4-(4-chlorophenyl)butan-2-one

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-[4′-(5-Amino-1-methyl-1H-pyrazol-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.125 g, 0.346 mmol) and 4-(4-chloro-phenyl)-butan-2-one (0.095 g, 0.52 mmol) were dissolved in MeOH (5 mL). Acetic acid (0.030 mL, 0.52 mmol) was added along with a few molecular sieves and the reaction stirred at 30° C. overnight. Sodium cyanoborohydride (0.033 g, 0.52 mmol) was then added and the reaction was heated to 60° C. for 4 hours. An additional 0.5 equivalents of sodium cyanoborohydride was added and the reaction continued heating for 1 hour. All solvent was removed and the residue was submitted to EtOAc/H2O workup. The residue was purified twice on silica gel (0-100% EtOAc in hexanes followed by 0-10% MeOH in CH2Cl2) to afford the title compound. the reaction was heated to 60° C. for 4 hours the reaction continued heating for 1 hour All solvent was removed The residue was purified twice on silica gel (0-100% EtOAc in hexanes followed by 0-10% MeOH in CH2Cl2)

反応条件: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-[4′-(5-Amino-1-methyl-1H-pyrazol-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.125 g, 0.346 mmol) and 4-(4-chloro-phenyl)-butan-2-one (0.095 g, 0.52 mmol) were dissolved in MeOH (5 mL). Acetic acid (0.030 mL, 0.52 mmol) was added along with a few molecular sieves and the reaction stirred at 30° C. overnight. Sodium cyanoborohydride (0.033 g, 0.52 mmol) was then added and the reaction was heated to 60° C. for 4 hours. An additional 0.5 equivalents of sodium cyanoborohydride was added and the reaction continued heating for 1 hour. All solvent was removed and the residue was submitted to EtOAc/H2O workup. The residue was purified twice on silica gel (0-100% EtOAc in hexanes followed by 0-10% MeOH in CH2Cl2) to afford the title compound. the reaction was heated to 60° C. for 4 hours the reaction continued heating for 1 hour All solvent was removed The residue was purified twice on silica gel (0-100% EtOAc in hexanes followed by 0-10% MeOH in CH2Cl2)

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

実験手順: 4-Chlorobenzylideneacetone (1 g, 5.5 mmol) was dissolved in EtOAc (10 mL) then platinum(IV) oxide (catalytic amount) was added. The mixture was purged with N2 (g) then H2 (g) then stirred under H2 atmosphere for 2 hours. The mixture was purged with N2 (g) then filtered to remove the catalyst. The crude material was purified on silica gel to yield the title compound. The mixture was purged with N2 (g) The mixture was purged with N2 (g) then filtered to remove the catalyst The crude material was purified on silica gel

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

実験手順: A mixture of 4-chlorobenzyl chloride (8.05 g, 55 mmol), acetylacetone (5.20 mL, 50 mmol), K2CO3 (6.90 g, 50 mmol), and anhydrous ethanol (50 mL) was refluxed for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed. Water (100 mL) was added to the residue and the mixture was extracted with Et2O (3×50 mL). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4 and concentrated to dryness. The resulting yellow oil was distilled under reduced pressure (0.1 Torr) and the fraction that distilled at 110° C. was collected as a clear, colorless oil (6.15 g, 67% yield). was refluxed for 16 h the solvent was removed Water (100 mL) was added to the residue the mixture was extracted with Et2O (3×50 mL) The combined organic layers were washed with brine (50 mL) dried over Na2SO4 concentrated to dryness The resulting yellow oil was distilled under reduced pressure (0.1 Torr) the fraction that distilled at 110° C.

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: Sodium hydride (0.4163 g, 17.35 mmol) was added slowly to a NaCl ice bath containing EtOH (5.3 mL, 2.5 M) stirring under N2. 66 (2.4253 g, 13.28 mmol) and diethyloxalate (1.803 g, 13.28 mmol) were mixed together, and then added to the chilled NaOEt solution. After stirring for 5 minutes, the reaction was warmed to room temperature. After 10 minutes, the reaction solidified and an additional 10 mL EtOH was added. After stirring for 5 h, the reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 1:1 Hexanes: CH2Cl2): Only pure fractions were combined and concentrated to obtain 67 (1.7561 g, 46.8%): 1H (CDCl3, 400 MHz): δ 14.27 (1H, broad s), 7.22 (2H, d, J=8.3 Hz), 7.10 (2H, d, J=8.3 Hz), 6.32 (1H, s), 4.31 (2H, q, J=7.2 Hz), 2.92 (2H, t, J=7.8 Hz), 2.78 (2H, t, J=7.8 Hz), 1.34 (3H, t, J=7.2 Hz) ppm. 13C (CDCl3, 100 MHz): δ 201.59, 166.07, 161.79, 138.51, 132.00, 128.53, 128.54, 101.72, 62.38, 42.08, 29.60, 13.88 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 13.88; CH2 carbons: 62.38, 42.08, 29.60; CH carbons: 129.53, 128.54, 101.72ppm. HPLC: 11.103 min. After stirring for 5 minutes After stirring for 5 h the reaction was quenched at 0° C. with 1N HCl extracted 2× with CH2Cl2 The combined organics were washed with H2O dried with Na2SO4 filtered concentrated purified by silica gel chromatography (Combiflash column, 1:1 Hexanes: CH2Cl2) concentrated

