WO2001007415A1 - Method of producing pyridazine-3,6-dicarboxylic acid esters - Google Patents

Method of producing pyridazine-3,6-dicarboxylic acid esters Download PDF

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WO2001007415A1
WO2001007415A1 PCT/EP2000/007167 EP0007167W WO0107415A1 WO 2001007415 A1 WO2001007415 A1 WO 2001007415A1 EP 0007167 W EP0007167 W EP 0007167W WO 0107415 A1 WO0107415 A1 WO 0107415A1
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dicarboxylic acid
pyridazine
palladium
alkyl
acid esters
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PCT/EP2000/007167
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German (de)
French (fr)
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Yves Bessard
Roger Crettaz
Walter Brieden
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Lonza Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to a process for the preparation of pyridazine-3,6-dicarboxylic acid esters of the general formula
  • C] _ ⁇ o-alkyl here and below are to be understood to mean all linear or branched primary, secondary or tertiary alkyl groups having 1 to 10 carbon atoms, that is to say for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl , Pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.
  • C 3-8 cycloalkyl for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl to understand.
  • Aryl-d - ⁇ - alkyl is to be understood as meaning aryl-substituted 4-alkyl groups, aryl preferably being understood to mean phenyl or naphthyl.
  • aryl Groups are, for example, benzyl, 1-phenylethyl, 2-phenylethyl and 3-phenylpropyl.
  • Pyridazine-3,6-dicarboxylic acid esters are potential intermediates for the synthesis of active pharmaceutical ingredients which contain a pyridazine system (WO-A-9411373, WO-A-9603380, WO-A-9700863).
  • the previously known pyridazine-3,6-dicarboxylic acid esters (I) in which R is methyl or ethyl were obtained by esterifying pyridazine-3,6-dicarboxylic acid or from the corresponding 1,2,4,5-tetrazine-3 , 6-dicarboxylic acid esters Diels-Alder reaction and nitrogen elimination. These processes are not suitable for the economical production of large quantities.
  • R C ⁇ _ ⁇ o-alkyl, C 3 - 8 cycloalkyl or means can be prepared by reacting 3,6-dichloropyridazine in the presence of a palladium-phosphine complex and a base with carbon monoxide and an alcohol of the general formula R - OH (II), in which R has the meaning given above.
  • the starting material 3,6-dichloropyridazine is easily accessible by chlorination of maleic acid hydrazide (3,6-dihydroxypyridazine).
  • a palladium complex of a diphosphine is preferably used as the palladium-phosphine complex.
  • Suitable ferrocenyldiphosphines are preferably 1,2-disubstituted or 1,1'-disubstituted ferrocenes in which the substituents are or contain phosphino groups.
  • L, l'-bis (diphenylphosphino) ferrocene is very particularly preferred.
  • the palladium-phosphine complex is preferably generated in situ from the corresponding phosphine and a soluble palladium ( ⁇ ) salt.
  • Palladium ( ⁇ ) acetate is preferably used as the soluble palladium ( ⁇ ) salt.
  • Weak bases are generally suitable as bases; alkali metal acetates or alkali metal carbonates are preferably used.
  • a particularly preferred base is sodium acetate.
  • the process according to the invention can be carried out in inert polar solvents such as tetrahydrofuran, but the reaction is preferably carried out in excess alcohol (II) as solvent.
  • inert polar solvents such as tetrahydrofuran
  • the reaction temperature is advantageously 20-200 ° C, preferably 50-150 ° C.
  • the process according to the invention is advantageously carried out in a pressure-resistant reactor, for example an autoclave, under elevated carbon monoxide pressure.
  • the pyridazine-3,6-dicarboxylic acid itself can also be easily obtained by hydrolysis of the pyridazine-3,6-dicarboxylic acid esters which can be prepared according to the invention.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a method of producing pyridazine-3,6-dicarboxylic acid esters of the general formula (I), wherein R represents C1-10 alkyl, C3-8 cycloalkyl or aryl-C1-4-alkyl, by reacting 3,6-dichloropyridazine with carbon monoxide and alcohols R-OH in the presence of palladium-phosphine complexes and bases. The invention also relates to novel pyridazine-3,6-dicarboxylic acid esters (I), wherein R represents C3-10 alkyl, C3-8 cycloalkyl or aryl-C1-4-alkyl. The pyridazine-3,6-dicarboxylic acid esters (I) are the potential intermediates for the synthesis of pharmaceutical active substances.

