1-(4-氟苄基)哌嗪

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-(4-Fluorobenzyl)piperazine (0.160 g, 0.81 mmol, 1.05 eq) was suspended in iPrOH (8 mL) and DIPEA (0.72 mL). To this solution, the 5-bromo-4-chloro-3-nitropyridin-2-amine (0.19 g, 0.77 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 60° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow solid (0.250 g, 75%); 1H-NMR (500 MHz, DMSO-d6): δ 2.43-2.55 (m, 4H, piperazine N(CH2)2), 3.05 (m, 4H, piperazine N(CH2)2), 3.51 (s, 2H, NCH2), 6.96 (br s, 2H, NH2), 7.14 (t, J=9.0 Hz, 2H, ArH), 7.35 (dd, J=8.5, 6.0 Hz, 2H, ArH), 8.15 (s, 1H, pyridine 6-H). LC (Method B)-MS (ESI, m/z): Rt=2.52 min—410/412 [(M+H+), Br isotopic pattern, 100%]. the reaction mixture was heated The mixture was filtered washed with iPrOH (3×3 mL), Et2O (2×3 mL) dried

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: A 28.7 g. (0.1 mole) portion of N-(p-fluorobenzyl)piperazine was dissolved in 25 ml. of ethanol and then added dropwise over 30 minutes to a stirred solution of 14.6 g. (0.1 mole) of dimethyl cyanodithioiminocarbonate in 200 ml. of ethanol. The mixture was refluxed for 6 hours, the evolved gas being led through a sodium hypochlorite trap. The mixture was then evaporated to a syrup. The mixture was refluxed for 6 hours the evolved gas being led through a sodium hypochlorite trap The mixture was then evaporated to a syrup

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

实验步骤: A 28.7 g. (0.1 mole) portion of N-(p-fluorobenzyl)piperazine was dissolved in 25 ml. of ethanol and then added dropwise over 30 minutes to a stirred solution of 14.6 g. (0.1 mole) of dimethyl cyanodithioiminocarbonate in 200 ml. of ethanol. The mixture was refluxed for 6 hours, the evolved gas being led through a sodium hypochlorite trap. The mixture was then evaporated to a syrup. The mixture was refluxed for 6 hours the evolved gas being led through a sodium hypochlorite trap The mixture was then evaporated to a syrup

