Preparation of 2-hydroxy-3-iodo-5-bromopyridine_Industrial additives

Preparation background and overview of 2-hydroxy-3-iodo-5-bromopyridine

2-Hydroxy-3-iodo-5-bromopyridine can be used as a pharmaceutical synthesis intermediate. 2-amino-5-bromo-3-iodopyridine can be prepared from 2-amino-5-bromopyridine as the reaction raw material, and then It can be prepared by further diazotization; it can also be prepared by iodination of 5-bromo-2-hydroxypyridine as the reaction raw material.

Preparation of 2-hydroxy-3-iodo-5-bromopyridine

Preparation method 1 of 2-hydroxy-3-iodo-5-bromopyridine:

Step 1: Dissolve 2-amino-5-bromopyridine (300g, 1.73mol) in a mixed solvent composed of acetic acid (1000mL) and water (200mL). Gradually add concentrated H₂SO₄ (30 mL) under stirring, then add acid hydrate (79.1g, 0.347mol) and iodine (176g, 0.693mol) periodically. ), stir at 80°C for 4h. Acid hydrate (40 g, 0.175 mol) and iodine (22 g, 0.086 mol) were added periodically to the reaction mixture, which was then further stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into ice (3 L) and neutralized to pH 7.0 with 5 N NaOH aqueous solution. The resulting precipitate was collected by filtration, dissolved in a mixed solvent of EtOAc/diethyl ether, washed successively with sodium thiosulfate aqueous solution, water, 1NNaOH aqueous solution and brine, and dried with MgSO₄. The solvent was evaporated to give 2-amino-5-bromo-3-iodopyridine, yield 392 g, 1.31 mol (76%).

Step 2: Gradually add 2-amino-5-bromo-3-iodopyridine (100g, 0.34mol) to concentrated sulfuric acid (300mL) under ice cooling, and stir the reaction mixture at room temperature for 2 hours. Chill it again on ice. Sodium nitrite (35g, 0.51mol) was gradually added, and then stirred at room temperature for 3 days and two nights. Pour the reaction solution onto ice (3L) and neutralize it with NaOH to pH 4.0. Collect the precipitate by filtration, wash with water, and dry with hot air at 60°C for 1 day and night to obtain, yield 102g, 0 basic magnesium carbonate. .34mol (>99%), brown solid. ¹HNMR (MHz, CDCl3) δ7.60 (d, J=2.4Hz, 1H), 8.14 (d, J=2.4Hz, 1H).

Preparation method two of 2-hydroxy-3-iodo-5-bromopyridine:

To a solution of 5-bromo-2-hydroxypyridine (2.622g, 15.1mmol) in acetonitrile was slowly added N-iodosuccinimide (4.465g, 19.9mmol) at room temperature, and the reaction mixture was Reflux under an argon atmosphere for 1 hour, remove the solvent under reduced pressure by rotary evaporation, and dilute the residue with ethyl acetate. The organic layer is washed with water, dried over MgSO₄, and concentrated to give 2- Hydroxy-3-iodo-5-bromopyridine orange solid, yield (3.951 g, 87%). ¹HNMR (600MHz, DMSO-d6) δ12.2 (brs, 1H), 8.20 (d, J=2.4Hz, 1H), 7.73 (d, J=2.4Hz, 1H); ¹³CNMR (151MHz, DMSO-d6) δ179.4, 158.9, 150.7, 136.8, 93.6.

References

[1] Discovery of 2-(2-Oxo-1-phenyl-5-pyridin-2-yl-1, 2-dihydropyridin-3-yl)benzonitrile (Perampanel): A Novel , Noncompetitive α-Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid (AMPA) Receptor Antagonist

[2] Synthesis of Well-Defined Poly(2-alkoxypyridine-3, 5-diyl) via Ni-Catalyst-Transfer Condensation Polymerization