystal with a melting point of 109 - 111°C.

Trinn D: [3-klor-4-(2-methylbutyryl)-fenoxy]-eddiksyre Step D: [3-chloro-4-(2-methylbutyryl)-phenoxy]-acetic acid

57,1 g (0,212 mol) [3-klor-4-(2-methylenbutyryl)-fenoxy]-eddiksyre oppløses i 200 ml isopropanol, og 3,0 g 5%-ig palladium på carbon tilsettes. Blandingen hydrogeneres ved et begynnelsestrykk på o 2,4 kg/cm 2 overtrykk på o et Parr-apparat. i løpet av 40 minutter absorberes den nødvendige mengde hydrogen. Oppløsningen oppvarmes og filtreres for å fjerne katalysatoren, alkoholen fordampes og residuet krystalliseres fra benzen. Man får 4l,2 g [3~klor-4-(2-methylbutyry1)-fenoxy]-eddiksyre med smeltepunkt 13° - 139,5°C. En prøve renset videre ved krystallisasjon fra benzen smelter ved 139 - i4o°c. 57.1 g (0.212 mol) of [3-chloro-4-(2-methylenebutyryl)-phenoxy]-acetic acid is dissolved in 200 ml of isopropanol, and 3.0 g of 5% palladium on carbon is added. The mixture is hydrogenated at an initial pressure of o 2.4 kg/cm 2 overpressure on o a Parr apparatus. within 40 minutes, the required amount of hydrogen is absorbed. The solution is heated and filtered to remove the catalyst, the alcohol is evaporated and the residue is crystallized from benzene. 41.2 g of [3~chloro-4-(2-methylbutyryl)-phenoxy]-acetic acid with a melting point of 13° - 139.5°C is obtained. A sample further purified by crystallization from benzene melts at 139 - 140°C.

Trinn E: [3~klor-4-(2-brom-2-methylbutyryl)-fenoxy]-eddiksyre Step E: [3~chloro-4-(2-bromo-2-methylbutyryl)-phenoxy]-acetic acid

IO g (0,037 mol) [3-klor-4-(2-methylbutyryl)-fenoxy]-eddiksyre oppløses i 200 ml eddiksyre, og 6^0 g (0,037 mol) brom i 50 ml eddiksyre tilsettes dråpevis under omrøring i løpet av ld - 15 minutter. (Reaksjonen initieres i begynnelsen ved tilsetning av 2 dråper 48%-ig hydrogenbromid). Blandingen tilsettes til 1 liter vann inneholdende litt natriumbisulfit. Det faste stoff som utskilles, oppsamles, vaskes med vann, tørres i luft ved 65°C og krystalliseres fra benzen. Produktet, [3-klor-4-(2-brom-2-met hyl-butyryl)-fenoxy]-eddiksyre (IO,9 g), smelter ved 123 - 124°C 10 g (0.037 mol) of [3-chloro-4-(2-methylbutyryl)-phenoxy]-acetic acid is dissolved in 200 ml of acetic acid, and 6^0 g (0.037 mol) of bromine in 50 ml of acetic acid is added dropwise with stirring during ld - 15 minutes. (The reaction is initiated at the beginning by adding 2 drops of 48% hydrogen bromide). The mixture is added to 1 liter of water containing a little sodium bisulphite. The solid which separates is collected, washed with water, dried in air at 65°C and crystallized from benzene. The product, [3-chloro-4-(2-bromo-2-methyl-butyryl)-phenoxy]-acetic acid (10.9 g), melts at 123 - 124°C

Trinn F: [ 3- klor- 4-( 2- methylcrotonoyl)- fenoxy]- eddiksyre Step F: [ 3- chloro- 4-( 2- methylcrotonoyl)- phenoxy]- acetic acid

14 g (0,04 mol) av bromforbindelsen fremstilt i trinn B, 14 g (0.04 mol) of the bromine compound prepared in step B,

5,1 g (0,12 mol) lithiumklorid og dimethylformamid ble blandet og oppvarmet ved 80 - 90°C i 4 timer. Blandingen ble helt i 500 ml vann. Det faste stoff som utskiltes, felles igjen 2 ganger fra natriumbicarbonat og krystalliseres fra benzen, hvorved man får 4,5 g [3-klor-4-(2-methylcrotonoyl)-fenoxy]-eddiksyre med smeltepunkt 114 - 116°C. 5.1 g (0.12 mol) of lithium chloride and dimethylformamide were mixed and heated at 80-90°C for 4 hours. The mixture was poured into 500 ml of water. The solid that separates is separated twice from sodium bicarbonate and crystallized from benzene, whereby 4.5 g of [3-chloro-4-(2-methylcrotonoyl)-phenoxy]-acetic acid with a melting point of 114 - 116°C is obtained.

Eksempel 2 Example 2

( 3- klor- 4- orethacryloylfenoxy)- eddiksyre (3-chloro-4-orethacryloylphenoxy)-acetic acid

Trinn A: ( 3- klor- 4- isobutyrylfenoxy)- eddiksyre Step A: (3-chloro-4-isobutyrylphenoxy)-acetic acid

En 1-liters, 4-halset kolbe forsynes med en effektiv rører, dråpetrakt, tilbakeløpskjøler og innvendig termometer. Kolben flammetørres under spyling med nitrogengass. 83,9' g (0,63 mol) pulverisert aluminiumklorid ble anbrakt i en kolbe sammen med 200 ml carbondisulfid. 37,3 g (0,20 mol) 3-klorfenoxyeddiksyre ble tilsatt i porsjoner under omrøring. 26,6 g (0,25 mol) isobutyrylklorid ble så tilsatt dråpevis under omrøring i løpet av 30 minutter. Temperaturen steg sakte fra 22°C til 26°C, og carbondisulfidet kokte rolig under tilbakeløp. Efter omrøring i en time ved værelsetemperatur ble reaksjonskolben neddykket i et vannbad, og vannbadtemperaturen ble holdt på 50°C i 3 timer. Efter en time gjorde utskillelsen av et viskøst bunnfall omrøring umulig. A 1-litre, 4-necked flask is provided with an efficient stirrer, dropping funnel, reflux condenser and internal thermometer. The flask is flame-dried while purging with nitrogen gas. 83.9 g (0.63 mol) of powdered aluminum chloride was placed in a flask along with 200 ml of carbon disulfide. 37.3 g (0.20 mol) of 3-chlorophenoxyacetic acid was added in portions with stirring. 26.6 g (0.25 mol) of isobutyryl chloride was then added dropwise with stirring over the course of 30 minutes. The temperature rose slowly from 22°C to 26°C, and the carbon disulphide slowly boiled under reflux. After stirring for one hour at room temperature, the reaction flask was immersed in a water bath, and the water bath temperature was maintained at 50°C for 3 hours. After an hour, the separation of a viscous precipitate made stirring impossible.

Efter at oppvarmningsperioden var avsluttet, ble carbondi-sulf idet fradekantert, og det viskøse aluminiumkompleks ble skrapet ut av kolben og tilsatt i porsjoner til en blanding av 500 g is og 125 ml konsentrert saltsyre. Et gult fast stoff utskiltes. Da isen var smeltet, ble blandingen ekstrahert med 250 ml benzen. På dette punkt ble der dannet et uoppløselig fast stoff på skille-flaten mellom benzen og vann. Vannskiktet ble fraskilt, og benzen-oppløsningen inneholdende det suspenderte, uoppløselige, faste stoff ble avkjølt i et isbad og derpå filtrert, hvorpå man fikk 23,9 g av et fuktig råprodukt. Det faste stoff ble tilsatt sakte til 200 ml mettet natriumbicarbonatoppløsning og triturert inntil nesten alt var oppløst. Da brusingen opphørte, var der en liten mengde uoppløst, gult, mykt, fast stoff tilbake. Dette ble fjernet ved filtrering, og filtratet ble forsiktig syret med konsentrert saltsyre. Efter avkjøling av blandingen i et isbad ble et visst bunnfall oppsamlet ved filtrering og tørret i en ovn ved 65°C. Utbyttet var 8,93 g (17,3%) (3~klor-4-isobutyrylfenoxy)-eddiksyre med smeltepunkt 137 - 139°C (korrigert). After the heating period was over, the carbon disulfide was decanted off, and the viscous aluminum complex was scraped from the flask and added in portions to a mixture of 500 g of ice and 125 ml of concentrated hydrochloric acid. A yellow solid is separated. When the ice had melted, the mixture was extracted with 250 ml of benzene. At this point, an insoluble solid formed on the interface between benzene and water. The aqueous layer was separated and the benzene solution containing the suspended insoluble solid was cooled in an ice bath and then filtered to give 23.9 g of a moist crude product. The solid was added slowly to 200 mL of saturated sodium bicarbonate solution and triturated until nearly all dissolved. When the effervescence ceased, a small amount of undissolved, yellow, soft, solid remained. This was removed by filtration, and the filtrate was carefully acidified with concentrated hydrochloric acid. After cooling the mixture in an ice bath, a certain precipitate was collected by filtration and dried in an oven at 65°C. The yield was 8.93 g (17.3%) of (3-chloro-4-isobutyrylphenoxy)-acetic acid with a melting point of 137-139°C (corrected).

Trinn B: [ 3- klor- 4-( 2- bromisobutyryi)- fenoxy]-eddiksyre Step B: [3-chloro-4-(2-bromisobutyryi)-phenoxy]-acetic acid

10,.17 g (0,0397 mol) ( 3-klor-4-isobutyrylf enoxy) -eddiksyre ble oppløst i 250 ml iseddik ved værelsetemperatur i en 500 ml rundbunnet kolbe forsynt med rører, dråpetrakt og utløpsrør. 6,34 g (0,0397 mol) brom i 30 ml iseddik ble tilsatt dråpevis til reak- 10.17 g (0.0397 mol) (3-chloro-4-isobutyryl enoxy)-acetic acid was dissolved in 250 ml glacial acetic acid at room temperature in a 500 ml round-bottomed flask fitted with a stirrer, dropping funnel and outlet tube. 6.34 g (0.0397 mol) bromine in 30 ml glacial acetic acid was added dropwise to the reaction

sjonsblandingen ved 25°C under omrøring i løpet av en time. Bromet reagerte lett, og noe hydrogenbromid ble utviklet. Omrøringen ble fortsatt i ytterligere en time, og derpå ble blandingen tilsatt til en blanding av 300 g is og 500 ml vann. Et hvitt, fast stoff utskiltes og ble frafiltrert ved sugning efter at isen var smeltet. Det faste stoff ble vasket på filteret med litt vann og tørret ved 65°C til konstant vekt. Råproduktet ble krystallisert fra 7o ml benzen og blandingen avkjølt til værelsetemperatur i løpet av 30 minutter og avkjølt ved 5°C i en time. 8,39 g (63%) [3~klor-4-(2-bromisobutyryl)-fenoxy]-eddiksyre ble oppsamlet ved sugefiltrering og tørret ved 65°C og hadde et smeltepunkt på 124,5 - 125°C (korrigert). tion mixture at 25°C with stirring during one hour. The bromine reacted readily, and some hydrogen bromide was evolved. Stirring was continued for a further hour, and then the mixture was added to a mixture of 300 g of ice and 500 ml of water. A white, solid substance separated and was filtered off by suction after the ice had melted. The solid was washed on the filter with a little water and dried at 65°C to constant weight. The crude product was crystallized from 70 ml of benzene and the mixture cooled to room temperature over 30 minutes and cooled at 5°C for one hour. 8.39 g (63%) of [3~chloro-4-(2-bromoisobutyryl)-phenoxy]-acetic acid was collected by suction filtration and dried at 65°C and had a melting point of 124.5 - 125°C (corrected) .

Trinn C: ( 3- klor- 4- methacryloylfenoxy)- eddiksyre Step C: (3-chloro-4-methacryloylphenoxy)-acetic acid

•5 g (0,Ol49 mol) av den bromerte forbindelse fra trinn B ble oppløst i 200 ml benzen i en 500 ml rundbunnet kolbe forsynt med rører og tilbakeløpskjøler. 5 g (0,02990 mol) sølvacetat ble tilsatt, og blandingen ble omrørt og kokt under tilbakeløp i 3 timer. Blandingen ble avkjølt, og 150 ml vann og 15 ml konsentrert saltsyre ble tilsatt. Vannfasen ble fraskilt, og benzenskiktet ble tørret over natriumsulfat og konsentrert til 50 ml. Ved avkjøling utskiltes 2,8 g av et fast stoff med smeltepunkt 125 - 127°C. Det faste stoff ble krystallisert fire ganger fra benzen for å få 1,05 g (3-klor-4-methacryloylfenoxy)-eddiksyre med smeltepunkt 128 - 129°C (korrigert). •5 g (0.0149 mol) of the brominated compound from step B was dissolved in 200 ml of benzene in a 500 ml round-bottomed flask fitted with a stirrer and a reflux condenser. 5 g (0.02990 mol) of silver acetate was added and the mixture was stirred and refluxed for 3 hours. The mixture was cooled and 150 ml of water and 15 ml of concentrated hydrochloric acid were added. The water phase was separated, and the benzene layer was dried over sodium sulfate and concentrated to 50 ml. On cooling, 2.8 g of a solid with a melting point of 125 - 127°C are separated. The solid was crystallized four times from benzene to give 1.05 g of (3-chloro-4-methacryloylphenoxy)-acetic acid, mp 128-129°C (corrected).

Eks empel 3 Example 3

( 4- methacryloylfenoxy)- eddiksyre (4-methacryloylphenoxy)-acetic acid

Trinn A: ( 4- isobutyrylfenoxy)- eddiksyre Step A: (4-isobutyrylphenoxy)-acetic acid

l6o g (1,2 mol) pulverisert aluminiumklorid og 200 ml carbon-disulf id ble anbrakt i en 1-liters, 4-halset kolbe forsynt med rører, dråpetrakt, tilbakeløpskjøler og innvendig termometer. 6l g (0,4 mol) fenoxyeddiksyre ble tilsatt i porsjoner under omrøring og derpå ble 53,5 g (0,5 mol),isobutyrylklorid tilsatt dråpevis under omrøring i løpet av en halv time med en temperatur på ca. 22 - 26°C. Efter omrøring i en time ved værelsetemperatur ble reaksjonskolben anbrakt i et vannbad og temperaturen holdt på 50°C i 3 timer. Carbondisulfidet ble så fradekantert, og det gjenværende aluminiumkompleks ble tilsatt til en blanding av 500 g is og 125 ml konsentrert saltsyre. Den gule olje som ble dannet, ble fraskilt og ga 160 g (1.2 mol) of powdered aluminum chloride and 200 ml of carbon disulfide were placed in a 1-liter, 4-necked flask equipped with a stirrer, dropping funnel, reflux condenser, and internal thermometer. 6l g (0.4 mol) of phenoxyacetic acid was added in portions with stirring and then 53.5 g (0.5 mol) of isobutyryl chloride was added dropwise with stirring during half an hour at a temperature of approx. 22 - 26°C. After stirring for one hour at room temperature, the reaction flask was placed in a water bath and the temperature maintained at 50°C for 3 hours. The carbon disulfide was then decanted off, and the remaining aluminum complex was added to a mixture of 500 g of ice and 125 ml of concentrated hydrochloric acid. The yellow oil which formed was separated to give

51,6 g (4-isobutyrylfenoxy)-eddiksyre med kokepunkt 185 - 190°C 51.6 g (4-isobutyrylphenoxy)-acetic acid with boiling point 185 - 190°C

(1 mm trykk). (1 mm pressure).

Trinn B: [4~( 2- bromisobutyryl)- fenoxy]- eddiksyre Step B: [4~(2-bromisobutyryl)-phenoxy]-acetic acid

35,6 g (0,l6 mol) (4-isobutyrylfenoxy)-eddiksyre ble tilsatt til 125 ml iseddik ved værelsetemperatur. 25,7 g (0,l6 mol) brom i 30 ml iseddik ble tilsatt dråpevis til reaksjonsblandingen ved 25°C under omrøring i løpet av en time. Omrøringen ble fortsatt i ytterligere en time, og derpå ble blandingen tilsatt til en blanding av 300 g is og 500 ml vann. Det faste stoff som utskiltes, ble oppsamlet på et filter, vasket og omkrystallisert fra benzen, hvorved man fikk 33 g [4-(2-bromisobutyryl)-fenoxy]-eddiksyre med smeltepunkt 144 - i45°c. 35.6 g (0.16 mol) of (4-isobutyrylphenoxy)-acetic acid was added to 125 ml of glacial acetic acid at room temperature. 25.7 g (0.16 mol) of bromine in 30 ml of glacial acetic acid was added dropwise to the reaction mixture at 25°C with stirring over the course of one hour. Stirring was continued for a further hour, and then the mixture was added to a mixture of 300 g of ice and 500 ml of water. The solid which separated was collected on a filter, washed and recrystallized from benzene, whereby 33 g of [4-(2-bromoisobutyryl)-phenoxy]-acetic acid with a melting point of 144-145°C was obtained.

