CH664754A5 - 5,6-di:chloro-nicotinic acid prodn. - by reacting 6-hydroxy-nicotinic acid with acid chloride, reacting prod. with chlorine, then with acid chloride and hydrolysing prod - Google Patents
5,6-di:chloro-nicotinic acid prodn. - by reacting 6-hydroxy-nicotinic acid with acid chloride, reacting prod. with chlorine, then with acid chloride and hydrolysing prod Download PDFInfo
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- CH664754A5 CH664754A5 CH269285A CH269285A CH664754A5 CH 664754 A5 CH664754 A5 CH 664754A5 CH 269285 A CH269285 A CH 269285A CH 269285 A CH269285 A CH 269285A CH 664754 A5 CH664754 A5 CH 664754A5
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- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 title claims abstract description 15
- BLHCMGRVFXRYRN-UHFFFAOYSA-N 6-hydroxynicotinic acid Chemical compound OC(=O)C1=CC=C(O)N=C1 BLHCMGRVFXRYRN-UHFFFAOYSA-N 0.000 title claims abstract description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 title claims description 6
- 239000000460 chlorine Substances 0.000 title claims description 6
- 229910052801 chlorine Inorganic materials 0.000 title claims description 6
- 230000003301 hydrolyzing effect Effects 0.000 title abstract 2
- IBRSSZOHCGUTHI-UHFFFAOYSA-N 2-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Cl IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 23
- DXPAQTUPQVXLTE-UHFFFAOYSA-N 5-chloro-6-oxo-1h-pyridine-3-carbonyl chloride Chemical compound OC1=NC=C(C(Cl)=O)C=C1Cl DXPAQTUPQVXLTE-UHFFFAOYSA-N 0.000 claims abstract description 14
- RNRLTTNKVLFZJS-UHFFFAOYSA-N 5,6-dichloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(Cl)C(Cl)=C1 RNRLTTNKVLFZJS-UHFFFAOYSA-N 0.000 claims abstract description 13
- ZTUJAURKGQRLFU-UHFFFAOYSA-N 6-oxo-1h-pyridine-3-carbonyl chloride Chemical compound OC1=CC=C(C(Cl)=O)C=N1 ZTUJAURKGQRLFU-UHFFFAOYSA-N 0.000 claims abstract description 8
- NZEAAWXZOUGYCH-UHFFFAOYSA-N 5,6-dichloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CN=C(Cl)C(Cl)=C1 NZEAAWXZOUGYCH-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000011065 in-situ storage Methods 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 4
- 150000001805 chlorine compounds Chemical class 0.000 claims description 4
- -1 inorganic acid chlorides Chemical class 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- KDKAJWVLNAHXRV-UHFFFAOYSA-N 5-(chloromethyl)-1h-pyridin-2-one Chemical compound OC1=CC=C(CCl)C=N1 KDKAJWVLNAHXRV-UHFFFAOYSA-N 0.000 claims description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims 1
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 claims 1
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CHXVGBPDDVLUTO-UHFFFAOYSA-N 2,4-dichloro-3-methylpyridine Chemical compound CC1=C(Cl)C=CN=C1Cl CHXVGBPDDVLUTO-UHFFFAOYSA-N 0.000 description 1
- BGIKXXKOLPMLOE-UHFFFAOYSA-N 3-chloro-5-(chloromethyl)-1h-pyridin-2-one Chemical compound ClCC1=CNC(=O)C(Cl)=C1 BGIKXXKOLPMLOE-UHFFFAOYSA-N 0.000 description 1
- XTCHZNJJTQACES-UHFFFAOYSA-N 5,6-dichloropyridin-3-amine Chemical compound NC1=CN=C(Cl)C(Cl)=C1 XTCHZNJJTQACES-UHFFFAOYSA-N 0.000 description 1
- JBMLYEZUHCZNKT-UHFFFAOYSA-N 5,6-dichloropyridine-3-carbonitrile Chemical compound ClC1=CC(C#N)=CN=C1Cl JBMLYEZUHCZNKT-UHFFFAOYSA-N 0.000 description 1
- OLTRUTPHSBQWAZ-UHFFFAOYSA-N 5-chloro-6-oxo-1h-pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CNC(=O)C(Cl)=C1 OLTRUTPHSBQWAZ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000011541 reaction mixture 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
- C07D213/60—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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
Prodn. of 5,6-dichloronicotinic acid (I) is effected by (a) reacting 6-hydroxynicotinic acid (II) with an acid chloride to form 6-hydroxynicotinoyl chloride (III); (b) isolating (III) or reacting it in situ with Cl2 gas to form 5-chloro-6-hydroxynicotinoyl chloride (IV); (c) reacting (IV) with an acid chloride; and (d) hydrolysing the resulting 5,6-dichloronicotinoyl chloride (V) with H2O. USE/ADVANTAGE - (I) is useful as a pharmaceutical intermediate. The process is simple and gives high yields, e.g. 60% based on (II), of (I) with a purity of ca. 95%, which can be increased to 99% by recrystn.
