反应详情

温度

25 °C

4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (prepared in example 45, 40 mg, 0.08 mmol) was suspended in methylene chloride (1 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (38 μL, 0.08 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (18 μL, 0.15 mmol) was added. The reaction continued to stir at 0° C. for 20 min. 3-Amino-propan-1-ol (7 μL, 0.09 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride (10 mL), washed with water (2×4 mL), saturated aqueous brine solution (1×4 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) followed by preparative thin layer chromatography (Merck Silica gel 60 F254, 500 μm, 20×20 cm; 100% ethyl acetate) afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-(3-hydroxy-propyl)-benzamide (14 mg, 32%) as a white waxy solid: ESI-LRMS m/e calcd for C29H35ClN4O5S [M+] 586.2, found 587.29 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.22 (m, 2H, CH2), 1.43-1.93 (m, 10H, 5×CH2), 2.15-2.31 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.57-3.67 (m, 3H, CH2 and CH), 3.73 (t, J=5.5 Hz, 2H, CH2), 5.18 (s, 2H, NCH2), 6.74 (d, J=2.3 Hz, 1H, Ar), 6.82 (brm, 1H, NH), 7.12 (d, Jo=8.1 Hz, 2H, Ar), 7.36 (d, J=2.3 Hz, 1H, Ar), 7.43 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.59 (d, Jm=1.6 Hz, 1H, Ar), 7.67 (d, Jo=8.1 Hz, 2H, Ar), 8.04 (d, Jo=8.1 Hz, 1H, Ar), 8.32 (s, 1H, NH).

1. temperatureThe solution was chilled to 0° C.
2. stirringto stir at 0° C. for 20 min
3. customthe ice bath was removed
4. stirringto stir at 25° C. for 16 h
5. additionThe reaction was diluted with methylene chloride (10 mL)
6. washwashed with water (2×4 mL), saturated aqueous brine solution (1×4 mL)
7. dry with materialdried over magnesium sulfate
8. concentrationconcentrated in vacuo to a beige foam
9. customPurification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run)