反应详情

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.

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