Reaction Steps
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 131 mg, 0.40 mmol) was dissolved in methylene chloride (2 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (200 μL, 0.40 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (92 μL, 0.79 mmol) was added. The reaction continued to stir at 0° C. for 15 min. 4-[1-(3-Amino-pyrazol-1-yl)-butyl]-benzoic acid methyl ester (108 mg, 0.40 mmol) was dissolved in methylene chloride (2 mL) and added dropwise to the reaction. The ice bath was removed and the reaction continued to stir at 25° C. for 30 min. The reaction was diluted with ethyl acetate (50 mL), washed with water (2×15 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to an orange foam. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded 4-(1-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-butyl)-benzoic acid methyl ester (110 mg, 47%) as a white foam: ESI-LRMS m/e calcd for C30H36ClN3O5S [M+] 585.2, found 586.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.93-1.02 (m, 3H, CH3), 1.05-1.22 (m, 2H, CH2), 1.22-1.40 (m, 2H, CH2), 1.42-2.00 (m, 8H, 4×CH2), 2.02-2.45 (m, 3H, CH2 and CH), 3.26 (s, 3H, SO2CH3), 3.52 (t, J=7.5 Hz, 1H, CH), 3.91 (s, 3H, OCH3), 5.11 (m, 1H, NCH), 6.74 (d, J=2.2 Hz, 1H, Ar), 7.27 (d, Jo=8.2 Hz, 2H, Ar), 7.40 (d, J=2.2 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.6 Hz, 1H, Ar), 7.58 (d, Jm=1.6 Hz, 1H, Ar), 7.98 (d, Jo=8.2 Hz, 2H, Ar), 8.04 (brs, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
