5-bromo-2-methoxy-3-(trifluoromethyl)pyridine

Intermediate 1 : 5-Bromo-2-methoxy-3-trifluoromethyl-pyridine To 2-methoxy-3-(trifluoromethyl)pyridine (20.0 g, 1 13.0 mmol) and 1 , 3-dibromo-5, 5- dimethylimidazolidine-2, 4-dione (43.6 g, 152.0 mmol) was added TFA (80 mL) and the resulting mixture stirred at rt for 18h under argon. The TFA was removed in vacuo (50 mbar, 45°C) and the residue suspended in tert-butyl methyl ether (200 mL). The resulting colourless solid was removed by filtration and washed with tert-butyl methyl ether (50 mL). The filtrate was concentrated in vacuo and suspended in EtOAc (50 mL) The insoluble colourless solid was removed by filtration and washed with EtOAc (50 mL).The filtrate was concentrated in vacuo, diluted with heptane/ tert-butyl methyl ether (5/1 , 20 mL) and the insoluble colourless solid was removed by filtration. The filtrate was purified by column chromatography on silica gel with heptane / EtOAc, 100/0 to 90/10. The crude product was filtered through a plug of NaHC0Intermediate 1 : 5-Bromo-2-methoxy-3-trifluoromethyl-pyridineTo 2-methoxy-3-(trifluoromethyl)pyridine (20.0 g, 1 13.0 mmol) and 1 , 3-dibromo-5, 5- dimethylimidazolidine-2, 4-dione (43.6 g, 152.0 mmol) was added TFA (80 mL) and the resulting mixture stirred at rt for 18h under argon. The TFA was removed in vacuo (50 mbar, 45°C) and the residue suspended in tert-butyl methyl ether (200 mL). The resulting colourless solid was removed by filtration and washed with tert-butyl methyl ether (50 mL). The filtrate was concentrated in vacuo and suspended in EtOAc (50 mL) The insoluble colourless solid was removed by filtration and washed with EtOAc (50 mL).The filtrate was concentrated in vacuo, diluted with heptane/ tert-butyl methyl ether (5/1 , 20 mL) and the insoluble colourless solid was removed by filtration. The filtrate was purified by column chromatography on silica gel with heptane / EtOAc, 100/0 to 90/10. The crude product was filtered through a plug of NaHC0To 2-methoxy-3-(trifluoromethyl)pyridine (20.0 g, 1 13.0 mmol) and 1 , 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione (43.6 g, 152.0 mmol) was added TFA (80 ml_) and the resulting mixture stirred at rt for 8h under argon. The TFA was removed in vacuo (50 mbar, 45°C) and the residue suspended in tert-butyl methyl ether (200 ml_). The resultingcolourless solid was removed by filtration and washed with tert-butyl methyl ether (50 mL). The filtrate was concentrated in vacuo and suspended in EtOAc (50 mL) The insoluble colourless solid was removed by filtration and washed with EtOAc (50 mL).The filtrate was concentrated in vacuo, diluted with heptane/ tert-butyl methyl ether (5/1 , 20 mL) and the insoluble colourless solid was removed by filtration. The filtrate was purified by column chromatography on silica gel with heptane / EtOAc, 100/0 to 90/10. The crude product was filtered through a plug of NaHC03 (20g) and the filtrate evaporated in vacuo to give a golden oil (27.9 g). The oil was dissolved in heptanes (20 mL) and purified by filtered through a plug of silica gel (80 g), eluting with heptane to give 5-bromo-2-methoxy-3-(trifluoromethyl)pyridine as a colourless oil (22.5g, 74percent yield).Intermediate 1 5-Bromo-2-methoxy-3-trifluoromethyl-pyridine 2-Methoxy-3-trifluoromethyl-pyridine (2.7 g, 14.79 mmol) and 1 , 3-dibromo-5, 5- dimethylhydantoin (5.28g, 18.48 mmol) were placed in a round-bottom flask. To this mixture was slowly added 40ml TFA. The mixture was stirred overnight at ambient temperature (16h). After completion of the reaction, TFA solvent was evaporated in vacuo and the resulting residue was neutralized to pH6-7 by the addition of saturated NaHC0Preparation Example 36 General Synthetic Scheme:General Scheme:

Molecular Weight:256.02
XLogP3:2.7
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:254.95066
Monoisotopic Mass:254.95066
Topological Polar Surface Area:22.1
Heavy Atom Count:13
Complexity:176
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes