DE1079062B - Process for the preparation of 5-sulfanilamido-3-propyl-1, 2, 4-thio-diazoles - Google Patents

Description

Process for the preparation of 5-sulfanilamido-3-propyl-1,2,4-thiodiazoles 4-aminobenzenesulfonyl derivatives of 5-amine # 1,2,4-thiodiazole, which can be substituted in the 3-position by a methyl or phenyl group , are known. They are prepared from the corresponding S-amino-1,2,4-thiodiazoles by reaction with those benzenesulfonic acid halides which have a substituent in the 4-position which can be converted into an amino group. The yields here are very low and, for example, for 5-pA #, ethylaminobenzene-sulfonamido-1,2,4-thiodiazoles, are 14% of theory (Chem. Ber. 87 [1954], pp. 57 to 67) . This process is therefore not technically useful. The hakteriostatischen properties of the compounds prepared by this method are known from Swedish Patent Specification 115,999. From USA. Patent 2358031 also the Unisetzung of p-acetylamino or p-nitrobenzenesulfonyl chloride with 5-amino-1,2,4-thiodiazolen which may be inter alia alkyl or aralkylstibstituiert in 3-position. , known, arise in the 3-alkyl- or 3-aralkyl-5-sulfanilami # do-1,2,4-thiodiazoils.

It has now been found that 5-sulfanilamide, o-3-propyl-1,214-thiodiazoles can be prepared in good yield by 5-I-Ial # ogen-3-prc> -pyl-1,2,4- thiodiazoles with benzenesulfonamides which carry an amino group in the 4-position or a group umwandelhare in the amino group, in the presence of acid-binding agents or with metal salts of the sulfonamides mentioned, advantageously in inert diluents such as. B. diphenyl ether, diphenyl methane, diphenyl, paraffin oil, etc., heated. The most favorable reaction temperatures are between 100 and 200 ° C. The yields in this procedure are about 70% of theory.

The process of reacting sulfonamides with halogen-substituted heterocycles is known per se. However, it is not used technically for any of the products because experience has shown that it is far inferior to the usual method of working from sulfochlorides and heterocyclically substituted amines (see, for example, Mietzsch and R. Behnisch, Therapeutically usable sulfonamide and sulfon 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 creation process fails. The success of the working method described could therefore not be foreseen7 and represents an important technical advance for the production of these therapeutic agents, which are effective for bacterial infections.

The 5-sulfanilamido-3-propyl-1,2,4-thiodiazoles are also superior to the above-mentioned known sulfa-1,2,4-thiodiazoles in terms of their bacteriostatic effectiveness. This is clear from the following results: Experiments on the bacteriostatic effect of 5-sulfanilamido-3-propyl-1,2,4-thiodiazoles Surface culture on blood casein agar, hemolyte. Streptococci. Incubation time 20 hours. 5-sulfanilamido- 5-sulfanilamido- 5-sulfanilamido- 5-sulfanilamido- Dilution 3-methyl- 3-phenyl- 3-n-propyl- 3-isopropyl- 1 1,2,4-thiodiazole 1,2,4-thiodiazole 1,2,4-thiodiazole 1,2,4-thiodiazole 1: 5000 2 - - 0 1: 10,000 2 0 0 0 1 20,000 2 0.5 0 0 1 40,000 2 2 0 0 1 80000 2 2 0 0 1: 160,000 2 2 0 0 1: 320,000 - 2 0.5 0.5 1: 640 000 - 2 2 - Controls 2 2 2 2 Explanation of symbols: 1.5 = little inhibited growth. 0.5 = very strongly inhibited growth. 2 = normal growth. 1 = considerable, stunted growth. 0 = no growth. EXAMPLE 96.5 g (0.45 mol) of p-acetylaminobenzene sulfonic acid, 63 g (0.45 mol) of anhydrous potassium carbonate and 4 g of copper powder are suspended in 450 cc of diphenyl ether. With vigorous stirring, is allowed at 200 'C bath temperature slowly over the course of 111zStunden 73g 5-chloro-3-isopropyl-1,2,4-thiadiazole (Kp.13 63' C, her-made in analogy to Chem. Ber., 90 [1957], p. 182, from isobutyronitrile via the amidine). The mixture is stirred for a further 4 hours, diphenyl ether is decanted after cooling, the residue is dissolved in 1.31 water at 60 ° C., filtered through charcoal and acidified (pi, 4 to 5). The crystalline precipitate is filtered off with suction, washed with water and recrystallized from 502% acetic acid. 5- (4-Acetylaminobenzol.sulfollamido) -3-isopropyl-1,2,4-thi, odiazole precipitates in colorless crystals, which melt at 229 to 230 ° C, in a yield of 105 g (= 6911 / o der Theory).

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

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

The reactants can also be reacted without adding a suspending agent, but the yield drops. By saponifying the above compound with 2N lye (1 hour at 50 to 1001 C) , 5- (4'-aminobenzenesulfonamido) -3-isopropyl-1,2,4-thiodiazole from Schinp is obtained. 198 to 1991 C.

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

Analogously, starting from 5-chloro-3-n-propyl-1,2,4-thiodiazole (boiling point 16 74 ' C, prepared in analogy to Chem. Ber., 90 [' 1957], p. 182, Buttersäurenitril from about Amidm.), 5- (4-Aminobenzolsulfonaniido) -3-n-propyl-1,2,4-t, hiodiazol mp. 162 to 164 'C.

Claims (1)

PATENT CLAIM: Process for the preparation of 5-Sullanilamido-3-prop.y1-1,2,4-tliiodiazoles, characterized in that 5-I-Ialogen-3-propyl-1,2,4-thiodiazoles with benzenesulfonic acid amides, which in 4-Stelaung carry an amino group or a group convertible into the amino group, 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 the group convertible into the amino group is optionally converted into the amino group. .