2,3-dihydro-1H-quinolin-4-one

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.04 g of 4-oxo-1,2,3,4-tetrahydroquinoline was dissolved in 20 mL of tetrahydrofuran at 25° C. To the solution were added 5.6 mL of benzyloxycarbonyl chloride, 15 mL of water and 4.73 g of potassium carbonate under ice-cooling, and the mixture was stirred at 25° C. for 24 hours. To the reaction solution was added ethyl acetate, and the organic layer was separated, dried over magnesium sulfate, and then filtered. The filtrate was concentrated and the residue was dissolved in 35 mL of isopropyl alcohol under heating. The solution was cooled gradually, and the precipitated crystals were collected by filtration under ice-cooled condition. The resulting crystals were washed with 25 mL of cold isopropyl alcohol, and then dried at 50° C. for 16 hours to give 8.98 g of 1-benzyloxycarbonyl-4-oxo-1,2,3,4-tetrahydroquinoline (93% yield). cooling the organic layer was separated dried over magnesium sulfate filtered The filtrate was concentrated the residue was dissolved in 35 mL of isopropyl alcohol under heating The solution was cooled gradually the precipitated crystals were collected by filtration under ice- cooled condition The resulting crystals were washed with 25 mL of cold isopropyl alcohol dried at 50° C. for 16 hours

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 20 mL of tetrahydrofuran was dissolved 5.04 g of 2,3-dihydro-4-quinolone at 25° C., then, to the solution were added 5.6 mL of benzyloxycarbonyl chloride, 15 mL of water and 4.73 g of potassium carbonate under ice-cooling, and said mixture was stirred at 25° C. for 24 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate, and then, filtered. The filtrate was concentrated, and the residue was dissolved in 35 mL of isopropyl alcohol under heating. Said solution was gradually cooled, and the precipitated crystals were collected by filtration under ice-cooling. The resulting crystals were washed with 25 mL of cold isopropyl alcohol, and dried at 50° C. for 16 hours to obtain 8.98 g (Yield: 93%) of 1-benzyloxycarbonyl-2,3-dihydro-4-quinolone. cooling the organic layer was separated dried over anhydrous magnesium sulfate filtered The filtrate was concentrated the residue was dissolved in 35 mL of isopropyl alcohol under heating was gradually cooled the precipitated crystals were collected by filtration under ice- cooling The resulting crystals were washed with 25 mL of cold isopropyl alcohol dried at 50° C. for 16 hours

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 20 mL of tetrahydrofuran was dissolved 5.04 g of 2,3-dihydro-4-quinolone at 25° C., then, to the solution were added 5.6 mL of benzyloxycarbonyl chloride, 15 mL of water and 4.73 g of potassium carbonate under ice-cooling, and said mixture was stirred at 25° C. for 24 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate, and then, filtered. The filtrate was concentrated, and the residue was dissolved in 35 mL of isopropyl alcohol under heating. Said solution was gradually cooled, and the precipitated crystals were collected by filtration under ice-cooling. The resulting crystals were washed with 25 mL of cold isopropyl alcohol, and dried at 50° C. for 16 hours to obtain 8.98 g (Yield: 93%) of 1-benzyloxycarbonyl-2,3-dihydro-4-quinolone. cooling the organic layer was separated dried over anhydrous magnesium sulfate filtered The filtrate was concentrated the residue was dissolved in 35 mL of isopropyl alcohol under heating was gradually cooled the precipitated crystals were collected by filtration under ice- cooling The resulting crystals were washed with 25 mL of cold isopropyl alcohol dried at 50° C. for 16 hours

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzoyl chloride (0.30 ml, 2.58 mmol) is added dropwise to a solution of 2,3-dihydro-1H-quinolin-4-one (260 mg, 1.77 mmol), triethylamine (0.32 ml, 2.30 mmol) and DMAP (10 mg) in CH2Cl2 at 0° C. The resulting mixture is stirred at room temperature for overnight. Water is added and the mixture is extracted with CH2Cl2 and washed with brine, dried over anhydrous sodium sulfate. After concentration, a residue is yielded, which is used “as is” for the next reaction without further purification. the mixture is extracted with CH2Cl2 washed with brine dried over anhydrous sodium sulfate After concentration a residue is yielded for the next reaction without further purification

