2,4-Dichloro-3-iodopyridine

Uses

2,4-Dichloro-3-iodopyridine can be used as a pharmaceutical synthesis intermediate. It is prepared by reacting 2,4-dichloropyridine with n-butyllithium and iodine, and can be used to prepare another intermediate, 2,4-dichloro-3-trifluoromethylpyridine. It can also be obtained by iodination of 2,4-dichloropyridine or by chlorination of 2,4-dihydroxy-3-iodopyridine with phosphorus oxychloride.

Synthesis

General procedure for the synthesis of 2,4-dichloro-3-iodopyridine from 2,4-dichloropyridine: To a solution of anhydrous tetrahydrofuran (THF, 40 mL) of 2,4-dichloropyridine (5.2 g, 35.137 mmol) and N,N-diisopropylethylamine (DIPEA, 3.911 g, 38.651 mmol), the solution was cooled to -50 °C under nitrogen protection. At -78 °C, n-butyllithium (n-BuLi, 24.157 mL, 38.651 mmol, 1.6 M in hexane solution) was added dropwise. The reaction mixture was stirred at -78 °C for 45 min. Subsequently, a solution of iodine (9.81 g, 38.651 mmol) in anhydrous THF (20 mL) was added dropwise. The mixture was continued to be stirred at -78 °C for 1 hour. Upon completion of the reaction, the mixture was slowly warmed to room temperature, diluted with ethyl acetate (EtOAc) and the reaction was quenched with saturated aqueous ammonium chloride (NH4Cl) and saturated aqueous sodium thiosulfate (Na2S2O3). The organic layer was separated, the organic extracts were combined, washed with saturated aqueous sodium bicarbonate (NaHCO3), dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel as stationary phase, heptane/dichloromethane gradient elution, dichloromethane up to 20%). The fraction containing the target product was collected and concentrated under reduced pressure to afford the intermediate compound 2,4-dichloro-3-iodopyridine (D5, 7.8 g, 81% yield).

References

[1] European Journal of Organic Chemistry, 2001, # 7, p. 1371 - 1376
[2] Patent: WO2010/130422, 2010, A1. Location in patent: Page/Page column 53
[3] Patent: WO2010/130423, 2010, A1. Location in patent: Page/Page column 53
[4] Patent: WO2010/130424, 2010, A1. Location in patent: Page/Page column 104-105
[5] Patent: WO2012/62752, 2012, A1. Location in patent: Page/Page column 26