Accelerated synthesis of immunomodulatory imide drugs and their derivatives via continuous flow chemistry

Immunomodulatory imide drugs are widely used in the treatment of multiple myeloma, yet existing production routes are often lengthy and inefficient, underscoring the need for more efficient and broadly applicable synthetic strategies. Herein, we report the synthesis of lenalidomide (63% overall yield) and pomalidomide (62% overall yield) using an integrated continuous flow platform with residence times of 42 minutes and 52 minutes, respectively. Additionally, both continuous flow processes are readily conducted on gram scale. Compared with known methods, our approach improves solvent compatibility across the reaction sequence and enables uninterrupted continuous flow synthesis of both drugs. The products are obtained without the need for column chromatography, and both immunomodulatory imide drugs (IMiDs) can be accessed from a common intermediate through our developed route. Furthermore, we explore the synthesis of CRBN ligand-linkers under continuous flow, affording a series of derivatives with diverse properties in yields exceeding 90%.