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With sodium azide; sulfuric acid In chloroform at 20 - 45℃; for 24 h;
[0105] A triphasic mixture of sodium azide (18.5 g, 284 mmol), sulfuric acid (18.8 M, 4.8 mL, 90 mmol), water (36 mL) and chloroform (144 mL) was stirred at 0°C for 2.5 h. The layers were separated and the organic layer was dried over sodium sulfate and filtered. The filtrate was added to a solution of 4-bromoindan-l-one (12.0 g, 56.9 mmol) in chloroform (215 mL). To this solution was added sulfuric acid (18.8 M, 18.7 mL, 351.6 mmol) dropwise over 10 min. The reaction mixture was stirred at 45°C for 4 h, then cooled to room temperature and stirred for 20 h. The mixture was poured onto ice (200 g) and neutralized by addition of 10percent aqueous sodium hydroxide (50 mL). The layers were separated and the aqueous layer was extracted with chloroform (100 mL). The combined organic layers were dried over sodium sulfate and evaporated. The crude product was recrystallized from ethanol (55 mL) to give the title compound (8.65 g, 38.2 mmol, 67percent) as an off-white powder. LCMS: 98percent, Rt 1.290, ESMS m/z 226 (M+H)+.
With triethylamine;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 180℃; for 4h;Microwave irradiation;
A mixture of 5-bromo-3,4-dihydroquinolin-2(lH)-one from Step A (50 mg, 0.22 mmol), ethyl acrylate (0.048 mL, 0.44 mmol), triethylamine (0.062 mL, 0.44 mmol), and (PPh3)4Pd (26 mg, 0.022 mmol) in DMF (0.5 mL) was heated at 180 C in a microwave reactor for 4 h. The reaction mixture was partitioned between CH2Cl2 (20 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was partially purified by HPLC using a reversed phase <n="55"/>C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H - 90:10:0.1 to 5:95:0.1 to give the title compound in sufficient purity for use in the next step. MS: mlz = 246 (M + 1).
With triethylamine;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 180℃; for 4h;microwave reactor;
A mixture of 5-bromo-3,4-dihydroquinolin-2(lH)-one from Step A (50 mg, 0.22 mmol), ethyl acrylate (0.048 mL, 0.44 mmol), triethylamine (0.062 mL, 0.44 mmol), and (PPh3)4Pd (26 mg, 0.022 mmol) in DMF (0.5 mL) was heated at 180 0C in a microwave reactor for 4 h. The reaction mixture was partitioned between CH2Cl2 (20 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was partially purified by HPLC using a reversed phase Cl 8 column and eluting with a gradient of H2O:CH3CN:CF3CO2H - 90: 10:0.1 to 5:95:0.1 to give the title compound in sufficient purity for use in the next step. MS: mlz = 246 (M + 1).
With sodium azide; sulfuric acid; In chloroform; at 20 - 45℃; for 24h;
[0105] A triphasic mixture of sodium azide (18.5 g, 284 mmol), sulfuric acid (18.8 M, 4.8 mL, 90 mmol), water (36 mL) and chloroform (144 mL) was stirred at 0C for 2.5 h. The layers were separated and the organic layer was dried over sodium sulfate and filtered. The filtrate was added to a solution of 4-bromoindan-l-one (12.0 g, 56.9 mmol) in chloroform (215 mL). To this solution was added sulfuric acid (18.8 M, 18.7 mL, 351.6 mmol) dropwise over 10 min. The reaction mixture was stirred at 45C for 4 h, then cooled to room temperature and stirred for 20 h. The mixture was poured onto ice (200 g) and neutralized by addition of 10% aqueous sodium hydroxide (50 mL). The layers were separated and the aqueous layer was extracted with chloroform (100 mL). The combined organic layers were dried over sodium sulfate and evaporated. The crude product was recrystallized from ethanol (55 mL) to give the title compound (8.65 g, 38.2 mmol, 67%) as an off-white powder. LCMS: 98%, Rt 1.290, ESMS m/z 226 (M+H)+.
To a stirred mixture of sodium azide (862 mg, 13.3 mmol) in H2O (1.7 mL) and CHCl3 (6.5 mL) was added cone. H2SO4 (0.23 mL, 4.14 mmol). The reaction mixture was stirred vigorously at 0 C for 2.5 h. The CHCl3 layer was separated, dried over Na2SO4, and added to a solution of 4-bromo-l-indanone (1.12 g, 5.31 mmol) in CHCl3 (20 mL). To this mixture was added cone. H2SO4 (1.75 mL, 31.5 mmol) dropwise over 10 min. The reaction mixture was heated at 45 C for 1 h then poured into ice-water, neutralized with 20% aqueous NaOH, and extracted with CH2Cl2 (100 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2C12:EtOAc - 100:0 to 80:20, to give the title compound. MS: mlz = 226 (M + 1).
