反应详情

温度

90 °C

A vial was charged with 2,2-dimethylpropan-1-ol (100 mg, 1.130 mmol) and DMSO (1130 μL). Sodium hydride (60% in mineral oil; 45.2 mg, 1.130 mmol) was added. The vial was placed in a 100° C. oil bath for 5 min. the reaction mixture was cooled to room temperature and (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (86 mg, 0.226 mmol) was added in one portion. The vial was sealed and heated in a 100° C. oil bath for 2 h. The mixture was cooled to room temperature, then diluted with water and EtOAc. Brine was added, and the layers were separated. The aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, and concentrated. The residue was purified by chromatography (0-100% EtOAc/Hexane) to give (S)-7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a light-yellow solid. Step 2: A vial was charged with (S)-7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (51 mg, 0.118 mmol), 2-fluoropyridin-3-ylboronic acid (33.2 mg, 0.236 mmol), potassium phosphate (75 mg, 0.354 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (4.18 mg, 5.90 μmol). The vial was flushed with Ar (g), then dioxane (442 μL) and water (147 μL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 20 min at 90° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography (30% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (S)-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (46.23 mg) as an off-white solid. MS m/z=449.2 [M+H]+.

1. customThe vial was flushed with Ar (g)
2. additiondioxane (442 μL) and water (147 μL) were added in sequence
3. customThe vial was sealed
4. extractionThe mixture was extracted with EtOAc (3×)
5. concentrationthe combined organic extracts were concentrated
6. customThe residue was purified by chromatography (
7. addition30% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM)