DK148082B - Analogifremgangsmaade til fremstilling af 1-ethyl-1,4-dihydro-6-(2-naphthyl)-4-oxo-nicotinsyrederivater - Google Patents
Analogifremgangsmaade til fremstilling af 1-ethyl-1,4-dihydro-6-(2-naphthyl)-4-oxo-nicotinsyrederivater Download PDFInfo
- Publication number
- DK148082B DK148082B DK287080AA DK287080A DK148082B DK 148082 B DK148082 B DK 148082B DK 287080A A DK287080A A DK 287080AA DK 287080 A DK287080 A DK 287080A DK 148082 B DK148082 B DK 148082B
- Authority
- DK
- Denmark
- Prior art keywords
- naphthyl
- oxo
- methyl
- ethyl
- dihydro
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 6
- 239000002253 acid Substances 0.000 title description 6
- -1 2-NAPHTHYL Chemical class 0.000 title description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- FHDQRDHNKMTDLF-UHFFFAOYSA-N 1-ethyl-6-naphthalen-2-yl-4-oxopyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC=C(C=CC=C2)C2=C1 FHDQRDHNKMTDLF-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- MIBDLWXWTGGZCY-UHFFFAOYSA-N methyl 3-methoxy-5-naphthalen-2-ylpenta-2,4-dienoate Chemical compound C1=CC=CC2=CC(C=CC(OC)=CC(=O)OC)=CC=C21 MIBDLWXWTGGZCY-UHFFFAOYSA-N 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 2
- WGASDMQEZHXQJP-UHFFFAOYSA-N methyl 5-naphthalen-2-yl-3-oxopent-4-enoate Chemical compound C1=CC=CC2=CC(C=CC(=O)CC(=O)OC)=CC=C21 WGASDMQEZHXQJP-UHFFFAOYSA-N 0.000 claims 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 claims 1
- 239000012043 crude product Substances 0.000 claims 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 239000000047 product Substances 0.000 claims 1
- 239000000741 silica gel Substances 0.000 claims 1
- 229910002027 silica gel Inorganic materials 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- XXPANQJNYNUNES-UHFFFAOYSA-N nomifensine Chemical compound C12=CC=CC(N)=C2CN(C)CC1C1=CC=CC=C1 XXPANQJNYNUNES-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 3
- 150000004057 1,4-benzoquinones Chemical class 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229960000632 dexamfetamine Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 231100001231 less toxic Toxicity 0.000 description 2
- 229950007554 levmetamfetamine Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 2
- IBRPASKYXURDBT-UHFFFAOYSA-N methyl 1-ethyl-6-naphthalen-2-yl-4-oxopyridine-3-carboxylate Chemical compound CCN1C=C(C(=O)OC)C(=O)C=C1C1=CC=C(C=CC=C2)C2=C1 IBRPASKYXURDBT-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229960001073 nomifensine Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- SSHRVPMSFQLCAG-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridine-5-carboxylic acid Chemical compound OC(=O)C1=CNCCC1 SSHRVPMSFQLCAG-UHFFFAOYSA-N 0.000 description 1
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 1
- HXIPLHBIHBQWGY-UHFFFAOYSA-N 2,3-dihydropyridine-3-carboxylic acid Chemical class OC(=O)C1CN=CC=C1 HXIPLHBIHBQWGY-UHFFFAOYSA-N 0.000 description 1
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- WFKLXLZKZUHFGY-UHFFFAOYSA-N 6-naphthalen-2-yl-4-oxo-1H-pyridine-3-carboxylic acid Chemical compound C1=C(C=CC2=CC=CC=C12)C=1NC=C(C(=O)O)C(C=1)=O WFKLXLZKZUHFGY-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical compound O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- BHVIPQUBOSCUMR-UHFFFAOYSA-N methyl 2-(ethylaminomethylidene)-5-naphthalen-2-yl-3-oxopent-4-enoate Chemical compound C1=CC=CC2=CC(C=CC(=O)C(C(=O)OC)=CNCC)=CC=C21 BHVIPQUBOSCUMR-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- FWYKRJUVEOBFGH-UHFFFAOYSA-M triphenyl(prop-2-enyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC=C)C1=CC=CC=C1 FWYKRJUVEOBFGH-UHFFFAOYSA-M 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/08—Preparation by ring-closure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyridine Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
148082
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte dihydronicotinsyrederivater, nemlig 1-ethyl-
1,4-dihydro-6-(2-naphthyl)-4-oxonicotinsyre og estere deraf med den almene formel I
o
COOR
CGnl 5 hvor R betegner hydrogen eller alkyl med 1-6 carbonatomer, eller et alkalimetal-, jordalkalimetal- eller ammoniumsalt af syren.
