NO751362L

NO751362L -

Info

Publication number: NO751362L
Application number: NO751362A
Authority: NO
Inventors: B Nicolaus
Original assignee: Isf Spa
Priority date: 1974-04-17
Filing date: 1975-04-16
Publication date: 1975-10-20
Also published as: IL47083A0; IT1044793B; NL7504598A; FI751145A7; LU72297A1; DD121935A5; ZA752432B; DK165975A; SE7504342L; DE2516623A1; FR2303010A1; RO72847A; JPS50137981A; ES436627A1; BG24672A3; IN142206B; RO72847B

Description

' Hensikten med foreliggende oppfinnelse er å frem-legge en metode for fremstilling av forbindelser med struk-turformel The purpose of the present invention is to provide a method for the preparation of compounds with structural formula

hvor R betegner hydrogen, halogen, usubstituert lavalkyl, lavalkyl substituert med halogen, hydroksy eller lav alkoksy, hydroksy, hydroksy foretret med en substituert eller usubstituert alkylkjede med fra 3 til 5 c-atomer inklusive, eventuelt symmetrisk bundet via en eterbinding i den andre enden til en identisk kromenstruktur. A betegner hydrogen, en mettet eller umettet hydrokarbongruppe. en ammoniumgruppe, et alkali- eller jordalkalimetallatom. where R denotes hydrogen, halogen, unsubstituted lower alkyl, lower alkyl substituted with halogen, hydroxy or lower alkoxy, hydroxy, hydroxy etherified with a substituted or unsubstituted alkyl chain with from 3 to 5 carbon atoms inclusive, optionally symmetrically bound via an ether bond at the other end to an identical chromium structure. A denotes hydrogen, a saturated or unsaturated hydrocarbon group. an ammonium group, an alkali or alkaline earth metal atom.

Mer spesielt tilveiebringes en ny fremgangsmåte for ringslutning av en chromenring ut fra en umettet forbindelse med en åpen kjede, mer spesielt akrylaldehyd-derivater. More particularly, a new method for ring closure of a chromene ring from an unsaturated compound with an open chain, more particularly acrylaldehyde derivatives, is provided.

Et annet trekk ved foreliggende oppfinnelse er frem-stillingen av nye forbindelser med strukturen til 4-substituerte chromen-2-karboksylsyrer: Another feature of the present invention is the production of new compounds with the structure of 4-substituted chromene-2-carboxylic acids:

hvor A og K har ovenstående betydninger og k, og n2 Kan være like eller forskjellige og betegner hydrogen, lav alkyl, fenyl, where A and K have the above meanings and k, and n2 Can be the same or different and denote hydrogen, lower alkyl, phenyl,

fenyl substituert med halogen, hydroksy, lav alkyl, lavere halogenalkyl, lavere hydroksyalkyl eller lavere alkoksyalkyl. cykloalkyl, eller R^og- R2 sammen med det felles C-atomer kan danne et alicyklisk system med 5 eller 6 C-atomer, hvilke forbindelser med fordel benyttes i henhold til oppfinnelsens metode som mellomprodukter og selv oppviser farmakologisk aktive virkninger som østrogene og anti-østrogene reagenser. Med betegnelsen "lav alkyl" mener man en rettkjedet atomgruppe med fra 1 til 4 C-atomer, inklusive, som metyl, etyl, propyl og butyl. phenyl substituted with halogen, hydroxy, lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxyalkyl. cycloalkyl, or R^ and R2 together with the common C atoms can form an alicyclic system with 5 or 6 C atoms, which compounds are advantageously used according to the method of the invention as intermediates and themselves exhibit pharmacologically active effects such as estrogenic and anti -estrogenic reagents. The term "lower alkyl" means a straight-chain atomic group with from 1 to 4 carbon atoms, inclusive, such as methyl, ethyl, propyl and butyl.

Med betegnelsen "lavere alkoksy" menes en rettkjedet C-atom gruppe med fra 1 til 4 C-atomer, inklusive, som metoksy, etoksy, propoksy og butoksy. The term "lower alkoxy" means a straight-chain C-atom group with from 1 to 4 C-atoms, inclusive, such as methoxy, ethoxy, propoxy and butoxy.

Med utrykket cykloalkyl menes en mettet karbon-ring med 5 eller 6 C-atomer, som cyklopentyl.og cykloheksyl. The expression cycloalkyl means a saturated carbon ring with 5 or 6 carbon atoms, such as cyclopentyl and cyclohexyl.

Med alkalimetall-atom betegnes natrium, kalium og litium, og med jordalkalimetall-atomer menes magnesium og kal-s ium. Alkali metal atoms mean sodium, potassium and lithium, and alkaline earth metal atoms mean magnesium and calcium.

Forbindelser med struktur I er kjente farmakologisk aktive stoffer hvorav de fleste finner anvendelse ved behandling av tilstander som skyldes antigen-antistoff-reaksjoner, særlig astmatilfeller. Compounds with structure I are known pharmacologically active substances, most of which are used in the treatment of conditions caused by antigen-antibody reactions, particularly asthma cases.

I henhold til foreliggende oppfinnelse tilveiebringes en metode for fremstilling av en forbindelse med formel According to the present invention, a method for producing a compound of formula is provided

hvor R har betydning som tidligere angitt og A^^betegner en mettet eller umettet hydrokarbongruppe, som består i at man ringslutter under egnede forhold et umettet aldehyd med formel where R has the meaning as previously indicated and A^^ denotes a saturated or unsaturated hydrocarbon group, which consists in ring closing under suitable conditions an unsaturated aldehyde with the formula

hvor R, R , R^og A^har de tidligere angitte bétydninger, where R, R , R^and A^ have the previously stated meanings,

hvorpå man oksyderer det nye mellomproduktet under egnede betingelser, hvilket mellomprodukt har formel after which the new intermediate is oxidized under suitable conditions, which intermediate has the formula

under dannelse av den ønskede forbindelse med formel III. while forming the desired compound of formula III.

, For å kunne fremstille disse forbindelser med formel I hvor A betegner hydrogen blir forbindelsene V med fordel hydrolysert før oksydasjon. , In order to be able to prepare these compounds of formula I where A denotes hydrogen, the compounds V are advantageously hydrolysed before oxidation.

For fremstilling av forbinbindelser med formel I hvor A betegner ammonium, alkali- eller jordalkalimetall-atomer, hydrolyseres forbindelsen V og saltdannes fortrinnsvis før oksydasjon. For the preparation of compounds of formula I where A denotes ammonium, alkali or alkaline earth metal atoms, the compound V is hydrolysed and salts are preferably formed before oxidation.

Når det foreligger frie hydroksyl-substituenter kan disse med fordel beskyttes ved egnede omsetninger, avhengig av de reagenser som brukes, og frigjøres ved å fjerne beksyt-telsesgruppene etter omsetningen. When free hydroxyl substituents are present, these can advantageously be protected by suitable reactions, depending on the reagents used, and released by removing the protecting groups after the reaction.

Foretring av en mulig fenolisk hydroksylgruppe gjør det mulig å fremstille bis-chromenforbindelser dannet av to chromenstrukturer som er symmetrisk bundet via en alkyj-ali-fatisk kjede med fra 3 til 5 C-atomer, eller en substituert alkylalifatisk kjede med fra 3 til 5 C-atomer. Etherification of a possible phenolic hydroxyl group makes it possible to prepare bis-chromene compounds formed by two chromene structures which are symmetrically linked via an alkyl-aliphatic chain with from 3 to 5 C atoms, or a substituted alkylaliphatic chain with from 3 to 5 C -atoms.

Aktivering av en fenolisk hydroksylgruppe kan skje før eller etter ringslutning, men gjennomføres i alle tilfel-le før den endelige oksydasjon. Activation of a phenolic hydroxyl group can take place before or after ring closure, but is carried out in all cases before the final oxidation.

Mer spesielt omsettes i henhold til foreliggende oppfinnelse derivater av alfa-substituerte aldehyder med formel IV i et egnet oppløsningsmiddel som toluen, benzen, etyleter, alifatiske hydrokarboner, med et egnet kondensasjons-reagens som metallisk natrium i nærvær av små mengder lavere alkylalkohol. More particularly, according to the present invention, derivatives of alpha-substituted aldehydes of formula IV are reacted in a suitable solvent such as toluene, benzene, ethyl ether, aliphatic hydrocarbons, with a suitable condensation reagent such as metallic sodium in the presence of small amounts of lower alkyl alcohol.

Reaksjonen forløper gradvis og gir høye utbytter av det tilsvarende chromenderivat V. The reaction proceeds gradually and gives high yields of the corresponding chromium derivative V.

Sistnevnte dannes, avhengig av formelen og utgangs-aldehydet samt det anvendte kondensasjonsmiddel, eventuelt som en blanding av cis- og trans-formene som kan skilles etter The latter is formed, depending on the formula and the starting aldehyde as well as the condensing agent used, possibly as a mixture of the cis and trans forms which can be distinguished by

kjente metoder.known methods.

De ringsluttede forbindelser som således fremstilles, som sådan eller i form av de tilsvarende frie 2-karboksylsyrer eller som de tilsvarende salter med ammonium eller med alkali- eller jordalkali-metaller, oksyderes ved hjelp av et egnet oksydasjonsmiddel som chromsyreanhydrid, ozon eller permanganat, hydrogen peroksyd eller osmium tetoksyd, fortrinnsvis blandet med periodsyre, og man får sluttforbin-delsen med formel I som separeres og renses på kjent måte. The ring-closed compounds thus produced, as such or in the form of the corresponding free 2-carboxylic acids or as the corresponding salts with ammonium or with alkali or alkaline earth metals, are oxidized by means of a suitable oxidizing agent such as chromic anhydride, ozone or permanganate, hydrogen peroxide or osmium tetoxide, preferably mixed with periodic acid, and the final compound with formula I is obtained, which is separated and purified in a known manner.

Ifølge en annen utførelse av foreliggende oppfinnelse fremlegges en ny metode for fremstilling av bis-chromen-derivater med formel According to another embodiment of the present invention, a new method for the production of bis-chromene derivatives with formula is provided

hvor A betegner hydrogen, en mettet eller umettet hydrokarbongruppe, ammonium, et alkali- eller jordalkali-metallatom, hvor en forbindelse med formel hvor A^har ovenstående betydning ringsluttet i egnet beskyttet form og deretter, for forbindelse VII, forbindes den ringsluttede forbindelse fortrinnsvis i 5-stilling med en identisk struktur gjennom en eventuelt beskyttet kjede where A represents hydrogen, a saturated or unsaturated hydrocarbon group, ammonium, an alkali or alkaline earth metal atom, where a compound of formula where A^ has the above meaning ring-closed in a suitable protected form and then, for compound VII, the ring-closed compound is preferably joined in 5-position with an identical structure through an optionally protected chain

derpå oksydert som sådan eller i form av den til- then oxidized as such or in the form of the added

svarende frie syre eller i form av det tilsvarende ammonium-, corresponding free acid or in the form of the corresponding ammonium,

alkali- eller jordalkalimetall-salt. Som et alternativ kan forbindelser med formel I hvor A betegner hydrogen, ammonium, alkali-metall eller jordalkalimetall, fremstilles ut fra forbindelser med formel alkali or alkaline earth metal salt. As an alternative, compounds of formula I where A denotes hydrogen, ammonium, alkali metal or alkaline earth metal can be prepared from compounds of formula

hvor R, R1 og R2har de tidligere angitte betydninger, ved omsetning med natriumhydroksyd eller tertiær alkylamin for fremstilling av det tilsvarende natrium- eller trialkylammo-nium-salt, som ringsluttes med eddiksyre anhydrid varmt ved temperaturer fra 100 til l40°C, eventuelt omdannes til ammonium-, alkali- eller jordalkali-metall-salt og derpå oksyderes til den ønskede forbindelse. where R, R1 and R2 have the previously stated meanings, by reaction with sodium hydroxide or tertiary alkylamine to produce the corresponding sodium or trialkylammonium salt, which is ring-closed with acetic anhydride hot at temperatures from 100 to 140°C, optionally converted to ammonium, alkali or alkaline earth metal salt and then oxidized to the desired compound.