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

実験手順: 1.6 M Methyl lithium (33.9 mL, 54.17 mmol) was added over 70 min to a stirring 0° C. solution of 3-(4-chlorophenyl)-propionic acid (5.0072 g, 27.08 mmol) in dry Et2O (135 mL, 0.2 M): The ice bath was removed, and the reaction was allowed to stir at room temperature overnight. The reaction was the poured into rapidly stirring ice water containing aq. HCl. The organic layer was removed, washed with NaHCO3 and brine, then dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 98:2 to 95:5 Hexanes: EtOAc) to achieve pure 66 (2.4253 g, 49.0%): 1H (CDCl3, 400 MHz): δ 7.14 (2H, d, J=8.3 Hz), 7.03 (2H, d, J=8.3 Hz), 2.77 (2H, t, J=7.5 Hz), 2.64 (2H, t, J=7.5 Hz), 2.04 (3H, s) ppm. 13C (CDCl3, 100 MHz): δ 207.12, 139.38, 131.59, 129.55, 128.35, 44.62, 29.82, 28.78 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 29.82; CH2 carbons: 44.62, 28.78; CH carbons: 129.55, 128.35 ppm. HPLC: 10.361 min. (Note: SM has HPLC retention time of 9.409 min.) The ice bath was removed poured into rapidly stirring ice water containing aq. HCl The organic layer was removed washed with NaHCO3 and brine dried with Na2SO4 filtered concentrated purified by silica gel chromatography (Combiflash column, 98:2 to 95:5 Hexanes: EtOAc) 10.361 min. (Note: SM has HPLC retention time of 9.409 min.)

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

実験手順: Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(4-chloro-phenyl)-butan-2-one. Prepared

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

実験手順: Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(4-chloro-phenyl)-butan-2-one. Prepared

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

実験手順: Sodium hydride (0.4163 g, 17.35 mmol) was added slowly to a NaCl ice bath containing EtOH (5.3 mL, 2.5 M) stirring under N2. 66 (2.4253 g, 13.28 mmol) and diethyloxalate (1.803 g, 13.28 mmol) were mixed together, and then added to the chilled NaOEt solution. After stirring for 5 minutes, the reaction was warmed to room temperature. After 10 minutes, the reaction solidified and an additional 10 mL EtOH was added. After stirring for ˜5 h, the reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 1:1 Hexanes:CH2Cl2): Only pure fractions were combined and concentrated to obtain 67 (1.7561 g, 46.8%): 1H (CDCl3, 400 MHz): δ 14.27 (1H, broad s), 7.22 (2H, d, J=8.3 Hz), 7.10 (2H, d, J=8.3 Hz), 6.32 (1H, s), 4.31 (2H, q, J=7.2 Hz), 2.92 (2H, t, J=7.8 Hz), 2.78 (2H, t, J=7.8 Hz), 1.34 (3H, t, J=7.2 Hz) ppm. 13C (CDCl3, 100 MHz): δ 201.59, 166.07, 161.79, 138.51, 132.00, 128.53, 128.54, 101.72, 62.38, 42.08, 29.60, 13.88 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 13.88; CH2 carbons: 62.38, 42.08, 29.60; CH carbons: 129.53, 128.54, 101.72 ppm. HPLC: 11.103 min. After stirring for 5 minutes After stirring for ˜5 h the reaction was quenched at 0° C. with 1N HCl extracted 2× with CH2Cl2 The combined organics were washed with H2O dried with Na2SO4 filtered concentrated purified by silica gel chromatography (Combiflash column, 1:1 Hexanes:CH2Cl2) concentrated

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

実験手順: 1.6 M Methyl lithium (33.9 mL, 54.17 mmol) was added over 70 min to a stirring 0° C. solution of 3-(4-chlorophenyl)-propionic acid (5.0072 g, 27.08 mmol) in dry Et2O (135 mL, 0.2 M): The ice bath was removed, and the reaction was allowed to stir at room temperature overnight. The reaction was the poured into rapidly stirring ice water containing aq. HCl. The organic layer was removed, washed with NaHCO3 and brine, then dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 98:2 to 95:5 Hexanes:EtOAc) to achieve pure 66 (2.4253 g, 49.0%): 1H (CDCl3, 400 MHz): δ 7.14 (2H, d, J=8.3 Hz), 7.03 (2H, d, J=8.3 Hz), 2.77 (2H, t, J=7.5 Hz), 2.64 (2H, t, J=7.5 Hz), 2.04 (3H, s) ppm. 13C (CDCl3, 100 MHz): δ 207.12, 139.38, 131.59, 129.55, 128.35, 44.62, 29.82, 28.78 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 29.82; CH2 carbons: 44.62, 28.78; CH carbons: 129.55, 128.35 ppm. HPLC: 10.361 min. (Note: SM has HPLC retention time of 9.409 min.) The ice bath was removed poured into rapidly stirring ice water containing aq. HCl The organic layer was removed washed with NaHCO3 and brine dried with Na2SO4 filtered concentrated purified by silica gel chromatography (Combiflash column, 98:2 to 95:5 Hexanes:EtOAc) 10.361 min. (Note: SM has HPLC retention time of 9.409 min.)