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of 3-phenylamino-propionic acid (1.22 g, 7.39 mmol) in Eaton's reagent (40 mL) is stirred at 70° C. for overnight. The resulting mixture is poured into ice and basified by the slow addition of NaOH (50%) solution. The basified mixture is extracted with ethyl acetate and washed by brine, and dried over anhydrous sodium sulfate. After concentration, the residue is purified by flash chromatography, and gives the title compound (0.5 g, 46.3% yield). The resulting mixture is poured into ice The basified mixture is extracted with ethyl acetate washed by brine dried over anhydrous sodium sulfate After concentration the residue is purified by flash chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,2,3,4-Tetrahydroquinolin-4-one (2.00 g) and 114 mg of p-toluenesulfonic acid were dissolved in 30 ml of acetic acid isopropenyl ether, and the solution was heated under reflux for 2 days simultaneously evaporating acetic acid. Then, saturated sodium bicarbonate aqueous solution was added and the mixture was extracted with ethyl acetate, followed by drying on anhydrous magnesium sulfate. After evaporating the solvent, the resulting residue was crystallized from chloroform-diethyl ether-hexane to obtain 518 mg of 4-acetoxy-1-tosyl-1,2-dihydroquinoline. the solution was heated the mixture was extracted with ethyl acetate by drying on anhydrous magnesium sulfate After evaporating the solvent the resulting residue was crystallized from chloroform-diethyl ether-hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,2,3,4-Tetrahydroquinolin-4-one (2.00 g) and 114 mg of p-toluenesulfonic acid were dissolved in 30 ml of acetic acid isopropenyl ether, and the solution was heated under reflux for 2 days simultaneously evaporating acetic acid. Then, saturated sodium bicarbonate aqueous solution was added and the mixture was extracted with ethyl acetate, followed by drying on anhydrous magnesium sulfate. After evaporating the solvent, the resulting residue was crystallized from chloroform-diethyl ether-hexane to obtain 518 mg of 4-acetoxy-1-tosyl-1,2-dihydroquinoline. the solution was heated the mixture was extracted with ethyl acetate by drying on anhydrous magnesium sulfate After evaporating the solvent the resulting residue was crystallized from chloroform-diethyl ether-hexane

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The internal pressure of a reaction vessel was reduced (−0.09 MPa or less) and thereto was charged nitrogen gas and added toluene (120 mL) at room temperature and then added tripotassium phosphate (41.51 g) under stirring. After cooling the mixture (internal temperature: 20° C. or lower), thereto was added sodium sulfate decahydrate (13.425 g) at the same temperature. To the mixture were added 1-(2-bromo-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (30.0 g), 4-oxo-1,2,3,4-tetrahydroquinoline (10.07 g), palladium acetate (219 mg) and Xantphos (849 mg), and the inside of the vessel was washed with toluene (15 mL). The internal pressure of the vessel was reduced (−0.09 MPa) and maintained for 5 minutes, and then nitrogen gas was charged thereto to restore the internal pressure (the procedure was carried out three times). The mixture was warmed to 45° C. to 65° C. under nitrogen stream and stirred at the same temperature for 15 hours. In the course of reaction, the internal temperature was maintained at about 47° C. over the initial 10 hours and, after that, maintained at about 57° C. After cooling the reaction mixture (internal temperature: 40° C.), thereto was added dropwise an aqueous citric acid solution (25.04 g of citric acid in 120 mL of water) at the same temperature, and thereto was added dropwise chloroform (150 mL). After warming the mixture at 45±5° C. (internal temperature), the mixture was filtered through Celite at 20° C. or more. The organic layer was separated from the filtrate and to the filtrate was added water (90 mL) at 20° C. or more and the mixture was stirred nearly for 10 minutes. The organic layer was separated and concentrated in vacuo at 60° C. or lower and to the residue was added toluene (90 mL) and the mixture was concentrated in vacuo at 60° C. or lower. The residue was allowed to stand at 20±5° C. or lower (internal temperature) nearly for one hour and the precipitated crystals were collected by filtration. The crystals were washed with a cold methanol (5±5° C., 60 mL) to obtain a toluene monosolvate of the captioned compound [c-11] as crystals. To the crystals was added a mixture of chloroform (60 mL) and methanol (6 mL) at 30±5° C. and the mixture was stirred nearly for 15 minutes. Thereto was added dropwise methanol (54 mL) at 15±5° C. over a period of one hour and the mixture was stirred at the same temperature for one hour. Subsequently, to the mixture was added methanol (39 mL) and the mixture was cooled to 5±5° C. and stirred at the same temperature for one hour. The precipitated crystals (a chloroform monosolvate of the captioned compound [c-11]) were collected by filtration, washed with a cold methanol (5±5° C., 90 mL) and dried in vacuo at 60° C. or lower to obtain the captioned compound (free form, 34.3 g) as pale yellow crystals (yield: 86%). The internal pressure of a reaction vessel was reduced (−0.09 MPa or less) and thereto was charged nitrogen gas the inside of the vessel was washed with toluene (15 mL) maintained for 5 minutes nitrogen gas was charged The mixture was warmed to 45° C. to 65° C. under nitrogen stream In the course of reaction the internal temperature was maintained at about 47° C. over the initial 10 hours after that, maintained at about 57° C After cooling the reaction mixture (internal temperature: 40° C.) After warming the mixture at 45±5° C. (internal temperature) the mixture was filtered through Celite at 20° C. or more The organic layer was separated from the filtrate and to the filtrate was added water (90 mL) at 20° C. or more the mixture was stirred nearly for 10 minutes The organic layer was separated concentrated in vacuo at 60° C. lower and to the residue was added toluene (90 mL) the mixture was concentrated in vacuo at 60° C. to stand at 20±5° C. lower (internal temperature) nearly for one hour the precipitated crystals were collected by filtration The crystals were washed with a cold methanol (5±5° C., 60 mL) to obtain a toluene monosolvate of the captioned compound [c-11] as crystals To the crystals was added the mixture was stirred nearly for 15 minutes the mixture was stirred at the same temperature for one hour the mixture was cooled to 5±5° C. stirred at the same temperature for one hour The precipitated crystals (a chloroform monosolvate of the captioned compound [c-11]) were collected by filtration washed with a cold methanol (5±5° C., 90 mL) dried in vacuo at 60° C.

