DE2130029A1 - Anthelmintic 2-pyrazolyl-benzimidazoles prodn - from 2-hydroxy -benzimidazoles and pyrazoles with phosphorus halides - Google Patents
Anthelmintic 2-pyrazolyl-benzimidazoles prodn - from 2-hydroxy -benzimidazoles and pyrazoles with phosphorus halidesInfo
- Publication number
- DE2130029A1 DE2130029A1 DE19712130029 DE2130029A DE2130029A1 DE 2130029 A1 DE2130029 A1 DE 2130029A1 DE 19712130029 DE19712130029 DE 19712130029 DE 2130029 A DE2130029 A DE 2130029A DE 2130029 A1 DE2130029 A1 DE 2130029A1
- Authority
- DE
- Germany
- Prior art keywords
- benzimidazoles
- hydroxy
- pyrazolyl
- benzimidazole
- halogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000008641 benzimidazolones Chemical class 0.000 title claims abstract description 6
- 150000003217 pyrazoles Chemical class 0.000 title claims abstract description 5
- 229910052698 phosphorus Inorganic materials 0.000 title claims description 7
- 239000011574 phosphorus Substances 0.000 title claims description 7
- -1 phosphorus halides Chemical class 0.000 title claims description 7
- 230000000507 anthelmentic effect Effects 0.000 title abstract 2
- IYTGPPNUOLLGBE-UHFFFAOYSA-N 2-(1h-pyrazol-3-yl)-1h-benzimidazole Chemical class N1C=CC(C=2NC3=CC=CC=C3N=2)=N1 IYTGPPNUOLLGBE-UHFFFAOYSA-N 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 238000009835 boiling Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract description 16
- 229910019213 POCl3 Inorganic materials 0.000 abstract description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 abstract description 2
- 229940124339 anthelmintic agent Drugs 0.000 abstract 1
- 239000000921 anthelmintic agent Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical compound C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 5
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 5
- PXUYWNZBZXDJEU-UHFFFAOYSA-N 1h-benzimidazol-2-ylhydrazine Chemical class C1=CC=C2NC(NN)=NC2=C1 PXUYWNZBZXDJEU-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- BADSZRMNXWLUKO-UHFFFAOYSA-N 4-chloro-1h-pyrazole Chemical compound ClC=1C=NNC=1 BADSZRMNXWLUKO-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- PYEHNKXDXBNHQQ-UHFFFAOYSA-N 3-methyl-1h-benzimidazol-2-one Chemical compound C1=CC=C2N(C)C(O)=NC2=C1 PYEHNKXDXBNHQQ-UHFFFAOYSA-N 0.000 description 1
- IQVUIJYEKLITAF-UHFFFAOYSA-N 4,6-dichloro-1,3-dihydrobenzimidazol-2-one Chemical compound ClC1=CC(Cl)=C2NC(=O)NC2=C1 IQVUIJYEKLITAF-UHFFFAOYSA-N 0.000 description 1
- HCHIWZADTVYYAR-UHFFFAOYSA-N 4-methyl-1,3-dihydrobenzimidazol-2-one Chemical compound CC1=CC=CC2=C1NC(O)=N2 HCHIWZADTVYYAR-UHFFFAOYSA-N 0.000 description 1
- NEXYNHXFBYYIHI-UHFFFAOYSA-N 4-nitro-1,3-dihydrobenzimidazol-2-one Chemical compound [O-][N+](=O)C1=CC=CC2=C1NC(=O)N2 NEXYNHXFBYYIHI-UHFFFAOYSA-N 0.000 description 1
- HQBYAESCKCDTDJ-UHFFFAOYSA-N 5,6-dichloro-1,3-dihydrobenzimidazol-2-one Chemical compound ClC1=C(Cl)C=C2NC(O)=NC2=C1 HQBYAESCKCDTDJ-UHFFFAOYSA-N 0.000 description 1
- AUPLVAKFTYFHTA-UHFFFAOYSA-N 5-methoxy-1,3-dihydrobenzimidazol-2-one Chemical compound COC1=CC=C2NC(=O)NC2=C1 AUPLVAKFTYFHTA-UHFFFAOYSA-N 0.000 description 1
- CTCHXZUMFHNSHM-UHFFFAOYSA-N 5-methyl-1,3-dihydrobenzimidazol-2-one Chemical compound CC1=CC=C2NC(=O)NC2=C1 CTCHXZUMFHNSHM-UHFFFAOYSA-N 0.000 description 1
- DLJZIPVEVJOKHB-UHFFFAOYSA-N 5-nitro-1,3-dihydrobenzimidazol-2-one Chemical compound [O-][N+](=O)C1=CC=C2NC(=O)NC2=C1 DLJZIPVEVJOKHB-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
- H01L31/00—Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof
- H01L31/08—Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof in which radiation controls flow of current through the device, e.g. photoresistors
- H01L31/10—Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof in which radiation controls flow of current through the device, e.g. photoresistors characterised by at least one potential-jump barrier or surface barrier, e.g. phototransistors
- H01L31/101—Devices sensitive to infrared, visible or ultraviolet radiation
- H01L31/112—Devices sensitive to infrared, visible or ultraviolet radiation characterised by field-effect operation, e.g. junction field-effect phototransistor
Abstract
Description
Verfahren zur Herstellung von 2-Pyrazolyl-(1 N7-benzimidazolen Die vorliegende Erfindung betrifft ein neues chemisch eigenartiges Verfahren zur Herstellung von teilweise bekannten 2-[Pyrazolyl-(1)]-benzimidazolen. Process for the preparation of 2-pyrazolyl- (1 N7-benzimidazoles Die The present invention relates to a novel chemically unique method of manufacture of some known 2- [pyrazolyl- (1)] benzimidazoles.
Es ist bereits bekannt geworden, daß man 2-tPyrazolyl-(i)7-benzimidazole erhält, wenn man 2-Hydrazino-benzimidazole mit 1,3-Dicarbonylverbindungen umsetzt. Die Produkte sind wertvolle Veterinärpharmazeutika und dienen zur Bekämpfung von Magen- und Darmwürmern bei Großtieren [Belgische Patentschrift 656.0162. Dieses Verfahren weist jedoch den Nachteil auf, daß die Darsteilung der als Zwischenprodukte benötigten 2-Hydrazino-benzimidazole ziemlich aufwendig ist.It has already become known that 2-t-pyrazolyl- (i) 7-benzimidazoles obtained when 2-hydrazino-benzimidazoles are reacted with 1,3-dicarbonyl compounds. The products are valuable veterinary pharmaceuticals and are used to combat Gastric and intestinal worms in large animals [Belgian patent specification 656.0162. This However, the process has the disadvantage that the preparation of the as intermediates required 2-hydrazino-benzimidazole is quite expensive.
Es wurde gefunden, daß man die teilweise bekannten 2-Pyrazol-(1)J-benzimidazole der Formel in welcher X für Wasserstoff, Alkyl (mit 1 bis 4 Kohlenstoffatomen), Alkoxy (mit 1 bis 4 Kohlenstoffatomen), Nitro, Halogen (vorzugsweise Chlor und Brom) oder Amino steht, für Wasserstoff oder Halogen (vorzugsweise Chlor und Brom) steht, Z für Wasserstoff oder Alkyl (mit. 1 bis 4 Kohlenstoffatomen) steht, R für Wasserstoff, Alkyl (mit 1 bis 4 Kohlenstoffatomen) oder Halogen (vorzugsweise Chlo-r und Brom) steht, erhält, wenn man 2-Hydroxybenzimidazole der Formel mit Pyrazolen der Formel worin R, X, Y und Z die oben angegebene Bedeutung besitzen, in Gegenwart von Halogeniden des Phosphors miteinander um-.It has been found that the partially known 2-pyrazole- (1) J-benzimidazoles of the formula in which X represents hydrogen, alkyl (with 1 to 4 carbon atoms), alkoxy (with 1 to 4 carbon atoms), nitro, halogen (preferably chlorine and bromine) or amino, represents hydrogen or halogen (preferably chlorine and bromine), Z is hydrogen or alkyl (having 1 to 4 carbon atoms), R is hydrogen, alkyl (having 1 to 4 carbon atoms) or halogen (preferably Chlo-r and bromine) is obtained when 2-hydroxybenzimidazoles of the formula with pyrazoles of the formula wherein R, X, Y and Z have the meaning given above, in the presence of halides of phosphorus with one another.
setzt.puts.
Halogenide des Phosphors sind beispielsweise Phosphortrichlorid, Phosphoroxychlorid und Phosphorpentachlorid.Phosphorus halides are, for example, phosphorus trichloride and phosphorus oxychloride and phosphorus pentachloride.
Es ist als ausgesprochen überraschend zu bezeichnen, daß gemäß der erfindungsgemäßen Umsetzung, in einer Eintopfreaktion praktisch ohne Nebenreaktionen und in außergewöhnlich hohen Ausbeuten 2-/Pyrazolyl-(1 (17-benzimidazole entstehen.It can be described as extremely surprising that according to the reaction according to the invention, in a one-pot reaction with practically no side reactions and 2- / pyrazolyl- (1 (17-benzimidazoles are formed in exceptionally high yields.
