Reaction Steps
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 125 mg, 0.38 mmol) was dissolved in methylene chloride (2 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (190 μL, 0.38 mmol) was added and the reaction stirred at 25° C. for 15 min. The solution was chilled to 0° C. and 2,6-lutidine (89 μL, 0.76 mmol) was added dropwise. The reaction continued to stir at 0° C. for 15 min. The 4-(3-amino-pyrazol-1-ylmethyl)-cyclohexanecarboxylic acid methyl ester (90 mg, 0.38 mmol) was added as a pre-dissolved reaction in methylene chloride (2 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride) afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-cyclohexanecarboxylic acid methyl ester (80 mg, 38%) as a white foam: ESI-LRMS m/e calcd for C27H36ClN3O5S [M+] 549.21, found 550.36 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.91-1.07 (m, 2H, CH2), 1.06-1.21 (m, 2H, CH2), 1.32-1.47 (m, 2H, CH2), 1.46-1.56 (m, 2H, CH2), 1.56-1.93 (m, 9H, CH and 4×CH2), 1.93-2.04 (m, 2H, CH2), 2.11-2.32 (m, 2H, 2×CH), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.5 Hz, 1H, CH), 3.66 (s, 3H, CO2CH3), 3.80 (d, J=7.0 Hz, 2H, NCH2), 6.64 (d, Jo=2.2 Hz, 1H, Ar), 7.21 (d, Jo=2.2 Hz, 1H, Ar), 7.46 (dd, Jo=8.1, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.58 (s, 1H, NH), 8.09 (d, Jo=8.1 Hz, 1H, Ar).
