反应详情

温度

25 °C

2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 200 mg, 0.61 mmol) was dissolved in methylene chloride (3 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (305 μL, 0.61 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (145 μL, 1.22 mmol) was added. The reaction continued to stir at 0° C. for 20 min. The 4-(3-amino-pyrazol-1-yl)-butan-1-ol (93 mg, 0.61 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 45 min. The reaction was diluted with methylene chloride (10 mL), washed with water (2×4 mL), saturated aqueous brine solution (1×4 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-hydroxy-butyl)-1H-pyrazol-3-yl]-propionamide (35 mg, 12%) as a white foam: ESI-LRMS m/e calcd for C22H30ClN3O4S [M+] 467.2, found 468.0 [M+H+], 450.1 [M−H2O+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.23 (m, 2H, CH2), 1.45-1.99 (m, 12H, 6×CH2), 2.17-2.30 (m, 1H, CH), 2.71 (brs, 1H, OH), 3.26 (s, 3H, SO2CH3), 3.60 (t, J=7.8 Hz, 1H, CH), 3.69 (t, J=6.2 Hz, 2H, OCH2), 4.09 (t, J=6.6 Hz, 2H, NCH2), 6.70 (s, 1H, Ar), 7.30 (s, 1H, Ar), 7.49 (d, Jo=8.3 Hz, 1H, Ar), 7.62 (s, 1H, Ar), 8.10 (d, Jo=8.6 Hz, 1H, Ar), 8.47 (brs, 1H, NH).

1. temperatureThe solution was chilled to 0° C.
2. stirringto stir at 0° C. for 20 min
3. customthe ice bath was removed
4. stirringto stir at 25° C. for 45 min
5. additionThe reaction was diluted with methylene chloride (10 mL)
6. washwashed with water (2×4 mL), saturated aqueous brine solution (1×4 mL)
7. dry with materialdried over magnesium sulfate
8. concentrationconcentrated in vacuo to a beige foam
9. customPurification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run)