Synthesis of (z) -5-(4-(2-(methyl (pyridin-2-il) amino) etoxy) benzylidene) thiazolidine-2,4-diona, in batch and capillary micro reactor

Abstract

The present project aims at the synthesis of (Z)-5-(4- (2-(methyl (pyridin-2-yl) amino) ethoxy) benzylidene) thiazolidine-2,4-dione, an intermediate of the drug Rosiglitazone, which is one of the anti-glycemic agents of the glitazone class, used to combat type 2 diabetes mellitus, and which works as an insulin sensitizer in humans. The synthesis of this intermediate will be carried out through the reaction of 2,4-thiazolidinedione (TZD) with 4-(2-(methyl (pyridin-2-yl) amino) ethoxy) benzaldehyde, with the main objective of transposing the synthesis reaction from the usual batch process to the flow process in a capillary microreactor, which has numerous advantages over the batch process. This project will be carried out as part of the research grant financed by Fapesp n. 2017/12830-9, entitled "Synthesis of Pioglitazone, Rosiglitazone and Lobeglitazone in continuous flow in capillary microreactors" running from October/2017 to June/2020. The catalyst normally used in this type of reaction is piperidine, however, it is currently unavailable since its use was restricted by the federal police. As an alternative to this problem, this work aims to use pyrrolidine as a catalyst and from there promote improvements in the process. Initially, the best conditions in the batch process will be determined, in terms of temperature, ideal concentration of the catalyst, the reaction time necessary to obtain the maximum yield, and the most suitable solvent for the reaction. The results obtained in the batch will determine the best conditions in which the transposition to the microreactor process will be carried out. This project will be part of a doctoral work financed by FAPESP n.2018/ 26717-2, which aims at the complete synthesis of the drug Rosiglitazone, which has been in development since January/2019 at the "Laboratory of Micro Reactor Technology - MRTLab" located in the Department of Biochemical-Pharmaceutical Technology of the School of Pharmaceutical Sciences of the University of São Paulo under the supervision of Prof. Mauri Palma. (AU)