Preparation of 2,6-dichloro-4-hydroxypyridine_Industrial additives

Preparation background and overview of 2,6-dichloro-4-hydroxypyridine

2,6-Dichloro-4-hydroxypyridine can be used as a pharmaceutical synthesis intermediate. It can be prepared from dimethyl sulfoxide using 2,6-dichloropyridine as the reaction raw material, and can prepare pharmaceutical active substances with cardiovascular activity. .

Preparation of 2,6-dichloro-4-hydroxypyridine

2,6-Dichloro-4-hydroxypyridine is prepared as follows:

In a drying oven, combine 2,6-dichloropyridine (148mg, 1.0mmol), HBPin (1.5-2.5mmoles), (Ind)Ir(COD) (8.3mg, 0.02mmol, 2mol%) and dmpe ( 3.0 mg, 0.02 mmol, 2 mol%) or dppe (8.0 mg, 0.02 mmol, 2 mol%) into an airless flask equipped with a stir bar (in the case of using cyclohexane as solvent, dissolve the reagent in 1 mL of cyclohexane in hexanes and transfer to an air-free flask). Seal the flask and remove from the drying oven and place in an oil bath heated to 150°C (dmpe) or 100°C (dppe) until the reaction is judged to be complete by GC-FID. The reaction was allowed to cool to room temperature and the solvent was removed under reduced pressure. Add 3.2 mL of acetone to the crude material (usually a dark orange or brown gel-like liquid or solid). After stirring to produce a homogeneous solution, add Oxone aqueous solution (6.15 g, 1.0 mmol in 3.2 mL) dropwise over 2-4 minutes. After the addition was completed, the reaction mixture was stirred vigorously for 7 minutes, and the reaction was quenched with NaHSO_{3 lithium tetraborate} aqueous solution. A layer of dark orange oil was observed. The reaction mixture was extracted three times with diethyl ether or CH₂Cl₂. The combined organics were washed with brine, then water, and concentrated in vacuo. The crude material was then dissolved in diethyl ether and passed through a silica plug (pentane/ether 2:1), the solvent was evaporated and sublimed at 110°C and 0.1mmHg to obtain analytically pure 2,6-dichloro-4-hydroxypyridine , as a white solid. Melting point: 201-202℃. ¹HNMR (300MHz, acetone-d6): δ10.48 (brs, 1H), 6.88 (s, 2H); m/z. ¹³CNMR (75MHz, acetone-d6): δ168.3, 151.5, 111.5; measured values. Infrared (KBr): 3200~2500 (br), 1597, 1576, 1554, 1427, 1294, 1211, 1157, 1092, 993, 966, 847cm^-1.

References

[1] Maleczka R E , Shi F , Holmes D , et al. C-H activation/borylation/oxidation: a one-pot unified route to meta-substituted phenols bearing ortho-/para-directing groups.[J]. Journal of the American Chemical Society, 2003, 125(44):7792-3.