Description
BESCHREIBUNG
Die Erfindung betrifft ein vorteilhaftes Verfahren zur Herstellung von 5 ,6-Dichlornikotinsäure. 5,6-Dichlornikotinsäure ist ein interessantes Ausgangsprodukt für pharmazeutische Wirkstoffe [Setcliff et al., J. of Chem. and Eng. Data, Vol 21, Nr. 2 (1976), S. 246].
Die bisher bekannt gewordenen Verfahren sind in verschiedener Hinsicht mit erheblichen Nachteilen behaftet. So beschreibt Graf im J. für prakt. Chemie, 138, 244 (1933), dass er durch Behandeln von Nikotinsäurechlorhydrat mit Thionylchlorid über 50 Stunden bei 150 "C im Einschlussrohr die 5,6 Dichlornikotinsäure in einer Ausbeute von 30% erhält.
Rath und Schiffmann, Ann. 487, (1931) setzen 2,3 Dichlor-5-cyanpyridin, das zuerst in 30%iger Ausbeute aus 2,3 Dichlor-5-aminopyridin gewonnen werden muss, mit Salzsäure innert 16 Stunden und in einer Ausbeute von 45% zur 5,6- Dichlornikotinsäure um.
Eine weitere Methode schlagen Setcliffet al., J. Chem. Eng.
Dat. 21, 246 (1976) vor. Ausgehend von Dichlor-3-picolin wird mit Kaliumpermanganat die 5,6-Dichlornikotinsäure in einer Ausbeute von 34% hergestellt.
Alle genannten Verfahren vermögen aufgrund bescheidener Ausbeuten oder aufgrund teurer Edukte und auch aus verfahrensmässigen Gründen den heutigen Anforderungen für ein technisches Verfahren nicht zu genügen.
Das Ziel der vorliegenden Erfindung ist es daher, ein Verfahren aufzuzeigen, das die genannten Nachteile nicht aufweist und das erlaubt, auf technisch einfache Weise in guter Ausbeute die 5,6-Dichlornikotinsäure herzustellen.
Dieses Ziel wird erreicht durch ein Verfahren gemäss Patentanspruch 1, worin man, ausgehend von 6-Hydroxynikotinsäure, mit einem Säurechlorid zum 6-Hydroxynilcotinsäurechlorid umsetzt, dieses entweder isoliert oder aber in situ direkt mit gasförmigem Chlor zum 5-Chlor-6-hydroxynikotinsäurechlorid chloriert, nochmals mit einem Säurechlorid zum 5,6-Dichlornikotinsäurechlorid umsetzt und schliesslich mit Wasser hydrolysiert.
Als zweckmässige Säurechloride, sowohl für die Umsetzung zum 6-Hydroxynikotinsäurechlorid als auch für die Umsetzung zum 5 ,6-Dichlornikotinsäurechlorid, finden die anorganischen Säurechloride, als bevorzugter Vertreter dieser Klasse Thionylchlorid, Phosphoroxychlorid oder Phosphorpentachlorid, Verwendung. Besonders bevorzugt wird Thionylchlorid verwendet.
Die Säurechloride werden üblicherweise im Überschuss, bezogen auf das stöchiometrische Verhältnis, eingesetzt. So wird für die Umsetzung zum 6-Hydroxynikotinsäurechlorid ein Verhältnis Säurechlond zu 6-Hydroxynikotinsäure von zweckmässig 5:1 bis 1:1, vorzugsweise 3,5:1 bis 1:1, zugesetzt.
Für die Umsetzung zum 5 ,6-Dichlornikotinsäurechlorid beträgt das Verhältnis Säurechlorid zu 5-Chlor-6-hydroxynikotinsäurechlorid zweckmässig 4:1 bis 1,2:1, vorzugsweise 2:1 bis 1,2:1.
Alle Verfahrensschritte werden zweckmäsig in Gegenwart eines Lösungsmittels, vorteilhaft über alle Stufen im gleichen Lösungsmittel, durchgeführt.
