High Performance Liquid Chromatography:Article Title: Modulators of the NMDA receptor
Article Snippet: Preparative HPLC (Method G): Instrument: Gilson GX-215 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: DYA-5 C18 150*25 mm*5 μm; Mobile Phase A: water (0.05% HCl v/v); Mobile phase B: MeCN; Gradient: B from 6% to 36% in 10 min then hold at 100% for 3 min; Flow Rate (ml/min): 25; Column temperature: 35° C. and Wavelength: 220 nm 254 nm.
Article Title: Prodrugs of modulators of the NMDA receptor
Article Snippet: Preparative HPLC (Method J): Instrument: Gilson GX-215 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: DYA-5 C18 150*25 mm*5 μm; Mobile Phase A: water (0.05% HCl v/v); Mobile phase B: MeCN; Gradient: B from 6% to 36% in 10 min then hold at 100% for 3 min; Flow Rate (ml/min): 25; Column temperature: 35° C. and Wavelength: 220 nm 254 nm.
Article Title: LRRK2 inhibitors
Article Snippet: The compound was prepared in a manner similar to Example 1 using 1-(3-((1-((2-oxabicyclo[2.1.1]hexan-1-yl)methyl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-3,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (230 mg, 0.49 mmol), Fe (137 mg, 2.5 mmol), and NH4Cl (131 mg, 2.5 mmol) in EtOH (93 mL) and H2O (13 mL) at 100° C. for 16 h, followed by work-up, and preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Welch Xtimate C18 150×30 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O+10 mM NH4HCO3) Mobile phase B: MeCN; Gradient: B from 27% to 57% in 9 min then hold at 100% for 3 min Flow Rate (mL/min): 30; Column temperature: 30° C.; Wavelength: 220 nm 254 nm) to afford the title compound (37 mg).
Article Title: Substituted pyrimido[1,2-b]pyridazines as positive allosteric modulators of the muscarinic acetylcholine receptor M
Article Snippet: The residue was purified by Combi Flash (silica gel, from 0 to 100%, Ethyl acetate in petroleum ether), followed by preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Xtimate C18 150×40 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O); Mobile phase B: MeCN; Gradient: B from 35% to 55% in 9 min then hold at 100% for 5 min; Flow Rate (ml/min): 60; Column temperature: 30° C.; Wavelength: 220 nm, 254 nm) to give 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (1.4 g).
Article Title: Leucine-rich repeat kinase 2 (LRRK2) inhibitors
Article Snippet: The residue was purified by chromatography on silica gel (eluent: petroleum ether:EtOAc (10 v % MeOH) 100:0→30:70) and the residue was further purified by preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A, column: Welch Xtimate C18 150×30 mm×5 μm, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: MeCN, gradient: B from 47% to 77% in 8 min then hold at 100% for 2 min, flow rate (mL/min): 30, column temperature: 30° C., wavelength: 220 nm 254 nm) give afford 3,6-dichloro-1-(3-((1-(2-ethylpyridin-3-yl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-1H-pyrazolo[3,4-d]pyrimidine (40 mg) of sufficient purity for the subsequent step.
Article Title: LRRK2 inhibitors
Article Snippet: The compound was prepared in a manner similar to Example 1 using 1-(3-((1-((2-oxabicyclo[2.1.1]hexan-1-yl)methyl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-3,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (230 mg, 0.49 mmol), Fe (137 mg, 2.5 mmol), and NH4Cl (131 mg, 2.5 mmol) in EtOH (93 mL) and H2O (13 mL) at 100° C. for 16 h, followed by work-up, and preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Welch Xtimate C18 150×30 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O+10 mM NH4HCO3) Mobile phase B: MeCN; Gradient: B from 27% to 57% in 9 min then hold at 100% for 3 min Flow Rate (mL/min): 30; Column temperature: 30° C.; Wavelength: 220 nm 254 nm) to afford the title compound (37 mg).
