1-fluoro-2-(1-fluoropyridin-1-ium-2-yl)pyridin-1-ium;ditetrafluoroborate

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 393 mg (1.10 mmol) of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was added to 7 ml of an acetonitrile solution containing 458 mg (1.84 mmol) of the 2, N,N-trimethyl-5-morpholin-4-ylbenzamide obtained in Step B of Example 80 under cooling on ice. The obtained mixture was stirred at 0° C. for 1 hour, then at a room temperature for 1 hour, then at 50° C. for 1 hour, then at 80° C. for 2.5 days, and then under heating to reflux for 2 hours. Thereafter, 357 mg (1.0 mmol) of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was further added to the reaction solution, and the obtained mixture was further stirred for 20 minutes. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was then concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 to 1:1), so as to obtain 25.8 mg (5.3%) of 4-fluoro-2,N,N-trimethyl-5-morpholin-4-ylbenzamide in the form of an oily substance, and also obtain 35.1 mg (7.2%) of 2-fluoro-6,N,N-trimethyl-3-morpholin-4-ylbenzamide in the form of an oily substance. under cooling on ice at a room temperature for 1 hour at 50° C. for 1 hour at 80° C. for 2.5 days under heating to reflux for 2 hours the obtained mixture was further stirred for 20 minutes the mixture was then extracted with ethyl acetate The extract was dried over anhydrous sodium sulfate was then concentrated The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 to 1:1)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 393 mg (1.10 mmol) of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was added to 7 ml of an acetonitrile solution containing 458 mg (1.84 mmol) of the 2, N,N-trimethyl-5-morpholin-4-ylbenzamide obtained in Step B of Example 80 under cooling on ice. The obtained mixture was stirred at 0° C. for 1 hour, then at a room temperature for 1 hour, then at 50° C. for 1 hour, then at 80° C. for 2.5 days, and then under heating to reflux for 2 hours. Thereafter, 357 mg (1.0 mmol) of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was further added to the reaction solution, and the obtained mixture was further stirred for 20 minutes. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was then concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 to 1:1), so as to obtain 25.8 mg (5.3%) of 4-fluoro-2,N,N-trimethyl-5-morpholin-4-ylbenzamide in the form of an oily substance, and also obtain 35.1 mg (7.2%) of 2-fluoro-6,N,N-trimethyl-3-morpholin-4-ylbenzamide in the form of an oily substance. under cooling on ice at a room temperature for 1 hour at 50° C. for 1 hour at 80° C. for 2.5 days under heating to reflux for 2 hours the obtained mixture was further stirred for 20 minutes the mixture was then extracted with ethyl acetate The extract was dried over anhydrous sodium sulfate was then concentrated The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 to 1:1)

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

実験手順: A mixture of tert-butyl {(1S)-2-[4-(6-ethoxypyrazolo[1,5-a]pyridin-2-yl)phenoxy]-1-methylethyl}carbamate (400 mg), 1,1′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) (358 mg) and acetonitrile (3 mL) was stirred at room temperature for 3 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (129 mg). extracted with ethyl acetate The separated organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate)

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.0 g of 2,2-dimethyl-5-(1-hydroxy-3-methylamino-2-butenylidene)-1,3-dioxane-4,6-dione was suspended in 20 ml of acetonitrile, 806 mg of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was added thereto, and this was stirred at room temperature for 1 hour and at 50° C. for 30 minutes. The reaction mixture was added to 100 ml of ice water and extracted with 100 ml of chloroform twice. The organic layer was dried with anhydrous magnesium sulfate and concentrated, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate) to obtain 480 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid represented by the formula: extracted with 100 ml of chloroform twice The organic layer was dried with anhydrous magnesium sulfate concentrated

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.0 g of 2,2-dimethyl-5-(1-hydroxy-3-methylamino-2-butenylidene)-1,3-dioxane-4,6-dione was suspended in 20 ml of acetonitrile, 806 mg of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was added thereto, and this was stirred at room temperature for 4 hours and at 50° C. for 30 minutes. The reaction mixture was added to 100 ml of ice water, and this was extracted with 100 ml of chloroform twice. The organic layer was dried with anhydrous magnesium sulfate and concentrated, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate) to obtain 480 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid represented by the formula: this was extracted with 100 ml of chloroform twice The organic layer was dried with anhydrous magnesium sulfate concentrated

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.0 g of 2,2-dimethyl-5-(1-hydroxy-3-methylamino-2-butenylidene)-1,3-dioxane-4,6-dione was suspended in 20 ml of acetonitrile, 806 mg of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was added thereto, and this was stirred at room temperature for 1 hour and at 50° C. for 30 minutes. The reaction mixture was added to 100 ml of ice water and extracted with 100 ml of chloroform twice. The organic layer was dried with anhydrous magnesium sulfate and concentrated, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate) to obtain 480 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid represented by the formula: extracted with 100 ml of chloroform twice The organic layer was dried with anhydrous magnesium sulfate concentrated

