FI77236C - Process for the preparation of benzimidazole derivatives - Google Patents

Description

1 77236

Process for the preparation of benzimidazole derivatives

The invention relates to a process for the preparation of benzimidazole derivatives of the formula wherein R is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or 1-trifluoromethyl and R is amino or N-alkoxycarb-15-carbonylamino.

The compounds of formula I in which R 5 is amino are novel.

It is known that some compounds of formula I have a valuable anthelmintic effect. Some of the compounds of formula I20 are useful as intermediates in the preparation of said anthelmintic compounds.

There is no process on an industrial scale for the preparation of compounds of formula I.

One method of preparing these compounds is described in HU Patent Publication 169,272. According to this method, 5 (6) -thiocyanato-2-methoxycarbonylaminobenzimidazole is prepared by reducing 1-amino-2-nitro-4-thiocyanato-benzene in concentrated hydrochloric acid at 30-40 ° C with the largest excess of stannous chloride used. The resulting 1,2-diamino-4-thiocyanato-benzene is extracted from the reaction mixture with chloroform and reacted in aqueous acetic acid medium with 1,3-bis- (methoxycarbonyl) -S-methyl-iso-35-thiourea to give mercaptan. The method 2,77236, on the one hand, has disadvantages due to the high cost of the reagents β-stannous chloride, 1,3-bis- (methoxycarbonyl) -S-methylisothiourea, on the other hand, due to environmental protection problems, and therefore cannot be used on an industrial scale.

The process according to the invention is characterized in that the compound of the formula "Ci."

B

wherein and have the same meaning as above, are reacted with chlorine gas and rhodanide of the formula R-SCN (III) wherein R is an alkali metal atom or an ammonium group.

Direct rhodanation of 2-substituted benzimidazole-20 derivatives of formula II has not been previously described. Although in the literature £ S. Patai: "The Chemistry of Cyanates and their Thio Derivates", Part 2, pp. 837 (1977), Wiley: Pharmazie 32 (4), 195 (1977). no rhodanation reaction has been performed so far. Halogenation of the compounds of formula II, which resembles rhodanization, is also not mentioned in the literature. Although halogenation of other types of 2-substituted benzimidazoles has been described, the halogenation 30 results in a mixture of different products, e.g.

For the formation of 4 (7) -halogen and 4,6 (5,7) -halogen-benzimidazoles.

The process uses chlorodhodane, which is prepared from rhodanidis-35 of formula III and chlorine gas, as the rhodanation reagent. Accordingly, chlorodhodane is prepared by reacting a rhodanide of formula 3 77236 III and chlorine gas in an anhydrous organic solvent and the solution is then added to a solution of the compound of formula II in an organic solvent. A solution of a compound of formula II can, of course, also be added to the chlorodhodane solution.

The process can also be carried out by introducing chlorine gas into a solution or suspension of the compounds of the formulas II and III in an organic solvent. In this case, the in situ nascendi-formed chloro-10 rirodane reacts immediately with the compound of formula III.

In the process according to the invention, the compound of the formula II and chlororodane are used in a molar ratio of 1: 1 to 1: 5, preferably 1: 1 to 1: 3.

According to another embodiment, to a solution of 1 mole of a compound of formula II in an anhydrous organic solvent or mixture of solvents is added 1 to 3 moles of rhodanide of formula III, followed by 1 to 4 moles of dry solvent at 15 to 40 ° C. chlorine gas.

Chlorine gas can also be added to a solution or suspension of compounds of formula II and III in the form of a solution formed with an organic solvent. Chlorine gas or a solution thereof is preferably added within a short time.

As the rhodanide of the general formula III, alkali metal rhodanides or ammonium rhodanide, preferably potassium rhodanide, sodium rhodanide or ammonium rhodanide, can be used.

Suitable organic solvents and / or diluents include dipolar, aprotic solvents in which the components are highly soluble, such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, low molecular weight carboxylic acids, esters, especially acetates, ethylates or formates, C dichloromethane or dichloroethane, further nitromethane or acetonitrile. A particularly preferred solvent is acetic acid.

4,77236

The reaction is carried out at a temperature of 0 to 100 ° C, preferably 15 to 40 ° C.

The following examples illustrate the invention.

Example 1 To a solution of 5 g of 2- (methoxycarbonylamino) benzimidazole and 7.5 g of dry potassium rhodanide in 100 ml of acetic acid is introduced 5.5 g of dry chlorine gas. The reaction mixture is diluted with 100 ml of water and the pH of the solution is adjusted to 5-norm. with sodium hydroxide solution to 4. The separated precipitate is filtered off, washed with water and dried at 60 ° C. 5.6 g (yield: 90%) of 5 (6) -thiocyanato-2- (methoxycarbonylamino) benzimidazole are obtained; mp. 252-254 ° C (dec.).

Example 2 A solution of 7.5 g of dry potassium rhodanide in 60 ml of anhydrous acetic acid is added to 70 ml of carbon tetrachloride containing 5.32 g of chlorine at 10-15 ° C with stirring. The reaction mixture is further stirred for a further 15 minutes, after which 5 g of 2- (methoxycarbonylamino) benzimide-20-azole in 25 ml of anhydrous acetic acid are added. After stirring at room temperature, the reaction mixture is poured into water. The carbon tetrachloride phase is separated, after which, and after decolorization with activated carbon, the pH of the aqueous solution is adjusted to 5-norm. with sodium hydroxide solution to 25 4. Filter the precipitate formed, wash with water and dry at 60 ° C. There is thus obtained 5 (6) -thiocyanato-2- (methoxycarbonylamino) benzimidazole; mp. 248-250 ° C (dec.).

Claims (3)

Process for the preparation of benzimidazole derivatives of the formula 5 Rfeci s 10 H wherein R * is hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or trifluoromethyl and R is amino or C 1-4 alkoxycarbonylamino, characterized in that the compound of formula 15 "" to 20 wherein R 1 and R 2 are as defined above, is reacted with chlorine gas and rhodanide of the formula 25 R-SCN (III) wherein R is an alkali metal atom or an ammonium group.