Preparation of 4-iodo-3-hydroxypyridine_Industrial additives

Preparation background and overview of 4-iodo-3-hydroxypyridine

4-Iodo-3-hydroxypyridine is an organic intermediate commonly used in the synthesis of various pharmaceutical and chemical products. There are literature reports that 4-iodo-3-hydroxypyridine can be prepared from 2-chloro-4-iodopyridine in one step or from 3-hydroxypyridine in three steps.

Preparation of 4-iodo-3-hydroxypyridine

Preparation Report 1 of 4-iodo-3-hydroxypyridine,

Reflux a mixture of 2-chloro-4-iodopyridine (0.505g), potassium tert-butoxide (2.5g) and redistilled tert-butanol (12.5mL) for 12-24 hours. After cooling, the solvent was removed in vacuo, ice/water was carefully added, and the aqueous layer was extracted with chloroform to remove unreacted raw materials. The aqueous layer was acidified with 3N hydrochloric acid, extracted with chloroform, washed with water, dried over anhydrous magnesium sulfate, and concentrated to obtain pure 4-iodo-3-hydroxypyridine, yield 0.237g, 51%. ¹H-NMR ( MHz, DMSO): δ / ppm = 8.20 (s&b, 1H), 7.20 (d, J = 6.77 Hz, 1H), 6.93 (d, J = 1.36 Hz, 1H ), 6.48 (dd, J = 6.78, 1.45Hz, 1H) 13C-NMR (DMSO, 100 MHz, 25℃): δ = 160.8, 135.7, 128.4, 114.7, 112.4 IR (KBr): ν~ / cm^-1 = 3254 (vw), 3086 (w), 2794 (s), 2384 (m), 1607 (s), 1496 (m), 1474 (s), 1342 (s), 1290 ( s), 1231 (s), 1211 (s), 1107 (m), 1071 (m), 1052 (m), 998 (s), 982 (s), 957 (m), 894 (s), 881 ( s), 856 (s), 808 (s), 760(s), 672 (m). HRMS (ESI, m/z): calculated for (M+H)⁺ 221.9415, found 221.9411.

Preparation Report 2 of 4-iodo-3-hydroxypyridine,

To a mixture of 3-hydroxypyridine (2.85 g, 30 mmol) in DMF/THF (8:3, 21 mL) was added potassium tert-butoxide (3.71 g, 33 mmol, 1.1 equivalent). After 20 minutes, add methoxymethyl chloride (MOMC1, 2.5 mL, 31.5 mmol, 1.05 equivalent), and after another 1 hour, add brine (20 mL) and water (20 mL) in sequence. The mixture was extracted with ethyl acetate (3 x 30 mL), the combined organic phases were washed with brine (2 x 40 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was distilled under vacuum to afford 3-methoxymethoxypyridine (2.76 g, 19.8 mmol, 66%).

To a solution of 3-methoxymethoxypyridine (1.39 g, 10 mmol) in anhydrous Et₂O (50 mL) under nitrogen atmosphere at -78°C To the barium carbonate was added tert-butyllithium (1.35 M in pentane, 8.2 mL, 11 mmol, 1.1 equiv). After 20 minutes, a solution of iodine (3.04 g, 12 mmol, 1.2 equiv) in Et₂O (30 mL) was added and the reaction mixture was kept at -78°C for 1 h. Water (40 mL) was added and the phases separated. The aqueous phase was extracted with Et₂O (2 × 25 mL), and the combined organic phases were washed with brine (40 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (50% ethyl acetate in heptane) to give 4-iodo-3-methoxymethoxypyridine (2.05 g, 7.73 mmol, 77%).

Place 4-iodo-3-methoxymethoxypyridine (1.55g, 5.84mmol) and PTSA (100mg) between water (10mL) and Et₂O (5mL) distribute. The resulting mixture was heated at reflux for 16 hours over sodium carbonate; the ether was then evaporated and an aliquot of water (10 mL) was added. After refluxing for an additional 8 hours, the mixture was cooled to room temperature and collected by filtration to give 4-iodo-3-hydroxypyridine (807 mg, 3.65 mmol, 62%).