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Stage #1: tributyl(1-ethoxyvinyl)stannane; 4-bromo-6-fluoroisoquinolin-1(2H)-one With bis-triphenylphosphine-palladium(II) chloride In 1,4-dioxane at 110℃; for 16h; Inert atmosphere;
Stage #2: With hydrogenchloride In 1,4-dioxane; water at 0 - 20℃; for 3h;
1 4-Acetyl-6-fluoroisoquinolin-1(2H)-one (XXb)
To a solution of 1.0 g (4.1 mmol, 1.0 eq.) of 4-bromo-6-fluoroisoquinolin-1(2H)-one (IIIb) in 10 mL of 1,4-dioxane was added 3.7 g (10.3 mmol, 2.5 eq.) of tributyl(1- ethoxyvinyl)tin. The mixture was degassed by purging with argon gas for 5 min and 0.29 g (0.41 mmol, 0.1 eq.) of bis(triphenylphosphine)palladium(II) dichloride was added. The mixture was then heated at 110 °C under an argon atmosphere for 16 h. The mixture was allowed to cool to room temperature and further cooled to 0 °C. The mixture was then diluted with 15 mL of 1 M aqueous HCl and the resulting solution stirred at room temperature for 3 h. The mixture was basified with 40 mL of saturated sodium bicarbonate solution and filtered through a CELITE pad. The filtrate was extracted with 3 x 50 mL of ethyl acetate and the combined organic extracts were washed with 30 mL of brine, dried (Na2SO4), filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography (SiO2, eluting with a linear gradient 50-70% ethyl acetate/petroleum ether) to provide 0.4 g (1.95 mmol, 47%) of 4-acetyl-6-fluoroisoquinolin-1(2H)-one (XXb). LCMS: m/z found 206.2 [M+H]+, RT = 1.86 min
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 16h;
1 4-Bromo-6-fluoroisoquinolin-1(2H)-one (IIIb)
To a solution of 0.8 g (4.9 mmol, 1.0 eq.) of 6-fluoroisoquinolin-1(2H)-one (IIb) in 8 mL of DMF was added 0.88 g (5.1 mmol, 1.05 eq.) of N-bromosuccinimide and the mixture was stirred for 16 h. The mixture was then diluted with 80 mL of water and the resulting precipitated solid was collected by filtration, washed with 2 x 40 mL of water and dried under vacuum. The collected solids were triturated with 10 mL of methyl tert-butyl ether, filtered and dried under vacuum to provide 1.0 g (4.13 mmol, 84%) of 4-bromo-6-fluoroisoquinolin- 1(2H)-one (IIIb). LCMS: m/z found 242.1 [M+H]+, RT = 2.08 min; 1H NMR (300 MHz, DMSO-d6): d 11.65 (bs, 1H), 8.33-8.27 (m, 1H), 7.65-7.62 (m, 1H), 7.49-7.42 (m, 2H).
Stage #1: 4-bromo-6-fluoroisoquinolin-1(2H)-one With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere;
Stage #2: methyl iodide In N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere;
Step-1:
Initially 4-bromo-6-fluoro-2H-isoquinolin-1-one (1000 mg, 4.13 mmol) was dissolved in DMF (38.41 mL) and cooled to 0°C before sodium hydride (198.29 mg, 8.26 mmol) was added in one portion and the mixture was stirred for 30 mins. Iodomethane (2.35 g, 16.53 mmol, 1.03 mL) was then added dropwise and the mixture was allowed to stir overnight at ambient temperature. The reaction was then quenched with ice water and the precipitated product was filtered off and washed with copious water followed by hexanes. The solid was dried to give 4- bromo-2,6-dimethoxy-benzaldehyde. Yield- 759 mg, 72%; LC-MS (ES+): m/z 256.0 [M+H]+.
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