Efficient Large-Scale Process for Tecovirimat via Reactive Distillation for the Preparation of Cycloheptatriene

This article describes an effective process for the large-scale synthesis of tecovirimat, an antiviral drug for treating monkeypox. A key intermediate of tecovirimat, cycloheptatriene, was efficiently obtained via a reactive distillation process of 7,7-dichlorobicyclo[4.1.0]heptane to give 82% (91.38% purity by GC) on a 44.8 kg scale. This method avoided the high temperatures (490–520 °C) and low yield that detracted from the previous synthesis. After the subsequent Diels–Alder reaction, the process proceeds with one step via the condensation of anhydride and benzohydrazine intermediates to produce the final compound in a 48% overall yield, resulting in a process mass intensity of 28 kg/kg. While many issues related to the previous reported method were avoided, this improved method has been scaled up to a 60 kg batch size with a satisfactory quality of tecovirimat for clinical investigations.