Purification:Article Title: Modulators of the NMDA receptor
Article Snippet: Preparative HPLC (Method G): Instrument: Gilson GX-215 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: DYA-5 C18 150*25 mm*5 μm; Mobile Phase A: water (0.05% HCl v/v); Mobile phase B: MeCN; Gradient: B from 6% to 36% in 10 min then hold at 100% for 3 min; Flow Rate (ml/min): 25; Column temperature: 35° C. and Wavelength: 220 nm 254 nm.
Article Title: Prodrugs of modulators of the NMDA receptor
Article Snippet: Preparative HPLC (Method J): Instrument: Gilson GX-215 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: DYA-5 C18 150*25 mm*5 μm; Mobile Phase A: water (0.05% HCl v/v); Mobile phase B: MeCN; Gradient: B from 6% to 36% in 10 min then hold at 100% for 3 min; Flow Rate (ml/min): 25; Column temperature: 35° C. and Wavelength: 220 nm 254 nm.
Article Title: LRRK2 inhibitors
Article Snippet: The compound was prepared in a manner similar to Example 1 using 1-(3-((1-((2-oxabicyclo[2.1.1]hexan-1-yl)methyl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-3,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (230 mg, 0.49 mmol), Fe (137 mg, 2.5 mmol), and NH4Cl (131 mg, 2.5 mmol) in EtOH (93 mL) and H2O (13 mL) at 100° C. for 16 h, followed by work-up, and preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Welch Xtimate C18 150×30 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O+10 mM NH4HCO3) Mobile phase B: MeCN; Gradient: B from 27% to 57% in 9 min then hold at 100% for 3 min Flow Rate (mL/min): 30; Column temperature: 30° C.; Wavelength: 220 nm 254 nm) to afford the title compound (37 mg).
Article Title: Substituted pyrimido[1,2-b]pyridazines as positive allosteric modulators of the muscarinic acetylcholine receptor M
Article Snippet: The residue was purified by Combi Flash (silica gel, from 0 to 100%, Ethyl acetate in petroleum ether), followed by preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Xtimate C18 150×40 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O); Mobile phase B: MeCN; Gradient: B from 35% to 55% in 9 min then hold at 100% for 5 min; Flow Rate (ml/min): 60; Column temperature: 30° C.; Wavelength: 220 nm, 254 nm) to give 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (1.4 g).
Article Title: Leucine-rich repeat kinase 2 (LRRK2) inhibitors
Article Snippet: The residue was purified by chromatography on silica gel (eluent: petroleum ether:EtOAc (10 v % MeOH) 100:0→30:70) and the residue was further purified by preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A, column: Welch Xtimate C18 150×30 mm×5 μm, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: MeCN, gradient: B from 47% to 77% in 8 min then hold at 100% for 2 min, flow rate (mL/min): 30, column temperature: 30° C., wavelength: 220 nm 254 nm) give afford 3,6-dichloro-1-(3-((1-(2-ethylpyridin-3-yl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-1H-pyrazolo[3,4-d]pyrimidine (40 mg) of sufficient purity for the subsequent step.
Article Title: LRRK2 inhibitors
Article Snippet: The compound was prepared in a manner similar to Example 1 using 1-(3-((1-((2-oxabicyclo[2.1.1]hexan-1-yl)methyl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-3,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (230 mg, 0.49 mmol), Fe (137 mg, 2.5 mmol), and NH4Cl (131 mg, 2.5 mmol) in EtOH (93 mL) and H2O (13 mL) at 100° C. for 16 h, followed by work-up, and preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Welch Xtimate C18 150×30 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O+10 mM NH4HCO3) Mobile phase B: MeCN; Gradient: B from 27% to 57% in 9 min then hold at 100% for 3 min Flow Rate (mL/min): 30; Column temperature: 30° C.; Wavelength: 220 nm 254 nm) to afford the title compound (37 mg).
Chromatography:Article Title: Modulators of the NMDA receptor
Article Snippet: Preparative HPLC (Method G): Instrument: Gilson GX-215 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: DYA-5 C18 150*25 mm*5 μm; Mobile Phase A: water (0.05% HCl v/v); Mobile phase B: MeCN; Gradient: B from 6% to 36% in 10 min then hold at 100% for 3 min; Flow Rate (ml/min): 25; Column temperature: 35° C. and Wavelength: 220 nm 254 nm.
Article Title: Prodrugs of modulators of the NMDA receptor
Article Snippet: Preparative HPLC (Method J): Instrument: Gilson GX-215 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: DYA-5 C18 150*25 mm*5 μm; Mobile Phase A: water (0.05% HCl v/v); Mobile phase B: MeCN; Gradient: B from 6% to 36% in 10 min then hold at 100% for 3 min; Flow Rate (ml/min): 25; Column temperature: 35° C. and Wavelength: 220 nm 254 nm.
Article Title: LRRK2 inhibitors
Article Snippet: The compound was prepared in a manner similar to Example 1 using 1-(3-((1-((2-oxabicyclo[2.1.1]hexan-1-yl)methyl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-3,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (230 mg, 0.49 mmol), Fe (137 mg, 2.5 mmol), and NH4Cl (131 mg, 2.5 mmol) in EtOH (93 mL) and H2O (13 mL) at 100° C. for 16 h, followed by work-up, and preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Welch Xtimate C18 150×30 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O+10 mM NH4HCO3) Mobile phase B: MeCN; Gradient: B from 27% to 57% in 9 min then hold at 100% for 3 min Flow Rate (mL/min): 30; Column temperature: 30° C.; Wavelength: 220 nm 254 nm) to afford the title compound (37 mg).
Article Title: Substituted pyrimido[1,2-b]pyridazines as positive allosteric modulators of the muscarinic acetylcholine receptor M
Article Snippet: The residue was purified by Combi Flash (silica gel, from 0 to 100%, Ethyl acetate in petroleum ether), followed by preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Xtimate C18 150×40 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O); Mobile phase B: MeCN; Gradient: B from 35% to 55% in 9 min then hold at 100% for 5 min; Flow Rate (ml/min): 60; Column temperature: 30° C.; Wavelength: 220 nm, 254 nm) to give 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (1.4 g).
Article Title: Leucine-rich repeat kinase 2 (LRRK2) inhibitors
Article Snippet: The residue was purified by chromatography on silica gel (eluent: petroleum ether:EtOAc (10 v % MeOH) 100:0→30:70) and the residue was further purified by preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A, column: Welch Xtimate C18 150×30 mm×5 μm, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: MeCN, gradient: B from 47% to 77% in 8 min then hold at 100% for 2 min, flow rate (mL/min): 30, column temperature: 30° C., wavelength: 220 nm 254 nm) give afford 3,6-dichloro-1-(3-((1-(2-ethylpyridin-3-yl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-1H-pyrazolo[3,4-d]pyrimidine (40 mg) of sufficient purity for the subsequent step.
Article Title: LRRK2 inhibitors
Article Snippet: The compound was prepared in a manner similar to Example 1 using 1-(3-((1-((2-oxabicyclo[2.1.1]hexan-1-yl)methyl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-3,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (230 mg, 0.49 mmol), Fe (137 mg, 2.5 mmol), and NH4Cl (131 mg, 2.5 mmol) in EtOH (93 mL) and H2O (13 mL) at 100° C. for 16 h, followed by work-up, and preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Welch Xtimate C18 150×30 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O+10 mM NH4HCO3) Mobile phase B: MeCN; Gradient: B from 27% to 57% in 9 min then hold at 100% for 3 min Flow Rate (mL/min): 30; Column temperature: 30° C.; Wavelength: 220 nm 254 nm) to afford the title compound (37 mg).
Nuclear Magnetic Resonance:Article Title: Modulators of the NMDA receptor
Article Snippet: Preparative HPLC (Method G): Instrument: Gilson GX-215 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: DYA-5 C18 150*25 mm*5 μm; Mobile Phase A: water (0.05% HCl v/v); Mobile phase B: MeCN; Gradient: B from 6% to 36% in 10 min then hold at 100% for 3 min; Flow Rate (ml/min): 25; Column temperature: 35° C. and Wavelength: 220 nm 254 nm.
Article Title: Prodrugs of modulators of the NMDA receptor
Article Snippet: Preparative HPLC (Method J): Instrument: Gilson GX-215 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: DYA-5 C18 150*25 mm*5 μm; Mobile Phase A: water (0.05% HCl v/v); Mobile phase B: MeCN; Gradient: B from 6% to 36% in 10 min then hold at 100% for 3 min; Flow Rate (ml/min): 25; Column temperature: 35° C. and Wavelength: 220 nm 254 nm.
Article Title: LRRK2 inhibitors
Article Snippet: The compound was prepared in a manner similar to Example 1 using 1-(3-((1-((2-oxabicyclo[2.1.1]hexan-1-yl)methyl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-3,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (230 mg, 0.49 mmol), Fe (137 mg, 2.5 mmol), and NH4Cl (131 mg, 2.5 mmol) in EtOH (93 mL) and H2O (13 mL) at 100° C. for 16 h, followed by work-up, and preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Welch Xtimate C18 150×30 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O+10 mM NH4HCO3) Mobile phase B: MeCN; Gradient: B from 27% to 57% in 9 min then hold at 100% for 3 min Flow Rate (mL/min): 30; Column temperature: 30° C.; Wavelength: 220 nm 254 nm) to afford the title compound (37 mg).
Article Title: Substituted pyrimido[1,2-b]pyridazines as positive allosteric modulators of the muscarinic acetylcholine receptor M
Article Snippet: The residue was purified by Combi Flash (silica gel, from 0 to 100%, Ethyl acetate in petroleum ether), followed by preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Xtimate C18 150×40 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O); Mobile phase B: MeCN; Gradient: B from 35% to 55% in 9 min then hold at 100% for 5 min; Flow Rate (ml/min): 60; Column temperature: 30° C.; Wavelength: 220 nm, 254 nm) to give 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (1.4 g).
Article Title: Leucine-rich repeat kinase 2 (LRRK2) inhibitors
Article Snippet: The residue was purified by chromatography on silica gel (eluent: petroleum ether:EtOAc (10 v % MeOH) 100:0→30:70) and the residue was further purified by preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A, column: Welch Xtimate C18 150×30 mm×5 μm, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: MeCN, gradient: B from 47% to 77% in 8 min then hold at 100% for 2 min, flow rate (mL/min): 30, column temperature: 30° C., wavelength: 220 nm 254 nm) give afford 3,6-dichloro-1-(3-((1-(2-ethylpyridin-3-yl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-1H-pyrazolo[3,4-d]pyrimidine (40 mg) of sufficient purity for the subsequent step.
Article Title: LRRK2 inhibitors
Article Snippet: The compound was prepared in a manner similar to Example 1 using 1-(3-((1-((2-oxabicyclo[2.1.1]hexan-1-yl)methyl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-3,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (230 mg, 0.49 mmol), Fe (137 mg, 2.5 mmol), and NH4Cl (131 mg, 2.5 mmol) in EtOH (93 mL) and H2O (13 mL) at 100° C. for 16 h, followed by work-up, and preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Welch Xtimate C18 150×30 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O+10 mM NH4HCO3) Mobile phase B: MeCN; Gradient: B from 27% to 57% in 9 min then hold at 100% for 3 min Flow Rate (mL/min): 30; Column temperature: 30° C.; Wavelength: 220 nm 254 nm) to afford the title compound (37 mg).
Residue:Article Title: Modulators of the NMDA receptor
Article Snippet: Preparative HPLC (Method G): Instrument: Gilson GX-215 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: DYA-5 C18 150*25 mm*5 μm; Mobile Phase A: water (0.05% HCl v/v); Mobile phase B: MeCN; Gradient: B from 6% to 36% in 10 min then hold at 100% for 3 min; Flow Rate (ml/min): 25; Column temperature: 35° C. and Wavelength: 220 nm 254 nm.