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The internal pressure of a reaction vessel was reduced (−0.09 MPa or less) and thereto was charged nitrogen gas and added toluene (120 mL) at room temperature and then added tripotassium phosphate (41.51 g) under stirring. After cooling the mixture (internal temperature: 20° C. or lower), thereto was added sodium sulfate decahydrate (13.425 g) at the same temperature. To the mixture were added 1-(2-bromo-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (30.0 g), 4-oxo-1,2,3,4-tetrahydroquinoline (10.07 g), palladium acetate (219 mg) and Xantphos (849 mg), and the inside of the vessel was washed with toluene (15 mL). The internal pressure of the vessel was reduced (−0.09 MPa) and maintained for 5 minutes, and then nitrogen gas was charged thereto to restore the internal pressure (the procedure was carried out three times). The mixture was warmed to 45° C. to 65° C. under nitrogen stream and stirred at the same temperature for 15 hours. In the course of reaction, the internal temperature was maintained at about 47° C. over the initial 10 hours and, after that, maintained at about 57° C. After cooling the reaction mixture (internal temperature: 40° C.), thereto was added dropwise an aqueous citric acid solution (25.04 g of citric acid in 120 mL of water) at the same temperature, and thereto was added dropwise chloroform (150 mL). After warming the mixture at 45±5° C. (internal temperature), the mixture was filtered through Celite at 20° C. or more. The organic layer was separated from the filtrate and to the filtrate was added water (90 mL) at 20° C. or more and the mixture was stirred nearly for 10 minutes. The organic layer was separated and concentrated in vacuo at 60° C. or lower and to the residue was added toluene (90 mL) and the mixture was concentrated in vacuo at 60° C. or lower. The residue was allowed to stand at 20±5° C. or lower (internal temperature) nearly for one hour and the precipitated crystals were collected by filtration. The crystals were washed with a cold methanol (5±5° C., 60 mL) to obtain a toluene monosolvate of the captioned compound [c-11] as crystals. To the crystals was added a mixture of chloroform (60 mL) and methanol (6 mL) at 30±5° C. and the mixture was stirred nearly for 15 minutes. Thereto was added dropwise methanol (54 mL) at 15±5° C. over a period of one hour and the mixture was stirred at the same temperature for one hour. Subsequently, to the mixture was added methanol (39 mL) and the mixture was cooled to 5±5° C. and stirred at the same temperature for one hour. The precipitated crystals (a chloroform monosolvate of the captioned compound [c-11]) were collected by filtration, washed with a cold methanol (5±5° C., 90 mL) and dried in vacuo at 60° C. or lower to obtain the captioned compound (free form, 34.3 g) as pale yellow crystals (yield: 86%). The internal pressure of a reaction vessel was reduced (−0.09 MPa or less) and thereto was charged nitrogen gas the inside of the vessel was washed with toluene (15 mL) maintained for 5 minutes nitrogen gas was charged The mixture was warmed to 45° C. to 65° C. under nitrogen stream In the course of reaction the internal temperature was maintained at about 47° C. over the initial 10 hours after that, maintained at about 57° C After cooling the reaction mixture (internal temperature: 40° C.) After warming the mixture at 45±5° C. (internal temperature) the mixture was filtered through Celite at 20° C. or more The organic layer was separated from the filtrate and to the filtrate was added water (90 mL) at 20° C. or more the mixture was stirred nearly for 10 minutes The organic layer was separated concentrated in vacuo at 60° C. lower and to the residue was added toluene (90 mL) the mixture was concentrated in vacuo at 60° C. to stand at 20±5° C. lower (internal temperature) nearly for one hour the precipitated crystals were collected by filtration The crystals were washed with a cold methanol (5±5° C., 60 mL) to obtain a toluene monosolvate of the captioned compound [c-11] as crystals To the crystals was added the mixture was stirred nearly for 15 minutes the mixture was stirred at the same temperature for one hour the mixture was cooled to 5±5° C. stirred at the same temperature for one hour The precipitated crystals (a chloroform monosolvate of the captioned compound [c-11]) were collected by filtration washed with a cold methanol (5±5° C., 90 mL) dried in vacuo at 60° C.

