DE1106765B - Process for the preparation of substituted benzimidazoles - Google Patents

Description

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.

It has now been found that by halogen substitution in the benzene ring (R4 = halogen, preferably chlorine) there is surprisingly an anti-inflammatory increase in activity of about double, although the halogenated substance also experiences a slight (about 200/0) increase in toxicity, but is much higher with the one therapeutic effect, there is a considerable range of variation within the therapeutic and toxic limits, as can be clearly seen from the table below: Edema - more therapeutic LD50 inhibition effective (%) effect 1 -ethyl-2-diethanolamino- methyl benzimidazole monochlorohydrate. . 448 25 0.056 l-ethyl-2-diethanolamino- methyl-5-chloro-benz- imidazole monochlorine hydrate. . ... 358 44 0.123 the LD50 was determined after intravenous administration to the mouse and the anti-inflammatory effect was tested in the rat after intraperitoneal pretreatment with the active substance at a dose of 2.80 mg / kg in formalin edema.

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.

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.

The new benzimidazoles can be converted into theirs in a manner known per se Transfer salts, especially the monochlorohydrate.

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.

That from the base by treatment with the calculated amount of hydrochloric acid produced monohydrochloride melts at 222 to 223 "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.

The monohydrochloride is prepared according to Example 1; F. 110.5 to 111.5 "C.

Claims (1)

PATENT CLAIM: Process for the production of substituted benzimidazoles with anti-inflammatory and analgesic properties of the general formula where Hal is halogen, in particular chlorine, Rl is hydrogen or alkyl, R2 and R3 is the atomic grouping - CH2 - CH2 - OH or R2 is the atomic grouping - CH2 - CH2 - OH and Ra is hydrogen or R2 and R3 together with the nitrogen atom is the morpholine residue, according to the main patent 1078132, characterized in that a) 2-halomethyl-5-halobenzimidazoles of the general formula in which R1 has the meaning given above, is reacted with ethanolamine, diethanolamine or morpholine, or that b) compounds of the general formula where R1 to R3 also have the meaning given above, subjects the ring closure reaction to give benzimidazole, which is known per se, and optionally converts the products thus obtained, in a manner known per se, into the corresponding water-soluble acid addition salts, preferably into the monochlorohydrate.