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Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.5 h; Stage #2: With aluminum (III) chloride In dichloromethane for 1.5 h; Reflux
To a solution of 3-(3-bromo-4-fluorophenyl)propanoic acid (3.5 g, 14.2 mmol) in DCM (25 mL) with DMF (0.5 mL) was added oxalylchloride (7.2 g, 56.7 mmol) at rt. The mixture was stirred for another 30 minutes and concentrated under reduced pressure to dryness. The residue was dissolved in DCM (50 mL) and was added dropwise to a refluxing suspension of aluminum trichloride (7.6 g, 56.7 mmol) in DCM (200 mL). The mixture was refluxed for 90 minutes and poured into ice/concentrated hydrochloride acid and extracted with DCM (3 x 200 mL). The organic layers were combined and concentrated under reduced pressure. The residue was purified via column chromatography (25 percent EtOAc in petroleum ether) to afford 5-Bromo-6-fluoro-indan-l-one as a light yellow solid (2.1 g, yield 68 percent). MS ESI calc'd. For C9H6BrFO [M + H]+ 229, found 229.
With hydrogen;5% rhodium-on-charcoal; In tetrahydrofuran; at 20.0℃; for 12h;
Reference Example 1; 3-(3-Bromo-4-fluorophenyl)propionic acid; Piperidine (1 ml) was added to a pyridine (250 ml) solution of 3-bromo-4-fluorobenzaldehyde (20 g) and malonic acid (51 g), followed by heating under reflux for 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, water was added, and this was neutralized with 1 N hydrochloric acid added thereto with stirring. The precipitated matter was collected by filtration, and the resulting (2E)-3-(3-bromo-4-fluorophenyl)acrylic acid was dissolved in THF (200 ml), followed by stirring with 5% Rh-C (3 g) in a hydrogen atmosphere at room temperature for 12 hours. The insoluble matter was removed by filtration, and the solvent was evaporated under reduced pressure to obtain the compound (15 g) of Reference Example 1.
With formic acid; triethylamine; In N,N-dimethyl-formamide; at 100.0℃;
A flask charged with triethylamine (16.6 mL, 118.2 mmol) was added formic acid (1 1.2 mL, 295.6 mmol) portionwise and the mixture was stirred for 15 minutes at rt. The mixture was then diluted with DMF (75 mL) and 3-bromo-4-fluoro-benzaldehyde (20 g, 98.5 mmol), Meldrum's acid (14.2 g, 98.5 mmol) were added. The mixture was then heated to 100 C overnight and then poured into ice/concentrated hydrochloride acid (800 mL). The mixture was extracted with DCM (2 x 300 mL). The organic layer was washed with 1 N sodium hydroxide (2x 200 mL). The aqueous layer was acidified to pH= 2 with concentrated hydrochloride acid and extracted with EtOAc (2x300 mL). The organic layer was dried and concentrated under reduced pressure to give crude acid as clear oil which was used directly (13 g). MS ESI calc'd. For C9H8BrF02 [M + H]+ 247, found 247.
To a solution of <strong>[866862-24-0]3-(3-bromo-4-fluorophenyl)propanoic acid</strong> (3.5 g, 14.2 mmol) in DCM (25 mL) with DMF (0.5 mL) was added oxalylchloride (7.2 g, 56.7 mmol) at rt. The mixture was stirred for another 30 minutes and concentrated under reduced pressure to dryness. The residue was dissolved in DCM (50 mL) and was added dropwise to a refluxing suspension of aluminum trichloride (7.6 g, 56.7 mmol) in DCM (200 mL). The mixture was refluxed for 90 minutes and poured into ice/concentrated hydrochloride acid and extracted with DCM (3 x 200 mL). The organic layers were combined and concentrated under reduced pressure. The residue was purified via column chromatography (25 % EtOAc in petroleum ether) to afford 5-Bromo-6-fluoro-indan-l-one as a light yellow solid (2.1 g, yield 68 %). MS ESI calc'd. For C9H6BrFO [M + H]+ 229, found 229.
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