Synthesis of (z)-5-(4-fluorobenzylidene)thiazolidine-2,4-dione, an intermediate of Rosiglitazone, in batch and capillary micro reactor

• Grant number: 19/11710-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: July 01, 2019
• End date: December 31, 2019
• Field of knowledge: Engineering - Chemical Engineering - Chemical Technology
• Principal Investigator: Mauri Sergio Alves Palma
• Grantee: Wesley Ferreira Santos Porto
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The present project aims at the synthesis of (Z)-5-(4-fluorobenzylidene)thiazolidine-2,4-dione, an intermediate of the Active Pharmaceutical Ingredient Rosiglitazone, which is one of the anti-glycemic agents of the class of glitazones, used to treat diabetes mellitus type 2, an insulin sensitization substance for humans. The synthesis of this intermediate will be made through the reaction between the 2,4-thiazolidinedione (TZD) with p-fluorobenzaldehyde, and the main objective is to transpose the synthesis from the usual batch process to continuous flow in capillary microreactor, which presents important advantages in relation to the batch process. This project will be carried out in the scope of the ongoing research project financed by Fapesp n. 2017/12830-9, entitled "Synthesis of Pioglitazone, Rosiglitazone and Lobeglitazone in continuous flow in capillary microreactors" effective from 10/01/2017 to 09/30/2019. The catalyst normally used in this type of reaction is the piperidine, however it is not available to purchase once its use restricted by the federal police. As an alternative for this problem, this project aims initially to use pyrrolidine as an alternative catalyst and with this new catalyst improve the synthesis process. In the batch process it will be determined the best reaction conditions in terms of temperature, catalyst concentration, time of reaction and solvent that maximizes the product yield. The best reaction conditions obtained in the batch process will be tested in the flow process in the microreactor. This project will be part of a PhD work that aims the complete synthesis of the API Rosiglitazone that has been under development since January 2019 in the "Micro Reactor Technology Laboratory - MRTLab" located at the Department of Biochemical-Pharmaceutical Technology of the School of Pharmaceutical Sciences of the University of São Paulo supervised by Prof. Mauri Palma. The student already attends the laboratory since April/2019 and has demonstrated great competence in the performed activities until now. The student is in the 10th semester of Chemical Engineering of the Faculties Oswaldo Cruz and intends to join the postgraduate program of the School of Pharmaceutical Sciences at the beginning of 2020. Thus, the student already has enough knowledge of organic chemistry, chemical reactor engineering, unit operations and chemical process planning, very important, for the development of his present and future scientific activities in our research group.