Trinn C: ( 4- methacryloylfenoxy)- eddiksyre Step C: (4-methacryloylphenoxy)-acetic acid

12 g (0,o4 mol) av den bromerte forbindelse erholdt i trinn B ble oppløst i 800 ml benzen, og 15 g (0,09 mol) sølvacetat ble tilsatt. Blandingen ble omrørt og kokt under tilbakeløp i 4 timer og derpå avkjølt. 150 ml vann og 15 ml konsentrert saltsyre ble tilsatt, hvorpå sølvsaltene ble felt og fjernet ved filtrering. Benzenet ble så inndampet til lite volum, fortynnet med hexan, og det faste stoff som utskiltes, ble krystallisert fra benzen, hvorved man fikk (4-methacryloylfenoxy)-eddiksyre med smeltepunkt 124,5 - 126,5°C i et utbytte på 4,1 g. 12 g (0.04 mol) of the brominated compound obtained in step B was dissolved in 800 ml of benzene, and 15 g (0.09 mol) of silver acetate was added. The mixture was stirred and refluxed for 4 hours and then cooled. 150 ml of water and 15 ml of concentrated hydrochloric acid were added, after which the silver salts were precipitated and removed by filtration. The benzene was then evaporated to a small volume, diluted with hexane, and the solid that separated was crystallized from benzene, whereby (4-methacryloylphenoxy)-acetic acid with a melting point of 124.5 - 126.5°C was obtained in a yield of 4 .1 g.

Eksempel 4 Example 4

[ 3- klor- 4-( 2- ethylidenbutyryl)-fenoxy]-eddiksyre [3-chloro-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid

Trinn A: 3- klor- 4-( 2- ethylbutyryl)- fenol Step A: 3-chloro-4-(2-ethylbutyryl)-phenol

Til en blanding av 31,52 g (0,2 mol) 3-klorfenetol og 26,92 g (0,2 mol) alfa-ethyl-butyrylklorid i petrolether ble 73,34 g (0,6 mol) aluminiumklorid tilsatt gradvis under omrøring ved 5°C i løpet av 0,5 timer. Blandingen ble omrørt ved 5°C i 20 minutter og fikk så lov til å oppvarmes til 25°C under omirøring i ytterligere 3 timer. Blandingen ble så holdt ved 25 - 30°C i 48 timer. Pet roi-etheren ble så fradekantert og residuet tilsatt til 500 g is inneholdende 40 ml konsentrert saltsyre. Den mørke olje som utskiltes, ble ekstrahert med ether og etheroppløsningen vasket med vann og ekstrahert med 2,5%-ig natriumhydroxyd. Natriumhydroxydekstraktet ble behandlet med Norite, filtrert fri for carbon og syret med saltsyre, hvorved man fikk en grønn olje som derpå ble ekstrahert med ether. Etherekstraktet ble tørret over natriumsulfat, etheren fordampet og residuet destillert ved 148 - l8l°C ved 0,3 mm trykk, hvorved man fikk 11,44 g (25%) 3-klor-4-(2-ethylbutyryl)-fenol. To a mixture of 31.52 g (0.2 mol) 3-chlorophenetol and 26.92 g (0.2 mol) alpha-ethyl-butyryl chloride in petroleum ether, 73.34 g (0.6 mol) aluminum chloride was added gradually under stirring at 5°C during 0.5 hours. The mixture was stirred at 5°C for 20 minutes and then allowed to warm to 25°C with stirring for an additional 3 hours. The mixture was then kept at 25-30°C for 48 hours. The petroi ether was then decanted off and the residue added to 500 g of ice containing 40 ml of concentrated hydrochloric acid. The dark oil which separated was extracted with ether and the ether solution washed with water and extracted with 2.5% sodium hydroxide. The sodium hydroxide extract was treated with Norite, filtered free of carbon and acidified with hydrochloric acid, whereby a green oil was obtained which was then extracted with ether. The ether extract was dried over sodium sulphate, the ether evaporated and the residue distilled at 148 - 181°C at 0.3 mm pressure, whereby 11.44 g (25%) of 3-chloro-4-(2-ethylbutyryl)-phenol was obtained.

Trinn B: [3-klor-4-(2-ethylbutyryl)-fenoxy]-eddiksyre Step B: [3-chloro-4-(2-ethylbutyryl)-phenoxy]-acetic acid

11,44 g (0,050 mol) 4-(2-ethylbutyryl)-3-klorfenol i til-strekkelig glycoldimethylether til å oppløse den ble tilsatt langsomt til en suspensjon av 2,42 g (0,05 mol) natriumhydrid (51% i mineralolje) i glycoldimethylether. Blandingen omrøres i 15 minutter, og 8,45 g (0,050 mol) ethylbromacetat tilsettes dråpevis under omrøring. Blandingen kokes så under tilbakeløp i 2,5 timer, og glycoldimethyletheren fordampes under nedsatt trykk ved (8o - 90°C. 4,14 g (0,101 mol) natriumhydroxyd i 30 ml vann tilsettes til residuet, blandingen omrøres og oppvarmes ved 90°C i 1,5 timer, og den gjenværende mineralolje ekstraheres med ether fra den avkjølte oppløsning. Vannskiktet syres med saltsyre, og det faste materiale som utskilles, oppløses i natriumbicarbonatoppløsning og behandles med "Nor it e", filtreres og. syres, hvorved man får 12,3 9 (85%) [3-klor-4-(2-ethylbutyryl)-fenoxy-eddiksyre, som efter tørring i luft smeltet ved 146 - l47°C. Krystallisasjon fra benzen ga et produkt som smelter ved 147 - l49°C. 11.44 g (0.050 mol) of 4-(2-ethylbutyryl)-3-chlorophenol in sufficient glycol dimethyl ether to dissolve it was added slowly to a suspension of 2.42 g (0.05 mol) of sodium hydride (51% in mineral oil) in glycol dimethyl ether. The mixture is stirred for 15 minutes, and 8.45 g (0.050 mol) of ethyl bromoacetate is added dropwise with stirring. The mixture is then refluxed for 2.5 hours, and the glycol dimethyl ether is evaporated under reduced pressure at (8o - 90°C. 4.14 g (0.101 mol) of sodium hydroxide in 30 ml of water is added to the residue, the mixture is stirred and heated at 90°C for 1.5 hours, and the remaining mineral oil is extracted with ether from the cooled solution. The aqueous layer is acidified with hydrochloric acid, and the solid material which separates is dissolved in sodium bicarbonate solution and treated with "Nor it e", filtered and. acidified, thereby obtaining 12.3 9 (85%) [3-chloro-4-(2-ethylbutyryl)-phenoxy-acetic acid, which after drying in air melted at 146 - 147° C. Crystallization from benzene gave a product melting at 147 - 149 °C.

Trinn C: f 3- klor- 4-( 2- ethy1- 2- brombutyryi)- fenoxy]- eddiksyre Step C: f 3-chloro-4-(2-ethyl-2-bromobutyryl)-phenoxy]-acetic acid

Til en oppløsning av IO,64 g (0,0374 mol) [3-klor-4-(2-ethyl-butyryl)-fenoxy]-eddiksyre i 200 ml eddiksyre tilsettes under om-røring 2 dråper 48%-ig hydrogenbromid, fulgt av dråpevis tilsetning av 6,0 g (0,0374 mol) brom i 50 ml eddiksyre. Efter at tilsetningen var avsluttet, ble blandingen omrørt i 15 minutter og derpå helt i en liter vann inneholdende 2 g natriumbisulfit. Det faste stoff som utskiltes, ble oppsamlet på et filter, vasket med vann, tørret i luft og krystallisert fra 55 ml benzen, hvorved man fikk lO,l6 g [3-klor-4-(2-ethyl-2-brombutyryl)-fenoxy]-eddiksyre som smeltet ved 130 - 131°C. To a solution of 10.64 g (0.0374 mol) [3-chloro-4-(2-ethyl-butyryl)-phenoxy]-acetic acid in 200 ml of acetic acid, 2 drops of 48% hydrogen bromide are added with stirring, followed by the dropwise addition of 6.0 g (0.0374 mol) of bromine in 50 ml of acetic acid. After the addition was finished, the mixture was stirred for 15 minutes and then poured into one liter of water containing 2 g of sodium bisulphite. The solid which separated was collected on a filter, washed with water, dried in air and crystallized from 55 ml of benzene to give 10.16 g of [3-chloro-4-(2-ethyl-2-bromobutyryl)- phenoxy]-acetic acid which melted at 130 - 131°C.

Trinn D; [3-klor-4-(2-ethylidenbutyryl)-fenoxy]-eddiksyre Step D; [3-Chloro-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid

6 g (0,0l85 mol) av bromketonet fremstilt i trinn B ble opp-løst i 400 ml varm benzen. 7 g (0,042 mol) pulverisert sølvacetat ble tilsatt sakte under mekanisk omrøring. Blandingen ble oppvarmet i ca. 5,5 timer og derpå syret med 6 N saltsyre. Sølvsaltene som ble dannet, ble fjernet ved filtrering, benzenskiktet ble fraskilt, og 6 g (0.0185 mol) of the bromoketone prepared in step B was dissolved in 400 ml of hot benzene. 7 g (0.042 mol) of powdered silver acetate was added slowly with mechanical stirring. The mixture was heated for approx. 5.5 hours and then acidified with 6 N hydrochloric acid. The silver salts which were formed were removed by filtration, the benzene layer was separated, and

2 g "Darco" ble tilsatt, og blandingen ble holdt ved 25 - 30°C i 2 g "Darco" was added and the mixture was kept at 25-30°C i

48 timer. Oppløsningen ble så filtrert, fortynnet med ether og ekstrahert med 5%-ig natriumbicarbonatoppløsning. Vannekstraktet ble behandlet med"Norite", og syret, hvorved man fikk [3-klor-4-(2-ethylidenbutyryl)-fenoxy]-eddiksyre som, efter tørring i luft ved 65°C og omkrystallisasjon fra benzen, smeltet ved 118 - 119°C. Utbyttet var 2,9 g. 48 hours. The solution was then filtered, diluted with ether and extracted with 5% sodium bicarbonate solution. The water extract was treated with "Norite", and the acid, whereby [3-chloro-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid was obtained which, after drying in air at 65°C and recrystallization from benzene, melted at 118 - 119°C. The yield was 2.9 g.

Eksempel 5 Example 5

[3-klor-4-(2-ethylidenbutyryl)-fenoxy]-eddiksyre [3-Chloro-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid

8,3 g (0,0228 mol) av bromketonet fremstilt i eksempel 5, trinn C, ble oppløst i 6o ml dimethylformamid, og 2,9 9 (0,0684 mol) vannfritt 1ithiumklorid ble tilsatt. Blandingen ble oppvarmet på dampbad i 2 timer under leilighetsvis ryst ing, avkjølt og helt i en liter koldt vann. Det faste stoff som utskiltes, ble oppsamlet ved filtrering, vasket med 500 ml vann og så oppløst i fortynnet natriumbicarbonatoppløsning. Oppløsningen ble rystet med"Norite" filtrert fri for fast stoff og syret. Det faste stoff som utskiltes, ble tørret i luft, hvorved man fikk 5 9 [3-klor-4-(2-ethyliden-butyryl)-fenoxy]-eddiksyre som, efter omkrystallisasjon fra benzen, smeltet ved 118 - 119°C. Utbyttet var 2,9 g. 8.3 g (0.0228 mol) of the bromoketone prepared in Example 5, step C, was dissolved in 60 ml of dimethylformamide, and 2.9 g (0.0684 mol) of anhydrous lithium chloride was added. The mixture was heated on a steam bath for 2 hours with occasional shaking, cooled and poured into one liter of cold water. The solid that separated was collected by filtration, washed with 500 ml of water and then dissolved in dilute sodium bicarbonate solution. The solution was shaken with "Norite" filtered free of solids and the acid. The solid which separated was dried in air, whereby 5 9 [3-chloro-4-(2-ethylidene-butyryl)-phenoxy]-acetic acid was obtained which, after recrystallization from benzene, melted at 118 - 119°C. The yield was 2.9 g.

Eksempel 6 Example 6

[3-klor-4~(crotonoyl)-fenoxy]-eddiksyre [3-Chloro-4~(crotonoyl)-phenoxy]-acetic acid

Trinn A: [3-klor-4-(3-klorbutyryl)-fenoxy]-eddiksyre Step A: [3-chloro-4-(3-chlorobutyryl)-phenoxy]-acetic acid

Til en suspensjon av 33,3 9 (0,25 mol) aluminiumklorid og To a suspension of 33.3 9 (0.25 mol) aluminum chloride and

9,4 g (0,05 mol) 3-klorfenoxyeddiksyre ble tilsatt en oppløsning av 7,75 g (0,055 mol) 3-klorbutyrylklorid i 25 ml carbondisulfid i løpet av 15 minutter ved værelsetemperatur. Blandingen ble omrørt ved værelsetemperatur i 30 minutter og carbondisulfidet fradekantert. Residuet ble avkjølt i et isbad og behandlet med 125 ml isvann og 25 ml konsentrert saltsyre. Produktet ble ekstrahert med ether, etherekstraktet ble vasket med vann, tørret over natriumsulfat, filtrert og inndampet til tørrhet på dampbad. Residuet ble krystallisert fra en blanding av benzen og hexan, hvorved man fikk [3-klor-4-(3-klorbutyryl)-fenoxy]-eddiksyre med smeltepunkt 102,5 - io4°c. 9.4 g (0.05 mol) of 3-chlorophenoxyacetic acid was added to a solution of 7.75 g (0.055 mol) of 3-chlorobutyryl chloride in 25 ml of carbon disulfide over 15 minutes at room temperature. The mixture was stirred at room temperature for 30 minutes and the carbon disulphide decanted off. The residue was cooled in an ice bath and treated with 125 ml of ice water and 25 ml of concentrated hydrochloric acid. The product was extracted with ether, the ether extract was washed with water, dried over sodium sulfate, filtered and evaporated to dryness on a steam bath. The residue was crystallized from a mixture of benzene and hexane, whereby [3-chloro-4-(3-chlorobutyryl)-phenoxy]-acetic acid with a melting point of 102.5 - 104°C was obtained.

Trinn B: [3-klor- 4-( crotonoyl)- fenoxy]- eddiksyre Step B: [3-chloro-4-(crotonoyl)-phenoxy]-acetic acid

En oppløsning av 1,5 g (0,005 mol) [3-klor-4-(3-klorbutyryl)-fenoxy]-eddiksyre i IO ml methanol inneholdende 1,5 g (0,015 mol) friskt smeltet kaliumacetat fikk lov til å stå ved værelsetemperatur i 5"timer og ble så inndampet til tørrhet i vakuum ved værelsetemperatur. Residuet ble oppløst i vann, syret med fortynnet saltsyre, og produktet ekstrahert med ether. Etherekstraktet ble vasket med vann, tørret over natriumsulfat, filtrert og inndampet til tørrhet på dampbad. Residuet ble krystallisert fra en blanding av benzen og methylcyclohexan, hvorved man fikk [3-klor-4~(crotonoyl)-fenoxy]-eddiksyre med smeltepunkt 117 - 119°C. A solution of 1.5 g (0.005 mol) of [3-chloro-4-(3-chlorobutyryl)-phenoxy]-acetic acid in 10 ml of methanol containing 1.5 g (0.015 mol) of freshly melted potassium acetate was allowed to stand room temperature for 5 hours and then evaporated to dryness in vacuo at room temperature. The residue was dissolved in water, acidified with dilute hydrochloric acid, and the product extracted with ether. The ether extract was washed with water, dried over sodium sulfate, filtered and evaporated to dryness on a steam bath The residue was crystallized from a mixture of benzene and methylcyclohexane, whereby [3-chloro-4~(crotonoyl)-phenoxy]-acetic acid with a melting point of 117 - 119°C was obtained.

Eksempel 7 Example 7

[ 3- methy1- 4-( 2- bromcrotonoyl)-fenoxy]-eddiksyre [3-methyl-4-(2-bromocrotonoyl)-phenoxy]-acetic acid

Trinn A: ( 3- methyl- 4- crotonoylfenoxy)- eddiksyre Step A: (3-methyl-4-crotonoylphenoxy)-acetic acid

Til en blanding av 16,6 g (0,1 mol) (3-methylfenoxy)-eddiksyre og IO,5 g (0,1 mol) propanoylklorid i 150 ml carbondisulfid, avkjølt i et isbad ble tilsatt 40 g (0,3 mol) aluminiumklorid porsjonsvis i løpet av 45 minutter. Blandingen ble holdt på en temperatur på mellom 0 - 15°C i 5 timer og derpå ved værelsetemperatur i l8 timer. Det gule kompleks ble oppsamlet på et filter og tilsatt porsjonsvis til en blanding av 250 mg is og 50 ml konsentrert saltsyre. Det fremstilte faste materiale ble ekstrahert med ether, og etherekstraktet ble vasket med vann, tørret over natriumsulfat, filtrert og inndampet til tørrhet. Residuet ble krystallisert fra en blanding av benzen og methylcyclohexan, hvorved man fikk (3-methyl-4-crotonoylfenoxy)-eddiksyre med smeltepunkt 85 - 87°C. 40 g (0.3 mol) of aluminum chloride in portions over the course of 45 minutes. The mixture was kept at a temperature of between 0 - 15°C for 5 hours and then at room temperature for 18 hours. The yellow complex was collected on a filter and added portionwise to a mixture of 250 mg of ice and 50 ml of concentrated hydrochloric acid. The solid material produced was extracted with ether, and the ether extract was washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was crystallized from a mixture of benzene and methylcyclohexane, whereby (3-methyl-4-crotonoylphenoxy)-acetic acid with a melting point of 85 - 87°C was obtained.

