1,8-Diazabicyclo(5.4.0)undec-7-ene → HCID 68172046, compound

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Reaction Steps

A solution of (2R,6S,13aS,14aR,16aS)-6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (215 mg, 0.316 mmol) and di(1H-imidazol-1-yl)methanone (Example 19d, 114 mg, 0.701 mmol) in dichloroethane (2 mL) was stirred for 2 h at room temperature. To this mixture was added cyclopropanesulfonamide (115 mg, 0.948 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.143 mL, 0.948 mmol, dried with 4 A sieves powder at 42° C. for 2 h prior to usage), and the solution was stirred for 2 h. The reaction mixture was diluted with ethyl acetate (7 mL) and washed with 10 mL of 0.1 N HCl followed by saturated aqueous sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure leaving 0.23 g crude solid which was purified via flash chromatography on silica gel (3% methanol/dichloromethane) to provide the title compound tert-butyl (2R,6S ,13aS,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (195 mg, 0.249 mmol, 79% yield). MS (ESI): m/z=784.1 [M+H]. Example 19 provided an IC50 of <0.1 nM in a 1a enzyme assay; an IC50 of <0.1 0 nM in a 1b enzyme assay; a HLM stability value of >100 μl/min/mg; an EC50 of <1.0 nM in a replicon cell line assay in a 1a-H77 background, and an EC50 of <1.0 nM in a replicon cell line assay in a 1-con1 background.

Provenance & Evidence