Hydrochloric Acid → HCID 178502474, compound

Participants

Reaction Steps

Hydrogen chloride in dioxane solution (4N, 1.51 mL, 6.05 mmol) was added to a solution of (S)-tert-butyl 2-(2′-((1S,3S,4R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (0.305 g, 0.403 mmol) in methylene chloride:methanol (4.0 mL: 0.80 mL). The suspension was allowed to stir at room temperature for two hours. Upon completion by LCMS, the reaction was concentrated to dryness and the crude product (assumed 0.403 mmol) was suspended in methylene chloride (4 mL). (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (0.093 g, 0.484 mmol) and DIPEA (0.282 mL, 1.61 mmol) were added and the slurry was cooled to −40° C. with an external dry ice/acetonitrile bath. COMU (0.259 g, 0.605 mmol) was added at −40° C. and the solution was stirred at reduced temperature for one hour. Upon completion, the crude reaction was diluted with DMF and concentrated in vacuo. The crude product was purified by reverse phase HPLC (Gilson, Gemini, 10-45% acetonitrile/water with 0.1% TFA modifier). Fractions containing product were combined and concentrated until aqueous layer remained. Aqueous sodium bicarbonate was added to aqueous product mixture to obtain a pH of 7-8 (as measured by pH paper) and precipitation was observed. The precipitate was filtered and dried under vacuum for 18 hours to give methyl {(1R)-2-[(2S)-2-{2′-[(1S,3S,4R)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl}pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (0.180 g, 53%) as a while solid. LCMS-ESI+: calc'd for C49H50N8O6: 846.39 (M+); Found: 847.8 (M+H+).

Provenance & Evidence