4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)aniline

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2 ml trimethylaluminium (2 M in toluene, 4 mMol) is added to a stirred solution of 355 mg (1.3 mMol) 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine in 20 ml toluene at 10° C. under an argon atmosphere. After 1 h at r t, a solution of 436 mg (1.3 mMol) 6-(6-acetylaminopyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid methyl ester (Step 9.2) in 5 ml THF is added and the reaction mixture is heated at 90° C. for 45 min. After cooling to 5° C., a solution of sat. aqueous ammonium chloride (50 ml) is added dropwise. The mixture is poured into EtOAc and filtered over hyflo. The separated aq. phase is extracted with EtOAc. The combined organic phases are washed with water and brine, dried (Na2SO4) and concentrated. The crude product is purified by chromatography (SiO2, CH2Cl2/EtOH/NH3 90:9:1) and is recrystallised from hot EtOAc and hexane to afford the title compound as a colourless solid: m.p.: 202-204° C. After cooling to 5° C. filtered over hyflo The separated aq. phase is extracted with EtOAc The combined organic phases are washed with water and brine dried (Na2SO4) concentrated The crude product is purified by chromatography (SiO2, CH2Cl2/EtOH/NH3 90:9:1) is recrystallised from hot EtOAc and hexane

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2 ml trimethylaluminium (2 M in toluene, 4 mMol) is added to a stirred solution of 355 mg (1.3 mMol) 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine in 20 ml toluene at 10° C. under an argon atmosphere. After 1 h at r t, a solution of 436 mg (1.3 mMol) 6-(6-acetylaminopyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid methyl ester (Step 9.2) in 5 ml THF is added and the reaction mixture is heated at 90° C. for 45 min. After cooling to 5° C., a solution of sat. aqueous ammonium chloride (50 ml) is added dropwise. The mixture is poured into EtOAc and filtered over hyflo. The separated aq. phase is extracted with EtOAc. The combined organic phases are washed with water and brine, dried (Na2SO4) and concentrated. The crude product is purified by chromatography (SiO2, CH2Cl2/EtOH/NH3 90:9:1) and is recrystallised from hot EtOAc and hexane to afford the title compound as a colourless solid: m.p.: 202-204° C. After cooling to 5° C. filtered over hyflo The separated aq. phase is extracted with EtOAc The combined organic phases are washed with water and brine dried (Na2SO4) concentrated The crude product is purified by chromatography (SiO2, CH2Cl2/EtOH/NH3 90:9:1) is recrystallised from hot EtOAc and hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: is obtained analogously to the method as described in Example 1 but using (4-benzoimidazol-1-yl-phenyl)-acetic acid instead of (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine instead of 3′-bromo-2-trifluoromethyl-biphen-4-ylamine as a starting material (see WO 03/099771). ES-MS: 508.0 [M+H]+; single peak at tR=2.84 min (System 1); Rf=0.10 (CH2Cl2/MeOH+1% NH3aq, 9:1). Starting material is prepared as follows: Step 2.1: (4-Benzoimidazol-1-yl-phenyl)-acetic acid is obtained analogously to the method Starting material is prepared

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: is obtained analogously to the method as described in Example 1 but using (4-benzoimidazol-1-yl-phenyl)-acetic acid instead of (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine instead of 3′-bromo-2-trifluoromethyl-biphen-4-ylamine as a starting material (see WO 03/099771). ES-MS: 508.0 [M+H]+; single peak at tR=2.84 min (System 1); Rf=0.10 (CH2Cl2/MeOH+1% NH3aq, 9:1). Starting material is prepared as follows: Step 2.1: (4-Benzoimidazol-1-yl-phenyl)-acetic acid is obtained analogously to the method Starting material is prepared

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Iodo-4-methylbenzoyl chloride (0.48 g, 1.7 mmol), prepared from the reaction of 3-iodo-4-methylbenzoic acid and SOCl2 (as previously described), was added to a solution of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (0.47 g, 1.7 mmol), N,N-diisopropylethylamine (0.26 g, 2.0 mmol), and a catalytic amount of DMAP in THF (10 mL). After stirring at rt for 2 h, the reaction was quenched with water. EtOAc was added and the layers separated. The combined organic layers were concentrated to dryness and purified by silica gel chromatography (eluted with 5% MeOH/DCM, MeOH was pre-saturated with ammonia gas), to provide 0.51 g of product as an off-white solid. the reaction was quenched with water EtOAc was added the layers separated The combined organic layers were concentrated to dryness purified by silica gel chromatography (eluted with 5% MeOH/DCM, MeOH was pre-saturated with ammonia gas)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine (1.23 g, 4 mmol) and sodium hydrosulfite (7.0 g, 85% pure from Aldrich, 40 mmol) in acetone and water (1:1, 20 mL) was refluxed for 3 h. Upon cooling, the volatile components (mainly acetone) were removed on rotavap, and the resulting mixture was subjected to filtration. The solid was thoroughly washed with EtOAc. The combined filtrate was extracted with n-BuOH (4×), and the combined organic layer was washed with saturated aq. NaHCO3, dried (Na2SO4), filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 5% MeOH/DCM, MeOH was pre-saturated with ammonia gas) to provide 0.71 g of product as a pale yellow solid. was refluxed for 3 h Upon cooling the volatile components (mainly acetone) were removed on rotavap the resulting mixture was subjected to filtration The solid was thoroughly washed with EtOAc The combined filtrate was extracted with n-BuOH (4×) the combined organic layer was washed with saturated aq. NaHCO3 dried (Na2SO4) filtered concentrated the resulting residue was purified by silica gel chromatography (eluted with 5% MeOH/DCM, MeOH was pre-saturated with ammonia gas)