1-(3,5-difluoro-2-hydroxyphenyl)ethanone

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

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

Procedure: In an analogous manner to that described in (α) 1-(3,5-difluoro-2-hydroxy-phenyl)-ethanone was alkylated with methyliodide to yield 1-(3,5-difluoro-2-methoxy-phenyl)-ethanone as beige needles; MS: 186 (M)+.

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

Procedure: A solution of 1-(3,5-difluoro-2-hydroxyphenyl)ethanone (4.98 g, 28.9 mmol), MeOH (50 mL), 1,3-difluoroacetone (5.44 g, 57.9 mmol), and pyrrolidine (4.79 mL, 57.9 mmol) was heated at 60° C. for 20 hours. The dark solution was cooled, concentrated, chased with toluene, and then passed through a silica gel plug, washing with toluene (200 mL) and MTBE (200 mL). The filtrate was washed with 2N NaOH (50 mL×2), dried (Na2SO4), filtered, and concentrated to afford the title compound (5.80 g, 23.37 mmol, 81%), which was used without further purification in the next step. MS (DCI) m/z 299 (M+51)+. The dark solution was cooled concentrated washing with toluene (200 mL) and MTBE (200 mL) The filtrate was washed with 2N NaOH (50 mL×2) dried (Na2SO4) filtered concentrated

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

Procedure: A solution of 1-(3,5-difluoro-2-hydroxyphenyl)ethanone (4.98 g, 28.9 mmol), MeOH (50 mL), 1,3-difluoroacetone (5.44 g, 57.9 mmol), and pyrrolidine (4.79 mL, 57.9 mmol) was heated at 60° C. for 20 hours. The dark solution was cooled, concentrated, chased with toluene, and then passed through a silica gel plug, washing with toluene (200 mL) and MTBE (200 mL). The filtrate was washed with 2N NaOH (50 mL×2), dried (Na2SO4), filtered, and concentrated to afford the title compound (5.80 g, 23.37 mmol, 81%), which was used without further purification in the next step. MS (DCI) m/z 299 (M+51)+. The dark solution was cooled concentrated washing with toluene (200 mL) and MTBE (200 mL) The filtrate was washed with 2N NaOH (50 mL×2) dried (Na2SO4) filtered concentrated

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 (50 mL) of 1-(3,5-difluoro-2-hydroxyphenyl)ethanone (2.8 g) in N,N-dimethylformamide were added potassium carbonate (6.7 g) and 2-bromo-1-cyclohexylethanone (4.0 g) synthesized in Example A51(1) at room temperature, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was allowed to cool to room temperature, and filtered through celite. Water was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (50 mL) again, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 mL) was added to the solution, and the mixture was stirred at 110° C. 1 hr with heating. After cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid, and the reaction mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the precipitated compound was recrystallized from diisopropyl ether-hexane to give the title object compound (3.1 g, 70%) as a colorless solid. synthesized in Example A51(1) at room temperature to cool to room temperature filtered through celite Water was added to the filtrate the mixture was extracted with diethyl ether The extract was washed with saturated brine dried over magnesium sulfate concentrated under reduced pressure The obtained residue was dissolved in N,N-dimethylformamide (50 mL) again 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 mL) was added to the solution the mixture was stirred at 110° C 1 hr with heating After cooling to room temperature the reaction mixture was quenched with 1N hydrochloric acid the reaction mixture was extracted with diethyl ether The extract was concentrated under reduced pressure the precipitated compound was recrystallized from diisopropyl ether-hexane

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

Procedure: In an analogous manner to that described in (α) 1-(3,5-difluoro-2-hydroxy-phenyl)-ethanone was alkylated with methyliodide to yield 1-(3,5-difluoro-2-methoxy-phenyl)-ethanone as beige needles; MS: 186 (M)+.

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

Procedure: In an analogous manner to that described in (α) 1-(3,5-difluoro-2-hydroxy-phenyl)-ethanone was alkylated with methyliodide to yield 1-(3,5-difluoro-2-methoxy-phenyl)-ethanone as beige needles; MS: 186 (M)+.

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

Procedure: A solution of 1-(3,5-difluoro-2-hydroxyphenyl)ethanone (4.98 g, 28.9 mmol), MeOH (50 mL), 1,3-difluoroacetone (5.44 g, 57.9 mmol), and pyrrolidine (4.79 mL, 57.9 mmol) was heated at 60° C. for 20 hours. The dark solution was cooled, concentrated, chased with toluene, and then passed through a silica gel plug, washing with toluene (200 mL) and MTBE (200 mL). The filtrate was washed with 2N NaOH (50 mL×2), dried (Na2SO4), filtered, and concentrated to afford the title compound (5.80 g, 23.37 mmol, 81%), which was used without further purification in the next step. MS (DCI) m/z 299 (M+51)+. The dark solution was cooled concentrated washing with toluene (200 mL) and MTBE (200 mL) The filtrate was washed with 2N NaOH (50 mL×2) dried (Na2SO4) filtered concentrated