CS254979B2 - Method of benzimidazolethiole's new derivatives production - Google Patents

Abstract

The process for the preparation of the novel benzimidazolethiol derivatives of the formula IV HS nh-coor (IV) in which R is C 1 -C 3 alkyl, characterized in that the alkyl ester of carbamic acid, wherein at the 5-position is hydrogen instead of the thiol group, is treated with chlorosulfonic acid or ole to form the 5-sulfonic acid; it is treated with chlorinating agents and the corresponding sulfonic acid chloride obtained is reduced. The compounds of formula IV produced have biological activity or can be used as intermediates to produce other valuable biologically active compounds.

Description

The present invention relates to a process for the preparation of novel benzimidazole thiol derivatives which are biologically active compounds or can be used as intermediates to produce other valuable biologically active compounds.

To date, 4-alkylthiophenylenediamine and the corresponding reagent have been used as starting materials in the preparation of analogous 5- (alkylthio) -1H-benzimidazoles, with alkoxycarbonylcyanamide or cyanogen bromide being suitable.

In the first case, the end product can be obtained immediately, in the second case 2-amino-5-alkylthiobenzimidazole is formed first, which is reacted with an alkyl chloroformate to give the end product.

The above processes are described in U.S. Patent No. 3,956,499 and in Hungarian Patent No. 172,538, where the production of one of the most prominent representatives of these compounds, i.e. 2 - [(methoxycarbonyl) amino] -5- ( propylthio-1H-benzimidazole This compound is used as an anthelmintic with a broad spectrum of activity.

A significant disadvantage of the above processes is that 4-alkylthio-1,2-phenylenediamine is difficult to manufacture and expensive, using toxic and odorous starting materials as well as hazardous and expensive hydrogenation processes.

The present invention relates to a process for the preparation of the novel 2 - [(alkoxycarbonyl] amino] -5-thio-1H-benzimidazoles of the general formula IV

HS

H

NH-COOR (IV) wherein

R represents an alkyl group having 1 to 3 carbon atoms by reaction of an alkyl ester of a carbamic acid of formula I

NH-COOR

H (I) wherein

R is as defined above, with chlorosulfonic acid or oleo, by reacting the resulting sulfonic acid derivative of the general formula II

HO ₃ S

in which

R is as defined above, with chlorinating agents, and by reducing the sulfonic acid chloride of formula III obtained

NH-COOR (III) wherein

R is as defined above, and isolating the obtained benzimidazole thiol of the above formula IV.

Possible chlorinating agents are:

phosphorus oxychloride, phosphorus pentachloride netm pyrocatechylphosphoric chloride.

The reduction of the compounds of the general formula (III) is preferably carried out in an aqueous, acidic medium by treatment with metals or metal salts.

Synthesis according to the invention produced by:

2 - [(alkoxycarbonyl) amino] -1H-benzimidazole-5-sulfonic acids (II) and their salts, 2 - [(alkoxycarbonyl) amino] -1H-benzimidazole-5-sulfonic acid chlorides (III), and their salts; and

2 - [(alkoxycarbonyllamino) -1H-benzimidazole-5-thiols (IV) and their salts are novel compounds.

(1H-Benzoimidazol-2-yl) -carbamic acid alkyl esters of formula (I) may be reacted with oleum at 30-60 ° C to give a 20% yield. The reaction mixture is poured into ether to give a white crystalline 2 - [( alkoxycarbonyl-amine 254979-N-1H-benzimidazole-S-sulfonic acid of formula II.

2 - [(Alkoxycarbonyl) amino] -1H-benzimidazole-5-sulfonic acid chloride of formula III is obtained when:

a) reacting the compound of formula I with chlorosulfonic acid at a temperature of 15 to 40 ° C, pouring the resulting reaction mixture into absolute alcohol or ice, whereby the compound of formula I

III is obtained in the form of the hydrochloride, or the reaction mixture obtained is poured into a mixture of ether and ethyl acetate and the compound of the formula III is isolated in the form of a sulfuric acid salt or by converting the compound of the formula II into methanol with sodium hydroxide. the salt is then melted at 110 ° C with phosphorus pentachloride, the melt is poured onto ice and the compound of formula III is isolated.

To the 2 - [(alkoxycarbonyl) amino] -1H-benzimidazole-5-sulfonic acid chloride of formula (III), metals or metal salts are added under acidic conditions and the reduction is carried out in the temperature range of 0 to 100 ° C to give 2- [(alkoxycarbonyl] amino] -1H-benzimidazole-5-thiol

IV as a white crystalline precipitate.

An advantage of the process of the present invention, which provides an intermediate, is that low-cost, mass-produced compounds of formula (I) are used as starting materials, from which the final product of formula (IV) is obtained by simple techniques using cheap reagents.