Trinn B: [ 3~ methyl- 4-( 2, 3- dibrombutyryl)- fenoxy]- eddiksyre Step B: [ 3~ methyl- 4-( 2, 3- dibromobutyryl)- phenoxy]- acetic acid

En oppløsning av 3,2 g (0,02 mol) brom i 25 ml kloroform bl<*>e tilsatt dråpevis i løpet av 30 minutter til en oppløsning av 4,7 9 (0,02 mol) [3-methyl-4-(crotonoyl)-fenoxy]-eddiksyre i 50 ml ether avkjølt i et isbad. Efter omrøring i 45 minutter ved værelsetemperatur ble oppløsningen inndampet til tørrhet i vakuum, og residuet ble krystallisert fra en blanding av benzen og methylcyclohexan, hvorved man fikk [3-methyl-4-(2,3-dibrombutyryl)-fenoxy]-eddiksyre med smeltepunkt 119 - 121°c. A solution of 3.2 g (0.02 mol) bromine in 25 ml chloroform was added dropwise over 30 minutes to a solution of 4.7 9 (0.02 mol) [3-methyl-4 -(crotonoyl)-phenoxy]-acetic acid in 50 ml of ether cooled in an ice bath. After stirring for 45 minutes at room temperature, the solution was evaporated to dryness in vacuo, and the residue was crystallized from a mixture of benzene and methylcyclohexane, whereby [3-methyl-4-(2,3-dibromobutyryl)-phenoxy]-acetic acid was obtained with melting point 119 - 121°c.

Trinn C: [3-methyl-4-(2-bromcrotonoyl)-fenoxy]-eddiksyre Step C: [3-methyl-4-(2-bromocrotonoyl)-phenoxy]-acetic acid

En oppløsning av 3,9 g (0,01 mol) [3-methyl-4-(2,3-dibrom-butyryi)-fenoxy]-eddiksyre i 50 ml methanol inneholdende 3,0 g A solution of 3.9 g (0.01 mol) [3-methyl-4-(2,3-dibromo-butyryl)-phenoxy]-acetic acid in 50 ml of methanol containing 3.0 g

(0,03 mol) kaliumacetat ble omrørt ved værelsetemperatur i 48 timer, filtrert og inndampet til tørrhet i vakuum. Residuet ble oppløst i vann, syret med fortynnet saltsyre, og produktet ble ekstrahert med ether. Etherekstraktet ble vasket med vann, tørret over natriumsulfat , filtrert, konsentrert og eluert med petrolether, hvorved man fikk [3-methyl-4-(2-bromcrotonoyl)-fenoxy]-eddiksyre med smeltepunkt 137 - i4o°c. (0.03 mol) of potassium acetate was stirred at room temperature for 48 hours, filtered and evaporated to dryness in vacuo. The residue was dissolved in water, acidified with dilute hydrochloric acid, and the product was extracted with ether. The ether extract was washed with water, dried over sodium sulfate, filtered, concentrated and eluted with petroleum ether, thereby obtaining [3-methyl-4-(2-bromocrotonoyl)-phenoxy]-acetic acid with a melting point of 137 - 140°C.

Eksempel 8 Example 8

[ 3- klor-4-(2-brom-3-fenylacryloyl)-f enoxy]-eddiksyre Trinn A: ( 3- klor- 4~ acetylfenoxy)- eddiksyre [ 3-chloro-4-(2-bromo-3-phenylacryloyl)-phenoxy]-acetic acid Step A: ( 3-chloro-4~ acetylphenoxy)-acetic acid

43,5 g (0,325 mol) pulverisert aluminiumklorid og 150 ml carbondisulfid ble anbrakt i en 1-liters, 4-halset kolbe forsynt med rører, dråpetrakt, tilbakeløpskjøler og innvendig termometer. 43.5 g (0.325 mol) of powdered aluminum chloride and 150 mL of carbon disulfide were placed in a 1-liter, 4-necked flask equipped with a stirrer, dropping funnel, reflux condenser, and internal thermometer.

17,06 g (0,1 mol) (3-klorfenoxy)-eddiksyre ble tilsatt porsjonsvis under omrøring, og derpå ble 7,85 g (0,125 mol) acetylklorid tilsatt dråpevis under omrøring i løpet av 0,5 timer ved en temperatur på ca. 22 - 26°C. Efter omrøring i en time ved værelsetemperatur ble reaksjonskolben anbrakt i et vannbad og temperaturen holdt ved 50°C i 3 timer. Carbondisulfidet ble så fradekantert, og aluminium-komplekset som var igjen, ble tilsatt til en blanding av 500 g is og 125 ml konsentrert saltsyre. Det erholdte produkt ble felt igjen fra en natriumbicarbonatoppløsning ved syring med saltsyre, hvorved man fikk et hvitt, fast stoff som, når det ble omkrystallisert fra benzen, ga 4,94 g (3-klor-4-acetylfenoxy)-eddiksyre med smeltepunkt 107 - 109°C. 17.06 g (0.1 mol) of (3-chlorophenoxy)-acetic acid was added portionwise with stirring, and then 7.85 g (0.125 mol) of acetyl chloride was added dropwise with stirring over 0.5 hours at a temperature of about. 22 - 26°C. After stirring for one hour at room temperature, the reaction flask was placed in a water bath and the temperature was maintained at 50°C for 3 hours. The carbon disulphide was then decanted off, and the remaining aluminum complex was added to a mixture of 500 g of ice and 125 ml of concentrated hydrochloric acid. The product obtained was precipitated again from a sodium bicarbonate solution by acidification with hydrochloric acid to give a white solid which, when recrystallized from benzene, gave 4.94 g of (3-chloro-4-acetylphenoxy)-acetic acid, m.p. 107 - 109°C.

Trinn B: [ 3- klor -4-( 3 - f enylacryloyl.) -f enoxy ]-eddiksyre Step B: [3-Chloro-4-(3-phenylacryloyl.)-phenoxy]-acetic acid

4,4 g (0,0193 mol) (3-klor-4-acetylfenoxy)-eddiksyre og 2,1 g (0,0193 mol) benzaldehyd ble oppløst i en blanding av 1,8 g (0,45 mol) natriumhydroxyd i l6o ml vann og 10 ml ethanol. Oppløsningen ble holdt ved 25 - 30°C i 16 timer. Ble så syret, og det faste stoff som utskiltes, ble oppsamlet, tørret ved 65°C og krystallisert fra benzen, hvorved man fikk 1,2 g [3-klor-4-(3-fenylacryloyl)-fenoxy]-eddiksyre med smeltepunkt 139 - l4o°C. 4.4 g (0.0193 mol) (3-chloro-4-acetylphenoxy)-acetic acid and 2.1 g (0.0193 mol) benzaldehyde were dissolved in a mixture of 1.8 g (0.45 mol) sodium hydroxide in 160 ml of water and 10 ml of ethanol. The solution was kept at 25-30°C for 16 hours. It was then acidified, and the solid which separated was collected, dried at 65°C and crystallized from benzene to give 1.2 g of [3-chloro-4-(3-phenylacryloyl)-phenoxy]-acetic acid of m.p. 139 - 140°C.

Trinn C: f 3-klor-4-(2, 3- dibrom- 3- f enylpropiony1)- f enoxy j- eddiksyre Step C: f 3-chloro-4-(2, 3-dibromo-3-phenylpropiony1)-phenoxy j-acetic acid

23,8 g (0.075 mol) [3-klor-4-(3-fenylacryloyl)-fenoxy|-eddiksyre, fremstilt som beskrevet i trinn B, ble oppløst i 300 ml eddiksyre ved 50°C, og 12 g (0,075 mol) brom i 20 ml eddiksyre ble tilsatt dråpevis under omrøring ved 4o - 50°C i løpet av 30 minutter. Reaksjonsblandingen ble så helt i en liter vann inneholdende 1 - 2 g natriumbisulfit. Et ufiltrerbart, voluminøst, hvitt, fast stoff ble dannet og ble ekstrahert med ether. Etherekstrakt et ble vasket med vann og tørret over nat riumsulfat. En prøve av det tørrede etherekst rakt, hvorved man fikk et blekt, gult, fast stoff som ble identifisert som [3-klor-4-(2,3-dibrom-3-fenylpropiony1)-fenoxy J-eddiksyre med smeltepunkt 157 - 158°C efter krystallisasjon fra benzen. 23.8 g (0.075 mol) of [3-chloro-4-(3-phenylacryloyl)-phenoxy|-acetic acid, prepared as described in step B, was dissolved in 300 ml of acetic acid at 50°C, and 12 g (0.075 mol ) bromine in 20 ml of acetic acid was added dropwise with stirring at 4o - 50°C during 30 minutes. The reaction mixture was then poured into one liter of water containing 1-2 g of sodium bisulphite. An unfilterable, bulky, white solid formed and was extracted with ether. The ether extract was washed with water and dried over sodium sulfate. A sample of the dried ether extract was extracted to give a pale yellow solid which was identified as [3-chloro-4-(2,3-dibromo-3-phenylpropiony1)-phenoxy J-acetic acid, m.p. 157 - 158 °C after crystallization from benzene.

Trinn D: [3-klor-4-( 2- brom- 3- fenylacryloyl)- fenoxy]- eddiksyre Step D: [3-chloro-4-(2-bromo-3-phenylacryloyl)-phenoxy]-acetic acid

300 ml eddiksyre ble tilsatt til den tørrede etheroppløsning erholdt i trinn C. Blandingen ble oppvarmet på dampbad i en åpen kolbe for å fordampe etheren. Bunnfallet som først ble dannet, oppløstes sakte. Da etheren var fullstendig fordampet, ble l8,8 g (0,135 mol) vannfritt natriumcarbonat tilsatt forsiktig. Blandingen ble så oppvarmet på dampbad i 5 timer, avkjølt og helt i en liter vann, og det blekt gule faste stoff som ble dannet, ble oppsamlet ved filtrering, vasket med en liter vann i små porsjoner og krystallisert fra en blanding av isopropylalkohol og vann, hvorved man fikk l8 g [3-klor-4-(2-brom-3~fenylacryloyl)-fenoxyj-eddiksyre med smeltepunkt 159 - l6o°C En liten prøve omkrystallisert to ganger til fra en blanding av isopropylalkohol <p>g vann smeltet ved I60 - l6l°C. 300 ml of acetic acid was added to the dried ether solution obtained in step C. The mixture was heated on a steam bath in an open flask to evaporate the ether. The precipitate that first formed slowly dissolved. When the ether was completely evaporated, 18.8 g (0.135 mol) of anhydrous sodium carbonate was carefully added. The mixture was then heated on a steam bath for 5 hours, cooled and poured into one liter of water, and the pale yellow solid that formed was collected by filtration, washed with one liter of water in small portions and crystallized from a mixture of isopropyl alcohol and water , thereby obtaining 18 g of [3-chloro-4-(2-bromo-3~phenylacryloyl)-phenoxyj-acetic acid with a melting point of 159 - 16o°C A small sample recrystallized two more times from a mixture of isopropyl alcohol <p>g water melted at 160 - 161°C.

Eksempel 9 Example 9

[2,3-diklor-4-(2-ethylidenbutyryi)-fenoxy]-eddiksyre [2,3-Dichloro-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid

Trinn A: 2- ethyl- 2', 3'- diklor- 4'- hydroxybutyrofenon Step A: 2- ethyl- 2', 3'- dichloro- 4'- hydroxybutyrophenone

En blanding av 53,11 g (0,35 mol) 2,3-dikloranisol, 350 ml carbondisulfid og 80,77 g (0,6 mol) 2-ethylbutyrylklorid ble behandlet under vannfrie betingelser med 4o,00 g (0,3 mol) aluminiumkloridpulver i 5 minutter under omrøring. Blandingen ble omrørt i 6 timer ved værelsetemperatur og fikk så stå ved værelsetemperatur over natten. Reaksjonsblandingen ble oppvarmet under omrøring i et 55°C vannbad, inntil utviklingen av hydrdgenklorid opphørte A mixture of 53.11 g (0.35 mol) of 2,3-dichloroanisole, 350 ml of carbon disulfide and 80.77 g (0.6 mol) of 2-ethylbutyryl chloride was treated under anhydrous conditions with 40.00 g (0.3 mol) aluminum chloride powder for 5 minutes with stirring. The mixture was stirred for 6 hours at room temperature and then allowed to stand at room temperature overnight. The reaction mixture was heated with stirring in a 55°C water bath until evolution of hydrogen chloride ceased.

(1,5 timer), avkjølt til værelsetemperatur og behandlet under vannfrie betingelser med 40,00 g (0,3 mol) aluminiumkloridpulver i 5 minutter under omrøring. Carbondisulfidet ble så fjernet under nedsatt trykk ved destillasjon. Et like stort volum tørr heptan ble tilsatt, og blandingen ble oppvarmet på dampbad under omrøring i 3 timer. Efter avkjøling til værelsetemperatur ble heptanet fradekantert, og det gummiaktige residuum ble tilsatt til en blanding av 450 g is og 45 ml konsentrert saltsyre. Den dannede olje ble ekstrahert med ether, tørret over vannfritt natriumsulfat, og etheren ble så fjernet under nedsatt trykk, hvorved man fikk et halv-fast residuum. Dette materiale ble behandlet med overskudd av 5%-ig vandig natriumhydroxydoppløsning og oppvarmet under tilbake-løp i en time, derpå avkjølt og ekstrahert med ether for å fjerne uoppløselig olje. Den klare, vandige oppløsning ble syret med konsentrert saltsyre, den dannede olje ble ekstrahert med ether, og den gjenværende olje ble destillert, hvorved man fikk 34,45 g (44%) produkt i form av en væske med kokepunkt l4o - l42°C ved 0,5 mm trykk. Efter tre omkrystallisasjoner fra hexan fikk man 2-ethyl-2',3'-diklor-4'-hydroxybutyrofenon i form av hvite nåler med smeltepunkt 85 - 86°C. (1.5 hours), cooled to room temperature and treated under anhydrous conditions with 40.00 g (0.3 mol) aluminum chloride powder for 5 minutes with stirring. The carbon disulphide was then removed under reduced pressure by distillation. An equal volume of dry heptane was added and the mixture was heated on a steam bath with stirring for 3 hours. After cooling to room temperature, the heptane was decanted off, and the gummy residue was added to a mixture of 450 g of ice and 45 ml of concentrated hydrochloric acid. The oil formed was extracted with ether, dried over anhydrous sodium sulfate, and the ether was then removed under reduced pressure, whereby a semi-solid residue was obtained. This material was treated with an excess of 5% aqueous sodium hydroxide solution and heated under reflux for one hour, then cooled and extracted with ether to remove insoluble oil. The clear aqueous solution was acidified with concentrated hydrochloric acid, the resulting oil was extracted with ether, and the remaining oil was distilled to give 34.45 g (44%) of product as a liquid, boiling point 140 - 142°C at 0.5 mm pressure. After three recrystallizations from hexane, 2-ethyl-2',3'-dichloro-4'-hydroxybutyrophenone was obtained in the form of white needles with a melting point of 85 - 86°C.

