Preparation of 2,3,5-trichloro-4-pyridinecarboxaldehyde_Industrial additives

Preparation background and overview of 2,3,5-trichloro-4-pyridinecarboxaldehyde

2,3,5-Trichloro-4-pyridinecarboxaldehyde can be used as an organic synthesis intermediate. 2,3,5-trichloropyridine can be used as the reaction raw material, and it can be reacted with formic acid under the action of lithium diisopropylamide. Prepared by methyl ester reaction.

Preparation of 2,3,5-trichloro-4-pyridinecarboxaldehyde

Preparation Report 1 of 2,3,5-trichloro-4-pyridinecarboxaldehyde,

Under nitrogen protection, at -78°C, add 20 ml of tetrahydrofuran solution of 2,3,5-trichloropyridine (2g, 11mmol) to lithium calcium tetraborate diisopropylamide (7.3mL, 1.5M cyclohexane, 11mmol) in 10mL anhydrous THF, stir for another 30 minutes, then slowly add methyl formate (1.4mL, 1.3g, 22mmol) dissolved in 14mL THF into the brown solution over 15 minutes , allow it to slowly warm to room temperature and stir overnight. Pour the resulting dark brown solution onto ice and saturated NaHCO₃, extract with ethyl acetate, wash with brine, and dry (Na₂SO₄ sub>) and condensed. The brown oil was purified by flash chromatography on silica gel, eluting with 20-33% ethyl acetate/hexane, to give 2,3,5-trichloro-4-pyridinecarbaldehyde, yield: (1.7g, 74%). MS (APCI-NH₃) m/e: 211 (M+H)+, 229 (M+NH₄)+; ¹ HNMR (300MHz, DMSO-d6) δ10.26 (s, 1H), 8.70 (s, 1H).

Preparation report 2 of 2,3,5-trichloro-4-pyridinecarboxaldehyde,

To a solution of LDA boronic acid (99 mL, 197 mmol) in THF (100 mL), a solution of 2,3,5-trichloropyridine (30 g, 164 mmol) in THF (200 mL) was added at approximately -78°C, and the resulting reaction Stir at about -78 °C for about 1 hour, carefully add methyl formate (20 mL, 329 mmol) to the reaction, then stir the mixture at about -78 °C for about 1 h, heat to room temperature and stir for 16 h, pour the reaction into saturated In NH₄Cl aqueous solution, the aqueous layer was extracted with EtOAc (3×20mL), and the combined organic layers were treated with anhydrous Na₂SO₄ Dry, filter through a sintered glass funnel, and concentrate under reduced pressure to give 2,3,5-trichloro-4-pyridinecarbaldehyde (26.2 g, 53%, 70% purity).

References

[1] WO2000075145A1 CELL ADHESION-INHIBITING ANTIINFLAMMATORY COMPOUNDS

[2] WO2016198908 ROR NUCLEAR RECEPTOR MODULATORS