反应详情
EQUATION
反应方程式
REACTANTS
反应物
PRODUCTS
生成物
AUXILIARIES
试剂、催化剂与溶剂
CONDITIONS
反应条件
- 温度
- 25 °C
PROCEDURE
实验过程
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (250 mg, 0.76 mmol, prepared as in PCT WO 2004/052869 A1, Example 1) was dissolved in methylene chloride (3.8 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (380 μL, 0.76 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (180 μL, 1.52 mmol) was added. The reaction continued to stir at 0° C. for 20 min. The 3-(3-amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester (176 mg, 0.76 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (40 mL), washed with water (2×10 mL), saturated aqueous brine solution (1×10 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 15% ethyl acetate/methylene chloride) afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid methyl ester (196 mg, 47%) as a white foam: ESI-LRMS m/e calcd for C27H30ClN3O5S [M+] 543.16, found 544.22 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.21 (m, 2H, CH2), 1.45-1.94 (m, 8H, 4×CH2), 2.15-2.34 (m, 1H, CH), 3.25 (s, 3H, SO2CH3), 3.52 (t, J=7.5 Hz, 1H, CH), 3.91 (s, 3H, CO2CH3), 5.19 (s, 2H, NCH2), 6.72 (d, J=2.2 Hz, 1H, Ar), 7.34 (m, 2H, Ar), 7.40 (d, Jo=7.7 Hz, 1H, Ar), 7.44 (dd, Jo=8.3, Jm=1.5 Hz. 1H, Ar), 7.58 (d, Jm=1.5 Hz, 1H, Ar), 7.84-7.91 (m, 2H, Ar and NH), 7.97 (d, Jo=7.7 Hz, 1H, Ar), 8.08 (d, Jo=8.3 Hz, 1H, Ar).
WORKUP
后处理
- temperatureThe solution was chilled to 0° C.
- stirringto stir at 0° C. for 20 min
- customthe ice bath was removed
- stirringto stir at 25° C. for 25 min
- additionThe reaction was diluted with methylene chloride (40 mL)
- washwashed with water (2×10 mL), saturated aqueous brine solution (1×10 mL)
- dry with materialdried over magnesium sulfate
- concentrationconcentrated in vacuo to a beige foam
- customPurification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride)