NO861804L - PROCEDURE FOR THE PREPARATION OF 2-THIOCHROMENYLIDEN-ACET EDC EDITORS. - Google Patents

PROCEDURE FOR THE PREPARATION OF 2-THIOCHROMENYLIDEN-ACET EDC EDITORS.

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Publication number
NO861804L
NO861804L NO861804A NO861804A NO861804L NO 861804 L NO861804 L NO 861804L NO 861804 A NO861804 A NO 861804A NO 861804 A NO861804 A NO 861804A NO 861804 L NO861804 L NO 861804L
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atoms
straight
chain
stands
branched alkyl
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NO861804A
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Norwegian (no)
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Gerhard Franckowiak
Siegfried Goldmann
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Bayer Ag
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Publication of NO861804L publication Critical patent/NO861804L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Compositions Of Macromolecular Compounds (AREA)

Description

Foreliggende oppfinnelse vedrører en fremgangsmåte til fremstilling av delvis kjente 2-tiokromenylidenaceteddikestere som kan anvendes til fremstilling av farmasøytiske virksomme stoffer. The present invention relates to a method for the production of partially known 2-thiochromenylidene acetic acid esters which can be used for the production of pharmaceutical active substances.

Det er kjent at man får 3-okso-l-(4-okso-2-fenyl-4H-tiokromen-8-yl)-1-buten-2-karboksylsyreester ved Knoevenagel-kondensasjon av 4-okso-2-fenyl-4H-tiokromen-8-karbaldehyd og de tilsvarende aceteddikestrene (se europeisk patentsøknad 123 112). Denne fremgangsmåten er imidlertid på grunn av den dårlige oppløseligheten for aldehydet meget omstendelig og gir bare lave utbytter. It is known that 3-oxo-1-(4-oxo-2-phenyl-4H-thiochromen-8-yl)-1-butene-2-carboxylic acid ester is obtained by Knoevenagel condensation of 4-oxo-2-phenyl- 4H-thiochromene-8-carbaldehyde and the corresponding acetacetic esters (see European patent application 123 112). However, due to the poor solubility of the aldehyde, this method is very time-consuming and gives only low yields.

Videre er det kjent at man får l-fenyl-2-nitro-buten-l-on-3, samt dens i fenyl substituerte derivater, når man omsetter nitroaceton med det tilsvarende Schiffske basene [se A. Dornow, W. Sassenberg, Liebigs Ann. Che. 602, 14-23 (1957)]. Furthermore, it is known that l-phenyl-2-nitro-buten-l-one-3, as well as its phenyl-substituted derivatives, is obtained when nitroacetone is reacted with the corresponding Schiff bases [see A. Dornow, W. Sassenberg, Liebigs Ann. Che. 602, 14-23 (1957)].

Videre er det kjent at reaksjonen av eddikestrene med aromatiske azometiner enten den er katalysert sur eller basisk gir de ønskede benzylidenforbindelsene i ett trinn [se Chemical Abstracts 7%_ 126 279, Furthermore, it is known that the reaction of the acetic esters with aromatic azomethines whether catalyzed acid or basic gives the desired benzylidene compounds in one step [see Chemical Abstracts 7%_ 126 279,

85, 77 829]. 85, 77 829].

Det er nå funnet at man får 2-tiokromenylidenaceteddikester av formel I: It has now been found that 2-thiochromenylidene acetic acid esters of formula I are obtained:

hvori in which

Ri står for rettkjedet eller forgrenet alkyl med inntil 4 C-atomer, ogRi stands for straight-chain or branched alkyl with up to 4 C atoms, and

R<2>står for rettkjedet eller forgrenet alkyl med inntil 4 C-atomer, som eventuelt er substituert med halogen eller med acyloksy med inntil 7 C-atomer, R<2> stands for straight-chain or branched alkyl with up to 4 C atoms, which is optionally substituted with halogen or with acyloxy with up to 7 C atoms,

når man omsetter Schiffske baser av generell formel II:when converting ship bases of general formula II:

hvori in which

R<3>står for rettkjedet eller forgrenet alkyl med inntil 6 C-atomer, med aceteddikestere av generell formel III: R<3> stands for straight-chain or branched alkyl with up to 6 C atoms, with acetate diesters of general formula III:

hvori in which

R<1>, R<2>har ovenfor angitte betydning,R<1>, R<2> have the meanings given above,

eventuelt i nærvær av inerte organiske fortynningsmidler med acyleringsmidler. optionally in the presence of inert organic diluents with acylating agents.

