7-bromo-4,5-difluoro-1-benzofuran

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

Procedure: Beginning with 5 gm (23.9 mMol) 2-bromo-4,5-difluorophenol, 7.05 gm (91%) 2-(2-bromo-4,5-difluorophenoxy)-acetaldehyde diethyl acetal were prepared essentially as described in Preparation IV. were prepared essentially

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,4-Dioxane (12 mL) and water (4 mL) were added to 2-fluoro-4-hydroxyphenylboronic acid (475 mg, 3.0 mmol), 7-bromo-4,5-difluoro-1-benzofuran (590 mg, 2.53 mmol), sodium carbonate (540 mg, 5.1 mmol), and Pd(dppf)Cl2 (catalytic amount), and stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and 1 N hydrochloric acid were added and stirred. After that, the insoluble material was filtered off, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. Then, to the resulting residue, methyl 3-(bromomethyl)benzoate (595 mg, 2.6 mmol), potassium carbonate (414 mg, 3.0 mmol), and DMF (4 mL) were added, and stirred overnight. After diluted with ethyl acetate, the resultant was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. To the resulting residue, methanol (5 mL), water (2 mL), THF (5 mL), and lithium hydroxide (210 mg, 5.0 mmol) were added, and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled away under reduced pressure, the resulting solid was collected by filtration to thus obtain the title compound. The reaction solution was concentrated under reduced pressure To the residue, ethyl acetate and 1 N hydrochloric acid were added stirred After that, the insoluble material was filtered off extraction The organic phase was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was distilled away under reduced pressure stirred overnight the resultant was washed with water and saturated brine dried over anhydrous magnesium sulfate The solvent was distilled away under reduced pressure stirred at room temperature overnight The reaction solution was concentrated under reduced pressure, and extraction The organic phase was washed with saturated brine dried over anhydrous magnesium sulfate After the solvent was distilled away under reduced pressure the resulting solid was collected by filtration

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,4-Dioxane (12 mL) and water (4 mL) were added to 2-fluoro-4-hydroxyphenylboronic acid (475 mg, 3.0 mmol), 7-bromo-4,5-difluoro-1-benzofuran (590 mg, 2.53 mmol), sodium carbonate (540 mg, 5.1 mmol), and Pd(dppf)Cl2 (catalytic amount), and stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and 1 N hydrochloric acid were added and stirred. After that, the insoluble material was filtered off, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. Then, to the resulting residue, methyl 3-(bromomethyl)benzoate (595 mg, 2.6 mmol), potassium carbonate (414 mg, 3.0 mmol), and DMF (4 mL) were added, and stirred overnight. After diluted with ethyl acetate, the resultant was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. To the resulting residue, methanol (5 mL), water (2 mL), THF (5 mL), and lithium hydroxide (210 mg, 5.0 mmol) were added, and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled away under reduced pressure, the resulting solid was collected by filtration to thus obtain the title compound. The reaction solution was concentrated under reduced pressure To the residue, ethyl acetate and 1 N hydrochloric acid were added stirred After that, the insoluble material was filtered off extraction The organic phase was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was distilled away under reduced pressure stirred overnight the resultant was washed with water and saturated brine dried over anhydrous magnesium sulfate The solvent was distilled away under reduced pressure stirred at room temperature overnight The reaction solution was concentrated under reduced pressure, and extraction The organic phase was washed with saturated brine dried over anhydrous magnesium sulfate After the solvent was distilled away under reduced pressure the resulting solid was collected by filtration

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the compound (1.67 g, 4.72 mmol) obtained in Step 1, 7-bromo-4,5-difluoro-1-benzofuran (1.1 g, 4.72 mmol), sodium carbonate (1.0 g, 9.44 mmol), and Pd(dppf)Cl2 (catalytic amount), 1,4-dioxane (24 mL) and water (8 mL) were added, and stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and 1 N hydrochloric acid were added and stirred. After that, the insoluble material was filtered off, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the solid was collected by filtration. The reaction solution was concentrated under reduced pressure To the residue, ethyl acetate and 1 N hydrochloric acid were added stirred After that, the insoluble material was filtered off extraction The organic phase was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was distilled away under reduced pressure the solid was collected by filtration

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

Procedure: Beginning with 5 gm (23.9 mMol) 2-bromo-4,5-difluorophenol, 7.05 gm (91%) 2-(2-bromo-4,5-difluorophenoxy)-acetaldehyde diethyl acetal were prepared essentially as described in Preparation IV. were prepared essentially

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

Procedure: Beginning with 4.0 gm (17.17 mMol) 4,5-difluoro-7-bromobenzofuran and 3.8 gm (18.88 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 2.6 gm (43%) of the desired compound were recovered as a yellow oil essentially as described in EXAMPLE 3.