Geeignete Lösungsmittel sind solche, die mit den Chlorierungsreagenzien nicht reagieren. Darunter fallen zweckmässig die halogenierten, aliphatischen Kohlenwasserstoffe, wie z. B.
Methylenchlorid, Chloroform oder Tetrachlorkohlenstoff.
Die Umsetzung zum 6-Hydroxynikotinsäurechlorid erfolgt vorteilhaft in Gegenwart eines tertiären Amins als Katalysator.
Zweckmässige Vertreter sind die Pyridine, die gegebenenfalls alkylsubstituiert sein können. Bevorzugt wird aber Pyridin als Katalysator eingesetzt.
Diese Aminkatalysatoren werden in Mengen von zweckmässig 0,01 bis 1 Mol, vorzugsweise 0,1 bis 0,3 Mol, bezogen auf 1 Mol 6-Hydroxynikotinsäure, eingesetzt.
Die Umsetzungstemperatur liegt zweckmässig in einem Bereich zwischen 0 und 80 "C, vorzugsweise zwischen 50 und 70 "C. Nach ungefähr 0,5 bis 5 Stunden ist die Umsetzung beendet.
Das entstandene 6-Hydroxynikotinsäurechlorid kann isoliert werden, vorzugsweise wird es aber direkt, ohne es zu isolieren, weiterchloriert zum 5-Chlor-6-hydroxynikotinsäurechlorid. Das geschieht zweckmässig durch Einleiten von Chlor in einem Überschuss von zweckmässig 0 bis 200%, vorzugsweise 10 bis 100% bei Temperaturen von 0 bis 60 "C über eine Dauervon zweckmässig 30 bis 180 Minuten.
Das entstandene 5-Chlor-6-hydroxynikotinsäurechlorid kann direkt zur Weiterumsetzung zum 5, 6-Dichlor-6-hydroxynikotinsäurechlorid herangezogen werden. Üblicherweise wird es aber isoliert.
Durch Hydrolyse mit Wasser kann das 5-Chlor-6-hydroxyni kotinsäurechlorid auch auf einfache Weise in die ebenfalls als Zwischenprodukt für Insektizide geeignete 5-Chlor-6-hydroxynikotinsäure überführt werden.
Zweckmässig wird das 5-Chlor-6-hydroxynikotinsäurechlorid mit der angegebenen Menge eines anorganischen Säurechlorids, vorzugsweise mit Thionylchlorid, in Gegenwart eines Carbonsäureamids als Katalysator zum 5,6-Dychlornikotinsäurechlorid umgesetzt.
Als Carbonsäureamid werden zweckmässig die niederen Carbonsäureamide, wie z. B. N'N-Dimethylformamid, in Mengen von zweckmässig 0,05 bis 1 Mol, vorzugsweise 0,1 bis 0,3 Mol, bezogen auf 1 Mol eingesetztes 5-Chlor-6-hydroxynikotinsäurechlorid, angewendet.
Die Umsetzungstemperatur liegt üblicherweise zwischen 40 und 110 "C. Nach ungefähr 1 bis 5 Stunden kann die Umsetzung als beendet betrachtet werden.
Das 5 ,6-Dychlornikotinsäurechlorid kann isoliert werden; üblicherweise wird es aber direkt mit Wasser zum Endprodukt der 5,6-Dichlornikotinsäure hydrolysiert. Diese kann auf einfache Weise, z. B. durch Filtration, aus dem Reaktionsgemisch abgetrennt werden.
Bereits dieses Rohprodukt weist einen Gehalt von ca. 95 % auf, und gegebenenfalls kann die Reinheit durch Umkristallisation auf 99% gesteigert werden.
Bezogen auf 6-Hydroxynikotinsäure sind mit dem erfindungsgemässen Verfahren, über alle Stufen gerechnet, Ausbeuten an 5,6-Dichlornikotinsäure von 60% ohne weiteres erreichbar.
Die folgenden Beispiele sollen das Verfahren näher erklären.
Beispiel 1 a) Herstellung von 5-Chlor-6-hydroxynikotinsäurechlorid
70 g (0,5 Mol) 6-Hydroxynikotinsäure wurden in 750 ml Chloroform und 10 g (0,12 Mol) Pyridin aufgeschlämmt. Unter Rückfluss gab man anschliessend langsam 190 g (1,6 Mol) Thionylchlorid zu. Man liess 60 min bei 55 "C nachreagieren.
