DK155281B - Fremgangsmaade til fremstilling af 1,2-dihydro-6-methyl-2-oxo-5-(pyridinyl)nicotinonitriler - Google Patents
Fremgangsmaade til fremstilling af 1,2-dihydro-6-methyl-2-oxo-5-(pyridinyl)nicotinonitriler Download PDFInfo
- Publication number
- DK155281B DK155281B DK394182A DK394182A DK155281B DK 155281 B DK155281 B DK 155281B DK 394182 A DK394182 A DK 394182A DK 394182 A DK394182 A DK 394182A DK 155281 B DK155281 B DK 155281B
- Authority
- DK
- Denmark
- Prior art keywords
- pyridinyl
- methyl
- dihydro
- oxo
- pyridinylmethyl
- Prior art date
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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
- C07D213/60—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
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Description
DK 155281B
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af 1,2-dihydro-6-methyl-2-oxo-5-(pyridi-ny1)nicotinonitril, hvori pyridinylgruppen er 3- eller 4-pyridinyl og kan være substitueret med en eller to 5 lavere alkylgrupper. Disse forbindelser er lægemidler med kardiotonisk virkning.
USA patentskrift nr. 4 276 293 omhandler en fremgangsmåde til fremstilling af 1,2-dihydro-6-(lavere-alkyl)-2-oxo-5-(pyridinyl)nicotinonitril ved først at omsætte en pyridi-10 nylmethyl lavere-alkylketon med dimethylformamid-di-(lavere- alkyl)acetal til fremstilling af en 1-(pyridinyl)-2-(di-methylamino)ethenyl lavere-alkylketon og herefter omsætning af ketonen med α-cyanoacetamid. USA patentskrift nr. 4 223 149 omhandler en fremgangsmåde til fremstilling 15 af en 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinonitril ved omsætning af a-(pyridinyl)-3-C di-(lavere-alkyl) amino]-acrolein med malononitril i en lavere-alkanol.
Opfindelsen tilvejebringer en fremgangsmåde der er ejendommelig ved at pyridinylmethyl-methylketon, hvori pyridi-20 nylgruppen er 3- eller 4-pyridinyl og kan være substitue ret med en eller to lavere alkylgrupper, omsættes med ethoxymethylenmalononitril i en lavere-alkanol. I en foretrukken udførelsesform opvarmes 4(eller 3)-pyridinylmethyl-methylketon og ethoxymethylenmalononitril i ethanol 25 til fremstilling af 1,2-dihydro-6-methyl-2-oxo-5-[4 (eller 3)-pyridinyl]nicotinonitril. I en særlig foretrukken udførelsesform opvarmes 4-pyridinylmethyl-methylketon og ethoxymethylenmalononitril under tilbagesvaling i ethanol til fremstilling af 1,2-dihydro-6-methyl-2-oxo-30 5-(4-pyridinyl)nicotinonitril.
Udtrykket "lavere-alkyl" anvendt i den foreliggende beskrivelse med krav, f.eks. som en substituent på "pyridinyl", betyder alkylgrupper med fra 1-4 carbonatomer, 2
DK 155281 B
der kan være lige eller forgrenede som f.eks. methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl eller iso-butyl.
Udtrykket "lavere-alkanol" anvendt i foreliggende be-5 skrivelse med krav betyder en alkanol med fra 1-4 carbonatomer som f.eks. methanol, ethanol, n-propanol, isopropanol og n-butanol.
Udtrykket "pyridinyl" anvendt i foreliggende beskrivelse med krav f.eks. i mellemprodukt pyridinylmethyl-methyl-10 ketonforbindelsen og som substituenten i nicotinonitril- forbindelsen i den omhandlede fremgangsmåde betyder 4- eller 3-pyridinyl. Den kan være substitueret med én eller to "lavere-alkyl" substituenter og er da f.eks. 2-methyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-13 3-pyridinyl, 2,6-dimethyl-4-pyridinyl, 6-methyl-3-pyri- dinyl (også betegnet 2-methyl-5-pyridinyl), 2,3-dimethyl- 4-pyridinyl, 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridi-nyl, 2-n-butyl-4-pyridinyl, 2,6-diethyl-4-pyridiny1 og 2,6-diisopropyl-4-pyridinyl.
