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. Formation of 2‐[methyl(pyridin‐2‐yl)amino]ethanol was followed vs. time. The use of microreactor technology led to a tenfold yield increase, and one capillary microreactor produced the equivalent of five batch reactors. Computed thermodynamic properties agree with those estimated by Eyring's equation, so the density functional theory energy estimation can serve as a starting basis for drug design.