The following examples illustrate the process according to the invention; however, they do not limit the scope of the invention in any way.

Example 1

Preparation of 2 - [(methoxycarbonyl) amino] -1H-benzimidazole-5-sulfonic acid

A 250 ml four-necked flask equipped with a stirrer, thermometer, and gas scrubber containing 250 ml of sulfuric acid was charged with 120 ml of 20% olea and 33.4 g of water were added at 30-40 ° C with gentle cooling in ice water over 15-20 minutes. (0.2 mol) of (1H-benzimidazol-2-yl) -carbamic acid methyl ester The temperature is raised to 55 to 0 ° C and the mixture is then stirred at this temperature for 2 hours, meanwhile 1200 ml of ethyl ether is cooled with ice / salt. The mixture of oleate and reaction mixture was poured into ether with stirring so that the temperature of the mixture did not exceed 0- ° C.

The product is obtained in the form of a white crystalline precipitate, the precipitate is filtered off, washed with cooled ether and 100 ml of cooled absolute ethanol (100 ml) and dried.

Weight: 43.5 g (theory: 54.26 g)

Yield: 80%

Analysis:

found:

C, 39.2; H, 3.5; N, 15.1; S, 12.1; calculated:

% C, 39.84;% H, 3.34;% N, 15.49.

11.8% S.

Example 2

Preparation of 2- ((methoxycarbonyl) amino] -1H-benzimidazole-5-sulfonic acid chloride hydrochloride

A 500 ml flask equipped with a stirrer was charged with 81.3 g (0.3 mol) of 2 - [(methoxycarbonyl) amino] -1H-benzimidazole-5-sulfonic acid and 300 ml of methanol and then added dropwise at room temperature to 40% aqueous sodium hydroxide solution until a pH of 7.5 is reached. The starting material dissolves and precipitates the sodium salt of 2 - [(methoxycarbonyl amino) -1H-benzimidazole-5-sulfonic acid After stirring for 1 hour, the mixture is filtered, the residue on the filter is washed with a small amount of methanol and dried.

90 g of the sodium salt are obtained.

The dried sodium sulfonic acid salt was melted at 110 ° C with 130 g (0.625 mol) of phosphorus pentachloride and the melt was stirred at that temperature for a further 2 hours.

The mixture is then poured onto 400 g of crushed ice, washed with ice water and then with 100 ml of absolute ethanol at -10 DEG C., and the isolated product is dried.

Weight: 82 g (theory: 97.86 g)

Yield: 84%

Analysis:

found:

H, 3.0; H, 21.6; N, 13.0; S, 9.75;

calculated:

C, 33.14; H, 2.78; Cl, 21.74.

N, 12.88. S, 9.83.

Example 3

Preparation of 2 - [(methoxycarbonyl) amino] -1H-benzimidazole-5-sulfonic acid chloride hydrochloride

A 250 ml four-necked flask equipped with a stirrer, thermometer and a sulfuric acid gas purge was charged with 100 ml (178.7 g; 1.53 mol) of chlorosulfonic acid and then added at 15-20 ° C over 30 minutes. 38.4 g (0.2 mole) of (1H-benzimidazol-2-yl) -carbamic acid methyl ester was added under gentle cooling with ice water and the mixture was heated to 40 ° C. The mixture was stirred at this temperature for 2.5 hours and then the reaction mixture was poured into 1000 mL of ethanol cooled to -10 ° C such that the temperature did not exceed 0 ° C. The reaction mixture is then cooled on ice with a significant addition of sodium chloride. The reaction product is deposited as white crystals. The product is filtered off, washed with 100 ml of cooled absolute ethanol and dried.

Weight: 60.6 g (theory: 62.2 g)

Yield: 93%

Melting point: 250 ° C

Analysis:

found ’

H, 3.02; H, 21.64;

N, 12.91; S, 9.81;

calculated:

C, 33.14; H, 2.78; Cl, 21.74.

12.88% N, 9.83 θ / o S.

Example 4

Preparation of 2 - [(methoxycarbonyl) amino] -1H-benzimidazole-5-sulfonic acid chloride hydrochloride

The procedure is as described in Example 3, but the product is isolated as follows:

The reaction mixture is poured onto 800 g of crushed ice, the precipitated product is filtered off, washed with a little ice water and 100 ml of absolute ethanol cooled to -10 DEG C. and dried.

Weight: 52.1 g (theory: 65.2 g)

Yield: 80%

The acid chloride isolated from water is expediently used without drying, since this product decomposes during drying.