Af alkylgrupper med 1-6 carbonatomer kan nævnes ligekædede eller forgrenede grupper, f.eks. methyl, ethyl, propyl, isopropyl eller tert. butyl.
10 Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man i
5,6-stillingen dehydrogenerer den tilsvarende 1,4,5,6-tetrahydroni-cotinsyre eller en ester deraf med den almene formel II
O
COOR
Cu" ^ 2 148082 hvor R har den ovenfor anførte betydning, og, om ønsket, hydrolyserer en vunden C^_g-alkylester og/eller omdanner den vundne syre til et alkalimetal-, jordalkalimetal- eller ammoniumsalt eller forestrer med en alkanol med 1-6 carbonatomer.
5 Dehydrogeneringen ifølge opfindelsen af en forbindelse med formlen II kan foretages på i og for sig kendt måde, hensigtsmæssigt med en substitueret benzoquinon såsom 2,3-dichlor-5,6-dicyan-1,4-benzo-quinon (DDQ) eller tetrachlor-l,4-benzoquinon (chloranil) i et inert organisk opløsningsmiddel, f.eks. methylenchlorid, benzen eller dio-10 xan, og inden for et temperaturområde, der ligger mellem stuetemperatur og reaktionsblandingens tifbagesvafingstemperatur. Generelt gås der frem på den måde, at man til opløsningen af tetrahydronico-ti nsy rederi vatet drypper en opløsning af substitueret benzoquinon, idet det påses, at ækvimolekylære mængder omsættes. Ved ufarvet 15 udgangsmateriale kan reaktionens afslutning let erkendes ved den indtrædende farvning af reaktionsblandingen. Reaktionsproduktet kan på sædvanlig måde isoleres fra blandingen og f.eks. renses ved omkrystallisation eller ved chromatografi.
Både forestringen af en forbindelse med formlen I, hvor R er hy-20 drogen, eller hydrolysen af en forbindelse med formlen I, hvor R er fx methyl, til dannelse af syren og omdannelsen deraf til salte, foretages på i og for sig kendt måde.
Udgangsforbindelserne med formlen II kan fremstilles ud fra 2-naph-thylaldehyd ifølge nedenstående reaktionsskema.
25 Mellemprodukterne med den almene formel II er hidtil ukendte.
Forbindelserne med formlen I er farmakologisk virksomme. De har især stimulerende virkning på centralnervesystemet, og de udmærker sig ved at have ringe akut toxicitet. Således er f.eks. 1-ethyl-1,4-dihy-dro-6-(2-naphthyl)-4-oxonicotinsyre virkningsmæssigt betydeligt 30 overlegen og mindre toxisk end 8-amino-1,2,3,4-tetrahydro-2-me-thyl-4-phenyl-isoquinolin (Nomifensin), medens den omhandlede forbindelse på fordelagtig måde udmærker sig fremfor d-amphetamin og d-methamph'etamin ved at være betydelig mindre toxisk ved omtrentlig 148082 3 lige så stærk virkning (jfr. Tabel I). De i tabellen angivne værdier er fundet ved en iagttagelsestid på 24 timer.
Fra J. Het. Chem., 1977, s. 477, kendes 1-ethyl-1,4-dihydro-5(eller 6)-phenyl(eller methyl)-4-oxonicotinsyrer, af hvilke man skulle for-5 vente en antibakteriel virkning. De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser adskiller sig strukturelt fra de nævnte forbindelser ved i 6-stillingen at indeholde en naphthylgruppe og virkningsmæssigt ved at have indvirkning på centralnervesystemet.
