FI73417B - BIS- (2-ALCOXYCARBONYLAMINOBENSIMIDAZOL-5-YL) DISULFIDERED SOM ANVAENDS SOM UTGAONGSMATERIAL VID FRAMSTAELLNING AV 5 (6) -TIOBENSIMIDAZOLDERIVAT. - Google Patents

Description

1,74141 7 Bis- (2-alkoxycarbonylaminobenzimidazol-5-yl) disulfide derivatives used as starting materials in the preparation of 5 (6) -thiobenzimidazole derivatives 5 Separated from application 781480 (patent 71557)

The invention relates to bis- (2-alkoxycarbonylaminobenzimidazol-5-yl) disulfide derivatives having the formula: NH-COOR5 (VI) 2

H J

15 2 wherein R is hydrogen, halogen, C 1-4 alkyl, trifluoromethyl 3. 3 or 5, or OR, wherein R is C 1-6 alkyl, and R is C 1-6 alkyl.

The compounds of the formula VI are useful as starting materials for the preparation of 5 (6) -thiobenzimidazole derivatives of the formula described in FI patent publication 71557 20 with the formula: 25 | } —NH-COOR5 (I)

B

2 wherein R is hydrogen, halogen, C 1-6 alkyl, trifluoromethyl 3 3 4 or OR, wherein R is C 1-6 alkyl, R is C 1-6 alkyl, C 1-6 cycloalkyl, C 3-6 alkenyl, C 1-6 alkyl; g-alkynyl f phenyl or benzyl and R 5 is C 1-4 alkyl, and salts thereof.

Particularly preferred starting materials of formula VI are the following derivatives: bis- (2-methoxycarbonylamino-benzimidazol-5-yl) -di-35-sulfide, 2,741,7 bis- (2-methoxycarbonylamino-6-methyl-benzimidazol-5-yl) - disulfide, bis- (2-methoxycarbonylamino-6-butyl-benzimidazol-5-yl) -disulfide, 5 bis- (2-methoxycarbonylamino-6-bromo-benzimidazol-5-yl) -disulfide, bis- (2-methoxycarbonylamino- 6-Chloro-benzimidazol-5-yl) -disulfide, bis- (2-methoxycarbonylamino-6-fluoro-benzimidazol-5-yl) -disulfide, bis- (2-methoxycarbonylamino-6-trifluoromethyl-benzimidazol-5 -yl) disulfide, bis- (2-methoxycarbonylamino-6-methoxybenzimidazol-5-yl) disulfide.

Compounds of formula VI may be prepared by a) reacting a compound of formula r 2> WH 2 20 I (VII) NH 2 --S 2 LJ 2 2 wherein R is as defined above with a compound of formula R5OOCN = C-NH-COOR5 (XII) A. » or NC-NH-COOR5 (XIII) 5 wherein R is as defined above, or b) a compound of formula

II

3 7341 7 'ΧΧ> "· S H 2

5 L

is reacted with a compound of formula X-COOR5 (XIV) 10 or (R50) 2CO (XV) wherein R1 is as defined above and X is halogen.

According to one embodiment of process variant a), a compound of formula VII is reacted with an isothiourea derivative of formula XII. The reaction is preferably carried out by heating the components in a protic solvent in the presence of an acid. Water or an organic solvent (e.g., a water-ethanol mixture) can be used as the reaction medium. The reaction is preferably carried out at a pH of 3-6, especially 3.5-5. The pH is adjusted with an inorganic acid (e.g. hydrochloric acid, sulfuric acid or phosphoric acid) or an organic acid (e.g. formic acid, acetic acid, propionic acid, etc.), preferably acetic acid. The reaction temperature is preferably 50 to 100 ° C, and most preferably the boiling point of the reaction mixture is worked.

Process variant a) According to another embodiment, the compound of formula VII is reacted with a carbalkoxycyanamide of formula XIII in a water-miscible organic solvent, e.g. methanol, ethanol, acetone, dioxane or pyridine, or a mixture of water and an organic solvent. The reaction is preferably carried out at a temperature between 20 ° C and the boiling point of the reaction mixture.

4,73417

In process variant b) a compound of formula Via is reacted with an alkyl haloformate of formula XIV. The reaction is preferably carried out in a basic organic solvent (e.g. pyridine) at 50-100 ° C.

Alternatively, a compound of formula Via may be reacted with a dialkyl carbonate of formula XV in the presence of an alkali alcoholate in an equimolar amount. Preferably, 10 alkanols are used as the solvent. As the reaction medium, an alcohol corresponding to the R 1 group of the alkali metal alcoholate can be preferably used. The reaction temperature is 20 to 120 ° C, preferably the boiling point of the alcohol used as solvent.

It will be apparent to those skilled in the art that the compounds set forth in Examples 15 may be named in two different ways depending on whether the numbering is initiated at the N atom or the NH group. Thus, bis- (2-methoxycarbonylaminobenzimidazol-5-yl) disulfide may also be referred to as bis (2-methoxycarbonylaminobenzimidazol-6-yl) disulfide.

All other compounds of formula VII except those in which R is hydrogen are new. To prepare this compound, a very cumbersome and complex seven-step synthesis has been described in the literature, in which the aniline is rhodanized, the amino group is protected with an acetyl group, the product is nitrated and hydrolyzed, and then converted to a disulfide which is then cleaved to 2-amino-4-mercaptoaniline. , which is finally formed into the disulfide ε Ber. 59, 190 (1926); J. Chem. Soc. 1928, 1364; Pharmazie 3, 151 (1948); Arzenimitte 1 Forschung 2, 455 (1952) _7. Due to the complex reaction steps and low yields, this method is unsuitable for industrial production.