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

实验步骤: To a solution of 5-chloro-6-(ethoxycarbonyl)nicotinic acid (0.201 g, 0.875 mmol, 1.0 eq) and 4-fluorobenzylpiperazine (0.204 g, 1.051 mmol, 1.2 eq) in dimethylformamide (4.0 mL) was added triethylamine (0.146 mL, 1.051 mmol, 1.2 eq) followed by HATU (0.366 g, 0.963 mmol, 1.1 eq). The reaction was shaken at room temperature for 3 hours before partitioning between EtOAc (80 mL) and water-NaHCO3 (2:1, 60 mL). The organics were further washed with brine (80 mL), water (80 mL) and brine (80 mL) before drying (Na2SO4) and concentrating under reduced pressure. MPLC (30→95% EtOAc-hexane, 2→25 min) yielded ethyl 3-chloro-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate as a white solid (0.265 g, 75%); 1H nmr (D6-DMSO) 8.54 (1H, d, J 1.5 Hz, pyH-2 or pyH-4), 7.83 (1H, d, J 1.0 Hz, pyH-2 or pyH-4), 7.26 (2H, m, 2H of C6H4F), 6.99 (2H, t, J 8.5 Hz, 2H of C6H4F), 4.48 (2H, q, J 7.0 Hz, OCH2CH3), 3.55 (4H, m, 4H of piz), 2.45 (4H, m, 4H of piz), 1.43 (3H, t, J 7.0 Hz, OCH2CH3); m/z 406, 408 [M+H]+. A solution of the ethyl 3-chloro-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate (0.265 g, 0.654 mmol, 1.0 eq) and N-Boc-propargylamine (0.122 g, 0.785 mmol, 1.2 eq) in dimethylformamide (7.0 mL) was degassed by bubbling argon through it. Triethylamine (0.14 mL, 0.981 mmol, 1.5 eq) was added followed by copper (I) iodide (0.006 g, 0.033 mmol, 0.05 eq) and tetrakis(triphenylphosphine)palladium (0.038 g, 0.033 mmol, 0.05 eq). The reaction mixture was further degassed before heating to 90° C. for 14 hours. The reaction was cooled and filtered through Celite®, eluting with EtOAc (80 mL). The filtrate was washed with water (100 mL), brine (80 mL), water (100 mL) and brine (80 mL). The organics were dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 70% EtOAc-hexane) yielded the ethyl 3-chloro-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate starting material and ethyl 3-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate as a colourless oil; 1H nmr (CDCl3) 8.60 (1H, d, J 2.0 Hz, pyH-2 or pyH-4), 7.87 (1H, d, J 2.0 Hz, pyH-2 or pyH-4), 7.26 (2H, m, 2H of C6H4F), 6.99 (2H, t, J 8.5 Hz, 2H of C6H4F), 4.87 (1H, br s, NH), 4.47 (2H, q, J 7.0 Hz, OCH2CH3), 4.21 (2H, d, J 5.5 Hz, CH2NHBoc), 3.77 (2H, m, 2H of piz), 3.37 (2H, m, 2H of piz), 2.51 (2H, m, 2H of piz), 2.38 (2H, m, 2H of piz), 1.47 (9H, s, C(CH3)3), 1.43 (3H, t, J 7.0 Hz, OCH2CH3); m/z 525 [M+H]+. A solution of lithium hydroxide monohydrate (0.010 g, 0.229 mmol, 2.0 eq) in water (0.5 mL) was added to a solution of the ethyl 3-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate (0.060 g, 0.115 mmol, 1.0 eq) in tetrahydrofuran-methanol (2:1, 1.5 mL). The reaction was stirred at room temperature for 40 minutes before neutralizing with HCl (approximately 0.2 mL of a 2M solution). The reaction mixture was concentrated to dryness to provide 3-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinic acid, which was used without purification; m/z 497 [M+H]+. To a solution of the crude 3-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinic acid (0.115 mmol, 1.0 eq) in dimethylformamide (2.0 mL) was added 1-(4-cyanobenzyl)-4-aminopiperidine dihydrochloride (0.040 g, 0.138 mmol, 1.2 eq) and HATU (0.052 g, 0.138 mmol, 1.2 eq). Triethylamine (0.056 mL, 0.403 mmol, 3.5 eq) was added and the reaction mixture was stirred at room temperature for 2.5 hours before partitioning between EtOAc (100 mL) and water (100 mL). The organics were further washed with brine (80 mL), water (80 mL) and brine (80 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 3→6% MeOH—CH2Cl2) yielded Compound 164 as a yellow foam; 1H nmr (CDCl3) δ 8.46 (1H, d, J 2.0 Hz, pyH-4 or pyH-6), 7.85 (1H, d, J 2.0 Hz, pyH-4 or pyH-6), 7.80 (1H, d, J 8.0 Hz, CONH), 7.60 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of C6H4CN), 7.29-7.25 (2H, m, 2H of C6H4F), 7.00 (2H, t, J 8.5 Hz, 2H of C6H4F), 4.88 (1H, m, NHCO2C), 4.23 (2H, d, J 5.5 Hz, CCH2NH), 3.99 (1H, m, pipH-4), 3.80-3.40 (4H, br m, 4H of piz), 3.56 (2H, s, CH2C6H4CN or CH2C6H4F), 3.51 (2H, s, CH2C6H4CN or CH2C6H4F), 2.80 (2H, m, 2H of pip), 2.46 (4H, m, 4H of piz), 2.23 (2H, t, J 11.0 Hz, 2H of pip), 2.01 (2H, m, 2H of pip), 1.63 (2H, m, 2H of pip), 1.46 (9H, s, C(CH3)3); m/z: 694 [M+H]+. before partitioning between EtOAc (80 mL) and water-NaHCO3 (2:1, 60 mL) The organics were further washed with brine (80 mL), water (80 mL) and brine (80 mL) before drying (Na2SO4) concentrating under reduced pressure

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

实验步骤: To a suspension of pyridine-2,6-dicarboxylic acid (0.200 g, 1.20 mmol, 1.0 eq) in tetrahydrofuran (6.0 mL) was added 4-fluorobenzylpiperazine (0.116 g, 0.60 mmol, 0.5 eq). Triethylamine (0.33 mL, 2.40 mmol, 2.0 eq) was added followed by HATU (0.319 g, 0.84 mmol, 0.7 eq) and the reaction was stirred at room temperature for 14 hours. The reaction mixture was diluted with methanol (3.0 mL) and (trimethylsilyl)diazomethane (2.0 mL of a 2M solution in hexane, 4.00 mmol). The reaction mixture was stirred at room temperature for 30 minutes before concentrating under reduced pressure. The residue was partitioned between NaHCO3 (50 mL) and EtOAc (50 mL). The organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 2→5% MeOH—CH2Cl2) yielded methyl 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate (0.214 g, 50%) as a white solid; m/z: 358 [M+H]+. To a solution of the methyl 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate (0.214 g, 0.60 mmol, 1.0 eq) in tetrahydrofuran (4.0 mL) was added a solution of lithium hydroxide monohydrate (0.050 g, 1.20 mmol, 2.0 eq) in water (3.0 mL). The reaction was stirred at room temperature for 25 minutes before neutralizing with HCl (approximately 0.6 mL of a 2M solution). The reaction mixture was concentrated to dryness to yield 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinic acid, which was used without further purification; m/z: 344 [M+H]+. To a solution of the crude 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinic acid (approximately 0.200 mmol, 1.0 eq) and triethylamine (0.083 mL, 0.600 mmol, 3.0 eq) in dimethylformamide (2.0 mL) was added 1-phenylpiperazine (0.036 mL, 0.240 mmol, 1.2 eq). HATU was added and the reaction shaken at room temperature for 2.5 hours before partitioning between EtOAc (50 mL) and NaHCO3-water (1:1, 50 mL). The organics were further washed with brine (50 mL), water (50 mL) and brine (50 mL) before drying (Na2SO4) and concentrating under reduced pressure. Column chromatography (silica, 3→7% MeOH—CH2Cl2) yielded Compound 94 as a colourless oil; 1H nmr (CDCl3) δ 7.92 (1H, t, J 7.5 Hz, pyH-4), 7.73 (1H, d, J 8.0 Hz, pyH-3 or pyH-5), 7.70 (1H, d, J 7.5 Hz, pyH-3 or pyH-5), 7.33-7.22 (4H, m, 2H of C6H4F and 2H of C6H5), 7.01-6.90 (5H, m, 2H of C6H4F and 3H of C6H5), 3.97 (2H, dd, J 5.5, 5.0 Hz, 2H of piz), 3.81 (2H, dd, J 5.0, 4.5 Hz, 2H of piz), 3.74 (2H, t, J 5.0 Hz, 2H of piz), 3.55 (2H, dd, J 5.0, 4.5 Hz, 2H of piz), 3.46 (2H, s, CH2C6H4F), 3.29 (2H, t, J 5.0 Hz, 2H of piz), 3.17 (2H, dd, J 5.5, 4.5 Hz, 2H of piz), 2.52 (2H, t, J 5.0 Hz, 2H of piz), 2.39 (2H, dd, 5.0, 4.5 Hz, 2H of piz); m/z: 488 [M+H]+. The reaction mixture was stirred at room temperature for 30 minutes before concentrating under reduced pressure The residue was partitioned between NaHCO3 (50 mL) and EtOAc (50 mL) The organics were washed with brine (50 mL) dried (Na2SO4) concentrated under reduced pressure