Water-soluble benzoazepine compound and its pharmaceutical composition
a benzoazepine compound and pharmaceutical technology, applied in the field of new drugs, can solve the problems of poor absorption by the intestinal canal, limited dosage form and administration route, etc., and achieve excellent water solubility, excellent absorption, excellent water solubility
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example 1
[0136]
[0137]A 1.0 g quantity of tolvaptan (compound (2)) and 460 mg of 1H-tetrazole were dissolved in 30 ml of methylene chloride, and 1.2 g of dibenzyl diisopropylphosphoramidite was added dropwise to this solution at room temperature with stirring. The mixture was then stirred for 2 hours at the same temperature.
[0138]The obtained reaction mixture was cooled to −40° C., and 6 ml of methylene chloride solution of 920 mg of metachloroperbenzoic acid was added dropwise thereto. The mixture was then stirred at the same temperature for 30 minutes, and at 0° C. for 30 minutes. The reaction mixture was washed with an aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate, and then dried over anhydrous sodium sulfate. The obtained reaction mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=1:1) to give 1.5 g of amorphous compound (1a-1) (yield 97.2%).
[0139]NMR (DMSO-d6, 100° C.) δ pp...
example 2
[0140]
[0141]A 4.5 g quantity of tolvaptan (compound (2)) and 2.2 g of 1H-tetrazole were dissolved in 120 ml of methylene chloride, and a solution of 4.0 g of di t-butyl diisopropylphosphoramidite dissolved in 10 ml of methylene chloride was added dropwise to this solution with ice-cooling and stirring. The mixture was then stirred at room temperature for 2 hours.
[0142]The obtained reaction mixture was cooled to −40° C., and 20 ml of methylene chloride solution of 4.0 g of metachloro perbenzoic acid was added dropwise thereto. The mixture was then stirred at the same temperature for 30 minutes, and at 0° C. for 40 minutes. The reaction mixture was washed with an aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate, and then dried over anhydrous sodium sulfate. The obtained reaction mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=1:1) to give 3.0 g of amorphous compound (1a-2)...
example 3
[0144]
[0145]A 5.3 g quantity of compound (1a-1) was dissolved in 100 ml of ethanol, and, using 2 g of 5% palladium-carbon as a catalyst, the solution was subjected to catalytic reduction at room temperature and atmospheric pressure for 10 minutes. The catalyst was removed from the solution by filtration, and the obtained filtrate was concentrated (4.2 g). The obtained residue was crystallized from methanol / water. The crystals were collected by filtration and then dried under reduced pressure (diphosphorus pentoxide) to give 3.5 g of white powdery compound (1b) (yield 88.5%).
[0146]Melting point: 150 to 152° C.
[0147]NMR (DMSO-d6-D2O, 100° C.) δ ppm; 7.50-6.70 (10H, m), 5.50-5.40 (1H, m), 5.00-2.50 (2H, m), 2.37 (6H, s), 2.40-1.50 (4H, m)
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