Anschliessend leitete man 70 g (0,98 Mol) Chlor innert 60 min bei einer Temperatur von 60 "C zur Lösung zu.
Nach Abkühlen auf Raumtemperatur fiel das 5-Chlor-6hydroxynikotinsäurechlorid als weisses Produkt aus. Dieses wurde abgenutscht, mit Chloroform gewaschen und unter Vakuum getrocknet.
Ausbeute: 57,6 g = 60%.
H-NMR (CDCl3): Ï (ppm) 8,18 (d); 8,5 (d).
b) Herstellung von 5,6-Dichlornikotinsäure
58,8 g (0,3 Mol) 5-Chlor-6-hydroxynikotinsäurechlorid und 6,1 g (0,08 Mol) N'N-Dimethylformamid wurden in 245 g Chloroform aufgeschlämmt. Unter Rückfiuss wurden 61,2 g (0,51 Mol) Thionylchlorid langsam innert 60 min zugetropft.
Nach 2,5 h war der Umsatz nach Dünnschichtchromatogramm vollständig. Die erhaltene Lösung wurde bei 60 "C in 500 g Wasser gegeben, wobei die 5,6-Dichlornikotinsäure ausfiel. Das weisse Produkt wurde abgenutscht, mit Wasser gewaschen und getrocknet. Man erhielt 55,9 g (entsprechend einer Ausbeute von 95%) 5,6-Dichlornikotinsaure mit einem Gehalt von 95%.
Durch Umkristallisation des Produktes in wässrigem Alkohol konnte die Reinheit auf 99% gesteigert werden.
tH-NMR (DMSO d6): ö (ppm) 8,48 (d); 8,85 (d).
DESCRIPTION
The invention relates to an advantageous process for the preparation of 5, 6-dichloronicotinic acid. 5,6-dichloronicotinic acid is an interesting starting product for active pharmaceutical ingredients [Setcliff et al., J. of Chem. And Eng. Data, Vol 21, No. 2 (1976), p. 246].
The methods that have become known to date have considerable disadvantages in various respects. Graf in J. for Prakt. Chemie, 138, 244 (1933) describes that by treating nicotinic acid chlorohydrate with thionyl chloride for 50 hours at 150 ° C. in the containment tube, he obtains 5,6 dichloronicotinic acid in a yield of 30%.
Rath and Schiffmann, Ann. 487, (1931) replace 2,3 dichloro-5-cyanopyridine, which must first be obtained in 30% yield from 2,3 dichloro-5-aminopyridine, with hydrochloric acid within 16 hours and in a yield of 45% to 5, 6- dichloronicotinic acid.
Another method proposed by Setcliff et al., J. Chem. Eng.
Date 21, 246 (1976). Starting from dichloro-3-picolin, the 5,6-dichloronicotinic acid is produced in a yield of 34% with potassium permanganate.
Due to modest yields or due to expensive educts and also for procedural reasons, all of the processes mentioned cannot meet today's requirements for an industrial process.
The aim of the present invention is therefore to provide a process which does not have the disadvantages mentioned and which allows 5,6-dichloronicotinic acid to be prepared in a technically simple manner and in good yield.
This object is achieved by a process according to claim 1, in which, starting from 6-hydroxynicotinic acid, reaction is carried out with an acid chloride to give 6-hydroxynilcotinic acid chloride, which is either isolated or chlorinated directly with gaseous chlorine to give 5-chloro-6-hydroxynicotinic acid chloride, reacted again with an acid chloride to give 5,6-dichloronicotinic acid chloride and finally hydrolyzed with water.
The inorganic acid chlorides, as preferred representatives of this class, thionyl chloride, phosphorus oxychloride or phosphorus pentachloride, are used as suitable acid chlorides, both for the conversion to 6-hydroxynicotinoyl chloride and for the conversion to 5, 6-dichloronicotinoyl chloride. Thionyl chloride is particularly preferably used.
The acid chlorides are usually used in excess, based on the stoichiometric ratio. For the conversion to 6-hydroxynicotinic acid chloride, a ratio of acid chloride to 6-hydroxynicotinic acid of 5: 1 to 1: 1, preferably 3.5: 1 to 1: 1, is advantageously added.
For the conversion to 5, 6-dichloronicotinoyl chloride, the ratio of acid chloride to 5-chloro-6-hydroxynicotinoyl chloride is advantageously 4: 1 to 1.2: 1, preferably 2: 1 to 1.2: 1.
