HU200168B - New process for producing benzimidazole derivatives - Google Patents

Abstract

Benzimidazole derivs. of general formula (1) (where R1 = 1-5C alkyl gp.) from a benzimidazole deriv. of formula (11) (where R1 = same) and a propyl-sulphonyl-halogenide of general formula (111) (where X = a halogen).

Description

The present invention relates to a novel process for the preparation of benzimidazole derivatives of formula I.

It is known that 5 (6) substituted benzimidazole-2-carbamate derivatives of formula I are useful in medicine due to their anthelmintic activity.

In the above general formula, the variable substituents in the present patent application are always as follows: R is C 1 -C 4 alkyl, X is halogen.

The position of the 5 (6) substituent is abbreviated to the 5-substituent, but is not intended to fix the position.

The description and synthesis of the product are described, for example, in the following patents: 1,123,317, 1,464,326. s. Great Britain, and 2,438,120. No. 817,763 of the USSR; s. Belgian, furthermore, 3,738,993. and 4,076,827. s. U.S. Patent Nos. 182,763; and 182,782. s. Hungarian patents.

For example, according to the patents mentioned above, the formation of the 5-alkylsulfenyl group can be accomplished in essentially 3 ways:

1) The 1,2-N-substituted-4-halobenzene or the 5-halobenzimidazole-2-carbamate is reacted with an alkali mercaptide or sodium bisulfide followed by an alkyl or aryl halide.

2) Obtained with an alkyl or aryl halide from a thiocyanic acid ester obtained from an 1,2-N-substituted-4-halobenzene or 5 (6) -halobenzimidazole-2-carbamate with an alkali-rhodanide by reduction with sodium sulfide. thioether (Hungarian Patent No. 182,763).

3) The 4-position of the 1,2-N-substituted benzene or the 5 (6) position of the abenzimidazole-2-carbamate is reduced, the resulting sulfochloride is reduced to the mercaptan or disulfide, and the thioether is converted to the alkylthio or aryl halide. Hungarian Patent No. 182,782).

A common feature of these pathways is that the molecule is constructed in several steps, and the yields of each step are often below the requirements of economical implementation and, due to the wide potential of side reactions, do not provide a uniform product. A new chapter in the preparation of the target compounds was opened by the idea that benzimidazole (II), a known fungicidal active ingredient and thus commercially manufactured to meet the needs of the pesticide industry, was used as a starting material. From this starting material, 187,782 is obtained. s. According to the examples, the Hungarian patent application shows approx. 43, respectively. It promises a 60% yield for Albendazole. No. 182,794. s. 5-rhodan derivative according to U.S. Pat. According to the patent, the reduction of sodium sulfide in the examples of the same with the same starting material is approx. 84-86% yield. However, in this variant of the process, there are significant problems with the start-up time: cyanide ions are formed during the reaction and require significant safety measures. Another problem is that the purity of the reaction product does not match: the product

VR's thin-layer chromatogram contains several impurities, which may indicate the presence of 7-8 by-products, 8-10% impurity. The process itself is at least 3 steps, and the sodium sulfide reduction produces an unpleasant odor.

The following process, which is the subject of the present invention, provides a new opportunity to construct the desired molecule according to a novel concept not yet employed in the art.

The present invention relates to a process for the preparation of benzimidazole derivatives of formula I by reacting a chlorobenzimidazole compound of formula II with propylsulfenyl halide of formula III.

The reaction is preferably carried out in the presence of an organic solvent at a temperature of 0 ° C to 80 ° C, in fact Friedel. Crafts type reaction.

The starting compounds of formula (ΠΙ) are known.

Aluminum chloride catalyst may be added to the reaction.

The reaction solvent may be acetic acid or formic acid. When using an aluminum chloride catalyst, hydrogen may also be used, for example dichloroethane, trichlorethylene, carbon tetrachloride.

The process of the present invention will be described in more detail in the examples, without limiting the scope of the invention to these examples.

Example 1

19.9 g of 2-carbomethoxyaminobenzimidazole are dissolved in 100 ml of glacial acetic acid (water content 0.1%) and 11.0 g of propylsulfenyl chloride is added dropwise with cooling. Then heat in a hot water bath until the evolution of hydrochloric acid is complete (3-4 hours). After cooling to room temperature, the suspension is filtered, the filter residue is washed with cold water to an acid-free solution and dried. The product is 23-24 g of 5-propylsulfenylcarbomethoxyaminobenzimidazole. Mp: 208-210 'C. Yield: 86.9%.

Example 2 1.1 g of 2-carbomethoxyaminobenzimidazole are suspended in 100 ml of carbon tetrachloride, 13.3 g of aluminum chloride are added, and 11 g of propylsulfenyl chloride are added dropwise at 0 ° C. The temperature is then carefully raised to reflux and maintained here until the evolution of hydrogen chloride gas is complete. It is then cooled to room temperature. Once the ice has melted, it is filtered, the filter residue is washed with water to remove acid, and dried. 21 g of 5-propylsulfenyl-2-carbomethoxy-aminobenzimidazole are obtained. Mp: 208-210 'C. Yield: 72.2%.

Claims (1)

Patent Claim Point A process for the preparation of benzimidazole derivatives of the formula I R ¹ is a C 1-4 alkyl group of a benzimidazole derivative of formula II R ¹ is as defined above, wherein the benzimidazole derivative of formula II is reacted with the above propylsulfenyl halide of formula (ΙΠ), X is halogen, in the presence of an organic solvent at a temperature of 0 to 80 ° C.