Abstract

Background: Gliclazide is a second generation sulfonyl urea which acts as hypoglycemic agent (oral antidiabetic agent). It improves the function of blood coagulation, has hypoglycemic effect, and thus has been widely used in clinical treatment. Several syntheses of Gliclazide have been reported, but all of them have some drawbacks. Therefore, there has been an ever-increasing interest in finding a novel route for Gliclazide using simple and easily commercial available chemicals.

Methods: A Novel and facile process of preparing Gliclazide is herein reported which is comprised of three steps. Aryl haloformate was reacted with amino heterocyclic compound to give carbamate. The salt of p-toluene sulfonamide was prepared with metal hydroxide or metal alkoxide, and this salt of sulfonamide was then reacted with carbamate to give Gliclazide.

Results: The carbamate produced from aryl haloformates was reacted with salt of p-toluene sulfonamide in the presence of base to produce Gliclazide with good yield and purity. The salt of p-toluene sulfonamide was prepared by two methods. In one method, salt was prepared using base at 100°C in polar aprotic solvent which was reacted with carbamate at 25°C to give Gliclazide. This method gives 70% yield of Gliclazide with purity above 99%. In another method, the salt of p-toluene sulfonamide was prepared at 100°C in polar aprotic solvent using base. The salt was isolated. The isolated salt of sulfonamide is stable at 25°C. This salt was reacted with carbamate at 25°C to give Gliclazide. This method gives 64% yield of Gliclazide with purity above 99%. The various solvents, bases were tested in this investigation. It was observed that excellent yield of the product was obtained when the reaction was carried out by using DMSO as solvent and potassium tert-butoxide as base.

Conclusion: In conclusion, we have developed new and effective process for the synthesis of Gliclazide via condensation of sulfonamide with various carbamates using a less expensive aryl haloformates with good yield and purity.

Keywords: Gliclazide, sulfonyl urea, hypoglycemic agent, carbamate, p-toluene sulfonamide, metal alkoxide/hydroxide.

Graphical Abstract