Preparation method of 3,5-difluoropyridine-4-carbaldehyde_Industrial additives

Background and overview of the preparation method of 3,5-difluoropyridine-4-carbaldehyde

3,5-Difluoropyridine-4-carbaldehyde, also called 3,5-difluorisonicotinaldehyde, can be prepared from 3,5-difluoropyridine as raw material through a one-step reaction.

Preparation method of 3,5-difluoropyridine-4-carbaldehyde

Report on the preparation method of 3,5-difluoropyridine-4-carbaldehyde 1.

Under argon, 44 ml of 2.5 M n-butyllithium in n-hexane (110 mmol, 1.1 equiv) was slowly added dropwise to 15.4 ml of diisopropylamine in 23 ml of THF at -70°C. (110 mmol, 1.1 equivalent). The resulting solution was warmed to 0 °C and stirred at this temperature for 30 min. The reaction mixture was then cooled to -70°C and diluted with 23 ml of THF, followed by dropwise addition of 11.5 g of 3,5-difluoropyridine (100 mmol, 1 eq.) dissolved in 72 ml of THF. The mixture was stirred at -70°C for an additional 30 min. Then 12.4 ml of methyl formate (200 mmol, 2 equiv) dissolved in 23 ml of THF was added slowly dropwise. After 1.5 h at -70°C, the reaction solution was slowly poured into 230 ml of saturated aqueous sodium bicarbonate solution and extracted with a total of 460 ml of ethyl acetate. The combined organic phases were washed twice with 115 ml of saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. 11.6 g (81% of theory) of the title compound were obtained.

Preparation method report 2 of 3,5-difluoropyridine-4-carbaldehyde

Combine anhydrous DMF (2.0L) and anhydrous THF (5.0L) and cool the resulting mixture to -20°C. Add LiHMDS (10.4L, 1.2equiv) while maintaining the temperature between -15°C and -25°C. The mixture was cooled to -30°C and 3,5-difluoropyridine (1.0 kg, 8.69 mol) was then added while maintaining the temperature between -20°C and -25°C. After one hour, the reaction mixture was added to a mixture of brine (4.0 kg NaCl in 16 L deionized water), THF (10 L) and concentrated aqueous HCl (2.2 L) at 0°C. The mixture was stirred for one hour, and then the layers were separated. The pH of the aqueous layer was adjusted to about 7.5 with 2 N HCl solution (about 100 mL), and extracted with MTBE/THF (1:1, 10 L). The organic layers were combined, washed with brine (1.0 kg NaCl in 4 L deionized water), and concentrated under reduced pressure to yield the title compound as a yellow-orange oily slurry.

References

[1] [Chinese invention] CN201580015369.2 Substituted imidazo[1,2-a]pyridinecarboxamide and its uses

[2Bromophenylboronic acid] [Invented in China] CN201180049289.0 Method for preparing azaindazole derivatives