Overraskende gir fremgangsmåten ifølge oppfinnelsen sluttproduktet I i ett trinn. Ved kjennskap til teknikkens stand var det ikke å vente at man skulle oppnå benzylidenforbindelsene på en så enkel måte med godt utbytte. Like lite var det ventet at et azometin med den voluminøse tiokromenylresten ville reagere så lett. Surprisingly, the method according to the invention gives the final product I in one step. Knowing the state of the art, it was not expected that the benzylidene compounds would be obtained in such a simple way with good yield. Just as little was expected that an azomethine with the bulky thiochromenyl residue would react so readily.

Fremgangsmåten ifølge oppfinnelsen har den fordelen at den raskt og enkelt kan gjennomføres som en entrinnsreaksjon. Videre er opparbeid-elsen og rensingen av sluttproduktene teknisk enkelt gjennomførbar. The method according to the invention has the advantage that it can be carried out quickly and easily as a one-step reaction. Furthermore, the preparation and purification of the end products is technically easy to implement.

De ved fremgangsmåten ifølge oppfinnelsen fremstilte forbindelsene er generelt definert ved formelen I. I denne forbindelsen står fortrinnsvis R<*>for rettkjedet eller forgrenet alkyl med inntil 4 C-atomer, The compounds produced by the method according to the invention are generally defined by the formula I. In this compound, R<*> preferably stands for straight-chain or branched alkyl with up to 4 C atoms,

R<2>for. rettkjedet eller forgrenet alkyl med inntil 4 C-atomer,R<2>for. straight-chain or branched alkyl with up to 4 C atoms,

for brommetyl eller klormetyl, eller .for bromomethyl or chloromethyl, or .

for acetyloksymetyl eller benzoylok sym etyl.for acetyloxymethyl or benzoyloxymethyl.

Dersom man som utgangsstoffer anvender 8-n-butyliminometyl-4-okso-2-fenyl-4H-tiokromen og aceteddiksyremetylester, kan reaksjonsforløpet tydeliggjøres ved hjelp av følgende formelskjema: If 8-n-butyliminomethyl-4-oxo-2-phenyl-4H-thiochromene and acetoacetic acid methyl ester are used as starting materials, the course of the reaction can be clarified using the following formula:

De som utgangsstoffer anvendte aceteddikestrene av formel III er kjente eller kan fremstilles ved kjente fremgangsmåter [se D. Borrmann i Houben-Weyl "Methoden der organischen Chemie" VII/4, 230 (1968), S. Gelin, P. Pollet Synth. Commun. 1980, 805; Tetrahedron 34, 1453 (1978)]. The acetate diesters of formula III used as starting materials are known or can be prepared by known methods [see D. Borrmann in Houben-Weyl "Methoden der organischen Chemie" VII/4, 230 (1968), S. Gelin, P. Pollet Synth. Commun. 1980, 805; Tetrahedron 34, 1453 (1978)].

De som utgangsstoffer anvendte Schiffske basene av formel II er nye. De kan fremstilles ved at man omsetter 4-okso-2-fenyl-4H-tiokromen-8-karbaldehyd av formel IV: med aminer av formel V: The Schiffske bases of formula II used as starting materials are new. They can be prepared by reacting 4-oxo-2-phenyl-4H-thiochromene-8-carbaldehyde of formula IV: with amines of formula V:

hvori in which

R<3>har den ovenfor angitte betydning,R<3> has the meaning given above,

i organiske oppløsningsmidler som alkoholer, f.eks. metanol, etanol, propanol, eller klorerte hydrokarboner, f.eks. di-, tri- eller tetraklormetan, eller aromatiske hydrokarboner som f.eks. benzen, toluen, xylen, fortrinnsvis i oppløsningsmidler som di- eller triklormetan, eventuelt ved tilsats av et vannopptagende stoff som nantriumsulfat, kaliumkarbonat, magnesiumsulfat eller molekylar sikt, ved temperaturer fra 0°C til 60"C, fortrinnsvis ved romtemperatur. De Schiffske basene krystalliserer etter frafiltrering av tilsatsstoffet, samt fjernelse av oppløsningsmidlet, henholdsvis oppløsningsmiddel-vann-blandingen. in organic solvents such as alcohols, e.g. methanol, ethanol, propanol, or chlorinated hydrocarbons, e.g. di-, tri- or tetrachloromethane, or aromatic hydrocarbons such as benzene, toluene, xylene, preferably in solvents such as di- or trichloromethane, optionally with the addition of a water-absorbing substance such as sodium sulfate, potassium carbonate, magnesium sulfate or molecular sieves, at temperatures from 0°C to 60°C, preferably at room temperature. The Schiff bases crystallizes after filtering off the additive, as well as removing the solvent, respectively the solvent-water mixture.

Som acyleringsmidler kommer ved fremgangsmåten ifølge oppfinnelsen alle vanlige acyleringsmidler på tale. Herunder hører fortrinnsvis karboksyl-syreanhydrider som f.eks. acetanhydrid eller propionsyreanhydrid, eller karboksylsyrehalogenider som f.eks. acetylklorid, acetylbromid, propion-syreklorid eller propionsyrebromid. Spesielt foretrukket som acyleringsmiddel er acetanhydrid. As acylating agents in the method according to the invention, all common acylating agents are used. This preferably includes carboxylic acid anhydrides such as e.g. acetic anhydride or propionic anhydride, or carboxylic acid halides such as acetyl chloride, acetyl bromide, propionic acid chloride or propionic acid bromide. Particularly preferred as acylating agent is acetic anhydride.

Reaksjonen kan gjennomføres med eller uten fortynningsmiddel. Som fortynningsmiddel kommer eventuelt de vanlige inerte oppløsningsmidlene på tale. Herunder hører fortrinnsvis aromatiske hydrokarboner som f.eks. benzen, toluen eller xylen, eller karboksylsyrer som f.eks. maursyre, eddiksyre eller propionsyre og halogenerte hydrokarboner som di-, tri-eller tetraklormetan. Omsetningen foregår ved temperaturer fra 0°C til 200 °C, fortrinnsvis fra 10 °C til 150 °C. The reaction can be carried out with or without a diluent. The usual inert solvents may be used as diluents. These preferably include aromatic hydrocarbons such as e.g. benzene, toluene or xylene, or carboxylic acids such as formic acid, acetic acid or propionic acid and halogenated hydrocarbons such as di-, tri- or tetrachloromethane. The reaction takes place at temperatures from 0°C to 200°C, preferably from 10°C to 150°C.

Omsetningen kan gjennomføres ved normaltrykk, men også ved forhøyet trykk. Generelt arbeider man ved normaltrykk. The turnover can be carried out at normal pressure, but also at elevated pressure. In general, you work at normal pressure.

Ved gjennomførering av fremgangsmåten ifølge oppfinnelsen anvender man til 1 mol av den Schiffske basken (II) 0,1 til 10, fortrinnsvis 1 til 5 mol av aceteddikesteren (III). Acyleringsmidlet anvendes generelt i en mengde fra 1 til 10 mol, fortrinnsvis 2 til 6 mol pr. mol Schiffsk base. Mest fortrinnsvis gjennomfører man reaksjonen med et inntil 6 molart over-skudd av acedanhydrid, som dermed både er oppløsningsmiddel og acyleringsmiddel. When carrying out the method according to the invention, 0.1 to 10, preferably 1 to 5, mol of the acetic acid ester (III) is used for 1 mol of the Schiff base (II). The acylating agent is generally used in an amount of from 1 to 10 mol, preferably 2 to 6 mol per mol Ship base. Most preferably, the reaction is carried out with an up to 6 molar excess of acedic anhydride, which is thus both solvent and acylating agent.

Forbindelsene av formel I lar seg ved kjente fremgangsmåter overføre til 1,4-dihydropyridiner med enaminer eller med aceteddikestere og aminer [se A. Hantzsch, Liebigs Ann. Chem. 215, 1, 1882: U. Eisner, J. Kuthan, Chem. Rev. 72, (1972)]. The compounds of formula I can be transferred by known methods to 1,4-dihydropyridines with enamines or with acetate diesters and amines [see A. Hantzsch, Liebigs Ann. Chem. 215, 1, 1882: U. Eisner, J. Kuthan, Chem. Fox. 72, (1972)].

Disse dihydropyridinene utgjør verdifulle farmasøytiske virksomme stoffer, som virker som kardiotonika til forbedring av hjertekontraktiliteten. Videre kan de, ved at de forhøyer kalsiuminnstrømningen i cellen, anvendes som antihypotonika, til senkning av blodsukkernivået, til avsvelling av slimhinner og til påvirkning av salt- og væskebalansen (se EP 123 112, EP 123 095). These dihydropyridines constitute valuable pharmaceutical active substances, which act as cardiotonics to improve cardiac contractility. Furthermore, by increasing the influx of calcium into the cell, they can be used as antihypotonics, to lower the blood sugar level, to deflate mucous membranes and to influence the salt and fluid balance (see EP 123 112, EP 123 095).

De følgende eksemplene illustrerer oppfinnelsen uten å virke begrensende. The following examples illustrate the invention without being limiting.

FremstillingseksemplerManufacturing examples

Eksempel 1Example 1

a) 8 -n-butyliminometyl -4 -ok so -2 - f enyl -4H -tiok romena) 8-n-butyliminomethyl-4-oxo-2-phenyl-4H-thiocromene

752 g (2,83 mol) 4-okso-2-fenyl-4H-tiokromen-8-karbaldehyd oppløses delvis i 4,25 1 diklormetan og 420 ml (4,24 mol) n-butylamin tilsettes. Etter flere timers omrøring får man en fullstendig oppløsning hvorpå reaksjonsvannet delvis er avsatt. Det inndampes i vakuum, deretter inndampes det på nytt etter tre gangers tilsats av 2 1 diklormetan til fullstendig fjernelse av restene av butylaminet. Oljen krystalliserer ved avkjøling. b) 4- acetoksy -3-okso- l-(4-okso-2-fenyl-4H-tiokromen-8 -yl) -l-buten-2-karboksylsyre-etylester 752 g (2.83 mol) of 4-oxo-2-phenyl-4H-thiochromene-8-carbaldehyde are partially dissolved in 4.25 1 of dichloromethane and 420 ml (4.24 mol) of n-butylamine are added. After several hours of stirring, a complete solution is obtained, on which the water of reaction has partially settled. It is evaporated in vacuo, then it is evaporated again after three times the addition of 2 1 of dichloromethane to completely remove the remains of the butylamine. The oil crystallizes on cooling. b) 4-acetoxy-3-oxo-1-(4-oxo-2-phenyl-4H-thiochromen-8-yl)-1-butene-2-carboxylic acid ethyl ester

920 g (2,83 mol) rå butyliminoforbindelse la blandes trinnvis og intenst med 585 g (3,11 mol) acetoksyeddiksyreetylester og 535 ml (5,66 mol) acetanhydrid. Man får i løpet av få minutter en temperaturøkning ved ytre avkjøling. Avkjølingen stoppes så snart temperaturen går tilbake. Det blandes med podekrystaller og blandingen krystalliserer under omrøring. Krystallgrøten røres deretter opp, avsuges over en glassfritte og etter-vaskes deretter med toluen/petroleumeter 1:1, deretter med petroleum-eter. 920 g (2.83 mol) of crude butylimino compound was mixed stepwise and intensively with 585 g (3.11 mol) of acetoxyacetic acid ethyl ester and 535 ml (5.66 mol) of acetic anhydride. You get an increase in temperature within a few minutes due to external cooling. Cooling is stopped as soon as the temperature returns. It is mixed with seed crystals and the mixture crystallizes under stirring. The crystal slurry is then stirred, filtered off over a glass frit and then washed with toluene/petroleum ether 1:1, then with petroleum ether.

