Réaction #2161263

Équation de réaction

Methyl bromoacetate

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

N2

Sodium hydride

→

title compound

Rendement 47.5%

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

Rendement 47.5%

Solvants

THF

Conditions de réaction

Traitement

1. 1
   AutreA 22 liter, three-neck, round bottom flask equipped with a mechanical stirrer
2. 2
   Autredid not exceed 15° C
3. 3
   Autredid not exceed 15° C
4. 4
   Autrewas then allowed to slowly reach room temperature overnight
5. 5
   FiltrationThe mixture was then filtered through celite
6. 6
   Lavagethe celite was washed with ethyl acetate
7. 7
   AutreThe 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
   AutreThe layers were separated
10. 10
    Extractionthe aqueous layer was extracted with ethyl acetate (2×3 L)
11. 11
    LavageThe combined organic layers were washed with brine
12. 12
    Séchagedried (Na2SO4)
13. 13
    Filtrationfiltered
14. 14
    Concentrationconcentrated
15. 15
    workup.ADDITIONThe mixture of isomers (80:20 by GC-MS)
16. 16
    Lavagewas then eluted through silica gel using 100% ethyl acetate
17. 17
    Concentrationwere concentrated
18. 18
    TempératureAfter heating to boiling, ethyl acetate (2 L)
19. 19
    workup.ADDITIONwas added until the solid
20. 20
    workup.DISSOLUTIONdissolved
21. 21
    TempératureAfter cooling overnight
22. 22
    Filtrationthe solid was filtered
23. 23
    Autredried under reduced vacuum

Mode opératoire

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)+.

Source