N1 and N4 substituted sulphanilamides : Synthesis of N- substituted, (anils, ancyls, sulphony1, and azo)-derivatives of sulphathiazole and sulphapyridine

Abstract

The present thesis consists of five parts, of which the first two deal with the preparation of the two well?known sulphanilamide drugs, sulphathiazole and sulphapyridine, and of their starting materials. The last three parts deal with the N??substituted derivatives of these same drugs. Part I deals with the preparation of sulphathiazole in improved yields and of the starting materials required for its production. The preparation of aminothiazole has been greatly simplified by the use of chloracetal instead of ?,??dichloroethyl ether. The condensation of aminothiazole with acetyl?sulphanilyl chloride has been thoroughly studied and an improved method for this condensation has been described. Part II of the thesis deals with the preparation of sulphapyridine and of the starting materials required for its production. Pure pyridine has been isolated from crude pyridine bases of Indian coal tar. The preparation of soda?amide by the action of dry ammonia on sodium, the preparation of aminopyridine by Tschitschibabin’s reaction, and the preparation of sulphapyridine are described in detail. Part III deals with the synthesis of the Schiff’s bases of sulphathiazole and sulphapyridine. Nine common aromatic aldehydes have been condensed with sulphathiazole and sulphapyridine respectively, yielding eighteen Schiff’s bases. Part IV describes the synthesis of N??acyl and sulphonyl derivatives of sulphathiazole and sulphapyridine. This part has been divided into three sections:

derivatives of aliphatic fatty acids, derivatives of aromatic acids (benzoic and substituted benzoic acids), and derivatives of aryl sulphonic acids.

All the required acid chlorides were prepared by the action of thionyl chloride on the corresponding acids. Part V of this thesis describes a series of azo?derivatives of sulphathiazole and sulphapyridine, formed by coupling phenols and amines with diazotised sulphathiazole and sulphapyridine. In this thesis, an attempt has been made to improve the therapeutic potency and reduce the toxicity of the two well?known sulphanilamide drugs, sulphathiazole and sulphapyridine, by preparing suitable derivatives such as anil (Schiff’s bases), acyl, sulphonyl, and azo derivatives. In total, 18 anils, 16 acyclic acyl derivatives, 16 isocyclic acyl derivatives, 10 sulphonyl derivatives, 16 phenolic azo dyes, and 10 amino?azo dyes of sulphathiazole and sulphapyridine have been synthesised. These compounds are characterised by low solubility and possibly low toxicity, which facilitates their prolonged retention in the system. They are currently undergoing pharmacological testing.