With sodium azide; sulfuric acid; In chloroform; at 45℃; for 1.16667h;
To a stirred mixture of sodium azide (862 mg, 13.3 mmol) in H2O (1.7 mL) and CHCl3 (6.5 mL) was added cone. H2SO4 (0.23 mL, 4.14 mmol). The reaction mixture was stirred vigorously at 0 0C for 2.5 h. The CHCl3 layer was separated, dried over Na2SO4, and added to a solution of 4-bromo- 1-indanone (1.12 g, 5.31 mmol) in CHCb (20 mL). To this mixture was added cone. H2SO4 (1.75 mL, 31.5 mmol) dropwise over 10 min. The reaction mixture was heated at 45 C for 1 h then poured into ice- water, neutralized with 20% aqueous NaOH, and extracted with CH2Cl2 (100 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2C12: EtOAc - 100:0 to 80:20, to give the title compound. MS: ml z = 226 (M + 1).
5-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5-Bromo-3,4-dihydroquinolin-2(1H)-one (300.0 mg, 1.327 mmol) was treated with KHMDS (1.33 mL, 1.327 mmol, 1.0 equiv., 1M solution in THF) in THF (3 mL) under a nitrogen atmosphere at -78 C. for 30 min. To the reaction mixture was added a solution of MeI (367.7 mg, 2.654 mmol, 2.0 equiv.) in THF (1 mL) at the same temperature. And then the reaction was allowed to warm to room temperature and stirred for 45 min. To the reaction mixture was added water (30 mL). The whole was extracted with CH2Cl2 (30 mL*3). Obtained organic layer was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure to give a crude product. The crude product was purified a silica gel column chromatography (MeOH:CH2Cl2=0:100-1:99) to give 5-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one. C10H10BrNO: MS. m/z 240.0 (M-1), 242.0 (M+1)
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0℃; for 1h;Inert atmosphere;
NaH (2.65 g, 66.4 mmol) was added to a solution of 5-bromo-3,4- dihydroquinolin-2(1H)-one (5.00 g, 22.1 mmol) in DMF (40 mL) at 0 C under nitrogen, followed by the addition of methyl iodide (2.07 mL, 33.2 mmol). The mixture was stirred for 1 hour, diluted with cold water, and extracted with ethyl acetate. The combined organic extracts were washed with cold water, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chroatography (0 - 5 % ethyl acetate in petroleum ether) to provide the title compound.
With hydrogenchloride; sodium azide; In water; at -10℃; for 1.0h;
In a 100 mL single-mouth bottle, 4-bromo-1-indanone (5.00 g, 23.70 mmol) was dissolved in concentrated hydrochloric acid (50 mL). The temperature was lowered to -10 C, NaN3 (3.08 g, 47.40 mmol) was slowly added, and stirred at low temperature for 1.0 h. Rise to room temperature, continueThe reaction was stirred continuously and the solution was white suspension. The reaction was monitored by TLC, extracted with EA (50mL×3), dried over anhydrous sodium sulfate and concentrated.Silica gel column chromatography,Rinse with PE/EA=40/1-10/1,5-bromo-3,4-dihydroisoquinolin-1(2H)-one 1.22 g of a white solid was obtained, yield 23%.
7-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3,4-dihydroquinolin-2(1H)-one dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92 Example 92
Example 92 7-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3,4-dihydroquinolin-2(1H)-one dihydrochloride 7-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3,4-dihydroquinolin-2(1H)-o ne was prepared in accordance with the steps in the method of Example 1 by using 5-bromo-3,4-dihydroquinolin-2(1H)-one and 2-methyloctahydropyrrolo[3,4-c]pyrrole as the raw materials, and the hydrochloride was formed in accordance with Example 3 to obtain the title compound. 1H NMR (400 MHz, Methanol-d4): δ 7.06 (m, 3H), 3.94 (m, 1H), 3.73 (d, J= 11.8 Hz, 1H), 3.70-3.30 (m, 8H), 3.03-2.89 (m, 5H), 2.56 (m, 2H). ESI-MS (m/z): 272.34 [M+H]+.
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