反应详情

温度

154.5 °C

A solution of (1R)-1-(4-chloro-5-ethynyl-3′-fluoro-6-[(E)-pyrrolidin-1-yldiazenyl]biphenyl-2-yl}ethanol (20 g, 54 mmol, ˜70% pure by HPLC) [CAUTION: this material was shown to exhibit a large energy release in its solid state during DSC analysis. Care should be taken in heating up this material in solution as an mild exotherm was observed in the initial heating of this reaction] in 1,2-dichlorobenzene (500 mL) was degassed with nitrogen for 10-15 minutes. The reaction mixture was heated in an oil bath that was pre-heated to 154-155° C. After 80-90 minutes, the heating was discontinued and the reaction mixture was cooled to room temperature, diluted with hexanes (500 mL), and stirred. Solid precipitated and settled at the bottom of the flask. The upper clear solution was filtered under vacuum through a pad of silica gel (30 g) packed in a filter funnel. The solid was rinsed with hexanes (100-200 mL) and the solution was filtered. The silica gel was mixed with the solid, diluted with dichloromethane (250 mL), and concentrated to dryness for solid loading flash column purification. The crude material adsorbed on silica gel was purified by flash column chromatography using ethyl acetate in hexanes (0 to 40% in 12 column volumes and then at 40% for 8 column volumes) to give the desired product (yields ranged from 5.6 to 7 g) as a brown foam. LCMS for C16H13ClFN2O (M+H)+: m/z=303.1; Found: 303.0; 1H NMR (300 MHz, CDCl3): δ 9.41 (d, J=6.2 Hz, 1H), 8.22-8.19 (m, 2H), 7.50-7.42 (m, 1H), 7.21-6.99 (m, 3H), 5.07-4.99 (m, 1H), 2.14-2.08 (m, 1H), 1.46-1.42 (m, 3H).

1. temperaturein heating up this material in solution as an mild exotherm
2. customwas degassed with nitrogen for 10-15 minutes
3. temperatureThe reaction mixture was heated in an oil bath that
4. temperaturethe reaction mixture was cooled to room temperature
5. additiondiluted with hexanes (500 mL)
6. customSolid precipitated
7. filtrationThe upper clear solution was filtered under vacuum through a pad of silica gel (30 g)
8. custompacked in a filter funnel
9. washThe solid was rinsed with hexanes (100-200 mL)
10. filtrationthe solution was filtered
11. additionThe silica gel was mixed with the solid
12. additiondiluted with dichloromethane (250 mL)
13. concentrationconcentrated to dryness for solid loading flash column purification
14. customwas purified by flash column chromatography