De følgende eksempler skal illustrere foreliggende oppfinnelse uten å begrense den. The following examples shall illustrate the present invention without limiting it.

Eksempel 1.Example 1.

4- chromon- 2- karboksylsyre- metylester.4- chromone- 2- carboxylic acid methyl ester.

Fremstilling av cx- ( 2- metoksykarbonyl- metoksyfenyl)-kanelsyrealdehyd. Preparation of c- (2-methoxycarbonyl-methoxyphenyl)-cinnamic acid aldehyde.

Til en oppløsning av 55 g o-allylfenol i 250 ml vannfri aceton, settes 50 g vannfri kaliumkarbonat og 85 g etyl monobromacetat og blandingen kokes under tilbakeløp i 5 timer under røring. Det faste stoff filtreres fra og filterresten destilleres etter avdamping av acetonet i vakuum og gir 75 g 2-etoksykarbonylmetoksy-allylbenzen med kokepunkt 102 - 103°C/0.1 mm Hg (bad temperatur 125-130°C). To a solution of 55 g of o-allylphenol in 250 ml of anhydrous acetone, 50 g of anhydrous potassium carbonate and 85 g of ethyl monobromoacetate are added and the mixture is refluxed for 5 hours with stirring. The solid is filtered off and the filter residue is distilled after evaporating the acetone in vacuum to give 75 g of 2-ethoxycarbonylmethoxy-allylbenzene with a boiling point of 102 - 103°C/0.1 mm Hg (bath temperature 125-130°C).

22 gram 2-etoksykarbonylmetoksy-allylbenzen opplø-ses i 300 ml vannfri metylenklorid, blandingen avkjøles med aceton-tørris og ozoniseres, tillates oppvarming til romtemperatur, fryses på nytt i isbad, derpå tilsettes 80 g sink-pulver og gradvis en oppløsning inneholdende 40 ml eddiksyre og 10 ml vann, den resulterende blanding holdes under omrø-ring i 1 time og filtreres. Filterresten destilleres etter tørking på natriumsulfat, i vakuum, og gir 15 g 2-etoksykar- o 22 grams of 2-ethoxycarbonylmethoxy-allylbenzene are dissolved in 300 ml of anhydrous methylene chloride, the mixture is cooled with acetone-dry ice and ozonized, allowed to warm to room temperature, frozen again in an ice bath, then 80 g of zinc powder is added and gradually a solution containing 40 ml acetic acid and 10 ml of water, the resulting mixture is kept under stirring for 1 hour and filtered. The filter residue is distilled after drying on sodium sulfate, in a vacuum, and yields 15 g of 2-ethoxycaro- o

bonylmetoksy-fenylacetaldehyd med k.p. 135 C/0,2 mm (bad temperatur 155°C). 0,42 g kaliumhydroksyd oppløses i 0,5 ml vann og man tilsetter 10 ml etanol, 5,4 g benzsyrealdehyd og 1 ml 27 %- lg, vandig kaliumhydroksyd. Blandingen røres og av-kjøles med is - salt til en» blandingstemperatur på under 5°0. 1 g 2-etoksykarbonylmétoksy-fenylacetaldehyd tilsettes gradvis fulgt umiddelbart av 1 ml 27 %- ig oppløsning av kaliumhydroksyd. Man gjentar skiftevis tilsetningene av 1 g 2-e-toksykarbonylmetoksyfenylacetaldehyd og 1 ml 27 $-ig kalium-hydroksydoppløsning inntil det i alt er tilsatt 10 g forbindelse, derpå hensettes blandingen i 12 timer ved 0°C. 100 ml vann tilsettes og den vandige suspensjon ekstraheres med toluen. Den vandige oppløsning surgjøres med saltsyre og ekstraheres med etylacetat. Etylacetatoppløsningen vaskes med vann, tørkes på natriumsulfat og inndampes. Residumet oppløses i 400 ml vannfri metanol, 1 g p-toluensulfonsyre tilsettes og oppløsningen holdes kokende i 4 timer. Metanol destilleres av og man får et residum som oppløst i metanol leverer 5 g krystaller av (2-metoksykarbonylmetoksyfenyl)-kanelaldehyd, smeltepunkt 95 - 97°C. bonylmethoxy-phenylacetaldehyde with b.p. 135 C/0.2 mm (bath temperature 155°C). 0.42 g of potassium hydroxide is dissolved in 0.5 ml of water and 10 ml of ethanol, 5.4 g of benzaldehyde and 1 ml of 27% strength aqueous potassium hydroxide are added. The mixture is stirred and cooled with ice - salt to a mixture temperature of below 5°C. 1 g of 2-ethoxycarbonylmethoxy-phenylacetaldehyde is gradually added followed immediately by 1 ml of a 27% solution of potassium hydroxide. The additions of 1 g of 2-e-toxycarbonylmethoxyphenylacetaldehyde and 1 ml of 27% potassium hydroxide solution are repeated alternately until a total of 10 g of compound has been added, after which the mixture is allowed to stand for 12 hours at 0°C. 100 ml of water are added and the aqueous suspension is extracted with toluene. The aqueous solution is acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution is washed with water, dried over sodium sulfate and evaporated. The residue is dissolved in 400 ml of anhydrous methanol, 1 g of p-toluenesulfonic acid is added and the solution is kept boiling for 4 hours. Methanol is distilled off and a residue is obtained which, dissolved in methanol, delivers 5 g of crystals of (2-methoxycarbonylmethoxyphenyl)-cinnamaldehyde, melting point 95 - 97°C.

