Diisopropylethylamine → 6-(1-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-yl}-ethyl)-quinoxaline

HRID 642878Notes

Reaction equation

HRID 642878 reaction equation
Br[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[N:7]2)[CH3:3].C(N(C(C)C)CC)(C)C.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[C:41]([N:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)[C:35]=3[N:34]=2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>CN1CCCC1=O.C(OCC)(=O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[C:41]([N:42]4[CH2:47][CH2:46][N:45]([CH:2]([C:4]5[CH:5]=[C:6]6[C:11](=[CH:12][CH:13]=5)[N:10]=[CH:9][CH:8]=[N:7]6)[CH3:3])[CH2:44][CH2:43]4)[C:35]=3[N:34]=2)=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 585927736-(1-Bromoethyl)quinoxalineHCID 592588032-(4-tert-Butyl-phenyl)-4-piperazin-1-yl-1H-benzoimidazole

Product 1

HCID 685774176-(1-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-yl}-ethyl)-quinoxalineYield 92.2%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

To a solution of 6-(1-Bromo-ethyl)-quinoxaline (0.2 g,0.084 mMol) in N-methyl-pyrrolidinone (3 mL) and diisopropylethylamine (0.029 mL, 0.1 7 mMol) was added 2-(4-tert-Butyl-phenyl)-4-piperazin-1-yl-1H-benzoimidazole (0.028 g, 0.084 mMol) and the mixture stirred overnight. Upon arrival the solution was diluted with ethyl acetate (200 mL) and washed with water (4×75mL) and brine (75 mL). The organic layer was dried (MgSO4), filtered, and concentrated to dryness on a rotary evaporator. Purification by flash column chromatography on silica gel using 5% methanol in dichloromethane yielded 38 mg (92% yield) of 6-(1-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-yl}-ethyl)-quinoxaline as a racemate. This material was separated into the (R) and (S) enantiomers by chiral HPLC using a Chiralcel-OD 250×4.6 mmcolumn with an isocratic 90:10 acetonitrile:ethanol eluant. The first peak had a (+) chirality by CD and a retention time of 5.86 and the second peak a (−) chirality by CD and a retention time of 6.941. The fractions were concentrated and freeze dried to obtain 10 mg of each enantiomers. NMR,MS,and analytical HPLC were identical. 1H NMR (DMSO-d6): δ=12.67 (s, 1H), 8.94 (dd, 2H, J=8.8, 1.8 Hz), 8.11 (d, 1H, J=8.7 Hz), 8.05 (s, 1H), 8.02 (d, 2H, J=8.5 Hz), 7.95 (dd, 1H, J=8.7, 1.7 Hz), 7.53 (d, 2H, J=8.6 Hz), 7.02 (m, 2H), 6.47 (dd, 1H, J=7, 1.4 Hz), 3.81 (q, 1H, J=6.8 Hz), 3.58 (br s, 4H), 2.75 (br s, 2H), 2.61 (br s, 2H), 1.49 (d, 3H, J=6.8 Hz), 1.32 (s, 9H). LC/MS (Method A), rt=1.07 mins., purity=99%, calculated mass=490, [M+H]+=491,[M−H]−=489. HPLC (Method C): rt=9.2mins., purity=94% @ 210-370 nm and 95.3% @ 304 nm.

Workup

  1. washwashed with water (4×75mL) and brine (75 mL)
  2. dry with materialThe organic layer was dried (MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated to dryness on a rotary evaporator
  5. customPurification by flash column chromatography on silica gel using 5% methanol in dichloromethane

Sources & evidence

ORD record
ord-4e5de523b0a0455aaa1b9fc6ffc0ebc7
Source dataset
uspto-grants-2010_04
Patent number
US07696210B2

Reaction notes

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