反应详情

(E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 157 mg, 0.45 mmol), 4-(3-amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester (117 mg, 0.50 mmol) and N,N-diisopropylethylamine (237 μL, 1.36 mmol) were combined in methylene chloride (20 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (173 mg, 0.45 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-4-{3-[2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetylamino]-pyrazol-1-ylmethyl}-benzoic acid methyl ester (188 mg, 74%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C26H27ClN4O6S [M+] 558.13, found 559 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.63 (m, 4 H, 2×CH2), 1.85 (m, 4 H, 2×CH2), 3.29 (s, 3 H, SO2CH3), 3.92 (s, 3 H, CO2CH3), 4.86 (m, 1 H, OCH), 5.29 (s, 2H, NCH2), 6.79 (d, J=2.3 Hz, 1 H, Ar), 7.23 (d, J=8.3 Hz, 2 H, Ar), 7.40 (d, J=2.3 Hz, 1 H, Ar), 7.55 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.65 (d, Jm=1.5 Hz, 1 H, Ar), 8.02 (d, J=8.3 Hz, 2 H, Ar), 8.18 (d, Jo=8.2 Hz, 1 H, Ar), 9.20 (s, 1 H, NH).

1. temperaturecooled in an ice bath
2. customthe ice bath was removed
3. customthe reaction mixture was evaporated in vacuo
4. additionThe residue was treated with saturated aqueous sodium bicarbonate solution (1 mL)
5. extractionextracted with chloroform (2×3 mL)
6. dry with materialThe combined organic phases were dried over sodium sulfate
7. customevaporated in vacuo
8. customThe residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes)