(4,4-difluorocyclohexyl)methanol

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 solution of Example 184A (8.5 g, 57 mmol) in dichloromethane (100 mL) were added triethylamine (Aldrich, 25 mL, 180 mmol) and tosyl chloride (Aldrich, 11.4 g, 60 mmol). The reaction mixture was stirred at room temperature for 16 hours and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to afford the title compound. 1H NMR (300 MHz, chloroform-d) δ ppm 1.17-1.42 (m, 2 H) 1.57-1.69 (m, 1 H), 1.70-1.91 (m, 4 H), 1.93-2.18 (m, 2 H), 2.46 (s, 3 H), 3.86 (d, J=6.4 Hz, 2 H), 7.35 (d, J=8.5 Hz, 2 H), 7.78 (d, J=8.1 Hz, 2 H). washed with water (50 mL) and brine (50 mL) The organic layer was dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography

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

Procedure: To a solution of Example 184A (8.5 g, 57 mmol) in dichloromethane (100 mL) were added triethylamine (Aldrich, 25 mL, 180 mmol) and tosyl chloride (Aldrich, 11.4 g, 60 mmol). The reaction mixture was stirred at room temperature for 16 hours and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to afford the title compound. 1H NMR (300 MHz, chloroform-d) δ ppm 1.17-1.42 (m, 2 H) 1.57-1.69 (m, 1 H), 1.70-1.91 (m, 4 H), 1.93-2.18 (m, 2 H), 2.46 (s, 3 H), 3.86 (d, J=6.4 Hz, 2 H), 7.35 (d, J=8.5 Hz, 2 H), 7.78 (d, J=8.1 Hz, 2 H). washed with water (50 mL) and brine (50 mL) The organic layer was dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography

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

Procedure: To a suspension of lithium aluminum hydride (2.6 g, 69 mmol) in diethyl ether (160 mL,) was added slowly a solution of commercially available ethyl 4,4-difluorocyclohexanecarboxylate (Matrix, 11.0 g, 57 mmol) in diethyl ether (20 mL). The reaction mixture was refluxed for 4 hours, then cooled in an ice bath, quenched cautiously with sequential addition of water (2.6 mL.), 15% NaOH (2.6 mL) and water (7.8 mL) and extracted with ethyl acetate (3×100 mL). The mixture was filtered and concentrated to afford the title compound. The reaction mixture was refluxed for 4 hours cooled in an ice bath quenched cautiously with sequential addition of water (2.6 mL.), 15% NaOH (2.6 mL) and water (7.8 mL) extracted with ethyl acetate (3×100 mL) The mixture was filtered concentrated

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

Procedure: To a suspension of lithium aluminum hydride (2.6 g, 69 mmol) in diethyl ether (160 mL,) was added slowly a solution of commercially available ethyl 4,4-difluorocyclohexanecarboxylate (Matrix, 11.0 g, 57 mmol) in diethyl ether (20 mL). The reaction mixture was refluxed for 4 hours, then cooled in an ice bath, quenched cautiously with sequential addition of water (2.6 mL.), 15% NaOH (2.6 mL) and water (7.8 mL) and extracted with ethyl acetate (3×100 mL). The mixture was filtered and concentrated to afford the title compound. The reaction mixture was refluxed for 4 hours cooled in an ice bath quenched cautiously with sequential addition of water (2.6 mL.), 15% NaOH (2.6 mL) and water (7.8 mL) extracted with ethyl acetate (3×100 mL) The mixture was filtered concentrated

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

Procedure: To a slurry of lithium aluminum hydride (0.24 g) in diethyl ether (15 mL) was added dropwise ethyl 4,4-difluorocyclohexanecarboxylate (1.0 g) in diethyl ether (2 mL). The reaction heated at reflux under nitrogen for 4 hours. The reaction was cooled to 0° C., followed by the careful addition of water (0.24 mL), 4N aqueous NaOH (0.24 mL), and water (0.72 mL). The reaction was diluted with diethyl ether (40 mL) and stirred with sodium sulfate for 30 minutes. The mixture was filtered though diatomaceous earth and the filtrate was concentrated to provide the title compound. The reaction heated at reflux under nitrogen for 4 hours The mixture was filtered though diatomaceous earth the filtrate was concentrated

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

Procedure: Lithium aluminum hydride (0.24 g) was added to diethyl ether (15 mL), to which was then added dropwise ethyl 4,4-difluorocyclohexanecarboxylate (1.0 g) in diethyl ether (2 mL), and the reaction was stirred at reflux under nitrogen for 4 hours. The reaction was cooled to 0° C., followed by the careful addition of water (0.24 mL), 4N aqueous NaOH (0.24 mL), and additional water (0.72 mL). Then Na2SO4 and diethyl ether (40 mL) were added and the mixture was stirred for 30 minutes. After filtration through diatomaceous earth and concentration, the title compound was used in the next step without further purification. at reflux under nitrogen for 4 hours the mixture was stirred for 30 minutes After filtration through diatomaceous earth and concentration the title compound was used in the next step without further purification

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

Procedure: Lithium aluminum hydride (0.24 g) was added to diethyl ether (15 mL), to which was then added dropwise ethyl 4,4-difluorocyclohexanecarboxylate (1.0 g) in diethyl ether (2 mL), and the reaction was stirred at reflux under nitrogen for 4 hours. The reaction was cooled to 0° C., followed by the careful addition of water (0.24 mL), 4N aqueous NaOH (0.24 mL), and additional water (0.72 mL). Then Na2SO4 and diethyl ether (40 mL) were added and the mixture was stirred for 30 minutes. After filtration through diatomaceous earth and concentration, the title compound was used in the next step without further purification. at reflux under nitrogen for 4 hours the mixture was stirred for 30 minutes After filtration through diatomaceous earth and concentration the title compound was used in the next step without further purification