Veratrole → (2,3-Dimethoxyphenyl)(4-pyridinyl)methanol

Participants

Reaction Conditions

Reaction Steps

A suitable reactor, maintained under an inert atmosphere is charged with veratrole (36 kg, 261 mol) and about 240 kg tetrahydrofuran. n-Butyllithium (63 kg, 242 mol, 24.6% in n-hexane) is added maintaining the temperature at about 0° C. The addition line is flushed with about 5 kg tetrahydrofuran. The reaction mixture is held at about 0° C. for at least 1 hour, then heated to about 25° C. and maintained there for about 3 hours. In a second suitable vessel, 4-pyridinecarboxaldehyde (9) (20 kg, 187 mol) is mixed with about 90 kg of tetrahydrofuran. The 4-pyridinecarboxaldehyde/tetrahydrofuran solution is added to the lithiated veratrole slurry at a rate to maintain the temperature at about −10° C. The reaction mixture is maintained at about −15° C. for at least 1 hour, then warmed to about 0° C. over about a 1 hour period. Water (about 100 kg) is added to the reaction mixture while maintaining the temperature at about 10° C. Toluene (about 160 kg) is added and the phases are separated. The organic phase is washed with about 50 kg of water and the phases are separated. The concentration of product in the organic phase is adjusted to about 20 wt % by atmospheric distillation. The optimum tetrahydrofuran range is about 10 to 20 wt % as determined by GC analysis. The solution is cooled to less than about −15° C., and 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine is collected by filtration. The wet cake is washed with about 20 kg of cold toluene to give the title compound (10) (30 kg, 70% yield).

Provenance & Evidence