3-BROMO-2-ETHOXYPYRIDINE

A 60percent dispersion of sodium hydride in mineral oil (7.4 g, 184.6 mmol) was suspended in anhydrous tetrahydrofuran (300 mL) under nitrogen. Absolute ethanol (10.0 mL, 170.4 mmol) was added dropwise at room temperature and the reaction mixture was stirred for 40 minutes at room temperature. 2-Fluoro-3-bromopyridine (25.0 g, 142.0 mmol) was added and the reaction mixture was stirred for 3 hours at room temperature. Water (250 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 x 200 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a light yellow oil (31 .5 g, 84percent). 3-Bromo-2-chloropyridine (10.0 g, 52.0 mmol) was dissolved in ethanol (100 mL) and a solution of sodium ethylate in ethanol (70.8 mL, 21 percent) was added. The mixture was heated to reflux overnight. The solvent was then removed in vacuo and the residue was dissolved in ethyl acetate and washed with satd. aqueous ammonium chloride solution. The organic layer was dried over sodium sulphate, and the solvent was evaporated. The crude product was purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1 ) to yield 7.26 g (69percent) of an yellow oil. Intermediate [Example Int22.13-bromo-2-ethoxypyridine3-Bromo-2-chloropyridine (10.0 g) was dissolved in ethanol (100 mL) and a solution of sodium ethylate in ethanol (70.8 mL, 21 percent) was added. The mixture was heated to reflux overnight. The solvent was then removed in vacuo and the residue was dissolved in ethyl acetate and washed with satd. aqueous ammonium chloride solution. The organic layer was dried over sodium sulphate, and the solvent was evaporated. The crude product was purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1 ) to yield 7.26 g (69percent) of an yellow oil.To a mixture of 3-bromo-2-chloropyridine (200 mg, 1 mmol) in EtOH (5 mL) was added t-BuOK (233 mg, 2 mmol) .The mixture was stirred at 80C for 12 hours. The reaction mixture was filtered and thefiltrate was concentrated in vacuo to give the crude product. The residue was purified by flash chromatography on silica gel (0%40% ethyl acetate in petroleum ether) to afford 3-bromo-2- ethoxypyrid me.To a mixture of 3-bromo-2-chloropyridine (200 mg, 1 mmol) in EtOH (5 ml_) was added t- BuOK (233 mg, 2 mmol) The mixture was stirred at 80C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product. The residue was purified by flash chromatography on silica gel (0%~40% ethyl acetate in petroleum ether) to afford To a mixture of 3-bromo-2-chloropyridine (200 mg, 1 mmol) in EtOH (5 mL) was added t-BuOK (233 mg, 2 mmol). The mixture was stirred at 80 C. for 12 hours. The reacettion mixture was filtered and the filtrate was concentrated in vacuo to give the crude product. The residue was purified by flash chromatography on silica gel (0%?40% ethyl acetate in petroleum ether) to afford To a mixture of 463 3-bromo-2-chloropyridine (200 mg, 1 mmol) in 25 EtOH (5 mL) was added 464 t-BuOK (233 mg, 2 mmol). The mixture was stirred at 80 C. for 12 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product. The residue was purified by flash chromatography on silica gel (0%?40% 56 ethyl acetate in 57 petroleum ether) to afford 465 To a mixture of 3-bromo-2-chloropyridine (200 mg, 1 mmol) in EtOH (5 mL) was added t-BuOK (233 mg, 2 mmol) .The mixture was stirred at 80C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product. The residue was purified by flash chromatography on silica gel (0%~40% ethyl acetate in petroleum ether) to afford 3-bromo-2- ethoxypyridine.To a solution of 3-bromo-2-ethoxy-pyridine (350 mg, 1 .7 mmol) in NMP (2 ml_) was added Zn(CN)2(244 mg, 2.1 mmol) and Pd(dppf)CI2(127 mg, 0.17 mmol). The mixture was degassed with N2and heated at 140C under microwave irradiation for 1 hour. The mixture was cooled to room temperature and filtered through celite. The filtered cake was washed with ethyl acetate (30 ml_). The filtrate was washed with water (20 ml_chi2) and brine (20 ml_), dried over Na2S04, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0%~20% ethyl acetate in petroleum ether) to give 2- ethoxynicotinonitrile.To a solution of 3-bromo-2-ethoxy-pyridine (350 mg, 1.7 mmol) in NMP (2 mL) was added Zn(CN)2 (244 mg, 2.1 mmol) and Pd(dppf)C12 (127 mg, 0.17 mmol). The mixture was degassed with N2 and heated at 140C under microwave irradiation for 1 hour. The mixture was cooled to roomtemperature and filtered through celite. The filtered cake was washed with ethyl acetate (30 mL). The filtrate was washed with water (20 mL x 2) and brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0%20% ethyl acetate in petroleum ether) to give 2-ethoxynicotinonitrile.To a solution of 3-bromo-2-ethoxy-pyridine (350 mg, 1.7 mmol) in NMP (2 mL) was added Zn(CN)2 (244 mg, 2.1 mmol) and Pd(dppf)Cl2 (127 mg, 0.17 mmol). The mixture was degassed with N2 and heated at 140 C. under microwave irradiation for 1 hour. The mixture was cooled to room temperature and filtered through celite. The filtered cake was washed with ethyl acetate (30 mL). The filtrate was washed with water (20 mL*2) and brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0%?20% ethyl acetate in petroleum ether) to give 2-ethoxynicotinonitrile.To a solution of 465 3-bromo-2-ethoxy-pyridine (350 mg, 1.7 mmol) in NMP (2 mL) was added 423 Zn(CN)2 (244 mg, 2.1 mmol) and Pd(dppf)Cl2 (127 mg, 0.17 mmol). The mixture was degassed with N2 and heated at 140 C. under microwave irradiation for 1 hour. The mixture was cooled to room temperature and filtered through celite. The filtered cake was washed with ethyl acetate (30 mL). The filtrate was washed with water (20 mL×2) and brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0%?20% 56 ethyl acetate in 57 petroleum ether) to give 467 2-ethoxynicotinonitrile.To a solution of 3-bromo-2-ethoxy-pyridine (350 mg, 1.7 mmol) in NMP (2 mL) was added Zn(CN)2 (244 mg, 2.1 mmol) and Pd(dppf)Cl2 (127 mg, 0.17 mmol). The mixture was degassed with lh and heated at 140C under microwave irradiation for 1 hour. The mixture was cooled to room temperature and filtered through celite. The filtered cake was washed with ethyl acetate (30 mL). The filtrate was washed with water (20 mL c 2) and brine (20 mL), dried over Na2S04, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0%~20% ethyl acetate in petroleum ether) to give 2-ethoxynicotinonitrile.

Molecular Weight:202.05
XLogP3:2.2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:200.97893
Monoisotopic Mass:200.97893
Topological Polar Surface Area:22.1
Heavy Atom Count:10
Complexity:99.6
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes