Iridium-Catalyzed
Asymmetric Hydrogenation of Heteroaromatics
with Multiple N Atoms via Substrate Activation: An Entry to 4,5,6,7-Tetrahydropyrazolo[1,5‑a]pyrimidine-3-carbonitrile Core of a Potent BTK Inhibitor
posted on 2024-03-11, 12:33authored byMu-Wang Chen, Hong-Wang Li, Ying-Qi Wang, Bo Wu, Zheng Liu, Xinzhong Lai, Joerg Deerberg, Yong-Gui Zhou
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.