Sodium hydride → 1-Tert-butyl 3-ethyl 2-(6-chloropyridazin-3-yl)-2-fluoromalonate

Temperature

0 °C

To a solution of 1-tert-butyl 3-ethyl 2-(6-chloropyridazin-3-yl)malonate 45A (86.5 g, 288 mmol) in THF (2400 mL) was added NaH (12.65 g, 316 mmol). The reaction was stirred at 0° C. for 15 min. A cloudy solution of Selectfluor (112 g, 316 mmol) in DMF (dry, 800 mL) was added drop-wise at 0° C. and then the reaction was allowed to warm to ambient temperature over a 2 hrs. The reaction was then quenched with saturated NH4Cl (250 mL) and reduced in volume to about 1500 mL. To this mixture, Et2O (300 mL) and water (50 mL) were added. Layers were separated, and the aqueous layer was extracted with Et2O (3×300 mL). The combined organic layers were then washed with saturated NaHCO3 solution (3×150 mL), dried with MgSO4, filtered, and concentrated to dryness via rotary evaporation. The residue was purified via MPLC (Hex:EtOAc, 8:2) to provide 1-tert-butyl 3-ethyl 2-(6-chloropyridazin-3-yl)-2-fluoromalonate 45B (70.2 g, 220 mmol, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (t, J=7.20 Hz, 3 H) 1.46 (s, 9 H) 4.28-4.43 (m, 2 H) 8.14 (s, 2 H). ESI-MS:m/z 319.2 (M+H)+.

1. temperatureto warm to ambient temperature over a 2 hrs
2. customThe reaction was then quenched with saturated NH4Cl (250 mL)
3. additionTo this mixture, Et2O (300 mL) and water (50 mL) were added
4. customLayers were separated
5. extractionthe aqueous layer was extracted with Et2O (3×300 mL)
6. washThe combined organic layers were then washed with saturated NaHCO3 solution (3×150 mL)
7. dry with materialdried with MgSO4
8. filtrationfiltered
9. concentrationconcentrated to dryness via rotary evaporation
10. customThe residue was purified via MPLC (Hex:EtOAc, 8:2)

ORD record

ord-0c82fe596bd64f809465511674373666

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08178534B2