Hydrochloric Acid → 4-Methoxy-2-(propan-2-yl)phenol

HRID 1675702Notes

Reaction equation

HRID 1675702 reaction equation
OC1C=CC(OC)=CC=1C(=O)C.C[Mg]Cl.O[C:17]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[OH:28])([CH3:19])[CH3:18].Cl>C1COCC1.[Pd].CC(=O)CC.O>[CH:17]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[OH:28])([CH3:19])[CH3:18]

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 697141-(2-Hydroxy-5-methoxyphenyl)ethan-1-one2×HCID 252417532-(2-Hydroxypropan-2-YL)-4-methoxyphenolHCID 178418332HCID 178418332, compound2×

Product 1

HCID 183649974-Methoxy-2-(propan-2-yl)phenol

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 962WaterSolventHCID 6569Methyl Ethyl KetoneSolventHCID 8028TetrahydrofuranSolvent3×

Procedure

To a cooled solution of 1-(2-hydroxy-5-methoxy-phenyl)-ethanone (10.0 kg) in 79.0 kg of THF was gradually added 46.4 kg of 3M solution of MeMgCl in THF at a rate such that the reaction mixture temperature did not exceed 25 degrees C. Following addition of the MeMgCl solution, the reaction mixture was stirred at ambient temperature for 18 hours, at which point HPLC (high pressure liquid chromatography) analysis showed more than 98% conversion of 1-(2-hydroxy-5-methoxy-phenyl)-ethanone to 2-(1-hydroxy-1-methyl-ethyl)-4-methoxy-phenol (not shown in Scheme D). To the stirred solution was then added 10% palladium on carbon (1.02 kg, 50% water wet) suspended in 3.5 Kg of THF. The reaction mixture was cooled and placed under a hydrogen atmosphere at 5 psi, and concentrated HCl (19.5 kg) was added while maintaining the reaction temperature at 25° C. The resultant mixture was stirred at ambient temperature for 18 hours, then treated with 44.4 kg water and filtered through a bed of Celite to remove suspended catalyst. The filter cake was rinsed with EtOAc and the combined filtrate was separated. The organic phase was washed with water, then concentrated by distillation to provide an oil. This oil was dissolved in 2-butanone (20.4 kg) and the crude solution was employed directly in the next step. A 161.8 g aliquot of the solution was concentrated under vacuum to provide 49.5 g of 2-isopropyl-4-methoxyphenol as an oil, projecting to 10.4 kg crude contained product in the bulk 2-butanone solution. 1H nmr (DMSO) delta: 1.14 (d, 6H, J=6.9 Hz), 3.18 (septet, 1H, J=6.9 Hz), 3.65 (s, 3H), 6.56, (dd, 1H, J=8.6 Hz, 3.1 Hz), 6.67 (d, 1H, J=3.1 Hz), 6.69 (d, 1H, 8.6 Hz).

Workup

  1. customdid not exceed 25 degrees C
  2. temperatureThe reaction mixture was cooled
  3. additionwas added
  4. temperaturewhile maintaining the reaction temperature at 25° C
  5. filtrationfiltered through a bed of Celite
  6. customto remove
  7. washThe filter cake was rinsed with EtOAc
  8. customthe combined filtrate was separated
  9. washThe organic phase was washed with water
  10. concentrationconcentrated by distillation
  11. customto provide an oil
  12. concentrationA 161.8 g aliquot of the solution was concentrated under vacuum

Sources & evidence

ORD record
ord-d8917ffffe6d48f1b354aff036df97aa
Source dataset
uspto-grants-2011_08
Patent number
US08003788B2

Reaction notes

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