7-fluoro-2,3-dihydrochromen-4-one

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the same procedure established in Example 1, the reactor was charged with meta-fluorophenol (28 grams), acrylic acid (27 grams), and phenothiazine (0.02 grams). The reactor was sealed, evacuated and cooled to -78° C. before the anhydrous hydrogen fluoride (125 grams) was added. The mixture was stirred and warmed to 40° C. for one hour then to 100° C. for 4.5 hours as the pressure was recorded at 140 psig. After venting the excess hydrogen fluoride the reactor was cooled to 5° C. and the mixture washed with D.I. water. Analysis by HPLC indicated no 4-Chromanones to be present. A mixture of by-products were seen. The reactor was sealed evacuated was added warmed to 40° C. for one hour was cooled to 5° C. the mixture washed with D.I A mixture of by-products

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

Procedure: To a stirred solution of 5.0 grams (0.03 mole) of 3,4-dihydro-7-fluoro-2H-1-benzopyran-4-one in 100 mL of methanol was added portionwise 3.4 grams (0.09 mole) of sodium borohydride during a one hour period, after which the reaction mixture was stirred for about 18 hours. The reaction mixture was then concentrated under reduced pressure to a residue, which was slurried in water and extracted with methylene chloride. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:hexane as the eluant. The product-containing fractions were combined and concentrated under reduce pressure, yielding 4.4 grams of 3,4-dihydro-7-fluoro-4-hydroxy-2H-1-benzopyran. The NMR spectrum was consistent with the proposed structure. This reaction was repeated several times. The reaction mixture was then concentrated under reduced pressure to a residue, which extracted with methylene chloride The extract was dried with magnesium sulfate filtered The filtrate was concentrated under reduced pressure to a residue, which concentrated

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

Procedure: To a solution of 3-(3-fluorophenoxy)-propionic acid (4.94 g, 26.8 mmol) in dichloromethane (135 mL) is added several drops of anhydrous dimethylformamide, followed by oxalyl chloride (4.68 mL, 53.6 mmol). The reaction is stirred at room temperature until gas evolution ceases (˜30 min), then evaporated under reduced pressure and reconstituted in dichloromethane (135 mL). Following the addition of aluminum trichloride (4.28 g, 32.1 mmol), the reaction is stirred for 1 h, then 2 M aqueous hydrochloric acid (100 mL) and dichloromethane (100 mL) are added. The layers are separated, and the aqueous layer extracted with dichloromethane (2×100 mL). The combined organic-layers are washed with brine (2×100 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude residue is recrystallized twice from 2-propanol to afford slightly impure title compound (1.79 g, 40%), and the mother liquor subjected to flash chromatography (silica gel, 3:1 pentane/Et2O) to afford pure title compound (1.15 g, 26%): Rf 0.45 (1:1 ethyl acetate/hexanes); mp 53-56 ° C.; 1 H NMR (300 MHz, CDCl3), δ2.75 (t, J=6.4 Hz, 2H), 4.51 (t, J=6.4 Hz, 2H), 6.61 (dd, J=2.3, 9.9 Hz, 1H), 6.65-6.72 (m, 1H), 7.87 (dd, J=6.7, 8.8 Hz, 1H); 19F NMR (282 MHz, CDCl3), δ-101.06; APCI MS m/z 167 [C9H7FO2+H]+. evaporated under reduced pressure the reaction is stirred for 1 h The layers are separated the aqueous layer extracted with dichloromethane (2×100 mL) The combined organic-layers are washed with brine (2×100 mL) dried over magnesium sulfate filtered evaporated under reduced pressure The crude residue is recrystallized twice from 2-propanol

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

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

Procedure: To a solution of 3-(3-fluorophenoxy)-propionic acid (4.94 g, 26.8 mmol) in dichloromethane (135 mL) is added several drops of anhydrous dimethylformamide, followed by oxalyl chloride (4.68 mL, 53.6 mmol). The reaction is stirred at room temperature until gas evolution ceases (˜30 min), then evaporated under reduced pressure and reconstituted in dichloromethane (135 mL). Following the addition of aluminum trichloride (4.28 g, 32.1 mmol), the reaction is stirred for 1 h, then 2 M aqueous hydrochloric acid (100 mL) and dichloromethane (100 mL) are added. The layers are separated, and the aqueous layer extracted with dichloromethane (2×100 mL). The combined organic-layers are washed with brine (2×100 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude residue is recrystallized twice from 2-propanol to afford slightly impure title compound (1.79 g, 40%), and the mother liquor subjected to flash chromatography (silica gel, 3:1 pentane/Et2O) to afford pure title compound (1.15 g, 26%): Rf 0.45 (1:1 ethyl acetate/hexanes); mp 53-56 ° C.; 1 H NMR (300 MHz, CDCl3), δ2.75 (t, J=6.4 Hz, 2H), 4.51 (t, J=6.4 Hz, 2H), 6.61 (dd, J=2.3, 9.9 Hz, 1H), 6.65-6.72 (m, 1H), 7.87 (dd, J=6.7, 8.8 Hz, 1H); 19F NMR (282 MHz, CDCl3), δ-101.06; APCI MS m/z 167 [C9H7FO2+H]+. evaporated under reduced pressure the reaction is stirred for 1 h The layers are separated the aqueous layer extracted with dichloromethane (2×100 mL) The combined organic-layers are washed with brine (2×100 mL) dried over magnesium sulfate filtered evaporated under reduced pressure The crude residue is recrystallized twice from 2-propanol