Example 5

Preparation of 2 - [(methoxycarbonyl), amino] -1H-benzimidazole-5-sulfonic acid hydrogen sulphate

A 200 ml four-necked flask equipped with a stirrer, thermometer and sulfuric acid scrubber was charged with 100 ml (178.7 g, 1.53 mol) of chlorosulfonic acid and glacial at 15-20 ° C for about 30 minutes with ice cooling. water (38.4 g, 0.2 mol) of (1H-benzimidazol-2-yl) carbamic acid methyl ester is added and the mixture is heated to 40 DEG C. The mixture is stirred at this temperature for 2.5 hours and then the reaction mixture is added to solution of 1000 ml of ethyl ether and 300 ml of ethyl acetate, cooled to -10 ° C, so that the temperature does not exceed 0.1 ° C.

The precipitated white, crystalline product is filtered off, washed with 200 ml of cooled ether, and dried in a vacuum desiccator. (The dried product is no longer hygroscopic. J

Weight: 64,40 g (theory: 77,4 g)

Yield: 83.2%

Melting point: 142 to 145 ° C (decomposition)

found:

27.52% C, 2.8% H, 9.18% Cl,

N, 10.12; S, 16.45;

calculated:

27.87% C, 2.6% H, 9.14% Cl,

N, 10.83. S, 16.54.

Example 6

Preparation of 2 - [(ethoxycarbonyl) amino] -1H-benzimidazole-5-sulfonic acid chloride hydrochloride

To 100 ml (178.8 g, 1.53 mol) of chlorosulfonic acid at 15-20 ° C was added 41 g (0.2 mol) of ethyl (1H-benzimidazol-2-yl) carbamic acid ethyl ester in about 30 minutes, The mixture was warmed to 40 ° C and stirred for 2.5 hours. The reaction mixture was then poured into absolute ethanol cooled to -10 ° C. The product is obtained in the form of white crystals. The crystals were filtered off and dried.

59 g of product are obtained (theory: 68 gj. Analysis):

found:

35.0% C, 3.1% H, 20.6% Cl, 12.7% N,

9.3% S; calculated:

35.3% C, 3.26 O / o H, 20.84% _C 1,

12.35 O / o N, 9.43% S.

Example 7

Preparation of 2 - [(methoxycarbonyl) amino] -1H-benzimidazole-5-thiol

6 g of tin powder are added to 100 ml of 10% hydrochloric acid at 0-10 ^and C, and then 10.8 g (0.033 mol) of 2 - [(methoxycarbonyl) amino] -1H-benzimidazole-5 chloride hydrochloride are added. -sulf o254979 new acids. The reaction mixture was stirred at below 10 ° C for 2 hours and at 25 ° C for 10 hours. The starting materials are dissolved and the reaction product precipitates from the reaction solution.

Weight: 6 g (81.5% of theory)

214 DEG-215 DEG C. (decomposition)

found:

H, 4.20; N, 18.52.

13.80% S;

calculated:

% C, 48.60;% H, 4.06;% N, 18.88.

14.39% S.

6 g of tin powder and 10.8 g (0.033 mol) of 2 - [(methoxycarbonyl) amino] -1H-benzimidazole-5-sulfonic acid chloride hydrochloride are added to 100 ml of 10% hydrochloric acid at 0-10 ° C. 2 hours at 0 to 10 ° C and then 10 hours at 25 ^Q C. the starting materials were dissolved and yellow crystals precipitated as the reaction product. the mixture was cooled to 5 "C, filtered and the filter residue was stirred in 200 ml of 10% sodium carbonate solution, the temperature is then raised to 60 DEG C., the insoluble matter is filtered off and the pH is adjusted to 7.5 with concentrated hydrochloric acid, and the product precipitates in the form of yellow crystals Weight: 6 g (81.5%). theory]

Analysis:

found:

H, 4.2%; N, 18.52;

13.80% S;

calculated:

% C, 48.60;% H, 4.06;% N, 18.88.

14,30% S.

Claims (3)

A process for the preparation of the novel benzimidazolthiol derivatives of the general formula IV 7 <1> HNH-COOR HO.S (IV) in which R represents an alkyl group having 1 to 3 carbon atoms, characterized in that the alkyl ester of the carbamic acid of the formula I R is as defined above, is treated with chlorinating agents and the sulfonic acid chloride of the general formula III in which: R is as defined above, acts with chlorosulfonic acid or oleo to produce the resulting sulfonic acid of formula II wherein: R is as defined above, is reduced. 2. A process according to claim 1 wherein the chlorinating agent is phosphorus oxychloride, phosphorus pentachloride or pyrocatechylphosphorotrl chloride. 3. The process according to claim 1, wherein the reduction is carried out by treatment with metals or metal salts in the presence of water and acid.