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Publication Number
US-10662155-B2
Publication Date
2020-05-26
Expiration Date
Abstract
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.
Core Innovation
The patent describes processes for preparing Tecovirimat (ST-246), an antiviral compound used for orthopoxvirus infections, through multiple synthetic routes. The disclosed approaches convert intermediate compounds, including compound 7 and compound 13, into Tecovirimat via staged transformations and final formation or installation steps.
Synthetic Route I includes carboxhydrazide or acid salt formation and an amide coupling involving 4-(trifluoromethyl)benzoyl chloride, leading to advanced intermediates and ultimately Tecovirimat (ST-246). Synthetic Route V describes forming compound 13 from compound 7 by reacting compound 7 with 4-Iodobenzoyl chloride under nitrogen and triethylamine conditions, followed by conversion of compound 13 to ST-246 with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in anhydrous DMF, with copper(I) iodide indicated as part of the transformation.
Across the routes, the description specifies preferred reagents and handling elements such as HCl, pyridine, 4-dimethylaminopyridine, tertiary amine bases, dimethylformamide, and column chromatography purification for product isolation. The disclosure reports LC-MS conversion, HPLC area, and purification in the synthetic sequence.
Claims Coverage
The claim set includes one independent method claim and dependent claims that refine reaction conditions, solvent and reagent presence, and downstream purification. Overall, the claims cover producing the specified N-[(3aR,4R,4aR,5aS,6S,6aS)-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide by a two-step sequence from compound 7 through compound 13; there are 3 main inventive features.
Two-step conversion from compound 7 to ST-246 via compound 13
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, comprising reacting compound 7 with 4-Iodobenzoyl chloride (compound 12) to form compound 13, reacting compound 13 with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, and collecting the target product.
Using a selected base for forming compound 13
The method further includes that the reaction step includes using a base selected from pyridine, 4-dimethylaminopyridine, triethylamine, or diisopropylethylamine.
Performing step (a) under nitrogen below 20 °C
The method is carried out with the reaction step under a nitrogen atmosphere at a temperature below 20 °C.
DMF with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate and copper(I) iodide in step (b)
The reaction step is performed in the presence of dimethylformamide, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, and copper(I) iodide.
Further purifying the collected product by column chromatography
The collected product is further purified using column chromatography.
The claims are centered on producing the specified benzamide target by converting compound 7 to compound 13 with 4-iodobenzoyl chloride, converting compound 13 to the target with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, and collecting the product, with dependent claims specifying particular bases, inert-atmosphere and temperature limits, DMF and copper(I) iodide presence, and column chromatography purification.
Stated Advantages
Documented Applications
Used for orthopoxvirus infections (Tecovirimat (ST-246) described as an antiviral compound for orthopoxvirus infections).
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