Hydrogen Bromide → methyl (R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

Participants

Reaction Steps

A mixture of (S)-benzyl 2-(5-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (260 mg, 0.33 mmol), 33% HBr in acetic acid (1 mL) and dichloromethane (4 mL) was vigorously stirred at room temperature for 30 minutes and then thoroughly concentrated. The crude material was diluted with dichloromethane and concentrated, letting the resulting residue sit under vacuum overnight. To this residue were sequentially added dichloromethane (2.4 mL), dimethylformamide (0.6 mL), (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (88 mg, 0.42 mmol), and COMU (154 mg, 0.36 mmol) and diisopropylethylamine (0.16 mL, 0.9 mmol). After stirring for 30 minutes at room temperature the reaction was diluted with ethyl acetate and washed sequentially with saturated aqueous NaHCO3 solution, water and brine. The organic layer was dried (MgSO4), then filtered through a freebasing column (Stratospheres™ PL-HCO3MP SPE, Part #: PL3540-C603). The filtrate was concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield methyl (R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (72 mg, 26%). LCMS-ESI+: calculated for C48H50N8O7: 850.96; observed [M+1]+: 851.93.

Provenance & Evidence