Trinn B: [2,3-diklor-4-(2-ethylbutyryi)-fenoxy]-eddiksyre Step B: [2,3-dichloro-4-(2-ethylbutyryi)-phenoxy]-acetic acid

En oppløsning av 2,53 9 (0,11 mol) natrium i 300 ml absolutt ethanol ble behandlet først med 26,12 g (0,1 mol) 2-ethy1-2',3'-diklor-4'-hydroxybutyrofenon og så med 20,04 9 (0,12 mol) ethylbromacetat, og den dannede klare oppløsning ble oppvarmet under til-bakeløp under omrøring i 2 timer. Derpå ble 11,22 g (0,2 mol) kaliumhydroxyd i form av en 5%-ig vandig oppløsning tilsatt, og kokingen under tilbakeløp med omrøring ble fortsatt i ytterligere en time. Alkoholen ble fjernet ved destillasjon ved atmosfæretrykk, og det kokende, vandige residuum ble gjort surt mot kongorødt papir ved tilsetning av konsentrert saltsyre. En olje utskiltes som størknet ved avkjøling til værelsetemperatur. Den ble ekstrahert med ether, etherekstraktet ble tørret over vannfritt natriumsulfat, og etheren ble fjernet under nedsatt trykk, hvorved man fikk 31,9 g (10O%) [2 ,3-diklor^4-(2-ethylbutyryl)-fenoxy ]-eddiksyre i form av et hvitt fast stoff med smeltepunkt 128 - 139°C. En omkrystallisasjon fra en blanding av benzen og cyclohexan ga 28,7 9 (90%) av produktet i form av nåler som smeltet ved 144,5 - l45,5°C. A solution of 2.53 g (0.11 mol) of sodium in 300 ml of absolute ethanol was treated first with 26.12 g (0.1 mol) of 2-ethyl-2',3'-dichloro-4'-hydroxybutyrophenone and then with 20.04 g (0.12 mol) of ethyl bromoacetate, and the resulting clear solution was heated under reflux with stirring for 2 hours. Then 11.22 g (0.2 mol) of potassium hydroxide in the form of a 5% aqueous solution was added, and refluxing with stirring was continued for a further hour. The alcohol was removed by distillation at atmospheric pressure, and the boiling, aqueous residue was acidified against Congo red paper by the addition of concentrated hydrochloric acid. An oil is separated as solidified on cooling to room temperature. It was extracted with ether, the ether extract was dried over anhydrous sodium sulfate, and the ether was removed under reduced pressure to give 31.9 g (100%) of [2,3-dichloro^4-(2-ethylbutyryl)-phenoxy]- acetic acid in the form of a white solid with a melting point of 128 - 139°C. A recrystallization from a mixture of benzene and cyclohexane gave 28.7 g (90%) of the product in the form of needles melting at 144.5 - 145.5°C.

Trinn C: [2,3-diklor-4-( 2- brom- 2- ethylbutyryl)- fenoxy]- eddiksyre Step C: [2,3-dichloro-4-(2-bromo-2-ethylbutyryl)-phenoxy]-acetic acid

Dette produkt ble fremstilt praktisk talt på samme måte som beskrevet i eksempel 4, trinn B, under anvendelse av følgende reagenser: 19,26 g (0,0603 mol) [2,3-diklor-4-(2-ethylbutyryl)-fenoxy ]-eddiksyre, 9,64 9 (0,o603 mol) brom og 530 ml iseddik. This product was prepared in substantially the same manner as described in Example 4, Step B, using the following reagents: 19.26 g (0.0603 mol) [2,3-dichloro-4-(2-ethylbutyryl)-phenoxy ]-acetic acid, 9.64 g (0.0603 mol) of bromine and 530 ml of glacial acetic acid.

Ovenstående fremgangsmåte gir 23,71 9 (99%) [2,3-diklor-4-(2-brom-2-ethylbutyryl)-fenoxy]-eddiksyre i form av et fast hvitt stoff med smeltepunkt 151,5 - 152,5°C. The above procedure gives 23.71 9 (99%) [2,3-dichloro-4-(2-bromo-2-ethylbutyryl)-phenoxy]-acetic acid in the form of a solid white substance with melting point 151.5 - 152.5 °C.

En omkrystallisasjon fra benzen ga produktet i form av hvite nåler med smeltepunkt 151,5 - 152,5°C. A recrystallization from benzene gave the product in the form of white needles with a melting point of 151.5 - 152.5°C.

Trinn D: |"2 ,3-diklor-4-( 2-et hy lidenbut y ryi) - f enoxy ]- eddiksyre Step D: |"2 ,3-Dichloro-4-(2-ethylidenbuty ryi)-phenoxy]-acetic acid

Dette produkt ble fremstilt på praktisk talt samme måte som beskrevet i eksempel 4, trinn C, under anvendelse av følgende reagenser: 19,91 g (0,05 mol) [2,3-diklor-4-(2-brom-2-ethylbutyryl)-fenoxy]-eddiksyre, 6,36 g (0,15 mol) lithiumklorid og 140 ml dimethylformamid. This product was prepared in substantially the same manner as described in Example 4, Step C, using the following reagents: 19.91 g (0.05 mol) [2,3-dichloro-4-(2-bromo-2- ethylbutyryl)-phenoxy]-acetic acid, 6.36 g (0.15 mol) lithium chloride and 140 ml of dimethylformamide.

En omkrystallisasjon fra en blanding av benzen og cyclohexan ga 14,52 g (92%) [2,3-diklor-4-(2-ethylidenbutyryi)-fenoxy]-eddiksyre i form av hvite nåler med smeltepunkt 124 - 125,5°C. En annen omkrystallisasjon fra samme oppløsningsmiddelblanding forandret ikke smeltepunktet. A recrystallization from a mixture of benzene and cyclohexane gave 14.52 g (92%) [2,3-dichloro-4-(2-ethylidenebutyryi)-phenoxy]-acetic acid in the form of white needles, m.p. 124 - 125.5° C. Another recrystallization from the same solvent mixture did not change the melting point.

Eksempel IO Example IO

[ 2- methyl-3-klor-4~(2-ethyl idenbut yryl)-fenoxy]-eddiksyre [ 2- methyl-3-chloro-4~(2-ethyl idenbutyryl)-phenoxy]-acetic acid

Trinn Ai [2-methy1-3-klor-4-(2-ethylbutyry1)-fenoxy]-eddiksyre Step Ai [2-methyl-3-chloro-4-(2-ethylbutyryl)-phenoxy]-acetic acid

36,0 g (0,15 mol) 2-ethyl-2'-methyl-3'-klor-4'-hydroxybutyrofenon i 120 ml vann ble forenet med en oppløsning av 24 g (0,6o mol) natriumhydroxyd i 5 ml vann. Til den dannede oppløsning ved 45°C ble tilsatt under omrøring en oppløsning av 28,3 g (0,30 mol) klor-eddiksyre i IO ml vann i løpet av en time ved en temperatur på 40 - 45°C. Temperaturen ble hevet til 100°C i løpet av 30 minutter, og omrøringen fortsatte ved 100°C i 40 minutter. Reaksjonsblandingen ved 100°C ble behandlet med en oppløsning av 5,2 g (0,055 mol) klor-eddiksyre i 10 ml vann i 2 timer. Samtidig og i løpet av de følg-ende 3 timers omrøring ved 100°C ble der tilsatt en oppløsning av 4,4 g (0,11 mol) natriumhydroxyd i 10 ml vann med mellomrom når det var nødvendig for å holde reaksjonsblandingen basisk. Den kokende 36.0 g (0.15 mol) of 2-ethyl-2'-methyl-3'-chloro-4'-hydroxybutyrophenone in 120 ml of water was combined with a solution of 24 g (0.60 mol) of sodium hydroxide in 5 ml water. To the solution formed at 45°C, a solution of 28.3 g (0.30 mol) of chloroacetic acid in 10 ml of water was added with stirring over the course of one hour at a temperature of 40 - 45°C. The temperature was raised to 100°C over 30 minutes and stirring continued at 100°C for 40 minutes. The reaction mixture at 100°C was treated with a solution of 5.2 g (0.055 mol) of chloroacetic acid in 10 ml of water for 2 hours. At the same time and during the following 3 hours of stirring at 100°C, a solution of 4.4 g (0.11 mol) of sodium hydroxide in 10 ml of water was added at intervals when necessary to keep the reaction mixture basic. The boiling one

oppløsning ble syret med konsentrert saltsyre. Oljen som utskiltes efter avkjøling i et isbad til værelsetemperatur, ble ekstrahert med ether, tørret over vannfritt natriumsulfat, og etheren ble fordampet under nedsatt trykk, hvorved man fikk en olje. Oljen ble oppløst i benzen, og benzenet ble fjernet under nedsatt trykk, hvorved man fikk et voksaktig fast materiale. Det erholdte råprodukt ble omkrystallisert fra 300 ml benzen og 500 ml cyclohexan, hvorved man fikk 20,0 g (45% utbytte) [2-methyl-3-klor-4-(2-ethyl-butyryl)-fenoxy]-eddiksyre som smeltet ved 143 - l44°C. solution was acidified with concentrated hydrochloric acid. The oil that separated after cooling in an ice bath to room temperature was extracted with ether, dried over anhydrous sodium sulfate, and the ether was evaporated under reduced pressure to give an oil. The oil was dissolved in benzene, and the benzene was removed under reduced pressure, yielding a waxy solid. The crude product obtained was recrystallized from 300 ml of benzene and 500 ml of cyclohexane, whereby 20.0 g (45% yield) of [2-methyl-3-chloro-4-(2-ethyl-butyryl)-phenoxy]-acetic acid was obtained as melted at 143 - 144°C.

Trinn B: [2-methyl-3-klor-4~(2-brom-2-ethylbutyryl)-fenoxy]-eddiksyre Step B: [2-methyl-3-chloro-4~(2-bromo-2-ethylbutyryl)-phenoxy]-acetic acid

Til en oppløsning av 14,8 g (0,06 mol) [2-methy1-3-klor-4-(2-ethylbutyryl)-fenoxy]-eddiksyre i 350 ml eddiksyre ble tilsatt under omrøring 2 dråper 48%-ig hydrogenbromid fulgt av dråpevis tilsetning av 9,63 g (0,06 mol) brom i 50 ml eddiksyre. Efter at tilsetningen var avsluttet, ble blandingen omrørt i 15 minutter og derpå helt i en liter vann inneholdende 2 g nat riumbisulfit. Det faste stoff som utskiltes, ble oppsamlet på et filter, vasket med vann, tørret i luft og krystallisert fra 55 ml benzen. Det således erholdte råprodukt (19,2 g, 85%) ble omkrystallisert fra lOO ml benzen og 350 ml cyclohexan, hvorved man fikk 16 g [2-methyl-3-klor-4~(2-brom-2-ethylbutyryl)-fenoxy]-eddiksyre som smeltet ved 136 - 137°C. To a solution of 14.8 g (0.06 mol) [2-methyl-3-chloro-4-(2-ethylbutyryl)-phenoxy]-acetic acid in 350 ml of acetic acid, 2 drops of 48% hydrogen bromide were added with stirring followed by the dropwise addition of 9.63 g (0.06 mol) of bromine in 50 ml of acetic acid. After the addition was finished, the mixture was stirred for 15 minutes and then poured into one liter of water containing 2 g of sodium bisulphite. The solid which separated was collected on a filter, washed with water, dried in air and crystallized from 55 ml of benzene. The crude product thus obtained (19.2 g, 85%) was recrystallized from 100 ml of benzene and 350 ml of cyclohexane, whereby 16 g of [2-methyl-3-chloro-4~(2-bromo-2-ethylbutyryl)- phenoxy]-acetic acid which melted at 136 - 137°C.

Trinn C: [ 2- methyl-3- klor- 4-( 2- ethylidenbutyryl)- fenoxy]-eddiksyre . Step C: [2-methyl-3-chloro-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid.

13,0 g (0,0345 mol) [2-methyl-3-klor-4-(2-brom-2-ethylbutyryl)-fenoxy]-eddiksyre, fremstilt som beskrevet ovenfor, ble oppløst i 90 ml dimethylformamid, og 4,4 Q (0,104 mol) vannfritt lithiumklorid ble tilsatt. Blandingen ble oppvarmet på dampbad under leilighetsvis ryst ing i 2 timer, avkjølt og helt i en liter koldt vann. Det faste stoff som utskiltes, ble oppsamlet ved filtrering, vasket med 500 ml vann og oppløst i fortynnet natriumbicarbonatopp-løsning. Oppløsningen ble rystet med "Nor it e", filtrert fri for fast stoff og syret. Råproduktet (9,8 g, 96%) som utskiltes ved syring, ble omkrystallisert fra lOO ml benzen og 300 ml cyclohexan, hvorved man fikk 9,0 g [2-methyl-3-klor-4-(2-ethylidenbutyryi)-fenoxy]-eddiksyre som smeltet ved 132,5 - 133,5°C. 13.0 g (0.0345 mol) of [2-methyl-3-chloro-4-(2-bromo-2-ethylbutyryl)-phenoxy]-acetic acid, prepared as described above, was dissolved in 90 ml of dimethylformamide, and 4 .4 Q (0.104 mol) of anhydrous lithium chloride was added. The mixture was heated on a steam bath with occasional shaking for 2 hours, cooled and poured into one liter of cold water. The solid that separated was collected by filtration, washed with 500 ml of water and dissolved in dilute sodium bicarbonate solution. The solution was shaken with "Nor it e", filtered free of solid matter and the acid. The crude product (9.8 g, 96%) separated by acidification was recrystallized from 100 ml of benzene and 300 ml of cyclohexane, whereby 9.0 g of [2-methyl-3-chloro-4-(2-ethylidenebutyryi)- phenoxy]-acetic acid which melted at 132.5 - 133.5°C.

Eksempel 11 Example 11

[2,3-dimethyl-4-(2- ethylidenbutyryi)- fenoxy]- eddiksyre Trinn A: [2, 3- dimethyl- 4~( 2- ethylbutyryl)- fenoxy]- eddiksyre [2,3-dimethyl-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid Step A: [2,3-dimethyl-4~(2-ethylbutyryl)-phenoxy]-acetic acid

Ovenstående produkt ble fremstilt ved praktisk talt samme fremgangsmåte som beskrevet i eksempel 3, trinn A, under anvendelse av følgende materialer: 90 g (0,50 mol) (2,3-dimethylfenoxy)-eddiksyre, 84 g (0,62 mol) 2-ethylbutyrylklorid, 400 ml carbondisulfid og 217 g (1,63 mol) aluminiumklorid. The above product was prepared by substantially the same procedure as described in Example 3, step A, using the following materials: 90 g (0.50 mol) (2,3-dimethylphenoxy)-acetic acid, 84 g (0.62 mol) 2-ethylbutyryl chloride, 400 ml of carbon disulphide and 217 g (1.63 mol) of aluminum chloride.

Man fikk på denne måte 65 g (47%) [2 ,3-dimeth<y>l ^-^-ethyl-butyryl)-f enoxy ]-eddiksyre som, efter omkrystallisasjon fra methylcyclohexan, smeltet ved 97 - 98°C. In this way, 65 g (47%) of [2,3-dimeth<y>1^-^-ethyl-butyryl)-phenoxy]-acetic acid was obtained which, after recrystallization from methylcyclohexane, melted at 97 - 98°C.

Trinn B: [2,3-dimethyl-4-(2-brom-2-ethylbutyryl)-fenoxy]-eddiksyre Step B: [2,3-dimethyl-4-(2-bromo-2-ethylbutyryl)-phenoxy]-acetic acid

Ovenstående produkt ble fremstilt ved praktisk talt samme fremgangsmåte som i eksempel 4» trinn B, under anvendelse av følg-ende materialer: IO,4 Q (0,0374 mol) [2,3-dimethyl-4-(2-ethyl-butyryl)-fenoxy]-eddiksyre, 6,0 g (0,0374 mol) brom og 250 ml iseddik . The above product was prepared by practically the same procedure as in Example 4, step B, using the following materials: 10.4 Q (0.0374 mol) [2,3-dimethyl-4-(2-ethyl-butyryl )-phenoxy]-acetic acid, 6.0 g (0.0374 mol) bromine and 250 ml glacial acetic acid.

Produktet, 13,4 g (100%) [2,3-dimethyl-4-(2-brom-2-ethyl-butyryl)-fenoxy]-eddiksyre, erholdt ved ovenstående fremgangsmåte, smeltet efter omkrystallisasjon fra l6o ml cyclohexan ved 117 - 118°C. The product, 13.4 g (100%) of [2,3-dimethyl-4-(2-bromo-2-ethyl-butyryl)-phenoxy]-acetic acid, obtained by the above procedure, melted after recrystallization from 160 ml of cyclohexane at 117 - 118°C.

Trinn C: [ 2, 3- dime thyl- 4-( 2- ethylidenbutyry1)- fenoxy]-eddiksyre Step C: [2,3-dimethyl-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid

Dette produkt ble fremstilt ved praktisk talt samme fremgangsmåte som beskrevet i eksempel 5 under anvendelse av følgende materialer: 8,15 g (0,0228 mol) [2,3-dimethyl-4-(2-brom-2-ethylbutyryl)-fenoxy]-eddiksyre, 2,90 g (0,o684 mol) vannfritt lithiumklorid og 6o ml dimethylformamid. This product was prepared by practically the same procedure as described in Example 5 using the following materials: 8.15 g (0.0228 mol) [2,3-dimethyl-4-(2-bromo-2-ethylbutyryl)-phenoxy ]-acetic acid, 2.90 g (0.0684 mol) of anhydrous lithium chloride and 60 ml of dimethylformamide.

Produktet (6,0 g, 74%) erholdt som beskrevet, ble omkrystallisert fra l8o ml methylcyclohexan, hvorved man fikk 5,0 g [2,3-dimethyl-4-(2-ethylidenbutyryl)-fenoxy]-eddiksyre som smeltet ved 103 - 104°C. The product (6.0 g, 74%) obtained as described was recrystallized from 180 ml of methylcyclohexane to give 5.0 g of [2,3-dimethyl-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid which melted at 103 - 104°C.

Eksempel 12 Example 12

[3-klor-4-(2- propylidenvaleryl)- fenoxy]- eddiksyre [3-chloro-4-(2-propylidenevaleryl)-phenoxy]-acetic acid

Trinn A: 3'- klor- 4'- hydroxy- 2- propylvalerofenon Step A: 3'-chloro-4'-hydroxy-2-propylvalerophenone

Til en blanding av 31,52 g (0,2 mol) 3-kloranisol og 26,92 g (0,2 mol) 2-propylvalerylklorid i petrolether ble tilsatt gradvis under omrøring ved 5°C i løpet av en halv time 73,34 g (0,6 mol) aluminiumklorid. Blandingen ble omrørt ved 5°C i 20 minutter og fikk så lov til å oppvarmes til 25°C under omrøring i ytterligere 3 timer. Blandingen ble så holdt ved 25 - 30°C i 48 timer. Petrol-etheren ble så fradekantert og residuet tilsatt til 500 g is inneholdende 40 ml konsentrert saltsyre. Den mørke olje som utskiltes, ble ekstrahert med ether, etheroppløsningen ble vasket med vann og ekstrahert med 2,5%-ig natriumhydroxyd. Nat riumhydroxydekstraktet ble behandlet med "Norite" og filtrert fri for carbon, syret med saltsyre, hvorved man fikk en grønn olje som så ble ekstrahert med ether. Etherekstraktet ble tørret over n at riumsulf at , etheren ble fordampet og residuet destillert, hvorved man fikk 12,96 g 3'-klor-4'-hydroxy-2-propylvalerofenon i form av en viskøs olje med kokepunkt l40°C ved 0,5 mm trykk. To a mixture of 31.52 g (0.2 mol) of 3-chloroanisole and 26.92 g (0.2 mol) of 2-propylvaleryl chloride in petroleum ether was added gradually with stirring at 5°C over half an hour 73, 34 g (0.6 mol) aluminum chloride. The mixture was stirred at 5°C for 20 minutes and then allowed to warm to 25°C with stirring for an additional 3 hours. The mixture was then kept at 25-30°C for 48 hours. The petroleum ether was then decanted and the residue added to 500 g of ice containing 40 ml of concentrated hydrochloric acid. The dark oil which separated was extracted with ether, the ether solution was washed with water and extracted with 2.5% sodium hydroxide. The sodium hydroxide extract was treated with "Norite" and filtered free of carbon, acidified with hydrochloric acid, whereby a green oil was obtained which was then extracted with ether. The ether extract was dried over sodium sulfate, the ether was evaporated and the residue distilled, whereby 12.96 g of 3'-chloro-4'-hydroxy-2-propylvalerophenone was obtained in the form of a viscous oil with a boiling point of 140°C at 0, 5 mm pressure.

Trinn B: [ 3 - klo r- 4-( 2 - pro py 1 va ler yl.) - fenoxy ] - eddiksyre Step B: [ 3 - chloro - 4-( 2 - propy 1 val er yl.) - phenoxy ] - acetic acid

13,21 g (0,05l8 mol) 3'-klor-4'-hydroxy-2-propylvalerofenon ble tilsatt til en oppløsning av 1,19 g (0,05l8 mol) natrium oppløst i 100 ml absolutt ethanol. Blandingen ble oppvarmet og omrørt mens 8,66 g (0,05l8 mol) ethylbromacetat ble tilsatt i løpet av 10 minutter. Efter oppvarmning i 6 timer på dampbad ble ethanolen fjernet ved nedsatt trykk og residuet behandlet med natriumhydroxyd og opparbeidet på praktisk talt samme måte som beskrevet i eksempel 5, hvorved man fikk 7,7 g [3-klor-4-(2-propylvaleryl)-fenoxy]-eddiksyre som efter omkrystallisasjon fra benzen smeltet ved 134 - 135°C 13.21 g (0.0518 mol) of 3'-chloro-4'-hydroxy-2-propylvalerophenone was added to a solution of 1.19 g (0.0518 mol) of sodium dissolved in 100 ml of absolute ethanol. The mixture was heated and stirred while 8.66 g (0.0518 mol) ethyl bromoacetate was added over 10 minutes. After heating for 6 hours on a steam bath, the ethanol was removed under reduced pressure and the residue treated with sodium hydroxide and worked up in practically the same way as described in example 5, whereby 7.7 g of [3-chloro-4-(2-propylvaleryl) -phenoxy]-acetic acid which after recrystallization from benzene melted at 134 - 135°C

Trinn C: [ 3- klor~ 4-( 2- propyl- 2- bromvaleryl)- fenoxy]- eddiksyre Step C: [ 3- chloro~ 4-( 2- propyl- 2- bromovaleryl)- phenoxy]- acetic acid

7,2 g (0,023 mol) av forbindelsen erholdt i trinn A ble oppløst i 100 ml eddiksyre og bromert ved praktisk talt samme fremgangsmåte som i eksempel 4, trinn B, hvorved man fikk 8,05 Q [3-klor-4-(2-propyl-2-bromvaleryl)-fenoxy]-eddiksyre som efter krystallisasjon fra en .9:2 blanding av cyclohexan og benzen smeltet ved 125 - 125,5°C. 7.2 g (0.023 mol) of the compound obtained in step A was dissolved in 100 ml of acetic acid and brominated by practically the same procedure as in example 4, step B, whereby 8.05 Q [3-chloro-4-( 2-propyl-2-bromovaleryl)-phenoxy]-acetic acid which after crystallization from a .9:2 mixture of cyclohexane and benzene melted at 125 - 125.5°C.

Trinn D: [ 3- klor- 4~( 2- propylidenvaleryl)- fenoxy]- eddiksyre Step D: [ 3- chloro- 4~( 2- propylidenevaleryl)- phenoxy]- acetic acid

7 g (0,02 mol) av bromforbindelsen erholdt i trinn B ble opp-løst i 40 ml dimethylformamid,. og 5,6 g (0,064 mol) lithiumbromid ble tilsatt. Blandingen ble oppvarmet ved 80 - 90°C i 4 timer og derpå opparbeidet ved praktisk talt samme fremgangsmåte som i eksempel 4, hvorved man fikk 3 g [3-klor-4-(2-propylidenvaleryl)-fenoxy]-eddiksyre som, efter krystallisasjon fra benzen, smeltet ved 114 - 114,5°C. 7 g (0.02 mol) of the bromine compound obtained in step B was dissolved in 40 ml of dimethylformamide. and 5.6 g (0.064 mol) of lithium bromide was added. The mixture was heated at 80 - 90°C for 4 hours and then worked up by practically the same method as in example 4, whereby 3 g of [3-chloro-4-(2-propylidenevaleryl)-phenoxy]-acetic acid was obtained which, after crystallization from benzene, melting at 114 - 114.5°C.

Eksempel 13 Example 13

[3-klor-4~(2-isopropylidenpropionyl)-fenoxy]-eddiksyre Trinn A: ( 3- klor- 4- isovalerylfenoxy)- eddiksyre [3-chloro-4~(2-isopropylidenepropionyl)-phenoxy]-acetic acid Step A: ( 3-chloro-4-isovalerylphenoxy)-acetic acid

Ved å anvende de følgende reagenser istedenfor dem som ble anvendt i eksempel 8, trinn A, og ved å følge praktisk talt samme fremgangsmåte som der beskrevet, fåes (3-klor-4-isovalerylfenoxy)-eddiksyre: 32,6 g (0,272 mol) isovalerylklorid, 44,7 g (0,24 mol) By using the following reagents instead of those used in Example 8, step A, and by following practically the same procedure as described there, (3-chloro-4-isovalerylphenoxy)-acetic acid is obtained: 32.6 g (0.272 mol ) isovaleryl chloride, 44.7 g (0.24 mol)

(3-klorfenoxy)-eddiksyre, IOI g (0,755 mol) aluminiumklorid og 250 ml carbondisulfid. (3-chlorophenoxy)-acetic acid, 101 g (0.755 mol) aluminum chloride and 250 ml of carbon disulphide.

Råproduktet fåes i form av et gummiaktig, fast stoff som ble triturert med en liter varm 5%-ig natriumbicarbonat, og den dannede oppløsning ble filtrert for uoppløselige aluminiumsalter. Filtratet ble behandlet med 5 g "Darco" (avfarvende trekull) og syret med saltsyre. Det faste stoff som utskiltes, ble tørret og krystallisert fra benzen, hvorved man fikk 33,8 g (3-klor-4-isovalerylfenoxy)-eddiksyre med smeltepunkt IO7 - lo8°C. The raw product is obtained in the form of a rubbery, solid substance that was triturated with one liter of hot 5% sodium bicarbonate, and the resulting solution was filtered for insoluble aluminum salts. The filtrate was treated with 5 g "Darco" (decolorizing charcoal) and acidified with hydrochloric acid. The solid which separated was dried and crystallized from benzene, whereby 33.8 g of (3-chloro-4-isovalerylphenoxy)-acetic acid with a melting point of 107 - 108°C was obtained.

Trinn B: [3-klor-4~(2-dimethylaminomethylisovaleryl)-fenoxy]-eddiksyre- hydroklorid Step B: [3-chloro-4~(2-dimethylaminomethylisovaleryl)-phenoxy]-acetic acid hydrochloride

I en 100 ml rundkolbe forsynt med utløpsrør egnet for påføring av leilighetsvis sug, ble en intim blanding av 27 g (0,1 mol) (3-klor-4-isovalerylfenoxy)-eddiksyre, 3 g (0,1 mol) paraformaldehyd, 8,15 g (0,1 mol) tørt dimethylamin-hydroklorid og 0,5 ml eddiksyre oppvarmet på dampbad i ca. 1,5 timer idet der leilighetsvis ble på-ført sug av omtrent 1 minutts varighet 5 eller 6 ganger. Den varme reaksjonsblanding ble oppløst i 5o ml varmt aceton. Det faste stoff (22 g) som utskiltes ved avkjøling, smeltet ved 159 - l63°C. Efter oppslutning av dette produkt i varmt aceton fikk man det rensede [3-klor-4-(2-dimethylaminomethyl)-isovalerylfenoxy]-eddiksyre-hydroklorid med smeltepunkt 167 - l69°C. In a 100 ml round bottom flask fitted with an outlet tube suitable for the application of occasional suction, an intimate mixture of 27 g (0.1 mol) (3-chloro-4-isovalerylphenoxy)-acetic acid, 3 g (0.1 mol) paraformaldehyde, 8.15 g (0.1 mol) dry dimethylamine hydrochloride and 0.5 ml acetic acid heated on a steam bath for approx. 1.5 hours, during which suction of approximately 1 minute's duration was occasionally applied 5 or 6 times. The hot reaction mixture was dissolved in 50 ml of hot acetone. The solid (22 g) which separated on cooling, melted at 159-163°C. After digesting this product in hot acetone, the purified [3-chloro-4-(2-dimethylaminomethyl)-isovalerylphenoxy]-acetic acid hydrochloride with a melting point of 167 - 169°C was obtained.

Trinn C: [ 3- klor- 4-( 2- methylenisovaleryl)- fenoxy]- eddiksyre Step C: [ 3- chloro- 4-( 2- methyleneisovaleryl)- phenoxy]- acetic acid

19 g (0,052 mol) av Mannich-forbindelsen erholdt som beskrevet ovenfor, ble oppløst i 25 ml vann og oppløsningen gjort svakt basisk ved tilsetning av 10%-ig natriumbicarbonatoppløsning. Den erholdte oppløsning ble oppvarmet i 25 minutter på dampbad, avkjølt og syret med 6 N saltsyre, hvorved man fikk [3-klor-4-(2-methylenisovaleryl)-fenoxy]-eddiksyre som, efter krystallisasjon fra benzen, smeltet ved 122,5 - 123,5°C i et utbytte av 9 g. 19 g (0.052 mol) of the Mannich compound obtained as described above was dissolved in 25 ml of water and the solution made weakly basic by the addition of 10% sodium bicarbonate solution. The resulting solution was heated for 25 minutes on a steam bath, cooled and acidified with 6 N hydrochloric acid, whereby [3-chloro-4-(2-methyleneisovaleryl)-phenoxy]-acetic acid was obtained which, after crystallization from benzene, melted at 122, 5 - 123.5°C in a yield of 9 g.

Trinn D: [ 3- klor- 4~( 2, 3- dimethylbutyryi)- fenoxy]- eddiksyre Step D: [ 3- chloro- 4~( 2, 3- dimethylbutyryi)- phenoxy]- acetic acid

10 g (0,0355 mol) [3-klor-4-(2-methylenisovaleryl)-fenoxy]-eddiksyre ble oppløst i 275 ml isopropanol og hydrogenert i nærvær av 5%-ig palladium på trekull ved 26°C og 756 mm trykk på et Parr-apparat. I løpet av ca. 4o minutter ble hydrogen absorbert. Opp-løsningen ble oppvarmet og filtrert for å fjerne katalysatoren, alkoholen ble fordampet og residuet krystallisert fra benzen, hvorved man fikk 8,4 g [3-klor-4-(2,3-dimethylbutyryl)-fenoxy]-eddiksyre som smeltet ved 132,5 - 133,5°C. 10 g (0.0355 mol) [3-chloro-4-(2-methyleneisovaleryl)-phenoxy]-acetic acid was dissolved in 275 ml of isopropanol and hydrogenated in the presence of 5% palladium on charcoal at 26°C and 756 mm press a Parr device. During approx. 4o minutes hydrogen was absorbed. The solution was heated and filtered to remove the catalyst, the alcohol evaporated and the residue crystallized from benzene to give 8.4 g of [3-chloro-4-(2,3-dimethylbutyryl)-phenoxy]-acetic acid which melted at 132.5 - 133.5°C.

Trinn E: [3-klor-4-(2,3-dimethyl-2-brombutyryl)-fenoxy]-eddiksyre Step E: [3-chloro-4-(2,3-dimethyl-2-bromobutyryl)-phenoxy]-acetic acid

2,96 g [3-klor-4-(2,3-dimethylbutyryl)-fenoxy]-eddiksyre fremstilt ved fremgangsmåten i trinn D, ble bromert ved å følge praktisk talt samme fremgangsmåte som i eksempel 4, trinn B, hvorved man fikk 2,8 g [3~klor-4-(2,3-dimethyl-2-brombutyryl)-fenoxy]-eddiksyre som, efter krystallisasjon fra benzen, smeltet ved 151,5 - 152°C. 2.96 g of [3-chloro-4-(2,3-dimethylbutyryl)-phenoxy]-acetic acid prepared by the procedure in step D was brominated by following practically the same procedure as in Example 4, step B, whereby one obtained 2.8 g of [3~chloro-4-(2,3-dimethyl-2-bromobutyryl)-phenoxy]-acetic acid which, after crystallization from benzene, melted at 151.5 - 152°C.

Trinn F: [ 3- klor-4-(2-isopropylidenpropionyl)-fenoxy]-eddiksyre Step F: [3-chloro-4-(2-isopropylidenepropionyl)-phenoxy]-acetic acid

6,5 g (0,Ol8 mol) av forbindelsen erholdt i trinn E ble opp-løst i 40 ml dimethylformamid, 2,3 g (0,054 mol) lithiumklorid ble tilsatt, og forbindelsen ble dehydrobromert ved praktisk talt samme fremgangsmåte.som i eksempel 4, hvorved man fikk 1,5 g [3-klor-4-(2-isopropylidenpropionyl)-fenoxy]-eddiksyre som efter gjentatte krystallisasjoner fra benzen, smeltet ved 144 - l46°C. 6.5 g (0.018 mol) of the compound obtained in step E was dissolved in 40 ml of dimethylformamide, 2.3 g (0.054 mol) of lithium chloride was added, and the compound was dehydrobrominated by practically the same procedure as in Example 4, whereby 1.5 g of [3-chloro-4-(2-isopropylidenepropionyl)-phenoxy]-acetic acid was obtained which, after repeated crystallizations from benzene, melted at 144 - 146°C.

