反应详情

Step 12 (C): (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4R)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-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, 21.1 mg, 0.067 mmol) in DMF (1 mL) was added HATU (30.0 mg, 0.081 mmol). A solution of (1S,2S)-2-amino-1-((2R,4R)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol (Step 12 (B), 34.5 mg, 0.067 mmol) in DMF (1 mL) was then added, followed by N-methylmorpholine (26 μl, 0.235 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 (46.1 mg, 80% yield) as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ 0.88 (3H, d, J=6 Hz), 0.99 (3H, t, J=6 Hz), 1.10-1.17 (1H, m), 1.53-1.63 (1H, m), 1.74-1.80 (1H, m), 1.88-1.98 (3H, m), 2.08 (2H, m), 2.21-2.29 (1H, m), 2.38-2.51 (2H, m), 2.61-3.06 (5H, m), 3.47-3.61 (3H, m), 3.69-3.75 (1H, m), 3.90-3.96 (3H, m), 4.11 (1H, brd s), 5.20 (1H, s), 5.70 (1H, m), 6.15 (1H, s), 6.89-7.01 (3H, m), 7.11-7.22 (5H, m), 7.30-7.40 (5H, m), 7.60 (2H, m), 7.72 (3H, d, J=6 Hz), 8.08 (1H, m), 9.83 (3H, brd s). HPLC retention time: 1.87 min (method A). MS (ESI) (M+H)+ 858.30.

1. additionbuffer was then added
2. customto quench
3. extractionThe mixture was extracted with ethyl acetate
4. washThe organic phase was washed with sat. aqueous NaCl
5. dry with materialdried (MgSO4)
6. concentrationconcentrated in vacuo
7. customThe crude mixture was purified by reverse phase Prep HPLC