DE1106765B - Process for the preparation of substituted benzimidazoles - Google Patents
Process for the preparation of substituted benzimidazolesInfo
- Publication number
- DE1106765B DE1106765B DESCH27821A DESC027821A DE1106765B DE 1106765 B DE1106765 B DE 1106765B DE SCH27821 A DESCH27821 A DE SCH27821A DE SC027821 A DESC027821 A DE SC027821A DE 1106765 B DE1106765 B DE 1106765B
- Authority
- DE
- Germany
- Prior art keywords
- general formula
- hydrogen
- morpholine
- known per
- given above
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/14—Radicals substituted by nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung substituierter Benzimidazole Zusatz zum Patent 1078132 In der deutschen Patentschrift 1078132 ist ein Verfahren zur Herstellung substituierter Benzimidazole der allgemeinen Formel beschrieben, worin R1 Alkyl, R2 und R3 die Atomgruppierung - CH2 - CH2 - OH oder R2 die Atomgruppierung - CH2 - CH2 - OH und R3 Wasserstoff oder R2 und R3 zusammen mit dem Stickstoffatom den Morpholinrest bedeuten und R4 Wasserstoff oder die Nitrogruppe darstellt. Diese z. B. als Monochlorhydrate angewandten wirksamen Produkte haben entzündungshemmende und analgetische Wirkung.Process for the preparation of substituted benzimidazoles Addition to the patent 1078132 In the German patent 1078132 there is a process for the preparation of substituted benzimidazoles of the general formula where R1 is alkyl, R2 and R3 is the atomic grouping - CH2 - CH2 - OH or R2 is the atomic grouping - CH2 - CH2 - OH and R3 is hydrogen or R2 and R3 together with the nitrogen atom is the morpholine radical and R4 is hydrogen or the nitro group. This z. Effective products used, for example, as monochlorohydrates have anti-inflammatory and analgesic effects.
Es wurde nun gefunden, daß durch Halogensubstitution im Benzolring
(R4 = Halogen, vorzugsweise Chlor) überraschend eine antiphlogistische Wirkungssteigerung
um etwa das Doppelte auftritt, wenngleich die halogenierte Substanz auch eine geringe
(etwa 200/0ige) Toxizitätssteigerung erfährt, ist doch mit dem viel höheren therapeutischen
Wirkungseffekt eine erhebliche Variationsbreite innerhalb der therapeutischen und
toxischen Grenzen gegeben, wie aus der angeführten Tabelle klar ersichtlich:
Die erfindungsgemäß hergestellten Benzimidazole der allgemeinen Formel worin R1 Wasserstoff, Alkyl, R2 und R8 die Atomgruppierung - CH2 - CH2 - OH oder R2 die Atomgruppierung - CH2 - CH2 - OH und R3 Wasserstoff oder R2 und R3 zusammen mit dem Stickstoffatom den Morpholinrest bedeuten, werden, wie in der Patentschrift 1078132 beschrieben, dargestellt: Man setzt 2-Halogenmethyl-5-halogenbenzimidazole der allgemeinen Formel worin R1 die oben angegebene Bedeutung hat, mit Äthanolamin, Diäthanolamin oder Morpholin um, oder man unterwirft Verbindungen der allgemeinen Formel worin R1 bis R3 ebenfalls die oben angegebene Bedeutung haben, der an sich bekannten Ringschlußreaktion zum Benzimidazol.The benzimidazoles of the general formula prepared according to the invention where R1 is hydrogen, alkyl, R2 and R8 are the atomic grouping - CH2 - CH2 - OH or R2 is the atomic grouping - CH2 - CH2 - OH and R3 is hydrogen or R2 and R3 together with the nitrogen atom are the morpholine radical, as described in patent 1078132 , shown: 2-Halomethyl-5-halobenzimidazoles of the general formula are used in which R1 has the meaning given above, with ethanolamine, diethanolamine or morpholine, or compounds of the general formula are subjected where R1 to R3 also have the meaning given above, the ring closure reaction known per se to form benzimidazole.
Die als Ausgangsprodukte benötigten 1-Alkyl-2-halogenmethyl-5-halogenbenzimidazole erhält man vorzugsweise aus handelsüblichem 2,6-Dichlor-nitrobenzol durch Umsetzung mit Alkylamin, anschließende Reduktion der Nitrogruppe mit Wasserstoff in Gegenwart von vorzugsweise Nickelkatalysatoren und schließlich Ringschlußreaktion mit Chloressigsäure zum l-Alkyl-2-chlormethyl-5-chlorbenzimidazol. The 1-alkyl-2-halomethyl-5-halobenzimidazoles required as starting materials is preferably obtained from commercially available 2,6-dichloro-nitrobenzene by reaction with alkylamine, subsequent reduction of the nitro group with hydrogen in the presence of preferably nickel catalysts and finally ring closure reaction with chloroacetic acid to the 1-alkyl-2-chloromethyl-5-chlorobenzimidazole.