All process steps are expediently carried out in the presence of a solvent, advantageously over all steps in the same solvent.
Suitable solvents are those that do not react with the chlorination reagents. This conveniently includes the halogenated, aliphatic hydrocarbons, such as. B.
Methylene chloride, chloroform or carbon tetrachloride.
The conversion to 6-hydroxynicotinyl chloride is advantageously carried out in the presence of a tertiary amine as a catalyst.
Appropriate representatives are the pyridines, which can optionally be alkyl-substituted. However, pyridine is preferably used as the catalyst.
These amine catalysts are advantageously used in amounts of 0.01 to 1 mol, preferably 0.1 to 0.3 mol, based on 1 mol of 6-hydroxynicotinic acid.
The reaction temperature is expediently in a range between 0 and 80 "C., preferably between 50 and 70" C. The reaction is complete after about 0.5 to 5 hours.
The resulting 6-hydroxynicotinic acid chloride can be isolated, but preferably it is further chlorinated directly without isolating it to 5-chloro-6-hydroxynicotinic acid chloride. This is expediently carried out by introducing chlorine in an excess of expediently 0 to 200%, preferably 10 to 100% at temperatures of 0 to 60 ° C. over a period of expediently 30 to 180 minutes.
The resulting 5-chloro-6-hydroxynicotinic acid chloride can be used directly for further conversion to 5, 6-dichloro-6-hydroxynicotinic acid chloride. However, it is usually isolated.
By hydrolysis with water, the 5-chloro-6-hydroxynicotinoyl chloride can also be converted in a simple manner into the 5-chloro-6-hydroxynicotinic acid, which is also suitable as an intermediate for insecticides.
The 5-chloro-6-hydroxynicotinic acid chloride is expediently reacted with the stated amount of an inorganic acid chloride, preferably with thionyl chloride, in the presence of a carboxamide as a catalyst to give 5,6-dychlornicotinic acid chloride.
As the carboxylic acid amide, the lower carboxylic acid amides such as. B. N'N-dimethylformamide, in amounts of appropriately 0.05 to 1 mol, preferably 0.1 to 0.3 mol, based on 1 mol of 5-chloro-6-hydroxynicotinyl chloride used.
The reaction temperature is usually between 40 and 110 "C. After approximately 1 to 5 hours, the reaction can be regarded as complete.
The 5, 6-dychloricotinic acid chloride can be isolated; Usually, however, it is hydrolyzed directly with water to the end product of 5,6-dichloronicotinic acid. This can be done in a simple manner, e.g. B. by filtration, separated from the reaction mixture.
This crude product already has a content of approximately 95%, and if necessary the purity can be increased to 99% by recrystallization.
Based on 6-hydroxynicotinic acid, 60% yields of 5,6-dichloronicotinic acid can easily be achieved with the process according to the invention, calculated over all stages.
The following examples are intended to explain the process in more detail.
Example 1 a) Preparation of 5-chloro-6-hydroxynicotinoyl chloride
70 g (0.5 mol) of 6-hydroxynicotinic acid was slurried in 750 ml of chloroform and 10 g (0.12 mol) of pyridine. 190 g (1.6 mol) of thionyl chloride were then slowly added under reflux. The mixture was left to react at 55 ° C. for 60 min.
70 g (0.98 mol) of chlorine were then passed to the solution within 60 min at a temperature of 60.degree.
After cooling to room temperature, the 5-chloro-6-hydroxynicotinoyl chloride precipitated out as a white product. This was suction filtered, washed with chloroform and dried under vacuum.
Yield: 57.6 g = 60%.
H-NMR (CDCl3): Ï (ppm) 8.18 (d); 8.5 (d).
b) Preparation of 5,6-dichloronicotinic acid
58.8 g (0.3 mol) of 5-chloro-6-hydroxynicotinoyl chloride and 6.1 g (0.08 mol) of N'N-dimethylformamide were slurried in 245 g of chloroform. Under reflux, 61.2 g (0.51 mol) of thionyl chloride were slowly added dropwise within 60 min.
After 2.5 h, the conversion according to the thin layer chromatogram was complete. The solution obtained was poured into 500 g of water at 60 ° C., the 5,6-dichloronicotinic acid precipitating out. The white product was filtered off with suction, washed with water and dried. 55.9 g (corresponding to a yield of 95%) 5 , 6-dichloronicotinic acid with a content of 95%.
