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

HRID 51260Notes

Reaction equation

HRID 51260 reaction equation
[C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].C([Li])CCC.[N:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=1.N1C=CC(C=O)=CC=1.O1CCCC1>C1(C)C=CC=CC=1.O.O1CCCC1>[OH:23][CH:22]([C:19]1[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=1)[C:8]1[CH:7]=[CH:6][CH:5]=[C:2]([O:3][CH3:4])[C:1]=1[O:9][CH3:10]

Participants

8

Reactant 4

HCID 7043Veratrole2×HCID 133894-PyridinecarboxaldehydeHCID 86586168HCID 86586168, compoundHCID 178418339Butyllithium

Product 1

HCID 314742(2,3-Dimethoxyphenyl)(4-pyridinyl)methanolYield 70%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

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).

Workup

  1. temperatureA suitable reactor, maintained under an inert atmosphere
  2. customThe addition line is flushed with about 5 kg tetrahydrofuran
  3. waitThe reaction mixture is held at about 0° C. for at least 1 hour
  4. temperatureheated to about 25° C.
  5. temperaturemaintained there for about 3 hours
  6. temperatureto maintain the temperature at about −10° C
  7. temperatureThe reaction mixture is maintained at about −15° C. for at least 1 hour
  8. temperaturewarmed to about 0° C. over about a 1 hour period
  9. temperaturewhile maintaining the temperature at about 10° C
  10. customthe phases are separated
  11. washThe organic phase is washed with about 50 kg of water
  12. customthe phases are separated
  13. distillationThe concentration of product in the organic phase is adjusted to about 20 wt % by atmospheric distillation
  14. temperatureThe solution is cooled to less than about −15° C.
  15. filtration4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine is collected by filtration
  16. washThe wet cake is washed with about 20 kg of cold toluene

Sources & evidence

ORD record
ord-c7fea60498dc491e9d6c3b1f104d4782
Source dataset
uspto-grants-2004_03
Patent number
US06713627B2

Reaction notes

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