반응 #2161263

반응 방정식

Methyl bromoacetate

4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl]pyridine

N2

Sodium hydride

→

title compound

수율 47.5%

methyl [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetate

수율 47.5%

용매

THF

반응 조건

후처리

1. 1
   기타A 22 liter, three-neck, round bottom flask equipped with a mechanical stirrer
2. 2
   기타did not exceed 15° C
3. 3
   기타did not exceed 15° C
4. 4
   기타was then allowed to slowly reach room temperature overnight
5. 5
   여과The mixture was then filtered through celite
6. 6
   세척the celite was washed with ethyl acetate
7. 7
   기타The majority of the THF was removed by rotary evaporation
8. 8
   workup.ADDITIONEthyl acetate (4 L) and water (4 L) were then added
9. 9
   기타The layers were separated
10. 10
    추출the aqueous layer was extracted with ethyl acetate (2×3 L)
11. 11
    세척The combined organic layers were washed with brine
12. 12
    건조dried (Na2SO4)
13. 13
    여과filtered
14. 14
    농축concentrated
15. 15
    workup.ADDITIONThe mixture of isomers (80:20 by GC-MS)
16. 16
    세척was then eluted through silica gel using 100% ethyl acetate
17. 17
    농축were concentrated
18. 18
    온도After heating to boiling, ethyl acetate (2 L)
19. 19
    workup.ADDITIONwas added until the solid
20. 20
    workup.DISSOLUTIONdissolved
21. 21
    온도After cooling overnight
22. 22
    여과the solid was filtered
23. 23
    기타dried under reduced vacuum

실험 절차

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)+.

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