Das erfindungsgemäße Verfahren weist gegenüber dem eingangs erwähnten Verfahren, Umsetzung von 2-Hydrazino-benzimidazolen mit 1,3-Dicarbonylverbindun.gen, den Vorteil auf, daß 2-Hydroxy-benzimidazole weitaus bequemer zugänglich sind als 2-Hydrazino-benzimidazole.The method according to the invention differs from that mentioned at the beginning Process, reaction of 2-hydrazino-benzimidazoles with 1,3-Dicarbonylverbindun.gen, the advantage that 2-hydroxy-benzimidazoles are much more easily accessible than 2-hydrazino-benzimidazoles.
Verwendet man 2-Hydroxy-benzimidazol und Pyrazol als Ausgangsstoffe, so kann der Reaktionsablauf durch das folgende Formelschema wiedergegeben werden: Die erfindungsgemäß verwendbaren 2-Hydroxy-benzimidazole sind bereits bekannt. Als Beispiele seien genannt 2-Hydroxy-benzimidazol 2-Hydroxy-4-methyl-benzimidazol 2-Hydroxy-5-methyl-benzimidazol 2-Hydroxy-5-methoxy-benzimidazol 2-Hydroxy-4-nitro-benzimidazol 2-ydroxy-5-nitro-benzimidazol 2-Wydroxy-4-amino-benzimidazol 2-Hydroxy-5-amino-benzimidazol 2-Hydrok.y-4-chlor-benzimidazol 2-HXdroxy-5-chlor-benzimidazol 2-Hydroxy-4, 6-dichlor-benzimidazol 2-Hydroxy-5, 6-dichlor-benzimidazol und 1-Met.hyl-2-hydroxy-benzimidazol.If 2-hydroxy-benzimidazole and pyrazole are used as starting materials, the course of the reaction can be represented by the following equation: The 2-hydroxy-benzimidazoles which can be used according to the invention are already known. Examples are 2-hydroxy-benzimidazole, 2-hydroxy-4-methyl-benzimidazole, 2-hydroxy-5-methyl-benzimidazole, 2-hydroxy-5-methoxy-benzimidazole, 2-hydroxy-4-nitro-benzimidazole, 2-hydroxy-5 -nitro-benzimidazole 2-hydroxy-4-amino-benzimidazole 2-hydroxy-5-amino-benzimidazole 2-Hydrok.y-4-chlorobenzimidazole 2-HXdroxy-5-chlorobenzimidazole 2-hydroxy-4, 6- dichloro-benzimidazole, 2-hydroxy-5, 6-dichloro-benzimidazole and 1-methyl-2-hydroxy-benzimidazole.
Die erfiGndungsgemäß verwendbaren Pyrazol sind bereits bekannt.The pyrazoles which can be used according to the invention are already known.
Als Beispiele seien genannt: Pyrazol 3-Me thyl-pyraz ol 3,5-Dimethyl-pyrazol und 4-Chlor-pyrazol.Examples include: pyrazole 3-methylpyrazole 3,5-dimethylpyrazole and 4-chloro-pyrazole.
Bei der Durchführung des erfindungsgemäßen Verfahrens setzt man auf 1 Mol eines 2-Hydroxybenzimidazols 1 Mol eines Pyrazols in einem Phosphorhalogenid- vorzugsweise Phosphoroxychlorid- bei Siedetemperatur um, wobei gegebenenfalls HCl-Gas in das Reaktionsgemisch eingeleitet wird. Nach beendeter Um setzung (mehrere Stunden) wird das Phosphorhalogenid falls es in großem ueberschuß eingesetzt worden ist, weitgehend entfernt. Bei den angewandten Reaktionsbedingungen können die freien Basen oder Hydrochloride entstehen. Aus letzterem werden die Basen mit herkömmlichen Methoden freigemacht.When carrying out the process according to the invention, one sets up 1 mole of a 2-hydroxybenzimidazole 1 mole of a pyrazole in a phosphorus halide preferably phosphorus oxychloride at boiling temperature, with optionally HCl gas is introduced into the reaction mixture. After completion of the implementation (several hours) If the phosphorus halide has been used in large excess, largely removed. In the reaction conditions used, the free Bases or hydrochlorides are formed. From the latter, the bases are made with conventional ones Methods released.
