Scalable and streamlined three-step synthesis of 3-(3-pyridyl)acrylic acid enabled by microreaction technology: Process intensification and integration

3-(3-Pyridyl)acrylic acid is a key cap motif in chidamide and related analogues. Conventional strategies, including Knoevenagel condensation, Horner-Wadsworth-Emmons reactions, and Heck couplings, suffer from limitations such as direct pyridine utilization, phosphorus-containing waste, or reliance on expensive palladium catalysts. Here, we presented a scalable, streamlined three-step platform for the synthesis of 3-(3-pyridyl)acrylic acid from ethyl acetate and 3-pyridine aldehyde. The process integrates sequential continuous-flow aldol condensation and hydrolysis with batch dehydration, coupled with online intermediate separation units. Each module was engineered to meet the kinetic and operational requirements of the subsequent step, thereby minimizing overall residence time. The aldol condensation, which typically requires cryogenic conditions and exhibits pronounced scale-up effects in batch reactors, was intensified in microreactors through precise residence time control, enabled room-temperature condensation to afford the β-hydroxy ester intermediate in 99% yield with a productivity of 116  g/h within 1.1  s. In the hydrolysis module, where the rate was constrained by mass transfer in the heterogeneous system, ethanol was introduced as a co-solvent to enhance phase interaction, enabling continuous-flow hydrolysis to deliver the β-hydroxy sodium salt intermediate in > 99% yield with a productivity of 88 g/h within 1  min at 60 °C. Subsequent batch dehydration, conducted at high concentration to maximize the reaction rate and optimized according to the upstream hydrolysis conditions, afforded 3-(3-pyridyl)acrylic acid in 96% yield (84% overall), producing 76 g/batch at 120 °C within 1 h. The product was isolated with ∼ 100% high performance liquid chromatography purity by simple pH-triggered precipitation, eliminating the need for recrystallization.