THE SYNTHESIS, KINETICS AND MECHANISM OF HYDROLYSIS OF ASPIRIN PRO-DRUGS

The syntheses of two aspirin pro-drugs, 1-O-(2'-acetoxy)benzoyl-(alpha)-D-glucopyranose and 1-O-(2'-acetoxy)benzoyl-(alpha)-D-2-deoxyglucopyranose are described. The compounds were synthesized by selectively benzylating all but the anomeric hydroxy functional groups of glucose or 2-deoxyglucose and reaction with the acid chloride of aspirin. Subsequent hydrogenolysis of the benzyl groups resulted in the pro-drug compounds.;The hydrolysis of 1-O-(2'-acetoxy)benzoyl-(alpha)-D-2-deoxyglucopyranose was studied as a function of pH, temperature, solvent dielectric constant, buffer concentration, and solvent deuterium isotope effect. The rate of hydrolysis was found to be first order with respect to pro-drug and hydrogen ion at pH values less than three and first order with respect to pro-drug but independent of pH from pH values of three to nine. Through the solvent dielectric effect, solvent deuterium isotope effect, and the entropy of activation, the mechanism of the pH independent reaction was shown to be uncatalyzed unimolecular decomposition.;The 2-deoxyglucose pro-drug is a neutral compound, which, upon contact with the gastric milieu, should generate a non-irritating solution of aspirin at an acceptable rate (the half-life at thirty-seven degrees is seven minutes). The impact of some other required physico-chemical and toxicological properties of a viable pro-drug candidate upon the compound are discussed.;The rates of generation of aspirin from solutions of the pro-drugs were determined spectrophotometrically or by high-pressure liquid chromatography. The generation of aspirin from the glucose pro-drug occurs with a half-life of forty-six hours at pH 2.4 and fifty degrees. Under the same reaction conditions, the 2-deoxyglucose compound generates aspirin two-thousand times faster. This profound influence of the glucose 2-hydroxy group on hydrolytic rate is discussed in terms of its mechanistic implications.