Reaction Steps
Triphenylphosphine (186 mg, 0.71 mmol) was dissolved in methylene chloride (3 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (143 mg, 0.81 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 157 mg, 0.47 mmol) was then added and it was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 30 min. The reaction was chilled to 0° C. and the combined solution of 1-(3-amino-pyrazol-1-yl)-3-hydroxy-3-methyl-butan-1-one (87 mg, 0.47 mmol) and 2,6-lutidine (0.165 mL, 1.42 mmol) in methylene chloride (4 mL) was added. The mixture was continued to stir at 0° C. for 30 min and then at 25° C. for 3 h. The reaction was diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and saturated aqueous brine solution (2×20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 40% ethyl acetate/hexanes) eluted the desired product and an impurity simultaneously. Further purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-3-methyl-butyryl)-1H-pyrazol-3-yl]-propionamide (28 mg, 12%) as a white powder: ESI-LRMS m/e calcd for C23H30ClN3O5S [M+] 495.2, found 496.2 [M+H+], 478.0 [M−H2O+H+], 396.0 [M−COCH2C(CH3)2OH]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.23 (m, 2H, CH2), 1.37 (s, 6H, 2×CH3), 1.44-1.98 (m, 8H, 4×CH2), 2.09-2.32 (m, 1H, CH), 3.23 (AB, Jgem=17.4 Hz, 2H, CH2), 3.27 (s, 3H, SO2CH3), 3.64 (t, J=7.5 Hz, 1H, CH), 7.02 (d, J=2.9 Hz, 1 H, Ar), 7.47 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.60 (d, Jm=1.7 Hz, 1H, Ar), 8.08 (d, Jo=8.2 Hz, 1H, Ar), 8.14 (d, J=2.9 Hz, 1H, Ar), 8.46 (s, 1H, NH).
