Rosiglitazone synthetic route development in batch process and capillary microreactor

• Grant number: 18/26717-2
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2019
• End date: December 31, 2021
• Field of knowledge: Engineering - Chemical Engineering - Chemical Technology
• Principal Investigator: Mauri Sergio Alves Palma
• Grantee: Paulo Victor Cuesta Calvo
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The chemical-pharmaceutical industries in Brazil employ batch reactors for the synthesis processes, however, they have limitations on temperature, operating pressure and mixing efficiency. The flow process in microreactors provides the reduction of the impact generated by the processes with substantial waste reduction. In addition, they provide an expressive increase in mass and heat transfer rates, which results in an easily controllable process allowing greater yield and selectivity compared to batch reactors. Considering these characteristics, it is imperative that TMR be more widespread in the chemical-pharmaceutical industry, as it is necessary to increase the scale of production to attend market demand in a faster and more efficient way and, thus, recover the investment applied during the research. Diabetes Mellitus is a chronic metabolic disorder characterized by excess glucose in the blood due to lack of insulin secretion, insufficient insulin causes failures in the uptake of glucose into the bloodstream and consequently in its transport to the various regions of the human body. Rosiglitazone is one of the glitazone class anti-glycemic agents used to combat Type 2 Diabetes Mellitus and works as an insulin sensitizer in humans. The present project aims at the synthesis of Rosiglitazone and its transposition from the usual process in the chemical-pharmaceutical industry (batch) to continuous flow in capillary microreactor. This PhD project will be developed within the Research Line "Synthesis of drugs in microrrators" of our research group at FCF/USP, which has the financial support of Fapesp through 2 individual research aids entitled "Synthesis of drugs in microreactors ", which was in effect from 01/09/2014 to 02/28/2017, and" Synthesis of Pioglitazone, Rosiglitazone and Lobeglitazone in continuous flow in capillary microreactors "in effect from 10/01/2017 to 09/30/2019. In this last aid we have the collaboration of Prof. Hans-Jorg Bart of the Technical University of Kaiserslautern, who works with flow microextractors, and Prof. Till Opatz of the Johannes-Gutenberg University of Mainz, Germany, which assists in the development of new routes of organic synthesis, and with coorientation of Prof. Lucas Colucci Ducati of the Institute of Chemistry of USP, who helps us in the theoretical and computational study of the mechanisms of the involved reactions. An internship is planned at the Laboratory of Separation and Reaction Engineering, Faculty of Engineering, University of Porto, Portugal, coordinated by Prof. Vitor Vilar for the synthesis of Rosiglitazone in a new millirreator, NETmix®, aiming at the comparison with capillary microreactors and the increasing of production scale. The student performed a short-term internship in the laboratory of Prof. Vilar from 11/26 to 12/07/2018, where he carried out preliminary tests on the NETmix® milirreactor. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SILVA, RENAN RODRIGUES DE OLIVEIRA; CALVO, PAULO VICTOR CUESTA; MERFELS, CHRISTIAN ADRIAN; LIMA, MIKAEL VITOR RODRIGUES; SANTANA, HARRSON S.; CONVERTI, ATTILIO; PALMA, MAURI SERGIO ALVES. Synthesis of Lobeglitazone intermediates seeking for continuous drug production in flow capillary microreactor. JOURNAL OF INDUSTRIAL AND ENGINEERING CHEMISTRY, v. 116, p. 11-pg., 2022-10-25. (18/01478-5, 17/12830-9, 18/26717-2)

CUESTA CALVO, PAULO VICTOR; BATISTA, PATRICK RODRIGUES; DE OLIVEIRA SILVA, RENAN RODRIGUES; CONVERTI, ATTILIO; AL ARNI, SALEH; SOLISIO, CARLO; DUCATI, LUCAS C.; ALVES PALMA, MAURI SERGIO. Flow Synthesis of 2-[Methyl(pyridin-2-yl)amino]ethanol: An Experimental and Computational Study. CHEMICAL ENGINEERING & TECHNOLOGY, v. 44, n. 2, DEC 2020. (18/07308-4, 17/12830-9, 18/26717-2, 20/10246-0, 18/01478-5, 17/17750-3)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

CALVO, Paulo Victor Cuesta. Rosiglitazone synthetic route development in batch process and capillary microreactor. 2021. Doctoral Thesis - Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) São Paulo.