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.0 g of 2,2-dimethyl-5-(1-hydroxy-3-methylamino-2-butenylidene)-1,3-dioxane-4,6-dione was suspended in 20 ml of acetonitrile, 806 mg of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was added thereto, and this was stirred at room temperature for 1 hour and at 50° C. for 30 minutes. The reaction mixture was added to 100 ml of ice water and extracted with 100 ml of chloroform twice. The organic layer was dried with anhydrous magnesium sulfate and concentrated, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate) to obtain 480 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid represented by the formula: extracted with 100 ml of chloroform twice The organic layer was dried with anhydrous magnesium sulfate concentrated

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.0 g of 2,2-dimethyl-5-(1-hydroxy-3-methylamino-2-butenylidene)-1,3-dioxane-4,6-dione was suspended in 20 ml of acetonitrile, 806 mg of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was added thereto, and this was stirred at room temperature for 4 hours and at 50° C. for 30 minutes. The reaction mixture was added to 100 ml of ice water, and this was extracted with 100 ml of chloroform twice. The organic layer was dried with anhydrous magnesium sulfate and concentrated, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate) to obtain 480 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid represented by the formula: this was extracted with 100 ml of chloroform twice The organic layer was dried with anhydrous magnesium sulfate concentrated

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.0 g of 2,2-dimethyl-5-(1-hydroxy-3-methylamino-2-butenylidene)-1,3-dioxane-4,6-dione was suspended in 20 ml of acetonitrile, 806 mg of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was added thereto, and this was stirred at room temperature for 1 hour and at 50° C. for 30 minutes. The reaction mixture was added to 100 ml of ice water and extracted with 100 ml of chloroform twice. The organic layer was dried with anhydrous magnesium sulfate and concentrated, and the residue was subjected to silica gel column chromatography (eluent:ethyl acetate) to obtain 480 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid represented by the formula: extracted with 100 ml of chloroform twice The organic layer was dried with anhydrous magnesium sulfate concentrated

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

実験手順: A solution of 0.581 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate in 5 ml of acetonitrile is admixed with 0.320 g of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) and the suspension is subsequently heated at reflux over 15 hours. The reaction mixture is poured onto 10 ml of saturated aqueous sodium thiosulpphate solution and the mixture is extracted with 2×50 ml of ethyl acetate. The combined organic phases are washed with 10 ml each of 0.5 M HCl and brine, dried over sodium sulphate and concentrated. The title compound is obtained as a colourless solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (2:1 EtOAc-heptane); Rt=3.80. the suspension is subsequently heated at reflux over 15 hours the mixture is extracted with 2×50 ml of ethyl acetate The combined organic phases are washed with 10 ml each of 0.5 M HCl and brine dried over sodium sulphate concentrated

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

実験手順: A solution of 0.581 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate in 5 ml of acetonitrile is admixed with 0.320 g of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) and the suspension is subsequently heated at reflux over 15 hours. The reaction mixture is poured onto 10 ml of saturated aqueous sodium thiosulphate solution and the mixture is extracted with 2×50 ml of ethyl acetate. The combined organic phases are washed with 10 ml each of 0.5 M HCl and brine, dried over sodium sulphate and concentrated. The title compound is obtained as a colourless solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (2:1 EtOAc-heptane); Rt=3.80. the suspension is subsequently heated at reflux over 15 hours the mixture is extracted with 2×50 ml of ethyl acetate The combined organic phases are washed with 10 ml each of 0.5 M HCl and brine dried over sodium sulphate concentrated

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 393 mg (1.10 mmol) of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was added to 7 ml of an acetonitrile solution containing 458 mg (1.84 mmol) of the 2, N,N-trimethyl-5-morpholin-4-ylbenzamide obtained in Step B of Example 80 under cooling on ice. The obtained mixture was stirred at 0° C. for 1 hour, then at a room temperature for 1 hour, then at 50° C. for 1 hour, then at 80° C. for 2.5 days, and then under heating to reflux for 2 hours. Thereafter, 357 mg (1.0 mmol) of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was further added to the reaction solution, and the obtained mixture was further stirred for 20 minutes. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was then concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 to 1:1), so as to obtain 25.8 mg (5.3%) of 4-fluoro-2,N,N-trimethyl-5-morpholin-4-ylbenzamide in the form of an oily substance, and also obtain 35.1 mg (7.2%) of 2-fluoro-6,N,N-trimethyl-3-morpholin-4-ylbenzamide in the form of an oily substance. under cooling on ice at a room temperature for 1 hour at 50° C. for 1 hour at 80° C. for 2.5 days under heating to reflux for 2 hours the obtained mixture was further stirred for 20 minutes the mixture was then extracted with ethyl acetate The extract was dried over anhydrous sodium sulfate was then concentrated The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 to 1:1)