Beispiel 1 Ein vorsichtig vereinigtes Gemisch aus 68 g Pyrazol, 134 g 2-Hydroxy-benzimidazol und 160 g Phosphoroxychlorid wird 3 Stunden lang zum Sieden erhitzt. Das noch 60 °C warme Reaktionsgut wird in eine Mischung aus 1 1 Eiswasser und 100 ml konz. Salzsäure eingeruhrt. Man hält 15 Minuten auf 30 - 400C, klärt die Lösung mit Kohle und dann mit Kieselgur und stellt unter Eiskühlung mit Ammoniak auf pg 7. Nach 1 Stunde wird das ausgefallene 2-(Pyrazolyl-(1)]-benzimidazol abgesaugt, mit Wasser gewaschen und getrocknet. Man erhält 150 g vom Fp. 218-220°. (81,5 ffi der Theorie).example 1 A carefully combined mixture of 68 g of pyrazole, 134 g of 2-hydroxy-benzimidazole and 160 g of phosphorus oxychloride is heated to the boil for 3 hours. The still 60 ° C warm reaction mixture is concentrated in a mixture of 1 1 ice water and 100 ml. Hydrochloric acid stirred in. The mixture is kept at 30-40 ° C. for 15 minutes, the solution is clarified with charcoal and then with kieselguhr and adjusted to pg 7 with ammonia while cooling with ice. After 1 hour, the 2- (pyrazolyl- (1)] benzimidazole which has precipitated is filtered off with suction and washed with water and dried, giving 150 g of melting point 218 ° -220 ° (81.5 ffi of theory).
Beispiel 2 Durch ein Gemisch aus 89 g 2-Hydroxy-5-nitro-benzimidazol, 250 ml Phosphoroxychlorid und 34 g Pyrazol leitet man bei 1000C 6 Stunden lang einen schwachen Chlorwasserstoff-Strom.Example 2 A gentle stream of hydrogen chloride is passed through a mixture of 89 g of 2-hydroxy-5-nitro-benzimidazole, 250 ml of phosphorus oxychloride and 34 g of pyrazole at 1000 ° C. for 6 hours.
Nach 1-stündigem Stehen gibt man zu dem entstandenen Kristallbrei 150 ml Essigester, saugt bei Oo ab und wäscht mit Essigester. Der Nutschkuchen wird in 800 ml Methanol durch Sättigung mit Ammoniakgas gelöst. Man klärt mit Kohle, verdUnnt mit 800 ml Wasser und stellt mit Salzsäure auf PH 1. Das ausgefallene 2- yrazolyl-(1 g-5-nitro-benzimidazol wird abgesaugt, mit Wasser gewaschen und getrocknet. Die Ausbeute beträgt 92 g. (80 % d.Th.) Beispiel 3 22,44 g 4-Chlor-pyrazol, 100 ml Phosphoroxychlorid und 26,8 g 2-Hydroxy-benzimidazol werden 8 Stunden rückfließend gekocht.After standing for 1 hour, 150 ml of ethyl acetate are added to the resulting crystal slurry, and the mixture is filtered off with suction at 0 ° and washed with ethyl acetate. The filter cake is dissolved in 800 ml of methanol by saturation with ammonia gas. It is clarified with charcoal, diluted with 800 ml of water and adjusted to pH 1 with hydrochloric acid. The 2-yrazolyl- (1 g-5-nitro-benzimidazole which has precipitated out is filtered off with suction, washed with water and dried. The yield is 92 g. (80%) % of theory) Example 3 22.44 g of 4-chloro-pyrazole, 100 ml of phosphorus oxychloride and 26.8 g of 2-hydroxy-benzimidazole are refluxed for 8 hours.
Man hydrolysiert vorsichtig mit 1 Ltr. Wasser und fügt vorsichtig kristallisierte Soda bis zur schwach alkalischen Reaktion hinzu. Das ausgeschiedene 2-(4-Chlor-pyrazolyl-(1)g-benzimidazol wird abgesaugt, mit Wasser gewaschen und getrocknet (31,5 g (72 s d.Th.) vom Fp. 180 - 182°C). Durch Umlösen aus Propanol erhält man die reine Verbindung vom Fp. 188-188,5°C.It is carefully hydrolyzed with 1 liter of water and carefully added crystallized soda was added until it had a weakly alkaline reaction. The excreted 2- (4-chloro-pyrazolyl- (1) g-benzimidazole is filtered off with suction, washed with water and dried (31.5 g (72 s of theory), melting point 180-182 ° C.). By dissolving from propanol the pure compound is obtained with a melting point of 188-188.5 ° C.
