4-Methylmorpholine → (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-phenoxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide

Participants

Reaction Steps

Step 11 (C): (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4R)-1-benzhydryl-4-phenoxypyrrolidin-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, 20.3 mg, 0.056 mmol) in DMF (1 mL) was added HATU (25.5 mg, 0.0672 mmol). A solution of (1S,2S)-2-amino-1-((2R,4R)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol (Step 11 (B), 29 mg, 0.056 mmol) in DMF (1 mL) was then added, followed by N-methylmorpholine (22 μl, 0.196 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 (27 mg, 56% yield) as a clear, slightly brown glass: 1H NMR (CDCl3, 300 MHz) δ 0.90 (3H, d, J=6 Hz), 1.01 (3H, m), 1.09-1.19 (1H, m), 1.51-1.61 (1H, m), 1.66-1.90 (5H, m), 2.00-2.08 (2H, m), 2.15-2.30 (1H, m), 2.40-2.49 (2H, m), 2.58-2.67 (2H, m), 2.89-3.14 (3H, m), 3.38-3.53 (3H, m), 3.71-3.96 (3H, m), 4.21-4.42 (1H, m), 5.02-5.14 (2H, m), 6.07 (1H, s), 6.53-6.63 (3H, m), 6.81 (2H, d, J=6 Hz), 6.97 (1H, m), 7.12-7.39 (13H, m), 7.56 (2H, m), 7.67 (2H, d, J=6 Hz), 9.14 (3H, brd s). HPLC retention time: 1.93 min (method A). MS (ESI) (M+H)+ 857.32.

Provenance & Evidence