Eksempel 14 Example 14

[ 3 - klo r-4-(2-isopropyliden but yry1)- f enoxy]- eddiks yre og [3-chloro-4-(2-isopropylidenebutyryl)-phenoxy]-acetic acid and

[ 3- klor-4-(2-ethyli den- 3- methylbutyry1)- fenoxy]- eddiksyre Trinn A: 2'- klor- 4'- hydroxy- 2- isopropylbutyrofenon [ 3- chloro-4-(2-ethylidene- 3- methylbutyry1)- phenoxy]- acetic acid Step A: 2'- chloro- 4'- hydroxy- 2- isopropylbutyrophenone

Til en blanding av 38,8 g (0,272 mol) 3-kloranisol og 25 g (0,168 mol) 2-isopropylbutyrylklorid i 250 ml carbondisulfid ble der tilsatt under omrøring 46,6 g (0,35 mol) aluminiumklorid. Blandingen ble så oppvarmet ved 50 - 6o°C i 5 timer. Carbondisulfidet ble så fjernet ved destillasjon, 300 ml heptan og 26,67 9 (0,2 mol) aluminiumklorid ble tilsatt og blandingen omrørt og oppvarmet på dampbad i 2 timer. Oppløsningsmidlet ble så fradekantert, og 400 ml isvann ble tilsatt sakte under ytre avkjøling i et isbad. Dette ble fulgt av tilsetning av 40 ml konsentrert saltsyre og ekstraksjon med ether. Etherekstrakt et ble vasket med vann, tørret over natriumsulfat, og etheren ble så fordampet og residuet destillert. Fraksjonen som kokte ved 156 - l67°C ved 0,5 mm trykk (15,8 g) ble oppsamlet. Produktet størknet, og efter krystallisasjon fra cyclohexan fikk man 7,l4 9 2 *-klor-4'-hydroxy-2-isopropylbutyrofenon med smeltepunkt 75 - 77°C. To a mixture of 38.8 g (0.272 mol) of 3-chloroanisole and 25 g (0.168 mol) of 2-isopropylbutyryl chloride in 250 ml of carbon disulphide, 46.6 g (0.35 mol) of aluminum chloride were added with stirring. The mixture was then heated at 50-6o°C for 5 hours. The carbon disulphide was then removed by distillation, 300 ml of heptane and 26.67 g (0.2 mol) of aluminum chloride were added and the mixture stirred and heated on a steam bath for 2 hours. The solvent was then decanted, and 400 ml of ice water was added slowly under external cooling in an ice bath. This was followed by the addition of 40 ml of concentrated hydrochloric acid and extraction with ether. The ether extract was washed with water, dried over sodium sulfate, and the ether was then evaporated and the residue distilled. The fraction boiling at 156-167°C at 0.5 mm pressure (15.8 g) was collected. The product solidified, and after crystallization from cyclohexane, 7.14 9 2 *-chloro-4'-hydroxy-2-isopropylbutyrophenone with melting point 75 - 77°C was obtained.

Trinn B: [3-klor-4-(2-isopropylbutyryl)-fenoxy]-eddiksyre Step B: [3-chloro-4-(2-isopropylbutyryl)-phenoxy]-acetic acid

Ved å erstatte fenolen anvendt i eksempel 4, trinn A, med en ekvimolar mengde 2'-klor-4'-hydroxy-2-isopropylbutyrofenon og ved å følge praktisk talt samme fremgangsmåte som beskrevet i trinn A av eksempel 4, fåes [3-klor-4-(2-isopropylbutyryl)-fenoxy]-eddiksyre som, efter krystallisasjon fra en blanding av benzen og hexan smelter ved 136 - 137°C. By replacing the phenol used in example 4, step A, with an equimolar amount of 2'-chloro-4'-hydroxy-2-isopropylbutyrophenone and by following practically the same procedure as described in step A of example 4, [3- chloro-4-(2-isopropylbutyryl)-phenoxy]-acetic acid which, after crystallization from a mixture of benzene and hexane, melts at 136 - 137°C.

Trinn C: [ 3- klor- 4-( 2- brom- 2- isopropylbutyryl)- fenoxy]-eddiksyre Step C: [3-chloro-4-(2-bromo-2- isopropylbutyryl)-phenoxy]-acetic acid

6,6l g (0,0221 mol) av produktet erholdt i trinn B ble bromert ved praktisk talt samme fremgangsmåte som i eksempel 4, trinn B, hvorved man fikk 4 9 [3-klor-4-(2-brom-2-isopropylbutyryl)-fenoxy]-eddiksyre som, efter krystallisasjon fra en blanding av benzen og hexan, smeltet ved 126 - 127°c. 6.6l g (0.0221 mol) of the product obtained in step B was brominated by practically the same procedure as in example 4, step B, whereby 4 9 [3-chloro-4-(2-bromo-2- isopropylbutyryl)-phenoxy]-acetic acid which, after crystallization from a mixture of benzene and hexane, melted at 126 - 127°c.

.Trinn D: [ 3- klor-4~( 2- isopropylidenbutyry1)- fenoxy]- eddiksyre .Step D: [ 3- chloro-4~( 2- isopropylidenebutyryl 1)- phenoxy]- acetic acid

og and

[ 3- klor- 4-( 2- ethyliden- 3- methylbutyryl)- fenoxy]- eddiksyre [ 3- chloro- 4-( 2- ethylidene- 3- methylbutyryl)- phenoxy]- acetic acid

4 g (0,0106 mol) av forbindelsen erholdt i trinn C i 25 ml dimethylformamid ble dehydrobromert ved praktisk talt samme fremgangsmåte som i eksempel 4> hvorved man fikk et fast materiale som smeltet ved 91 _ 94°C. Det faste materiale ble ekstrahert med 8oo ml varm hexan i fire porsjoner. Ved forening og avkjøling fikk man 1,2 g av en blanding av [3-klor-4~(2-isopropylidenbutyryl)-fenoxy]-eddiksyre og [3-klor-4-(2-ethyliden-3-methylbutyryl)-fenoxy]-eddiksyre i form av farveløse krystaller med smeltepunkt 95 - 97°C. Kjernemagnetiske resonnansspektra viste at produktet var en hovedsakelig 1:1 blanding av forbindelsene. 4 g (0.0106 mol) of the compound obtained in step C in 25 ml of dimethylformamide was dehydrobrominated by practically the same method as in example 4> whereby a solid material was obtained which melted at 91 - 94°C. The solid material was extracted with 800 ml of hot hexane in four portions. By combining and cooling, 1.2 g of a mixture of [3-chloro-4~(2-isopropylidenebutyryl)-phenoxy]-acetic acid and [3-chloro-4-(2-ethylidene-3-methylbutyryl)-phenoxy ]-acetic acid in the form of colorless crystals with a melting point of 95 - 97°C. Nuclear magnetic resonance spectra showed that the product was an essentially 1:1 mixture of the compounds.

Eksempel 15 Example 15

[3-met hyl-4-(2-isopropyliden-3-methylbutyry1)-fenoxy]-eddiksyre Trinn A: 2- isopropyl- 3, 2'- dimethyl- 4'- hydroxybutyrofenon [3-methyl-4-(2-isopropylidene-3-methylbutyryl)-phenoxy]-acetic acid Step A: 2-isopropyl-3,2'-dimethyl-4'-hydroxybutyrophenone

Til en omrørt blanding av 24,43 9 (0,2 mol) 3-methoxytoluen, 32,53 g (0,2 mol) 2-isopropyl-3-methylbutyrylklorid og 200 ml carbondisulfid i en 1-liters kolbe forsynt med tilbakeløpskjøler og rører ble tilsatt 26,6 g (0,2 mol) aluminiumklorid sakte under om-røring ved 10 - 20°C ved hjelp av en Erlenmeyer-kolbe forbundet med en Gooch-hylse til halsen av reaksjonskolben. Blandingen ble så kokt forsiktig i 6,5 timer, og carbondisulfidet ble så fjernet ved destillasjon. lOO ml n-heptan og 26,67 9 aluminiumklorid ble så tilsatt og blandingen kokt under tilbakeløp i 7 timer, avkjølt, og 400 ml isvann ble tilsatt forsiktig under omrøring og avkjøling i et isbad. Blandingen ble så syret med 40 ml konsentrert saltsyre og de organiske bestanddeler ekstrahert med ether. Etheroppløsningen ble vasket med vann og ekstrahert med overskudd av 10%-ig natriumhydroxyd i flere porsjoner. De basiske ekstrakter ble forenet og vasket med ether og syret med saltsyre. Det lysebrune, faste materiale som utskiltes (smeltepunkt 114 - H9°C, 12,85 g) , ble krystallisert fra benzen, hvorved man fikk 9,67 g 2-isopropyl-3,2•-dimethyl-4'-hydroxy-butyrofenon med smeltepunkt 123 - 124,5°C. To a stirred mixture of 24.43 g (0.2 mol) of 3-methoxytoluene, 32.53 g (0.2 mol) of 2-isopropyl-3-methylbutyryl chloride and 200 ml of carbon disulfide in a 1 liter flask fitted with a reflux condenser and stirrer, 26.6 g (0.2 mol) of aluminum chloride was added slowly with stirring at 10-20°C using an Erlenmeyer flask connected to a Gooch sleeve to the neck of the reaction flask. The mixture was then gently boiled for 6.5 hours, and the carbon disulphide was then removed by distillation. 100 ml of n-heptane and 26.67 g of aluminum chloride were then added and the mixture refluxed for 7 hours, cooled, and 400 ml of ice water was added carefully while stirring and cooling in an ice bath. The mixture was then acidified with 40 ml of concentrated hydrochloric acid and the organic components extracted with ether. The ether solution was washed with water and extracted with an excess of 10% sodium hydroxide in several portions. The basic extracts were combined and washed with ether and acidified with hydrochloric acid. The light brown, solid material that separated (melting point 114 - H9°C, 12.85 g) was crystallized from benzene, whereby 9.67 g of 2-isopropyl-3,2•-dimethyl-4'-hydroxy-butyrophenone was obtained with melting point 123 - 124.5°C.

Trinn B: [ 3- methy1- 4-(2-i sopropyl- 3- methylbutyryl)- fenoxy]- eddiksyre Step B: [3-methyl-4-(2-isopropyl-3-methylbutyryl)-phenoxy]-acetic acid

0,8l6 g (0,0355 g atom) natrium ble oppløst i 100 ml vannfri ethanol i et egnet apparat og 8,30 g (0,0355 mol) av produktet frem- 0.8l6 g (0.0355 g atom) of sodium was dissolved in 100 ml of anhydrous ethanol in a suitable apparatus and 8.30 g (0.0355 mol) of the product prepared

stilt i trinn A ble tilsatt til oppløsningen. Blandingen ble oppvarmet til kokning, og 5,93 g (0,0355 mol) ethylbromacetat ble tilsatt og blandingen oppvarmet i 4 timer. Alkoholen ble så fordampet og residuet oppvarmet ved 8o - 90°C med 50 ml 10%-ig natriumhydroxyd i 4 timer. Blandingen ble avkjølt, ekstrahert med ether og syret med saltsyre, og det faste stoff som utskiltes, ble ekstrahert med ether. Etherekstraktet ble fraskilt, vasket med vann og tørret over natriumsulfat, etheren ble fordampet og residuet krystallisert fra en blanding av benzen og cyclohexan, hvorved man fikk 1,9 g [3-methyl-4~(2-isopropy1-3-methylbutyry1)-fenoxy]-eddiksyre med smeltepunkt 95 - 95,5°C. set in step A was added to the solution. The mixture was heated to boiling, and 5.93 g (0.0355 mol) of ethyl bromoacetate was added and the mixture heated for 4 hours. The alcohol was then evaporated and the residue heated at 8o - 90°C with 50 ml of 10% sodium hydroxide for 4 hours. The mixture was cooled, extracted with ether and acidified with hydrochloric acid, and the solid which separated was extracted with ether. The ether extract was separated, washed with water and dried over sodium sulphate, the ether was evaporated and the residue crystallized from a mixture of benzene and cyclohexane, whereby 1.9 g of [3-methyl-4~(2-isopropy1-3-methylbutyry1)- phenoxy]-acetic acid with a melting point of 95 - 95.5°C.

Trinn C: [3~methyl-4-(2-brom-2-isopropy1-3-methylbutyryl)-fenoxy]-eddiksyre 5 g (0,017 mol) av produktet fremstilt i trinn B ble oppløst i 40 ml eddiksyre og oppløsningen oppvarmet til 50°C og noen dråper av en oppløsning av 2,56 g (0,016 mol) brom i 20 ml eddiksyre ble tilsatt. Bromfarven vedvarte i 30 minutter, på hvilket tidspunkt 0,5 ml 48%-ig hydrogenbromid ble tilsatt, og den røde bromfarve forsvant langsomt. Blandingen fikk lov til å avkjøle til 20 - 25°C, og ca. halvparten av den gjenværende bromoppløsning ble tilsatt i løpet av 30 minutter. Efter ytterligere 2 timer ved 20 - 30°C ble reak-sjons blandingen, som igjen var lysegul, oppvarmet til 50°C, og resten av bromoppløsningen ble tilsatt i løpet av 30 minutter. Blandingen ble holdt ved 20 - 25°C i 17 timer, og derpå helt i vann inneholdende litt natriumbisulfit. Det faste stoff som utskiltes, ble oppsamlet ved filtrering, vasket godt med vann, hvorved man fikk 6,3 g [3-methyl-4-(2-brom-2-isopropyl-3-methylbutyryl)-fenoxy]-eddiksyre med smeltepunkt ca. l4o - l4l°C. Da forbindelsen er ustabil, ble den anvendt direkte i neste trinn. Step C: [3~methyl-4-(2-bromo-2-isopropyl-3-methylbutyryl)-phenoxy]-acetic acid 5 g (0.017 mol) of the product prepared in step B was dissolved in 40 ml of acetic acid and the solution heated to 50°C and a few drops of a solution of 2.56 g (0.016 mol) of bromine in 20 ml of acetic acid were added. The bromine color persisted for 30 minutes, at which time 0.5 ml of 48% hydrogen bromide was added, and the red bromine color slowly disappeared. The mixture was allowed to cool to 20 - 25°C, and approx. half of the remaining bromine solution was added over 30 minutes. After a further 2 hours at 20 - 30°C, the reaction mixture, which was again pale yellow, was heated to 50°C, and the rest of the bromine solution was added over the course of 30 minutes. The mixture was kept at 20 - 25°C for 17 hours, and then poured into water containing a little sodium bisulphite. The precipitated solid was collected by filtration, washed well with water to give 6.3 g of [3-methyl-4-(2-bromo-2-isopropyl-3-methylbutyryl)-phenoxy]-acetic acid of m.p. about. 140 - 141°C. As the compound is unstable, it was used directly in the next step.

Trinn D-, [ 3 -met hy 1 -4-( 2-isopropy liden -3-met hy lbut yry 1) -f enoxy ] -eddiksyre Step D-, [ 3 -meth hy 1 -4-(2-isopropyl lidene -3-meth hy lbut y ry 1) -phenoxy ] -acetic acid

5,2 g (0,0141 mol) av bromforbindelsen fremstilt i trinn C og 3,59 g (0,04ll mol) lithiumbromid ble anbrakt i 34 ml dimethylformamid og oppvarmet til 80 - 90°C i 5 timer. Blandingen ble så tilsatt til vann, og det faste stoff som utskiltes, ble oppsamlet og krystallisert fra en blanding av hexan og benzen, idet den samtidig ble avfarvet med aktivt carbon, hvorved man fikk 1,8 g [3-methyl-4-(2-isopropyliden-3-methylbutyryl)-fenoxy]-eddiksyre med smeltepunkt HO - 112°C. 5.2 g (0.0141 mol) of the bromine compound prepared in step C and 3.59 g (0.0411 mol) of lithium bromide were placed in 34 ml of dimethylformamide and heated to 80-90°C for 5 hours. The mixture was then added to water, and the solid which separated was collected and crystallized from a mixture of hexane and benzene, being at the same time decolorized with activated carbon, whereby 1.8 g of [3-methyl-4-( 2-isopropylidene-3-methylbutyryl)-phenoxy]-acetic acid with melting point HO - 112°C.

Eksempel l6 Example 16

j" 3- klor- 4-( 3- methylcrotonoyl) - f enoxy ]- eddiksyre j" 3-chloro-4-(3-methylcrotonoyl)-phenoxy]-acetic acid

Trinn A: [3-klor-4-(2-bromisovalery1)-fenoxy]-eddiksyre Step A: [3-chloro-4-(2-bromosovaleryl)-phenoxy]-acetic acid

14,6 g (0,0054 mol) av (3-klor-4-isovalerylfenoxy)-eddiksyren fremstilt som beskrevet i eksempel 13, trinn A, ble oppløst i ca. lOO ml eddiksyre, og 8,7 Q (0,054 mol) brom i 20 ml eddiksyre ble tilsatt dråpevis under omrøring i løpet av 10 - 15 minutter. Reaksjonen ble initiert ved tilsetning av 2 dråper 48%-ig hydrogenbromid. Blandingen ble tilsatt til ca. 1 liter vann inneholdende litt natriumbisulfit, og det faste stoff som utskiltes, ble opp-, samlet, vasket med vann og tørret. Det erholdte produkt ble krystallisert fra isopropylalkohol, hvorved man fikk 17,0 g [3~klor-4-(2-bromisovaleryl)-fenoxy]-eddiksyre med smeltepunkt 171 - 172°C. 14.6 g (0.0054 mol) of the (3-chloro-4-isovalerylphenoxy)-acetic acid prepared as described in Example 13, step A, was dissolved in approx. 100 ml of acetic acid, and 8.7 Q (0.054 mol) of bromine in 20 ml of acetic acid were added dropwise with stirring during 10 - 15 minutes. The reaction was initiated by adding 2 drops of 48% hydrogen bromide. The mixture was added to approx. 1 liter of water containing a little sodium bisulphite, and the solid which separated was collected, washed with water and dried. The product obtained was crystallized from isopropyl alcohol, whereby 17.0 g of [3-chloro-4-(2-bromoisovaleryl)-phenoxy]-acetic acid with a melting point of 171 - 172°C was obtained.

