Reaction Steps
Triphenylphosphine (202 mg, 0.77 mmol) was dissolved in methylene chloride (3 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (156 mg, 0.88 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, 171 mg, 0.52 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-(S)-1,2-diol (81 mg, 0.52 mmol) and 2,6-lutidine (180 μL, 1.55 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-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (56 mg, 23%) as a pale pink powder: ESI-LRMS m/e calcd for C21H28ClN3O5S [M+] 469.1, found 470.1 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.20 (m, 2H, CH2), 1.32-1.91 (m, 8H, 4×CH2), 2.10-2.33 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.34 (dd, J=11.5, 5.3 Hz, 1H, CH of OCH2), 3.43 (dd, J=11.5, 3.2 Hz, 1H, CH of OCH2), 3.48-3.99 (br.s., 2H, 2×OH), 3.68 (t, J=7.5 Hz, 1H, CH), 3.81-3.97 (m, 3H, OCH and NCH2), 6.57 (d, J=2.2, 1H, Ar), 7.22 (d, J=2.2, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.4 Hz. 1H, Ar), 7.59 (d, Jm=1.4 Hz, 1H, Ar), 8.00 (d, Jo=8.2, 1 H, Ar), 9.12 (s, 1H, NH).
