7-氟苯酞

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of trimethylaluminum (2.0 M in hexane, 1 eq) was added slowly to a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1 eq) in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for 15 min then a solution of 7-fluoro-2-benzofuran-1(3H)-one (1 eq, Chem. Pharm. Bull., 1985, 33(7), 2809-2820) in DCM was added dropwise. The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C. To the stirred solution was added dropwise thionyl chloride (1 eq.). The reaction mixture was warmed to room temperature, stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM. The organic phase was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude 2-(chloromethyl)-6-fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide thus obtained was dissolved in methanol and cooled to 0° C. To the stirred solution was added sodium methoxide (1.2 eq.) portionwise. The solution was warmed to room temperature and stirred for 18 hours. The solution was concentrated and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SPE cartridge (Silica) eluting with DCM-methanol (96:4) affording the title compound (yield 24%). The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate The organic phase was dried over sodium sulfate concentrated under reduced pressure The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM The organic phase was dried over sodium sulfate filtered the solvent removed under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of trimethylaluminium (2.0 M in hexane, 1 eq) was added slowly to a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1 eq) in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for 15 min then a solution of 7-fluoro-2-benzofuran-1(3H)-one (1 eq, Chem. Pharm. Bull., 1985, 33(7), 2809-2820) in DCM was added dropwise. The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C. To the stirred solution was added dropwise thionyl chloride (1 eq.). The reaction mixture was warmed to room temperature, stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM. The organic phase was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude 2-(chloromethyl)-6-fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide thus obtained was dissolved in methanol and cooled to 0° C. To the stirred solution was added sodium methoxide (1.2 eq.) portionwise. The solution was warmed to room temperature and stirred for 18 hours. The solution was concentrated and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SPE cartridge (Silica) eluting with DCM-methanol (96:4) affording the title compound (yield 24%). The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate The organic phase was dried over sodium sulfate concentrated under reduced pressure The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM The organic phase was dried over sodium sulfate filtered the solvent removed under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of trimethylaluminium (2.0 M in hexane, 1 eq) was added slowly to a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1 eq) in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for 15 min then a solution of 7-fluoro-2-benzofuran-1(3H)-one (1 eq, Chem. Pharm. Bull., 1985, 33(7), 2809-2820) in DCM was added dropwise. The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C. To the stirred solution was added dropwise thionyl chloride (1 eq.). The reaction mixture was warmed to room temperature, stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM. The organic phase was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude 2-(chloromethyl)-6-fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide thus obtained was dissolved in methanol and cooled to 0° C. To the stirred solution was added sodium methoxide (1.2 eq.) portionwise. The solution was warmed to room temperature and stirred for 18 hours. The solution was concentrated and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SPE cartridge (Silica) eluting with DCM-methanol (96:4) affording the title compound (yield 24%). The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate The organic phase was dried over sodium sulfate concentrated under reduced pressure The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM The organic phase was dried over sodium sulfate filtered the solvent removed under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of trimethylaluminium (2.0 M in hexane, 1 eq) was added slowly to a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1 eq) in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for 15 min then a solution of 7-fluoro-2-benzofuran-1(3H)-one (1 eq, Chem. Pharm. Bull., 1985, 33(7), 2809-2820) in DCM was added dropwise. The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C. To the stirred solution was added dropwise thionyl chloride (1 eq.). The reaction mixture was warmed to room temperature, stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM. The organic phase was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude 2-(chloromethyl)-6-fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide thus obtained was dissolved in methanol and cooled to 0° C. To the stirred solution was added sodium methoxide (1.2 eq.) portionwise. The solution was warmed to room temperature and stirred for 18 hours. The solution was concentrated and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SPE cartridge (Silica) eluting with DCM-methanol (96:4) affording the title compound (yield 24%). The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate The organic phase was dried over sodium sulfate concentrated under reduced pressure The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM The organic phase was dried over sodium sulfate filtered the solvent removed under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of trimethylaluminium (2.0 M in hexane, 1 eq) was added slowly to a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1 eq) in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for 15 min then a solution of 7-fluoro-2-benzofuran-1(3H)-one (1 eq, Chem. Pharm. Bull., 1985, 33(7), 2809-2820) in DCM was added dropwise. The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C. To the stirred solution was added dropwise thionyl chloride (1 eq.). The reaction mixture was warmed to room temperature, stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM. The organic phase was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude 2-(chloromethyl)-6-fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide thus obtained was dissolved in methanol and cooled to 0° C. To the stirred solution was added sodium methoxide (1.2 