反应详情

温度

25 °C

A solution of 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Intermediate 94, 51.5 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) at 25° C. was treated with 2-chloro-3-trifluoromethyl-phenol (23.6 mg, 0.12 mmol) and cesium carbonate (65.2 mg, 0.20 mmol). The reaction was stirred at 25° C. over 3 nights. At this time, the reaction was warmed to 80° C. overnight. At this time, the reaction was filtered, rinsed with dimethylsulfoxide (1 mL) and then purified by HPLC chromatography (50-100% acetonitrile/water, C18 Pursuit Agilient, 20×150 mm, 30 ml/min) to afford 2-[4-(2-chloro-3-trifluoromethyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a white solid as a mixture of diastereomers (39 mg, 67%); ES+-HRMS m/e calcd for C26H29N5O5F3Cl [M+H+] 584.1882 found 584.1885. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79-0.95 (m, 6H), 1.24 (s, 3H), 1.29, 1.30 (2×s, 3H), 1.45 (br. s., 1H), 1.69-1.87 (m, 1H), 1.99-2.32 (m, 1H), 3.73 (dd, J=8.4, 5.7 Hz, 1H), 4.00 (dd, J=8.4, 6.2 Hz, 1H), 4.04-4.22 (m, 2H), 4.27-4.43 (m, 1H), 5.53 (dd, J=11.2, 4.2 Hz, 1H), 5.95 (d, J=2.7 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 7.59 (s, 1H), 7.70 (t, J=8.2 Hz, 1H), 7.87 (t, J=7.5 Hz, 2H), 8.25 (d, J=2.7 Hz, 1H), 10.85 (s, 1H)

1. temperatureAt this time, the reaction was warmed to 80° C. overnight
2. filtrationAt this time, the reaction was filtered
3. washrinsed with dimethylsulfoxide (1 mL)
4. custompurified by HPLC chromatography (50-100% acetonitrile/water, C18 Pursuit Agilient, 20×150 mm, 30 ml/min)