4 148082
Reaktionsskema @§r: Λϊ-
VII ®Br VI
o o >s_ >s. JL .cooch3 >\yv/κΑ/°00Η3
V ^Jk^QC^ IV I
0CH3 •^N»h2 o νΝ^ΟΟΟΟΗ3 0 .
dmp (OK^
Ilb HO/'HgO 'Nw o ' . dd&N* o
Jk^.COOH >S^COOCH3 @ojV . β3@ιχ! «a \ Ib DDQ\ I M0^/^ N J^^coo» / / .i J / .
©@r\ la 5 148082
Tabel I
Forbindelse LD^-Værdi "Turning rat-test" * (mg/kg) minimal aktiv dosis (mus) (mg/kg) intraperito- 5 nealt 1-ethyl-1,4-dihydro-6-(2-naph- thyl)-4-oxonicotinsyre 2500-5000 p.o. 1
Nomifensin 300-600 p.o. 3 10 d-amphetamin. 1/2 HjSO^ 35 p.o. 1 14 i.v.
22 s.c.
d-methamphetamin.HCI 9,5 i.v. 1 14 s.c.
15 _ * Arch. int. Pharmacodyn. Ther. 2/7, 118-130 (1975).
De omhandlede forbindelser med formlen I kan derfor i form af farmaceutiske præparater med direkte eller forsinket frigørelse af aktivstoffet i blanding med et til oral eller parenteral applikation egnet orga-20 nisk eller uorganisk inert bærestof, f.eks. vand, gelatine, gummi arabicum, lactose, stivelse, magnesiumstearat, talkum, vegetabilske olier, polyalkylenglycoler eller vaseline, anvendes til stimulation af centralnervesystemet.
Fremgangsmåden ifølge opfindelsen belyses nærmere ved nedenstående 25 eksempel:
EKSEMPEL
12 g (38,8 millimol) methyl-2-[(ethylamino)methylen]-5-(2-naphthyl)- 3-oxo-4-pentenoat opløses i 100 ml dimethylformamid og omrøres i 4 timer ved 150°C. Efter afdampning af opløsningsmidlet under høj- 6 148082 vakuum ved 60°C fås 12 g af en mørkerød, sej olie, som opløses i 60 ml toluen. Der opvarmes til kogning under tilbagesvaling, og en opslæmning af 10,6 g (42,6 millimol) chloranil i 50 ml toluen tildryppes langsomt. Til den vundne reaktionsblanding sættes ethylacetat, og der 5 udrystes tre gange med iskold 3N saltsyreopløsning. De sure udtræk indstilles på pH-værdi 6 ved tilsætning af 4N natriumhydroxidopløsning under afkøling, og der ekstraheres tre gange med methylenchio-rid. De organiske ekstrakter vaskes med mættet kogsaltopløsning, tørres over natriumsulfat og inddampes. Der fås 10 g af en brunlig 10 olie, som krystalliseres af ether/methanol, hvorved der fås 8,7 g (73% af det teoretiske) 1-ethyl-1,4-dihydro-6-(2-naphthyl)-4-oxonicotinsy-remethylestér i form af farveløse krystaller med smeltepunkt 138-139°C.
3,8 g 1-ethyl-l,4-dihydro-6-(2-naphthyl)4-oxo-nicotinsyremethylester 15 opløses i 10 ml methanoi og tilsættes 20 ml IN natriumhydroxidopløsning. Efter 15 minutters omrøring ved stuetemperatur ekstraheres reaktionsblandingen to gange med ethylacetat, og den vandige fase neutraliseres med IN s'altsyreopløsning under afkøling. Den derved udfældede frie syre frasuges, vaskes med koldt vand og ether og 20 omkrystalliseres af ethanol/methylenchlorid. Der fås 3,1 g (85,5% af det teoretiske) 1-ethyl-1,4-dihydro-6-(2-naphthyl)4-oxonicotinsyre i form af farveløse krystaller med smeltepunkt 209-210°C.
