Efficient Continuous Synthesis of β-Hydroxy-α-Phenyl Esters under Mild Conditions Using a Microreactor

β-Hydroxy-α-phenyl esters are valuable intermediates in pharmaceutical synthesis. However, their preparation via strong base-mediated aldol condensation typically requires cryogenic conditions to achieve high yields. Herein, a continuous-flow strategy was developed for the efficient synthesis of β-hydroxy-α-phenyl esters at room temperature or slightly above, using the lithium diisopropylamide (LDA)-mediated aldol condensation of methyl phenylacetate with 3-pyridine aldehyde as a model electrophile. In batch processing, the product yield dropped markedly from 68% at −60 °C to 27% at 20 °C, accompanied by increased byproduct formation. In contrast, the continuous-flow platform enabled rapid mixing and precise residence time control, allowing the enolate to be delivered immediately to the subsequent electrophilic addition step, thereby suppressing side reactions. As a result, high yields of 77–88% were achieved at 20–40 °C with reduced byproduct formation. The effects of key operating parameters were systematically investigated, and the product diastereoselectivity was found to be primarily affected by temperature.