3-ethylsulfanylphenol

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

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

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-5-fluoro-N-[cis-4-(2-methoxy-acetylamino)-cyclohexyl]-nicotinamide (110 mg, 0.32 mmol), 3-ethylsulfanyl-phenol (54 mg, 0.35 mmol) and caesium carbonate (156 mg, 0.48 mmol) were suspended in dimethylformamide (2 ml) and the reaction was heated to 55° C. and stirred at this temperature under nitrogen for 18 h. The reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20 ml). The solvent was removed under reduced pressure and the residue was triturated with diethylether (5 ml) to give 2-(3-ethylsulfanyl-phenoxy)-5-fluoro-N-[cis-4-(2-methoxy-acetylamino)-cyclohexyl]-nicotinamide (57 mg) as an off-white solid. The reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1 ml) the organic phase was collected washing with ethyl acetate (20 ml) The solvent was removed under reduced pressure the residue was triturated with diethylether (5 ml)

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-5-fluoro-N-[cis-4-(2-methoxy-acetylamino)-cyclohexyl]-nicotinamide (110 mg, 0.32 mmol), 3-ethylsulfanyl-phenol (54 mg, 0.35 mmol) and caesium carbonate (156 mg, 0.48 mmol) were suspended in dimethylformamide (2 ml) and the reaction was heated to 55° C. and stirred at this temperature under nitrogen for 18 h. The reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20 ml). The solvent was removed under reduced pressure and the residue was triturated with diethylether (5 ml) to give 2-(3-ethylsulfanyl-phenoxy)-5-fluoro-N-[cis-4-(2-methoxy-acetylamino)-cyclohexyl]-nicotinamide (57 mg) as an off-white solid. The reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1 ml) the organic phase was collected washing with ethyl acetate (20 ml) The solvent was removed under reduced pressure the residue was triturated with diethylether (5 ml)

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

Procedure: Ethyl 2-chloro-5-fluoro-nicotinate (J. Med. Chem. 1993, 36, 2676, M. Winn et. al.) (5.0 g, 24 mmol), 3-ethylsulfanylphenol (3.8 g, 24 mmol) and caesium carbonate (7.98 g, 24 mmol) were suspended in dioxan (50 ml) and the reaction was heated to 100° C. and stirred at this temperature under nitrogen for 8 h. The reaction was cooled to room temperature, filtered and the solid washed with ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with cyclohexane:ethyl acetate (95:5) to give 5-fluoro-2-(3-ethylsulfanyl-phenoxy)-nicotinic acid ethyl ester (1.16 g). The reaction was cooled to room temperature filtered the solid washed with ethyl acetate (50 ml) The filtrate was concentrated under reduced pressure the residue was purified by flash column chromatography on silica gel eluting with cyclohexane:ethyl acetate (95:5)

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

Procedure: Boron tribromide (1M in dichloromethane, 70 ml, 70 mmol) was added dropwise to a solution of 1-(ethylsulfanyl)-3-methoxybenzene (5.9 g, 35 mmol) in dichloromethane (150 ml) at 0° C. The mixture was allowed to warm to room temperature, stirred for 18 h then cooled to 0° C. A solution of diethanolamine (20 ml) in dichloromethane (40 ml) was added dropwise (Caution—strong exotherm!) and the mixture was stirred at ambient temperature for 15 min once addition was complete, then poured onto ice water. The mixture was extracted with dichloromethane and the organic phase was washed with 2N hydrochloric acid, water, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (20:80 to 30:70) as eluant to give 3-(ethylsulfanyl)phenol (4.53 g) as a colourless oil. then cooled to 0° C the mixture was stirred at ambient temperature for 15 min once addition poured onto ice water The mixture was extracted with dichloromethane the organic phase was washed with 2N hydrochloric acid, water dried over MgSO4 the solvent removed under reduced pressure The residue was purified by flash column chromatography