Description

Verfahren zur Herstellung von Pyridazin-3,6-dicarbonsäureesternProcess for the preparation of pyridazine-3,6-dicarboxylic acid esters
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von Pyridazin-3,6-di- carbonsäureestern der allgemeinen FormelThe present invention relates to a process for the preparation of pyridazine-3,6-dicarboxylic acid esters of the general formula
Figure imgf000002_0001
Figure imgf000002_0001
worin R d-io-Alkyl, C3_g-Cycloalkyl oder
Figure imgf000002_0002
bedeutet, sowie neue Pyridazin- 3,6-dicarbonsäureester (I).wherein R d-io-alkyl, C 3 _g-cycloalkyl or
Figure imgf000002_0002
means, as well as new pyridazine-3,6-dicarboxylic acid esters (I).
Unter C]_ιo- Alkyl sind hier und im folgenden alle linearen oder verzweigten primären, sekundären oder tertiären Alkylgruppen mit 1 bis 10 Kohlenstoffatomen zu verstehen, also beispielsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sec-Butyl, tert-Butyl, Pentyl, Isopentyl, Neopentyl, Hexyl, Heptyl, Octyl, Nonyl, Decyl usw.C] _ιo-alkyl here and below are to be understood to mean all linear or branched primary, secondary or tertiary alkyl groups having 1 to 10 carbon atoms, that is to say for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl , Pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.
Unter C3-8-Cycloalkyl sind beispielsweise Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl oder Cyclooctyl zu verstehen.Among C 3-8 cycloalkyl for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl to understand.
Unter Aryl-d-^-alkyl sind arylsubstituierte _4- Alkylgruppen zu verstehen, wobei unter Aryl vorzugsweise Phenyl oder Naphthyl zu verstehen ist. Arylsubstituierte
Figure imgf000002_0003
gruppen sind beispielsweise Benzyl, 1-Phenylethyl, 2-Phenylethyl und 3-Phenylpropyl.Aryl-d - ^ - alkyl is to be understood as meaning aryl-substituted 4-alkyl groups, aryl preferably being understood to mean phenyl or naphthyl. aryl
Figure imgf000002_0003
Groups are, for example, benzyl, 1-phenylethyl, 2-phenylethyl and 3-phenylpropyl.
Pyridazin-3,6-dicarbonsäureester sind potentielle Zwischenprodukte für die Synthese von pharmazeutischen Wirkstoffen, die ein Pyridazinsystem enthalten (WO-A-9411373, wO-A-9603380, WO-A-9700863). Die bisher bekannten Pyridazin-3,6-dicarbonsäureester (I), in denen R Methyl oder Ethyl ist, wurden durch Veresterung der Pyridazin-3,6-di- carbonsäure oder aus den entsprechenden l,2,4,5-Tetrazin-3,6-dicarbonsäureestern durch Diels-Alder-Reaktion und Stickstoffeliminierung hergestellt. Diese Verfahren sind für die wirtschaftliche Herstellung grösserer Mengen nicht geeignet.Pyridazine-3,6-dicarboxylic acid esters are potential intermediates for the synthesis of active pharmaceutical ingredients which contain a pyridazine system (WO-A-9411373, WO-A-9603380, WO-A-9700863). The previously known pyridazine-3,6-dicarboxylic acid esters (I) in which R is methyl or ethyl were obtained by esterifying pyridazine-3,6-dicarboxylic acid or from the corresponding 1,2,4,5-tetrazine-3 , 6-dicarboxylic acid esters Diels-Alder reaction and nitrogen elimination. These processes are not suitable for the economical production of large quantities.
Aufgabe der vorliegenden Erfindung war es, ein für die Durchführung im technischen Massstab geeignetes Verfahren zur Herstellung von Pyridazin-3,6-dicarbonsäureestern (I) bereitzustellen, mit dem auch bisher nicht bekannte Verbindungen dieser Klasse herstellbar sind.It was an object of the present invention to provide a process for the preparation of pyridazine-3,6-dicarboxylic acid esters (I) which is suitable for being carried out on an industrial scale and by means of which compounds of this class which have not hitherto been known can also be prepared.
