反应详情

Intermediate 19b (85.0 mg, 0.250 mmol) and (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (US2004/192653, 99 mg, 0.300 mmol) were dissolved in 1,4-dioxane (3 mL) and DIPEA (70 μL, 0.400 mmol). The reaction was heated at reflux for 1.75 h, then more (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (35 mg, 0.100 mmol) and DIPEA (3 drops) were added. After a further 4 h the mixture was concentrated in vacuo. The residue was purified by FCC, using 0-15% MeOH in DCM, to give impure product (82 mg). Further purification twice by HPLC (C18 X-select column, 40-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (44 mg, 34%). LCMS (Method 5): Rt 3.83 min, m/z 520.1 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.21 (9H, s), 1.35-1.43 (6H, m), 1.85-2.25 (4H, m), 3.51-3.62 (4H, m), 4.80-4.91 (1H, m), 5.50-5.57 (1H, m), 6.02 (1H, s), 7.09 (1H, d, J 8.8), 7.11-7.17 (2H, m), 7.20 (1H, dd, J 9.6, 2.2), 7.44-7.50 (1H, m), 7.69 (1H, d, J 9.6), 8.22 (1H, br d), 8.40 (1H, s).

1. temperatureThe reaction was heated
2. temperatureat reflux for 1.75 h
3. concentrationAfter a further 4 h the mixture was concentrated in vacuo
4. customThe residue was purified by FCC