Utbytte: 758 g (61,5% av teoretisk)Yield: 758 g (61.5% of theoretical)

Smeltepunkt: 135° C (cis/trans-blanding)Melting point: 135° C (cis/trans mixture)

Analogt denne fremgangsmåten ble det fremstilt:Analogous to this procedure, the following was produced:

Eksempel 2Example 2

3-ok so-1 -(4- okso -2-f enyl -4H-tiokromen -8—yl)-1 -buten-2 -karboksylsyre-metylester 3-oxo-1-(4-oxo-2-phenyl-4H-thiochromen-8-yl)-1-butene-2-carboxylic acid methyl ester

Utbytte: 73% av teoretisk Yield: 73% of theoretical

Smeltepunkt: 155°C (cis/trans-blanding)Melting point: 155°C (cis/trans mixture)

Eksempel 3Example 3

4-klor-3 -okso-1- (4-okso-2-fenyl-4H-tiokromen-8-yl)-l-buten-2-karboksyl-syreisopropylester 4-chloro-3-oxo-1-(4-oxo-2-phenyl-4H-thiochromen-8-yl)-1-butene-2-carboxylic acid isopropyl ester

Utbytte: 67% av teoretisk Yield: 67% of theoretical

Smeltepunkt: 76°C (cis/trans-blanding)Melting point: 76°C (cis/trans mixture)

Eksempel 4Example 4

4-klor-3 -okso-1- (4-okso-2-fenyl-4H-tiokromen-8-yl)-l-buten-2-karboksyl-syreetylester 4-Chloro-3-oxo-1-(4-oxo-2-phenyl-4H-thiochromen-8-yl)-1-butene-2-carboxylic acid ethyl ester

Utbytte: 61% av teoretisk Yield: 61% of theoretical

Smeltepunkt; 89"C (cis/trans-blanding)Melting point; 89"C (cis/trans mixture)

Eksempel 5 Example 5

2-metyl- 4- (4-oks o-2-f eny l-4H-tio kromen-8 -yl) -5-o kso-1,4,5,7-tetrahydro-furo [3,4-b] -pyridin-3-karboksylsyreetylester 2-methyl-4-(4-oxo-2-phenyl-4H-thiochromen-8-yl)-5-oxo-1,4,5,7-tetrahydro-furo[3,4-b ] -pyridine-3-carboxylic acid ethyl ester

1,283 kg (2,94 mol) 4-acetoksy-3-okso-l-(4-okso-2-fenyl-4H-tiokromen-8-yl)-l-buten-2-karboksylsyreetylester (eksempel lb) suspenderes i 2,3 1 etanol og 379,7 g (2,94 mol) e-aminokrotonsyreetylester tilsettes. Det oppvarmes til tilbak est rømning i 8 timer, etter tilsats av 150 ml mettet etanolisk HCL oppvarmes det i ytterligere 3 timer til tilbakestrømning. Blandingen får stå for krystallisasjon ved romtemperatur og krystallgrøten frasuges over en glassfritte. Filterkaken utkokes to ganger, hver gang med 1,5 1 etanol, og tørkes etter frasuging i vakuum-tørkeskap i 48 timer ved 120 °C og 1 torr. 1.283 kg (2.94 mol) of 4-acetoxy-3-oxo-1-(4-oxo-2-phenyl-4H-thiochromen-8-yl)-1-butene-2-carboxylic acid ethyl ester (Example 1b) is suspended in 2 .3 1 ethanol and 379.7 g (2.94 mol) ε-aminocrotonic acid ethyl ester are added. It is heated to reflux for 8 hours, after adding 150 ml of saturated ethanolic HCL it is heated for a further 3 hours to reflux. The mixture is allowed to crystallize at room temperature and the crystal slurry is suctioned off over a glass frit. The filter cake is boiled twice, each time with 1.5 1 ethanol, and dried after extraction in a vacuum drying cabinet for 48 hours at 120 °C and 1 torr.

