SYNTHESIS OF ATENOLOL® IN FLOW FROM 2-(4-HYDROXYPHENYL)ACETAMIDE

• Grant number: 25/14075-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2025
• End date: August 31, 2026
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Mauri Sergio Alves Palma
• Grantee: Bruna Bezerra Soares da Palma
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Atenolol® is a cardioselective ¿-blocker widely used in the treatment of cardiovascular diseases such as hypertension, angina, and cardiac arrhythmias. Its mechanism of action involves the selective blockade of ¿1-adrenergic receptors, leading to a reduction in heart rate and contractility, thereby decreasing cardiac output and myocardial oxygen demand. Currently, its synthesis is predominantly carried out using the batch process, under non-optimized operational conditions regarding temperature, concentration, and reaction time to stabilize the conversion of the limiting reagent and improve product yield.This project aims to synthesize Atenolol® initially using the batch process from 2-(4-hydroxyphenyl)acetamide, followed by transferring the reaction to a continuous flow process using capillary microreactors. Microreactor technology offers several advantages over batch processing, including increased reaction rates, high conversion, yield and selectivity, enhanced safety when handling toxic or hazardous substances, and reduced waste generation. These benefits arise from the high surface-to-volume ratio and more efficient reagent mixing.Initially, the optimal operational conditions for the batch process (reactant concentration, temperature, and solvent) will be determined to maximize conversion, yield, and product selectivity. A kinetic study will also be conducted by determining the reaction rate constant (k), and a thermodynamic study will be performed by calculating the activation energy (Ea) using the Arrhenius model, and the entropy (¿S*), enthalpy (¿H*), and Gibbs free energy (¿G*) of the transition state using the Eyring model and the van't Hoff equation.The best operational conditions identified in the batch process will be applied to the flow process using a capillary microreactor, aiming to minimize the number of microreactors required to achieve performance equivalent to the batch process. In the flow process, the influence of the residence time of the reaction medium and the reaction temperature-above the normal boiling point of the solvent-will be investigated.This project will be developed within the scope of the FAPESP-funded research grant no. 2022/16165-8, entitled "Synthesis of Atenolol®, Metoprolol®, and Ranolazine® in flow using glycerol-derived reagents," active from 04/01/2023 to 03/31/2026. It will be conducted at the Microreactor Technology Laboratory (MRTLab), located in the Department of Biochemical and Pharmaceutical Technology at the School of Pharmaceutical Sciences of the University of São Paulo (FCF-USP), under the coordination of Prof. Dr. Mauri Palma. (AU)