Erfindungsgemäss wird diese Aufgabe durch das Verfahren nach Patentanspruch 1 gelöst.According to the invention, this object is achieved by the method according to claim 1.
Es wurde gefunden, dass Pyridazin-3,6-dicarbonsäureester der allgemeinen FormelIt has been found that pyridazine-3,6-dicarboxylic acid ester has the general formula
Figure imgf000003_0001
Figure imgf000003_0001
worin R Cι_ιo-Alkyl, C3-8-Cycloalkyl oder
Figure imgf000003_0002
bedeutet, dadurch hergestellt werden können, dass 3,6-Dichlorpyridazin in Gegenwart eines Palladium-Phosphin- Komplexes und einer Base mit Kohlenmonoxid und einem Alkohol der allgemeinen Formel R — OH (II), worin R die oben genannte Bedeutung hat, umgesetzt wird.wherein R Cι_ιo-alkyl, C 3 - 8 cycloalkyl or
Figure imgf000003_0002
means can be prepared by reacting 3,6-dichloropyridazine in the presence of a palladium-phosphine complex and a base with carbon monoxide and an alcohol of the general formula R - OH (II), in which R has the meaning given above.
Das Ausgangsmaterial 3,6-Dichlorpyridazin ist durch Chlorierung von Maleinsäure- hydrazid (3,6-Dihydroxypyridazin) leicht zugänglich.The starting material 3,6-dichloropyridazine is easily accessible by chlorination of maleic acid hydrazide (3,6-dihydroxypyridazine).
Als Palladium-Phosphin-Komplex wird vorzugsweise ein Palladiumkomplex eines Diphosphins eingesetzt.A palladium complex of a diphosphine is preferably used as the palladium-phosphine complex.
Besonders bevorzugte Diphosphine sind Bis-(diphenylphosphino)alkane der Formel (C6H5)2P — (CH2)„ — P(C6H5)2 mit n = 3 bis 5, also l,3-Bis(diphenylphosphino)propan, l,4-Bis(diphenylphosphino)butan und l,5-Bis(diphenylphosphino)pentan, sowieParticularly preferred diphosphines are bis (diphenylphosphino) alkanes of the formula (C 6 H 5 ) 2 P - (CH 2 ) "- P (C 6 H 5 ) 2 with n = 3 to 5, ie 1,3-bis (diphenylphosphino) )propane, 1,4-bis (diphenylphosphino) butane and 1,5-bis (diphenylphosphino) pentane, and
Ferrocenyldiphosphine.Ferrocenyldiphosphines.
Als Ferrocenyldiphosphine eignen sich vorzugsweise 1,2-disubstituierte oder 1,1 '-di- substituierte Ferrocene, in denen die Substituenten Phosphinogruppen sind oder solche enthalten. Ganz besonders bevorzugt ist l,l'-Bis(diphenylphosphino)ferrocen.Suitable ferrocenyldiphosphines are preferably 1,2-disubstituted or 1,1'-disubstituted ferrocenes in which the substituents are or contain phosphino groups. L, l'-bis (diphenylphosphino) ferrocene is very particularly preferred.
Der Palladium-Phosphin-Komplex wird vorzugsweise in situ aus dem entsprechenden Phosphin und einem löslichen Palladium(π)salz erzeugt.The palladium-phosphine complex is preferably generated in situ from the corresponding phosphine and a soluble palladium (π) salt.
Als lösliches Palladium(π)salz wird vorzugsweise Palladium(π)acetat eingesetzt.Palladium (π) acetate is preferably used as the soluble palladium (π) salt.
Als Basen eignen sich allgemein schwache Basen, vorzugsweise werden Alkaliacetate oder Alkalicarbonate eingesetzt.Weak bases are generally suitable as bases; alkali metal acetates or alkali metal carbonates are preferably used.
Eine besonders bevorzugte Base ist Natriumacetat.A particularly preferred base is sodium acetate.
Das erfindungsgemässe Verfahren kann in inerten polaren Lösungsmitteln wie beispielsweise Tetrahydrofuran durchgeführt werden, vorzugsweise wird die Umsetzung jedoch in überschüssigem Alkohol (II) als Lösungsmittel durchgeführt.The process according to the invention can be carried out in inert polar solvents such as tetrahydrofuran, but the reaction is preferably carried out in excess alcohol (II) as solvent.
