SYNTHESIS OF N-(2,6-DIMETHYLPHENYL)-2-(1-PIPERAZINYL)ACETAMIDE IN BATCH AND IN FLOW IN A MICRORREACTOR AIMING FOR THE SYNTHESIS OF RANOLAZINE®

• Grant number: 24/20314-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: February 01, 2025
• End date: January 31, 2026
• Field of knowledge: Engineering - Chemical Engineering - Chemical Technology
• Principal Investigator: Mauri Sergio Alves Palma
• Grantee: Luiz Riccardo Guimarães Merlin
• 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 present project aims to synthesize N-(2,6-dimethylphenyl)-2-(piperazin-1-yl)acetamide, an intermediate in the synthesis of the drug Ranolazine®, used in the treatment of chronic angina. The synthesis of this intermediate will be carried out through the reaction of piperazine and 2-chloro-N-(2,6-dimethylphenyl)acetamide, with the main goal of transitioning the reaction from conventional batch processes to a continuous flow process in a capillary microreactor. This technology offers numerous advantages over batch processing, such as increased reaction speeds, high conversion rates, yields, and selectivity, enhanced safety when working with toxic and hazardous reagents and products, as well as reduced waste generation. These characteristics arise from a high surface-to-volume ratio and enhanced homogeneity of the reagents. Initially, the optimal conditions for the batch process will be determined (reactant concentration, temperature, and solvent) in order to maximize the conversion of the limiting reagent, yield, and selectivity of the product, as well as to achieve higher production rates and productivity. Additionally, kinetic studies will be conducted to determine the reaction rate constant, and thermodynamic studies will be carried out to determine entropy, enthalpy, and Gibbs free energy using Eyring models and the van't Hoff equation. The best conditions obtained from the batch process will be adapted for the continuous flow process in the capillary microreactor, aiming to minimize the number of equivalent microreactors. In the flow process, the influence of the average residence time and temperature, above the normal boiling point of the solvent, will be investigated. This project will be developed under an individual research grant funded by Fapesp, no. 2022/16165-8, titled Síntese do Atenolol® , Metoprolol® e Ranolazine® em fluxo utilizando derivados do glicerol como reagentes" effective from 04/01/2023 to 03/31/2025, and will be conducted at the Microreactor Technology Laboratory (MRTLab), located in the Department of Biochemical-Pharmaceutical Technology at the School of Pharmaceutical Sciences of USP, coordinated by Prof. Dr. Mauri Palma.