Hydrochloric Acid → methyl (S)-1-((S)-2-(5-(4'-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Participants

Reaction Conditions

Reaction Steps

A solution of (S)-tert-butyl 2-(6-(4′-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (368 mg, 0.50 mmol), concentrated HCl (1 mL) and ethanol (6 mL) was heated to 60° C. for one hour. The reaction was concentrated and redissolved in a minimal amount of methanol. An equal volume of dichloromethane was added and the solution was again concentrated. Dichloromethane was added to the resulting residue and concentrated off three more times, until the crude material was a yellow powder. The crude material was dissolved in a 5:1 mixture of dichloromethane:dimethylformamide (4.9 mL) and cooled to 0° C. To the solution are sequentially added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (119 mg, 0.57 mmol), COMU (232 mg, 0.54 mmol) and diisopropylethylamine (0.26 mL, 1.5 mmol). After one hour, the reaction is diluted with acetonitrile (2 mL) and methanol (2 mL). To this solution was added ten drops of 5M aqueous NaOH solution and stirring was continued for 30 minutes. The reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined aqueous washings were extracted three times with ethyl acetate, and the combined organic layers were dried (MgSO4) and concentrated. The crude material was purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H), followed by flash column chromatography to yield methyl (S)-1-((S)-2-(5-(4′-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (270 mg, 66%). LCMS-ESI+: calculated for C47H50N8O6: 822.95; observed [M+1]+: 823.90.

Provenance & Evidence