Trinn B: f 3- klor- 4~( 3- methylcrotonoyl)- fenoxy]- eddiksyre Step B: f 3- chloro- 4~( 3- methylcrotonoyl)- phenoxy]- acetic acid

12,3 g (0,035 mol) [3-klor-4-(2-bromisovaleryl)-fenoxy]-eddiksyre ble tilsatt til en oppløsning av 23,6 g (0,4 mol) trimethylamin i 150 ml absolutt ethanol. Oppløsningen ble innelukket i en glass-foret autoklav og oppvarmet ved 8o°C i 18 timer. Ved avkjøling og åpning av autoklaven viste det seg at reaksjonsblandingen besto av en rødbrun oppløsning og et hvitt krystallinsk bunnfall av trimethylamin-hydrobromid. Det faste stoff ble fjernet ved filtrering og filtratet konsentrert til lite volum ved inndampning på dampbad. Da residuet ble tilsatt til vann, dannet der seg en blakket oppløs-ning av trimethylaminsaltet av produktet. Ved syring med 6 N saltsyre dannet der seg et fast bunnfall som ble oppsamlet ved filtrering og oppløst i fortynnet natriumbicarbonat. Oppløsningen ble rystet med avfarvende trekull, filtrert og syret med saltsyre. Det mørkt ravfarvede faste stoff som utskiltes (7,3 g med smeltepunkt 120 - 130°C), ble krystallisert fra en blanding av 50 ml cyclohexan og 70 ml benzen, og derpå fra benzen, hvorved man fikk 1,4 g [3-klor-4-(3-methylcrotonoyl)-fenoxy]-eddiksyre med smeltepunkt 134 - 136°C. 12.3 g (0.035 mol) of [3-chloro-4-(2-bromoisovaleryl)-phenoxy]-acetic acid was added to a solution of 23.6 g (0.4 mol) of trimethylamine in 150 ml of absolute ethanol. The solution was enclosed in a glass-lined autoclave and heated at 80°C for 18 hours. On cooling and opening the autoclave, it turned out that the reaction mixture consisted of a reddish-brown solution and a white crystalline precipitate of trimethylamine hydrobromide. The solid was removed by filtration and the filtrate concentrated to a small volume by evaporation on a steam bath. When the residue was added to water, a cloudy solution of the trimethylamine salt of the product was formed. On acidification with 6 N hydrochloric acid, a solid precipitate formed which was collected by filtration and dissolved in diluted sodium bicarbonate. The solution was shaken with decolorizing charcoal, filtered and acidified with hydrochloric acid. The dark amber solid that separated (7.3 g with melting point 120 - 130°C) was crystallized from a mixture of 50 ml of cyclohexane and 70 ml of benzene, and then from benzene, whereby 1.4 g of [3- chloro-4-(3-methylcrotonoyl)-phenoxy]-acetic acid with melting point 134 - 136°C.

Eksempel 17 Example 17

[ 3- klor- 4~(2-propy1idenpropionyl)-f enoxy]-eddiksyre Trinn A: ( 3- klor- 4- n- valerylfenoxy)- eddiksyre [ 3-Chloro-4~(2-propy1idenpropionyl)-phenoxy]-acetic acid Step A: ( 3-Chloro-4-n-valerylphenoxy)-acetic acid

En tørr 1-liters rundkolbe ble forsynt med rører og tilbake-løpskjøler. I kolben ble anbrakt 36,2 g (0,30 mol) n-valerylklorid, 44,7 g (0,24 mol) (3-klorfenoxy)-eddiksyre og 240 ml carbondisulfid. lOl g (0,755 mol) pulverisert aluminiumklorid ble tilsatt i små porsjoner ved 10°C under mekanisk omrøring. Efter at halvparten av aluminiumkloridet var tilsatt, ble blandingen temmelig viskøs, og resten av aluminiumkloridet ble tilsatt under håndomrøring. Da blandingen ble bevegelig nok, ble mekanisk omrøring gjenopptatt og fortsatt i en time. Blandingen ble så oppvarmet under 50°C under omrøring i ytterligere 3 timer. Carbondisulfidet ble avdekantert, A dry 1-liter round bottom flask was fitted with a stirrer and reflux condenser. 36.2 g (0.30 mol) of n-valeryl chloride, 44.7 g (0.24 mol) of (3-chlorophenoxy)-acetic acid and 240 ml of carbon disulphide were placed in the flask. 100 g (0.755 mol) of powdered aluminum chloride was added in small portions at 10°C with mechanical stirring. After half of the aluminum chloride had been added, the mixture became rather viscous, and the rest of the aluminum chloride was added while stirring by hand. When the mixture became mobile enough, mechanical stirring was resumed and continued for one hour. The mixture was then heated below 50°C with stirring for a further 3 hours. The carbon disulfide was decanted off,

og residuet ble tilsatt til en blanding av 1 kg is og 30 ml konsentrert saltsyre. Oljen som utskiltes, ble ekstrahert med ether, and the residue was added to a mixture of 1 kg of ice and 30 ml of concentrated hydrochloric acid. The oil which separated was extracted with ether,

og etherekstraktet ble så ekstrahert med 10%-ig natriumbicarbonat-oppløsning. Bicarbonatekstraktet ble syret med konsentrert saltsyre, og det erholdte råprodukt ble krystallisert fra en 2:1 blanding av ligroin og benzen, hvorved man fikk 30 g (3-klor-4-n-valerylfenoxy)-eddiksyre med smeltepunkt 82,5 - 83,5°C (korrigert). and the ether extract was then extracted with 10% sodium bicarbonate solution. The bicarbonate extract was acidified with concentrated hydrochloric acid, and the crude product obtained was crystallized from a 2:1 mixture of ligroin and benzene, whereby 30 g of (3-chloro-4-n-valerylphenoxy)-acetic acid with a melting point of 82.5 - 83 was obtained, 5°C (corrected).

Trinn B: / h~[ 2-( diraethylaminomethyl) -va ler yl ] -3-klorf enoxy_/-eddiksyre - hydroklorid Step B: / h~[ 2-( diraethylaminomethyl) -valeryl] -3-chlorophenoxy_/-acetic acid - hydrochloride

I en 100 ml rundkolbe forsynt med utløpsrør egnet for påføring av leilighetsvis sug ble en intim blanding av 6,76 g (0,025 mol) In a 100 ml round bottom flask fitted with an outlet tube suitable for the application of occasional suction, an intimate mixture of 6.76 g (0.025 mol)

(3-klor-4-n-valerylfenoxy)-eddiksyre, 0,825 g (0,0275 mol) paraformaldehyd, 2,24 g (0,0275 mol) tørt dimethylamin-hydroklorid og 4 dråper eddiksyre oppvarmet på dampbad i ca. 1,5 timer, i løpet av hvilke sug ble påført i tidsrom på ca. 1 minutt fem eller seks ganger. Det erholdte sirupaktige residuum ble triturert med ether, hvorved man fikk 5,4 g /3-klor-4-[2-(dimethylaminomethyl)-valeryl]-fenoxy/- eddiksyre-hydroklorid i form av et fast stoff som ble oppsamlet og anvendt i det neste trinn uten videre rensning. (3-chloro-4-n-valerylphenoxy)-acetic acid, 0.825 g (0.0275 mol) paraformaldehyde, 2.24 g (0.0275 mol) dry dimethylamine hydrochloride and 4 drops of acetic acid heated on a steam bath for approx. 1.5 hours, during which suction was applied for a period of approx. 1 minute five or six times. The resulting syrupy residue was triturated with ether, whereby 5.4 g of /3-chloro-4-[2-(dimethylaminomethyl)-valeryl]-phenoxy/-acetic acid hydrochloride was obtained in the form of a solid which was collected and used in the next step without further purification.

Trinn C: [ 3- klor- 4-( 2- methylenvaleryl)- fenoxy]- eddiksyre Step C: [ 3- chloro- 4-( 2- methylenevaleryl)- phenoxy]- acetic acid

/3-klor-4-[2-(dimethylaminomethyl) -valeryl ]-f enoxy_/-eddiksyre-hydrokloridet fremstilt som beskrevet ovenfor, ble oppløst i vann The /3-chloro-4-[2-(dimethylaminomethyl)-valeryl]-phenoxy_/-acetic acid hydrochloride prepared as described above was dissolved in water

og filtrert for å fjerne blakning. Den klare oppløsning ble så and filtered to remove fading. The clear resolution was then

gjort basisk med natriumbicarbonat og oppvarmet i 25 minutter på dampbad. Den erholdte oppløsning ble så avkjølt og syret med 6 N saltsyre, hvorved man fikk 1,8 g [3-klor-4-(2-methylenvaleryl)-fenoxy]-eddiksyre i form av et fast stoff, som efter krystallisasjon fra benzen, ga 1,4 g renset [3-klor-4-(2-methylenvalery1)-fenoxy]-eddiksyre med smeltepunkt 101 - 102°C. made basic with sodium bicarbonate and heated for 25 minutes on a steam bath. The resulting solution was then cooled and acidified with 6 N hydrochloric acid, whereby 1.8 g of [3-chloro-4-(2-methylenevaleryl)-phenoxy]-acetic acid was obtained in the form of a solid, which after crystallization from benzene, gave 1.4 g of purified [3-chloro-4-(2-methylenevaleryl)-phenoxy]-acetic acid with melting point 101 - 102°C.

Trinn D: [ 3- klor- 4-( 2- methylvaleryl)- fenoxy]- eddiksyre Step D: [ 3- chloro- 4-( 2- methylvaleryl)- phenoxy]- acetic acid

8,7 g [3-klor-4-(2-methylenvaleryl)-fenoxy]-eddiksyre, fremstilt som beskrevet i trinn C, ble oppløst i 250 ml isopropylalkohol og 3 g 5%-ig apalladium på trekull ble tilsatt. Blandingen ble hydrogenert ved et begynnelsestrykk på o 2,4 kg/cm 2 i et Parr-apparat. I løpet av ca. 4o minutter var den nødvendige mengde hydrogen absorbert. Oppløsningen ble oppvarmet og filtrert for å fjerne katalysatoren, alkoholen ble fordampet og residuet krystallisert fra benzen, hvorved man fikk 4,8 g [2-klor-4-(2-methyl-valeryl)-fenoxy]-eddiksyre som, efter krystallisasjon fra benzen, smeltet ved 123 - 124,5°C 8.7 g of [3-chloro-4-(2-methylenevaleryl)-phenoxy]-acetic acid, prepared as described in step C, was dissolved in 250 ml of isopropyl alcohol and 3 g of 5% apalladium on charcoal was added. The mixture was hydrogenated at an initial pressure of about 2.4 kg/cm 2 in a Parr apparatus. During approx. In 40 minutes, the required amount of hydrogen had been absorbed. The solution was heated and filtered to remove the catalyst, the alcohol evaporated and the residue crystallized from benzene to give 4.8 g of [2-chloro-4-(2-methyl-valeryl)-phenoxy]-acetic acid which, after crystallization from benzene, melted at 123 - 124.5°C

Trinn E: [3-klor-4~(2-brom-2-methylvalery1)-fenoxy]-eddiksyre Step E: [3-chloro-4~(2-bromo-2-methylvalery1)-phenoxy]-acetic acid

2,15 g (0,0075 mol) av [3-klor-4-(2-methylvalery1)-fenoxy]-eddiksyren erholdt i trinn D ble bromert ved å følge praktisk talt samme fremgangsmåte som beskrevet i eksempel 10, trinn B, hvorved man fikk 2,1 g [ 3 -klor-4-( 2 -brom -2 -met hyl valery 1) -f enoxy ] -eddiksy re som, efter krystallisasjon fra en 2:1 blanding av cyclohexan og benzen, smeltet ved 115 - 117°C. 2.15 g (0.0075 mol) of the [3-chloro-4-(2-methylvalery1)-phenoxy]-acetic acid obtained in step D was brominated by following practically the same procedure as described in Example 10, step B, whereby 2.1 g of [3-chloro-4-(2-bromo-2-methyl valeryl 1)-phenoxy]-acetic acid was obtained which, after crystallization from a 2:1 mixture of cyclohexane and benzene, melted at 115 - 117°C.

Trinn F: [ 3- klor- 4~( 2- propylidenpropionyl)- fenoxy]- eddiksyre Step F: [ 3- chloro- 4~( 2- propylidenepropionyl)- phenoxy]- acetic acid

12,8 g (0,0352 mol) [3-klor-4-(2-brom-2-methylvaleryl)-fenoxy]-eddiksyre fremstilt som beskrevet i trinn E, ble oppløst i 60 ml dimethylformamid, og 2,9 g (0,0684 mol) vannfritt lithiumklorid ble tilsatt. Blandingen ble oppvarmet på dampbad under leilighetsvis omrystning i 2 timer, avkjølt og helt i en liter koldt vann. Det faste stoff som utskiltes, ble oppsamlet ved filtrering, vasket med 500 ml vann og så oppløst i fortynnet natriumbicarbonat-oppløsning. Oppløsningen ble rystet med "Norite", filtrert fri for faststoff og syret. Det faste stoff som utskiltes, ble tørret i luft, hvorved man fikk 2, 2, g [3-klor-4-(2-propylidenpropionyl)-fenoxy]-eddiksyre som, efter krystallisasjon fra en blanding av ether og ligroin, smeltet ved 96 - 97°C. 12.8 g (0.0352 mol) of [3-chloro-4-(2-bromo-2-methylvaleryl)-phenoxy]-acetic acid prepared as described in step E was dissolved in 60 ml of dimethylformamide, and 2.9 g (0.0684 mole) of anhydrous lithium chloride was added. The mixture was heated on a steam bath with occasional shaking for 2 hours, cooled and poured into one liter of cold water. The solid that separated was collected by filtration, washed with 500 ml of water and then dissolved in dilute sodium bicarbonate solution. The solution was shaken with "Norite", filtered free of solids and the acid. The solid which separated was dried in air to give 2.2 g of [3-chloro-4-(2-propylidenepropionyl)-phenoxy]-acetic acid which, after crystallization from a mixture of ether and ligroin, melted at 96 - 97°C.

Eksempel 18 Example 18

[3-klor-4-(2-isobutylidenpropionyl)-fenoxy]-eddiksyre Trinn A: [ 3- klor- 4-(4- methylvaleryl)- fenoxy]- eddiksyre [3-chloro-4-(2-isobutylidenepropionyl)-phenoxy]-acetic acid Step A: [ 3-chloro-4-(4-methylvaleryl)-phenoxy]-acetic acid

Dette produkt ble fremstilt ved å. følge praktisk talt samme fremgangsmåte som beskrevet i eksempel 20, trinn A, under anvendelse av følgende reaktanter: 134,6 g (0,272 mol) 4-methylvalerylklorid, 44,8 g (0,24 mol) (3-klorfenoxy)-eddiksyre, 108 g (0,755 mol) aluminiumklorid og 250 ml carbondisulfid. This product was prepared by following substantially the same procedure as described in Example 20, Step A, using the following reactants: 134.6 g (0.272 mol) 4-methylvaleryl chloride, 44.8 g (0.24 mol) ( 3-chlorophenoxy)-acetic acid, 108 g (0.755 mol) aluminum chloride and 250 ml carbon disulfide.

produktet, [3-klor-4-(4-methylvaleryl)-fenoxy]-eddiksyre, ble erholdt i form av et farveløst fast stoff, og, efter krystallisasjon fra en blanding av ether og ligroin, fikk man 20 g [3-klor-4-(4-methylvaleryl)-fenoxy]-eddiksyre med smeltepunkt 89,5 - 90°C. the product, [3-chloro-4-(4-methylvaleryl)-phenoxy]-acetic acid, was obtained as a colorless solid, and, after crystallization from a mixture of ether and ligroin, 20 g of [3-chloro -4-(4-methylvaleryl)-phenoxy]-acetic acid with melting point 89.5 - 90°C.

