Iridium-Catalyzed Asymmetric Hydrogenation of Heteroaromatics with Multiple N Atoms via Substrate Activation: An Entry to 4,5,6,7-Tetrahydropyrazolo[1,5-<i>a</i>]pyrimidine-3-carbonitrile Core of a Potent BTK Inhibitor
Mu‐Wang Chen, Hong-Wang Li, Yingqi Wang, Bo Wu, Zheng Liu, Xinzhong Lai, Joerg Deerberg, Yong‐Gui Zhou
Abstract
High Resolution Image Download MS PowerPoint Slide The chiral 4,5,6,7-tetrahydropyrazolo[1,5- a ]pyrimidine is the key core skeleton of potent Bruton’s tyrosine kinase (BTK) inhibitor Zanubrutinib, and the catalyst-controlled asymmetric hydrogenation of planar multinuclear pyrimidine heteroarenes with multiple N atoms could provide an efficient route toward its synthesis. Owing to the strong aromaticity and poisoning effect toward chiral transition metal catalyst, asymmetric hydrogenation of pyrazolo[1,5- a ]pyrimidines with multiple nitrogen atoms is still a challenge for synthesizing the chiral 4,5,6,7-tetrahydropyrazolo[1,5- a ]-pyrimidine. Herein, an efficient iridium-catalyzed asymmetric hydrogenation of pyrazolo[1,5- a ]pyrimidines has been developed using substrate activation strategy, with up to 99% ee. The decagram scale synthesis further demonstrated the potential and promise of this procedure in the synthesis of Zanubrutinib. In addition, a mechanistic study indicated that the hydrogenation starts with 1,2-hydrogenation.