Dimethylformamide → 8-Bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Temperatur

65 °C

A 250 mL round bottomed flask was charged with a mixture of 6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylic acid and 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid (1.0 g, 4.31 mmol) 1D, 1,2-dichloroethane (33.2 mL), and DMF (0.267 mL, 3.45 mmol). To the resulting white suspension under nitrogen at room temperature was added oxalyl chloride (6.46 mL, 12.93 mmol) solution slowly via syringe, carefully monitoring gas evolution. Following cessation of bubbling, the reaction mixture was fitted with a reflux condenser and heated to 65° C. for 1 h, whereupon it slowly became a light yellow, homogeneous solution. The mixture was cooled to room temperature, toluene was added, and the solution was concentrated in vacuo. (This process was repeated two more times to remove excess oxalyl chloride.) The resulting solid was dried in vacuo. The light yellow solid was then suspended in 1,2-dichloroethane (33.2 mL) and charged with 3-fluoropyridin-4-amine (1.160 g, 10.34 mmol) and DIEA (4.52 mL, 25.9 mmol). The resulting light tan suspension stirred overnight at room temperature. The light brown suspension was filtered and washed with copious amounts of dichloromethane, which furnished a mixture of 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (1.240 g, 84% yield) as a tan solid. LC/MS, m/z 325.0 (M+1). HPLC Rt=2.823 min. LC/MS, m/z 369.8 (M+1). HPLC Rt=2.946 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min.

1. customof bubbling
2. customthe reaction mixture was fitted with a reflux condenser
3. temperatureThe mixture was cooled to room temperature
4. additiontoluene was added
5. concentrationthe solution was concentrated in vacuo
6. customto remove excess oxalyl chloride
7. custom) The resulting solid was dried in vacuo
8. filtrationThe light brown suspension was filtered
9. washwashed with copious amounts of dichloromethane, which
10. customfurnished

ORD-Eintrag

ord-91c85ddf31a440608a69c2833ca245fc

Quelldatensatz

uspto-grants-2013_03

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08389527B2