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2,4-Difluoroanisole → (2,6-difluoro-3-methoxyphenyl)[1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-yl]methanol

HRID 572898
Notes
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Reaction equation

HRID 572898 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([N-]C(C)C)(C)C.[Li+].[CH3:19][Si:20]([CH3:37])([CH3:36])[CH2:21][CH2:22][O:23][CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[CH:34]=[O:35]>O1CCCC1>[F:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][CH:5]=[C:6]([F:8])[C:7]=1[CH:34]([C:26]1[N:25]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:36])([CH3:37])[CH3:19])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=1)[OH:35]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 1362932,4-DifluoroanisoleHCID 2724682Lithium diisopropylamideHCID 120171281-(2-Trimethylsilylethoxymethyl)-2-formyl-benzimidazole

Product 1

HCID 66836061(2,6-difluoro-3-methoxyphenyl)[1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-yl]methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent
3×

Procedure

To a solution of 2,4-difluoro-1-methoxybenzene (156 mg) in tetrahydrofuran (5 mL) at −78° C. is added a 2M solution of lithium diisopropylamide in THF (540 μL). After stirring for 45 min a solution of 1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole-2-carbaldehyde (which can be prepared according to US2003/220341 or U.S. Pat. No. 6,476,041 for example) (300 mg) in tetrahydrofuran (5 mL) is added at −78° C. and the reaction mixture allowed to warm to room temperature. After hydrolysis with aqueous saturated ammonium chloride and extraction with ethyl acetate, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 95/5) to afford (2,6-difluoro-3-methoxyphenyl)[1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-yl]methanol.

Workup

  1. customcan be prepared
  2. customis added at −78° C.
  3. customAfter hydrolysis
  4. extractionwith aqueous saturated ammonium chloride and extraction with ethyl acetate
  5. dry with materialthe organic phase is dried over magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe residue is purified by chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 95/5)

Sources & evidence

ORD record
ord-a5d8541f54864d7ca6d89d0624c70997
Source dataset
uspto-grants-2015_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09029357B2

Reaction notes

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