20 Molekylopbygningen af forbindelsen fremstillet ved frem gangsmåden ifølge opfindelsen bestemtes på basis af infrarøde-, kernemagnetiske resonans- og massespektre, ved chro-matografisk mobilitet og ved sammenligning mellem beregnede og fundne værdier af elementaranalyser i de pågældende 25 eksempler.
Den omhandlede fremgangsmåde udføres sædvanligvis ved at opvarme reaktanterne dvs. en pyridinylmethyl-methylketon og ethoxymethylenmalononitril i en lavere-alkanol ved ca. 60 °C til 120 °C, fortrinsvis ved ca. 75 °C til 100 °C, fortrins-50 vis i ethanol, der koger med.tilbagesvaling.
Fremgangsmåden ifølge opfindelsen er i besiddelse af fordele frem for de tidligere kendte fremgangsmåder angivet i 3
DK 155281 B
USA patentskrift nr. 4 276 273. Ued den omhandlede fremgangsmåde anvendes som et mellemprodukt ethoxymethylenmalo-nonitril, der er billigere og lettere tilgængeligt i de store mængder, der er nødvendig for produktion i stor måle-3 stok eller ved kommerciel udnyttelse, end mellemproduktet dimethylformamid-dimethylacetal anvendt i det omtalte USA patentskrift. Den omhandlede fremgangsmåde indeholder også færre trin, hvorved der anvendes færre kemikalier, kræves mindre tid, og fremgangsmåden er billigere at udføre. I 10 den tidligere kendte fremgangsmåde, der anvender a-cyano-acetamid, må denne foretages i alkali, hvilket kræver et yderligere trin til at syrne «åen alkaliske reaktionsblanding for at opnå det ønskede produkt. I modsætning hertil kræves til den omhandlede fremgangsmåde intet alkali eller 15 syre.
Følgende eksempler illustrerer opfindelsen nærmere.
EKSEMPEL 1 ~
En blanding indeholdende 13,5 g 4-pyridinylmethyl-methyl-keton, 12,2 g ethoxymethylenmalononitril og 100 ml ethanol 20 opvarmedes med tilbagesvaling under omrøring i 5 timer, hvorefter blandingen henstod for at afkøle til stuetemperatur. Den udskilte krystallinske forbindelse opsamledes, vaskedes med kold ethanol og tørredes i en vakuumovn ved 60 °C, hvorved der opnåedes 14,2 g 1,2-dihydro-6-methyl-2-25 oxo-5-(4-pyridinyl)nicotinonitril med smp. !> 300 °C. Det kernemagnetiske resonans infrarøde spektrum af denne forbindelse var identisk med de tilsvarende spektre af samme forbindelse, der var fremstillet ved en anden fremgangsmåde dvs. ved omsætning af l-(4-pyridinyl)-2-(dimethyl-30 amino)ethenylmethylketon med α-cyanoacetamid. Også et blan dingssmeltepunkt med denne forbindelse fremstillet ved den anden fremgangsmåde viste ingen smeltepunktsnedsættelse.
DK 155281 B
4
Ved at anvende fremgangsmåden i eksempel 1 men i stedet for 4-pyridinylmethyl-methylketon at anvende en molær ækvivalent mængde af den pågældende (alkyl)pyridinylmethyl-methylketon fremstilledes de tilsvarende 1,2-dihydro-6-methyl-2-oxo-5-5 [(alkyl)pyridinyl]nicotinonitriler angivet i eksemplerne 2-5.
EKSEMPEL 2 1.2- Dihydro-6-methyl-2-oxo-5-(3-pyridinyl)nicotinonitril under anvendelse af 3-pyridinylmethyl-methylketon.
