Sodium Bicarbonate → 4-[4-(4'-{2-[(2S,4S)-4-Methoxy-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-piperazin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester

Participants

Reaction Conditions

Reaction Steps

A solution of [(S)-1-((2S,4S)-4-methoxy-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (35.5 mg, 0.067 mmol; Preparation 26), 4-[4-(4-bromo-3-trifluoromethoxy-phenylcarbamoyl)-piperazin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (37.1 mg, 0.067 mmol) and sodium bicarbonate (29.4 mg, 0.35 mmol) in 1,4-dioxane (2.8 mL) and water (129 μL) was degassed with nitrogen for 20 min. Pd2(dba)3 (12.33 mg, 0.013 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (32.09 mg, 0.067 mmol) were added and the reaction was degassed with nitrogen for 15 min. The resulting solution was heated at 90° C. for 60 h, concentrated, diluted with methanol, filtered through a pad of Celite®, concentrated under vacuum, and purified by reverse phase HPLC. Fractions containing product were combined and lyophilised overnight to afford a white powder. Impure fractions were combined and concentrated under vacuum, dissolved in 1:1 acetic acid:ACN solution to provide the di-TFA salt of the title compound (40 mg, 54% yield) (m/z): [M+H]+ calcd for C43H57F3N8O8 871.43 found 871.8.

Provenance & Evidence