Synthesis of Lobeglitazone intermediates seeking for continuous drug production in flow capillary microreactor

Author(s)

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

• Document type: Journal article
• Source: JOURNAL OF INDUSTRIAL AND ENGINEERING CHEMISTRY; v. 116, p. 11-pg., 2022-10-25.

Abstract

Continuous flow synthesis in microreactors has been integrated into chemical-pharmaceutical industry in recent years as an alternative to the batch process due to its advantages, especially process intensification, which can reduce the time for a new drug to be placed on the market on a large scale. This work aimed to transpose the synthesis of Lobeglitazone, a drug employed in the treatment of diabetes mellitus type 2, from batch to flow process in a microreactor as well as to determine the reaction kinetics of each step. The synthesis was carried out in five-steps, being synthesized intermediates 4-chloro-6-(4-methox yphenoxy)pyrimidine (I1), 2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl]methylamino)ethanol (I2), 4-(2-{[ 6-(4-methoxyphenoxy)pyrimidin-4-yl]methylamino)ethoxy)benzaldehyde (I3), 5-[4-(2-{[6-(4-methoxy phenoxy)pyrimidin-4-yl]methylamino)ethoxy)benzylidene]thiazolidine-2,4-dione (I4) and Lobeglitazone. Intermediates I1 and I4 were synthesized in flow, while I4 was synthesized either in a continuous flow multistep synthesis or in a one-pot batch process. The flow syntheses of I1, I2 and I4 showed 28.0 %, 61.8 % and 32.0 % yields at 25, 160 and 120 degrees C, respectively, while the yield of I3 in batch process was 73.3 % at 60 degrees C. In one-pot batch process and continuous flow multistep synthesis, I2 was obtained with 13 and 16 % yields, respectively. These preliminary results constitute a starting point for the synthesis of this drug in flow on an industrial scale, with the aim of improving reaction performance using this new technology.(c) 2022 The Korean Society of Industrial and Engineering Chemistry. Published by Elsevier B.V. All rights reserved. (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
• FAPESP's process: 17/12830-9 - Synthesis of Pioglitazone, Rosiglitazone and Lobeglitazone in continuous flow in capillary microreactors
• Grantee: Mauri Sergio Alves Palma
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/26717-2 - Rosiglitazone synthetic route development in batch process and capillary microreactor
• Grantee: Paulo Victor Cuesta Calvo
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)