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, 248 mg, 0.75 mmol) was dissolved in methylene chloride (4 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (0.376 mL, 0.75 mmol) was added and the reaction stirred at 25° C. for 15 min. The solution was chilled to 0° C. and 2,6-lutidine (175 μL, 1.50 mmol) was added dropwise. The reaction continued to stir at 0° C. for 15 min. The 1-(3-amino-pyrazol-1-ylmethyl)-cyclopropanol (115 mg, 0.75 mmol) was added as a pre-dissolved reaction in methylene chloride (4 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 (50 mL), washed with water (2×25 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 80% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(1-hydroxy-cyclopropylmethyl)-1H-pyrazol-3-yl]-propionamide (158 mg, 45%) as a white brittle foam: ESI-LRMS m/e calcd for C22H28ClN3O4S [M+] 465.15, found 466.20 [M+H+], 488.11 [M+Na+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.65-0.72 (m, 2H, CH2), 0.87-0.92 (m, 2H, CH2), 1.08-1.25 (m, 2H, CH2), 1.44-1.98 (m, 8H, 4×CH2), 2.15-2.38 (m, 1H, CH), 3.24 (brs, 1H, OH), 3.28 (s, 3H, SO2CH3), 3.60 (t, J=7.5 Hz, 1H, CH), 4.06 (s, 2H, NCH2), 6.71 (d, Jo=2.3 Hz, 1H, Ar), 7.32 (d, Jo=2.3 Hz, 1H, Ar), 7.49 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.62 (d, Jm=1.7 Hz, 1H, Ar), 8.09 (d, Jo=8.2 Hz, 1H, Ar), 8.12 (s, 1H, NH).

1. temperatureThe solution was chilled to 0° C.
2. stirringto stir at 0° C. for 15 min
3. customthe ice bath was removed
4. stirringto stir at 25° C. for 25 min
5. additionThe reaction was diluted with methylene chloride (50 mL)
6. washwashed with water (2×25 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 80% ethyl acetate/methylene chloride)