反应详情

温度

90 °C

To a mixture of (3R,4R)-3-methyl-4-[(R)-4-methyl-3-oxo-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperidine-1-carboxylic acid (0.028 g, 0.052 mmol), 2-bromo-1,3-difluoro-benzene (0.015 g, 0.078 mmol) and sodium carbonate (0.018 g, 0.130 mmol) in 1,4-dioxane (3.0 mL) and water (0.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (0.008 g, 0.010 mmol) and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was partitioned between EtOAc (20 mL) and water (20 mL). The organic portion was separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Table 3, Method 36) to give (3R,4R)-4-[(R)-7-(2,6-difluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.005 g, 18%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.41-7.51 (m, 1H), 7.08 (m, 2H), 6.95 (s, 1H), 6.82 (s, 1H), 4.57-4.65 (m, 5H), 4.25 (m, 1H), 3.83 (m, 1H), 2.80 (m, 1H), 2.43-2.74 (m, 2H), 2.15-2.30 (m, 1H), 1.40-1.51 (m, 12H), 1.29 (s, 3H). LC/MS (Table 1, Method 25) Rt=0.930 min; MS (ESI): m/z 527 [M+H]+.

1. temperatureThe reaction mixture was cooled to ambient temperature
2. filtrationfiltered
3. customThe filtrate was partitioned between EtOAc (20 mL) and water (20 mL)
4. customThe organic portion was separated
5. extractionthe aqueous layer was extracted with EtOAc (3×50 mL)
6. dry with materialThe combined organic phase was dried over anhydrous sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated in vacuo
9. customThe residue was purified by preparative HPLC (Table 3, Method 36)