Reaction Steps
To a solution of [(S)-1-benzyl-2-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (Example 27, step A, 0.26 g, 2.6 mmol) in CH2Cl2 (5 mL) was added 4 M HCl solution in 1,4-dioxane (2 mL). The mixture was stirred at rt for 4 h, and then the solvent was removed. The residue was redissolved in MeOH (10 mL) and treated with basic resin (Dowex 550A OH anion-exchange resin) for 2 h. The resin was filtered off, and the solvents were removed from the filtrate under reduced pressure. The residue was dissolved in DMF (1 mL) and added to a solution of HOBT (0.095 g, 0.7 mmol), EDCl (0.134 g, 0.7 mmol) and [4-(4-chloro-phenoxy)-phenylamino]-acetic acid (0.13 g, 0.47 mmol) in DMF (5 mL). N-Methyl-morpholine (0.095 g, 0.94 mmol) was then added dropwise. The reaction mixture was stirred at rt overnight, and H2O (10 mL) was then added. The aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with 1 N NaOH (2×10 mL) and brine (30 mL), dried (MgSO4), and concentrated. Purification by column chromatography [0–20% (1% NH4OH/MeOH)/CH2Cl2] afforded 0.104 g (42%) of the desired product. MS (electrospray): mass calculated for C30H35ClN4O3, 534.24; m/z found, 535.24 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.63 (d, J=8.6 Hz, 1H), 7.19–7.13 (m, 6H), 7.10–7.08 (m, 2H), 6.80–6.76 (m, 4H), 6.58–6.45 (m, 2H), 6.13 (s, 1H), 4.43–4.40 (m, 1H), 4.18 (s, 1H), 3.72–3.65 (m, 2H), 3.34–3.27 (m, 1H), 3.25–3.16 (m, 1H), 2.92 (dd, J=13.6, 6.5 Hz, 1H), 2.71 (dd, J=13.6, 8.1 Hz, 1H), 2.51 (t, J=6.0 Hz, 2H), 2.44 (s, 4H), 2.33 (dd, J=15.0, 4.87 Hz, 1H), 2.21 (dd, J=15.1, 5.37 Hz, 1H), 1.81 (s, 2H), 1.71 (s, 4H).
