Reaction Steps
Step 1 (B): Preparation of(S)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide. To a solution of (S)-N-((1S,2S)-1-((2R,4R)-1-(4-methoxybenzyl)-4-(allyloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-4-phenylbutanamide (Step 1 (A), 55 mg, 0.071 mmol) in MeOH (5 ml) was added a catalytic amount of Pd(OH)2. The reaction mixture was stirred under 1 atm. of H2 for 18 h. The mix was then filtered through Celite and concentrated in vacuo. Flash chromatography (silica gel, 0-30% methanol/chloroform) gave 29.9 mg (64%) of (S)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide, the title compound of Example 1 as an opaque glass: 1H NMR (CDCl3, 500 MHz) δ 0.88 (3H, t, J=7.5 Hz), 1.00 (6H, dd, J=5, 7.5 Hz), 1.54 (3H, q, J=5 Hz), 1.69 (1H, dd, J=5, 15 Hz), 1.85 (1H, m), 1.92-1.97 (1H, m), 1.99 (3H, s), 2.11-2.17 (3H, m), 2.36-2.48 (3H, m), 2.52-2.57 (1H, m), 2.72 (1H, dd, J=10, 15 Hz), 2.92 (1H, dd, J=5, 15 Hz), 3.12-3.19 (3H, m), 3.29-3.42 (4H, m), 3.62 (1H, dd, J=5, 10 Hz), 3.98 (1H, m), 4.09-4.15 (1H, m), 4.63 (2H, brd s), 6.06 (1H, s), 6.52 (1H, m), 6.84 (2H, d, J=5 Hz), 7.10 (2H, d, J=5 Hz), 7.15 (1H, t, J=7.5 Hz), 7.24 (2H, t, J=7.5 Hz), 7.54 (1H, d, J=10 Hz). HPLC retention time: 1.69 min (method A). MS (ESI) (M+H)+ 657.38.
