Work

Synthesis of Antiviral Drug Tecovirimat and Its Key Maleimide Intermediates Using Organocatalytic Mumm Rearrangement at Ambient Conditions

Year: 2025

Type: article

Abstract: Tecovirimat is an antiviral agent approved for the treatment of orthopoxvirus infections including smallpox, cowpox and monkeypox. A key challenge in its synthesis lies in the generation of maleimide intermediates, which traditionally requires high-temperature thermal rearrangement and often results in low-to-moderate yields. Classical methods rely on heating in toluene above 70 °C, limiting scalability and efficiency. Herein, we present a mild and efficient organocatalytic approach to the synthesis of tecovirimat intermediates, using a room-temperature Mumm rearrangement of isomaleimide precursors. The reaction is catalyzed by 10 mol% imidazole and N-hydroxysuccinimide. As a representative example for one of the tecovirimat synthesis methods, intermediate N-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-(trifluoromethyl)benzamide was synthesized from p-trifluoromethylbenzohydrazide at a 71% yield over two steps. Additionally, N-(2,5-dioxopyrrol-1-yl)(tert-butoxy)formamide was obtained from Boc-hydrazide at a 37% yield. The methodology was sufficiently extended to other benzohydrazide-derived isomaleimides. To support the mechanistic rationale, preliminary PM7 semiempirical computational studies were performed, highlighting the electronic features facilitating the transformation. This work offers a practical and scalable route to tecovirimat intermediates, overcoming key synthetic bottlenecks and enhancing the efficiency of antiviral drug production.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27010061