Til 0,35 g natrium dispergert i 2u.ml vannfri toluen settes 5 ml vannfri etyleter og deretter 1 ml oppløsning inneholdende 4,2 g cC-(2-metoksykarbonylmetoksyfenyl)-kånelaldehyd til ovenstående suspensjon som stadig holdes under omrøring, videre 9 ml vannfri toluen og 0,1 ml absolutt etanol ved ca. 40°C. Reaksjonsblandingen oppvarmes til 35 - 40°C til begyn-nende reaksjon og temperaturen senkes til ca. 20°C hvoretter restoppløsningen inneholdende -2-metoksykarbonylmetoksyfenyl-kanelaldehyd tilsettes langsomt. To 0.35 g of sodium dispersed in 2 u.ml of anhydrous toluene, 5 ml of anhydrous ethyl ether and then 1 ml of a solution containing 4.2 g of cC-(2-methoxycarbonylmethoxyphenyl)-canelaldehyde are added to the above suspension which is constantly kept under stirring, further 9 ml of anhydrous toluene and 0.1 ml absolute ethanol at approx. 40°C. The reaction mixture is heated to 35 - 40°C until the reaction starts and the temperature is lowered to approx. 20°C, after which the residual solution containing -2-methoxycarbonylmethoxyphenyl-cinnamaldehyde is added slowly.

Etter avsluttet tilsetning hensettes blandingen 12 timer ved romtemperatur, derpå tilsettes etylacetat og oppløs-ningen vaskes med vann og tørkes over natriumsulfat. Ved filtrering og inndampning får man et residum som oppløses i benzen og kromatograferes på aluminiumoksyd, hvilket gir 4-benzy-2 After the addition has been completed, the mixture is allowed to stand for 12 hours at room temperature, then ethyl acetate is added and the solution is washed with water and dried over sodium sulphate. Filtration and evaporation gives a residue which is dissolved in benzene and chromatographed on aluminum oxide, which gives 4-benzy-2

liden-A -chromen-2-karboksylsyremetylester.lidene-A -chromene-2-carboxylic acid methyl ester.

100 milligram 4-bensyliden-A -chromen-2-karboksyl-syremetylester som smelter ved 100 - 102°C oppløses i 6 ml 50 $-ig eddiksyre, oppløsningen oppvarmes til 50 - 60°C og en blanding inneholdende HOmg kromsyreanhydrid i 2,5 ml vann tilsettes. Reaksjonsblandingen hensettes til romtemperatur, 100 milligrams of 4-benzylidene-A -chromene-2-carboxylic acid methyl ester which melts at 100 - 102°C is dissolved in 6 ml of 50% acetic acid, the solution is heated to 50 - 60°C and a mixture containing HOmg of chromic anhydride in 2, 5 ml of water is added. The reaction mixture is allowed to reach room temperature,

fortynnet med vann og ekstraheres med etylacetat. Etylacetat-oppløsningen vaskes med vann, oppløsning av kallumbikarbonat og igjen med vann. Ved tørking på natriumsulfat, filtrering og inndamping får manmetylesteren av 4-chromon-2-karboksylsyre som krystallisert - fra metanol smelter ved 121-122°C. diluted with water and extracted with ethyl acetate. The ethyl acetate solution is washed with water, calcium bicarbonate solution and again with water. By drying on sodium sulphate, filtering and evaporating, the manmethyl ester of 4-chromone-2-carboxylic acid is obtained as crystallized - from methanol melting at 121-122°C.

Eksempel 2.Example 2.

4- chromon- 2- karboksylsyre.4- chromone- 2- carboxylic acid.

2,8 g 4-benzyliden-A -chromen-2-karboksylsyre-metylester fremstilt som ovenfor behandles med 50 ml etanol og deretter en oppløsning inneholdende 0,5 g natriumhydroksyd i 20 ml vann. Oppløsningen varmes feil 50 - 60°C i 1 time og den dannede oppløsning konsentreres i vakuum til et lite volum. 2.8 g of 4-benzylidene-A-chromene-2-carboxylic acid methyl ester prepared as above is treated with 50 ml of ethanol and then a solution containing 0.5 g of sodium hydroxide in 20 ml of water. The solution is heated to 50 - 60°C for 1 hour and the resulting solution is concentrated in vacuo to a small volume.

Den vandige oppløsning ekstraheres med etylacetat og surgjøres med saltsyre til 2,1 g 4-benzyliden-A 2-chromen-2-karbbksylsyre som ved behandling med kromsyreanhydrid gir 4-chromon-2-karboksylsyre The aqueous solution is extracted with ethyl acetate and acidified with hydrochloric acid to 2.1 g of 4-benzylidene-A 2-chromene-2-carboxylic acid, which on treatment with chromic anhydride gives 4-chromone-2-carboxylic acid

3,<1>g -(2-metoksykarbonylmetoksyfenyl)-kanelalde-hyd fremstilt som beskrevet i eksempel 1 behandles med 50 ml etanol og derpå tilsettes en oppløsning som inneholder 0,5 g natriumhydroksyd i 20 ml vann. Blandingen oppvarmes til 50 - 60°C i 1 timerog den dannede oppløsning konsentreres i vakuum til et lite volum, derpå tilsetter man 30 ml vann og blandingen ekstraheres med etylacetat. Den vandige oppløsning sur-gjøres med saltsyre og ekstraheres med etylacetat. Etylace-tatoppløsningen tørkes og inndampes og til residumet settes 1 g trietylamin og 3 g eddiksyreanhydrid. Blandingen oppvarmes til 105 - 110°C i noen timer, derpå avkjøles til romtemperatur og overskuddet av eddiksyreanhydrid avdampes i vakuum, man tilsetter vann og is og blandingen surgjøres med saltsyre for utfelling av 4-benzyliden-A 2-chromen-2-karboksylsyre som behandles med kromsyreanhydrid gir 4-chromon-2-karboksylsyre. 3.<1>g of -(2-methoxycarbonylmethoxyphenyl)-cinnamaldehyde prepared as described in example 1 is treated with 50 ml of ethanol and then a solution containing 0.5 g of sodium hydroxide in 20 ml of water is added. The mixture is heated to 50 - 60°C for 1 hour and the resulting solution is concentrated in vacuo to a small volume, then 30 ml of water is added and the mixture is extracted with ethyl acetate. The aqueous solution is acidified with hydrochloric acid and extracted with ethyl acetate. The ethylacetate solution is dried and evaporated and 1 g of triethylamine and 3 g of acetic anhydride are added to the residue. The mixture is heated to 105 - 110°C for a few hours, then cooled to room temperature and the excess of acetic anhydride is evaporated in vacuo, water and ice are added and the mixture is acidified with hydrochloric acid to precipitate 4-benzylidene-A 2-chromene-2-carboxylic acid which treated with chromic anhydride gives 4-chromone-2-carboxylic acid.

