Reaktion #2161287

Reaktionsgleichung

2-hydrazinoethanol

methyl isonicotinate

4-fluorophenylacetone

sodium methoxide

→

title compound

2-[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]ethanol

Lösungsmittel

EtOH

AcOH

THF

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.ADDITIONwas added in one portion
2. 2
   workup.ADDITIONadded (3 mL)
3. 3
   Sonstigeforming a dark orange solution
4. 4
   workup.STIRRINGthe mix stirred for 16 hours at room temperature
5. 5
   SonstigeThe volatiles were removed in vacuo
6. 6
   workup.ADDITIONthe residue diluted with EtOAc (250 mL)
7. 7
   Waschenwashed with water (3×50 mL), brine (50 mL)
8. 8
   Trocknendried over MgSO4
9. 9
   Filtrationfiltered
10. 10
    workup.ADDITIONa mixture of regioisomers that
11. 11
    Sonstigewere purified by Biotage flash chromatography
12. 12
    Wascheneluting with 2-6% MeOH/DCM
13. 13
    Sonstigeseparated by chiral SF chromatography
14. 14
    Sonstigeto afford pure isomers that

Vorschrift

To a solution of methyl isonicotinate (2 g, 14.58 mmol) in THF (50 mL) was added 4-fluorophenylacetone (2.54 mL, 18.9 mmol) and sodium methoxide powder (1.6 g, 29.17 mmol) was added in one portion with stirring. The resulting suspension was heated to 75° C. for 2 hours under nitrogen, then cooled to ambient and AcOH added (3 mL) followed by EtOH (60 mL) forming a dark orange solution. 2-hydrazinoethanol (3.5 mL, excess) was then added and the mix stirred for 16 hours at room temperature. The volatiles were removed in vacuo and the residue diluted with EtOAc (250 mL) and washed with water (3×50 mL), brine (50 mL), dried over MgSO4, filtered and stripped to a red oil. TLC revealed a mixture of regioisomers that were purified by Biotage flash chromatography, eluting with 2-6% MeOH/DCM, then separated by chiral SF chromatography to afford pure isomers that were characterized by NOE NMR. The title compound was isolated as a white solid, 1.0 g, 23%. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 8.48-8.62 (2 H, m), 7.52-7.65 (2 H, m), 7.14 (2 H, dd, J=8.59, 5.31 Hz), 6.94-7.08 (2 H, m), 6.38 (1 H, s), 4.05-4.14 (2 H, m), 3.94-4.05 (4 H, m), 3.42-3.60 (1 H, m); m/z (APCI+) for C17H16N3FO 297.9 (M+H)+.

Quelle