哌嗪乙酸乙酯二盐酸盐/1-乙氧羰基甲基哌嗪二盐酸盐

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

实验步骤: In N,N-dimethylformamide (50 ml) was dissolved 1-(tert-butoxycarbonyl)piperazine (942 mg). After the addition of triethylamine (1.40 ml), ethyl bromoacetate (1.13 ml) was added, followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby a colorless foam was obtained. The resulting substance was dissolved in a saturated hydrochloric acid—ethanol solution (10 ml) and the resulting solution was concentrated under reduced pressure. The solid thus precipitated was collected by filtration while being washed with ethyl acetate, whereby the title compound (841 mg) was obtained as a colorless solid. was added The reaction mixture was concentrated under reduced pressure Ethyl acetate was added to the residue the mixture was washed with water The organic layer was dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby a colorless foam was obtained the resulting solution was concentrated under reduced pressure The solid thus precipitated was collected by filtration while being washed with ethyl acetate, whereby the title compound (841 mg) was obtained as a colorless solid

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

实验步骤: To a solution of ethyl 2-(piperazin-1-yl)acetate hydrochloride (400 mg, 1.92 mmol) in DMF (10 mL) was added {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (500 mg), DIEA (440 mg, 3.40 mmol), HATU (460 mg, 1.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by flash chromatography on silica eluting with 4.5% MeOH in DCM to afford 59.4 mg (11%) of ethyl 2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetate as a white solid. LCMS (Method 20) [M+H]+=617.2, RT=2.68 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.07 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 4.07 (q, 2H, J=7.2 Hz), 3.52-3.49 (m, 4H), 3.28 (s, 2H), 3.17-3.16 (m, 1H), 2.59-2.50 (m, 4H), 1.18 (t, 3H, J=7.2 Hz). concentrated under vacuum The residue was purified by flash chromatography on silica eluting with 4.5% MeOH in DCM

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

实验步骤: To a solution of ethyl 2-(piperazin-1-yl)acetate hydrochloride (400 mg, 1.92 mmol) in DMF (10 mL) was added {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (500 mg), DIEA (440 mg, 3.40 mmol), HATU (460 mg, 1.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by flash chromatography on silica eluting with 4.5% MeOH in DCM to afford 59.4 mg (11%) of ethyl 2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetate as a white solid. LCMS (Method 20) [M+H]+=617.2, RT=2.68 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.07 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 4.07 (q, 2H, J=7.2 Hz), 3.52-3.49 (m, 4H), 3.28 (s, 2H), 3.17-3.16 (m, 1H), 2.59-2.50 (m, 4H), 1.18 (t, 3H, J=7.2 Hz). concentrated under vacuum The residue was purified by flash chromatography on silica eluting with 4.5% MeOH in DCM

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

实验步骤: In N,N-dimethylformamide (50 ml) was dissolved 1-(tert-butoxycarbonyl)piperazine (942 mg). After the addition of triethylamine (1.40 ml), ethyl bromoacetate (1.13 ml) was added, followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby a colorless foam was obtained. The resulting substance was dissolved in a saturated hydrochloric acid—ethanol solution (10 ml) and the resulting solution was concentrated under reduced pressure. The solid thus precipitated was collected by filtration while being washed with ethyl acetate, whereby the title compound (841 mg) was obtained as a colorless solid. was added The reaction mixture was concentrated under reduced pressure Ethyl acetate was added to the residue the mixture was washed with water The organic layer was dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby a colorless foam was obtained the resulting solution was concentrated under reduced pressure The solid thus precipitated was collected by filtration while being washed with ethyl acetate, whereby the title compound (841 mg) was obtained as a colorless solid

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

实验步骤: In N,N-dimethylformamide (50 ml) was dissolved 1-(tert-butoxycarbonyl)piperazine (942 mg). After the addition of triethylamine (1.40 ml), ethyl bromoacetate (1.13 ml) was added, followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby a colorless foam was obtained. The resulting substance was dissolved in a saturated hydrochloric acid—ethanol solution (10 ml) and the resulting solution was concentrated under reduced pressure. The solid thus precipitated was collected by filtration while being washed with ethyl acetate, whereby the title compound (841 mg) was obtained as a colorless solid. was added The reaction mixture was concentrated under reduced pressure Ethyl acetate was added to the residue the mixture was washed with water The organic layer was dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby a colorless foam was obtained the resulting solution was concentrated under reduced pressure The solid thus precipitated was collected by filtration while being washed with ethyl acetate, whereby the title compound (841 mg) was obtained as a colorless solid

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

实验步骤: To a solution of ethyl 2-(piperazin-1-yl)acetate hydrochloride (400 mg, 1.92 mmol) in DMF (10 mL) was added {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (500 mg), DIEA (440 mg, 3.40 mmol), HATU (460 mg, 1.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by flash chromatography on silica eluting with 4.5% MeOH in DCM to afford 59.4 mg (11%) of ethyl 2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetate as a white solid. LCMS (Method 20) [M+H]+=617.2, RT=2.68 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.07 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 4.07 (q, 2H, J=7.2 Hz), 3.52-3.49 (m, 4H), 3.28 (s, 2H), 3.17-3.16 (m, 1H), 2.59-2.50 (m, 4H), 1.18 (t, 3H, J=7.2 Hz). concentrated under vacuum The residue was purified by flash chromatography on silica eluting with 4.5% MeOH in DCM

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

实验步骤: In N,N-dimethylformamide (50 ml) was dissolved 1-(tert-butoxycarbonyl)piperazine (942 mg). After the addition of triethylamine (1.40 ml), ethyl bromoacetate (1.13 ml) was added, followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby a colorless foam was obtained. The resulting substance was dissolved in a saturated hydrochloric acid—ethanol solution (10 ml) and the resulting solution was concentrated under reduced pressure. The solid thus precipitated was collected by filtration while being washed with ethyl acetate, whereby the title compound (841 mg) was obtained as a colorless solid. was added The reaction mixture was concentrated under reduced pressure Ethyl acetate was added to the residue the mixture was washed with water The organic layer was dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby a colorless foam was obtained the resulting solution was concentrated under reduced pressure The solid thus precipitated was collected by filtration while being washed with ethyl acetate, whereby the title compound (841 mg) was obtained as a colorless solid