An Alternative Synthetic Route to Rilzabrutinib via an E-Configured Cyanoacrylic Acid Intermediate

In this manuscript, an alternative route of synthesis for making rilzabrutinib via amide formation was described. The two segments for the amide formation are pyrazolopyrimidine-piperidine 20 and E-cyanoacrylic acid 21. The yield of 20 from Mitsunobu reaction was doubled compared with the existing route, and the Knoevenagel-derived 21 exhibited exclusive E-configuration. This route, in contrast to Sanofi’s medicinal chemistry route, avoids Z/E isomer separation, achieves a 20-fold increase in overall yield, and improves sustainability through transition-metal-free catalysis and chromatography-free intermediates purification.