Preparation of 2-bromo-3-fluoro-4-methylpyridine_Industrial additives

Preparation background and overview of 2-bromo-3-fluoro-4-methylpyridine

2-Bromo-3-fluoro-4-methylpyridine is a fluorine-containing pyridine compound. Pyridine derivatives are an important class of pharmaceutical intermediates and can be used as raw materials for the synthesis of steroids, sulfonamides, resistamines, spirocyclic amides and other drugs. Fluorine-containing pyridine compounds are important pyridine derivatives and are widely used in organic synthesis and pharmaceutical intermediate synthesis. Since the atomic radii of fluorine atoms and hydrogen atoms are quite close, when the hydrogen atoms in the molecule are replaced by fluorine atoms, tricyclohexylphosphine fluoroborate will not cause significant changes in the three-dimensional configuration of the molecule. However, due to the strong electron-attracting ability of fluorine atoms, it often causes great changes in the electronic properties of the original molecules. As a result, fluorine-containing pyridines have good stability and large dielectric anisotropy. Therefore, in recent years, fluorine-containing pyridines have become more popular. Pyridine compounds play a very important role in medicine, especially in the synthesis of anti-cancer drugs and drugs for the treatment of cardiovascular and cerebrovascular diseases.

Preparation of 2-bromo-3-fluoro-4-methylpyridine

Step 1: Add 2-hydroxy-3-nitro-4-methylpyridine, compound E1 (22.8g, 0.148mol, 1.0eq) to 120mL acetonitrile, and slowly add tribromide to this mixture After the addition of oxyphosphorus (84.1g, 0.296mol, 2.0eq), the reaction temperature was raised to 110°C to 130°C, and the reaction was continued for 3 hours. Cool the reaction solution and slowly add it to the ice-water mixture to quench, adjust to neutrality with saturated sodium bicarbonate solution, extract with dichloromethane (150mL*3), dry with anhydrous sodium sulfate, filter, and spin dry to obtain 2-bromo-3-nitro-4-methylpyridine deuterated tetrahydrofuran, i.e. 29.3g of crude compound E2, with a yield of 91.6%

Second step: Add crude E2 (29.3g, 0.136mol) to 150 ml of methanol, add 15g of Raney nickel, and react at room temperature under hydrogen pressure (pressure is 40 Psi) for 5 hours. The reaction solution was filtered and spin-dried to obtain a crude compound. The crude product was recrystallized with an ethyl acetate/petroleum ether system to obtain 2-hydroxy-3-amino-4-methylpyridine, namely compound E3 (23.3g, 0.125mol, 92.1%)

Step 3: Dissolve compound E3 (23.3g, 0.125mol) in anhydrous hydrogen fluoride (70mL). The reaction vessel is a polytetrafluoroethylene jar. Sodium nitrite (11.0 g, 0.160 mol) was added to this mixed solution at -78°C. After the addition is completed, stir the reaction solution at -5°C to 5°C for 30 minutes, then raise the reaction temperature to 30°C to 70°C and react for 30 minutes to 1 hour. The reaction solution was cooled, quenched with a mixture of ice and water, and then adjusted to neutrality with saturated sodium bicarbonate solution. Extract with dichloromethane (100mL*3) and combine the organic phases, dry with anhydrous sodium sulfate, spin dry, and recrystallize with ethyl acetate/petroleum ether system to obtain a light yellow solid: 2-bromo-3-fluoro-4- Methylpyridine (20.6g, 0.109mol, yield 87.3%).

References

[1][Chinese invention] CN201210409184.8 Preparation method of fluorine-containing pyridine compounds