17282-04-1

124-38-9

628691-93-0

1. In a dry reaction flask, lithium diisopropylamide (2M in heptane/tetrahydrofuran/ethylbenzene, 16.7 ml) was mixed with tetrahydrofuran (30 ml) and cooled to -78 °C. 2. A solution of 2-chloro-3-fluoropyridine (4.0 g, 30.4 mmol) in tetrahydrofuran (30 ml) pre-cooled to -78°C was added dropwise to the above cooled mixture over a period of 20 min. 3. After 3 hours of reaction, carbon dioxide was bubbled into the cold reaction mixture for 20 minutes. 4. The reaction mixture was gradually heated to -30 °C for 1 h and then continued to 0 °C. The reaction mixture was heated to -30 °C for 1 h and then continued to 0 °C. 5. The reaction was quenched by addition of water (75 ml) and the aqueous phase was washed with ether (100 ml). 6. The pH of the aqueous phase was adjusted to 2 with 2N hydrochloric acid to produce a white precipitate, which was aged for 18 h. The mixture was filtered and air-dried to give 2-chloro-3-fluoroisonicotinic acid (4.22 g, 79%). 7. 2-Chloro-3-fluoroisonicotinic acid (3.30 g, 18.8 mmol) was suspended in thionyl chloride (40 ml) and heated to reflux for 2.5 hours. 8. The solvent was evaporated and the residue was azeotropically dried with toluene (100 ml) to give a light yellow oil. 9. The oily substance was dissolved in dichloromethane (20 ml), cooled to 0 °C and methanol (2.42 g, 75.3 mmol) was added dropwise over 15 min. 10. After the dropwise addition, the mixture was warmed to room temperature and stirred for 18 hours. 11. The solvent was evaporated and the mixture was partitioned between water (75 ml) and dichloromethane (100 ml). 12. The aqueous phase was further extracted with dichloromethane (100 ml), the organic layers were combined, washed with brine (75 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give methyl 2-chloro-3-fluoroisonicotinate (3.32 g, 93%). 13. 2-Chloro-3-fluoroisonicotinic acid methyl ester (3.32 g, 17.5 mmol) was converted to 8-fluoroimidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (1.4 g, 41%). 14. 8-Fluoroimidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (0.19 g, 1.0 mmol) was brominated to give methyl 3-bromo-8-fluoroimidazo[1,2-a]pyridine-7-carboxylate (195 mg, 71%). 15. 3-Bromo-8-fluoroimidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (0.10 g, 0.37 mmol) was coupled with 4,2'-difluoro-5'-(5,5-dimethyl[1,3,2]dioxaborolan-2-yl)biphenyl-2-ylcarbonitrile (0.15 g, 0.44 mmol) to give 3-(2'-cyano-2,4'-difluoro-biphenyl- 5-yl)-8-fluoroimidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (79 mg, 53%).