10 EKSEMPEL 3 1.2- Dihydro-6-methyl-5-(2-methyl-4-pyridinyl)-2-oxonicoti-nonitril under anvendelse af (2-methyl-4-pyridinyl)methyl-methylketon.
EKSEMPEL 4 15 5-(2-Ethyl-4-pyridinyl)-l,2-dihydro-6-methyl-2-oxonicotino-nitril under anvendelse af (2-ethyl-4-pyridinyl)methyl-methylketon.
EKSEMPEL 5 1.2- Dihydro-6-methyl-5-(2,6-dimethyl-4-pyridinyl)-2-oxo-20 nicotinonitril under anvendelse af (2,6-dimethyl-4-pyridi- nyl)methyl-methylketon.
Claims (3)
1. Fremgangsmåde til fremstilling af 1,2-dihydro-6-methyl-2-OXO-5-(pyridinyl)nicotinonitril, hvori pyridinylgruppen er 3- eller 4-pyridinyl og kan være substitueret med 5 en eller to alkylgrupper, kendetegnet ved, at man omsætter pyridinylmethyl-methylketon, hvori pyridinylgruppen er 3- eller 4-pyridinyl og kan være substitueret med en eller to alkylgrupper, med ethoxymethylenmalononitril i en alkanol.
2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at 4(eller 3)-pyridinylmethyl-methylketon og ethoxymethylenmalononitril opvarmes i ethanol til fremstilling af 1,2-dihydro-6-methyl-2-oxo-5[4(eller 3)-pyridinyl]nico-tinonitril.
3. Fremgangsmåde ifølge krav 1, kendetegnet ved, at 4-pyridinylmethyl-methylketon og ethoxymethylenmalononitril opvarmes med tilbagesvaling i ethanol til fremstilling af 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)-nicotinonitril.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/303,178 US4347363A (en) | 1981-09-17 | 1981-09-17 | Process for preparing 1,2-dihydro-6-methyl-2-oxo-5-(pyridinyl)nicotinonitriles |
| US30317881 | 1981-09-17 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK394182A DK394182A (da) | 1983-03-18 |
| DK155281B true DK155281B (da) | 1989-03-20 |
| DK155281C DK155281C (da) | 1989-07-24 |
Family
ID=23170862
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK394182A DK155281C (da) | 1981-09-17 | 1982-09-03 | Fremgangsmaade til fremstilling af 1,2-dihydro-6-methyl-2-oxo-5-(pyridinyl)nicotinonitriler |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US4347363A (da) |
| EP (1) | EP0075116B1 (da) |
| JP (1) | JPS5865277A (da) |
| AU (1) | AU548671B2 (da) |
| CA (1) | CA1167851A (da) |
| DE (1) | DE3263757D1 (da) |
| DK (1) | DK155281C (da) |
| GR (1) | GR78049B (da) |
| IE (1) | IE53551B1 (da) |
| NZ (1) | NZ201536A (da) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ204175A (en) * | 1982-05-24 | 1985-12-13 | Sterling Drug Inc | Preparation of 1,2-dihydro-6-(lower alkyl)-2-oxo-5-(pyridinyl)-nicotinonitriles and nicotinamides;and pyridine intermediates therefor |
| US4469871A (en) * | 1982-05-24 | 1984-09-04 | Sterling Drug Inc. | Process for preparing 2-(lower-alkoxy)-1-(pyridinyl) ethenyl lower-alkyl ketones |
| US4463008A (en) * | 1982-11-10 | 1984-07-31 | Sterling Drug Inc. | 2-Alkoxy-5-(pyridinyl)pyridines and cardiotonic use thereof |
| US4769380A (en) * | 1983-04-29 | 1988-09-06 | Merrell Dow Pharmaceuticals Inc. | Cardiotonic 5-benzoyl-1,2-dihydro-2-oxo-3-pyridinecarboxylates |
| EP0200024B1 (de) | 1985-04-30 | 1992-07-01 | ARZNEIMITTELWERK DRESDEN GmbH | 3-Cyan-pyridine, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung |
| US4681944A (en) * | 1985-06-11 | 1987-07-21 | Ippolito Robert M | Process for preparing certain 1-lower alkanoyl or benzoyl-4-(lower alkanoyl or benzoyl-methylidene)-1,4-dihydropyridines or acid addition salts thereof |
| US5595985A (en) * | 1989-03-10 | 1997-01-21 | Endorecherche Inc. | Combination therapy for prophylaxis and/or treatment of benign prostatic hyperplasia |
| US5372996A (en) * | 1989-03-10 | 1994-12-13 | Endorecherche, Inc. | Method of treatment of androgen-related diseases |
| EP0480950B1 (en) * | 1989-07-07 | 1999-03-24 | Endorecherche Inc. | Combination therapy for prophylaxis and/or treatment of benign prostatic hyperplasia |
| HUT60139A (en) * | 1989-07-07 | 1992-08-28 | Endorecherche Inc | Process for producing pharmaceutical composition suitable for treating prostate cancer connected with androgen |
| AU4258493A (en) * | 1992-05-21 | 1993-12-13 | Endorecherche Inc. | Inhibitors of testosterone 5alpha-reductase activity |
| US6118002A (en) * | 1999-03-02 | 2000-09-12 | Wyckoff Chemical Company, Inc. | Purification of 1,2-dihydro-6-alkyl-2-oxo-5-(pyridinyl)-nicotinonitriles |
| CN102558044A (zh) * | 2011-12-29 | 2012-07-11 | 方晏燕 | 米力农的结晶方法 |
| CN103664773A (zh) * | 2013-12-18 | 2014-03-26 | 南京易亨制药有限公司 | 米力农的制备方法和精制方法 |
| CN111377857B (zh) * | 2018-12-30 | 2023-04-18 | 鲁南制药集团股份有限公司 | 一种米力农的合成方法 |
| CN113493412A (zh) * | 2020-03-20 | 2021-10-12 | 鲁南制药集团股份有限公司 | 一种制备米力农的新工艺 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4223149A (en) * | 1979-07-26 | 1980-09-16 | Sterling Drug Inc. | Process for producing 3-cyano-5-(pyridinyl)-2(1H)-pyridinones |
| US4276293A (en) * | 1980-03-28 | 1981-06-30 | Sterling Drug Inc. | Compositions and their preparation |
-
1981
- 1981-09-17 US US06/303,178 patent/US4347363A/en not_active Expired - Lifetime
-
1982
- 1982-07-30 CA CA000408542A patent/CA1167851A/en not_active Expired
- 1982-08-03 IE IE1870/82A patent/IE53551B1/en not_active IP Right Cessation
- 1982-08-06 AU AU86917/82A patent/AU548671B2/en not_active Expired
- 1982-08-09 NZ NZ201536A patent/NZ201536A/en unknown
- 1982-08-12 GR GR69027A patent/GR78049B/el unknown
- 1982-08-19 DE DE8282107603T patent/DE3263757D1/de not_active Expired
- 1982-08-19 EP EP82107603A patent/EP0075116B1/en not_active Expired
- 1982-09-03 DK DK394182A patent/DK155281C/da active
- 1982-09-06 JP JP57155081A patent/JPS5865277A/ja active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| EP0075116B1 (en) | 1985-05-22 |
| IE53551B1 (en) | 1988-12-07 |
| EP0075116A1 (en) | 1983-03-30 |
| DK394182A (da) | 1983-03-18 |
| JPH0261948B2 (da) | 1990-12-21 |
| DE3263757D1 (en) | 1985-06-27 |
| AU548671B2 (en) | 1986-01-02 |
| GR78049B (da) | 1984-09-26 |
| IE821870L (en) | 1983-03-17 |
| DK155281C (da) | 1989-07-24 |
| US4347363A (en) | 1982-08-31 |
| NZ201536A (en) | 1985-01-31 |
| AU8691782A (en) | 1983-03-24 |
| CA1167851A (en) | 1984-05-22 |
| JPS5865277A (ja) | 1983-04-18 |
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