NO122754B - - Google Patents

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NO122754B
NO122754B NO2126/69A NO212669A NO122754B NO 122754 B NO122754 B NO 122754B NO 2126/69 A NO2126/69 A NO 2126/69A NO 212669 A NO212669 A NO 212669A NO 122754 B NO122754 B NO 122754B
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carboxylic acid
dihydro
benzofuran
butyryl
general formula
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NO2126/69A
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Norwegian (no)
Inventor
B Libis
E Habicht
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Geigy Ag J R
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Publication of NO122754B publication Critical patent/NO122754B/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/14—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by free hydroxyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Furan Compounds (AREA)

Description

Analogifremgangsmåter for fremstilling av nye, terapeutisk virksomme, heterocykliske karboksylsyrer. Analogy methods for the preparation of new, therapeutically active, heterocyclic carboxylic acids.

Nærværende oppfinnelse vedrorer analogifremgangsmåter for fremstilling av nye, heterocykliske karboksylsyrer med den generelle formel I, hvor R betyr en alkylgruppe med hoyst 6 karbonatomer, X oksygen eller svovel,. The present invention relates to analogous methods for the production of new, heterocyclic carboxylic acids with the general formula I, where R means an alkyl group with at most 6 carbon atoms, X oxygen or sulphur.

og Y2 hydrogen eller metylgrupper, og og Z 2 hydrogen, fluor, klor, brom, alkyl- eller alkoksygrupper med hver hoyst 2 karbonatomer, and Y2 hydrogen or methyl groups, and and Z 2 hydrogen, fluorine, chlorine, bromine, alkyl or alkoxy groups with at most 2 carbon atoms each,

såvel som deres salter med uorganiske eller organiske baser. as well as their salts with inorganic or organic bases.

Disse nye forbindelser er 2,3-dihydro-derivater av de i den norske patentansokning nr. 2864/68 beskrevne forbindelser som oppviser diuretisk og saluretisk aktivitet. These new compounds are 2,3-dihydro derivatives of the compounds described in the Norwegian patent application no. 2864/68 which exhibit diuretic and saluretic activity.

Som det nå er funnet, har de nye forbindelsene verdifulle farmakologiske egenskaper ved siden av en hoy terapeutisk in-deks. Ved hjelp av standardforsok [sml. E.G. Stenger et al., Schweiz. med. Wochenschr. 89, 1126 (1959)3 ble det påvist hos hund at de oppviser diuretisk og saluretisk virkning. Disse egenskaper karakteriserer de nye forbindelser som egnet til behandling av forstyrrelser som er betinget ved mangelfull ut-skillelse av elektrolytter, spesielt av natriumklorid. Slike forstyrrelser er årsak til odemer og hypertonier. i As has now been found, the new compounds have valuable pharmacological properties in addition to a high therapeutic index. Using standard experiments [cf. E. G. Stenger et al., Schweiz. with. Wochenschr. 89, 1126 (1959)3 it was demonstrated in dogs that they exhibit diuretic and saluretic effects. These properties characterize the new compounds as suitable for the treatment of disorders caused by insufficient excretion of electrolytes, especially of sodium chloride. Such disturbances are the cause of edema and hypertension. in

I de etterfølgende tabeller a) og b) er resultatene av den farmakologiske undersokelse av forbindelsene ifolge nærværende In the following tables a) and b) are the results of the pharmacological examination of the compounds according to the present

oppfinnelse og norsk patentansokning nr. 2864/68 stilt opp mot' hverandre. Den totale mengde natrium<*> i milliekvivalenter som utskilles i lopet av de forste 3 1/2 timer etter p.o. ad- I ministrasjon av produktet, er angitt. Doseringen er henh. 1 til 5 mg/kg. ftkningen av Cl~- og vannutskillelsen forloper ved disse forbindelser temmelig parallelt til Na<+->ekskresjon. Kalium<+->utskillelsen er gjennomgående mindre. Den akutte tok-j sisitet ble bestemt peroralt hos mus. 1 invention and Norwegian patent application no. 2864/68 placed against each other. The total amount of sodium<*> in milliequivalents excreted during the first 3 1/2 hours after p.o. administration of the product, is indicated. The dosage is according to 1 to 5 mg/kg. The reduction of Cl~- and the excretion of water in these compounds proceed rather parallel to Na<+->excretion. Potassium<+->excretion is consistently less. The acute toxicity was determined orally in mice. 1

a) Provede forbindelser ifolge nærværende ansokning og resultater. b) Provede forbindelser ifolge norsk patentansokning nr. 2864/68 og resultater (sammenligningsforbindelser). a) Tested connections according to the present application and results. b) Tested compounds according to Norwegian patent application no. 2864/68 and results (comparison compounds).

Fra tabellene a) og b) fremgår det at forbindelsene I, II, III og IV ifolge nærværende oppfinnelse er de tilsvarende forbin- I deiser XI, XII, XIII henh. XV ifolge norsk patentansokning nr. 2864/68 vesentlig overlegne med hensyn til deres saluretis-ke virkning. Også forbindelsene V, VIII, IX og X er meget aktive forbindelser, som likeledes har en mere utpreget saluretisk virkning enn deres nærmest beslektede (forbindelsene XII, XV henh. XVi) ifolge den siterte norske ansokning. From tables a) and b) it appears that the compounds I, II, III and IV according to the present invention are the corresponding compounds XI, XII, XIII acc. XV, according to Norwegian patent application no. 2864/68, significantly superior with regard to their saluretic effect. Compounds V, VIII, IX and X are also very active compounds, which likewise have a more pronounced saluretic effect than their closest relatives (compounds XII, XV and XVi) according to the cited Norwegian application.

I de heterocykliske karboksylsyrer med den generelle formel I inntar Z^ 4- eller 6-stillingen og Z^ 6- eller 7-stillingen. In the heterocyclic carboxylic acids of the general formula I, Z^ occupies the 4- or 6-position and Z^ the 6- or 7-position.

R betyr en metyl-, etyl-, propyl-, isopropyl-, butyl-, sek. R means a methyl, ethyl, propyl, isopropyl, butyl, sec.

butyl-, tert.butyl-, amyl- eller heksylgruppe, og Z^ såvel son Z2 som alkylgrupper metyl- eller etylgrupper og som alkoksygrupper metoksy- eller etoksygrupper. j i butyl, tert.butyl, amyl or hexyl group, and Z^ as well as Z2 as alkyl groups, methyl or ethyl groups and as methoxy groups, methoxy or ethoxy groups. j i

For fremstilling ifolge oppfinnelsen av forbindelser med den generelle formel I spalter man en forbindelse med den generelle formel II, For the preparation according to the invention of compounds of the general formula I, a compound of the general formula II is cleaved,

hvor R, X, Y|, Z-, °9 ^ har den under formel I angitte betydning og Am betyr resten av en sekundær organisk nitrogenbase, under avspaltning av en nitrogenbase med den generelle formel III, where R, X, Y|, Z-, °9 ^ has the meaning indicated under formula I and Am means the residue of a secondary organic nitrogen base, during cleavage of a nitrogen base of the general formula III,

hvor Am har den under formel II angitte betydning, where Am has the meaning given under formula II,

og overforer, hvis dnsket, reaksjonsproduktet med en uorganisk eller organisk base til et salt. and, if desired, converts the reaction product with an inorganic or organic base into a salt.

Am kan som rest av en sekundær organisk base f.eks. være di-metylamino-, dietylamino-, 1-pyrrolidinyl-, piperidino-, heksa-hydro-lH-azepin-l-yl- eller morfolinogruppen. Am can, as a residue of a secondary organic base, e.g. be the dimethylamino, diethylamino, 1-pyrrolidinyl, piperidino, hexahydro-1H-azepin-1-yl or morpholino group.

En forbindelse med den generelle formel II spaltes fortrinnsvis ved oppvarmning i nærvær av en svak base i et hydroksylgruppe-holdig oppldsningsmiddel. Som svake baser kommer f.eks. natriumacetat eller natriumhydrogenkarbonat i betraktning. De anvendes fortrinnsvis i iseddik henh. vann. A compound of the general formula II is preferably decomposed by heating in the presence of a weak base in a solvent containing a hydroxyl group. As weak bases, e.g. sodium acetate or sodium bicarbonate into account. They are preferably used in glacial acetic acid according to water.

Egnede utgangsstoffer med den generelle formel II er Suitable starting materials of the general formula II are

forbindelser hvis rester R, X, Y-^, Y^ Z^ og Z~ stemmer overens med gruppene som er oppregnet i tilknytning til formel I. Disse utgangsstoffer kan f.eks. fremstilles som folger: Man går ut fra karboksylsyrer med den generelle formel IV, som er utgangsstoffer for den andre fremgangsmåte ifolge oppfinnelsen. compounds whose residues R, X, Y-^, Y^ Z^ and Z~ correspond to the groups listed in connection with formula I. These starting substances can e.g. is prepared as follows: One starts from carboxylic acids with the general formula IV, which are starting materials for the second process according to the invention.

Disse forbindelser kondenserer man ifolge Friedel-Crafts ved hjelp av aluminiumklorid i karbondisulfid med karboksylsyreklorider med den generelle formel IVa, According to Friedel-Crafts, these compounds are condensed using aluminum chloride in carbon disulphide with carboxylic acid chlorides of the general formula IVa,

hvor R har den under formel I angitte betydning, til forbindelser med den generelle formel IVb, where R has the meaning given under formula I, to compounds with the general formula IVb,

hvor R, X, Y-^, Y^ Z-^ og 2.^ har den under formel I angitte betydning. where R, X, Y-^, Y^ Z-^ and 2.^ have the meaning given under formula I.

De erholdte reaksjonsprodukter overfores deretter ved hjelp av formaldehyd eller paraformaldehyd og en sekundær organisk base til de tilsvarende Mannichderivater med den generelle formel II. The reaction products obtained are then transferred by means of formaldehyde or paraformaldehyde and a secondary organic base to the corresponding Mannich derivatives of the general formula II.

