Boron trifluoride etherate → 5-Acetoxy-3-ethyl-2-fluoropyridine

Temperature

0 °C

To a stirred solution of the 5-amino-3-ethyl-2-fluoropyridine from Step 126d above (2.30 g, 16.4 mmol) in 3:1 dimethoxyethane:CH2Cl2 (50 mL) at −10° C. was slowly added borontrifluoride etherate (Aldrich, 4.23 mL, 34.5 mmol). t-Butylnitrite (Aldrich, 2.34 mL, 19.7 mmol) was added over the course of 15 min., keeping the reaction temperature below −5° C. The reaction mixture was warmed to 0° C. and stirred for 30 minutes. Pentane (500 mL) was added and the solid tetrafluoroborate diazonium salt was collected by filtration. The diazonium salt was dissolved in acetic anhydride (40 mL) and heated at 95° C. for 2 h (N2 evolution was noted at 85° C.). The solvent was evaporated, the residue was dissolved in Et2O (250 mL), and washed with saturated aqueous NaHCO3 (2×150 mL). The combined aqueous phases were extracted with Et2O (2×150 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO4), and concentrated. The crude product was purified by column chromatography (silica gel; EtOAc/hexane, 4:6) to afford the title compound as a yellow oil (2.22 g, 74%): 1H NMR (CDCl3, 300 MHz) δ1.26 (t, J=7.5 Hz, 3H), 2.32 (s, 3H), 2.67 (q, J=7.0 Hz, 2H), 7.35 (dd, J=2.5, 8.0 Hz, 1H), 7.84 (m, 1H); MS (CI/NH3) m/z 184 (M+H)+, 201 (M+NH4)+.

1. customat −10° C.
2. customthe reaction temperature below −5° C
3. filtrationthe solid tetrafluoroborate diazonium salt was collected by filtration
4. dissolutionThe diazonium salt was dissolved in acetic anhydride (40 mL)
5. temperatureheated at 95° C. for 2 h (N2 evolution was noted at 85° C.)
6. customThe solvent was evaporated
7. dissolutionthe residue was dissolved in Et2O (250 mL)
8. washwashed with saturated aqueous NaHCO3 (2×150 mL)
9. extractionThe combined aqueous phases were extracted with Et2O (2×150 mL)
10. washThe combined organic phases were washed with brine (50 mL)
11. dry with materialdried (MgSO4)
12. concentrationconcentrated
13. customThe crude product was purified by column chromatography (silica gel; EtOAc/hexane, 4:6)

ORD record

ord-a8a79695d2b14fecb7d47ad491a2a6bd

Source dataset

uspto-grants-2002_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06403575B1