反应详情

Step 13 (C): (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4R)-1-benzhydryl-4-(pyridin-3-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, 18.1 mg, 0.050 mmol) in DMF (1 mL) was added HATU (22.8 mg, 0.06 mmol). A solution of (1S,2S)-2-amino-1-((2R,4R)-1-benzhydryl-4-(pyridin-3-yloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol (Step 13 (B), 25.9 mg, 0.050 mmol) in DMF (1 mL) was then added, followed by N-methylmorpholine (23 μl, 0.21 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 (34 mg, 79% yield) as a clear, slightly brown glass: 1H NMR (CDCl3, 300 MHz) δ 0.89 (3H, d, J=6 Hz), 1.00 (3H, m), 1.10-1.16 (1H, m), 1.59-2.16 (1H, m), 2.37 (1H, m), 2.47-2.54 (1H, m), 2.64 (1H, m), 2.90 (3H, m), 3.11-3.13 (2H, m), 3.27 (1H, m), 3.50 (2H, m), 3.96-3.99 (3H, m), 4.30 (1H, brd s), 5.19 (1H, s), 5.43 (1H, s), 6.58-6.60 (3H, m), 6.87 (1H, m), 7.11-7.38 (10H, m), 7.56 (2H, m), 7.71 (2H, d, J=6 Hz), 7.81 (1H, m), 8.00 (1H, d, J=6 Hz), 8.40 (1H, d, J=3 Hz), 8.77 (1H, s). HPLC retention time: 1.73 min (method A). MS (ESI) (M+H)+ 858.31.

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