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.04 g of 4-oxo-1,2,3,4-tetrahydroquinoline was dissolved in 20 mL of tetrahydrofuran at 25° C. To the solution were added 5.6 mL of benzyloxycarbonyl chloride, 15 mL of water and 4.73 g of potassium carbonate under ice-cooling, and the mixture was stirred at 25° C. for 24 hours. To the reaction solution was added ethyl acetate, and the organic layer was separated, dried over magnesium sulfate, and then filtered. The filtrate was concentrated and the residue was dissolved in 35 mL of isopropyl alcohol under heating. The solution was cooled gradually, and the precipitated crystals were collected by filtration under ice-cooled condition. The resulting crystals were washed with 25 mL of cold isopropyl alcohol, and then dried at 50° C. for 16 hours to give 8.98 g of 1-benzyloxycarbonyl-4-oxo-1,2,3,4-tetrahydroquinoline (93% yield). cooling the organic layer was separated dried over magnesium sulfate filtered The filtrate was concentrated the residue was dissolved in 35 mL of isopropyl alcohol under heating The solution was cooled gradually the precipitated crystals were collected by filtration under ice- cooled condition The resulting crystals were washed with 25 mL of cold isopropyl alcohol dried at 50° C. for 16 hours

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.04 g of 4-oxo-1,2,3,4-tetrahydroquinoline was dissolved in 20 mL of tetrahydrofuran at 25° C. To the solution were added 5.6 mL of benzyloxycarbonyl chloride, 15 mL of water and 4.73 g of potassium carbonate under ice-cooling, and the mixture was stirred at 25° C. for 24 hours. To the reaction solution was added ethyl acetate, and the organic layer was separated, dried over magnesium sulfate, and then filtered. The filtrate was concentrated and the residue was dissolved in 35 mL of isopropyl alcohol under heating. The solution was cooled gradually, and the precipitated crystals were collected by filtration under ice-cooled condition. The resulting crystals were washed with 25 mL of cold isopropyl alcohol, and then dried at 50° C. for 16 hours to give 8.98 g of 1-benzyloxycarbonyl-4-oxo-1,2,3,4-tetrahydroquinoline (93% yield). cooling the organic layer was separated dried over magnesium sulfate filtered The filtrate was concentrated the residue was dissolved in 35 mL of isopropyl alcohol under heating The solution was cooled gradually the precipitated crystals were collected by filtration under ice- cooled condition The resulting crystals were washed with 25 mL of cold isopropyl alcohol dried at 50° C. for 16 hours