Eksempel 3-Example 3-

4- chromon- 2- karboksylsyre- natriu. msalt.4- chromone- 2- carboxylic acid sodium. msalt.

1,3 g 4-benzyliden-A 2-chromen-2-karboksylsyre fremstilt som tidligere beskrevet oppløses i en oppløsning av 25 ml 0,2 N natriumhydroksyd. Blandingen avkjøles til lav temperatur og man innføres 5,2 mol ozon. Etter avsluttet tilsetning behandles oppløsningen med Raney-nikkel og filtreres. Den 1.3 g of 4-benzylidene-A 2-chromene-2-carboxylic acid prepared as previously described is dissolved in a solution of 25 ml of 0.2 N sodium hydroxide. The mixture is cooled to a low temperature and 5.2 mol of ozone are introduced. After the addition is complete, the solution is treated with Raney nickel and filtered. It

filtrerte oppløsning ekstraheres med'etyleter og vannoppløs-ningen konsentreres i vakuum hvorpå etanol tilsettes flere ganger. Ved avkjøling får man 0.8 g 4-chromon-2-karboksylsyre-natriumsalt. filtered solution is extracted with ethyl ether and the water solution is concentrated in vacuum, after which ethanol is added several times. On cooling, 0.8 g of 4-chromone-2-carboxylic acid sodium salt is obtained.

Eksempel 4. Example 4.

6- metyl- 4- chromon- 2- karboksylsyre- metylester. 6- methyl- 4- chromone- 2- carboxylic acid methyl ester.

Fremstilling av °t- ( 5- metyl- 2- metoksykarbonylmetok-syfenyl)- kanelaldehyd. Preparation of °t-(5-methyl-2-methoxycarbonylmethoxyphenyl)-cinnamaldehyde.

Operasjonen er som beskrevet i eksempel 1: ut fra 11 g o-allyl-p-cresol (j. Org. Chem. 5, 212) som omsettes med etylbromacetat til 15 g 5-metyl-2-etoksykarbonylmetoksyallyl-benzen hvorav man tar 11 g 5-metyl-2-etoksykarbonylmetoksy-allylbenzen som ozoniseres og gir 7 g 5-metyl-2-etoksykar-bonylmetoksyfehyl-acetaldehyd. Ved kondensasjon av 10 g 5-,metyl-2-etoksykarbonylmetoksyfenylacetaldehyd med benzosyre-aldehyd og forestring med metanol får man 6 g (5-metyl-2-metoksykarbonyImetoksyfenyl)-kanelaldehyd. The operation is as described in example 1: starting from 11 g of o-allyl-p-cresol (j. Org. Chem. 5, 212) which is reacted with ethyl bromoacetate to 15 g of 5-methyl-2-ethoxycarbonylmethoxyallyl-benzene from which 11 g of 5-methyl-2-ethoxycarbonylmethoxy-allylbenzene which is ozonized to give 7 g of 5-methyl-2-ethoxycarbonylmethoxyphenylacetaldehyde. Condensation of 10 g of 5-,methyl-2-ethoxycarbonylmethoxyphenylacetaldehyde with benzoic aldehyde and esterification with methanol yields 6 g of (5-methyl-2-methoxycarbonylmethoxyphenyl)cinnamaldehyde.

Man går frem som i eksempel 1 og 6 g (5-metyl-2-metoksy-karbonylmetoksyfenyl)-kanelaldehyd ringsluttes og gir 3,5 g 6-metyl-4-benzyliden-A -chromen-2-karboksylsyremetylester som etter oksydasjon med kromsyreanhydrid gir 6-metyl-4-chromen-2-karboksylsyremetylester. One proceeds as in example 1 and 6 g of (5-methyl-2-methoxy-carbonylmethoxyphenyl)-cinnamaldehyde is ring-closed to give 3.5 g of 6-methyl-4-benzylidene-A-chromene-2-carboxylic acid methyl ester which after oxidation with chromic anhydride gives 6-methyl-4-chromene-2-carboxylic acid methyl ester.

Eksempel 5»Example 5»

Dimetylester av 1, 3~ bis( 2- karboksychromon- 5- yloksy)-2- acetoksy propan. 30 g 2-allylresorcinol fremstilt som angitt i Béil-stein (fjerde opplag 6, 5020) behandles med 200 ml aceton og 18 g etylkloracetat og 20 g kaliumbikarbonat tilsettes. Blandingen kokes under tilbakeløp i 20 timer omtrent, derpå fjernes acetonet ved destillasjon, inndampningsresten tas opp med metylenklorid og det organiske skjiktet ekstraheres flere ganger med vann. Oppløsningen av metylenklorid tørkes og 2-etoksykarbonylmetoksy-6-hydroksyallylbenzen høyvakuum-destilleres ved ca. 130°C. Produktet viser Rf lik ca. 0,46 (benzen: etyleter = 9:1). Dimethyl ester of 1,3~ bis(2-carboxychromon-5-yloxy)-2-acetoxy propane. 30 g of 2-allylresorcinol prepared as indicated in Béil-stein (fourth edition 6, 5020) is treated with 200 ml of acetone and 18 g of ethyl chloroacetate and 20 g of potassium bicarbonate are added. The mixture is refluxed for approximately 20 hours, then the acetone is removed by distillation, the evaporation residue is taken up with methylene chloride and the organic layer is extracted several times with water. The solution of methylene chloride is dried and 2-ethoxycarbonylmethoxy-6-hydroxyallylbenzene is high-vacuum distilled at approx. 130°C. The product shows Rf equal to approx. 0.46 (benzene: ethyl ether = 9:1).

