2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-quinolin-4-amine

2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-quinolin-4-amine Chemische Eigenschaften,Einsatz,Produktion Methoden

• Originator

  Abanquil,Onbio Inc.

• Manufacturing Process

  Synthesis of 1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethanone:
  To a stirred solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (3.00 g, 15.4 mmol, 1.00 equiv.) in anhydrous pyridine (100 mL) under argon at room temperature was added acetic anhydride (14.5 mL, 154 mmol, 10.0 equiv.) over 15 min. The resulting mixture was stirred at room temperature for 2 h, and then at reflux for 6 h. The volatiles were removed by rotary evaporation at 80°C under high vacuum. The residue was flash chromatographed on silica gel (MeOH-CH2Cl2 8:92) to afford 3.21 g (89%) of 1-(6,7-dimethoxy-3,4- dihydro-1H-isoquinolin-2-yl)ethanone as a viscous brown oil. The H-NMR spectrum reflected the presence of two slowly interconverting conformers in a ratio of 1.2:1 at room temperature.
  Synthesis of 2-[1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl)ethylidineamino]-4,5-dimethoxybenzonitrile:
  To a stirred solution of 1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl)ethanone (1.00 g, 4.25 mmol, 1.00 equiv.) in CHCl3 at room temperature under argon was added POCl3 (143 μL, 1.53 mmol, 0.36 equiv.). After 10 min, 2-amino-4,5-dimethoxybenzonitrile (763 mg, 4.28 mmol, 1.01 equiv.) was added and the mixture was heated at reflux overnight. The mixture was cooled to room temperature and poured into 1 M aq. NaOH solution (50 mL), and the aqueous phase was extracted with CH2Cl2. The combined organic solutions were dried over MgSO4 and concentrated. The residue was flash chromatographed on silica gel (MeOH-CH2Cl2, 2 5:95) to afford 482 mg (28%) of 2-[1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethylidineamino]-4,5- dimethoxybenzonitrile as an yellow solid.
  Synthesis of 2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7- dimethoxyquinolin-4-ylamine hemifumarate hydrate (abanoquil):
  To a stirred solution of 2-[1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl)ethylidineamino]-4,5-dimethoxybenzonitrile (471 mg, 1.19 mmol, 1.00 equiv.) in refluxing anhydrous N,N-dimethylacetamide (24 mL) under argon was added ZnCl2 (339 mg, 2.49 mmol, 2.10 equiv.) in three portions over 1 h. The solvent was removed by distillation at 70°C under high vacuum. Ether (40 mL) was added to the residue, which was broken up with a stirring rod, and the mixture was stirred at 0°C to precipitate the product. The supernatant was discarded, and the precipitate was washed twice more at 0°C with ether. The solid residue was stirred with 1 M aq. NaOH (25 mL) and CH2Cl2 (25 mL) for 10 min, and the aqueous phase was extracted with CH2Cl2. The combined organic solutions were dried over MgSO4 and concentrated to give 493 mg of brown oil, which was flash chromatographed on silica gel (MeOH-CH2Cl2,12:88 followed by 2-propylamine-CH2Cl2, 5:95) to afford 151 mg (38%) of 2-(6,7- dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxyquinolin-4-ylamine as a tan solid.
  To a solution of 2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7- dimethoxyquinolin-4-ylamine (150 mg) in hot CH2Cl2 (4.5 mL) and MeOH (1.5 mL) was added a solution of fumaric acid (22.8 mg, 0.196 mmol, 0.50 equiv.) in hot MeOH (3.0 mL). The resulting mixture was concentrated and the product was recrystallized from MeOH with hot filtration to afford, after filtration, 85 mg of light brown solid: m.p. 239-240°C.

• Therapeutic Function

  Antiarrhythmic, Coronary vasodilator

2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-quinolin-4-amine Upstream-Materialien And Downstream Produkte

2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-quinolin-4-amine Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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