Methods of preparing Tecovirimat
Disclosed are methods for the preparation of Tecovirimat for the treatment or prophylaxis of viral infections and diseases associated therewith, particularly those viral infections and associated diseases caused by the orthopoxvirus.
1. A method for producing N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide, wherein said method comprises:
(a) reacting compound 4 of formula:
with maleic anhydride to form compound 9 of formula:
(b) reacting compound 9 with cycloheptatriene; and
(c) collecting N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide.
2. The method of claim 1 , wherein step (a) is carried out in o-xylene and reactants heated to reflux.
3. The method of claim 1 , wherein step (b) is carried out in toluene at a temperature of at least 75° C.
4. The method of claim 1 , wherein said N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide collected in step (c) is further purified by column chromatography.
5. Compound 9 of formula: