Iodine → HCID 58961248, compound

To a stirred solution of sodium hydride (2 eq.) in rigorously degassed THF (approximately 50 mL/g) at 0° C., was added dropwise a solution of (2,6-difluorophenyl)-(5-bromopyridin-2-yl)-amine (1 eq.) in THF (approximately 15 mL/g). The solution was allowed to warm slowly to room temperature over 1 hour, after which time the solution was cooled to −78° C. n-Butyllithium (approximately 1.6 M in hexanes, 1.1 eq.) was added dropwise over 15 minutes and the resultant solution was stirred at −78° C. for 1 hour. Zinc chloride/TMEDA complex (prepared as described by Isobe et al., Chem. Lett., 1977, 679) was added as a solid in a single portion and the solution was allowed to warm to 0° C. over 30 minutes, and was stirred at 0° C. for a further 1 hour. A solution of iodine (1.1 eq.) in THF (approximately 10 mL/g) was added and the solution was allowed to warm to room temperature. After stirring at room temperature for at least 1 hour, the reaction was quenched with a saturated aqueous solution of ammonium chloride. The solution was extracted with diethyl ether (3 times approximately 50 mL/g of 5-Bromopyridin-2-yl)-(2,6-difluorophenyl)-amine used). The combined organic layer was washed successively with 10% aqueous sodium sulfite solution (approximately 50 mL/g), saturated aqueous sodium thiosulfate solution (approximately 50 mL/g) and water (approximately 50 mL/g), dried over MgSO4 and concentrated in vacuo to give the crude reaction product as an orange oil. Purification by column chromatography, using 10% ethyl acetate:hexane as eluant, provided (2,6-Difluoro-phenyl)-(5-iodo-pyridin-2-yl)-amine (Rf 0.22) in approximately 50% yield.

1. additionwas added dropwise over 15 minutes
2. additionZinc chloride/TMEDA complex (prepared as described by Isobe et al., Chem. Lett., 1977, 679) was added as a solid in a single portion
3. temperatureto warm to 0° C. over 30 minutes
4. temperatureto warm to room temperature
5. stirringAfter stirring at room temperature for at least 1 hour
6. customthe reaction was quenched with a saturated aqueous solution of ammonium chloride
7. extractionThe solution was extracted with diethyl ether (3 times approximately 50 mL/g of 5-Bromopyridin-2-yl)-(2,6-difluorophenyl)-amine
8. washThe combined organic layer was washed successively with 10% aqueous sodium sulfite solution (approximately 50 mL/g), saturated aqueous sodium thiosulfate solution (approximately 50 mL/g) and water (approximately 50 mL/g)
9. dry with materialdried over MgSO4
10. concentrationconcentrated in vacuo
11. customto give the crude
12. customreaction product as an orange oil
13. customPurification by column chromatography

ORD record

ord-a938405f05e0451f8caf20b49ed83044

Source dataset

uspto-grants-2007_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07271181B2