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

• Conditions for flow synthesis of Lobeglitazone intermediates have been investigated. • Temperature, time, concentrations, reactants, etc. of each batch step were optimized. • Synthesis in flow of the second and fourth Lobeglitazone intermediates was successful. • Kinetic and thermodynamic parameters of each synthesis step have been estimated. 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-methoxyphenoxy)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-methoxyphenoxy)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 °C, respectively, while the yield of I3 in batch process was 73.3 % at 60 °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.