Til 47,25 g 2-etoksykarbonylmetoksy-6-hydroksyallyl-benzen oppløst i 100 ml vannfri etylalkohol settes en oppløs-ning av 6,8 g natriumetylat i 100 ml vannfri etylalkohol og videre 9,5 g epiklorhydrin. Blandingen kokes under tilbakeløp i l6 timer, etylalkoholen fjernes og resten tas opp med etylacetat hvorpå den organiske oppløsning ekstraheres med vann og inndampes. 2-etoksykarbonylmetoksy-6-hydroksyallylbenzen som ikke har reagert avdestilleres i høyvakuum og man får 1,3-bis(2-ally1-3-etoksykarbonylmetoksyfenoksy)-2-hydroksy-propan med Rf ca 0,27 (benzen:etyleter = 9:1). To 47.25 g of 2-ethoxycarbonylmethoxy-6-hydroxyallyl-benzene dissolved in 100 ml of anhydrous ethyl alcohol is added a solution of 6.8 g of sodium ethylate in 100 ml of anhydrous ethyl alcohol and further 9.5 g of epichlorohydrin. The mixture is boiled under reflux for 16 hours, the ethyl alcohol is removed and the residue is taken up with ethyl acetate, after which the organic solution is extracted with water and evaporated. Unreacted 2-ethoxycarbonylmethoxy-6-hydroxyallylbenzene is distilled off under high vacuum and 1,3-bis(2-ally1-3-ethoxycarbonylmethoxyphenoxy)-2-hydroxy-propane is obtained with Rf approx. 0.27 (benzene:ethyl ether = 9: 1).

Til 40 g 1,3-bis-(2-allyl-3-etoksykarbonylmetoksy-fenoksy)-2-hydroksypropan oppløst i 40 ml vannfri pyridin settes 100 g vannfri eddiksyre og blandingen holdes 12 ti- To 40 g of 1,3-bis-(2-allyl-3-ethoxycarbonylmethoxy-phenoxy)-2-hydroxypropane dissolved in 40 ml of anhydrous pyridine is added 100 g of anhydrous acetic acid and the mixture is kept for 12 ti-

mer ved romtemperatur. Den inndampes under vakuum, inndampningsresten oppløses i etylacetat og oppløsningen vaskes med 2N saltsyre, vann og inndampes til tørrhet. Man får et residum av 1,3-bis-(2-allyl-3-etoksykarbonylmetoksyfenoksy)-2-acetoksypropan som har Rf ca. 0,47 (benzen:etyleter = 9:1)-40 g 1,3-bis-(2-allyl-3-etoksykarbonylmetoksyfenok-sy )-2-acetoksypropan oppløst i 400 ml vannfri metylenklorid mettes med ozon idet blandingen holdes i et bad av aceton og tørris. Man tilsetter 120 g sink og en blanding av 60 ml eddiksyre og 15 ml vann. Oppløsningen røres i noen timer, filtreres og vaskes med kaliumbikarbonatoppløsning og med vann. Etter inndampning av oppløsningsmiddelet får man 1,3-bis-(2-etylaldehyd-3-etoksykarbonyImetoksyfenoksy)-2-acetoksypropan som har Rf ca. 0,5 (benzen:etyleter = 1:1). more at room temperature. It is evaporated under vacuum, the evaporation residue is dissolved in ethyl acetate and the solution is washed with 2N hydrochloric acid, water and evaporated to dryness. A residue of 1,3-bis-(2-allyl-3-ethoxycarbonylmethoxyphenoxy)-2-acetoxypropane is obtained which has Rf approx. 0.47 (benzene:ethyl ether = 9:1)-40 g of 1,3-bis-(2-allyl-3-ethoxycarbonylmethoxyphenoxy)-2-acetoxypropane dissolved in 400 ml of anhydrous methylene chloride is saturated with ozone while keeping the mixture in a bath of acetone and dry ice. 120 g of zinc and a mixture of 60 ml of acetic acid and 15 ml of water are added. The solution is stirred for a few hours, filtered and washed with potassium bicarbonate solution and with water. After evaporation of the solvent, 1,3-bis-(2-ethylaldehyde-3-ethoxycarbonylImethoxyphenoxy)-2-acetoxypropane is obtained, which has Rf approx. 0.5 (benzene:ethyl ether = 1:1).

