Preparation method of methyl 4-methoxypyridinecarboxylate_Industrial additives

Background and overview of the preparation method of methyl 4-methoxypyridinecarboxylate

4-Methoxypyridinecarboxylic acid methyl ester is an organic intermediate. It can be prepared from 2-pyridinecarboxylic acid as raw material, first chlorinated to obtain 4-chloro-2-pyridinecarboxylic acid, and then esterified with methanol to obtain 4- Methyl methoxypicolinate.

Preparation method of methyl 4-methoxypicolinate

Preparation method report 1 of 4-methoxypyridinecarboxylic acid methyl ester

Add 2-picolinic acid (9.92g, 80.7mmol) and sodium bromide (0.90g, 8.7mmol) to thionyl chloride (70mL), and heat the mixture to reflux for 16 hours. The reaction was concentrated in vacuo and cooled to 0°C. MeOH (30 mL) was added carefully and the reaction was heated to reflux for 36 h. Remove the solvent in vacuo, and dissolve the residue in CH₂Cl₂ (100 mL), add sodium carbonate (12.8 g, 121 mmol), and stir the mixture for 3 small battery steps When lithium carbonate. H₂O (100 mL) was added, and the reaction was extracted with CH₂Cl₂ (5 × 50 mL). The combined organic extracts were dried (MgSO₄) and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO₂, eluting with Et₂O, then 5:95 MeOH-CH₂Cl ₂ elution) purification and recrystallization (hexane) gave the white needle product 4-methoxypyridinecarboxylic acid methyl ester (9.03g, 67%).

Preparation method report 2 of 4-methoxypyridinecarboxylic acid methyl ester

To a 250 ml flask equipped with a reflux condenser and a CaCl2 drying tube, add 2-picolinic acid (50.0 g, 0.41 mol), NaBr (2.1 g, 0.021 mol, 0.05 eq, 5 mol%) and SOCl ₂ (150 mL, 2.04 mol, 5.0 eq) mixture was heated to reflux in an oil bath for 24 hours. Carefully remove excess SOCl₂ on a rotating film evaporator. Methanol (85 mL, 2.1 mol, 5.0 equiv) was carefully added to the resulting dark red residue at 0 °C, and the mixture was heated to reflux. After 36 hours, the methanol was evaporated and the sticky brown residue (pH 8) was neutralized with saturated KHCO₃ solution (approximately 200 mL). The aqueous solution was extracted with EtOAc (3 × 150 mL), and the combined organic extracts were washed with brine (1 × 250 mL), dried over MgSO₄, and concentrated in vacuo to give the crude product as a dark red oil. Solidified on cooling (0 °C) to give a light brown solid (74.3 g). Purified by flash column chromatography on SiO2 gel (with 100% CH₂Cl₂ to 5% CH₃OH/CH₂Cl₂ elution; add a few drops of NEt₃ to the eluent) to purify 7.0 g of this material to obtain the title compound, which is Off-white needle-like crystals.

References

[1] Timothy, J, Donohoe, et al. Partial Reduction of Pyridinium Salts as a Versatile Route to Dihydropyridones.[J]. ChemInform, 2005, Pyridine dihydrochloride 36(24).

[2] Synthetic approaches towards the marine natural products typified by variolin B. A novel fused pyrimidino-7-azaindole, By Meigh, Jon-Paul K.From No pp.; 2000