Udgangsmaterialet fremstilles på følgende måde:
Til en opløsning af 25 g (0,16 mol) 1-naphthylaldehyd og 78 g (0,165 25 mol) 2-methoxy-3-(methoxycarbonyl)allyltriphenylphosphoniumbromid i 300 ml methylenchlorid dryppes under omrøring ved stuetemperatur 84 ml 50%'s natriumhydroxidopløsning. Efter 3 timers omrøring ved stuetemperatur og 1 times omrøring ved 40°C skilles faserne. Den vandige fase ekstraheres to gange med methylenchlorid, og de samlede orga-30 niske faser vaskes neutrale med vand. Efter tørring over natriumsulfat og afdampning af opløsningsmidlet fås en viskos, lysegul olie, som delvis krystalliserer. Blandingen digereres med ether/ethylacetat, inddampes og omkrystalliseres af methanol. Der fås 29,4 g (68,5% af det teoretiske) methyf-3-methoxy-5-(2-naphthyl)-2,4-pentadienoat i 35 form af farveløse krystaller med smeltepunkt 94-96°C.
Claims (2)
148082 Til en opløsning af 23,5 g (87,7 millimol) methyl-3-methoxy-5-(2-naphthyl)-2,4-pentadienoat i 500 ml methanol sættes 50 ml koncentreret saltsyre. Efter ca. 3 minutters omrøring ved stuetemperatur udfældes et hvidt, krystallinsk produkt, som frafiltreres, vaskes med 5 koldt vand og opløses i methylenchlorid. Den organiske fase udrystes to gange med iskold, mættet natriumhydrogencarbonatopløsning, tørres over natriumsulfat og inddampes. Efter omkrystallisation af den krystallinske remanens af methanol fis 20,8 g (93% af det teoretiske) methyl-5-(2-naphthyl)-3-oxo-4-pentenoat i form af farveløse krystaller 10 med smeltepunkt 86-87°C. 9 g (35,4 millimol) methyl-5-(2-naphthyl)3-oxo-4-pentenoat og 4,7 g (39 millimol) dimethylformamid-dimethylacetal opløses i 100 ml toluen og omrøres ved 60°C i 22 timer. Efter afkøling inddampes reaktionsblandingen. Der fås ca. 10 g af en mørkerød, sej olie, som tilsættes en 15 opløsning af 100 g ethylamin i 1 liter toluen. Reaktionsblandingen omrøres i 20 timer ved stuetemperatur og inddampes, og råproduktet renses ved søjlechromatografi (silicagel, methylenchlorid/methanol i volumenforholdet 19:1). Efter omkrystallisation af ether/pentan fås 6,0 g (55% af det teoretiske) methyl-2-[(ethylamino)methylen]-5-(2-20 naphthyl)-3-oxo-4-pentenoat i form af lyse gullige krystaller med smeltepunkt 80-82°C.
1. Analogifremgangsmåde til fremstilling af 1-ethyl-1,4-dihydro-6-(2-naphthyl)-4-oxonicotinsyre eller estere deraf med den almene 25 formel I o COOR οχί
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH655579 | 1979-07-13 | ||
| CH655579 | 1979-07-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK287080A DK287080A (da) | 1981-01-14 |
| DK148082B true DK148082B (da) | 1985-02-25 |
Family
ID=4311435
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK287080AA DK148082B (da) | 1979-07-13 | 1980-07-02 | Analogifremgangsmaade til fremstilling af 1-ethyl-1,4-dihydro-6-(2-naphthyl)-4-oxo-nicotinsyrederivater |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US4278798A (da) |
| EP (1) | EP0023593B1 (da) |
| JP (1) | JPS5615269A (da) |
| KR (1) | KR840001034B1 (da) |
| AR (1) | AR225447A1 (da) |
| AT (1) | ATE2520T1 (da) |
| AU (1) | AU537900B2 (da) |
| CA (1) | CA1125762A (da) |
| DE (1) | DE3062022D1 (da) |
| DK (1) | DK148082B (da) |
| ES (1) | ES493355A0 (da) |
| FI (1) | FI802097A7 (da) |
| GR (1) | GR69304B (da) |
| HU (1) | HU180589B (da) |
| IL (1) | IL60513A (da) |
| MC (1) | MC1335A1 (da) |
| NO (1) | NO802099L (da) |
