Flow synthesis of Atenolol®, Metoprolol® and Ranolazine® using Glycerol derivatives as reactants

• Grant number: 22/16165-8
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2023
• End date: March 31, 2026
• Field of knowledge: Engineering - Chemical Engineering - Chemical Process Industries
• Principal Investigator: Mauri Sergio Alves Palma
• Grantee: Mauri Sergio Alves Palma
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Harrson Silva Santana ; Lucas Colucci Ducati
• Associated research grant(s): 23/12412-3 - Ultra-Precision Machining and Two-Photon Lithography in the Fabrication of Micro- and Milli-reactors for the Synthesis of Chlorohydrin-Based Drugs, AP.R SPRINT
• Associated scholarship(s): 24/20314-4 - SYNTHESIS OF N-(2,6-DIMETHYLPHENYL)-2-(1-PIPERAZINYL)ACETAMIDE IN BATCH AND IN FLOW IN A MICRORREACTOR AIMING FOR THE SYNTHESIS OF RANOLAZINE®, BP.IC; 24/20179-0 - Synthesis of Metoprolol® in flow in Capillary Microreactors from 2-[(4-(2-Methoxyethyl)phenoxy)methyl]oxirane, BP.IC

Abstract

The synthesis of drugs in flow has significant advantages over the usual batch process and, due to the high added value and low demand of the drugs, there is great potential in the expansion of its synthesis in in flow in micro-milirreactors, which allow excellent heat and mass transfer, very high surface/volume ratio with a laminar and pistonflow and have also been used in the creation of libraries of chemical compounds with pharmacological potential, continuous synthesis in multiple stages, particularly for rapid and quite exothermic reactions, in the intensification of chemical processes and with chemical reactions involving hazardous, toxic or explosive products. Some advantages of drug synthesis in microreactors are the drastic reduction of reaction times, due to the elimination of the effects of inefficient mixing and increased yield and selectivity of reactions and reduction of waste generation. The Chemical-Pharmaceutical Industry is the largest beneficiary of this new technology, because microreactors can generate a quantity of compounds, with pharmacological potential, several orders of magnitude greater than in the traditional batch process in a shorter time, can reduce in years the time for commercial production of a new drug and can be extremely small and compact industrial units. The objective of this work is to use capillary microreactors and milireactors to synthesize in flow APIs that use chlorohydrins as reagents, being: 1) epichlorohydrin, 2) 3-Chloro-1,2-propanediol, 3) 1,3-dichloro-2-propanol and 4) glycidol. Chlorohydrins can be synthesized sustainably from glycerol, a byproduct of biodiesel synthesis, which is widely available in the Brazilian and world market, besides being nontoxic and already having wide use in pharmaceutical and food formulations. This project is connected to a ongoing PhD, under my supervision, which deals with the chemical synthesis of biodiesel in flow, at the Micro Reactor Technology Laboratory (MRTLab/FBT/FCF/USP), of which I am responsible. The Active Pharmaceutical Ingredients (API), Atenolol®, Metoprolol® and Ranolazine® will be synthesized for the first time in flow, and the kinetics of intermediate reactions and the best operating conditions for each synthesis, in batch and flow process will be determined. This project will be developed in collaboration with Prof. Agostino Cilibrizzi, King's College, London, UK, and Prof. Lucas Ducati (IQ/USP). I visited Prof. Cilibrizzi from 7th to 20th november, 2022, to follow the work of one of my PhD students, and have technical meetings with researchers, aiming at future work of technical-scientific collaboration. Prof. Agostino Cilibrizzi will provide intellectual support in the development of new drug synthesis routes. Prof. Lucas Ducati co-supervise one of my PhD students, and had co-supervised a second PhD student, and will give intellectual support in the molecular mathematical modeling of the chemical reactions involved in the synthesis of these drugs. (AU)