反应详情

To a solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (30 mg, 0.07 mmol; see Example 1, Step 8) in methanol (3 mL) was added 10% Pd/C (30 mg of 50% wet catalyst). The flask was evacuated and back-filled with hydrogen from a hydrogen balloon. The mixture was stirred at room temperature for 1.5 h under 1 atm hydrogen and then the catalyst was removed by filtration. The filtrate was concentrated in vacuo. The residue was dissolved in isopropanol (3 mL) and charged sequentially with 4-chloro-6-(trifluoromethyl)quinazoline (19.4 mg, 1.2 eq) and diisopropylethylamine (18 mg, 2 eq). The mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was purified by preparative reverse-phase HPLC to provide the title compound as its TFA salt (47 mg, 93%). LC/MS found [M+H]+=493. 1H-NMR (400 MHz, CD3OD), δ ppm: 8.90 (1H, s), 8.81 (1H, s), 8.25-8.29 (1H, m), 7.96 (1H, d, J=8.65 Hz), 5.44 (1H, t, J=9.92 Hz), 4.42 (1H, d, J=2.54 Hz), 4.15-4.24 (1H, m), 3.90 (1H, t, J=8.65 Hz), 3.70-3.79 (1H, m), 3.46-3.62 (2H, m), 2.56-2.67 (1H, m), 2.33-2.47 (1H, m), 1.70-2.23 (9H, m), 1.35 (6H, d, J=6.10 Hz).

1. customThe flask was evacuated
2. additionback-filled with hydrogen from a hydrogen balloon
3. customthe catalyst was removed by filtration
4. concentrationThe filtrate was concentrated in vacuo
5. dissolutionThe residue was dissolved in isopropanol (3 mL)
6. stirringThe mixture was stirred at room temperature for 1 h
7. customThe solvent was removed under reduced pressure
8. customThe residue was purified by preparative reverse-phase HPLC