Til en oppløsning av 25 g kaliumhydroksyd i 150 ml vann tilsettes 500 ml etylalkohol. Blandingen avkjøles til ca. 0°C og man tilsetter langsomt en blanding av 33 g 1,3-bis-(2-etylaldehyd-3-etoksykarbonyImetoksyfenoksy)-2-acetok-sypropan og 64 g benzosyrelaldehyd. Oppløsningen hensettes i 12 timer og man tilsetter deretter 50 g kaliumbikarbonat. Blandingen inndampes i vakuum og oppløsningsmiddelet og overskuddet av benzaldehyd fjernes. Avdampningsresten tas opp med 100 ml vann og ekstraheres med toluen, vannoppløsningen sur-gjøres deretter med saltsyre og ekstraheres med etylacetat og ekstraktet forestres med metanol og paratoluensulfonsyre til 1,3-bis-(3-metoksykarbonyImetoksy-2-benzyliden-etylaldehyd-fenoksy)-2-hydroksypropan med R^ ca. 0,9 (etylacetat).' 45 g 1,3-bis-(3-metoksykarbonylmetoksy-2-benzyliden-etylaldehydfenoksy)-2-hydroksypropan oppløses i 90 ml vannfri toluen og 1 ml vannfri etylalkohol og denne oppløsningen set^tes gradvis til en suspensjon av 3,5 g natrium i 20 ml vann fri toluen og 50 ml vannfri etyleter. Blandingen holdes mel-lom 35 og 40°C inntil tilsetningen er fullstendig. Man hen-setter den ved romtemperatur i 12 timer etter avdamping av oppløsningsmiddelet og tilsetter metylenklorid og 2N saltsyre. Metylenkloridoppløsningen tørkes, og man får dimetylesteren av 1,3-bis-(2-karboksy-4-benzilidenchromen-5-yloksy)-2-hydrok-sypropan. 500 ml of ethyl alcohol is added to a solution of 25 g of potassium hydroxide in 150 ml of water. The mixture is cooled to approx. 0°C and a mixture of 33 g of 1,3-bis-(2-ethylaldehyde-3-ethoxycarbonylImethoxyphenoxy)-2-acetoxypropane and 64 g of benzosylaldehyde is slowly added. The solution is allowed to stand for 12 hours and 50 g of potassium bicarbonate is then added. The mixture is evaporated in vacuo and the solvent and excess benzaldehyde are removed. The evaporation residue is taken up with 100 ml of water and extracted with toluene, the water solution is then acidified with hydrochloric acid and extracted with ethyl acetate and the extract is esterified with methanol and paratoluenesulfonic acid to 1,3-bis-(3-methoxycarbonylImethoxy-2-benzylidene-ethylaldehyde-phenoxy) -2-hydroxypropane with R^ approx. 0.9 (ethyl acetate).' 45 g of 1,3-bis-(3-methoxycarbonylmethoxy-2-benzylidene-ethylaldehydephenoxy)-2-hydroxypropane is dissolved in 90 ml of anhydrous toluene and 1 ml of anhydrous ethyl alcohol and this solution is gradually added to a suspension of 3.5 g of sodium in 20 ml anhydrous toluene and 50 ml anhydrous ethyl ether. The mixture is kept between 35 and 40°C until the addition is complete. It is left at room temperature for 12 hours after evaporation of the solvent and methylene chloride and 2N hydrochloric acid are added. The methylene chloride solution is dried, and the dimethyl ester of 1,3-bis-(2-carboxy-4-benzylidenechromen-5-yloxy)-2-hydroxypropane is obtained.

Til 10 g 1,3-bis-(2-karboksy-4-benzilidenchromen-5-yloksy)-2-hydroksypropan oppløst i 30 ml vannfri pyridin settes 25 g eddiksyreanhydrid. Blandingen hensettes ved romtemperatur i 12 timer, inndampes i vakuum og residumet oppløses i metylenklorid. Oppløsningen vaskes med 2N saltsyre, vann og deretter tørkes den til 1,3-bis-(2-karboksy-4-benzilidenchro-men-5-yloksy)-2-acetoksypropandimetylester. 25 g of acetic anhydride are added to 10 g of 1,3-bis-(2-carboxy-4-benzylidenechromen-5-yloxy)-2-hydroxypropane dissolved in 30 ml of anhydrous pyridine. The mixture is left at room temperature for 12 hours, evaporated in vacuo and the residue dissolved in methylene chloride. The solution is washed with 2N hydrochloric acid, water and then dried to 1,3-bis-(2-carboxy-4-benzylidenechromen-5-yloxy)-2-acetoxypropane dimethyl ester.

10 g 1,3-bis-(2-karboksy-4-benzilidenchromen-5-y-loksy)-2-acetoksypropandimetylester behandles i 300 ml 50 $-ig eddiksyre, oppvarmes til 50 - 60°C og tilsettes derpå en opp-løsning av 9 g kromsyreanhydrid i 200 ml vann. Blandingen oppvarmes til romtemperatur, fortynnes med vann og ekstraheres 10 g of 1,3-bis-(2-carboxy-4-benzylidenechromene-5-yl-loxy)-2-acetoxypropane dimethyl ester is treated in 300 ml of 50 µg acetic acid, heated to 50 - 60°C and then added a solution of 9 g of chromic anhydride in 200 ml of water. The mixture is warmed to room temperature, diluted with water and extracted

med metylenklorid. Metylenkloridoppløsningen vaskes vann, kaliumbikarbonat og igjen med vann. Etter tørking og fjerning av dimetylesteren får man 1,3-bis-(2-karboksychromon-5-ylok-sy)-2-acetoksypropan som smelter ved ca. 220°C, R^0,55 (etylacetat). with methylene chloride. The methylene chloride solution is washed with water, potassium bicarbonate and again with water. After drying and removal of the dimethyl ester, 1,3-bis-(2-carboxychromon-5-yloxy)-2-acetoxypropane is obtained which melts at approx. 220°C, R = 0.55 (ethyl acetate).

Forsåpning av l,3-bis-(2-karboksychromon-5-yloksy)-2-acetoksypropandimetylester gir 1,3-bis-(karboksychromon-5-yloksy)-2-hydroksypropan som kan forestres med f or .--eksempel metylalkohol til en 1,3-bis(2-karboksychromon-5-yloksy)-2-hydroksypropandimetylester. Saponification of 1,3-bis-(2-carboxychromon-5-yloxy)-2-acetoxypropane dimethyl ester yields 1,3-bis-(carboxychromon-5-yloxy)-2-hydroxypropane which can be esterified with for example methyl alcohol to a 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane dimethyl ester.

Eksempel 6. Example 6.

1, 3- bis-( 2- karboksychromon- 5- yloksy)- 2- hydroksypro-pandinatriumsalt. 32 g 1,3-bis-(2-karboksy-4-benzilidenchromen-5-ylok-sy)-2-hydroksypropan fremstilt ved forsåpning av den tilsvarende dimetylester som ovenfor beskrevet behandles med pyridin og eddiksyreanhydrid og gir 1,3-bis-(2-karboksy-4-benzi-lidenchromen-5-yloksy)-2-acetoksypropan. 33 g 1,3-bis-(2-karboksy-4-benzilidenchromen-5-yloksy)-2-acetoksypropan behandles i 500 ml 0,2N natriumhy-droksydoppløsning og avkjøles. Den avkjølte oppløsning be handles med teoretisk mengde ozon og etter avsluttet tilsetning påfylles Raney-nikkel og man filtrerer. Oppløsningen ekstraheres med etyleter og til den vandige oppløsning tilsettes 4,4 g natriumbikartaonat. Av den vandige oppløsning får man ved konsentrering 1,3-bis-(2-karboksychromon-5-yloksy) -2-hydroksypropandinatriumsalt. 1, 3- bis-(2- carboxychromon-5- yloxy)- 2- hydroxypropane sodium salt. 32 g of 1,3-bis-(2-carboxy-4-benzylidenechromen-5-yloxy)-2-hydroxypropane produced by saponification of the corresponding dimethyl ester as described above is treated with pyridine and acetic anhydride and gives 1,3-bis- (2-Carboxy-4-benzylidenchromen-5-yloxy)-2-acetoxypropane. 33 g of 1,3-bis-(2-carboxy-4-benzylidenechromen-5-yloxy)-2-acetoxypropane are treated in 500 ml of 0.2N sodium hydroxide solution and cooled. The cooled solution is treated with a theoretical amount of ozone and, after the addition has been completed, Raney nickel is topped up and filtered. The solution is extracted with ethyl ether and 4.4 g of sodium bicarbonate is added to the aqueous solution. The aqueous solution is concentrated to obtain 1,3-bis-(2-carboxychromon-5-yloxy)-2-hydroxypropane disodium salt.

