Configurational and Conformational Proclivity of an a-Cyanoacrylamide Derivative of Ibrutinib

a-Cyanoacrylamide derivatives of ibrutinib are reversible inhibitors of Bruton 39;s tyrosine kinase (BTK), an important target in B-cell-mediated cancers. We prepared the methyl derivative 1 as part of a larger study and observed interesting complex isomerization behavior that warranted further investigation. Herein, we characterize the solution-state configurational and conformational behavior of 1 by 1D and 2D temperature-dependent NMR and LC-MS. Synthesis of 1 by various routes leads to mixtures of E and Z configurational isomers about its alkene centered at C-31 and C-32. Isomers (E)-1 and (Z)-1 can be separated by reversed-phase HPLC and are stable at room temperature in solution. Interestingly, each configurational isomer undergoes cis/trans conformational isomerization about their respective acrylamide bonds at N-28 with rates dependent on the alkene configuration at C-31. Further, the configurational integrity of the alkene can be compromised at elevated temperatures. Warming pure (E)-1 affords a mixture of E- and Z-isomers resulting in the same relative ratio as observed in the initial synthesis of the compound, with each again exhibiting conformational isomerization about their amide bonds. Warming pure (Z)-1 affords the same results. Knowledge of the isomerization behavior of a-cyanoacrylamides can inform the synthesis, purification, and utility of this class of molecules.

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