It has now been found that compounds of formula VII can be readily prepared on an industrial scale without by-products by heating a compound of formula 5 73417 RVip 5 The reaction is preferably carried out in a suitable solvent in the presence of a catalyst.

As the solvent, water or a lower alkanol, e.g. methanol, ethanol or propanol, or a mixture of water and a lower alkanol can be used. The catalyst may be an inorganic base (preferably sodium hydroxide or potassium hydroxide), an alkali metal carbonate (e.g. sodium carbonate or potassium carbonate) or preferably ammonium hydroxide.

The preparation of the final products of formula I is described in FI patent 71557.

The following examples illustrate the invention.

Example 1 2.78 g of 3,3 ', 4,4'-tetraaminodiphenyl disulphide and 5.0 g of S-methylisothiourea diurethane are dissolved in 100 ml of 50% vol. Alcohol, and 1 ml of acetic acid is added to the solution. . The mixture is boiled until the evolution of methyl mercaptan ceases (about 3 hours), then the precipitated bis- (2-methoxycarbonylbenzimidazol-5-yl) disulfide is filtered off, washed and dried. 4.2 g (95%) of product are obtained, m.p. 328 ° C (decomposes).

Example 2 8.8 g of sodium hydroxide are dissolved in 50 ml of water, and 4.2 g of cyanamide are added to the solution. The mixture is cooled to 10 ° C and 9.4 g of chloroformic acid methyl ester are added dropwise over 30-45 minutes. The mixture is stirred for a further 30 minutes, then added to a solution of 13.9 g of 3,3 ', 4,4'-tetraaminodiphenyl disulphide in 200 ml of 75% strength by volume alcohol. The reaction mixture is boiled, and the pH is maintained in the range of 3-4 by the occasional addition of concentrated hydrochloric acid. After boiling for 90 minutes, the mixture is cooled to room temperature and the precipitated product is isolated by filtration. 19.0 g of bis- (2-methoxycarbonylaminobenzimidazol-5-yl) disulfide are obtained, m.p. 325 ° C (decomposes).

6,73417

Example 3

The procedure of Examples 1-2 is followed and the following o-phenylenediamine derivatives are used as starting materials: 2,2'-dimethyl-4,4 ', 5,5'-tetraaminodiphenyl disulfide, 2,2'-dibutyl-4,4', 5, 5'-tetraaminodiphenyl disulfide, 2,2'-dibromo-4,4 ', 5,5'-tetraaminodiphenyl disulfide, 2,2'-dichloro-4,4', 5,5'-tetraaminodiphenyl disulfide, 2 , 2'-difluoro-4,4 ', 5,5'-tetraaminodiphenyl disulfide, 2,2'-di (trifluoromethyl) -4,4', 5,5'-tetraaminodiphenyl-10 disulfide, 2.2 dimethoxy-4,4 ', 5,5'-tetra-aminodifenyylidisulfidi.

The following compounds are obtained: bis- (2-methoxycarbonylamino-6-methylbenzimidazol-5-yl) disulfide, m.p. 305-310 ° C, 15 bis- (2-methoxycarbonylamino-6-butylbenzimidazol-5-yl) disulfide, m.p. 295-298 ° C, bis- (2-methoxycarbonylamino-6-bromobenzimidazol-5-yl) disulfide, m.p. 310 ° C (decomposes), bis- (2-methoxycarbonylamino-6-chlorobenzimidazol-5-20 yl) disulfide, m.p. 305-310 ° C (decomposes), bis- (2-methoxycarbonylamino-6-fluorobenzimidazol-5-yl) disulfide, m.p. 285-288 ° C, bis- (2-methoxycarbonylamino-6-trifluoromethylbenzimidazol-5-yl) disulfide, m.p. above 340 ° C, 25 bis- (2-methoxycarbonylamino-6-methoxybenzimidazol-5-yl) disulfide, m.p. 297-300 ° C (decomposes).

Example 4 3.32 g of bis- (2-aminobenzimidazol-5-yl) disulfide are dissolved in 300 ml of pyridine, and 2.0 g of chloroformic acid methyl ester are added to the solution under cooling. The mixture is allowed to stand overnight, then heated in a water bath for 90-120 minutes. The pyridine is distilled off in vacuo, water is added to the residue, and the precipitated crystals are filtered off, washed and dried. 3.4 g (78%) of bis- (2-35 methoxycarbonylaminobenzimidazol-5-yl) disulphide are obtained, m.p. 325 ° C (decomposes).

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Example 5 3.32 g of (2-aminobenzimidazol-5-yl) disulphide are dissolved in 30 ml of methyl alcohol, and 1.80 g of dimethyl carbonate and 0.46 g of metallic sodium dissolved in 30 ml of methyl alcohol are added to the solution. The mixture is boiled for one hour. The mixture is then acidified with acetic acid to pH 5.5-6 and the precipitated bis- (2-methoxycarbonylamino-benzimidazol-5-yl) -disulfide is filtered off. Weight: 4.1 g (92.5%). Sp. 325 ° C (decomposes).

Claims (3)

A bis- (2-alkoxycarbonylamino-benzimidazol-5-yl) -disulfide derivative useful as a starting material for the preparation of 5 (6) -thiobenzimidazole derivatives of the formula R 1 -NN-v-NH-COOR 5 (I) R 4 S '2 is wherein R is hydrogen, halogen, C 1-6 alkyl, trifluoromethyl or OR 1, wherein R 2 is C 1-6 alkyl, R 2 is C 1-6 alkyl, C 1-6 cycloalkyl, C 1-6 alkenyl, C 1-6 alkynyl, phenyl or benzyl and R 6 is C 1-6 alkyl, and salts thereof, characterized in that it has the formula 20 M / NH -COOR5 (VI) _ H _ 2 5 2 where R and R are as defined above.