NO861804L - PROCEDURE FOR THE PREPARATION OF 2-THIOCHROMENYLIDEN-ACET EDC EDITORS. - Google Patents
PROCEDURE FOR THE PREPARATION OF 2-THIOCHROMENYLIDEN-ACET EDC EDITORS.Info
- 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
- Authority
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- Norway
- Prior art keywords
- atoms
- straight
- chain
- stands
- branched alkyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title claims description 4
- -1 2-thiochromenylidene acetic acid esters Chemical class 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000005997 bromomethyl group Chemical group 0.000 claims description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 150000002168 ethanoic acid esters Chemical class 0.000 description 4
- PLGBCMYZYBKTFZ-UHFFFAOYSA-N 4-oxo-2-phenylthiochromene-8-carbaldehyde Chemical compound O=CC1=CC=CC(C(C=2)=O)=C1SC=2C1=CC=CC=C1 PLGBCMYZYBKTFZ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002262 Schiff base Substances 0.000 description 3
- 150000004753 Schiff bases Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 3
- 229960001701 chloroform Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 229950005499 carbon tetrachloride Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- QCDJOJKIHZQJGX-UHFFFAOYSA-N 1-nitropropan-2-one Chemical compound CC(=O)C[N+]([O-])=O QCDJOJKIHZQJGX-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ZWCRLFIZIYVXMG-UHFFFAOYSA-N ethyl 2-acetyloxyacetate Chemical compound CCOC(=O)COC(C)=O ZWCRLFIZIYVXMG-UHFFFAOYSA-N 0.000 description 1
- AKUGNQXVMIUZST-UHFFFAOYSA-N ethyl 2-methyl-5-oxo-4-(4-oxo-2-phenylthiochromen-8-yl)-4,7-dihydro-1h-furo[3,4-b]pyridine-3-carboxylate Chemical compound CCOC(=O)C1=C(C)NC(COC2=O)=C2C1C1=CC=CC(C(C=2)=O)=C1SC=2C1=CC=CC=C1 AKUGNQXVMIUZST-UHFFFAOYSA-N 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940052308 general anesthetics halogenated hydrocarbons Drugs 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- RIBFXMJCUYXJDZ-UHFFFAOYSA-N propanoyl bromide Chemical compound CCC(Br)=O RIBFXMJCUYXJDZ-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- 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)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19853517950 DE3517950A1 (en) | 1985-05-18 | 1985-05-18 | Process for the preparation of 2-thiochromenylideneacetoacetic esters |
Publications (1)
Publication Number | Publication Date |
---|---|
NO861804L true NO861804L (en) | 1986-11-19 |
Family
ID=6271079
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO861804A NO861804L (en) | 1985-05-18 | 1986-05-06 | PROCEDURE FOR THE PREPARATION OF 2-THIOCHROMENYLIDEN-ACET EDC EDITORS. |
Country Status (11)
Country | Link |
---|---|
JP (1) | JPS61268679A (en) |
KR (1) | KR860009006A (en) |
CN (1) | CN86103229A (en) |
DE (1) | DE3517950A1 (en) |
DK (1) | DK229986A (en) |
ES (1) | ES8706663A1 (en) |
FI (1) | FI862043A (en) |
GR (1) | GR861285B (en) |
HU (1) | HUT43579A (en) |
NO (1) | NO861804L (en) |
PT (1) | PT82607B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
IL89840A (en) * | 1988-04-06 | 1996-10-31 | Lipha | Substituted flavonoid compounds and salts thereof their preparation and pharmaceutical composition containing them |
-
1985
- 1985-05-18 DE DE19853517950 patent/DE3517950A1/en not_active Withdrawn
-
1986
- 1986-05-06 NO NO861804A patent/NO861804L/en unknown
- 1986-05-09 CN CN198686103229A patent/CN86103229A/en active Pending
- 1986-05-15 FI FI862043A patent/FI862043A/en not_active Application Discontinuation
- 1986-05-15 JP JP61109715A patent/JPS61268679A/en active Pending
- 1986-05-16 ES ES555029A patent/ES8706663A1/en not_active Expired
- 1986-05-16 GR GR861285A patent/GR861285B/en unknown
- 1986-05-16 PT PT82607A patent/PT82607B/en unknown
- 1986-05-16 HU HU862084A patent/HUT43579A/en unknown
- 1986-05-16 DK DK229986A patent/DK229986A/en not_active Application Discontinuation
- 1986-05-17 KR KR1019860003845A patent/KR860009006A/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
PT82607A (en) | 1986-06-01 |
DK229986D0 (en) | 1986-05-16 |
GR861285B (en) | 1986-09-16 |
PT82607B (en) | 1988-04-22 |
KR860009006A (en) | 1986-12-19 |
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 |
HUT43579A (en) | 1987-11-30 |
ES8706663A1 (en) | 1987-07-01 |
CN86103229A (en) | 1986-11-19 |
DK229986A (en) | 1986-11-19 |
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