Reaction Steps
Triphenylphosphine (172 mg, 0.66 mmol) was dissolved in methylene chloride (3 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (133 mg, 0.75 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, 146 mg, 0.44 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 3-(3-amino-pyrazol-1-yl)-propane-(R)-1,2-diol (69 mg, 0.44 mmol) and 2,6-lutidine (154 μL, 1.32 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; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (73 mg, 35%) as a pale pink powder: ESI-LRMS m/e calcd for C21H28ClN3O5S [M+] 469.1, found 470.1 [M+H+], 452.1 [M−H2O+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.20 (m, 2H, CH2), 1.41-1.94 (m, 8H, 4×CH2), 2.14-2.26 (m, 1H, CH), 3.02 (br.s., 2H, 2×OH), 3.27 (s, 3H, SO2CH3), 3.44-3.53 (m, 1H, CH of OCH2), 3.56 (dd, J=11.4, 4.2 Hz, 1H, CH of OCH2), 3.63 (t, J=7.6 Hz, 1H, CH), 3.91-4.11 (m, 3H, OCH and NCH2), 6.65 (d, J=2.3, 1H, Ar), 7.29 (d, J=2.3, 1H, Ar), 7.48 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.62 (d, Jm=1.7 Hz, 1H, Ar), 8.07 (d, Jo=8.2, 1H, Ar), 8.44 (s, 1H, NH).