Trinn B: [3-klor-4-(2-m ethylen- 4~ methylvaleryl)- fenoxy]- eddiksyre Step B: [3-chloro-4-(2-methylene-4-methylvaleryl)-phenoxy]-acetic acid

En blanding av 17,5 g (0,063 mol) [3-klor-4-(4-methylvalery1)-fenoxy]-eddiksyre, 1,91 g (0,063 mol) paraformaldehyd, 5,15 g (0,063 mol) dimethylamin-hydroklorid og 0,5 ml eddiksyre ble oppvarmet ved 90 - 100°C i 4 timer. Blandingen ble så oppløst i 40 ml aceton og ether tilsatt inntil intet videre bunnfall ble dannet. Ether-acetonblandingen (a) ble fradekantert og residuet oppløst i vann. Den vandige oppløsning (b) ble ekstrahert med ether, gjort basisk med 10%-ig natriumbicarbonat, oppvarmet ved 80 - 90°C i 15 minutter og syret. Det faste stoff som utskiltes, ble oppsamlet ved filtrering, og hadde smeltepunkt 114 - ll6°C. Ether-aceton-ekstraktet (a) ble ekstrahert med 5%-ig natriumbicarbonatoppløsning i porsjoner inntil syring av det vandige ekstrakt ikke ga ytterligere bunnfall. Bicarbonatekst raktene ble forenet og syret med saltsyre, hvorved man fikk et faststoff med smeltepunkt 111 - ll4°C. De to utbytter av fast materiale ble tørret i luft ved 65°C og så krystallisert fra en 9:10 blanding av cyclohexan og benzen og derpå fra benzen, hvorved man fikk 14,1 g [3-klor-4-(2-methylen-4-methyl-valeryl)-fenoxy]-eddiksyre med smeltepunkt 115 - ll6°C. A mixture of 17.5 g (0.063 mol) [3-chloro-4-(4-methylvalery1)-phenoxy]-acetic acid, 1.91 g (0.063 mol) paraformaldehyde, 5.15 g (0.063 mol) dimethylamine hydrochloride and 0.5 ml of acetic acid was heated at 90-100°C for 4 hours. The mixture was then dissolved in 40 ml of acetone and ether added until no further precipitate formed. The ether-acetone mixture (a) was decanted off and the residue dissolved in water. The aqueous solution (b) was extracted with ether, basified with 10% sodium bicarbonate, heated at 80-90°C for 15 minutes and acidified. The solid which separated was collected by filtration, and had a melting point of 114 - 116°C. The ether-acetone extract (a) was extracted with 5% sodium bicarbonate solution in portions until acidification of the aqueous extract gave no further precipitate. The bicarbonate extracts were combined and acidified with hydrochloric acid, whereby a solid with a melting point of 111 - 114°C was obtained. The two yields of solid material were dried in air at 65°C and then crystallized from a 9:10 mixture of cyclohexane and benzene and then from benzene to give 14.1 g of [3-chloro-4-(2-methylene -4-methyl-valeryl)-phenoxy]-acetic acid with melting point 115 - 116°C.

Trinn C: [ 3- klor- 4-( 2- isobutylpropiony1)- fenoxy]- eddiksyre Step C: [ 3- chloro- 4-( 2- isobutylpropiony1)- phenoxy]- acetic acid

19,05 g (0,0642 mol) [3-klor-4-(2-methylen-4-methylvaleryl)-fenoxy]-eddiksyre, fremstilt som beskrevet i trinn B, ble hydrogenert ved praktisk talt samme fremgangsmåte som beskrevet i eksempel 17, trinn D, hvorved man fikk 13,1 g [3-klor-4-(2-isobutyl-propionyl)-fenoxy]-eddiksyre som, efter krystallisasjon fra benzen, smeltet ved 127 -128,5°C. 19.05 g (0.0642 mol) of [3-chloro-4-(2-methylene-4-methylvaleryl)-phenoxy]-acetic acid, prepared as described in step B, was hydrogenated by practically the same procedure as described in Example 17, step D, whereby 13.1 g of [3-chloro-4-(2-isobutyl-propionyl)-phenoxy]-acetic acid was obtained which, after crystallization from benzene, melted at 127-128.5°C.

Trinn P: [ 3- klor- 4-( 2- brom- 2- isobutylpropiony1)- fenoxy]-eddiksyre Step P: [3-chloro-4-(2-bromo-2- isobutylpropiony1)-phenoxy]-acetic acid

Til en oppløsning av 12,1 g (0,o4o5 mol) [3-klor-4-(2-isobutyl-propionyl)-fenoxy]-eddiksyre i 200 ml eddiksyre ble tilsatt under omrøring 2 dråper 48%-ig hydrogenbromid fulgt av dråpevis tilsetning av 6,0 g (0,0374 mol) brom i 50 ml eddiksyre. Efter at tilsetningen var avsluttet, ble blandingen omrørt i 15 minutter og derpå helt i en liter vann inneholdende 2 g natriumbisulfit. Det faste stoff som utskiltes, ble oppsamlet på et filter, vasket med vann, tørret i luft og krystallisert fra 55 ml benzen, hvorved man fikk 14,4 g [3-klor-4-(2-brom-2-isobutylpropionyl)-fenoxy]-eddiksyre med smeltepunkt 115 - 116°C. To a solution of 12.1 g (0.0405 mol) [3-chloro-4-(2-isobutyl-propionyl)-phenoxy]-acetic acid in 200 ml of acetic acid, 2 drops of 48% hydrogen bromide were added with stirring, followed by dropwise addition of 6.0 g (0.0374 mol) bromine in 50 ml acetic acid. After the addition was finished, the mixture was stirred for 15 minutes and then poured into one liter of water containing 2 g of sodium bisulphite. The solid which separated was collected on a filter, washed with water, dried in air and crystallized from 55 ml of benzene to give 14.4 g of [3-chloro-4-(2-bromo-2-isobutylpropionyl)- phenoxy]-acetic acid with a melting point of 115 - 116°C.

Trinn E: [ 3- klor-4-(2-isobutylidenpropionyl)-fenoxy]-eddiksyre Step E: [ 3-chloro-4-(2-isobutylidenepropionyl)-phenoxy]-acetic acid

9,5 g (0,025 mol) [3-klor-4-(2-brom-2-isobutylpropionyl)-fenoxy]-eddiksyre, fremstilt som beskrevet i trinn D, ble oppløst i 60 ml dimethylformamid og 2,9 g (0,0684 mol) vannfritt lithiumklorid 9.5 g (0.025 mol) of [3-chloro-4-(2-bromo-2-isobutylpropionyl)-phenoxy]-acetic acid, prepared as described in step D, was dissolved in 60 ml of dimethylformamide and 2.9 g (0 .0684 mol) anhydrous lithium chloride

ble tilsatt. Blandingen ble oppvarmet på dampbad under leilighetsvis rystning i 2 timer, avkjølt og helt i en liter koldt vann. Det faste stoff som utskiltes, ble oppsamlet ved filtrering, vasket med 500 ml vann og så oppløst i fortynnet natriumbicarbonatoppløsning. Oppløsningen ble rystet med "Norite" , filtrert fri for faststoff og syret. Det faste stoff som utskiltes, ble tørret i luft, hvorved man fikk 1,8 g [3-klor-4-(2-isobutylidenpropionyl)-fenoxy]-eddiksyre som, efter krystallisasjon fra benzen, smeltet ved 123 - 124°C. was added. The mixture was heated on a steam bath with occasional shaking for 2 hours, cooled and poured into one liter of cold water. The solid that separated was collected by filtration, washed with 500 ml of water and then dissolved in dilute sodium bicarbonate solution. The solution was shaken with "Norite", filtered free of solids and the acid. The solid which separated was dried in air, whereby 1.8 g of [3-chloro-4-(2-isobutylidenepropionyl)-phenoxy]-acetic acid was obtained which, after crystallization from benzene, melted at 123 - 124°C.

Eksempel 19 Example 19

[ 3- klor- 4~(3-brom-2-ethyliden-propionyl)-fenoxy]-eddiksyre [ 3-chloro-4~(3-bromo-2-ethylidene-propionyl)-phenoxy]-acetic acid

Trinn A: /3-klor-4-[2-(dimethylaminomethyl) -buty ry 1 ]-f enoxy_7-eddiksyre Step A: /3-chloro-4-[2-(dimethylaminomethyl)-buty ry 1 ]-phenoxy_7-acetic acid

I en 100 ml rundkolbe forsynt med utløpsrør egnet for påfør-ing av leilighetsvis sug ble en intim blanding av 14,52 g (0,06 mol) In a 100 ml round bottom flask fitted with an outlet tube suitable for the application of occasional suction, an intimate mixture of 14.52 g (0.06 mol)

(3~klor-4-butyrylfenoxy)-eddiksyre, fremstilt ved fremgangsmåten beskrevet i eksempel 1, trinn A, 2,1 g (0,072 mol) paraformaldehyd, 5,34 g ('0,066 mol) tørt dimethylamin-hydroklorid og 4 dråper eddiksyre oppvarmet på dampbad i ca. 1,5 timer i løpet av hvilken tid sug ble påført i ca. 1 minutts perioder fem eller seks ganger. Ved av-kjøling fikk man 19 g av et faststoff som ble triturert med aceton. Det hvite, faste stoff som ble dannet, ble krystallisert fra acetonitril og isopropylalkohol, hvorved man fikk /3-klor-4-[2-dimethyl-aminomethyl) -butyryl ] -f enoxy_/-eddiksy re-hydroklorid med smelt epunkt 127 - 129°C. (3-Chloro-4-butyrylphenoxy)-acetic acid, prepared by the method described in Example 1, step A, 2.1 g (0.072 mol) paraformaldehyde, 5.34 g (0.066 mol) dry dimethylamine hydrochloride and 4 drops of acetic acid heated in a steam bath for approx. 1.5 hours during which time suction was applied for approx. 1 minute periods five or six times. Upon cooling, 19 g of a solid was obtained which was triturated with acetone. The white solid that was formed was crystallized from acetonitrile and isopropyl alcohol to give /3-chloro-4-[2-dimethyl-aminomethyl)-butyryl]-phenoxy_/-acetic acid hydrochloride with a melting point of 127 - 129°C.

Trinn B: [ 3- klor- 4-( 2- methylenbutyryl) -, f enoxy ] - eddiksyre Step B: [3-chloro-4-(2-methylenebutyryl)-,phenoxy]-acetic acid

1 g (0,003 mol) av Mannich-forbindelsen erholdt som beskrevet i trinn A, ble oppløst i 25 ml vann og oppløsningen ble gjort svakt basisk med tilsetning av 10%-ig natriumbicarbonatoppløsning. Den dannede oppløsning ble oppvarmet i 25 minutter på dampbad, avkjølt og syret med 6 N saltsyre, hvorved man fikk 0,7 9 fast [3-klor-4-(2-methylenbutyryl)-fenoxyeddiksyre. Efter omkrystallisasjon fra en blanding av cyclohexan og benzen fikk man [3-klor-4~(2-methylenbutyryl)-fenoxy]-eddiksyre i form av farveløse krystaller med smeltepunkt 109 - H0°C. 1 g (0.003 mol) of the Mannich compound obtained as described in step A was dissolved in 25 ml of water and the solution was made weakly basic by the addition of 10% sodium bicarbonate solution. The resulting solution was heated for 25 minutes on a steam bath, cooled and acidified with 6 N hydrochloric acid, whereby 0.7 g of solid [3-chloro-4-(2-methylenebutyryl)-phenoxyacetic acid was obtained. After recrystallization from a mixture of cyclohexane and benzene, [3-chloro-4~(2-methylenebutyryl)-phenoxy]-acetic acid was obtained in the form of colorless crystals with a melting point of 109 - H0°C.

Trinn C: /3-klor-4-[2-brom-2-(brommethyl) -butyrylf enoxy_/-eddiksyre Step C: /3-chloro-4-[2-bromo-2-(bromomethyl)-butyryl enoxy_/-acetic acid

4,03 g (0,0l5 mol) [3-klor-4-(2-methylenbutyryl)-fenoxy]-eddiksyre ble oppløst i 150 ml kokende carbontetraklorid og en opp-løsning av 2,4 g (0,Ol5 mol) brom i 50 ml carbontetraklorid ble tilsatt i løpet av 5 minutter. Bromfarven forsvant hurtig efter tilsetning til den kokende oppløsning. Oppløsningen ble avkjølt, og det hvite faste stoff som utskiltes, ble fjernet ved filtrering og vasket med friskt carbontetraklorid, hvorved man fikk 5,94 9 (92%) /3-klor-4-[2-brom-2-(brommethyl)-butyryl]-fenoxy7-eddiksyre med smeltepunkt 146 - l49°C. Produktet ble omkrystallisert vekselvis fra toluen og så acetonitril, hvorved man fikk et materiale som smeltet ved 153,5 - 155°C (korrigert). 4.03 g (0.015 mol) of [3-chloro-4-(2-methylenebutyryl)-phenoxy]-acetic acid was dissolved in 150 ml of boiling carbon tetrachloride and a solution of 2.4 g (0.015 mol) bromine in 50 ml of carbon tetrachloride was added over 5 minutes. The bromine color disappeared quickly after addition to the boiling solution. The solution was cooled and the white solid which separated was removed by filtration and washed with fresh carbon tetrachloride to give 5.94 9 (92%) of /3-chloro-4-[2-bromo-2-(bromomethyl) -butyryl]-phenoxy7-acetic acid with melting point 146 - 149°C. The product was recrystallized alternately from toluene and then acetonitrile, whereby a material was obtained which melted at 153.5 - 155°C (corrected).

Dehydrohalogenering av /3-klor-4-[2-brom-2-(brommethyl)-butyryi]-fenoxy/-eddiksyre ved å følge praktisk talt samme fremgangsmåte som beskrevet i eksempel 4, trinn D, ga forbindelsen [3-klor-4-(3-brom-2-ethyliden-propionyl)-fenoxy]-eddiksyre. Dehydrohalogenation of /3-chloro-4-[2-bromo-2-(bromomethyl)-butyryl]-phenoxy/-acetic acid following practically the same procedure as described in Example 4, step D, gave the compound [3-chloro- 4-(3-Bromo-2-ethylidene-propionyl)-phenoxy]-acetic acid.

Eksempel 20 Example 20

[3-klor-4~(3-methylerotonoyl)-fenoxy]-eddiksyre [3-Chloro-4~(3-methylerotonoyl)-phenoxy]-acetic acid

En blanding av 5,8 g (0,0165 mol) [3-klor-4-(2-bromisovaleryl)-fenoxy]-eddiksyre erholdt som beskrevet i trinn A av eksempel 16, og 2,12 g (0,05 mol) lithiumklorid ble oppløst i 60 ml dimethylformamid og oppvarmet på dampbad i 3 timer. Den erholdte farveløse oppløs-ning ble tilsatt til 500 ml vann, og det faste stoff som utskiltes, ble krystallisert fra benzen, hvorved man fikk 4,0 g [3-klor-4-(2-' klorisovaleryl)-fenoxy]-eddiksyre med smeltepunkt 146 - l47°C. A mixture of 5.8 g (0.0165 mol) of [3-chloro-4-(2-bromoisovaleryl)-phenoxy]-acetic acid obtained as described in step A of Example 16, and 2.12 g (0.05 mol ) lithium chloride was dissolved in 60 ml of dimethylformamide and heated on a steam bath for 3 hours. The colorless solution obtained was added to 500 ml of water, and the solid which separated was crystallized from benzene, whereby 4.0 g of [3-chloro-4-(2-chloroisovaleryl)-phenoxy]-acetic acid was obtained with melting point 146 - 147°C.

Dehydrohalogenering av [3-klor-4-(2-klorisovaleryl)-fenoxy]-eddiksyre ved å følge praktisk talt samme fremgangsmåte som beskrevet i eksempel 16, trinn D, ga forbindelsen [3-klor-4-(3-methylcroton-oy1)-fenoxy]-eddiks yre. Dehydrohalogenation of [3-chloro-4-(2-chloroisovaleryl)-phenoxy]-acetic acid following substantially the same procedure as described in Example 16, step D, gave the compound [3-chloro-4-(3-methylcroton-oy1 )-phenoxy]-acetic acid.

Claims

Procedure for the preparation of a therapeutically active compound of the formula:

where R is hydrogen, halogen, lower alkyl, phenyl or benzyl, R"*" is hydrogen, lower alkyl, phenyl, chloro- or hydroxy-substituted phenyl or phenoxy, R 2 is hydrogen or lower alkyl, or together R 1 and R 2 form an alkylene chain with 3 - 5 carbon atoms, Y~ 2> ^3» ^5 oa; x6' which may be the same or different, is hydrogen, halogen, lower alkyl, lower alkoxy or together X_ and X~ or X- and X^ may be united to form a hydrocarbylene chain containing 4 carbon atoms between its attachment points, and n is a whole number from 1 to 5, as well as salts, esters and amides thereof, characterized in that a compound of the formula: 12

where R, R , R , X^, X^, X^, X^ and n are as indicated above, and Z and Z<2>, which are the same or different, are hydrogen or halogen, at least one of which is halogen, is reacted with a dehydrohalogenating agent, and that the acid obtained, if desired, is transferred to a salt, an ester or the amide thereof in a manner known per se.