5-Iodo-4-methyl-pyridin-2-ylamine

Synthesis

General procedure for the synthesis of 2-amino-5-iodo-4-methylpyridine from 2-amino-4-methylpyridine: To a stirred solution of 2-amino-4-methylpyridine (30 g, 278 mmol, 1.0 eq.) in acetic acid (167 mL) was added sequentially periodate (12.7 g, 55.6 mmol, 0.2 eq.), sulfuric acid (4.8 mL, 90.8 mmol, 0.34 equiv), water (33.3 mL) and iodine (28.7 g, 111.1 mmol, 0.4 equiv). The reaction mixture was heated and stirred at 80 °C for 6 h. After the completion of the reaction was monitored by TLC, the mixture was cooled to room temperature and slowly poured into sodium thiosulfate solution (200 mL) to precipitate a red oily substance. After separation of the oily material, the aqueous phase was alkalized with 50% sodium hydroxide solution (100 mL) and a yellow solid was precipitated. The solid was extracted with ether (2 x 200 mL), the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a brown semi-solid crude product (60 g). The crude product was purified by column chromatography on silica gel (100-200 mesh), and the fraction containing the target compound was collected by using hexane solution of 15% ethyl acetate as eluent and concentrated under reduced pressure to give 2-amino-5-iodo-4-methylpyridine as a light brown solid (50.7 g, 78% yield). The product was characterized by 1H NMR (400 MHz, CDCl3): δ 2.27 (s, 3H), 4.46 (bs, 2H), 6.44 (s, 1H), 8.24 (s, 1H).

References

[1] Patent: WO2014/39484, 2014, A1. Location in patent: Page/Page column 60
[2] Tetrahedron Letters, 2001, vol. 42, # 23, p. 3795 - 3797
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 25, p. 6383 - 6391
[4] Tetrahedron Letters, 2003, vol. 44, # 14, p. 2971 - 2973
[5] Synlett, 2012, # 2, p. 208 - 214