Die Reaktionstemperatur liegt vorteilhaft bei 20-200 °C, vorzugsweise bei 50-150 °C. Das erfindungsgemässe Verfahren wird vorteilhaft in einem druckfesten Reaktor, beispielsweise einem Autoklaven, unter erhöhtem Kohlenmonoxiddruck durchgeführt.The reaction temperature is advantageously 20-200 ° C, preferably 50-150 ° C. The process according to the invention is advantageously carried out in a pressure-resistant reactor, for example an autoclave, under elevated carbon monoxide pressure.
Durch Hydrolyse der erfindungsgemäss herstellbaren Pyridazin-3,6-dicarbonsäureester ist auch die Pyridazin-3,6-dicarbonsäure selbst auf einfache Weise zugänglich. ie Pyridazin-3,6-dicarbonsäureester der allgemeinen FormelThe pyridazine-3,6-dicarboxylic acid itself can also be easily obtained by hydrolysis of the pyridazine-3,6-dicarboxylic acid esters which can be prepared according to the invention. he pyridazine-3,6-dicarboxylic acid ester of the general formula
Figure imgf000005_0001
Figure imgf000005_0001
worin R C -ι0- Alkyl, C3-8-Cycloalkyl oder
Figure imgf000005_0002
bedeutet, sind neue Verbindungen und ebenfalls Gegenstand der vorliegenden Erfindung.wherein RC -ι 0 - alkyl, C 3 - 8 cycloalkyl or
Figure imgf000005_0002
means, are new compounds and also the subject of the present invention.
Die folgenden Beispiele verdeutlichen die Durchführung des erfmdungsgemässen Verfahrens, ohne dass darin eine Einschränkung zu sehen ist.The following examples illustrate the implementation of the method according to the invention, without any limitation being seen therein.
Beispiel 1 3,6-DichlorpyridazinExample 1 3,6-dichloropyridazine
Unter Stickstoff wurde Maleinsäurehydrazid (25,1 g, 224 mmol) mit Phosphorylchlorid (300 ml) 5 h am Rückfluss gekocht, wobei die Temperatur langsam von 92 auf 108 °C anstieg. Anschliessend wurde das überschüssige Phosphorylchlorid im Vakuum abdestilliert und der Rückstand nach dem Abkühlen auf ein Gemisch aus 200 g Eis und 100 ml Wasser gegossen. Dann wurde langsam konzentrierte wässrige Ammoniaklösung zugege- ben, bis ein pH von 8,0 erreicht war. Der hellbraune Feststoff wurde abfiltriert, mit Wasser (2x100 ml) gewaschen und im Vakuum getrocknet (20 °C, 16 h). Das graubraune Rohprodukt (24,35 g, 73%) wurde zur Reinigung im Vakuum sublimiert (58 °C/0,03 mbar). Ausbeute: 65,4%, reinweisse Kristalle Schmp.: 67,5-68,5 °C Η NMR (CDC13): δ = 7,50 (s). Beispiel 2Maleic acid hydrazide (25.1 g, 224 mmol) was refluxed with phosphoryl chloride (300 ml) under nitrogen for 5 h, the temperature slowly increasing from 92 to 108 ° C. The excess phosphoryl chloride was then distilled off in vacuo and, after cooling, the residue was poured onto a mixture of 200 g of ice and 100 ml of water. Then concentrated aqueous ammonia solution was slowly added until a pH of 8.0 was reached. The light brown solid was filtered off, washed with water (2x100 ml) and dried in vacuo (20 ° C., 16 h). The gray-brown crude product (24.35 g, 73%) was sublimed for cleaning in vacuo (58 ° C / 0.03 mbar). Yield: 65.4%, pure white crystals mp: 67.5-68.5 ° C Η NMR (CDC1 3 ): δ = 7.50 (s). Example 2
Pyridazin-3,6-dicarbonsäurediethylesterPyridazine-3,6-dicarboxylic acid diethyl ester
Ein 100 ml- Autoklav aus rostfreiem Stahl mit Tefloneinsatz und Magnetrührer wurde nacheinander mit Ethanol (20 ml), Natriumacetat (2,46 g, 30 mmol), 3,6-DichlorpyridazinA 100 ml stainless steel autoclave with Teflon insert and magnetic stirrer was added sequentially with ethanol (20 ml), sodium acetate (2.46 g, 30 mmol), 3,6-dichloropyridazine
(1,49 g, 10 mmol), l, -Bis(diphenylphosphino)ferrocen (166 mg, 0,3 mmol) und Palla- dium(n)acetat (12 mg, 50 μmol) beschickt. Die Luft im Autoklaven wurde durch Kohlen- monoxid verdrängt und der Druck auf 15 bar eingestellt. Das Reaktionsgemisch wurde dann auf 100 °C (Aussentemperatur) erhitzt und bei dieser Temperatur 2 h gerührt. Dann wurde das Reaktionsgemisch auf Raumtemperatur abgekühlt und durch Celite® filtriert.(1.49 g, 10 mmol), 1, -bis (diphenylphosphino) ferrocene (166 mg, 0.3 mmol) and palladium (n) acetate (12 mg, 50 μmol). The air in the autoclave was displaced by carbon monoxide and the pressure was set to 15 bar. The reaction mixture was then heated to 100 ° C. (outside temperature) and stirred at this temperature for 2 hours. Then the reaction mixture was cooled to room temperature and filtered through Celite ® .
