1,2-Diamino-4,5-difluorobenzene → (RS)-2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester

HRID 2377990Notes

Reaction equation

HRID 2377990 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][C:25](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][C:25]1[NH:9][C:5]2[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=2[N:10]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]

Participants

4

Reactant 2

HCID 27367551,2-Diamino-4,5-difluorobenzeneHCID 50585361-Boc-2-Piperidineacetic Acid2×

Product 1

HCID 66968258(RS)-2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidine-1-carboxylic acid tert-butyl esterYield 15.7%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

4,5-Difluoro-benzene-1,2-diamine (1.00 g, 6.9 mmol) and 2 carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Beckett et al, J. Med. Chem., 563,1969) (1.69 g, 6.9 mmol) were heated at 120° C. with stirring, under argon for 4 h. A further portion of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.85 g) was added and heating was continued for a further 2 h. The cooled reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate (2×) and brine, dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 0-30% ethyl acetate-pentane) to give a yellow solid which was triturated with diethyl ether to afford the title compound as a pale brown solid (0.38 g, 15%).

Workup

  1. temperatureheating
  2. waitwas continued for a further 2 h
  3. customThe cooled reaction mixture
  4. washwashed with saturated aqueous sodium bicarbonate (2×) and brine
  5. dry with materialdried (MgSO4)
  6. customthe solvent removed in vacuo
  7. customThe residue was chromatographed (silica gel, 0-30% ethyl acetate-pentane)
  8. customto give a yellow solid which
  9. customwas triturated with diethyl ether

Sources & evidence

ORD record
ord-1b7b519c45754531ae85ef4b16fe58b7
Source dataset
uspto-grants-2008_12
Patent number
US07470710B2

Reaction notes

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