反应详情

To a solution containing (±)-1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (1.17 g, 2.6 mmol), EXAMPLE 784, Part B, 5-chlorothiophen-2-yloxyacetic acid (0.5 g, 2.6 mmol), EXAMPLE 24, and N-methylmorpholine (0.58 g, 5.72 mmol) in anhydrous DMF (10 mL) is added HATU (1.09 g, 2.86 mmol) at ambient temperature. After 1.5 h, the reaction mixture is diluted with CH2Cl2 (100 mL) and aqueous NaHCO3 (100 mL) and the layers are separated. The aqueous phase is washed four times with CH2Cl2 (100 mL) and the combined organic phase is washed once with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude amide is purified by flash silica gel chromatography (hexane/EtOAc, 4:1 to 1:2) to afford 1.5 g of the title compound which is used directly in the next reaction. 1H NMR (300 MHz, CDCl3, ˜2:1 mixture of rotomers) major rotomer: δ3.55 (d, J=15.2 Hz, 1H), 3.60 (m, 1H), 3.69 (m, 5H), 4.37 (d, J=17.7 Hz, 1H), 4.62 (m, 2H), 4.79 (d, J=13.3 Hz, 1H), 5.35 (d, J=15.2 Hz, 1H), 6.05 (d, J=3.9 Hz, 1H), 6.52 (m. 2H), 6.84 (d, J=8.1 Hz, 1H), 7.18-7.49 (m, 11H), 7.76 (m, 1H) ppm; MS (ISP loop): m/z 627 (M+H).

1. customthe layers are separated
2. washThe aqueous phase is washed four times with CH2Cl2 (100 mL)
3. washthe combined organic phase is washed once with brine
4. dry with materialdried over anhydrous Na2SO4
5. filtrationfiltered
6. concentrationconcentrated
7. customThe crude amide is purified by flash silica gel chromatography (hexane/EtOAc, 4:1 to 1:2)