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

Procedure: Alternatively, a mixture of 0.484 gm (2.08 mMol) 4,5-difluoro-7-bromobenzofuran and 0.065 gm (2.67 mMol) magnesium in 5 mL tetrahydrofuran was heated at reflux. Two drops of 1,2-dibromomethane were added and the mixture heated at reflux for 45 minutes. To this mixture were added 260 μL (2.29 mMol) trimethylborate and heating was continued for an additional 45 minutes. After cooling to room temperature, 2.3 mL 1N hydrochloric acid were added and the mixture stirred for 45 minutes. The mixture was then extracted well with diethyl ether. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was slurried in 4 mL hexanes, the solvent removed by decantation, and the residual solid dried under reduced pressure to provide 0.402 gm (97.8%) of the title compound. was heated at reflux the mixture heated at reflux for 45 minutes heating The mixture was then extracted well with diethyl ether The combined organic extracts were dried over sodium sulfate concentrated under reduced pressure the solvent removed by decantation the residual solid dried under reduced pressure

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2.0 gm (8.58mMol) 4,5-difluoro-7-bromobenzofuran and 0.202 gm (8.58 mMol) magnesium in 10 mL tetrahydrofuran was heated at reflux for 50 minutes. The resulting mixture was then cooled to −5° C. and treated dropwise with 1.01 mL (8.93 mMol) trimethylborate over 20 minutes. The reaction mixture was stirred at room temperature for 1.5 hours and was then concentrated under reduced pressure. The residue was partitioned between 50 mL deionized water and 50 mL ethyl acetate. The mixture was treated with 0.3 mL acetic acid to adjust to a neutral pH. The phases were separated and the aqueous phase was extracted well with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure to provide 2.1 gm of the title compound. was heated at reflux for 50 minutes was then concentrated under reduced pressure The residue was partitioned between 50 mL The mixture was treated with 0.3 mL acetic acid The phases were separated the aqueous phase was extracted well with ethyl acetate dried over magnesium sulfate concentrated under reduced pressure

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

Procedure: Beginning with 5 gm (23.9 mMol) 2-bromo-4,5-difluorophenol, 7.05 gm (91%) 2-(2-bromo-4,5-difluorophenoxy)acetaldehyde diethyl acetal were prepared essentially as described in Preparation IV. were prepared essentially

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

Procedure: Beginning with 5 gm (23.9 mMol) 2-bromo-4,5-difluorophenol, 7.05 gm (91%) 2-(2-bromo-4,5-difluorophenoxy)-acetaldehyde diethyl acetal were prepared essentially as described in Preparation IV. were prepared essentially

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,4-Dioxane (12 mL) and water (4 mL) were added to 2-fluoro-4-hydroxyphenylboronic acid (475 mg, 3.0 mmol), 7-bromo-4,5-difluoro-1-benzofuran (590 mg, 2.53 mmol), sodium carbonate (540 mg, 5.1 mmol), and Pd(dppf)Cl2 (catalytic amount), and stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and 1 N hydrochloric acid were added and stirred. After that, the insoluble material was filtered off, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. Then, to the resulting residue, methyl 3-(bromomethyl)benzoate (595 mg, 2.6 mmol), potassium carbonate (414 mg, 3.0 mmol), and DMF (4 mL) were added, and stirred overnight. After diluted with ethyl acetate, the resultant was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. To the resulting residue, methanol (5 mL), water (2 mL), THF (5 mL), and lithium hydroxide (210 mg, 5.0 mmol) were added, and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled away under reduced pressure, the resulting solid was collected by filtration to thus obtain the title compound. The reaction solution was concentrated under reduced pressure To the residue, ethyl acetate and 1 N hydrochloric acid were added stirred After that, the insoluble material was filtered off extraction The organic phase was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was distilled away under reduced pressure stirred overnight the resultant was washed with water and saturated brine dried over anhydrous magnesium sulfate The solvent was distilled away under reduced pressure stirred at room temperature overnight The reaction solution was concentrated under reduced pressure, and extraction The organic phase was washed with saturated brine dried over anhydrous magnesium sulfate After the solvent was distilled away under reduced pressure the resulting solid was collected by filtration

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the compound (1.67 g, 4.72 mmol) obtained in Step 1, 7-bromo-4,5-difluoro-1-benzofuran (1.1 g, 4.72 mmol), sodium carbonate (1.0 g, 9.44 mmol), and Pd(dppf)Cl2 (catalytic amount), 1,4-dioxane (24 mL) and water (8 mL) were added, and stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and 1 N hydrochloric acid were added and stirred. After that, the insoluble material was filtered off, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the solid was collected by filtration. The reaction solution was concentrated under reduced pressure To the residue, ethyl acetate and 1 N hydrochloric acid were added stirred After that, the insoluble material was filtered off extraction The organic phase was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was distilled away under reduced pressure the solid was collected by filtration