Synthesis of Pioglitazone and Lobeglitazone in batch and capillary microreactor

Author(s)

Renan Rodrigues de Oliveira Silva

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2023-07-04

Examining board members

Mauri Sergio Alves Palma; Joao Carlos Monteiro de Carvalho; Mauricio Marques Pinto da Silva; Ardson dos Santos Vianna Junior

• Advisor: Mauri Sergio Alves Palma; Lucas Colucci Ducati

Abstract

Flow synthesis in microreactors is an alternative to the batch process and has been incorporated into the chemical-pharmaceutical industry in recent years due to its advantages, particularly the process intensification, which can lead to a reduction in the time for a new drug to be placed the market. Glitazones are a drug class that mainly fight type 2 diabetes mellitus, one of the biggest concern in the health area. This work aimed to transpose the synthesis of Pioglitazone (Actos®) and Lobeglitazone (Duvie®) from batch to flow process in a capillary microreactor, indicating equivalence of both processes by the number of microreactors in parallel (nMR) and determine kinetic and thermodynamic parameters of each step of both reactions. Additionally, we sought to determine the reaction mechanisms of each stage of the synthesis of these drugs using the Gaussian 09® software. Additionally, determining the reaction mechanisms of each step of both synthesis pathways of these drugs using the Gaussian 09® software. The results obtained for the intermediate reactions of the synthesis of Pioglitazone, 2-(5-ethylpyridin-2- yl)ethylmethanesulfonate (2P) and (Z)-5-(4-(2-(5-ethylpyridin-2- yl)ethoxy)benzylidene)thiazolidine-2,4-dione (4P) reached yields of 66 and 85.3% and nMR = 4.4 and 2 at 25 and 120°C, respectively, in flow process, while 4-(2-(5-ethylpyridin-2- yl)ethoxy)benzaldehyde (3P) and Pioglitazone reached 54% and 100% at 25? in batch. A new synthesis route for this drug was developed and patented (BR 10 2021 006604 0). For Lobeglitazone, 4-chloro-6-(4-methoxyphenoxy)pyrimidine (1L), 2-[[6-(4- methoxyphenoxy)pyrimidin-4-yl](methylamino]ethan-1-ol (2L) and 5-[4-(2-{[6-(4- methoxyphenoxy)pyrimidin-4-yl]methylamino}ethoxy)benzylidene]thiazolidine-2,4-dione (4L) achieved yields of 28, 61 and 32% nMR = 1. 4, 0.8 and 2.5 at 25, 160 and 120°C respectively in flow, while 4-(2-((6-(4-methoxyphenyl)pyrimidin-4- yl)(methyl)amino)ethoxy)benzaldehyde (3L) and Lobeglitazone reached 73 and 100% at 60 and 25°C, respectively, in batch process. All kinetic and thermodynamic parameters of the intermediate product reactions of both drugs were determined. The results indicate that the transposition of both syntheses from the batch to flow process in microreactors can be advantageous on an industrial scale. (AU)

• FAPESP's process: 18/01478-5 - Synthesis of pioglitazone in batch and capillary microreactor
• Grantee: Renan Rodrigues de Oliveira Silva
• Support Opportunities: Scholarships in Brazil - Doctorate