1-(5-fluoro-2-hydroxyphenyl)ethanone

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of sodium hydride (Aldrich, 60% dispersion in mineral oil) (1.2 g, 30.0 mmol) and diethyl carbonate (Aldrich) (5.9 g, 50 mmol) in anhydrous benzene (Aldrich) (100 mL) under a dry nitrogen atmosphere was added dropwise a solution of 5'-fluoro-2'-hydroxy-acetophenone (Aldrich) (1.54 g, 10 mmol) in anhydrous benzene. The mixture was then refluxed under a nitrogen atmosphere overnight. The reaction mixture was cooled and 50 mL 1N NaOH was added. The mixture was stirred at room temperature for 1 hour. The aqueous layer was separated and washed with ether (100 mL×2). The dark solution was acidified to pH 2 with 6N HCl. The white precipitate was collected by filtration, washed with water and dried to afford product (4) (4-hydroxy-6-fluoro-coumarin) as an off-white solid (1.38 g, 7.66 mmol, 77%). 300-MHz 1H-NMR (CDCl3) δ 5.79 (s,1H), 7.25-7.28 (m,2H), 7.52 (d,1H). Mass/EI: 179 (M-H). The mixture was then refluxed under a nitrogen atmosphere overnight The reaction mixture was cooled The aqueous layer was separated washed with ether (100 mL×2) The white precipitate was collected by filtration washed with water dried

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Fluoro-2-hydroxyacetophenone (20.0 g) was dissolved in concentrated sulphuric acid (150 ml), and the mixture was cooled to -20° C. A mixture of concentrated nitric acid (17.0 ml; s.g. 1.42) in concentrated sulphuric acid (18.0 ml) was then added to it, dropwise with stirring, keeping the temperature of the reaction mixture between -15° and -5° C. The reaction mixture was then allowed to warm up to -5° C. and was poured into iced water (2 liters). The yellow precipitated product was filtered off and recrystallised from ethanol to give 5-fluoro-2-hydroxy-3-nitroacetophenone (11.9 g), m.p. 87°-90° C. was then added to it the temperature of the reaction mixture between -15° and -5° C to warm up to -5° C. The yellow precipitated product was filtered off recrystallised from ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Conc. HNO3 (22.49 g, 357 mmol) was added to a solution 1-(5-fluoro-2-hydroxyphenyl)ethanone (50 g, 325 mmol) in acetic acid (300 mL) at 0° C. and stirring was continued at 20° C. for 3 h. The reaction mixture was quenched with ice cold water. The separated solid was filtered and washed with cold water and dried to afford 1-(5-fluoro-2-hydroxy-3-nitrophenyl)ethanone (Int-19) (65 g, 98.48% yield) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.6 (1H, s), 8.3-8.2 (1H, dd), 8.2-8.1 (1H, dd), 2.7 (3H, s) ppm. The reaction mixture was quenched with ice cold water The separated solid was filtered washed with cold water dried

Conditions: temp:17.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 20 g of 5′-fluoro-2′-hydroxyacetophenone (13 mol) in 100 ml of THF was slowly added at 5-10° C. to a solution of 52 ml of 30% sodium methoxide in methanol (0.30 mol). The temperature was then allowed to reach 15° C. and 22 g of diethyloxalate (0.15 mol) were added between 15 to 25° C. to give a complete solution. The reaction progress was monitored by TLC until less than 5% of raw starting material was present. The mixture was adjusted to pH 1-2 by the addition of 20 ml of 36% HCl (0.24 mol) and 100 ml of water between 5 to 15° C. The solid residue formed was removed by filtration then the aqueous layer removed by decantation. The organic layer was then washed with 40 ml of an aqueous solution of 15% NaCl and concentrated under reduced pressure at 40-50° C. to give a yellow oil. This residual oil was dissolved in 100 ml of glacial acetic acid and 100 ml of water at reflux for 17-20 h. After cooling to 15-20° C., the suspension of the title compound was filtered to give after drying 20 g of a white or off-white solid (yield: 75%). A second crop can be obtained after concentration of the mother liquor and the residue warmed up in 50 ml glacial acetic acid and 50 ml water to reflux for 20 h to hydrolyze the ester to give an additional batch of the title compound (2-3 g). to reach 15° C. to give a complete solution The solid residue formed was removed by filtration the aqueous layer removed by decantation The organic layer was then washed with 40 ml of an aqueous solution of 15% NaCl concentrated under reduced pressure at 40-50° C. to give a yellow oil

Conditions: temp:17.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 20 g of 5′-fluoro-2′-hydroxyacetophenone (13 mol) in 100 ml of THF was slowly added at 5-10° C. to a solution of 52 ml of 30% sodium methoxide in methanol (0.30 mol). The temperature was then allowed to reach 15° C. and 22 g of diethyloxalate (0.15 mol) were added between 15 to 25° C. to give a complete solution. The reaction progress was monitored by TLC until less than 5% of raw starting material was present. The mixture was adjusted to pH 1-2 by the addition of 20 ml of 36% HCl (0.24 mol) and 100 ml of water between 5 to 15° C. The solid residue formed was removed by filtration then the aqueous layer removed by decantation. The organic layer was then washed with 40 ml of an aqueous solution of 15% NaCl and concentrated under reduced pressure at 40-50° C. to give a yellow oil. This residual oil was dissolved in 100 ml of glacial acetic acid and 100 ml of water at reflux for 17-20 h. After cooling to 15-20° C., the suspension of the title compound was filtered to give after drying 20 g of a white or off-white solid (yield: 75%). A second crop can be obtained after concentration of the mother liquor and the residue warmed up in 50 ml glacial acetic acid and 50 ml water to reflux for 20 h to hydrolyze the ester to give an additional batch of the title compound (2-3 g). to reach 15° C. to give a complete solution The solid residue formed was removed by filtration the aqueous layer removed by decantation The organic layer was then washed with 40 ml of an aqueous solution of 15% NaCl concentrated under reduced pressure at 40-50° C. to give a yellow oil

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Thionyl chloride (17.8 g, 0.15 mole) was added dropwise over 30 minutes to 1H-imidazole (41.1 g, 0.60 mole) in dried methylene chloride (200 ml) with stirring and ice-cooling. After stirring for additional 30 minutes, 2-hydroxy-5-fluoroacetophenone (15.4 g, 0.10 mole) in dried methylene chloride (50 ml) was added dropwise over 30 minutes. After stirring for 1 hour, methylene chloride (200 ml), water (400 ml) and an aqueous saturated solution of sodium bicarbonate (200 ml) were added to the reaction mixture and the mixture was stirred for 5 minutes. Then, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate to obtain the title compound (3.71 g, 18.2%), m.p. 164°-166° C. ice-cooling After stirring for additional 30 minutes After stirring for 1 hour the mixture was stirred for 5 minutes Then, the organic layer was separated washed with water dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure the residue was recrystallized from ethyl acetate