Reaction Steps
Step 14 (B): (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4R)-1-benzhydryl-4-hydroxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-4-phenylbutanamide. To a solution of (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-4-phenylbutanoic acid (Preparation A, 22.6 mg, 0.063 mmol) in DMF (1 mL) was added HATU (28.7 mg, 0.076 mmol). A solution of (3R,5R)-5-((1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl)-1-benzhydrylpyrrolidin-3-ol (Step 14 (A), 27.5 mg, 0.063 mmol) in DMF (1 mL) was then added, followed by N-methylmorpholine (24.2 μl, 0.221 mmol). The reaction mixture was stirred at rt for 3 h. pH 4 buffer was then added to quench. The mixture was extracted with ethyl acetate. The organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. The crude mixture was purified by reverse phase Prep HPLC to give the title compound (32 mg, 65% yield) as a slightly yellow oil: 1H NMR (CDCl3, 500 MHz) δ 0.88 (3H, d, J=10 Hz), 1.00 (3H, m), 1.07-1.18 (1H, m), 1.55-1.61 (1H, m), 1.72-1.78 (1H, m), 1.95-2.03 (4H, m), 2.05-2.11 (2H, m), 2.30 (2H, d, J=15 Hz), 2.38-2.47 (1H, m), 2.48-2.53 (1H, m), 2.64-2.70 (1H, m), 2.88 (1H, m), 3.03-3.08 (3H, m), 3.17-3.20 (1H, m), 3.49 (1H, s), 3.53-3.61 (3H, m), 3.91 (1H, d, J=10 Hz), 3.96 (3H, s), 4.11 (1H, m), 4.47 (1H, brd s), 4.96 (1H, brd s), 6.13 (1H, brd s), 6.58-6.67 (3H, m), 7.04-7.37 (10H, m), 7.49 (2H, m), 7.67 (2H, d, J=10 Hz). HPLC retention time: 1.67 min (method A). MS (ESI) (M+H)+ 781.35.