For fremstilling av forbindelser med den generelle formel 'I etter en andre fremgangsmåte ifolge oppfinnelsen omsetter man en-forbindelse den generelle formel IV, For the preparation of compounds of the general formula 'I according to a second method according to the invention, one reacts a compound of the general formula IV,

hvor X, Y-p Y2) Z-^ og Zp har den under formel I angitte where X, Y-p Y2) Z-^ and Zp have the under formula I indicated

betydning, importance,

med et karboksylsyrehalogenid med den generelle formel V, with a carboxylic acid halide of the general formula V,

.eller med et karboksylsyreanhydrid med den generelle formel VI, .or with a carboxylic acid anhydride of the general formula VI,

hvor R har den under formel I angitte betydning og where R has the meaning given under formula I and

Q betyr halogen, Q means halogen,

ifolge Friedel-Crafts og overforer, hvis onsket, reaksjonsproduktet med en uorganisk eller organisk base til et salt. according to Friedel-Crafts and, if desired, converts the reaction product with an inorganic or organic base into a salt.

Som halogen er Q fortrinnsvis klor eller brom. Egnede katalysa-torer for omsetningen ifolge Friedel-Crafts er f.eks.: spesielt aluminiumklorid og tinn-(IV)-klorid, videre sinkklorid, konsentrert svovelsyre, fosforsyre, polyfosforsyre eller pyrofosfor-syre. De nevnte syrer anvendes fortrinnsvis, når acylerings-midlet er et karboksylsyreanhydrid. Omsetningen foretas fortrinnsvis i et oppldsningsmiddel. Man kan som opplosningsmiddel f.eks. anvende alifatiske eller cykloalifatiske hydrokarboner, som heptan eller cykloheksan, nitrohydrokarboner, som nitrometan, nitrocykloheksan eller nitrobenzen, eller halogenhydrokarboner, som karbontetraklorid, etylenklorid, metylenklorid, o-diklor-benzen, og videre karbondisulfid. As halogen, Q is preferably chlorine or bromine. Suitable catalysts for the reaction according to Friedel-Crafts are, for example: especially aluminum chloride and stannous (IV) chloride, further zinc chloride, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid or pyrophosphoric acid. The aforementioned acids are preferably used when the acylating agent is a carboxylic acid anhydride. The turnover is preferably carried out in a solvent. As a solvent, e.g. use aliphatic or cycloaliphatic hydrocarbons, such as heptane or cyclohexane, nitrohydrocarbons, such as nitromethane, nitrocyclohexane or nitrobenzene, or halohydrocarbons, such as carbon tetrachloride, ethylene chloride, methylene chloride, o-dichloro-benzene, and further carbon disulphide.

Som utgangsstoffer med den generelle formel IV med et oksygen-atom som X egner seg forbindelser hvis rester Y^, Y2, As starting substances with the general formula IV with an oxygen atom such as X are suitable compounds whose residues Y^, Y2,

Z-^ og Z2 stemmer overens med gruppene som er oppregnet i til-; knytning til formel I. Av denne type forbindelser er f.eks. 2,3-dihydro-benzofuran-2-karboksylsyre [sml. R. Fittig og G. Ebert, Ann.Chem. 216 (1883)] og 2,3-dihydro-6-metoksy-benzo-furan-2-karboksylsyre [sml. W. Will og P. Beck, Chem.Ber. 19, 1783 (1886)] kjent. Ytterligere forbindelser fra denne rekke kan f.eks. fremstilles ved å gå ut fra substituerte 2-allyl-fenoler som folger: Man oksyderer de substituerte 2-allyl-fenoler med pereddiksyre til tilsvarende 2-(2,3-epoksy-propyl)-fenoler og omleirer disse ved oppvarmning til de tilsvarende 2,3-dihydro-2-hydroksymetyl-benzofuraner, hvilke man oksyderer med kaliumpermanganat til tilsvarende 2,3-dihydro-benzofuran-2-karboksylsyrer. F.eks. fremstilles 2,3-dihydro-6-klor-benzo-furan-2-karboksylsyre ved å gå ut fra 2-allyl-5-klor-fenol via mellomproduktene 2-(2,3-epoksy-propyl)-5-klor-fenol og 2,3-dihydro-2-hydroksymetyl-6-klor-benzofuran etter denne fremgangsmåte. Videre kan også forbindelser med den generelle formel IV oppnås, når man reduserer eventuelt substituerte benzofuran-2-karboksylsyrer f.eks. med natriumamalgam til tilsvarende 2,3-dihydro-benzofuran-2-karboksylsyrer. F.eks. fremstilles 2,3-dihydro-6-metyl-benzofuran-2-karboksylsyre ved å gå ut fra 6-metyl-benzofuran-2-karboksylsyre [sml. K. von Auwers, Ann.Chem. 408, 255 (1955)] etter denne fremgangsmåte. Z-^ and Z2 correspond to the groups enumerated in to-; connection to formula I. Of this type of compounds are e.g. 2,3-dihydro-benzofuran-2-carboxylic acid [cf. R. Fittig and G. Ebert, Ann.Chem. 216 (1883)] and 2,3-dihydro-6-methoxy-benzo-furan-2-carboxylic acid [comp. W. Will and P. Beck, Chem.Ber. 19, 1783 (1886)] known. Further connections from this series can e.g. are prepared starting from substituted 2-allyl-phenols as follows: The substituted 2-allyl-phenols are oxidized with peracetic acid to the corresponding 2-(2,3-epoxy-propyl)-phenols and rearranged by heating to the corresponding 2 ,3-dihydro-2-hydroxymethyl-benzofurans, which are oxidized with potassium permanganate to corresponding 2,3-dihydro-benzofuran-2-carboxylic acids. E.g. 2,3-dihydro-6-chloro-benzo-furan-2-carboxylic acid is prepared starting from 2-allyl-5-chloro-phenol via the intermediates 2-(2,3-epoxy-propyl)-5-chloro- phenol and 2,3-dihydro-2-hydroxymethyl-6-chloro-benzofuran according to this procedure. Furthermore, compounds with the general formula IV can also be obtained, when optionally substituted benzofuran-2-carboxylic acids are reduced, e.g. with sodium amalgam to corresponding 2,3-dihydro-benzofuran-2-carboxylic acids. E.g. 2,3-dihydro-6-methyl-benzofuran-2-carboxylic acid is prepared by starting from 6-methyl-benzofuran-2-carboxylic acid [cf. K. von Auwers, Ann.Chem. 408, 255 (1955)] following this procedure.

Utgangsstoffer med den generelle formel II med et svovelatom Starting substances of the general formula II with a sulfur atom

som X lar seg fremstille på analog måte ved reduksjon av tilsvarende substituerte benzo[b]tiofen-2-karboksylsyrer med natriumamalgam.' Av de hertil nodvendige benzo[b]tiofen-2-karboksylsyrer er noen, som f.eks. 6-metyl-benzo[b]tiofen-2-karboksylsyre [sml. >Y. Matsuki, T. Kanda, Nippon Kagaku Zasshi 86, 99 - 102 (1965)] kjent og ytterligere fremstillbar analogt de kjente, f.eks. ved karboksylering av tilsvarende substituerte. benzo[b]tiofener. Videre oppnår man substituerte benzo[b]tio-fen-2-karboksylsyrer ved kondensasjon av tilsvarende definisjonen for Z-^ og Z2 substituerte o-halogenbenzaldehyder til tilsvarende substituerte 5-(o-halogenbenzyliden)-rhodaniner og koking av de sistnevnte med natronlut og, om nddvendig, etterfølgende oppvarmning med natriummetylat i dietylenglykol til ca. 150 - 160°C, [sml. M.D. Castle, R.G. Plevey og Y.C. Tatlow, J. Chem. Soc. 1968, 1225 - 1227]. which X can be prepared in an analogous way by reduction of correspondingly substituted benzo[b]thiophene-2-carboxylic acids with sodium amalgam.' Some of the benzo[b]thiophene-2-carboxylic acids required for this, such as e.g. 6-methyl-benzo[b]thiophene-2-carboxylic acid [comp. >Y. Matsuki, T. Kanda, Nippon Kagaku Zasshi 86, 99 - 102 (1965)] known and further producible analogously to those known, e.g. by carboxylation of correspondingly substituted. benzo[b]thiophenes. Furthermore, substituted benzo[b]thio-phen-2-carboxylic acids are obtained by condensation of the corresponding definition for Z-^ and Z2 substituted o-halobenzaldehydes to correspondingly substituted 5-(o-halobenzylidene)-rhodanines and boiling the latter with caustic soda and , if necessary, subsequent heating with sodium methylate in diethylene glycol to approx. 150 - 160°C, [comp. MD Castle, R.G. Plevey and Y.C. Tatlow, J. Chem. Soc. 1968, 1225 - 1227].

Etter en tredje fremgangsmåte ifolge oppfinnelsen fremstiller man forbindelser med den generelle formel I, idet man avhalogenerer en forbindelse med den generelle formel VII, hvor R, X, Y-p Y2 5 Z-^ og Z^ har den under formel I angitte betydning og According to a third method according to the invention, compounds of the general formula I are prepared by dehalogenating a compound of the general formula VII, where R, X, Y-p Y2 5 Z-^ and Z^ have the meaning indicated under formula I and

Q betyr halogen, Q means halogen,

og overforer, hvis dnsket, reaksjonsproduktet med en uorganisk eller organisk base til et salt. and, if desired, converts the reaction product with an inorganic or organic base into a salt.

Som halogen er Q fortrinnsvis klor eller brom. Avhalogeneringen kan foretas ved hjelp av metaller, som f. eks. kobber, mag-nesium, aluminium, jern og spesieTt ved hjelp av sinkstdv. Da avhalogeneringen i almindelighet er en utpreget eksoterm reaksjon, gjennomføres den fortrinnsvis i et opplosningsmiddel. Anvender man sinkstov som dehalogeneringsmiddel, så er f.eks. lavere alkanoler, som metanol eller etanol, egnede oppldsnings-midler. Ved siden av de metalliske dehalogeneringsmidler kommer også ikke-metalliske, f.eks. alkalimetalljodider, på tale. Som eksempler skal natrium- eller kaliumjodid nevnes, som likeledes anvendes fortrinnsvis i et opplosningsmiddel. Oppldsningsmidler som egner seg, er f.eks. lavere alkanoler, som metanol eller As halogen, Q is preferably chlorine or bromine. The dehalogenation can be carried out with the help of metals, such as copper, magnesium, aluminium, iron and specieTt by means of zinc stdv. As the dehalogenation is generally a distinctly exothermic reaction, it is preferably carried out in a solvent. If zinc dust is used as a dehalogenating agent, then e.g. lower alkanols, such as methanol or ethanol, suitable solvents. Alongside the metallic dehalogenating agents, there are also non-metallic ones, e.g. alkali metal iodides, in speech. As examples, sodium or potassium iodide should be mentioned, which are likewise used preferably in a solvent. Suitable lighting agents are e.g. lower alkanols, such as methanol or

etanol, eller lavere alkanoner, som aceton eller me tyletylketon. ethanol, or lower alkanones, such as acetone or methyl ethyl ketone.

1 Som utgangsstoffer med den generelle formel VII kan forbindelser anvendes hvis grupper Q, R, X, Yp Y2, Z^ og Z2 stemmer overens med gruppene som er oppregnet i tilknytning til formel I henh. VII. Slike forbindelser oppnår man f.eks. ved å gå ut fra karboksylsyrer med den generelle formel IV, som er 1 As starting substances with the general formula VII, compounds can be used if groups Q, R, X, Yp Y2, Z^ and Z2 correspond to the groups listed in connection with formula I acc. VII. Such connections are obtained, e.g. by starting from carboxylic acids of the general formula IV, which are

utgangssto ffer for den andre fremgangsmåte ifolge oppfinnelsen. Disse karboksylsyrer kan f.eks. acyleres i 5-stilling ifolge Friedel-Crafts ved hjelp av aluminiumklorid i nitrobenzen med karboksylsyreklorider med den generelle formel Vila, starting materials for the second method according to the invention. These carboxylic acids can e.g. is acylated in the 5-position according to Friedel-Crafts using aluminum chloride in nitrobenzene with carboxylic acid chlorides of the general formula Vila,

hvor R har den under formel I angitte betydning og Q betyr fortrinnsvis klor eller brom. where R has the meaning given under formula I and Q preferably means chlorine or bromine.

De nye aktivstoffer eller de farmasoytisk aksepterbare salter av de samme administreres fortrinnsvis peroralt. Til salt-dannelse kan uorganiske eller organiske baser, som f.eks. alkali- eller jordalkalimetallhydroksyder, karbonater eller bikarbonater, trietanolamin eller cholin anvendes. De dag-lige doser beveger seg mellom 0,5 og 5 mg/kg for varmblodige dyr. The new active substances or the pharmaceutically acceptable salts thereof are preferably administered orally. For salt formation, inorganic or organic bases, such as e.g. alkali or alkaline earth metal hydroxides, carbonates or bicarbonates, triethanolamine or choline are used. The daily doses range between 0.5 and 5 mg/kg for warm-blooded animals.

De etterfølgende eksempler redegjor nærmere for fremstillin-gen av de nye forbindelser med den generelle formel I og av hittil ikke beskrevne mellomprodukter. Temperaturene er angitt i Celsiusgrader. The following examples give a more detailed account of the preparation of the new compounds of the general formula I and of previously undescribed intermediates. The temperatures are indicated in degrees Celsius.

EKSEMPEL 1 EXAMPLE 1

a) 20,0 g 2, 3-dihydro-5-butyryl-6-metyl-benzofuran-2-karboksylsyre kokes med 4,1 g paraformaldehyd og 8,2 g dimetylamin-hydroklorid i 125 ml dioksan i 8 timer under roring ved tilbakelop. Deretter inndampes reaksjonsblåndingen i vakuum. Til den erholdte, rå 2,3-dihydro-5-(2-dimetylaminometyl-butyryl)-6-metyl-benzo-furan-2-karboksylsyre-hydroklorid tilforer man 21,0 g vannfritt natriumacetat og 200 ml iseddik. Man koker den erholdte blanding i 2 timer under roring ved tilbakelop og inndamper den under vakuum. Resten rores med 100 ml vann, den erholdte suspensjon innstilles på pH 2 med konsentrert saltsyre og rores i 1 time ved 20°. Man ekstraherer den organiske syre ved tre gangers utrystning med 150 ml eter. Eteropplosningen torkes over natriumsulfat og inndampes. Mari omkrystalliserer resten fra cykloheksan og xylen-heksan, hvoretter 2,3-dihydro-5-(2-metylen-butyryl)-6-metyl-benzo f uran-2-karboksyl syre smelter ved 100-10 2°.. a) 20.0 g of 2,3-dihydro-5-butyryl-6-methyl-benzofuran-2-carboxylic acid is boiled with 4.1 g of paraformaldehyde and 8.2 g of dimethylamine hydrochloride in 125 ml of dioxane for 8 hours while stirring at backflow. The reaction mixture is then evaporated in vacuo. To the crude 2,3-dihydro-5-(2-dimethylaminomethyl-butyryl)-6-methyl-benzo-furan-2-carboxylic acid hydrochloride obtained, 21.0 g of anhydrous sodium acetate and 200 ml of glacial acetic acid are added. The resulting mixture is boiled for 2 hours with stirring at reflux and evaporated under vacuum. The residue is stirred with 100 ml of water, the resulting suspension is adjusted to pH 2 with concentrated hydrochloric acid and stirred for 1 hour at 20°. The organic acid is extracted by shaking three times with 150 ml of ether. The ether solution is dried over sodium sulfate and evaporated. Mari recrystallizes the residue from cyclohexane and xylene-hexane, after which 2,3-dihydro-5-(2-methylene-butyryl)-6-methyl-benzofuran-2-carboxylic acid melts at 100-10 2°..

Den som utgangsstoff anvendte 2,3-dihydro-5-butyryl-6-metyl-benzofuran-2-karboksylsyre fremstilles som folger: b) 35,0 g 6-metyl-benzofuran-2-karboksylsyre [sml. K. von Auwers, Ann.Chem. 408, 255 (1915)] opploses i 500 ml av en mettet, vandig natriumhydrogenkarbonatopplosning, og opplosningen avkjoles i isbad til 5°. Man tilsetter 500,0 g 5 %'ig natriumamalgam, fjerner reaksjonsblandingen etter 2 timer fra isbadet og lar den stå i 24 timer ved 20°. Deretter skilles opplosningen fra kvikksolv, filtreres, og filtratet innstilles på pH 1 med konsentrert saltsyre. Det utfelte bunnfall filtreres fra, vaskes med 300 ml vann og torkes. Den erholdte 2,3-dihydro-6-metyl-benzo furan-2-karboksylsyre smelter ved 157° og etter omkrystal-1isasjon fra metanol-vann ved 158°. c) 25,2 g av den etter b) erholdte karboksylsyre oppslemmes med 135 ml nitrobenzen og tilsettes porsjonsvis i lopet av 30 The 2,3-dihydro-5-butyryl-6-methyl-benzofuran-2-carboxylic acid used as starting material is prepared as follows: b) 35.0 g of 6-methyl-benzofuran-2-carboxylic acid [cf. K. von Auwers, Ann.Chem. 408, 255 (1915)] is dissolved in 500 ml of a saturated aqueous sodium bicarbonate solution, and the solution is cooled in an ice bath to 5°. 500.0 g of 5% sodium amalgam is added, the reaction mixture is removed after 2 hours from the ice bath and left to stand for 24 hours at 20°. The solution is then separated from mercury solution, filtered, and the filtrate is adjusted to pH 1 with concentrated hydrochloric acid. The precipitate that precipitates is filtered off, washed with 300 ml of water and dried. The 2,3-dihydro-6-methyl-benzofuran-2-carboxylic acid obtained melts at 157° and after recrystallization from methanol-water at 158°. c) 25.2 g of the carboxylic acid obtained according to b) is slurried with 135 ml of nitrobenzene and added in portions over the course of 30

minutter under roring og avkjoling 69,-5 g aluminiumklorid, slik at temperaturen ikke overstiger 10°. Ved den samme temperatur tildrypper man i lopet av 30 minutter»22,3 g butyrylklorid. Deretter rores reaksjonsblandingen videre i 5 timer i isbad, minutes while stirring and cooling 69.5 g of aluminum chloride, so that the temperature does not exceed 10°. At the same temperature, 22.3 g of butyryl chloride is added dropwise over the course of 30 minutes. The reaction mixture is then stirred for 5 hours in an ice bath,

står til henstand i 16 timer ved værelsetemperatur, oppvarmes ennå i 1 time ved 40° og helles på 500,0 g is. Man tilsetter til den erholdte suspensjon 50 ml konsentrert saltsyre. Etter at aluminiumkloridkomplekset har spaltet seg, ekstraheres reaksjonsblandingen tre ganger hver gang med 150 ml eter. Man torker eterekstraktet over natriumsulfat og inndamper det. Resten oppslemmes i heksan, omrystes, skilles igjen fra heksan og omkrystalliseres fra benzen. Den erholdte 2,3-dihydro-5-butyryl-6-metyl-benzofuran-2-karboksylsyre smelter ved 140 - 141°. left to stand for 16 hours at room temperature, heated for a further 1 hour at 40° and poured onto 500.0 g of ice. 50 ml of concentrated hydrochloric acid is added to the resulting suspension. After the aluminum chloride complex has split, the reaction mixture is extracted three times each time with 150 ml of ether. The ether extract is dried over sodium sulphate and evaporated. The residue is suspended in hexane, shaken, separated again from hexane and recrystallized from benzene. The 2,3-dihydro-5-butyryl-6-methyl-benzofuran-2-carboxylic acid obtained melts at 140 - 141°.

EKSEMPEL 2 EXAMPLE 2

a) Analogt eksempel la) oppnår man ved å gå ut fra 2,3-dihydro-5-butyryl-7-klor-benzofuran-2-karboksylsyre med paraformaldehyd a) Analogous example la) is obtained by starting from 2,3-dihydro-5-butyryl-7-chloro-benzofuran-2-carboxylic acid with paraformaldehyde

og dimetylamin-hydroklorid det rå 2,3-dihydro-5-(2-dimetylamino-metyl-butyryl)-7-klor-benzofuran-2-karboksylsyre-hydroklorid, som overfores med natriumacetat og iseddik til 2,3-dihydro-5-(2-metylen-butyryl)-7-klor-benzofuran-2-karboksylsyre med smp. 144° (fra benzen). and dimethylamine hydrochloride the crude 2,3-dihydro-5-(2-dimethylamino-methyl-butyryl)-7-chloro-benzofuran-2-carboxylic acid hydrochloride, which is converted with sodium acetate and glacial acetic acid to 2,3-dihydro-5 -(2-methylene-butyryl)-7-chloro-benzofuran-2-carboxylic acid with m.p. 144° (from benzene).

