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, 469 mg, 1.42 mmol,) was suspended in methylene chloride (7 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (710 mL, 1.42 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (331 μL, 2.84 mmol) was added dropwise. The reaction continued to stir at 0° C. for 10 min. The 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (200 mg, 1.42 mmol) was added as a pre-dissolved reaction in methylene chloride (7 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (262 mg, 41%) as a white powder: ESI-LRMS m/e calcd for C21H28ClN3O4S [M+] 453.15, found 454.26 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.23 (m, 2H, CH2), 1.45-1.92 (m, 8H, 4×CH2), 2.14-2.33 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.31 (s, 3H, OCH3), 3.53 (t, J=7.6 Hz, 1H, CH), 3.67 (t, J=5.2 Hz, 2H, OCH2), 4.13 (t, J=5.2 Hz, 2H, NCH2), 6.65 (d, Jo=2.3 Hz, 1H, Ar), 7.33 (d, Jo=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.58 (d, Jm=1.7 Hz, 1H, Ar), 7.81 (s, 1 H, NH), 8.08 (d, Jo=8.2 Hz, 1H, Ar).

1. temperatureThe solution was chilled to 0° C.
2. stirringto stir at 0° C. for 10 min
3. customthe ice bath was removed
4. stirringto stir at 25° C. for 25 min
5. additionThe reaction was diluted with methylene chloride (100 mL)
6. washwashed with water (2×30 mL), saturated aqueous brine solution (1×20 mL)
7. dry with materialdried over magnesium sulfate
8. concentrationconcentrated in vacuo to a beige foam
9. customPurification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride)