Flow Synthesis of 2-[Methyl(pyridin-2-yl)amino]ethanol: An Experimental and Computational Study

Microreactor technology is increasingly applied in the chemical-pharmaceutical industry for safer and more efficient drug production as compared to the traditional batch process. This technology is employed for the first time to study the production of 2-[methyl(pyridin-2-yl)amino]ethanol, the first intermediate in rosiglitazone synthesis. Under the optimum operating conditions, a single microreactor chip at 160 °C allowed to produce the equivalent of more than five batch reactors at 120 °C. The kinetic study indicated that the reaction is second order. Thermodynamic parameters were determined by the Eyring equation and density functional theory (DFT) calculations with good agreement. DFT results suggested a concerted nucleophilic aromatic substitution reaction mechanism.