Reaktion #423053

Reaktionsgleichung

4-bromo-3-fluorophenol

2,2,6,6-tetramethylpiperidine

n-butyllithium

2-fluoro-5-iodopyridine

potassium carbonate

→

2-(4-bromo-3-fluorophenoxy)-5-iodonicotinic acid

Ausbeute 69.7%

Lösungsmittel

THF

THF

THF

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.STIRRINGAfter stirring for an additional 30 min
2. 2
   SonstigeCO2 was bubbled through the red solution for 10 minutes
3. 3
   SonstigeThe cooling bath was removed
4. 4
   SonstigeCO2 was bubbled through the reaction mixture for an additional hour
5. 5
   EinengenThe reaction mixture was concentrated in vacuo
6. 6
   Sonstigetriturated with hexanes
7. 7
   Einengenagain concentrated in vacuo
8. 8
   TemperaturThe resulting mixture was heated to 120° C. for 18 h
9. 9
   TemperaturThe reaction mixture was cooled to rt
10. 10
    Filtrationfiltered through celite
11. 11
    workup.ADDITIONThe filtrate was diluted with EtOAc (500 mL)
12. 12
    WaschenThe organics were washed with water, brine
13. 13
    Trocknendried over MgSO4
14. 14
    Einengenconcentrated in vacuo
15. 15
    SonstigeThe crude residue was triturated with ether/hexanes
16. 16
    Sonstigethe derived solid was dried under a stream of nitrogen

Vorschrift

A solution of n-butyllithium (150 mL, 375 mmol) in 950 mL THF was cooled to −10° C. and treated with a solution of 2,2,6,6-tetramethylpiperidine (72.7 mL, 428 mmol) in 50 mL THF. After stirring for 15 min, the solution was cooled to −78° C. and 2-fluoro-5-iodopyridine (80 g, 357 mmol) was added as a solution in 400 mL THF dropwise via addition funnel over 60 minutes. After stirring for an additional 30 min, CO2 was bubbled through the red solution for 10 minutes. The cooling bath was removed, and CO2 was bubbled through the reaction mixture for an additional hour. The reaction mixture was concentrated in vacuo, triturated with hexanes and again concentrated in vacuo. The crude residue was taken up in 360 mL DMF and was treated with 4-bromo-3-fluorophenol (68.1 g, 357 mmol) followed by potassium carbonate (61.6 g, 446 mmol). The resulting mixture was heated to 120° C. for 18 h. The reaction mixture was cooled to rt and filtered through celite. The filtrate was diluted with EtOAc (500 mL) and was acidified to pH 3 with 6 N HCl. The organics were washed with water, brine, dried over MgSO4 and concentrated in vacuo. The crude residue was triturated with ether/hexanes, and the derived solid was dried under a stream of nitrogen to provide 2-(4-bromo-3-fluorophenoxy)-5-iodonicotinic acid (108.93 g, 249 mmol) as a brown solid.

Quelle