Facile Synthesis of the Neuraminidase Inhibitor Peramivir

Abstract

An improved and convenient synthetic route for the synthesis of peramivir has been developed with a total 34% yield. The process was improved from previous methods in three key reaction steps including 1,3-dipolar cycloaddition, reductive ring cleavage of the isoxazoline, and incorporation of the peripheral guanidino group. First, an activated sodium hypochlorite (Cl% = 10%) was employed for the catalytic 1,3-dipolar cycloaddition, and 61–68% yields were obtained. Second, the NaBH₄-NiCl₂ was used as a new reducing reagent instead of the expensive catalyst PtO₂. Most important, an innovative and environmentally friendly method of guanylation in the final step was developed using chloroformamidine hydrochloride as the amidino reagent, which avoided the use of the highlytoxic reagent of HgCl₂ and made the process greener.

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GRAPHICAL ABSTRACT

Keywords:

• Anti-influenza virus
• neuraminidase inhibitor
• peramivir
• synthesis

ACKNOWLEDGMENT

This work was financially supported by the Guangdong Production and Research Joint Project (2009B090300331).

Notes

Substrate (a); compound 3; oxime (b); 2-ethyl-butyraldehyde oxime.

a/b: the substrate (compound 4) and sodium borohydride.

Authors Fei Jia and Juan Hong contributed equally to this work.