The purity could be increased to 99% by recrystallization of the product in aqueous alcohol.
tH-NMR (DMSO d6): ö (ppm) 8.48 (d); 8.85 (d).
Claims (12)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH269285A CH664754A5 (en) | 1985-06-25 | 1985-06-25 | 5,6-di:chloro-nicotinic acid prodn. - by reacting 6-hydroxy-nicotinic acid with acid chloride, reacting prod. with chlorine, then with acid chloride and hydrolysing prod |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH269285A CH664754A5 (en) | 1985-06-25 | 1985-06-25 | 5,6-di:chloro-nicotinic acid prodn. - by reacting 6-hydroxy-nicotinic acid with acid chloride, reacting prod. with chlorine, then with acid chloride and hydrolysing prod |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH664754A5 true CH664754A5 (en) | 1988-03-31 |
Family
ID=4239429
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH269285A CH664754A5 (en) | 1985-06-25 | 1985-06-25 | 5,6-di:chloro-nicotinic acid prodn. - by reacting 6-hydroxy-nicotinic acid with acid chloride, reacting prod. with chlorine, then with acid chloride and hydrolysing prod |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH664754A5 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5144038A (en) * | 1990-07-17 | 1992-09-01 | Lonza Ltd. | Process for the production of 2-hydroxy-3-halo-5-nitropyridines |
| US5264362A (en) * | 1991-03-18 | 1993-11-23 | Lonza Ltd. | Microbiological process for the production of 6-hydroxynicotinic acid |
| US5266469A (en) * | 1991-03-18 | 1993-11-30 | Lonza Ltd. | Microbiological process for the production of 6-hydroxynicotinic acid |
| US5516661A (en) * | 1991-12-05 | 1996-05-14 | Lonza Ltd. | Microbiological process for the production of aromatic hydroxy-heterocyclic carboxylic acids |
| US5922870A (en) * | 1996-03-21 | 1999-07-13 | Lonza Ag | Process for the preparation of arylamides of heteroaromatic carboxylic acids |
| US5925765A (en) * | 1996-07-23 | 1999-07-20 | Lonza Ag | Process for preparing pyridinecarboxylic esters |
| US6169183B1 (en) | 1996-07-23 | 2001-01-02 | Lonza, Ltd. | Process for preparing pyridinecarboxylic esters |
| US6635766B1 (en) | 1996-03-28 | 2003-10-21 | Lonza Ag | Process for the preparation of arylamides of heteroaromatic carboxylic acids |
| US7009058B1 (en) | 1996-07-23 | 2006-03-07 | Lonza Ag | Method for preparing pyridine-2,3-dicarboxylic acid esters |
-
1985
- 1985-06-25 CH CH269285A patent/CH664754A5/en not_active IP Right Cessation
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5144038A (en) * | 1990-07-17 | 1992-09-01 | Lonza Ltd. | Process for the production of 2-hydroxy-3-halo-5-nitropyridines |
| US5264362A (en) * | 1991-03-18 | 1993-11-23 | Lonza Ltd. | Microbiological process for the production of 6-hydroxynicotinic acid |
| US5266469A (en) * | 1991-03-18 | 1993-11-30 | Lonza Ltd. | Microbiological process for the production of 6-hydroxynicotinic acid |
| US5516661A (en) * | 1991-12-05 | 1996-05-14 | Lonza Ltd. | Microbiological process for the production of aromatic hydroxy-heterocyclic carboxylic acids |
| US5922870A (en) * | 1996-03-21 | 1999-07-13 | Lonza Ag | Process for the preparation of arylamides of heteroaromatic carboxylic acids |
| US6635766B1 (en) | 1996-03-28 | 2003-10-21 | Lonza Ag | Process for the preparation of arylamides of heteroaromatic carboxylic acids |
| US5925765A (en) * | 1996-07-23 | 1999-07-20 | Lonza Ag | Process for preparing pyridinecarboxylic esters |
| US6022973A (en) * | 1996-07-23 | 2000-02-08 | Lonza Ltd. | Process for preparing pyridinecarboxylic esters |
| US6162921A (en) * | 1996-07-23 | 2000-12-19 | Lonza, Ltd | Process for preparing pyridinecarboxylic esters |
| US6169183B1 (en) | 1996-07-23 | 2001-01-02 | Lonza, Ltd. | Process for preparing pyridinecarboxylic esters |
| US7009058B1 (en) | 1996-07-23 | 2006-03-07 | Lonza Ag | Method for preparing pyridine-2,3-dicarboxylic acid esters |
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