Synthesis of Metoprolol® in flow in Capillary Microreactors from 2-[(4-(2-Methoxyethyl)phenoxy)methyl]oxirane

• Grant number: 24/20179-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2025
• End date: December 31, 2025
• Field of knowledge: Engineering - Chemical Engineering - Chemical Technology
• Principal Investigator: Mauri Sergio Alves Palma
• Grantee: Fernanda de Souza Chagas
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 22/16165-8 - Flow synthesis of Atenolol®, Metoprolol® and Ranolazine® using Glycerol derivatives as reactants, AP.R

Abstract

The Microreactor Technology (MRT) enables efficient organic syntheses that follow theprinciples of Green Chemistry, benefiting both science and the world simultaneously. Thepresent research project aims to produce Metoprolol®, a cardioselective beta-blocker drugindicated by doctors for the treatment of heart failure and hypertension. The synthesis of thisdrug involves a reaction between two reagents: 2-[(4-(2-methoxyethyl)phenoxy)methyl]oxiraneand isopropylamine. The main objective is to transition the synthesis of Metoprolol® from aconventional batch process to a continuous flow production in a capillary microreactor. Thistransposition presents several economic and environmental advantages, as well as a betterquality of the final product. Initially, the batch process will be optimized to obtain a product withbetter yield and selectivity, and then, finally, this synthesis will be transferred to the flow processin a capillary microreactor, where the influence of the residence time will be studied. Thereaction kinetics will be investigated using rate law kinetics, and the reaction rate constant, k,will be determined by the results of the components concentration over time. Additionally, theArrhenius model, the Eyring model, and the Van't Hoff relation will be used to determine theactivation energy, Ea, the thermodynamic parameters at the transition state (¿H* and ¿S*), andthe Gibbs free energy (¿G*), respectively. That way, the studies in this important area ofchemical reaction engineering will be expanded, which unfortunately still lacks significantadherence from Brazilian Chemical-Pharmaceutical Industries. This project will be developedunder the individual research grant funded by FAPESP (no. 2022/16165-8), entitled "Synthesisof Atenolol®, Metoprolol®, and Ranolazine® in flow using glycerol derivatives as reagents,"valid from 04/01/2023 to 03/31/2025, and will be conducted at the Microreactor TechnologyLaboratory - MRTLab, coordinated by Prof. Dr. Mauri Palma, located in the Department ofBiochemical-Pharmaceutical Technology at the Faculty of Pharmaceutical Sciences of USP.