Utgangsstoffet, 2,3-dihydro-5-butyryl-7-klor-benzofuran-2-karboksylsyre, fremstilles som folger: b) 112,0 g 2-allyl-6-klor-fenol [sml. D.S. Tarbell og J.W. Wilson, J.Am.Chem.Soc. 64, 1066 (1942)] tilsettes under roring i lopet av 30 minutter til en omhyggelig avkjolt blanding av 6,5 g vannfritt natriumacetat og 160,0 g 40 %'ig pereddiksyre. Reaksjonstemperaturen bor i lopet av 24 timer ikke overstige 15 - 20°. Deretter tilsetter man et overskudd av vandig, mettet natriumhydrogenkarbonatopplosning. Den eteriske opplosning vaskes med mettet, vandig natriumhydrogenkarbonat-, natriumklorid- og jern-(II)-sulfat-opplosning, slik at det hele overskudd av pereddiksyre spaltes. (Man påviser den overskytende pereddiksyre med kaliumjodid i vann). Deretter torkes eteropplosningen over natriumsulfat og inndampes. Man oppvarmer resten, det rå 6-klor-2-(2,3-epoksy-propyl)-fenol, i 20 minutter til 110° og destillerer reaksjonsblandingen under hoyvakuum. Det erholdte 2,3-dihydro-2-hyrJroksymetyl-7-klor-benzofuran koker ved 101- 108°/0,02 Torr. c) 15,0 g 2,3-dihydrb-2-hydroksymetyl-7-klor-benzofuran oppslemmes i 120 ml 4-n natronlut ved kraftig rysting og avkjdles til 5°. Deretter tilsetter man på en gang en oppldsning av 72,0 g kaliumpermanganat i 1,3 liter vann til suspensjonen og ryster den energisk under kjoling, slik at temperaturen ikke stiger over 25°. Etter at reaksjonsblandingen er avfarget, filtrerer man fra mangandioksyd og ettervasker dette med 300 ml varmt vann. Den avkjolte oppldsning innstilles på pH 1 med konsentrert saltsyre og ekstraheres så tre ganger med hver gang 500 ml eter. Man tdrker eteropplosningen over natriumsulfat og inndamper den. Resten omkrystalliseres fra karbontetraklorid-benzen, hvoretter 2,3-dihydro-7-klor-benzo furan-2-karboksylsyre smelter ved 145 - 146°. d) Den etter c) erholdte karboksylsyre acyieres analogt eksempel lc) med butyrylklorid til 2,3-dihydro-5-butyryl-7-klor-benzofuran-2-karboksylsyre med smp. 161° (fra benzen). The starting material, 2,3-dihydro-5-butyryl-7-chloro-benzofuran-2-carboxylic acid, is prepared as follows: b) 112.0 g of 2-allyl-6-chloro-phenol [cf. D. S. Tarbell and J.W. Wilson, J. Am. Chem. Soc. 64, 1066 (1942)] is added with stirring over 30 minutes to a carefully cooled mixture of 6.5 g of anhydrous sodium acetate and 160.0 g of 40% peracetic acid. The reaction temperature should not exceed 15 - 20° over the course of 24 hours. An excess of aqueous, saturated sodium bicarbonate solution is then added. The ethereal solution is washed with saturated, aqueous sodium bicarbonate, sodium chloride and iron (II) sulphate solution, so that the entire excess of peracetic acid is decomposed. (The excess peracetic acid is detected with potassium iodide in water). The ether solution is then dried over sodium sulphate and evaporated. The residue, the crude 6-chloro-2-(2,3-epoxy-propyl)-phenol, is heated for 20 minutes to 110° and the reaction mixture is distilled under high vacuum. The 2,3-dihydro-2-hydroxymethyl-7-chloro-benzofuran obtained boils at 101-108°/0.02 Torr. c) 15.0 g of 2,3-dihydrob-2-hydroxymethyl-7-chloro-benzofuran are suspended in 120 ml of 4-n caustic soda with vigorous shaking and cooled to 5°. A solution of 72.0 g of potassium permanganate in 1.3 liters of water is then added all at once to the suspension and vigorously shaken while cooling, so that the temperature does not rise above 25°. After the reaction mixture has been decoloured, manganese dioxide is filtered off and washed with 300 ml of hot water. The cooled solution is adjusted to pH 1 with concentrated hydrochloric acid and then extracted three times with 500 ml of ether each time. The ether solution is dried over sodium sulfate and evaporated. The residue is recrystallized from carbon tetrachloride-benzene, after which 2,3-dihydro-7-chloro-benzofuran-2-carboxylic acid melts at 145 - 146°. d) The carboxylic acid obtained after c) is acylated analogously to example lc) with butyryl chloride to 2,3-dihydro-5-butyryl-7-chloro-benzofuran-2-carboxylic acid with m.p. 161° (from benzene).

EKSEMPEL 3 EXAMPLE 3

Analogt eksempel la) oppnår man fra 2,3-dihydro-5-butyryl-benzo-furan-2-karboksylsyre med paraformaldehyd og dimetylamin-hydroklorid det rå 2,3-dihydro-5-(2-dimetylaminometyl-butyryl)-benzo-furan-2-karboksylsyre-hydroklorid, som med natriumacetat og iseddik overfores til 2,3-dihydro-5-(2-metylen-butyryl)-benzo-furan-2-karboksylsyre med smp. 97,5° (fra karbontetraklorid). Analogously to example la), crude 2,3-dihydro-5-(2-dimethylaminomethyl-butyryl)-benzo- furan-2-carboxylic acid hydrochloride, which with sodium acetate and glacial acetic acid is converted to 2,3-dihydro-5-(2-methylene-butyryl)-benzo-furan-2-carboxylic acid with m.p. 97.5° (from carbon tetrachloride).

Utgangsstoff et, 2,3-dihydro-5-butyryl-benzofuran-2-karboksyl-syren, med smp. 133° (fra eddiksyreetylester), fremstilles analogt eksempel lc) fra 2,3-dihydro-benzofuran-2-karboksylsyre [sml. R. Fittig og G. Ebert, Ann.Chem. 216, 166 (1883)] og butyrylklorid i nærvær av aluminiumklorid i nitrobenzen. Starting material, 2,3-dihydro-5-butyryl-benzofuran-2-carboxylic acid, with m.p. 133° (from acetic acid ethyl ester), is prepared analogously to example lc) from 2,3-dihydro-benzofuran-2-carboxylic acid [cf. R. Fittig and G. Ebert, Ann.Chem. 216, 166 (1883)] and butyryl chloride in the presence of aluminum chloride in nitrobenzene.

EKSEMPEL 4 EXAMPLE 4

Analogt eksempel la) oppnår man fra 2,3-dihydro-5-butyryl-6-metoksy-benzofuran-2-karboksylsyre med paraformaldehyd og dimetylamin-hydroklorid det rå 2,3-dihydro-5-(2-dimetylaminometyl-bu tyr yl )-6-metoksy-benzofuran-2-karboksylsyre-hydroklorid, som med natriumacetat og iseddik overfores til 2,3-dihydro-5-(2-metylen-butyryl)-6-metoksy-benzofuran-2-karboksylsyre med smp. 124° Analogous to example la) the crude 2,3-dihydro-5-(2-dimethylaminomethyl-butyryl) is obtained from 2,3-dihydro-5-butyryl-6-methoxy-benzofuran-2-carboxylic acid with paraformaldehyde and dimethylamine hydrochloride )-6-methoxy-benzofuran-2-carboxylic acid hydrochloride, which with sodium acetate and glacial acetic acid is converted to 2,3-dihydro-5-(2-methylene-butyryl)-6-methoxy-benzofuran-2-carboxylic acid with m.p. 124°

(fra benzen).. (from benzene)..

Utgangsstof f et, 2,3-dihydro-5-butyryl-6-metoksy-benzofuran-2-karboksylsyre med smp. 170° (fra toluen-eddiksyreetylester), fremstilles analogt eksempel lc) fra 2,3-dihydro-6-metoksy-benzofuran-2-karboksylsyre [sml. W. Will og P. Beck, Chem.Ber. 19, 1783 (1886)] og butyrylklorid i nærvær av aluminiumklorid i nitrobenzen. Starting material f et, 2,3-dihydro-5-butyryl-6-methoxy-benzofuran-2-carboxylic acid with m.p. 170° (from toluene-acetic acid ethyl ester), is prepared analogously to example lc) from 2,3-dihydro-6-methoxy-benzofuran-2-carboxylic acid [cf. W. Will and P. Beck, Chem.Ber. 19, 1783 (1886)] and butyryl chloride in the presence of aluminum chloride in nitrobenzene.

EKSEMPEL 5 EXAMPLE 5

Analogt eksempel la) oppnår man fra '2,3-dihydro-5-butyryl-6-klor-benzofuran-2-karboksylsyre med paraformaldehyd og dimetylamin-hydroklorid det rå 2,3-dihydro-5-(2-dimetylaminometyl-butyryl)-6-klor-benzofuran-2-karboksylsyre-hydroklorid, som med natriumacetat og iseddik overfores til 2,3-dihydro-5-(2-metylen-butyryl)-6-klor-benzofuran-2-karboksylsyre med smp. 110° (fra benzen). Analogously to example la) one obtains from 2,3-dihydro-5-butyryl-6-chloro-benzofuran-2-carboxylic acid with paraformaldehyde and dimethylamine hydrochloride the crude 2,3-dihydro-5-(2-dimethylaminomethyl-butyryl) -6-chloro-benzofuran-2-carboxylic acid hydrochloride, which with sodium acetate and glacial acetic acid is converted to 2,3-dihydro-5-(2-methylene-butyryl)-6-chloro-benzofuran-2-carboxylic acid with m.p. 110° (from benzene).

Utgangs stoffet, 2,3-dihydro-5-butyryl-6-klor-benzofuran-2-karboksylsyre, fremstiller man som folger: Analogt eksempel 2b) overfores blandingen av 2-allyl-3-klor-fenol og 2-allyl-5-klor-fenol [sml. W.N. White, CD. Slater, J.Org.Chem. 26, 3631 (1961)] til blandingen av 2,3-dihydro-2-hydrokbymetyl-4-klor-benzofuran og 2,3-dihydro-2-hydroksyrnetyl-6-klor-benzofuran, som destillerer ved 95 - 115°/0,02 Torr. Man skiller destillatet ved elueringskromatografi over silikagel med eddiksyreetylester-benzen (3:100) som elueringsmiddel. The starting substance, 2,3-dihydro-5-butyryl-6-chloro-benzofuran-2-carboxylic acid, is prepared as follows: Analogously to example 2b) the mixture of 2-allyl-3-chloro-phenol and 2-allyl-5 -chloro-phenol [cf. W. N. White, CD. Slater, J. Org. Chem. 26, 3631 (1961)] to the mixture of 2,3-dihydro-2-hydroxymethyl-4-chlorobenzofuran and 2,3-dihydro-2-hydroxymethyl-6-chlorobenzofuran, which distils at 95 - 115°/ 0.02 Torr. The distillate is separated by elution chromatography over silica gel with acetic acid ethyl ester-benzene (3:100) as eluent.