Utbytte: 990 g (73% av teoretisk)Yield: 990 g (73% of theoretical)

Smeltepunkt: 266 "C (dekomponering) Melting point: 266 "C (decomposition)

Claims (4)

1. Fremgangsmåte til fremstilling av 2-tiokromenylidenaceteddikester av formel (I): 1. Process for the preparation of 2-thiochromenylidene acetic acid esters of formula (I): hvori Ri står for rettkjedet eller forgrenet alkyl med inntil 4 C-atomer, og R <2> står for rettkjedet eller forgrenet alkyl med inntil 4 C-atomer, som eventuelt er substituert med halogen eller med acyloksy med inntil 7 C-atomer, karakterisert ved at man omsetter Schiffske baser av generell formel (II): in which Ri stands for straight-chain or branched alkyl with up to 4 C atoms, and R <2> stands for straight-chain or branched alkyl with up to 4 C atoms, which is optionally substituted by halogen or by acyloxy with up to 7 C atoms, characterized by converting Schiffske bases of general formula (II): hvori R <3> står for rettkjedet eller forgrenet alkyl med inntil 6 C-atomer, med aceteddikestere av generell formel III: in which R <3> stands for straight-chain or branched alkyl with up to 6 C atoms, with acetate diesters of general formula III: hvori R <1> , R <2> har ovenfor angitte betydning, eventuelt i nærvær av inerte organiske fortynningsmidler med acyleringsmidler.in which R <1> , R <2> have the meanings given above, optionally in the presence of inert organic diluents with acylating agents. 2. Fremgangsmåte ifølge krav 1 til fremstilling av forbindelser av formel (I) i krav 1, karakterisert ved at Ri står for rettkjedet eller forgrenet alkyl med inntil 4 C-atomer, og R <2> står for rettkjedet eller forgrenet alkyl med inntil 4 C-atomer, for brommetyl eller klormetyl, eller for acetylok sym etyl eller benzoyloksymetyl.2. Process according to claim 1 for the preparation of compounds of formula (I) in claim 1, characterized in that Ri stands for straight-chain or branched alkyl with up to 4 C atoms, and R <2> stands for straight-chain or branched alkyl with up to 4 C atoms, for bromomethyl or chloromethyl, or for acetyloxy sym ethyl or benzoyloxymethyl. 3. Fremgangsmåte ifølge krav 1 og 2, karakterisert ved at man gjennomfører reaksjonen ved temperaturer fra 0 til 200 "C.3. Method according to claims 1 and 2, characterized in that the reaction is carried out at temperatures from 0 to 200 "C. 4. Fremgangsmåte ifølge krav 1 og 2, karakterisert ved at man gjennomfører reaksjonen ved temperaturer fra 10 til 150 °C.4. Method according to claims 1 and 2, characterized in that the reaction is carried out at temperatures from 10 to 150 °C.
NO861804A 1985-05-18 1986-05-06 PROCEDURE FOR THE PREPARATION OF 2-THIOCHROMENYLIDEN-ACET EDC EDITORS. NO861804L (en)

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CN (1) CN86103229A (en)
DE (1) DE3517950A1 (en)
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ES (1) ES8706663A1 (en)
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US5116954A (en) * 1988-04-06 1992-05-26 Lipha, Lyonnaise Industrielle Pharmaceutique Pharmaceutically useful flavonoic compounds containing at least one substituent on the benzopyranone ring moiety
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JPS61268679A (en) 1986-11-28
DE3517950A1 (en) 1986-11-20
FI862043A (en) 1986-11-19
FI862043A0 (en) 1986-05-15
ES555029A0 (en) 1987-07-01
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DK229986A (en) 1986-11-19

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