反应详情

温度

25 °C

Fmoc-beta-Alanine (3.1 g, 9.90 mmol), HATU (3.8 g, 9.90 mmol), and diisopropylethylamine (2.1 ml, 12.0 mmol) were added sequentially to a solution of 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (4.2 g, 9.90 mmol) in DMF (100 ml) at 25° C. The reaction mixture was stirred for 14 h at 25° C., then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (200 ml) and EtOAc (2×200 ml). the combined organic layers were dried over Mg2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 7% CH3OH in CH2Cl2) afforded (2-{1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl}-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (6.89 g, 97%) as a white foam. LCMS (Method G, ESI): RT=0.85 min, m+H=718.5. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.14 (t, J=10.3 Hz), 7.84 (s), 7.75 (dd, J=15.2, 7.5 Hz), 7.60-7.54 (m), 7.50 (d, J=4.1 Hz), 7.44 (t, J=7.8 Hz), 7.37 (t, J=7.4 Hz), 7.28 (t, J=5.8 Hz), 6.52 (t, J=4.7 Hz), 5.50 (d, J=11.4 Hz), 4.70 (s), 4.40 (s), 4.33 (d, J=7.1 Hz), 4.19 (t, J=6.6 Hz), 3.64 (td, J=13.3, 6.7 Hz), 3.51 (d, J=21.9 Hz), 3.39 (d, J=5.4 Hz), 2.80-2.47 (m), 2.35 (s), 2.30-2.07 (m), 1.93 (d, J=12.0 Hz), 1.51 (dt, J=13.5, 6.8 Hz).

1. concentrationwas concentrated under reduced pressure
2. customThe residue was partitioned between half-saturated NaHCO3 (200 ml) and EtOAc (2×200 ml)
3. dry with materialthe combined organic layers were dried over Mg2SO4
4. filtrationfiltered
5. concentrationthe filtrate was concentrated under reduced pressure
6. customPurification of the residue by column chromatography on silica gel (gradient: 0 to 7% CH3OH in CH2Cl2)