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
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- 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
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- naphthyl
- oxo
- methyl
- ethyl
- dihydro
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- 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, ***e
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- 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)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (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) | ES8105712A1 (da) |
| FI (1) | FI802097A (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 |
| US9988373B2 (en) | 2013-12-26 | 2018-06-05 | Shionogi & Co., Ltd. | Nitrogen-containing six-membered cyclic derivatives and pharmaceutical composition comprising the same |
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/xx unknown
- 1980-07-01 FI FI802097A patent/FI802097A/fi not_active Application Discontinuation
- 1980-07-02 DK DK287080AA patent/DK148082B/da unknown
- 1980-07-07 US US06/166,506 patent/US4278798A/en not_active Expired - Lifetime
- 1980-07-07 AU AU60153/80A patent/AU537900B2/en not_active Ceased
- 1980-07-07 NZ NZ194258A patent/NZ194258A/en unknown
- 1980-07-07 IL IL60513A patent/IL60513A/xx unknown
- 1980-07-07 HU HU80801689A patent/HU180589B/hu unknown
- 1980-07-07 AR AR281682A patent/AR225447A1/es active
- 1980-07-07 ZA ZA00804079A patent/ZA804079B/xx unknown
- 1980-07-08 EP EP80103895A patent/EP0023593B1/de not_active Expired
- 1980-07-08 AT AT80103895T patent/ATE2520T1/de not_active IP Right Cessation
- 1980-07-08 DE DE8080103895T patent/DE3062022D1/de not_active Expired
- 1980-07-09 PH PH24260A patent/PH16046A/en unknown
- 1980-07-11 GR GR62435A patent/GR69304B/el unknown
- 1980-07-11 JP JP9410780A patent/JPS5615269A/ja active Pending
- 1980-07-11 NO NO802099A patent/NO802099L/no unknown
- 1980-07-11 PT PT71542A patent/PT71542B/pt unknown
- 1980-07-12 KR KR1019800002785A patent/KR840001034B1/ko active
- 1980-07-12 ES ES493355A patent/ES8105712A1/es not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DK287080A (da) | 1981-01-14 |
| AU537900B2 (en) | 1984-07-19 |
| EP0023593B1 (de) | 1983-02-16 |
| CA1125762A (en) | 1982-06-15 |
| US4278798A (en) | 1981-07-14 |
| NO802099L (no) | 1981-01-14 |
| ZA804079B (en) | 1981-07-29 |
| KR830003423A (ko) | 1983-06-20 |
| ES493355A0 (es) | 1981-06-16 |
| HU180589B (en) | 1983-03-28 |
| ATE2520T1 (de) | 1983-03-15 |
| JPS5615269A (en) | 1981-02-14 |
| FI802097A (fi) | 1981-01-14 |
| IL60513A (en) | 1983-10-31 |
| PH16046A (en) | 1983-06-02 |
| GR69304B (da) | 1982-05-14 |
| NZ194258A (en) | 1984-07-06 |
| KR840001034B1 (ko) | 1984-07-26 |
| PT71542A (en) | 1980-08-01 |
| DE3062022D1 (en) | 1983-03-24 |
| MC1335A1 (fr) | 1981-04-21 |
| EP0023593A1 (de) | 1981-02-11 |
| AU6015380A (en) | 1981-01-15 |
| ES8105712A1 (es) | 1981-06-16 |
| IL60513A0 (en) | 1980-09-16 |
| AR225447A1 (es) | 1982-03-31 |
| PT71542B (en) | 1981-12-14 |
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