5,7-difluoro-2,3-dihydrochromen-4-one

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.00 g (10.86 mmol) of the compound from Example 170A were dissolved in 40 ml of diethyl ether at 0° C., and 32.6 ml (16.29 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, addition of water and diethyl ether to the reaction solution and separation of the phases. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). The acetonitrile was removed from the combined product phases in a rotary evaporator, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. 0.66 g (27% of theory) of the title compound was obtained. by warming to RT to the reaction solution and separation of the phases The aqueous phase was extracted with diethyl ether the combined organic phases were dried over sodium sulfate filtered the solvents were removed in vacuo The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) The acetonitrile was removed from the combined product phases in a rotary evaporator the aqueous phase was extracted with dichloromethane The combined organic phases were dried over sodium sulfate filtered the solvents were removed in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.00 g (10.86 mmol) of the compound from Example 170A were dissolved in 40 ml of diethyl ether at 0° C., and 5.4 ml (16.29 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, addition of water and diethyl ether to the reaction solution and separation of the phases. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane). 2.03 g (93% of theory) of the title compound were obtained. by warming to RT to the reaction solution and separation of the phases The aqueous phase was extracted with diethyl ether the combined organic phases were dried over sodium sulfate filtered the solvents were removed in vacuo The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.00 g (10.86 mmol) of the compound from Example 170A were dissolved in 40 ml of diethyl ether at 0° C., and 5.4 ml (16.29 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, addition of water and diethyl ether to the reaction solution and separation of the phases. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane). 2.03 g (93% of theory) of the title compound were obtained. by warming to RT to the reaction solution and separation of the phases The aqueous phase was extracted with diethyl ether the combined organic phases were dried over sodium sulfate filtered the solvents were removed in vacuo The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane)

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

Procedure: 0.5 ml of DMF and 7.35 ml (84.29 mmol) of oxalyl chloride were slowly added dropwise to a solution of 11.36 g (42.15 mmol) of the compound from Example 169A in 400 ml of dichloromethane at RT. After stirring at RT for 3 h, the solvents were removed in a rotary evaporator, and the residue was again taken up in 200 ml of dichloromethane. 6.74 g (50.57 mmol) of aluminum trichloride were added in portions to the reaction mixture, and the mixture was stirred for 1 h. 150 ml of 2N hydrochloric acid and 200 ml of dichloromethane were added, the phases were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane). 6.46 g (80% of theory) of the title compound were obtained. the solvents were removed in a rotary evaporator the mixture was stirred for 1 h the phases were separated the aqueous phase was extracted twice with dichloromethane The combined organic phases were dried over sodium sulfate filtered the solvents were removed in vacuo The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane)

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

Procedure: To a mixture of 1 M (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole toluene solution (5.43 mL, 5.43 mmol) and tetrahydrofuran (40 mL) was added 2M borane-methyl sulfide complex tetrahydrofuran solution (29.8 mL, 59.7 mmol) at 0° C. and the mixture was stirred for 20 minutes. To the mixture was added a solution of 5,7-difluoro-2,3-dihydro-4H-chromen-4-one (10.0 g, 54.3 mmol, STEP 7) in tetrahydrofuran (70 mL) at 0° C. over a period of 1 hour, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with methanol (50 mL) and stirred for 30 minutes at room temperature. The mixture was concentrated in vacuum and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1 as an eluent) to afford crude white solids (8.85 g, 86% ee). The solids were recrystallized from hexane (300 mL) to give the title compound as a colorless needle crystal (5.90 g, 58%, >99% ee). the mixture was stirred at the same temperature for 1 hour The reaction mixture was quenched with methanol (50 mL) stirred for 30 minutes at room temperature The mixture was concentrated in vacuum the residue was purified by column chromatography on silica gel (hexane ethyl acetate=4:1 as an eluent) to afford crude white solids (8.85 g, 86% ee) The solids were recrystallized from hexane (300 mL)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 3-(3,5-difluorophenoxy)propanoate (11.6 g, 53.7 mmol, STEP 6) and trifluoromethanesulfonic acid (23.2 mL, 2.0 mL/g of substrate) was stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (120 mL), and extracted with toluene (120 mL). The organic layer was washed successively with aqueous solution of potassium carbonate (50 mL), water (50 mL), and dried over magnesium sulfate. The organic mixture was concentrated in vacuum to afford the title compound (8.75 g, 88%) as a white solid, which was used in the next step without further purification. After cooling to room temperature extracted with toluene (120 mL) The organic layer was washed successively with aqueous solution of potassium carbonate (50 mL), water (50 mL) dried over magnesium sulfate The organic mixture was concentrated in vacuum

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

Procedure: To a solution of 5,7-difluoro-2,3-dihydro-4H-chromen-4-one (14.2 g, 77.0 mmol, US 20050038032) in methanol (200 mL) was added sodium borohydride (3.50 g, 92.5 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 (9.64 g, 67%). 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:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5,7-difluoro-2,3-dihydro-4H-chromen-4-one (14.2 g, 77.0 mmol, US 20050038032) in methanol (200 mL) was added sodium borohydride (3.50 g, 92.5 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 (9.64 g, 67%). 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:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.00 g (10.86 mmol) of the compound from Example 170A were dissolved in 40 ml of diethyl ether at 0° C., and 32.6 ml (16.29 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, addition of water and diethyl ether to the reaction solution and separation of the phases. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). The acetonitrile was removed from the combined product phases in a rotary evaporator, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. 0.66 g (27% of theory) of the title compound was obtained. by warming to RT to the reaction solution and separation of the phases The aqueous phase was extracted with diethyl ether the combined organic phases were dried over sodium sulfate filtered the solvents were removed in vacuo The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) The acetonitrile was removed from the combined product phases in a rotary evaporator the aqueous phase was extracted with dichloromethane The combined organic phases were dried over sodium sulfate filtered the solvents were removed in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.00 g (10.86 mmol) of the compound from Example 170A were dissolved in 40 ml of diethyl ether at 0° C., and 5.4 ml (16.29 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, addition of water and diethyl ether to the reaction solution and separation of the phases. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane). 2.03 g (93% of theory) of the title compound were obtained. by warming to RT to the reaction solution and separation of the phases The aqueous phase was extracted with diethyl ether the combined organic phases were dried over sodium sulfate filtered the solvents were removed in vacuo The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane)