反应详情

A dry 100 mL, 3-neck round bottom flask was fitted with an additional needle/septa, and inert atmosphere inlet, and a septa. The flask was charged with 2,2,6,6-tetramethylpiperidine (0.47 ml, 2.8 mmol), 5 mL dry THF and a stirbar. The flask was immersed in a ice-water bath and treated with a 1.6 M solution of butyllithium in hexanes (1.4 ml, 2.2 mmol) added over 15 minutes via syringe pump. The solution was stirred an additional 5 minutes and the ice-water bath was replaced with a dry ice acetone bath. To the stirring cold solution was added 6-fluoro-3-((2-methoxyethoxy)methoxy)-2-(trifluoromethyl)pyridine (0.5030 g, 1.9 mmol) dissolved in 5 mL dry THF over 2 minutes. The reaction was stirred for 1 h at −78° C. after which time a solution of iodine (0.12 ml, 2.2 mmol) dissolved in 5 mL dry THF was added via cannula over a 3 minute period. The reaction was stirred for 15 minutes, and then the cooling bath was removed. After stirring 5 minutes, the solution was poured onto sodium thiosulfate (1.8 ml, 19 mmol) dissolved in 50 mL water. The mixture was stirred for 10 minutes, and the layers were separated. The aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with water (3×20 mL) and dried over MgSO4. The slurry was filtered and the filtrate was concentrated in vacuo. The sample was purified in one injection using 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. 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 24.4 to 26.1 minutes was isolated. The solvent was removed in vacuo to afford 2-fluoro-3-iodo-5-((2-methoxyethoxy)methoxy)-6-(trifluoromethyl)pyridine (0.3253 g, 44% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.39-3.42 (m, 3H) 3.60-3.65 (m, 2H) 4.00-4.06 (m, 2H) 5.26 (s, 2H) 7.65 (dd, J=4.11, 0.49 Hz, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −71.79 (d, J=3.90 Hz, 1 F)-65.02 (s, 3 F). 13C NMR (101 MHz, chloroform-d) 8 ppm 59.09 (s, 1 C) 70.25 (s, 1 C) 71.47 (s, 1 C) 100.53 (dq, J=1.73, 1.59 Hz, 1 C) 109.88 (d, J=8.67 Hz, 1 C) 119.98 (dq, J=275.70, 1.30 Hz, 1 C) 124.54 (dq, J=40.53, 1.08 Hz, 1 C) 137.97 (qd, J=35.04, 14.09 Hz, 1 C) 150.60 (d, J=5.20 Hz, 1 C) 157.42 (dq, J=245.79, 0.87 Hz, 1 C).

1. customA dry 100 mL, 3-neck round bottom flask was fitted with an additional needle/septa, and inert atmosphere inlet
2. customThe flask was immersed in a ice-water bath
3. additionadded over 15 minutes via syringe pump
4. additionwas added via cannula over a 3 minute period
5. stirringThe reaction was stirred for 15 minutes
6. customthe cooling bath was removed
7. stirringAfter stirring 5 minutes
8. additionthe solution was poured onto sodium thiosulfate (1.8 ml, 19 mmol)
9. stirringThe mixture was stirred for 10 minutes
10. customthe layers were separated
11. extractionThe aqueous layer was extracted with DCM (2×50 mL)
12. washThe combined organic layers were washed with water (3×20 mL)
13. dry with materialdried over MgSO4
14. filtrationThe slurry was filtered
15. concentrationthe filtrate was concentrated in vacuo
16. customThe sample was purified in one injection
17. custom0→4 min@20 mL/min, 40% B
18. custom4→5 min, 20→100 mL/min
19. custom5→25 min@100 mL/min, linear gradient
20. custom25→35 min 100 mL/min
21. custom35 min, step
22. custom35→50 min
23. custom50 min, step
24. custom60 min end
25. washA fraction that eluted from 24.4 to 26.1 minutes
26. customwas isolated
27. customThe solvent was removed in vacuo