Diisopropylethylamine → HCID 86695326, compound

HRID 572888Notes

Reaction equation

HRID 572888 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=2)[C:16](O)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[C:32]([F:33])=[C:31]([F:34])[CH:30]=[C:29]([NH2:35])[C:28]=1[NH2:36].[I-].ClC1C=CC=C[N+]=1C.C(N(C(C)C)CC)(C)C>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:16](=[O:17])[NH:36][C:28]2[C:29]([NH2:35])=[CH:30][C:31]([F:34])=[C:32]([F:33])[C:27]=2[F:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 1670692-Chloro-1-methylpyridinium iodideHCID 27739583,4,5-Trifluorobenzene-1,2-diamineHCID 66835697HCID 66835697, compound

Product 1

HCID 86695326HCID 86695326, compound

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a solution of 4-[(3-bromophenyl)carboxymethoxy]piperidine-1-carboxylic acid tert-butyl ester (general procedure 165D+saponification)(1 g) in acetonitrile (10 mL) are added 3,4,5-trifluorobenzene-1,2-diamine (470 mg), 2-chloro-1-methylpyridinium iodide (802 mg) and dropwise diisopropylethylamine (1.1 mL). The reaction mixture is stirred at room temperature for 2 hours. Solvent is removed under reduced pressure and the residue diluted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to get 4-[(6-amino-2,3,4-trifluorophenylcarbamoyl)(3-bromophenyl)methoxy]piperidine-1-carboxylic acid tert-butyl ester. This intermediate is dissolved in acetic acid (15 mL) and the reaction mixture is refluxed for 3 hours. Acetic acid is removed under reduced pressure. Water is added to the residue and the solution is basified by adding a solution of saturated sodium hydrogencarbonate to pH 10. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to yield 2-[(3-bromophenyl)(piperidin-4-yloxy)methyl]-5,6,7-trifluoro-1H-benzimidazole.

Workup

  1. customSolvent is removed under reduced pressure
  2. additionthe residue diluted with ethyl acetate
  3. washThe organic phase is washed with water
  4. dry with materialdried over magnesium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customThe residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1)

Sources & evidence

ORD record
ord-3b00073dd98543ab89b1126d185034bc
Source dataset
uspto-grants-2015_05
Patent number
US09029357B2

Reaction notes

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