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

Procedure: Boron tribromide (1M in dichloromethane, 70 ml, 70 mmol) was added dropwise to a solution of 1-(ethylsulfanyl)-3-methoxybenzene (5.9 g, 35 mmol) in dichloromethane (150 ml) at 0° C. The mixture was allowed to warm to room temperature, stirred for 18 h then cooled to 0° C. A solution of diethanolamine (20 ml) in dichloromethane (40 ml) was added dropwise (Caution—strong exotherm!) and the mixture was stirred at ambient temperature for 15 min once addition was complete, then poured onto ice water. The mixture was extracted with dichloromethane and the organic phase was washed with 2N hydrochloric acid, water, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (20:80 to 30:70) as eluant to give 3-(ethylsulfanyl)phenol (4.53 g) as a colourless oil. then cooled to 0° C the mixture was stirred at ambient temperature for 15 min once addition poured onto ice water The mixture was extracted with dichloromethane the organic phase was washed with 2N hydrochloric acid, water dried over MgSO4 the solvent removed under reduced pressure The residue was purified by flash column chromatography

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

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

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-5-fluoro-N-[cis-4-(2-methoxy-acetylamino)-cyclohexyl]-nicotinamide (110 mg, 0.32 mmol), 3-ethylsulfanyl-phenol (54 mg, 0.35 mmol) and caesium carbonate (156 mg, 0.48 mmol) were suspended in dimethylformamide (2 ml) and the reaction was heated to 55° C. and stirred at this temperature under nitrogen for 18 h. The reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20 ml). The solvent was removed under reduced pressure and the residue was triturated with diethylether (5 ml) to give 2-(3-ethylsulfanyl-phenoxy)-5-fluoro-N-[cis-4-(2-methoxy-acetylamino)-cyclohexyl]-nicotinamide (57 mg) as an off-white solid. The reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1 ml) the organic phase was collected washing with ethyl acetate (20 ml) The solvent was removed under reduced pressure the residue was triturated with diethylether (5 ml)

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

Procedure: Ethyl 2-chloro-5-fluoro-nicotinate (J. Med. Chem. 1993, 36, 2676, M. Winn et. al.) (5.0 g, 24 mmol), 3-ethylsulfanylphenol (3.8 g, 24 mmol) and caesium carbonate (7.98 g, 24 mmol) were suspended in dioxan (50 ml) and the reaction was heated to 100° C. and stirred at this temperature under nitrogen for 8 h. The reaction was cooled to room temperature, filtered and the solid washed with ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with cyclohexane:ethyl acetate (95:5) to give 5-fluoro-2-(3-ethylsulfanyl-phenoxy)-nicotinic acid ethyl ester (1.16 g). The reaction was cooled to room temperature filtered the solid washed with ethyl acetate (50 ml) The filtrate was concentrated under reduced pressure the residue was purified by flash column chromatography on silica gel eluting with cyclohexane:ethyl acetate (95:5)

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

Procedure: Boron tribromide (1M in dichloromethane, 70 ml, 70 mmol) was added dropwise to a solution of 1-(ethylsulfanyl)-3-methoxybenzene (5.9 g, 35 mmol) in dichloromethane (150 ml) at 0° C. The mixture was allowed to warm to room temperature, stirred for 18 h then cooled to 0° C. A solution of diethanolamine (20 ml) in dichloromethane (40 ml) was added dropwise (Caution—strong exotherm!) and the mixture was stirred at ambient temperature for 15 min once addition was complete, then poured onto ice water. The mixture was extracted with dichloromethane and the organic phase was washed with 2N hydrochloric acid, water, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (20:80 to 30:70) as eluant to give 3-(ethylsulfanyl)phenol (4.53 g) as a colourless oil. then cooled to 0° C the mixture was stirred at ambient temperature for 15 min once addition poured onto ice water The mixture was extracted with dichloromethane the organic phase was washed with 2N hydrochloric acid, water dried over MgSO4 the solvent removed under reduced pressure The residue was purified by flash column chromatography