Br[C:2]1[N:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.C(OCC)(=O)C>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[N:7]3[CH:8]=2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]The mixture of isomeric bromides prepared in Example 17 (0.054 g, 0.165 mmol) was dissolved in DMSO (3.5 mL) and treated with piperazine (0.568 g, 6.60 mmol). The mixture was shaken at 160° C. overnight. The mixture was diluted with ethyl acetate (20 mL) and washed with 10% HCl (2×20 mL). The aqueous layers were separated, basified with saturated sodium carbonate and re-extracted with ethyl acetate (3×20 mL). The organic solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 0.051 g of crude material. The crude material could be purified by semi-preparative RP-HPLC (Method C). The purified fractions were combined and concentrated under reduced pressure to remove acetonitrile. The aqueous residue was basified with saturated sodium carbonate and extracted with ethyl acetate (3×15 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 13 mg (25%) of the title compound. Alternatively, the crude material could be used directly in the next step. HPLC (Method B): r.t.=6.2 min., purity 100% at 210-370 nm, 97.4% at 250 nm. HRMS: calcd for C21H26N4+H+, 335.22302; found (ESI, [M+H]+), 335.2228.
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