| NZ (1) | NZ194258A (da) |
| PH (1) | PH16046A (da) |
| PT (1) | PT71542B (da) |
| ZA (1) | ZA804079B (da) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1110234A (en) * | 1978-01-18 | 1981-10-06 | Hoffmann-La Roche Limited | 4-pyridone-3-carboxylic acids and process for the preparation thereof |
| US4649157A (en) * | 1986-03-28 | 1987-03-10 | G. D. Searle & Co. | Pharmaceutical compositions containing 5-phenyl-1,3-dioxoalkenyl compounds |
| WO2015099107A1 (ja) | 2013-12-26 | 2015-07-02 | 塩野義製薬株式会社 | 含窒素６員環誘導体およびそれらを含有する医薬組成物 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4051142A (en) * | 1976-05-24 | 1977-09-27 | Rohm And Haas Company | 1-Aryl-4-pyridones |
| EP0001041A3 (en) * | 1977-07-27 | 1979-06-27 | Sandoz Ag | Alpha(pyridonecarboxylamino)-alpha substituted acetamido penicillins and -cephalosporins, process for their preparation, their use in pharmaceuticals; pyridones used in the process |
| CA1110234A (en) * | 1978-01-18 | 1981-10-06 | Hoffmann-La Roche Limited | 4-pyridone-3-carboxylic acids and process for the preparation thereof |
-
1980
- 1980-06-09 CA CA353,626A patent/CA1125762A/en not_active Expired
- 1980-06-11 MC MC801452A patent/MC1335A1/fr unknown
- 1980-07-01 FI FI802097A patent/FI802097A7/fi not_active Application Discontinuation
- 1980-07-02 DK DK287080AA patent/DK148082B/da unknown
- 1980-07-07 AU AU60153/80A patent/AU537900B2/en not_active Ceased
- 1980-07-07 ZA ZA00804079A patent/ZA804079B/xx unknown
- 1980-07-07 US US06/166,506 patent/US4278798A/en not_active Expired - Lifetime
- 1980-07-07 NZ NZ194258A patent/NZ194258A/en unknown
- 1980-07-07 IL IL60513A patent/IL60513A/xx unknown
- 1980-07-07 AR AR281682A patent/AR225447A1/es active
- 1980-07-07 HU HU80801689A patent/HU180589B/hu unknown
- 1980-07-08 EP EP80103895A patent/EP0023593B1/de not_active Expired
- 1980-07-08 DE DE8080103895T patent/DE3062022D1/de not_active Expired
- 1980-07-08 AT AT80103895T patent/ATE2520T1/de not_active IP Right Cessation
- 1980-07-09 PH PH24260A patent/PH16046A/en unknown
- 1980-07-11 NO NO802099A patent/NO802099L/no unknown
- 1980-07-11 JP JP9410780A patent/JPS5615269A/ja active Pending
- 1980-07-11 PT PT71542A patent/PT71542B/pt unknown
- 1980-07-11 GR GR62435A patent/GR69304B/el unknown
- 1980-07-12 KR KR1019800002785A patent/KR840001034B1/ko not_active Expired
- 1980-07-12 ES ES493355A patent/ES493355A0/es active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| FI802097A7 (fi) | 1981-01-01 |
| NO802099L (no) | 1981-01-14 |
| PT71542A (en) | 1980-08-01 |
| AU6015380A (en) | 1981-01-15 |
| ES8105712A1 (es) | 1981-06-16 |
| MC1335A1 (fr) | 1981-04-21 |
| KR840001034B1 (ko) | 1984-07-26 |
| PT71542B (en) | 1981-12-14 |
| EP0023593B1 (de) | 1983-02-16 |
| NZ194258A (en) | 1984-07-06 |
| AU537900B2 (en) | 1984-07-19 |
| DK287080A (da) | 1981-01-14 |
| ZA804079B (en) | 1981-07-29 |
| DE3062022D1 (en) | 1983-03-24 |
| ATE2520T1 (de) | 1983-03-15 |
| US4278798A (en) | 1981-07-14 |
| EP0023593A1 (de) | 1981-02-11 |
| IL60513A (en) | 1983-10-31 |
| CA1125762A (en) | 1982-06-15 |
| AR225447A1 (es) | 1982-03-31 |
| GR69304B (da) | 1982-05-14 |
| PH16046A (en) | 1983-06-02 |
| JPS5615269A (en) | 1981-02-14 |
| HU180589B (en) | 1983-03-28 |
| IL60513A0 (en) | 1980-09-16 |
| KR830003423A (ko) | 1983-06-20 |
| ES493355A0 (es) | 1981-06-16 |
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