Imidazo[1,2-a]pyridine, 6-fluoro- (9CI) synthesis

Yield:-

Reaction Conditions:

with sodium hydrogencarbonate at 0 - 70;

Steps:

15
Example 15 β-fluoro-imidazofl ,2-α]pydine (26)Synthesis of β-fluoro-imidazofl ,2-α]pydine (26) is shown schematically in Fig. 5. Concentrated HCI (34 ml_, 345 mmol) was added drop-wise to 2-bromo-1 ,1-diethoxyethane 17 (26.37g, 133.8 mmol) at room temperature in a 250-mL three neck round bottomed flask. The mixture was then heated at 55⁰C for 30 minutes. The pale yellow mixture was then cooled to O⁰C and excess anhydrous Na₂SO₄ (64g) added and the reaction stirred for 1.0 hr. The reaction mixture now containing crude bromoacetaldehyde 18 was filtered into a three neck 1000 ml. round bottomed flask and the cake washed with ethanol (100 ml_). The flask was then cooled to O⁰C and 2-amino-5-fluoropyridine (10.Og, 50 mmol) added portion-wise followed by the addition of NaHCO₃ (42g, 500 mmol). There was evolution of gas. After the bubbling had ceased, the mixture was refluxed at 7O⁰C for 1.0 hour. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. CH₂CI₂ was added to the residue at O⁰C and 40% NaOH (30 ml.) added to pH 10. The mixture was then diluted with water (100 ml.) and the organic phase separated, dried (Na₂SO₄ ) and concentrated under reduced pressure. Purification on silica gel (CombiFlash, Heptanes/EtOAc elution) afforded 6-fluoro-imidazo[1 ,2-α]pyridine 26 as a brown solid. 5.52g, 85%, yield.¹H NMR (300 MHz, CDCI₃, 297K) δ 7.06 (m, 1 H), 7.56 (m, 3H), 8.04 (m, 1 H).¹⁹F NMR (282.2 MHz, CDCI₃, 297K) δ:21.61.ESI MS (MeOH) calcd for C₇H₅FN₂ 136.13, found m/z (M⁺+1 ) 137.

References:

ISIS INNOVATION LTD.;EBETINO, Frank, Hallock;MAZUR, Adam;LUNDY, Mark, Walden;RUSSELL, Robert, Graham Goodwin WO2010/33978, 2010, A2 Location in patent:Page/Page column 33