Asymmetric Synthesis of Functionalized trans-Cyclopropoxy Building Block for Grazoprevir
Feng Xu1, Yong-Li Zhong1, Hongming Li1
1Department of Process Research and Development, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Abstract:
A practical and asymmetric synthesis of a functionalized trans-cyclopropoxy building block for the preparation of the HCV NS3/4a protease inhibitor grazoprevir is reported. Intramolecular SN2 displacement-ring closure, followed by a Baeyer-Villiger oxidation, yields the desired trans-cyclopropanol with full control of diastereoselectivity. A terminal alkyne is then effectively installed using LiNH(CH2)2NEt2. Starting from (S)-epichlorohydrin, the cyclopropoxy building block is prepared in 51% overall yield with >99.8% optical purity without isolation of any intermediates.
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