Das Filtrat wurde im Vakuum eingeengt und mit Ethylacetat/Hexan (v/v = 3:1) überThe filtrate was concentrated in vacuo and over with ethyl acetate / hexane (v / v = 3: 1)
Kieselgel chromatographiert („Flash-Chromatographie").Chromatographed silica gel ("flash chromatography").
Ausbeute: 2,04 g (91,0%)Yield: 2.04 g (91.0%)
Schmp.: 112,9-113,1 °C 1H NMR (CDC13): δ = 8,30 (s, 2H); 4,55 (q, 4H); 1 ,49 (t, 6H)M.p .: 112.9-113.1 ° C 1H NMR (CDC1 3 ): δ = 8.30 (s, 2H); 4.55 (q, 4H); 1, 49 (t, 6H)
MS (m/z): 225; 224 (M+); 180; 179; 152; 79.MS (m / z): 225; 224 (M + ); 180; 179; 152; 79th
Beispiel 3 Pyridazin-3,6-dicarbonsäurediisopropylesterExample 3 Diisopropyl pyridazine-3,6-dicarboxylate
Es wurde verfahren wie in Beispiel 2 beschrieben, jedoch wurde an Stelle von Ethanol Isopropylalkohol eingesetzt und die Reaktionstemperatur betrug 120 °C. Ausbeute: 1,90 g (75,3%) Schmp.: 121,3-122,0 °CThe procedure was as described in Example 2, but isopropyl alcohol was used instead of ethanol and the reaction temperature was 120 ° C. Yield: 1.90 g (75.3%) mp: 121.3-122.0 ° C
Η NMR (CDCI3): δ = 8,28 (s, 2H); 5,40 (sept., 2H); 1,47 (d, 12H) MS (m/z): 253; 252 (M+); 237; 209; 195; 166; 151; 121; 79; 59; 43.Η NMR (CDCI 3 ): δ = 8.28 (s, 2H); 5.40 (sept., 2H); 1.47 (d, 12H) MS (m / z): 253; 252 (M + ); 237; 209; 195; 166; 151; 121; 79; 59; 43rd
Beispiel 4Example 4
Pyridazin-3,6-dicarbonsäuredibutylesterPyridazine-3,6-dicarbonsäuredibutylester
Es wurde verfahren wie in Beispiel 2 beschrieben, jedoch wurde an Stelle von Ethanol Butanol eingesetzt.The procedure was as described in Example 2, but instead of ethanol Butanol used.
Ausbeute: 2,62 g (93,6%) Schmp.: 83,8-85,4 °CYield: 2.62 g (93.6%) mp: 83.8-85.4 ° C
1H NMR (CDC13): δ = 8,30 (s, 2H); 4,50 (t, 4H); 1,85 (quint., 4H); 1,50 (quint., 4H); 1,00 (t, 6H)1H NMR (CDC1 3 ): δ = 8.30 (s, 2H); 4.50 (t. 4H); 1.85 (quint., 4H); 1.50 (quint., 4H); 1.00 (t, 6H)
MS (m/z): 281; 280 (M+); 225; 207; 194; 180; 151; 135; 108; 79; 57; 41.MS (m / z): 281; 280 (M + ); 225; 207; 194; 180; 151; 135; 108; 79; 57; 41st
Beispiel 5 Pyridazin-3,6-dicarbonsäuredicycIohexyIesterExample 5 Pyridazine-3,6-dicarboxylic acid dicyclohexyl ester
Es wurde verfahren wie in Beispiel 2 beschrieben, jedoch wurde an Stelle von Ethanol Cyclohexanol eingesetzt und die Reaktionstemperatur betrug 120 °C. Ausbeute: 2,08 g (62,6%) Schmp.: 121-129 °CThe procedure was as described in Example 2, but cyclohexanol was used instead of ethanol and the reaction temperature was 120 ° C. Yield: 2.08 g (62.6%) mp: 121-129 ° C
1H NMR (CDCI3): δ - 8,28 (s, 2H); 5,18 (m, 2H); 2,1-1,1 (m, 20H) MS (m/z): 332 (M+); 251; 206; 169; 151; 124; 99; 83; 55.1H NMR (CDCI 3 ): δ - 8.28 (s, 2H); 5.18 (m. 2H); 2.1-1.1 (m, 20H) MS (m / z): 332 (M + ); 251; 206; 169; 151; 124; 99; 83; 55th
Beispiel 6Example 6
Pyridazin-3,6-dicarbonsäurePyridazine-3,6-dicarboxylic acid
Pyridazin-3,6-dicarbonsäurediethylester (1,12 g, 5,0 mmol) und Kaliumhydroxid (87%, 0,8 g, 12 mmol) wurden in Ethanol (35 ml) 2 h zum Rückfluss erhitzt. Das Lösungsmittel wurde abdestilliert und der Rückstand mit kaltem Wasser (100 ml) versetzt. Die so erhaltene Lösung wurde mit konzentrierter Salzsäure auf pH 3,0 angesäuert. Das ausgefallene Produkt wurde abfiltriert, mit Wasser (2*10 ml) gewaschen und im Vakuum getrocknet. Ausbeute: 0,72 g (86,7%), weisser Feststoff Schmp.: >220 °C Η NMR (CDC13): δ = 8,31 (s, 2H).Diethyl pyridazine-3,6-dicarboxylate (1.12 g, 5.0 mmol) and potassium hydroxide (87%, 0.8 g, 12 mmol) were refluxed in ethanol (35 ml) for 2 h. The solvent was distilled off and cold water (100 ml) was added to the residue. The solution thus obtained was acidified to pH 3.0 with concentrated hydrochloric acid. The precipitated product was filtered off, washed with water (2 × 10 ml) and dried in vacuo. Yield: 0.72 g (86.7%), white solid, mp:> 220 ° C Η NMR (CDC1 3 ): δ = 8.31 (s, 2H).
MS (m/z): 169; 168 (M+); 124; 79; 53; 44. MS (m / z): 169; 168 (M + ); 124; 79; 53; 44th

Claims

Patentansprüche claims
1. Verfahren zur Herstellung von Pyridazin-3,6-dicarbonsäureestern der allgemeinen Formel1. Process for the preparation of pyridazine-3,6-dicarboxylic acid esters of the general formula
Figure imgf000008_0001
Figure imgf000008_0001
worin R Cι_ιo-Alkyl, C3_8-Cycloalkyl oder Aryl-d^-alkyl bedeutet, dadurch gekennzeichnet, dass 3,6-Dichlorpyridazin in Gegenwart eines Palladium-Phosphin- Komplexes und einer Base mit Kohlenmonoxid und einem Alkohol der allgemeinenwherein R is Cι_ιo-alkyl, C 3 _ 8 -cycloalkyl or aryl-d ^ -alkyl, characterized in that 3,6-dichloropyridazine in the presence of a palladium-phosphine complex and a base with carbon monoxide and an alcohol of the general
Formel R — OH (II), worin R die oben genannte Bedeutung hat, umgesetzt wird.Formula R - OH (II), in which R has the meaning given above, is implemented.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass als Palladium-Phosphin- Komplex ein Palladiumkomplex eines Diphosphins eingesetzt wird.2. The method according to claim 1, characterized in that a palladium complex of a diphosphine is used as the palladium-phosphine complex.