Det isolerte 2,3-dihydro-2-hydroksymetyl-6-klor-benzofuran oksy-deres så analogt eksempel 2c) til 2,3-dihydro-6-klor-benzofuran-2-karboksylsyre. med smp. 163° (fra benzen), som analogt eksempel lc) acyleres med butyrylklorid til 2,3-dihydro-5-butyryl-6-klor-benzofuran-2-karboksylsyre med smp. 110° (fra benzen). The isolated 2,3-dihydro-2-hydroxymethyl-6-chloro-benzofuran is then oxidized analogously to example 2c) to 2,3-dihydro-6-chloro-benzofuran-2-carboxylic acid. with m.p. 163° (from benzene), as analogous example lc) is acylated with butyryl chloride to 2,3-dihydro-5-butyryl-6-chloro-benzofuran-2-carboxylic acid with m.p. 110° (from benzene).

Analogt eksempel la) oppnår man fra de tilsvarende 5-alkanoyl-benzofuran-2-karboksylsyrer eller 5-alkanoyl-benzo[b]tiofen-2-karboksylsyrer (sml. tabell II) de i tabell I sammenstilte forbindelser med den generelle formel: De tilsvarende 5-alkanoylforbindelser med den generelle formel VIII fremstilles analogt som beskrevet i eksempel lc ifolge Friedel-Crafts acylering: Analogously to example la) one obtains from the corresponding 5-alkanoyl-benzofuran-2-carboxylic acids or 5-alkanoyl-benzo[b]thiophene-2-carboxylic acids (cf. Table II) the compounds compiled in Table I with the general formula: corresponding 5-alkanoyl compounds of the general formula VIII are prepared analogously as described in example 1c according to Friedel-Crafts acylation:

De er sammenstilt i tabell II. They are compiled in table II.

EKSEMPEL 19 EXAMPLE 19

25,2 g 2,3-dihydro-6-metyl-benzofuran-2-karboksylsyre oppslemmes med 135 ml nitrobenzen og tilsettes porsjonsvis i lopet av 30 minutter under roring og avkjdling 69,5 g aluminiumklorid, slik at temperaturen ikke stiger over 10°. Ved den samme temperatur tildrypper man i lopet av 30 minutter 25 g 2-metylenbutyryl-klorid. Deretter rores reaksjonsblandingen videre i 5 timer i isbad, og sa i 16 timer ved værelsetemperatur. Deretter heller man blandingen på 500 g is, tilsetter 50 ml konsentrert saltsyre og ekstraherer med eter. Eteropplosningen ekstraheres med natriumhydrogenkarbonatoppldsning, denne vandige oppldsning ansyres med saltsyre til pH 1 og ekstraheres med eter. Den etter inndampning av eterekstrakte erholdte 2,3-dihydro-5-(2-metylen-butyryl)-6-metyl-benzofuran-2-karboksylsyre renses ved .sdyle-kromatografi. Smp. 100 - 104°. 25.2 g of 2,3-dihydro-6-methyl-benzofuran-2-carboxylic acid is slurried with 135 ml of nitrobenzene and 69.5 g of aluminum chloride is added in portions over the course of 30 minutes while stirring and cooling, so that the temperature does not rise above 10° . At the same temperature, 25 g of 2-methylenebutyryl chloride is added dropwise over the course of 30 minutes. The reaction mixture is then stirred for 5 hours in an ice bath, and then for 16 hours at room temperature. The mixture is then poured onto 500 g of ice, 50 ml of concentrated hydrochloric acid is added and extracted with ether. The ether solution is extracted with sodium bicarbonate solution, this aqueous solution is acidified with hydrochloric acid to pH 1 and extracted with ether. The 2,3-dihydro-5-(2-methylene-butyryl)-6-methyl-benzofuran-2-carboxylic acid obtained after evaporation of ether extracts is purified by .sdyle chromatography. Temp. 100 - 104°.

EKSEMPEL 20 EXAMPLE 20

Analogt eksempel 19 acyleres 2,3-dihydro-6-metyl-benzofuran-2-karboksylsyre i nitrobenzen i nærvær av aluminiumklorid med 2-metylakrylsyre-anhydrid [sml. T.K. Brotheaton, J. Smith Jr. og J.W. Lyrin, J. Org. Chem. 26, 1283 - 4 (1961)] til 2,3-dihydro-5-(2-metyl-akrylyl)-6-metyl-benzofuran-2-karboksylsyre. Smp. Analogous to example 19, 2,3-dihydro-6-methyl-benzofuran-2-carboxylic acid is acylated in nitrobenzene in the presence of aluminum chloride with 2-methylacrylic anhydride [cf. T.K. Brotheaton, J. Smith Jr. and J.W. Lyrin, J. Org. Chem. 26, 1283-4 (1961)] to 2,3-dihydro-5-(2-methyl-acrylyl)-6-methyl-benzofuran-2-carboxylic acid. Temp.

100 - 10 2°. 100 - 10 2°.

EKSEMPEL 21 EXAMPLE 21

a) 8,7 g 2,3-dihydro-5-(2-brom-2-brommetyl-butyryl)-6-metyl-benzofuran-2-karboksylsyre kokes med 20 g kaliumjodid i 100 ml a) 8.7 g of 2,3-dihydro-5-(2-bromo-2-bromomethyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid are boiled with 20 g of potassium iodide in 100 ml

etanol i 10 minutter under tilbakelop og avkjdles. Etter avkjdling tilsettes blandingen vandig natriumtiosulfatoppldsning i overskudd; ansyres så med saltsyre og utrystes med eter. Den eteriske oppldsning konsentreres, og resten renses ved sdylekro-matografi, idet man oppnår 2,3-dihydro-5-(2-metylen-butyryl)-6-metyl-benzofuran-2-karboksylsyre med smp. 100 - 102°. ethanol for 10 minutes under reflux and cool. After cooling, an excess of aqueous sodium thiosulphate solution is added to the mixture; then acidify with hydrochloric acid and shake out with ether. The ethereal solution is concentrated, and the residue is purified by silica chromatography, obtaining 2,3-dihydro-5-(2-methylene-butyryl)-6-methyl-benzofuran-2-carboxylic acid with m.p. 100 - 102°.

b) Utgangsforbindelsen fremstilles som folger: b) The output connection is produced as follows:

Analogt eksempel 19 acyleres 25,2 g 2,3-dihydro-6-metyl-benzo-furan-2-karboksylsyre i 125 ml nitrobenzen i nærvær av 69,5 g aluminiumklorid med 59 g 2-brom-2-brommetyl-butyrylklorid til 2\ 3-dihydro-5-(2-brom-2-brommetyl-butyryl)-6-metyl-benzofuran-2-karboksylsyre med smp. 157° (fra cykloheksan-eddiksyreetyl-ester). Analogously to example 19, 25.2 g of 2,3-dihydro-6-methyl-benzo-furan-2-carboxylic acid is acylated in 125 ml of nitrobenzene in the presence of 69.5 g aluminum chloride with 59 g of 2-bromo-2-bromomethyl-butyryl chloride to 2\ 3-dihydro-5-(2-bromo-2-bromomethyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid with m.p. 157° (from cyclohexane-acetic acid ethyl ester).

EKSEMPEL 22 EXAMPLE 22

10 g 2,3-dihydro-5-(2-brom-2-brommetyl-butyryl)-6-metyl-benzo-furan-2-karboksylsyre kokes med 3 g sinkstov i 100 ml etanol i 1 time under tilbakelop; deretter filtreres opplosningen og inndampes. 2,3-dihydro-5-(2-metylen-butyryl)-6-metyl-benzofuran-2-karboksylsyre med smp. 100 - 10 2° renses ved soylekromato-grafi. 10 g of 2,3-dihydro-5-(2-bromo-2-bromomethyl-butyryl)-6-methyl-benzo-furan-2-carboxylic acid are boiled with 3 g of zinc dust in 100 ml of ethanol for 1 hour under reflux; then the solution is filtered and evaporated. 2,3-dihydro-5-(2-methylene-butyryl)-6-methyl-benzofuran-2-carboxylic acid with m.p. 100 - 10 2° is purified by soil chromatography.

EKSEMPEL 23 EXAMPLE 23

20 g 2,3-dihydro-5-butyryl-6-metyl-benzofuran-2-karboksylsyre kokes med 4,1 g paraformaldehyd og 12,5 g morfolinhydroklorid i 125 ml dioksan i 8 timer under roring ved tilbakelop. Deretter konsentreres reaksjonsblandingen i vakuum. Til den erholdte, rå 2,3-dihydro-5-(2-morfolinometyl-butyryl)-6-metyl-benzo furan-2-karboksylsyre-hydroklorid tilsetter man 21 g vannfritt natriumacetat og 200 ml iseddik. Man koker den erholdte blanding i 2 timer under roring ved tilbakelop og inndamper den under vakuum. Resten rores med 100 ml vann, den erholdte suspensjon innstilles på pH 2 med konsentrert saltsyre og rores i 1 time ved 20°. Man ekstraherer den organiske syre ved tre gangers utrystning med 150 ml eter. Eteropplosningen torkes over natriumsulfat og inndampes. Man omkrystalliserer resten fra cykloheksan og xylen-heksan, hvoretter 2,3-dihydro-5-(2-metylen-butyryl)-6-metyl-benzofuran-2-karboksylsyre smelter ved 100 - 10 2°. 20 g of 2,3-dihydro-5-butyryl-6-methyl-benzofuran-2-carboxylic acid are boiled with 4.1 g of paraformaldehyde and 12.5 g of morpholine hydrochloride in 125 ml of dioxane for 8 hours while stirring at reflux. The reaction mixture is then concentrated in vacuo. To the crude 2,3-dihydro-5-(2-morpholinomethyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid hydrochloride obtained, 21 g of anhydrous sodium acetate and 200 ml of glacial acetic acid are added. The resulting mixture is boiled for 2 hours with stirring at reflux and evaporated under vacuum. The residue is stirred with 100 ml of water, the resulting suspension is adjusted to pH 2 with concentrated hydrochloric acid and stirred for 1 hour at 20°. The organic acid is extracted by shaking three times with 150 ml of ether. The ether solution is dried over sodium sulfate and evaporated. The residue is recrystallized from cyclohexane and xylene-hexane, after which 2,3-dihydro-5-(2-methylene-butyryl)-6-methyl-benzofuran-2-carboxylic acid melts at 100 - 10 2°.

