Síntese, análise estrutural e conformacional da “Impureza E” do fármaco captopril

Abstract

The drug captopril is one of the most consolidated in the treatment of patients with hypertension. Due to its abilityto inhibity the angiotensin converting enzyme (ACE), it acts by preventing the conversion of angiotensin I to angiotensin II. Captopril, like all drugs, is subjected to stability studies in which the use of reference standards is required. The 1- (Isobutyryl) pyrrolidine-2-carboxylic acid (2a) is one of the impurities in the synthesis of the drug captopril, also known as "Impurity E". Such Impurity is one of the products monitored and used as reference standard in the stability study of the drug captopril. The importance of pattern synthesis is due to the expensive and difficult of access, which encourages the use of alternative methods that facilitate the process and save time and money. In this work, the "Impurity E" was synthesized by a new method developed with the use of microwave irradiation. The product was obtained in crystalline form and analyzed by spectroscopic methods. The nuclear magnetic resonance (NMR) analysis of 1H and 13C in solution showed two stable conformational states, probably confounding starch, while X-ray diffraction analysis showed only one form. To elucidate the behavior of this compound in solution the NMR study was performed at different temperatures and solvents. Temperatures of -50°C to 80°C and the solvents DMSO-d6, methanol-d4, acetone-d6 and chloroform-d1 were used. At the temperatures used, there was no significant variation in the proportion of the confomers analyzed. However, the solvents used provided a high variation in the ratio between the conformations, in which chloroform, as the most apolar solvent, was the solvent that most stabilized the confomer of the largest population. Thus, it can be concluded that there is an equilibrium in solution and there is a high energy barrier between the confomers that can be overcome by the use of solvents with a low polarity, thus allowing intramolecular hydrogen bonding, resulting in stabilization of the most stable confomer.