3. Verfahren nach Anspruch 2, dadurch gekennzeichnet, dass als Diphosphin ein Bis- (diphenylphosphino)alkan der Formel (C6H5)2P — (CH2)„ — P(C6H5)2 mit n = 3 bis 5 oder ein Ferrocenyldiphosphin eingesetzt wird.3. The method according to claim 2, characterized in that as a diphosphine a bis (diphenylphosphino) alkane of the formula (C 6 H 5 ) 2 P - (CH 2 ) "- P (C 6 H 5 ) 2 with n = 3 to 5 or a ferrocenyl diphosphine is used.
4. Verfahren nach Anspruch 3, dadurch gekennzeichnet, dass als Ferrocenyldiphosphin l,l'-Bis(diphenylphosphino)ferrocen eingesetzt wird.4. The method according to claim 3, characterized in that l, l'-bis (diphenylphosphino) ferrocene is used as the ferrocenyldiphosphine.
5. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass der Palladium-Phosphin-Komplex in situ aus dem entsprechenden Phosphin und einem löslichen Palladium(n)salz erzeugt wird. 5. The method according to any one of claims 1 to 4, characterized in that the palladium-phosphine complex is generated in situ from the corresponding phosphine and a soluble palladium (s) salt.
6. Verfahren nach Anspruch 5, dadurch gekennzeichnet, dass als lösliches Palladium(π)- salz Palladium(π)acetat eingesetzt wird.6. The method according to claim 5, characterized in that palladium (π) acetate is used as the soluble palladium (π) salt.
7. Verfahren nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, dass als Base ein Alkaliacetat oder Alkalicarbonat eingesetzt wird.7. The method according to any one of claims 1 to 6, characterized in that an alkali acetate or alkali carbonate is used as the base.
8. Verfahren nach Anspruch 7, dadurch gekennzeichnet, dass als Base Natriumacetat eingesetzt wird.8. The method according to claim 7, characterized in that sodium acetate is used as the base.
9. Verfahren nach einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, dass die Umsetzung in überschüssigem Alkohol (II) als Lösungsmittel durchgeführt wird.9. The method according to any one of claims 1 to 8, characterized in that the reaction is carried out in excess alcohol (II) as a solvent.
10. Pyridazin-3,6-dicarbonsäureester der allgemeinen Formel10. Pyridazine-3,6-dicarboxylic acid ester of the general formula
Figure imgf000009_0001
Figure imgf000009_0001
worin R C -ιo-Alkyl, C3_8-Cycloalkyl oder
Figure imgf000009_0002
bedeutet. wherein RC -ιo-alkyl, C 3 _ 8 cycloalkyl or
Figure imgf000009_0002
means.
PCT/EP2000/007167 1999-07-28 2000-07-26 Method of producing pyridazine-3,6-dicarboxylic acid esters WO2001007415A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0819679A2 (en) * 1996-07-18 1998-01-21 Lonza Ag Process for the preparation of pyrimidine-2-carboxylique acid esters
EP0820987A1 (en) * 1996-07-23 1998-01-28 Lonza Ag Process for the preparation of pyridine-2,3-dicarboxylic acid esters
EP0864565A1 (en) * 1997-03-12 1998-09-16 Lonza Ag Process for the preparation of 2,6-pyridinedicarboxylic esters

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0819679A2 (en) * 1996-07-18 1998-01-21 Lonza Ag Process for the preparation of pyrimidine-2-carboxylique acid esters
EP0820987A1 (en) * 1996-07-23 1998-01-28 Lonza Ag Process for the preparation of pyridine-2,3-dicarboxylic acid esters
EP0864565A1 (en) * 1997-03-12 1998-09-16 Lonza Ag Process for the preparation of 2,6-pyridinedicarboxylic esters

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SUEUR S ET AL: "New Synthesis of Polyaza Derivatives. Crystal Structure of Pyridazine-3,6-dicarboxylic Acid", JOURNAL OF HETEROCYCLIC CHEMISTRY., vol. 24, no. 5, 1987, HETEROCORPORATION. PROVO., US, pages 1285 - 11289, XP000943408, ISSN: 0022-152X *
TAKEUCHI R ET AL: "Palladium-catalyzed carbonylation of N-heteroaromatic chloride", JOURNAL OF MOLECULAR CATALYSIS,CH,LAUSANNE, vol. 66, no. 3, 15 June 1991 (1991-06-15), pages 277 - 288, XP002037142 *

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