Die neuen Benzimidazole kann man in an sich bekannter Weise in ihre Salze, besonders das Monochlorhydrat, überführen. The new benzimidazoles can be converted into theirs in a manner known per se Transfer salts, especially the monochlorohydrate.
Beispiel 1 1 -Äthyl-2-morpholinomethyl-5-chlorbenzimiclazol 4,3g 1-Äthyl-2-chlormethyl-5-chlorbenzimidazolwerden mit 20ml Benzol versetzt. Unter Rühren tropft man langsam 4,1 g Morpholin, die mit 5 ml verdünnt sind, hinzu, läßt dann über Nacht bei Raumtemperatur weiterreagieren und spült nun das Reaktionsgemisch mit Wasser und Benzol in einen Scheidetrichter über, wäscht die Benzolphase mit Wasser neutral und trocknet sie mit wasserfreiem Kaliumcarbonat. Nach dem Verdampfen des Benzols im Vakuum hinterbleibt ein fester Rückstand, der aus Methanol umkristallisiert wird und das reine 1 -Äthyl-2-morpholinomethyl-5-chlorbenzimidazol in einer Ausbeute von 630in der Theorie ergibt; F. 172 bis 175°C. Example 1 1-Ethyl-2-morpholinomethyl-5-chlorobenzimiclazole 4.3g 1-Ethyl-2-chloromethyl-5-chlorobenzimidazole are mixed with 20 ml of benzene. Under 4.1 g of morpholine, which are diluted with 5 ml, are slowly added dropwise while stirring then continue to react overnight at room temperature and now rinse the reaction mixture with water and benzene into a separating funnel, the benzene phase washes with it Water neutral and dry them with anhydrous potassium carbonate. After evaporation of the benzene in vacuo, a solid residue remains which is recrystallized from methanol and the pure 1-ethyl-2-morpholinomethyl-5-chlorobenzimidazole in one yield of 630 results in theory; 172-175 ° C.
Das aus der Base durch Behandlung mit der berechneten Menge Salzsäure hergestellte Monohydrochlorid schmilzt bei 222 bis 223"C. That from the base by treatment with the calculated amount of hydrochloric acid produced monohydrochloride melts at 222 to 223 "C.
Beispiel 2 1 -Äthyl-2-diäthanolaminomethyl-5-chlorbenzimidazol 4,3 g 1-Äthyl-2-chlormethyl-5-chlorbenzimidazol in 25 ml Chloroform werden tropfenweise und unter Rühren mit 5 g Diäthanolamin, die mit 5 ml Chloroform verdünnt sind, versetzt. Das Reaktionsgemisch läßt man nun über Nacht bei Raumtemperatur ausreagieren. Die Aufarbeitung erfolgt gemäß Beispiel 1. Das nach dem Verdampfen des Chloroforms erhaltene rohe 1-Äthyl-2-diäthylaminomethyl-5-chlorbenzimidazol fällt als feste Substanz in einer Ausbeute von 710in Theorie an. Die Rohbase wird aus Essigester umkristallisiert und schmilzt bei 133 bis 134,5"C. Example 2 1-Ethyl-2-diethanolaminomethyl-5-chlorobenzimidazole 4.3 g of 1-ethyl-2-chloromethyl-5-chlorobenzimidazole in 25 ml of chloroform are added dropwise and 5 g of diethanolamine diluted with 5 ml of chloroform are added while stirring. The reaction mixture is then allowed to react to completion overnight at room temperature. the Work-up is carried out as in Example 1. That obtained after evaporation of the chloroform Crude 1-ethyl-2-diethylaminomethyl-5-chlorobenzimidazole falls as a solid Substance in a yield of 710 in theory. The raw base is recrystallized from ethyl acetate and melts at 133 to 134.5 "C.
Das Monohydrochlorid wird gemäß Beispiel 1 dargestellt; F. 110,5 bis 111,5"C. The monohydrochloride is prepared according to Example 1; F. 110.5 to 111.5 "C.
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DESCH27821A DE1106765B (en) | 1960-04-28 | 1960-04-28 | Process for the preparation of substituted benzimidazoles |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DESCH27821A DE1106765B (en) | 1960-04-28 | 1960-04-28 | Process for the preparation of substituted benzimidazoles |
Publications (1)
Publication Number | Publication Date |
---|---|
DE1106765B true DE1106765B (en) | 1961-05-18 |
Family
ID=7430906
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DESCH27821A Pending DE1106765B (en) | 1960-04-28 | 1960-04-28 | Process for the preparation of substituted benzimidazoles |
Country Status (1)
Country | Link |
---|---|
DE (1) | DE1106765B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1241286B (en) * | 1963-08-21 | 1967-05-24 | John Deere Lanz Ag | Hydraulic servo device for vehicle steering |
-
1960
- 1960-04-28 DE DESCH27821A patent/DE1106765B/en active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1241286B (en) * | 1963-08-21 | 1967-05-24 | John Deere Lanz Ag | Hydraulic servo device for vehicle steering |
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