An Alternative Synthetic Route to Rilzabrutinib via an E-Configured Cyanoacrylic Acid Intermediate
Daibao Wei1, Jinbo Guo2, Fuqiang Zhu3
1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
None:
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.
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