EKSEMPEL 24 EXAMPLE 24

20 g 2,3-dihydro-5-butyryl-6-metyl-benzofuran-2-karboksylsyre kokes med 4,1 g paraformaldehyd og 12 g piperidinhydroklorid i 125 ml dioksan i 8 timer under roring ved tilbakelop. Deretter konsentreres reaksjonsblandingen i vakuum. Til den erholdte rå 2,3-dihydro-5-(2-piperidinometyl-butyryl)-6-metyl-benzofuran-2-karboksylsyrehydroklorid tilsetter man 21 g vannfritt natriumacetat og 200 ml iseddik. Man koker den erholdte blanding i 2 timer under roring ved tilbakelop og inndamper den under vakuum. Resten rores med 100 ml vann, den erholdte suspensjon innstilles på pH 2 med konsentrert saltsyre og rores i 1 time ved 20°. Man ekstraherer den organiske syre ved tre gangers utrystning med 150 ml eter. Eteropplosningen torkes over na-triumsulf at og inndampes. Man omkrystalliserer resten fra cykloheksan og xylen-heksan, hvoretter 2,3-dihydro-5-(2-metylen-butyryl)-6-metyl-benzofuran-2-karboksylsyre smelter ved 100 - 10 2°. 20 g of 2,3-dihydro-5-butyryl-6-methyl-benzofuran-2-carboxylic acid are boiled with 4.1 g of paraformaldehyde and 12 g of piperidine hydrochloride in 125 ml of dioxane for 8 hours while stirring at reflux. The reaction mixture is then concentrated in vacuo. To the crude 2,3-dihydro-5-(2-piperidinomethyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid hydrochloride obtained, 21 g of anhydrous sodium acetate and 200 ml of glacial acetic acid are added. The resulting mixture is boiled for 2 hours with stirring at reflux and evaporated under vacuum. The residue is stirred with 100 ml of water, the resulting suspension is adjusted to pH 2 with concentrated hydrochloric acid and stirred for 1 hour at 20°. The organic acid is extracted by shaking three times with 150 ml of ether. The ether solution is dried over sodium sulphate and evaporated. The residue is recrystallized from cyclohexane and xylene-hexane, after which 2,3-dihydro-5-(2-methylene-butyryl)-6-methyl-benzofuran-2-carboxylic acid melts at 100 - 10 2°.

EKSEMPEL 25 EXAMPLE 25

a) 22,2 g 2,3-dihydro-5-valeryl-6,7-dimetyl-benzofuran-2-karboksylsyre kokes med 4,1 g paraformaldehyd og 8,2 g dimetylamin-hydroklorid i 125 ml dioksan 8 timer under omroring og tilbakelop. Derefter inndampes reaksjonsblandingen i vakuum. a) 22.2 g of 2,3-dihydro-5-valeryl-6,7-dimethyl-benzofuran-2-carboxylic acid are boiled with 4.1 g of paraformaldehyde and 8.2 g of dimethylamine hydrochloride in 125 ml of dioxane for 8 hours with stirring and backflow. The reaction mixture is then evaporated in vacuo.

Til det erholdte, rå 2,3-dihydro-5-(2-dimetylaminometyl-valeryl)-6,7-dimetyl-benzofuran-2-karboksylsyre-hydroklorid tilsetter man 21 g vannfritt natriumacetat og 200 ml iseddik. Man koker den erholdte blandingen 2 timer under omroring og tilbakelop og inndamper den i vakuum. Resten omrores med 100 ml vann, To the crude 2,3-dihydro-5-(2-dimethylaminomethyl-valeryl)-6,7-dimethyl-benzofuran-2-carboxylic acid hydrochloride obtained, 21 g of anhydrous sodium acetate and 200 ml of glacial acetic acid are added. The resulting mixture is boiled for 2 hours with stirring and reflux and evaporated in a vacuum. The residue is stirred with 100 ml of water,

den erholdte suspensjonen stilles med konsentrert saltsyre til pH 2, og rores en time ved 20°. Man ekstraherer den organiske syren ved tre gangers utrystning med 150 ml eter. Eter-losningen torkes over natriumsulfat og inndampes. Man omkrystalliserer resten i heptan, hvorefter 2,3-dihydro-5-(2-metylen-valeryl)-6,7-dimetyl-benzofuran-2-karboksylsyre smelter ved 82°. the resulting suspension is brought to pH 2 with concentrated hydrochloric acid, and stirred for one hour at 20°. The organic acid is extracted by shaking three times with 150 ml of ether. The ether solution is dried over sodium sulphate and evaporated. The residue is recrystallized in heptane, after which 2,3-dihydro-5-(2-methylene-valeryl)-6,7-dimethyl-benzofuran-2-carboxylic acid melts at 82°.

Utgangsstoffet fremstilles som folger: The starting material is produced as follows:

b) 45 g 2,3-dimetyl-fenol og 50 g eplesyre pulveriseres og blandes godt. Blandingen tilsettes lOO ml kons. svovelsyre og oppvarmes under langsom omroring, slik at reaksjonstemperaturen efter 30 minutter utgjor 130°. Man holder losningen ytterligere 30 minutter ved denne temperatur, heller den derefter på 1 kg is og rorer den dannede suspensjonen 30 minutter. De utfelte krystallene nutsjes fra og omkrystalliseres i etanol. Man erholder 7,8-dimetyl-kumarin med smp. 128 - 130°; utbytte 36,3 g. b) 45 g of 2,3-dimethylphenol and 50 g of malic acid are powdered and mixed well. 100 ml conc. is added to the mixture. sulfuric acid and heated with slow stirring, so that the reaction temperature after 30 minutes is 130°. The solution is kept at this temperature for a further 30 minutes, then poured onto 1 kg of ice and the resulting suspension is stirred for 30 minutes. The precipitated crystals are ground off and recrystallized in ethanol. 7,8-dimethylcoumarin is obtained with m.p. 128 - 130°; yield 36.3 g.

c) 34,8 g av det ifolge b) erholdte kumarin loses i 60 ml kloroform. Man drypper til denne losningen under roring og c) 34.8 g of the coumarin obtained according to b) is dissolved in 60 ml of chloroform. This solution is added dripping while stirring and

leilighetsvis avkjoling med is en losning av 32,5 g brom i 20 ml kloroform, slik at reaksjonstemperatur er 20 - 25°. Blandingen rores ytterligere 20 minutter ved romtemperatur og derefter i vakuum slik at kloroformen fullstendig fordamper. occasionally cooling with ice a solution of 32.5 g of bromine in 20 ml of chloroform, so that the reaction temperature is 20 - 25°. The mixture is stirred for a further 20 minutes at room temperature and then in a vacuum so that the chloroform completely evaporates.

Man tilsetter resten porsjonsvis til en blanding av 90 g kaliumhydroksyd med 300 ml etanol og holder reaksjonstemperaturer ved isavkjoling mellom 30 og 40°. Blandingen rores derefter 30 minutter ved 40° og 30 minutter ved 80° og helles derefter i 2 liter isvann. Den vandige, alkaliske losningen vaskes to ganger med hver gang 400 ml eter og stilles på pH 2 - 3 med konsentrert saltsyre. Man rorer den erholdte suspensjonen 1/2 time ved romtemperatur. De utfelte krystallene nutsjes fra og omkrystalliseres i etanol. Man erholder 6,7-dimetyl-benzofuran-2-karboksylsyre med smp. 237 - 239°. The residue is added in portions to a mixture of 90 g of potassium hydroxide with 300 ml of ethanol and the reaction temperatures are maintained by ice cooling between 30 and 40°. The mixture is then stirred for 30 minutes at 40° and 30 minutes at 80° and then poured into 2 liters of ice water. The aqueous, alkaline solution is washed twice with 400 ml of ether each time and adjusted to pH 2 - 3 with concentrated hydrochloric acid. The resulting suspension is stirred for 1/2 hour at room temperature. The precipitated crystals are ground off and recrystallized in ethanol. 6,7-dimethyl-benzofuran-2-carboxylic acid is obtained with m.p. 237 - 239°.

d) 35 g av den ifolge c) erholdte syre opploses i 500 ml av en mettet, vandig natriumhydrogenkarbonatlosning og losningen d) 35 g of the acid obtained according to c) is dissolved in 500 ml of a saturated, aqueous sodium bicarbonate solution and the solution

avkjoles i isbad til 5°. Man tilsetter 500 g 5%'ig natriumamalgam, fjerner reaksjonsblandingen efter 2 timer fra isbadet og lar den stå 24 timer ved 20°. Derefter skilles losningen fra kvikksolvet, filtreres og filtratet stilles med konsentrert saltsyre til pH 1. Det utfelte bunnfallet filtreres fra, vaskes med 300 ml vann og torkes. Den erholdte 2,3-dihydro-6,7-dimetyl-benzofuran-2-karboksylsyre smelter ved 182° (i etanol). e) 27,2 g av den ifolge d) erholdte karboksylsyre tilsettes 135 ml nitrobenzen og blandingen tilsettes porsjonsvis i lopet cooled in an ice bath to 5°. 500 g of 5% sodium amalgam is added, the reaction mixture is removed from the ice bath after 2 hours and left to stand for 24 hours at 20°. The solution is then separated from the mercury solution, filtered and the filtrate adjusted to pH 1 with concentrated hydrochloric acid. The precipitate that has formed is filtered off, washed with 300 ml of water and dried. The 2,3-dihydro-6,7-dimethyl-benzofuran-2-carboxylic acid obtained melts at 182° (in ethanol). e) 27.2 g of the carboxylic acid obtained according to d) is added to 135 ml of nitrobenzene and the mixture is added portionwise in the flow

av 30 minutter under omroring og avkjoling 69,5 g aluminiumklorid, slik at temperaturen ikke overstiger 10°. Ved den samme temperaturen tildrypper man i lopet av 30 minutter 25,3 g of 30 minutes while stirring and cooling 69.5 g of aluminum chloride, so that the temperature does not exceed 10°. At the same temperature, 25.3 g are added drop by drop over the course of 30 minutes

valerylklorid. Derefter rores reaksjonsblandingen ytterligere 5 timer i isbad, står så til henstand 16 timer ved romtemperatur, oppvarmes en time til 40° og helles på 500 g is. Man tilsetter til den erholdte suspensjonen 50 ml konsentrert saltsyre. valeryl chloride. The reaction mixture is then stirred for a further 5 hours in an ice bath, then allowed to stand for 16 hours at room temperature, heated for one hour to 40° and poured onto 500 g of ice. 50 ml of concentrated hydrochloric acid is added to the resulting suspension.

