4-(4-乙基哌嗪-1-甲基)-3-三氟甲基苯胺

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

实验步骤: The procedures of Steps (1), (2) and (3) of Example 2 were repeated step by step, except for using 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline obtained in Step (3) above instead of aniline in Step (1) of Example 2 to obtain the title compound (0.032 g, 12%).

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

实验步骤: 1-Ethyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine (21.7 g, 68.3 mmol) obtained in Step (2) above was stirred in a solution of methanol. The reaction solution was mixed with Pd/C (1.8 g, 17.08 mmol), followed by stirring under hydrogen conditions for about 12 hours at room temperature. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with methanol. The filtrate was concentrated under reduced pressure to obtain the title compound (19.4 g, 99%). The reaction mixture was filtered through a Celite pad under reduced pressure washed with methanol The filtrate was concentrated under reduced pressure

反应条件: temp:26.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (247 mg, 0.858 mmol) in DCM (35 mL) was added to a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (200 mg, 0.858 mmol) in DCM (35 mL). HOBt (197 mg, 1.287 mmol), EDC (247 mg, 1.287 mmol) and Et3N (0.359 mL, 2.57 mmol) was added and the mixture was stirred at 26° C. for 3 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=10/1). All fractions found to contain product by TLC (PE/EA=5/1, Rf=0.6) were combined and concentrated to yield a light yellow solid of 2-(4-bromo-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide (413 mg, 0.822 mmol, 96.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.98-7.91 (m, 1H), 7.79-7.67 (m, 2H), 7.40-7.27 (m, 3H), 3.74 (s, 2H), 3.61 (s, 2H), 2.58-2.39 (m, 11H), 1.09 (s, 4H); ES-LCMS m/z 502.0 (M+H). Then the solution was concentrated The combined organic extract was washed with brine dried over MgSO4 filtered concentrated The crude material was purified by silica column chromatography (PE/EA=10/1) concentrated

反应条件: temp:26.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (247 mg, 0.858 mmol) in DCM (35 mL) was added to a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (200 mg, 0.858 mmol) in DCM (35 mL). HOBt (197 mg, 1.287 mmol), EDC (247 mg, 1.287 mmol) and Et3N (0.359 mL, 2.57 mmol) was added and the mixture was stirred at 26° C. for 3 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=10/1). All fractions found to contain product by TLC (PE/EA=5/1, Rf=0.6) were combined and concentrated to yield a light yellow solid of 2-(4-bromo-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide (413 mg, 0.822 mmol, 96.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.98-7.91 (m, 1H), 7.79-7.67 (m, 2H), 7.40-7.27 (m, 3H), 3.74 (s, 2H), 3.61 (s, 2H), 2.58-2.39 (m, 11H), 1.09 (s, 4H); ES-LCMS m/z 502.0 (M+H). Then the solution was concentrated The combined organic extract was washed with brine dried over MgSO4 filtered concentrated The crude material was purified by silica column chromatography (PE/EA=10/1) concentrated

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of (4-amino-2-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (20 g, 66.4 mmol) in THF (500 mL) was added BH3.DMS (19.91 mL, 199 mmol) dropwise. Then the mixture was stirred at 80° C. for 4 h. The mixture was quenched by adding MeOH and then concentrated. The residue was purified by silica column chromatography on silica gel (PE:EA=2:1, Rf=0.35) to give a white solid of 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (14 g, 46.0 mmol, 69.4% yield): 1H NMR (400 MHz, CDCl3) δ: 7.48 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.8 Hz, 1H), 6.79 (dd, J=2.4, 8.4 Hz, 1H), 3.76 (s, 2H), 3.53 (s, 2H), 2.45-2.39 (m, 8H), 1.08 (t, J=7.2 Hz, 3H); ES-LCMS m/z 288 (M+H). was added BH3 The mixture was quenched by adding MeOH concentrated The residue was purified by silica column chromatography on silica gel (PE:EA=2:1, Rf=0.35)

反应条件: temp:26.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (247 mg, 0.858 mmol) in DCM (35 mL) was added to a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (200 mg, 0.858 mmol) in DCM (35 mL). HOBt (197 mg, 1.287 mmol), EDC (247 mg, 1.287 mmol) and Et3N (0.359 mL, 2.57 mmol) was added and the mixture was stirred at 26° C. for 3 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=10/1). All fractions found to contain product by TLC (PE/EA=5/1, Rf=0.6) were combined and concentrated to yield a light yellow solid of 2-(4-bromo-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide (413 mg, 0.822 mmol, 96.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.98-7.91 (m, 1H), 7.79-7.67 (m, 2H), 7.40-7.27 (m, 3H), 3.74 (s, 2H), 3.61 (s, 2H), 2.58-2.39 (m, 11H), 1.09 (s, 4H); ES-LCMS m/z 502.0 (M+H). Then the solution was concentrated The combined organic extract was washed with brine dried over MgSO4 filtered concentrated The crude material was purified by silica column chromatography (PE/EA=10/1) concentrated

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of (4-amino-2-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (20 g, 66.4 mmol) in THF (500 mL) was added BH3.DMS (19.91 mL, 199 mmol) dropwise. Then the mixture was stirred at 80° C. for 4 h. The mixture was quenched by adding MeOH and then concentrated. The residue was purified by silica column chromatography on silica gel (PE:EA=2:1, Rf=0.35) to give a white solid of 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (14 g, 46.0 mmol, 69.4% yield): 1H NMR (400 MHz, CDCl3) δ: 7.48 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.8 Hz, 1H), 6.79 (dd, J=2.4, 8.4 Hz, 1H), 3.76 (s, 2H), 3.53 (s, 2H), 2.45-2.39 (m, 8H), 1.08 (t, J=7.2 Hz, 3H); ES-LCMS m/z 288 (M+H). was added BH3 The mixture was quenched by adding MeOH concentrated The residue was purified by silica column chromatography on silica gel (PE:EA=2:1, Rf=0.35)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Into a solution of 4-(4-Ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (8.0 g, 27.9 mmol, 1.0 eq.) in dichloromethane (140 ml) is added diisopropylethyl amine (5.27 ml, 30.69 mmol, 1.1 eq.). The solution is cooled to 0° C., after which 4-Methyl-3-nitrobenzoylchloride (4.18 ml, 28.73 mmol, 1.03 eq.) is added in portions into the reaction mixture which is further equilibrated for 30 minutes. The reaction mixture is then partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated to afford the desired product which is used in the next step without further purification. The reaction mixture is then partitioned between dichloromethane and water The organic layer is separated the aqueous layer is extracted with dichloromethane The combined organic extracts are washed with water dried over Na2SO4 filtered concentrated

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

实验步骤: The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (disclosed in WO 03/099771). Title compound: ES-MS: 537.0 [M+H]+; tR=3.18 min (System 1); Rf=0.16 (CH2Cl2/MeOH, 95:5+0.1% NH3aq). The title compound is prepared

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

实验步骤: The title compound is prepared as described in Example 1 but using (2-chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 16.1) and 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 556.9 [M+H]+; single peak at tR=3.36 min (System 1); Rf=0.13 (CH2Cl2/MeOH+1% NH33aq, 9:1). The title compound is prepared

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

实验步骤: The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 523.0 [M+H]+; single peak at tR=3.00 min (System 1); Rf=0.12 (CH2Cl2/MeOH+1% NH3aq, 95:5). The title compound is prepared

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

实验步骤: The procedure of Step 5 of Example 1 was repeated except for using 3-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 4 of Example 8 and 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzenamine to obtain the title compound (see Table 1).