[C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.BrC1[CH:20]=[C:19]([F:21])[C:18]([CH3:22])=[CH:17][C:16]=1[Cl:23].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[ClH:23].[Cl:23][C:16]1[CH:17]=[C:18]([CH3:22])[C:19]([F:21])=[CH:20][C:1]=1[N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1To a mixture of 1-Boc-piperazine (1.9 g), 1-bromo-2-chloro-5-fluoro-4-methylbenzene (2.2 g), palladium acetate (112 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (312 mg) and sodium tert-butoxide (1.4 g) was added toluene (20 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform). The obtained compound was dissolved in chloroform (3 mL), 4N hydrogen chloride/ethyl acetate (3 mL) was added, and the mixture was stirred at room temperature for 3 hr. Filtration gave 1-(2-chloro-5-fluoro-4-methylphenyl)piperazine hydrochloride (2 g). To a mixture of 1-(2-chloro-5-fluoro-4-methylphenyl)piperazine hydrochloride (1.1 g), 4-bromo-2-methanesulfonylbenzoic acid (1.1 g) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.5 g) were added chloroform (50 mL), methanol (50 mL) and N-methylmorpholine (440 μL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (chloroform:methanol) to give (4-bromo-2-methanesulfonylphenyl)[4-(2-chloro-5-fluoro-4-methylphenyl)piperazin-1-yl]methanone (1.9 g). To a mixture of (4-bromo-2-methanesulfonylphenyl)[4-(2-chloro-5-fluoro-4-methylphenyl)piperazin-1-yl]methanone (1.9 g), oxazolidin-2-one (418 mg), potassium carbonate (1.7 g) and copper (I) iodide (152 mg) were added toluene (4 mL) and N,N′-dimethylethylenediamine (180 μL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (0.5 g).
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