Efter at aluminiumklorid-komplekset er blitt spaltet, ekstraheres reaksjonsblandingen tre ganger med hver gang 150 ml eter. Man torker eterekstraktet over natriumsulfat og inndamper det. Resten oppslemmes i heksan, omrystes, skilles igjen fra heksan og omkrystalliseres i eddiksyreetylester-heksan. Den erholdte 2,3-dihydro-5-valeryl-6,7-dimetyl-benzofuran-2-karboksylsyre smelter ved 128 - 12 9°. After the aluminum chloride complex has been cleaved, the reaction mixture is extracted three times with 150 ml of ether each time. The ether extract is dried over sodium sulphate and evaporated. The residue is suspended in hexane, shaken, separated again from hexane and recrystallized in acetic acid ethyl ester-hexane. The 2,3-dihydro-5-valeryl-6,7-dimethyl-benzofuran-2-carboxylic acid obtained melts at 128-129°.

EKSEMPEL 26 EXAMPLE 26

Analogt eksempel 19 oppnår man folgende sluttprodukter: Analogous to example 19, the following end products are obtained:

a) Fra 19,2 g 2,3-dihydro-6,7-dimetyl-benzofuran-2-karboksylsyre og 23 g 2-metyl-akrylsyreanhydrid 2,3-dihydro-5-(2-metyl-akrylyl ) -6-metyl-benzof uran- 2-karboksylsyre med smp. 118° a) From 19.2 g of 2,3-dihydro-6,7-dimethyl-benzofuran-2-carboxylic acid and 23 g of 2-methyl-acrylic anhydride 2,3-dihydro-5-(2-methyl-acrylyl)-6- methyl-benzofuran-2-carboxylic acid with m.p. 118°

(fra toluen-heptan). (from toluene-heptane).

b) Fra 17,8 g 2,3-dihydro-6-metyl-benzofuran-2-karboksylsyre og 15,2 g 2-metylen-isovalerylklorid [sml. V.P. Gol'mov, CA 47, 9269c (1963)] 2,3-dihydro-5-(2-metylen-3-metyl-butyryl)-6-metyl-benzofuran-2-karboksylsyre med smp. 115 - 116° (fra eddiksyreetylester). c) Fra 19,2 g 2,3-dihydro-6,7-dimetyl-benzofuran-2-karboksylsyre og 14,0 g 2-metylen-butyrylklorid 2,3-dihydro-5-(2-metylen-butyryl)-6,7-dimetyl-benzofuran-2-karboksylsyre med smp. 10 2 - 104° (fra karbontetraklorid). d) Fra 19,7 g 2,3-dihydro-6-klor-benzofuran-2-karboksylsyre og 14,0 g 2-metylen-butyrylklorid 2,3-dihydro-5-(2-metylen-butyryl)-6-klor-benzofuran-2-karboksylsyre med smp. 110° (fra benzen). b) From 17.8 g of 2,3-dihydro-6-methyl-benzofuran-2-carboxylic acid and 15.2 g of 2-methylene-isovaleryl chloride [cf. V.P. Gol'mov, CA 47, 9269c (1963)] 2,3-dihydro-5-(2-methylene-3-methyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid with m.p. 115 - 116° (from acetic acid ethyl ester). c) From 19.2 g of 2,3-dihydro-6,7-dimethyl-benzofuran-2-carboxylic acid and 14.0 g of 2-methylene-butyryl chloride 2,3-dihydro-5-(2-methylene-butyryl)- 6,7-dimethyl-benzofuran-2-carboxylic acid with m.p. 10 2 - 104° (from carbon tetrachloride). d) From 19.7 g of 2,3-dihydro-6-chloro-benzofuran-2-carboxylic acid and 14.0 g of 2-methylene-butyryl chloride 2,3-dihydro-5-(2-methylene-butyryl)-6- chloro-benzofuran-2-carboxylic acid with m.p. 110° (from benzene).

EKSEMPEL 27 EXAMPLE 27

a) Analogt eksempel 19 oppnår man fra 21,0 g 2,3-dihydro-6-klor-7-metyl-benzofuran-2-karboksylsyre og 17,0 g 2-metylen-butyrylklorid 2,3-dihydro-5-(2-metylen-butyryl)-6-klor-7-metyl-benzofuran-2-karboksylsyre med smp. 15 2 - 153°. a) Analogously to example 19, one obtains from 21.0 g of 2,3-dihydro-6-chloro-7-methyl-benzofuran-2-carboxylic acid and 17.0 g of 2-methylene-butyryl chloride 2,3-dihydro-5-( 2-methylene-butyryl)-6-chloro-7-methyl-benzofuran-2-carboxylic acid with m.p. 15 2 - 153°.

Utgangsforbindelsen fremstilles som folger: The output connection is produced as follows:

b) 30,0 g 2-metyl-3-klor-fenol [sml. F. Ullmann og L. Panchaud, A. 350, 108 (1906)], 28,6 g eplesyre og 57 ml konsentrert svovelsyre oppvarmes under roring til 90 - 100°, inntil ingen karbonoksydutvikling mere kan fastslås. Deretter heller man reaksjonsblandingen på is og ekstraherer råproduktet med eter. Den eteriske opplosning inndampes og resten omkrystalliseres fra etanol. Man oppnår 7-klor-8-metyl-kumarin med smp. 143°. c) 17,2 g av det etter b) fremstilte kumarin suspenderes i 35 ml kloroform. Til denne suspensjon tildrypper man under b) 30.0 g of 2-methyl-3-chloro-phenol [comp. F. Ullmann and L. Panchaud, A. 350, 108 (1906)], 28.6 g of malic acid and 57 ml of concentrated sulfuric acid are heated with stirring to 90 - 100°, until no more carbon dioxide evolution can be determined. The reaction mixture is then poured onto ice and the crude product is extracted with ether. The ethereal solution is evaporated and the residue recrystallized from ethanol. One obtains 7-chloro-8-methyl-coumarin with m.p. 143°. c) 17.2 g of the coumarin produced according to b) is suspended in 35 ml of chloroform. This suspension is dripped under

roring i lopet av 20 minutter ved 25° 4,7 ml brom i 10 ml kloroform. Man rorer reaksjonsblandingen videre i 30 minutter og inndamper den i vakuum. Den tilbakeblivende olje tildryppes under roring til en opplosning av 39,5 g kaliumhydroksyd i 120 ml etanol, slik at temperaturen ikke stiger over 40°. Man rorer ennå i 30 minutter ved 25° og i 30 minutter ved 80°. Deretter heller man suspensjonen på is. Den erholdte opplosning innstilles med 4-n svovelsyre på pH 7, vaskes med eter og tilsettes konsentrert saltsyre inntil kongosur reaksjon. Man ekstraherer den utfelte, rå karboksylsyre med eter, torker eteropplosningen over natriumsulfat og inndamper den. Man krystalliserer resten fra cykloheksan-eddiksyre-etylester, hvoretter 6-klor-7-metyl-benzofuran-2-karboksylsyre smelter ved 225°. stirring for 20 minutes at 25° 4.7 ml of bromine in 10 ml of chloroform. The reaction mixture is stirred for 30 minutes and evaporated in vacuo. The remaining oil is added dropwise while stirring to a solution of 39.5 g of potassium hydroxide in 120 ml of ethanol, so that the temperature does not rise above 40°. Stirring is continued for 30 minutes at 25° and for 30 minutes at 80°. The suspension is then poured over ice. The obtained solution is adjusted to pH 7 with 4-n sulfuric acid, washed with ether and concentrated hydrochloric acid is added until a Congo acid reaction. The precipitated crude carboxylic acid is extracted with ether, the ether solution is dried over sodium sulphate and evaporated. The residue is crystallized from cyclohexane-acetic acid ethyl ester, after which 6-chloro-7-methyl-benzofuran-2-carboxylic acid melts at 225°.

d) Analogt eksempel lb) reduseres 41,5 g av den etter c) erholdte karboksylsyre med 500 g 5 %'ig natriumamalgam til 39,6 g d) Analogous to example lb), 41.5 g of the carboxylic acid obtained after c) is reduced with 500 g of 5% sodium amalgam to 39.6 g

2,3-dihydro-6-klor-7-metyl-benzofuran-2-karboksylsyre med smp. 133° (fra cykloheksan-eddiksyreetylester). 2,3-dihydro-6-chloro-7-methyl-benzofuran-2-carboxylic acid with m.p. 133° (from cyclohexane-acetic acid ethyl ester).

EKSEMPEL 28 EXAMPLE 28

a) Analogt eksempel 21a) oppnår man fra 5,0 g rå 2,3-dihydro- a) Analogous to example 21a) one obtains from 5.0 g crude 2,3-dihydro-

i 5-(2-brom-2-brommetyl-3-metyl-butyryl)-6-metyl-benzofuran-2-karboksylsyre og 10 g kaliumjodid i 50 ml etanol 2,3-dihydro-5-(2-metylen-3-metyl-butyryl)-6-metyl-benzofuran-2-karboksylsyre med smp. 115 - 116° (fra eddiksyreetyl-ester). in 5-(2-bromo-2-bromomethyl-3-methyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid and 10 g potassium iodide in 50 ml ethanol 2,3-dihydro-5-(2-methylene-3 -methyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid with m.p. 115 - 116° (from acetic acid ethyl ester).

Utgangsforbindelsen fremstilles som folger: The output connection is produced as follows:

b) Analogt eksempel 19 acyleres 4,0 g 2,3-dihydro-6-metyl-benzof uran- 2-karboksylsyre i 20 ml nitrobenzen i nærvær av 14 g b) Analogously to example 19, 4.0 g of 2,3-dihydro-6-methyl-benzofuran-2-carboxylic acid is acylated in 20 ml of nitrobenzene in the presence of 14 g

aluminiumklorid med 10 g 2-brom-2-brommetyl-3-metyl-butyrylklorid. Den dannede 2,3-dihydro-5-(2-brom-2-brommetyl-3-metyl-butyryl) -6-metyl-benzof uran- 2-karboksyl syre viderearbeides som råprodukt. aluminum chloride with 10 g of 2-bromo-2-bromomethyl-3-methyl-butyryl chloride. The formed 2,3-dihydro-5-(2-bromo-2-bromomethyl-3-methyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid is further processed as a crude product.

