反应详情

A vial was charged with (E)-7′-bromo-4′-fluoro-2′-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine (158 mg, 0.341 mmol), 2-fluoropyridin-3-ylboronic acid (96 mg, 0.682 mmol), potassium phosphate (217 mg, 1.023 mmol), and AmPhos (12.07 mg, 0.017 mmol) were added. The vial was flushed with Ar (g), then 1,4-dioxane (1279 μL) and water (426 μL) were added in sequence. The vial was heated to 90° for 45 min. The mixture was cooled to RT and extracted with EtOAc (3×). The combined organic extracts were concentrated, and the crude product was purified by chromatography on silica gel (10-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (E)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.24 (td, J=1.5, 4.8 Hz, 1 H), 8.10 (ddd, J=1.9, 7.5, 10.4 Hz, 1 H), 7.64-7.53 (m, 2 H), 7.49 (ddd, J=1.9, 5.0, 7.3 Hz, 1 H), 7.34 (d, J=8.3 Hz, 1 H), 6.95 (dd, J=2.7, 12.4 Hz, 1 H), 6.81 (dd, J=1.4, 2.7 Hz, 1 H), 6.11 (br. s., 2 H), 3.84-3.69 (m, J=4.2 Hz, 2 H), 3.67-3.54 (m, 4 H), 2.98-2.75 (m, 2 H), 1.06-0.95 (m, 9 H). MS m/z=480.2. Calc'd for C27H28F2N3O3: 480.2. The purified racemates (58 mg) were separated using a chiral SFC column, eluting with 55% MeOH with diethylamine, to afford (S)-enantiomer (peak 1) and (R)-enantiomer (peak 2) as white solids.

1. additionwere added
2. customThe vial was flushed with Ar (g)
3. addition1,4-dioxane (1279 μL) and water (426 μL) were added in sequence
4. temperatureThe vial was heated to 90° for 45 min
5. extractionextracted with EtOAc (3×)
6. concentrationThe combined organic extracts were concentrated
7. customthe crude product was purified by chromatography on silica gel (
8. addition10-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM)