反应详情

温度

5 °C

A 22 liter, three-neck, round bottom flask equipped with a mechanical stirrer, Claisen adapter with a thermocouple and N2 inlet adapter, and a 250 ml addition funnel was charged with THF (10 L), and 4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl]pyridine (385.5 g, 1.52 mol). The resulting solution was cooled to 5° C. using a water/ice/salt bath. Sodium hydride (60% dispersion in mineral oil, 66.9 g, 1.67 mol) was then added in several portions at such that the internal temperature did not exceed 15° C. The resulting red mixture was stirred at 5° C. for 1.5 hours. Methyl bromoacetate (254 g, 1.67 mol) was then added drop-wise at such a rate that the temperature did not exceed 15° C. The mixture was then allowed to slowly reach room temperature overnight. The mixture was then filtered through celite, and the celite was washed with ethyl acetate. The majority of the THF was removed by rotary evaporation. Ethyl acetate (4 L) and water (4 L) were then added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×3 L). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The mixture of isomers (80:20 by GC-MS) was then eluted through silica gel using 100% ethyl acetate. The fractions that contained the isomers were concentrated and the solid suspended in ether (3 L). After heating to boiling, ethyl acetate (2 L) was added until the solid dissolved, followed by hexanes (4 L). After cooling overnight, the solid was filtered and dried under reduced vacuum to give the title compound as a red solid (235 g, 47%). 1H NMR (400 MHz, CD2Cl2) δ ppm 8.56 (d, 2 H) 7.61 (d, 2 H) 7.20 (t, 2 H) 7.03 (t, 2 H) 6.42 (s, 1 H) 4.86 (s, 2 H) 3.96 (s, 2 H) 3.71 (s, 3 H); m/z (APCI+) for C18H16N3O2F 326.1 (M+H)+.

1. customA 22 liter, three-neck, round bottom flask equipped with a mechanical stirrer
2. customdid not exceed 15° C
3. customdid not exceed 15° C
4. customwas then allowed to slowly reach room temperature overnight
5. filtrationThe mixture was then filtered through celite
6. washthe celite was washed with ethyl acetate
7. customThe majority of the THF was removed by rotary evaporation
8. additionEthyl acetate (4 L) and water (4 L) were then added
9. customThe layers were separated
10. extractionthe aqueous layer was extracted with ethyl acetate (2×3 L)
11. washThe combined organic layers were washed with brine
12. dry with materialdried (Na2SO4)
13. filtrationfiltered
14. concentrationconcentrated
15. additionThe mixture of isomers (80:20 by GC-MS)
16. washwas then eluted through silica gel using 100% ethyl acetate
17. concentrationwere concentrated
18. temperatureAfter heating to boiling, ethyl acetate (2 L)
19. additionwas added until the solid
20. dissolutiondissolved
21. temperatureAfter cooling overnight
22. filtrationthe solid was filtered
23. customdried under reduced vacuum