反应详情

温度

80 °C

A solution of methyl 5-chloro-2-hydroxy-3-nitro-4-[(trimethylsilyl)ethynyl]benzoate (380 g, 1.2 mol) in toluene (3.7 L) at −12° C. was treated with triethylamine (320 mL, 2.3 mol), followed by trifluoromethanesulfonic anhydride (270 mL, 1.6 mol) dropwise over a 15 minute period (temperature was −3° C. at the end of the addition). The dry ice/isopropanol bath was removed. The reaction mixture was kept at −15 to 20° C. for 3 hours. The reaction mixture was treated with water (3.2 L) and stirred for 20 minutes. The organic layer was separated and rinsed with water (2×1.6 L). The organic layer containing the triflate intermediate was used immediately without further purification. The triflate solution was treated with water (1.9 L), sodium bicarbonate (390 g, 4.6 mol), (3-fluorophenyl)boronic acid (210 g, 1.5 mol) and the mixture was degassed with nitrogen for approximately 10 minutes. The reaction mixture was treated with tetrakis(triphenylphosphine)palladium(0) (27 g, 23 mmol), degassed with nitrogen for an additional 10 minutes, and heated to 80° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (2 L) and water (2 L), and stirred. The organic layer was separated and washed with water (2×2 L) and brine. Celite (150 g) was added to the organic layer and the mixture was stirred for 30 minutes. The organic layer was filtered through a pad of celite, rinsed with ethyl acetate (1 L), and concentrated to give a dark green solid. The solid was diluted with isopropanol (3 L) and heated to 70° C. which gave a dark green solution. The solution was stirred at room temperature for 2 hours and at 0° C. for 30 minutes. The solid was collected by filtration, rinsed with isopropanol (800 mL), and dried to give the desired product (330 g, 71%) as a green solid. HPLC 98.9% pure @ 220 nm. LCMS for C19H18ClFNO4Si (M+H)+: m/z=406.1; Found: 405.9; 1H NMR (300 MHz, DMSO-d6): δ 8.27 (s, 1 H), 7.52-7.41 (m, 1 H), 7.35-7.23 (m, 1 H), 7.19-7.11 (m, 1 H), 7.09-7.02 (m, 1 H), 3.58 (s, 3 H), 0.22 (s, 9 H).

1. addition(temperature was −3° C. at the end of the addition)
2. customThe dry ice/isopropanol bath was removed
3. additionThe reaction mixture was treated with water (3.2 L)
4. customThe organic layer was separated
5. washrinsed with water (2×1.6 L)
6. additionThe organic layer containing the triflate intermediate
7. customwas used immediately without further purification
8. customthe mixture was degassed with nitrogen for approximately 10 minutes
9. customdegassed with nitrogen for an additional 10 minutes
10. temperatureThe reaction mixture was cooled to room temperature
11. additiondiluted with ethyl acetate (2 L) and water (2 L)
12. stirringstirred
13. customThe organic layer was separated
14. washwashed with water (2×2 L) and brine
15. additionCelite (150 g) was added to the organic layer
16. stirringthe mixture was stirred for 30 minutes
17. filtrationThe organic layer was filtered through a pad of celite
18. washrinsed with ethyl acetate (1 L)
19. concentrationconcentrated
20. customto give a dark green solid
21. temperatureheated to 70° C. which
22. customgave a dark green solution
23. stirringThe solution was stirred at room temperature for 2 hours and at 0° C. for 30 minutes
24. filtrationThe solid was collected by filtration
25. washrinsed with isopropanol (800 mL)
26. customdried