eq.) portionwise. The solution was warmed to room temperature and stirred for 18 hours. The solution was concentrated and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SPE cartridge (Silica) eluting with DCM-methanol (96:4) affording the title compound (yield 24%). The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate The organic phase was dried over sodium sulfate concentrated under reduced pressure The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM The organic phase was dried over sodium sulfate filtered the solvent removed under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: According to a similar procedure to that described in Example 4-(5), 7-fluoro-1(3H)-isobenzofuranone (described in Tetrahedron, 54, 7485 (1998); 1.67 g, 11 mmol) was reacted with an aqueous solution of sodium hydroxide (1.008N; 10.9 ml, 11 mmol), 4-methoxybenzyl chloride (1.57 g, 10 mmol), tetrazole (1.40 g, 20 mmol), bis(allyloxy)(diisopropylamino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 3.1 g, 12.6 mmol), and tert-butyl hydroperoxide (80% di-tert-butyl peroxide solution; Merck; 2.7 g, 24 mmol), and the reaction mixture was worked up to afford, after extraction, an oily residue. The oily residue was subjected to chromatography on a silica gel (100 g) column (eluent; ethyl acetate:hexane=2:3) to afford a mixture of a solid and an oily material. The mixture was washed with a mixed solvent of ethyl acetate and hexane, the washings were concentrated under reduced pressure to give a residue. The residue was subjected to chromatography on a silica gel (50 g) column (eluent; ethyl acetate:hexane=1:4˜1:2) to afford the title compound (1.08 g, 24% yield) as a colorless oil. to afford after extraction to afford a mixture of a solid The mixture was washed with a mixed solvent of ethyl acetate and hexane the washings were concentrated under reduced pressure to give a residue

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of trimethylaluminium (2.0 M in hexane, 1 eq) was added slowly to a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1 eq) in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for 15 min then a solution of 7-fluoro-2-benzofuran-1(3H)one (1 eq, Chem. Pharm. Bull., 1985, 33(7), 2809-2820) in DCM was added dropwise. The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C. To the stirred solution was added dropwise thionyl chloride (1 eq.). The reaction mixture was warmed to room temperature, stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM. The organic phase was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude 2-(chloromethyl)-6-fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide thus obtained was dissolved in methanol and cooled to 0° C. To the stirred solution was added sodium methoxide (1.2 eq.) portionwise. The solution was warmed to room temperature and stirred for 18 hours. The solution was concentrated and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SPE cartridge (Silica) eluting with DCM-methanol (96:4) affording the title compound (yield 24%). The free base could be converted into its dihydrochloride salt by dissolving the compound in dichloromethane and adding a 1M ethereal solution of HCl (2.1 eq) dropwise. A yellow solid precipitated and the suspension was stirred for 15 min. The solvent was removed under reduced pressure affording a crude material which was triturated with ether. The final compound was then recovered by filtration (yield quantitative). The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate The organic phase was dried over sodium sulfate concentrated under reduced pressure The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM The organic phase was dried over sodium sulfate filtered the solvent removed under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of trimethylaluminum (2.0 M in hexane, 1 eq) was added slowly to a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1 eq) in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for 15 min then a solution of 7-fluoro-2-benzofuran-1(3H)-one (1 eq, Chem. Pharm. Bull., 1985, 33(7), 2809-2820) in DCM was added dropwise. The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C. To the stirred solution was added dropwise thionyl chloride (1 eq.). The reaction mixture was warmed to room temperature, stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM. The organic phase was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude 2-(chloromethyl)-6-fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide thus obtained was dissolved in methanol and cooled to 0° C. To the stirred solution was added sodium methoxide (1.2 eq.) portionwise. The solution was warmed to room temperature and stirred for 18 hours. The solution was concentrated and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SPE cartridge (Silica) eluting with DCM-methanol (96:4) affording the title compound (yield 24%). The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate The organic phase was dried over sodium sulfate concentrated under reduced pressure The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM The organic phase was dried over sodium sulfate filtered the solvent removed under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of trimethylaluminium (2.0 M in hexane, 1 eq) was added slowly to a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1 eq) in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for 15 min then a solution of 7-fluoro-2-benzofuran-1(3H)-one (1 eq, Chem. Pharm. Bull., 1985, 33(7), 2809-2820) in DCM was added dropwise. The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C. To the stirred solution was added dropwise thionyl chloride (1 eq.). The reaction mixture was warmed to room temperature, stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM. The organic phase was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude 2-(chloromethyl)-6-fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide thus obtained was dissolved in methanol and cooled to 0° C. To the stirred solution was added sodium methoxide (1.2 eq.) portionwise. The solution was warmed to room temperature and stirred for 18 hours. The solution was concentrated and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SPE cartridge (Silica) eluting with DCM-methanol (96:4) affording the title compound (yield 24%). The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate The organic phase was dried over sodium sulfate concentrated under reduced pressure The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM The organic phase was dried over sodium sulfate filtered the solvent removed under reduced pressure