EKSEMPEL 29 EXAMPLE 29

a) Analogt eksempel 21a) oppnår man fra 5,2 g rå 2,3-dihydro-5-(2-brom-2-brommetyl-butyryl)-6-klor-7-metyl-benzofuran-2-karboksylsyre og 10 g kaliumjodid i 50 ml etanol 2,3-dihydro-5-(2-metylen-butyryl)-6-klor-7-metyl-benzofuran-2-karboksylsyre med smp. 152 - 153°. a) Analogous to example 21a) one obtains from 5.2 g crude 2,3-dihydro-5-(2-bromo-2-bromomethyl-butyryl)-6-chloro-7-methyl-benzofuran-2-carboxylic acid and 10 g potassium iodide in 50 ml ethanol 2,3-dihydro-5-(2-methylene-butyryl)-6-chloro-7-methyl-benzofuran-2-carboxylic acid with m.p. 152 - 153°.

Utgangsforbindelsen fremstilles som folger: The output connection is produced as follows:

b) Analogt eksempel 19 acyleres 4,5 g 2,3-dihydro-6-klor-7-metyl-benzofuran-2-karboksylsyre i 20 ml nitrobenzen i nærvær b) Analogous to example 19, 4.5 g of 2,3-dihydro-6-chloro-7-methyl-benzofuran-2-carboxylic acid is acylated in 20 ml of nitrobenzene in the presence

av 14 g aluminiumklorid med 8 g 2-brom-2-brommetyl-butyrylklorid. Den dannede 2,3-dihydro-5-(2-brom-2-brommetyl-butyryl)-6-klor-7-metyl-benzofuran-2-karboksylsyre anvendes som råprodukt. of 14 g of aluminum chloride with 8 g of 2-bromo-2-bromomethyl-butyryl chloride. The 2,3-dihydro-5-(2-bromo-2-bromomethyl-butyryl)-6-chloro-7-methyl-benzofuran-2-carboxylic acid formed is used as crude product.

EKSEMPEL 30 EXAMPLE 30

a) Analogt eksempel 22 oppnår man fra 11,0 g rå 2,3-dihydro-5-(2-brom-2-brommetyl-propionyl)-6,7-dimetyl-benzofuran-2-karboksy1syre med 3 g sinkstov i 100 ml etanol 2,3-dihydro-5-(2-metylen-propionyl)-6,7-dimetyl-benzofuran-2-karboksylsyre med smp. 118° (fra toluen-heptan). a) Analogously to example 22, one obtains from 11.0 g crude 2,3-dihydro-5-(2-bromo-2-bromomethyl-propionyl)-6,7-dimethyl-benzofuran-2-carboxylic acid with 3 g zinc dust in 100 ml ethanol 2,3-dihydro-5-(2-methylene-propionyl)-6,7-dimethyl-benzofuran-2-carboxylic acid with m.p. 118° (from toluene-heptane).

Utgangsforbindelsen fremstilles som folger: The output connection is produced as follows:

b) Analogt eksempel 19 acyleres 8,0 g 2,3-dihydro-6,7-dimetyl-benzof uran- 2-karboksylsyre i 40 ml nitrobenzen i nærvær av 30 g b) Analogously to example 19, 8.0 g of 2,3-dihydro-6,7-dimethyl-benzofuran-2-carboxylic acid is acylated in 40 ml of nitrobenzene in the presence of 30 g

aluminiumklorid med 16 g 2-brom-2-brommetyl-propionylklorid. Den dannede 2,3-dihydro-5-(2-brom-2-brommetyl-propionyl)-6,7-dimetyl-benzofuran-2-karboksylsyre anvendes som råprodukt. aluminum chloride with 16 g of 2-bromo-2-bromomethyl-propionyl chloride. The 2,3-dihydro-5-(2-bromo-2-bromomethyl-propionyl)-6,7-dimethyl-benzofuran-2-carboxylic acid formed is used as crude product.

EKSEMPEL 31 EXAMPLE 31

a) Analogt eksempel 21a) oppnår man fra 5,0 g rå 2,3-dihydro-5-(2-brom-2-brommetyl-butyryl)-6,7-dimetyl-benzofuran-2-karboksylsyre og IO g kaliumjodid i 50 ml etanol 2,3-dihydro-5-(2-metylen-butyryl)-6,7-dimetyl-benzofuran-2-karboksylsyre med smp. 10 2 - 104° (fra karbontetraklorid). a) Analogous to example 21a), one obtains from 5.0 g crude 2,3-dihydro-5-(2-bromo-2-bromomethyl-butyryl)-6,7-dimethyl-benzofuran-2-carboxylic acid and 10 g potassium iodide in 50 ml ethanol 2,3-dihydro-5-(2-methylene-butyryl)-6,7-dimethyl-benzofuran-2-carboxylic acid with m.p. 10 2 - 104° (from carbon tetrachloride).

Utgangsforbindelsen fremstilles som folger: The output connection is produced as follows:

b) Analogt eksempel 19 acyleres 4,9 g 2,3-dihydro-6,7-dimetyl-benzof uran-2-karboksylsyre i 20 ml nitrobenzen i nærvær av 15 g b) Analogously to example 19, 4.9 g of 2,3-dihydro-6,7-dimethyl-benzofuran-2-carboxylic acid is acylated in 20 ml of nitrobenzene in the presence of 15 g

aluminiumklorid med 8 g 2-brom-2-brommetyl-butyrylklorid. Den dannede 2,3-dihydro-5-(2-brom-2-brommetyl-butyryl)-6,7-dimetyl-benzof uran- 2-karboksylsyre anvendes som råprodukt. <1>aluminum chloride with 8 g of 2-bromo-2-bromomethyl-butyryl chloride. The 2,3-dihydro-5-(2-bromo-2-bromomethyl-butyryl)-6,7-dimethyl-benzofuran-2-carboxylic acid formed is used as crude product. <1>

EKSEMPEL 32 EXAMPLE 32

a) Analogt eksempel 22 oppnår man fra 5,3 g rå 2,3-dihydro-5-(2-brom-2-brommetyl-butyryl)-6-klor-benzofuran-2-karboksylsyre med 1,6 g sinkstdv i 50, ml etanol 2,3-dihydro-5-(2-metylen-butyryl)-6-klor-benzofuran-2-karboksylsyre med smp. 110° (fra benzen). i Utgangsforbindelsen fremstilles som folger: b) Analogt eksempel 19 omsettes 4,0 g 2,3-dihydro-6-klor- > benzofuran-2-karboksylsyre med 20 ml nitrobenzen i nærvær av 14 g aluminiumklorid med 8 g 2-brom-2-brommetyl-butyrylklorid. i Den erholdte 2,3-dihydro-5-(2-brom-2-brommetyl-butyryl)-6-klor-benzofuran-2-karboksylsyre viderearbeides som råprodukt. a) Analogously to example 22, one obtains from 5.3 g crude 2,3-dihydro-5-(2-bromo-2-bromomethyl-butyryl)-6-chloro-benzofuran-2-carboxylic acid with 1.6 g zinc stdv in 50 , ml ethanol 2,3-dihydro-5-(2-methylene-butyryl)-6-chloro-benzofuran-2-carboxylic acid with m.p. 110° (from benzene). i The starting compound is prepared as follows: b) Analogous to example 19, 4.0 g of 2,3-dihydro-6-chloro- > benzofuran-2-carboxylic acid is reacted with 20 ml of nitrobenzene in the presence of 14 g of aluminum chloride with 8 g of 2-bromo-2 -bromomethyl-butyryl chloride. i The 2,3-dihydro-5-(2-bromo-2-bromomethyl-butyryl)-6-chloro-benzofuran-2-carboxylic acid obtained is further processed as crude product.

Claims (1)

Analogifremgangsmåter for fremstilling av nye, terapeutisk virksomme, heterocykliske karboksylsyrer med den generelle formel I,Analogous methods for the preparation of new, therapeutically active, heterocyclic carboxylic acids of the general formula I, hvor R betyr en alkylgruppe med hoyst 6 karbonatomer, X oksygen eller svovel, Y^ og Y2 hydrogen eller metylgrupper og Z^ og Z2 hydrogen, fluor, klor, brom, alkyl- ellerwhere R means an alkyl group with at most 6 carbon atoms, X oxygen or sulphur, Y^ and Y2 hydrogen or methyl groups and Z^ and Z2 hydrogen, fluorine, chlorine, bromine, alkyl- or alkoksygrupper med hver hoyst 2 karbonatomer, og deres salter med uorganiske eller organiske baser,karakterisert veda) at man spalter en forbindelse med den generelle formel II,alkoxy groups with each at most 2 carbon atoms, and their salts with inorganic or organic bases, characterized by) that one cleaves a compound with the general formula II, hvor R, X, Y^, Y2, Z^ og Z^ har den under formel I angitte betydning, ogwhere R, X, Y^, Y2, Z^ and Z^ have the meaning given under formula I, and Am betyr resten av en sekundær organisk nitrogenbase, under avspaltning av en nitrogenbase med den generelle formel III,Am means the residue of a secondary organic nitrogen base, during cleavage of a nitrogen base of the general formula III, hvor Am har den under formel II angitte betydning, where Am has the meaning given under formula II, eller b) at man omsetter en forbindelse med den generelle formel IV,or b) that one converts a compound of the general formula IV, hvor X, Yp Y£, Z-^ og Z^ har den under formel I angitte betydning,where X, Yp Y£, Z-^ and Z^ have the meaning given under formula I, med et karboksylsyrehalogenid med den generelle formel V,with a carboxylic acid halide of the general formula V, eller med et karboksylsyreanhydrid med den generelle formel VI,or with a carboxylic anhydride of the general formula VI, hvor R har den under formel I angitte betydning, og Q betyr halogen,where R has the meaning given under formula I, and Q means halogen, ifolge Friedel-Crafts, eller c) at man avhalogenerer en forbindelse med den generelle formel VII,according to Friedel-Crafts, or c) that one dehalogenates a compound with the general formula VII, hvor R, X, Yp. Y^ t Z, og Z^ har den under formel I angitte betydning,ogwhere R, X, Yp. Y^ t Z, and Z^ has the meaning given under formula I, and Q betyr halogen, og overforer, hvis onsket, reaksjonsproduktene med uorganiske eller organiske baser til salter.Q means halogen, and, if desired, converts the reaction products with inorganic or organic bases into salts.
NO2126/69A 1968-05-30 1969-05-23 NO122754B (en)

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