反应详情

A dry 25 mL was charged with potassium fluoride (1.0 g, 18 mmol), copper(I) iodide (3.4 g, 18 mmol) and a stirbar. The flask was evacuated to <1 mm Hg and the solid was heated using a 170° C. oil bath for 2 h. The flask was cooled to room temperature and the vacuum was released with nitrogen. The flask was fitted with a septa/inert atmosphere inlet. The solids were treated with 5 mL freshly distilled DMF, trimethyl(trifluoromethyl)silane (2.7 ml, 18 mmol), and a solution of 6-fluoro-2-iodo-3-((2-methoxyethoxy)methoxy)pyridine (3.90 g, 12 mmol) in 5 mL dry NMP. The reaction was stirred at room temperature for 16 h, and then poured onto 150 mL dry DCE. The slurry was stirred for 1 h, and then filtered through a 0.22 μm PTFE membrane. The solids were washed with DCE (2×50 mL), and the combined DCE filtrates were concentrated in vacuo. The residue was taken up in 250 mL dry EtOH, and cooled using an ice-water bath. The slurry was filtered through a pad of Celite® (diatomaceous earth), and concentrated in vacuo to afford ˜7 mL of sample (in NMP). The sample was loaded onto a Waters Xterra Prep C18 MS Packed by Vydac/The Separations Group (50 mm×300 mm, PN PA0000-050730, 10 μm particle size, spherical shape; gradient: 0→4 min@20 mL/min, 40% B; 4→5 min, 20→100 mL/min@ 40% B; 5→25 min@100 mL/min, linear gradient to 70% B; 25→35 min@100 mL/min, isocratic at 70% B; 35 min, step to 100% B @100 mL/min; 35→50 min@100 mL/min, 100% B; 50 min, step to 40% B @ 100 mL/min; 60 min end. A fraction that eluted from 19.3 to 21.7 minutes was isolated. The solvent was removed in vacuo to afford 6-fluoro-3-((2-methoxyethoxy)methoxy)-2-(trifluoromethyl)pyridine (2.0964 g, 65% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.36 (s, 3H) 3.52-3.59 (m, 2H) 3.84-3.90 (m, 2H) 5.35 (s, 2H) 7.10 (ddd, J=8.95, 3.77, 0.59 Hz, 1H) 7.86 (ddd, J=9.00, 6.06, 0.59 Hz, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −75.45 (dd, J=6.50, 3.90 Hz, 1 F) −66.65 (s, 3 F). 13C NMR (101 MHz, chloroform-d) δ ppm 58.91 (s, 1 C) 68.32 (s, 1 C) 71.30 (s, 1 C) 113.61 (q, J=1.01 Hz, 1 C) 114.00 (d, J=0.87 Hz, 1 C) 120.73 (qd, J=274.47, 1.52 Hz, 1 C) 133.80 (dq, J=35.26, 13.00 Hz, 1 C) 149.84 (d, J=5.20 Hz, 1 C) 156.28 (dq, J=238.58, 1.00, 0.87 Hz, 1 C). HPLC-MS: 2.04 min (>99%@215 nm; >99% @254 nm; m/z=270.0, calculated for C10H11F4NO3+H+=270.1).

1. customThe flask was evacuated to <1 mm Hg
2. temperaturethe solid was heated
3. customusing a 170° C.
4. customfor 2 h
5. customThe flask was fitted with a septa/inert atmosphere inlet
6. stirringThe slurry was stirred for 1 h
7. filtrationfiltered through a 0.22 μm PTFE membrane
8. washThe solids were washed with DCE (2×50 mL)
9. concentrationthe combined DCE filtrates were concentrated in vacuo
10. temperaturecooled
11. filtrationThe slurry was filtered through a pad of Celite® (diatomaceous earth)
12. concentrationconcentrated in vacuo
13. customto afford ˜7 mL of sample (in NMP)
14. custom0→4 min@20 mL/min, 40% B
15. custom4→5 min, 20→100 mL/min
16. custom5→25 min@100 mL/min, linear gradient
17. custom25→35 min@100 mL/min
18. custom35 min, step
19. custom35→50 min@100 mL/min, 100% B
20. custom50 min, step
21. custom60 min end
22. washA fraction that eluted from 19.3 to 21.7 minutes
23. customwas isolated
24. customThe solvent was removed in vacuo