Optimization and validation of a biphasic system for clean and solid-free synthesis of a ranolazine intermediate

• Grant number: 25/22905-2
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: December 01, 2025
• End date: March 31, 2026
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Mauri Sergio Alves Palma
• Grantee: Samuel Gustavo Alves de Almeida Vieira
• Supervisor: Agostino Cilibrizzi
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: King's College London, England
• Associated to the scholarship: 24/20177-7 - SYNTHESIS OF N-(2,6-DIMETHYLPHENYL)-CHLOROACETAMIDE IN BATCH AND FLOW IN MICROREACTORS, BP.IC

Abstract

This project aims to consolidate and validate a biphasic system for the clean and solid-free synthesis of a ranolazine intermediate, an antianginal drug. It continues the FAPESP-funded research project (Grant nº 2024/20177-7), which developed an innovative biphasic methodology that successfully prevented solid formation and enabled reaction monitoring by chromatographic and spectroscopic methods. The BEPE internship, to be carried out at King's College London (KCL) under the supervision of Prof. Dr. Agostino Cilibrizzi, will focus on mechanistic understanding, analytical validation, and assessment of the robustness and reproducibility of this biphasic system.At the University of São Paulo, a Box-Behnken experimental design was implemented to study the effects of temperature, aqueous base concentration, and organic phase proportion on product yield. The optimized condition led to the successful synthesis of N-(2,6-dimethylphenyl)chloroacetamide, without solid formation, validating the efficiency of the proposed biphasic reaction. The product was characterized by HPLC, NMR (¹H and ¹³C), and LC-MS, confirming its identity and purity. Additionally, chloroacetyl chloride, a key reagent not commercially available in Brazil, was synthesized in-house, and a quenching solution was developed to stop the reaction for kinetic analyses, ensuring sample stability for chromatographic evaluation.During the internship at KCL, the research will emphasize mechanistic and analytical validation of the biphasic system. Systematic experiments will be conducted to study phase behavior, solvent effects, and reaction kinetics under controlled variations of temperature, mixing, and composition. Advanced analytical techniques, including NMR, HPLC, and MS, will be employed to investigate diffusion between phases and to understand how operational parameters affect selectivity and stability. Robustness testing will be performed to confirm reproducibility and identify critical operational tolerances, providing validated data for future implementation in continuous-flow microreactors.The infrastructure and expertise of Prof. Cilibrizzi's group-renowned for research in organic synthesis and medicinal chemistry-will provide the student with advanced technical and analytical training using state-of-the-art facilities unavailable in Brazil. The internship will promote the integration between traditional organic synthesis and modern process-intensification strategies, strengthening collaboration between USP and King's College London. The expected outcomes include a mechanistically validated and analytically robust reaction model ready for flow translation, joint publications, and enhanced scientific formation of the student in synthetic and analytical chemistry.