APE1/Ref-1 Redox Inhibitor APX3330 → 4-Methyl-2,6-dimethoxyphenol

HRID 1527655Notes

Reaction equation

HRID 1527655 reaction equation
CCCCCCCCC/C(/C(O)=O)=C\[C:12]1[C:18](=[O:19])[C:17]([O:20]C)=[C:16]([O:22][CH3:23])[C:14](=O)[C:13]=1[CH3:24].Br[C:29]1C(Br)=C(C)C=C(Br)[C:30]=1[OH:38]>CC1C=C(OC)C(O)=C(OC)C=1OC>[CH3:23][O:22][C:16]1[CH:14]=[C:13]([CH3:24])[CH:12]=[C:18]([O:19][CH3:29])[C:17]=1[OH:20].[CH3:23][O:22][C:16]1[CH:14]=[C:13]([CH3:24])[C:12]([O:38][CH3:30])=[CH:18][C:17]=1[OH:20]

Participants

5

Reactant 2

HCID 6439397APE1/Ref-1 Redox Inhibitor APX3330HCID 126005252,3,6-Tribromo-4-methylphenol

Product 2

HCID 2409254-Methyl-2,6-dimethoxyphenolYield 10%HCID 27759582,5-Dimethoxy-4-methylphenolYield 5%

Reagents, catalysts & solvents 1

HCID 249755962,3,6-Trimethoxy-4-methylphenolSolvent

Procedure

The second step in the synthesis of E3330 is the most problematic, where the Ullmann-type methanolysis of 2,3,6-tribromo-4-methylphenol (5) results in multiple reduction byproducts that are not disclosed in the literature.13,14 The optimized Ullmann conditions in our hands result in a mixture of 4-methyl-2,3,6-trimethoxyphenol (11, 75-85%), 2,6-dimethoxy-4-methylphenol (12, 10-15%), and 2,5-dimethoxy-4-methylphenol (13, 5-10%). (Scheme 2) The resulting phenols are alkylated to generate 2,3,4,5-tetramethoxytoluene (6) and the two trimethoxytoluenes (14 and 15). The isolated yield is considerably lower than the observed conversion by NMR, and removal of the two reaction sideproducts is necessary because both lead to E3330 derivatives missing crucial methoxy substituents.

Workup

  1. customresults in multiple reduction byproducts that

Sources & evidence

ORD record
ord-34cc4c7b15044dae8f35e923dbb7d348
Source dataset
uspto-grants-2015_07
Patent number
US09089605B2

Reaction notes

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