Beispiel 4 Eine aus 37,5 g Pyrazol, 200 ml Phosphoroxychlorid und 74,5 g 2-Hydroxy-5-amino-bensimidazol bestehende Mischung wird 10 Stunden rückfließend gekocht. Dann wird das überschüssige POCl3 bei 60-80° i.V. weitestgehend entfernt und der Rückstand vorsichtig mit 125 ml konz. HOl versetzt. Nach abgeklungener Reaktion fügt man bei 50° vorsichtig 190 ml Methanol hinzu und hält 3 Stunden lang bei 00. Das ausgefallene Dihydrochlorid des 2-Pydrazolyl-(1 g-5-amino-benzimidazols wird abgesaugt, mit eiskaltem Methanol gewaschen und getrocknet.Example 4 A mixture consisting of 37.5 g of pyrazole, 200 ml of phosphorus oxychloride and 74.5 g of 2-hydroxy-5-aminobensimidazole is refluxed for 10 hours. Then the excess POCl3 is largely removed at 60-80 ° iV and the residue carefully with 125 ml of conc. HOl shifted. After the reaction has subsided, 190 ml of methanol are carefully added at 50 ° and kept at 00 for 3 hours. The precipitated dihydrochloride of 2-pydrazolyl- (1 g-5-aminobenzimidazole is filtered off with suction, washed with ice-cold methanol and dried.
Die Ausbeute beträgt 102 g. (75,5 % d.Th.) Durch Lösen in Wasser und Versetzen mit Soda erhält man die freie Base vom Fp. 183,5-184°.The yield is 102 g. (75.5% of theory) by dissolving in water and Adding soda gives the free base of melting point 183.5-184 °.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19712130029 DE2130029A1 (en) | 1971-06-18 | 1971-06-18 | Anthelmintic 2-pyrazolyl-benzimidazoles prodn - from 2-hydroxy -benzimidazoles and pyrazoles with phosphorus halides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19712130029 DE2130029A1 (en) | 1971-06-18 | 1971-06-18 | Anthelmintic 2-pyrazolyl-benzimidazoles prodn - from 2-hydroxy -benzimidazoles and pyrazoles with phosphorus halides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2130029A1 true DE2130029A1 (en) | 1972-12-21 |
Family
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| DE19712130029 Pending DE2130029A1 (en) | 1971-06-18 | 1971-06-18 | Anthelmintic 2-pyrazolyl-benzimidazoles prodn - from 2-hydroxy -benzimidazoles and pyrazoles with phosphorus halides |
Country Status (1)
| Country | Link |
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| DE (1) | DE2130029A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003035065A1 (en) * | 2001-10-26 | 2003-05-01 | Aventis Pharmaceuticals Inc | Benzimidazoles and analogues and their use as protein kinases inhibitors |
| WO2003035644A1 (en) * | 2001-10-26 | 2003-05-01 | Aventis Pharma S.A. | Benzimidazole derivatives and their use as kdr protein kinase inhibitors |
| FR2831537A1 (en) * | 2001-10-26 | 2003-05-02 | Aventis Pharma Sa | Composition useful for treating inflammatory disease, cancer, chronic obstructive pulmonary disease, asthma, allergic rhinitis, or atopic dermatitis comprises benzimidazoles derivatives |
| US6897208B2 (en) | 2001-10-26 | 2005-05-24 | Aventis Pharmaceuticals Inc. | Benzimidazoles |
-
1971
- 1971-06-18 DE DE19712130029 patent/DE2130029A1/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003035065A1 (en) * | 2001-10-26 | 2003-05-01 | Aventis Pharmaceuticals Inc | Benzimidazoles and analogues and their use as protein kinases inhibitors |
| WO2003035644A1 (en) * | 2001-10-26 | 2003-05-01 | Aventis Pharma S.A. | Benzimidazole derivatives and their use as kdr protein kinase inhibitors |
| FR2831537A1 (en) * | 2001-10-26 | 2003-05-02 | Aventis Pharma Sa | Composition useful for treating inflammatory disease, cancer, chronic obstructive pulmonary disease, asthma, allergic rhinitis, or atopic dermatitis comprises benzimidazoles derivatives |
| FR2831536A1 (en) * | 2001-10-26 | 2003-05-02 | Aventis Pharma Sa | NOVEL BENZIMIDAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION, THEIR USE AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND NOVEL USE IN PARTICULAR AS KDR INHIBITORS |
| US6897208B2 (en) | 2001-10-26 | 2005-05-24 | Aventis Pharmaceuticals Inc. | Benzimidazoles |
| AU2002334217B2 (en) * | 2001-10-26 | 2008-07-03 | Aventis Pharmaceuticals Inc. | Benzimidazoles and analogues and their use as protein kinases inhibitors |
| US8288425B2 (en) | 2001-10-26 | 2012-10-16 | Aventis Pharmaceuticals Inc. | Benzimidazoles |
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