Article Title: Prodrugs of modulators of the NMDA receptor
Article Snippet: Preparative HPLC (Method J): Instrument: Gilson GX-215 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: DYA-5 C18 150*25 mm*5 μm; Mobile Phase A: water (0.05% HCl v/v); Mobile phase B: MeCN; Gradient: B from 6% to 36% in 10 min then hold at 100% for 3 min; Flow Rate (ml/min): 25; Column temperature: 35° C. and Wavelength: 220 nm 254 nm.
Article Title: LRRK2 inhibitors
Article Snippet: The compound was prepared in a manner similar to Example 1 using 1-(3-((1-((2-oxabicyclo[2.1.1]hexan-1-yl)methyl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-3,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (230 mg, 0.49 mmol), Fe (137 mg, 2.5 mmol), and NH4Cl (131 mg, 2.5 mmol) in EtOH (93 mL) and H2O (13 mL) at 100° C. for 16 h, followed by work-up, and preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Welch Xtimate C18 150×30 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O+10 mM NH4HCO3) Mobile phase B: MeCN; Gradient: B from 27% to 57% in 9 min then hold at 100% for 3 min Flow Rate (mL/min): 30; Column temperature: 30° C.; Wavelength: 220 nm 254 nm) to afford the title compound (37 mg).
Article Title: Substituted pyrimido[1,2-b]pyridazines as positive allosteric modulators of the muscarinic acetylcholine receptor M
Article Snippet: The residue was purified by Combi Flash (silica gel, from 0 to 100%, Ethyl acetate in petroleum ether), followed by preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Xtimate C18 150×40 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O); Mobile phase B: MeCN; Gradient: B from 35% to 55% in 9 min then hold at 100% for 5 min; Flow Rate (ml/min): 60; Column temperature: 30° C.; Wavelength: 220 nm, 254 nm) to give 7-((2R,4S)-4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one (1.4 g).
Article Title: Leucine-rich repeat kinase 2 (LRRK2) inhibitors
Article Snippet: The residue was purified by chromatography on silica gel (eluent: petroleum ether:EtOAc (10 v % MeOH) 100:0→30:70) and the residue was further purified by preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A, column: Welch Xtimate C18 150×30 mm×5 μm, mobile phase A: water (NH3H2O+NH4HCO3), mobile phase B: MeCN, gradient: B from 47% to 77% in 8 min then hold at 100% for 2 min, flow rate (mL/min): 30, column temperature: 30° C., wavelength: 220 nm 254 nm) give afford 3,6-dichloro-1-(3-((1-(2-ethylpyridin-3-yl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-1H-pyrazolo[3,4-d]pyrimidine (40 mg) of sufficient purity for the subsequent step.
Article Title: LRRK2 inhibitors
Article Snippet: The compound was prepared in a manner similar to Example 1 using 1-(3-((1-((2-oxabicyclo[2.1.1]hexan-1-yl)methyl)-5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)-3,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (230 mg, 0.49 mmol), Fe (137 mg, 2.5 mmol), and NH4Cl (131 mg, 2.5 mmol) in EtOH (93 mL) and H2O (13 mL) at 100° C. for 16 h, followed by work-up, and preparative HPLC (Instrument: Gilson GX-215 Liquid Handler, SHIMADZU LC-20AP, SHIMADZU SPD-20A; Column: Welch Xtimate C18 150×30 mm×5 μm; Mobile Phase A: water (0.05% NH3H2O+10 mM NH4HCO3) Mobile phase B: MeCN; Gradient: B from 27% to 57% in 9 min then hold at 100% for 3 min Flow Rate (mL/min): 30; Column temperature: 30° C.; Wavelength: 220 nm 254 nm) to afford the title compound (37 mg).
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