DE1079063B - Process for the preparation of 5-sulfanilamido-3-benzyl-1, 2, 4-thio-diazoles - Google Patents

Description

Process for the preparation of 5-sulfanilamido-3-benzyl-1,2,4-thiodiazoles 4-aminobenzenesulfonyl derivatives of 5-amino-1,2,4-thiodiazole, which are in the 3-position by a methyl or phenyl group can be substituted are known. you will be from the corresponding 5-amino-1,2,4-thiodiazoles by reaction with such. Benzenesulfonic acid halides produced which in the 4-position has a substituent which can be converted into an amino group wear. The yields are very low and are, for example, for 5-p-acetylaminobenzene-sulfonamido-1,2,4-thiodiazole 141% of theory (Chem. Ber., 87 [1954], pp. 57 to 67). This process is therefore not technically useful. The bacteriostatic properties of the compounds produced by this process are known from the Swedish patent specification 115 999. From the U.S. Patent 2,358,031 is also the conversion of p-acetylamino- or p-nitrobenzo, isulfonyl chloride with 5-amino-1,2,4-thiodiazoles, which are alkyl or aralky1-substituted in the 3-position, among other things can be known in the case of 3-alkyl- or 3-aralkyl-5-sulfanilamido-1,2,4-thiodiazoles develop.

It has now been found that 5-sulfanilamido-3-benzyl-1,2,4-thiodiazoles can be produced in good yield by using 5-halo-3-benzyl-1,2,4-thiodiazoles, which can be substituted by halogen in the benzene nucleus of the benzyl radical, with benzenesulfonamides, that in the 4-position is an amino group or a group which can be converted into the amino group carry, in the presence of acid-binding agents or with metal salts of the sulfonamides mentioned, expediently in inert diluents, such as. B. diphenyl ether, diphenyl methane, Diphenyl or paraffin oil, heated. The most favorable reaction temperatures are between 100 and 200 ° C. The yields in this procedure are about 70% the theory.

The process, sulfonamides with halogen-substituted heterocycles to implement is known per se. However, it doesn't get technical for any of the products used because experience has shown that it is the usual working method from sulfochlorides and is far inferior to heterocyclically substituted amines (see e.g. F. Mietzsch and R. Behnisch, Therapeutically Usable Sulphonamide and Sulphone Compounds, Verlag Chemie, 1955. p. 6, third section). So far, no case has become known in which the process described is successful where the usual manufacturing process fails. The success of the working method described could therefore not be foreseen and provides for the manufacture of these therapeutics effective against bacterial infections represents an important technical advance.

The 5-sulfanilamido-3-benzyl-1,2,4-thiodiazoles are also superior to the above-mentioned known sulfa-1,2,4-thiodiazoles with regard to their bacteriological effectiveness. This is evident from the following. Results clearly show: Experiments on the bacteriostatic effect of 5-sulfanilamido-1,2,4-thiodiazoles Surface culture on blood casein agar, hemolyte. Streptococci. Incubation time 20 hours. 5-sulfanilamido- 5-sulfanilamido- 5-sulfanilamido- 5-sulfanilamido- 5-sulfanilamido- Dilution 3-methyl- 3-phenyl- 3-benzyl- 3-o-chlorobenzyl- 3-p-chlorobenzyl- 1,2,4-thiodiazole 1,2,4-thiodiazole 1,2,4-thiodiazole 1,2,4-thiodiazole 1,2,4-thiodiazole 1: . 5,000 2 - - - - 1: 10,000 2 0 0 0 0 1: 20,000 2 0.5 0 0 0 1: 40,000 2 2 0 1 0 1: 80,000 2 2 0.5 2 0.5 1: 160,000 2 2 2 2 1.5 1: 320 000 - 2 2 2 2 1: 640000 - 2 2 - 2 Controls - 2 2. 2 2 2 Explanation of symbols: 1.5 = little inhibited growth. 0.5 = very strongly inhibited growth. 2 = normal growth. 1 = significantly inhibited growth. 0 = no growth. EXAMPLE 53.5 g (0.25 mol) of p-acetylaminobenzenesulfonic acid amide, 35 g (0.25 mol) of anhydrous potassium carbonate and 2.5 g of copper powder are suspended in 250 cc of diphenyl ether. While stirring vigorously, 53 g (0.25 mol) of 5-chloro-3-benzyl-1,2,4-thiodiazole (prepared according to Chem. Ber. , 90 [1957], pp. 182 to 187). The mixture is stirred for a further 4 hours, the diphenyl ether is decanted after cooling, the residue is dissolved in 750 cc of water at 60 ° C., filtered through charcoal and acidified (pH 4 to 5). The crystalline precipitate is filtered off with suction, washed with water and recrystallized from 75% acetic acid. The 5- (4'-Acetylamir_obenzolsulfonamido) -3-benzyl-1,2,4-thiodiazole falls in colorless crystals, which melt at 191 to 192 ° C, in a yield of 63 g (= 65% of theory) at.

Instead of diphenyl ether can also be used with the same success use other high-boiling, inert diluents, e.g. B. Diphenylmethane, paraffin oil, Decalin, tetralin.

Instead of p-acetylaminobenzenesulfonic acid amide and potassium carbonate the sodium salt of p-acetylaminobenzenesulfonic acid amide can also be used.

The reactants can also be without the addition of a suspending agent implement, but the yield drops.

By saponifying the above compound with 2N lye (1 hour at 50 to 100 ° C) the 5- (4 'aminobenzoisulfonamido) -3-bepzyl-1; 2,4-thiodiazole is obtained from m.p. 235 to 236 ° C.

This compound is also formed directly by an analogous conversion of 5-chloro-3-benzyl-1,2,4-thiodiazole with the sodium or potassium salt of p-aminobenzenesulfonic acid amide.

Analogously, starting from 5-chloro-3-o-chlorobenzyl-1,2,4-thiodiazole (Boiling point 140 to 141 ° C., prepared in analogy to Chem. Ber., 90 [1957], p. 182 bis 187, from o @ chlorobenzyl cyanide via the amidine) and from 5-chloro-3-p-chlorobenzyl-1,2,4-thiodiazole (Kp..i 146 to 149 ° C, made from p-chlorobenzyl cyanide via the amidine), the 5- (4'-AminobenzoIsulphonamido) -3-o-chlorobenzyl-1,2,4-thiodiazole from m.p. 191 to 192 ° C and the 5- (4'-aminobenzenesulfonamido) -3-pchlorobenzyl-1,2,4-thiodiazole vom Mp. 226 to 227 ° C.

Claims (1)

PATENT CLAIM: Process for the production of 5-sulfanilamido-3-benzyl-1,2,4-thiodiazoles, characterized in that 5-halo-3-benzyl-1,2,4-thiodiazoles, which are in the benzene nucleus of the benzyl radical can be substituted by halogen, with benzenesulfonic acid amides, that in the 4-position is an amino group or a group which can be converted into the amino group carry, in the form of their salts or in free form in the presence of acid-binding agents at temperatures between 100 and 200 ° C and converted into the amino group convertible group is optionally converted into the amino group.