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

Procedure: To a solution of 7-fluoro-2,3-dihydro-4H-chromen-4-one (6.25 g, 37.6 mmol, US 20050038032) in methanol (60 mL) was added sodium borohydride (1.57 g, 41.4 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 1 hour, and evaporated to remove methanol. The residue was quenched with water, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1 as an eluent) to afford the title compound as a pale gray solid (4.70 g, 74%): evaporated to remove methanol The residue was quenched with water extracted with ethyl acetate The extract was washed with brine dried over magnesium sulfate concentrated in vacuum The residue was purified by column chromatography on silica gel (hexane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the same procedure established in Example 1, the reactor was charged with meta-fluorophenol (28 grams), acrylic acid (27 grams), and phenothiazine (0.02 grams). The reactor was sealed, evacuated and cooled to -78° C. before the anhydrous hydrogen fluoride (125 grams) was added. The mixture was stirred and warmed to 40° C. for one hour then to 100° C. for 4.5 hours as the pressure was recorded at 140 psig. After venting the excess hydrogen fluoride the reactor was cooled to 5° C. and the mixture washed with D.I. water. Analysis by HPLC indicated no 4-Chromanones to be present. A mixture of by-products were seen. The reactor was sealed evacuated was added warmed to 40° C. for one hour was cooled to 5° C. the mixture washed with D.I A mixture of by-products

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

Procedure: Triethylamine (0.19 ml) was added to a solution of the compound 5-1 synthesized from 7-fluorochroman-4-one according to Example 4 (200 mg) in tetrahydrofuran (3.0 ml), cooled in an ice bath. A solution of methanesulfonyl chloride (177 mg) in tetrahydrofuran (2.0 ml) was added dropwise at the same temperature, followed by stirring for 1.5 hours. After confirming disappearance of the raw material, the reaction mixture was added to aqueous sodium bicarbonate to terminate the reaction. The aqueous layer was extracted with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (214 mg), which was used for the next reaction as a crude product. cooled in an ice bath to terminate the reaction The aqueous layer was extracted with ethyl acetate The aqueous layer was further extracted with ethyl acetate the combined organic layers were dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the same procedure established in Example 1, the reactor was charged with meta-fluorophenol (28 grams), acrylic acid (27 grams), and phenothiazine (0.02 grams). The reactor was sealed, evacuated and cooled to -78° C. before the anhydrous hydrogen fluoride (125 grams) was added. The mixture was stirred and warmed to 40° C. for one hour then to 100° C. for 4.5 hours as the pressure was recorded at 140 psig. After venting the excess hydrogen fluoride the reactor was cooled to 5° C. and the mixture washed with D.I. water. Analysis by HPLC indicated no 4-Chromanones to be present. A mixture of by-products were seen. The reactor was sealed evacuated was added warmed to 40° C. for one hour was cooled to 5° C. the mixture washed with D.I A mixture of by-products

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

Procedure: To a stirred solution of 5.0 grams (0.03 mole) of 3,4-dihydro-7-fluoro-2H-1-benzopyran-4-one in 100 mL of methanol was added portionwise 3.4 grams (0.09 mole) of sodium borohydride during a one hour period, after which the reaction mixture was stirred for about 18 hours. The reaction mixture was then concentrated under reduced pressure to a residue, which was slurried in water and extracted with methylene chloride. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:hexane as the eluant. The product-containing fractions were combined and concentrated under reduce pressure, yielding 4.4 grams of 3,4-dihydro-7-fluoro-4-hydroxy-2H-1-benzopyran. The NMR spectrum was consistent with the proposed structure. This reaction was repeated several times. The reaction mixture was then concentrated under reduced pressure to a residue, which extracted with methylene chloride The extract was dried with magnesium sulfate filtered The filtrate was concentrated under reduced pressure to a residue, which concentrated

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

Procedure: To a solution of 3-(3-fluorophenoxy)-propionic acid (4.94 g, 26.8 mmol) in dichloromethane (135 mL) is added several drops of anhydrous dimethylformamide, followed by oxalyl chloride (4.68 mL, 53.6 mmol). The reaction is stirred at room temperature until gas evolution ceases (˜30 min), then evaporated under reduced pressure and reconstituted in dichloromethane (135 mL). Following the addition of aluminum trichloride (4.28 g, 32.1 mmol), the reaction is stirred for 1 h, then 2 M aqueous hydrochloric acid (100 mL) and dichloromethane (100 mL) are added. The layers are separated, and the aqueous layer extracted with dichloromethane (2×100 mL). The combined organic-layers are washed with brine (2×100 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude residue is recrystallized twice from 2-propanol to afford slightly impure title compound (1.79 g, 40%), and the mother liquor subjected to flash chromatography (silica gel, 3:1 pentane/Et2O) to afford pure title compound (1.15 g, 26%): Rf 0.45 (1:1 ethyl acetate/hexanes); mp 53-56 ° C.; 1 H NMR (300 MHz, CDCl3), δ2.75 (t, J=6.4 Hz, 2H), 4.51 (t, J=6.4 Hz, 2H), 6.61 (dd, J=2.3, 9.9 Hz, 1H), 6.65-6.72 (m, 1H), 7.87 (dd, J=6.7, 8.8 Hz, 1H); 19F NMR (282 MHz, CDCl3), δ-101.06; APCI MS m/z 167 [C9H7FO2+H]+. evaporated under reduced pressure the reaction is stirred for 1 h The layers are separated the aqueous layer extracted with dichloromethane (2×100 mL) The combined organic-layers are washed with brine (2×100 mL) dried over magnesium sulfate filtered evaporated under reduced pressure The crude residue is recrystallized twice from 2-propanol