Claims

1. Process for the preparation of compounds of formula

where R denotes hydrogen, halogen, unsubstituted lower alkyl, lower alkyl substituted with halogen, hydroxy or lower alkoxy, hydroxy, hydroxy etherified with substituted or unsubstituted alkyl with from 3-5 C atoms inclusive, optionally symmetrically bonded with an ether bond at the other end of an identical chromene structure, A denotes hydrogen, saturated or unsaturated hydrocarbon, ammonium, et; alkali or alkaline earth tally atom, in that a compound of formula

where R has the above meaning, A^ denotes saturated or unsaturated hydrocarbon, R^ and R2 may be the same or different and denote hydrogen, lower alkyl, phenyl, phenyl substituted with halogen, hydroxy, lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxyalkyl , cycloalkyl or R-^ and R2 together with the common C atom can form an alicyclic system with 5 or 6 C atoms is treated with a suitable ring closing agent to produce a compound of the formula

where R, R^ and R2 have the previously indicated meaning and the thus produced compounds as such or in the form of the corresponding free 2-carboxylic acids or ammonium, alkali or alkaline earth metal salts, are treated with a suitable oxidizing agent for the production of the desired connection.

2. Method as stated in claim 1, characterized in that when R denotes free hydroxyl or an alkyl chain containing free hydroxyl, this can be protected in a suitable manner and the protective group is later cleaved off while restoring the free hydroxyl group in the end product.

3. Process as stated in claims 1 and 2, characterized in that the ring closing agent is sodium in the presence of a lower alkyl alcohol.

4. Method as stated in claims 1-3 for the preparation of a compound of formula

where R has the above meaning and denotes a saturated or unsaturated hydrocarbon group, whereby a compound with formula

where R, A, R and R2 have the previously indicated meaning, is treated with an oxidizing agent to produce the desired compound.

5. Procedure as specified in requirements 1-3 for the position of a compound with formula

where R has the previously stated meaning, in that a for- bond with formula

where R, A , R^ and Rg have the previously stated meanings, hydrolyzed and oxidized to the desired compound.

6. Method as stated in claims 1-3 for the preparation of a compound of formula

where R has the above meaning and Ag denotes an ammonium group, an alkali or alkaline earth metal atom, in that a for- bond with formula

where R, A^ . R and R^ have the previous meanings, hydrolyzed and converted to the corresponding ammonium, alkali or alkaline earth metal salt and then oxidized to the desired compound.

7- Compounds with formula

where R denotes hydrogen, halogen, unsubstituted lower alkyl, lower alkyl substituted with halogen, hydroxy or lower alkoxy, hydroxy, hydroxy etherified with a substituted or unsubstituted alkyl chain with from 3 to 5 C atoms inclusive, possibly symmetrically bound through an ether bond in the other end of an identical chromene structure, A denotes hydrogen, saturated or unsaturated hydrocarbon, an ammonium group, alkali or alkaline earth metal, R^ and R^ may be the same or different and denote hydrogen, lower alkyl, phenyl, phenyl substituted with halogen, hydroxy, lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxyalkyl, cycloalkyl , or R^ and R^ together with the C atom which they have in common may form an alicyclic system with 5 or 6 C atoms.

8. Compounds with formula

where R denotes hydrogen, halogen, unsubstituted lower alkyl, lower alkyl substituted by halogen, hydroxy or lower alkoxy, hydroxy, R^ and R^ may be the same or different and denote J.hydrogen, lower alkyl, phenyl, phenyl substituted by halogen, hydroxy, lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxyalkyl, or cycloalkyl, or R^ and Rg together with the common C atom may form an alicyclic system with 5 or 6 C atoms, A^ denotes hydrogen or a saturated or unsaturated hydrocarbon group, an ammonium group, alkali or alkaline earth metal.

9. Process for the preparation of a compound of formula

where A denotes hydrogen, a saturated or unsaturated hydrocarbon group, ammonium group, alkali or alkaline earth metal atom, and Alk denotes an alkyl chain with 3 to 5 C atoms or an optionally protected hydroxyl-substituted alkyl chain with from 3 to 5 C atoms, in that a connection with formula

where Alk has the above meaning and A^ denotes a saturated or unsaturated hydrocarbon group, R-^ and R^ may be the same or different and denote, hydrogen, lower alkyl, phenyl, phenyl substituted with halogen, hydroxy, lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxyalkyl, cycloalkyl or R^ and R^ together with the C atom which they have in common may form an alicyclic system with 5 or 6 C atoms, treated with a suitable ring-closing agent for manufacture of a compound of formula

where Alk, A^ , R^ and R^ have the previously indicated meanings and the thus produced compounds as such or in the form of the corresponding free two carboxylic acids or ammonium, alkali or alkaline earth metal salts, are treated with a suitable oxidizing agent to produce the desired compound.

10. Method as set forth in claim 9*characterized by the fact that Alk denotes -CHg - CH - CH^ -, OH possibly protected.

11. Method as stated in claim 10, characterized in that the protective group is removed to restore the free hydroxyl group.