3-methoxy-4-methylsulfanylphenol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Chloro-5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-nicotinamide (150 mg, 0.55 mmol), 4-methylsulfanyl-3-methoxy-phenol (94 mg, 0.55 mmol) and caesium carbonate (358 mg, 1.10 mmol) were suspended in DMF (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 (1.5 ml) and water (1.5 ml) and the organic phase was collected by passing the mixture through a Chemelute™ cartridge, washing with ethyl acetate. The solvent was removed on a Genevac™ and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 96:4, by volume) to give 5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-2-(4-methylsulfanyl-3-methoxy-phenoxy)-nicotinamide (99 mg) as an off-white foam. The reaction was quenched with sat. ammonium chloride solution (1.5 ml) and water (1.5 ml) the organic phase was collected washing with ethyl acetate The solvent was removed on a Genevac™ the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 96:4, by volume)

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Chloro-5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-nicotinamide (150 mg, 0.55 mmol), 4-methylsulfanyl-3-methoxy-phenol (94 mg, 0.55 mmol) and caesium carbonate (358 mg, 1.10 mmol) were suspended in DMF (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 (1.5 ml) and water (1.5 ml) and the organic phase was collected by passing the mixture through a Chemelute™ cartridge, washing with ethyl acetate. The solvent was removed on a Genevac™ and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 96:4, by volume) to give 5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-2-(4-methylsulfanyl-3-methoxy-phenoxy)-nicotinamide (99 mg) as an off-white foam. The reaction was quenched with sat. ammonium chloride solution (1.5 ml) and water (1.5 ml) the organic phase was collected washing with ethyl acetate The solvent was removed on a Genevac™ the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 96:4, by volume)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium borohydride (18.92 g, 0.5 mol) was added portionwise to a solution of 4-(allyloxy)-2-methoxy-1-(methylsulfanyl)benzene (26.0 g, 0.124 mol), and tetrakis(triphenylphosphine)palladium (0) (7.14 g, 6.18 mol) in THF (600 ml) at 5° C. The resultant solution was allowed to warm to RT and then heated to 45° C. for 14 h whilst protected under an atmosphere of nitrogen. After cooling in an ice-bath, the reaction mixture was acidified to pH5 with HCl (2M, 200 ml). Water (200 ml) and EtOAc (300 ml) were added, and the aqueous phase separated and extracted with EtOAc (2×200 ml). The combined organics were dried over MgSO4 and concentrated to a black solid (40 g) which was purified by flash column chromatography on silica gel eluting with EtOAc:pentane (1:9 to 3:7) to afford the title compound as a white solid (11.85 g, 0.07 mol). heated to 45° C. for 14 h After cooling in an ice-bath the aqueous phase separated extracted with EtOAc (2×200 ml) The combined organics were dried over MgSO4 concentrated to a black solid (40 g) which was purified by flash column chromatography on silica gel eluting with EtOAc:pentane (1:9 to 3:7)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium borohydride (18.92 g, 0.5 mol) was added portionwise to a solution of 4-(allyloxy)-2-methoxy-1-(methylsulfanyl)benzene (26.0 g, 0.124 mol), and tetrakis(triphenylphosphine)palladium (0) (7.14 g, 6.18 mol) in THF (600 ml) at 5° C. The resultant solution was allowed to warm to RT and then heated to 45° C. for 14 h whilst protected under an atmosphere of nitrogen. After cooling in an ice-bath, the reaction mixture was acidified to pH5 with HCl (2M, 200 ml). Water (200 ml) and EtOAc (300 ml) were added, and the aqueous phase separated and extracted with EtOAc (2×200 ml). The combined organics were dried over MgSO4 and concentrated to a black solid (40 g) which was purified by flash column chromatography on silica gel eluting with EtOAc:pentane (1:9 to 3:7) to afford the title compound as a white solid (11.85 g, 0.07 mol). heated to 45° C. for 14 h After cooling in an ice-bath the aqueous phase separated extracted with EtOAc (2×200 ml) The combined organics were dried over MgSO4 concentrated to a black solid (40 g) which was purified by flash column chromatography on silica gel eluting with EtOAc:pentane (1:9 to 3:7)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The benzylether from stage (iii) (9.27 g, 39.5 mmol) was dissolved in DCM (5 mL), ethanethiol (5 mL) and BF3.OEt2 (5 mL, 39.5 mol) were then added at room temperature under a nitrogen atmosphere. The mixture was stirred overnight before the reaction was quenched with hydrochloric acid (2 M) and stirred for a further 30 mins. The mixture was then basified by the addition of sodium hydroxide (2 M) until pH 10 was attained. The mixture was then washed with ethyl acetate (3×50 mL). The aqueous layer was reacidified by the addition of hydrochloric acid (2 M) to pH 1 and extracted with ethyl acetate (4×50 mL). The extracts were combined, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography [SiO2; EtOAc/ pentane (1:9→1:4)] afforded the desired phenol compound as a colourless solid (1.73 g, 28%); δH(CDCI3, 400 MHz) 2.21 (3 H, s), 3.70 (3 H, s), 6.30 (1 H, d), 6.35 (1 H, s), 6.96 (1 H, d), 9.39 (1 H, brs) was quenched with hydrochloric acid (2 M) stirred for a further 30 mins The mixture was then basified by the addition of sodium hydroxide (2 M) until pH 10 The mixture was then washed with ethyl acetate (3×50 mL) The aqueous layer was reacidified by the addition of hydrochloric acid (2 M) to pH 1 extracted with ethyl acetate (4×50 mL) dried (MgSO4) evaporated to an oil Purification by flash chromatography [SiO2; EtOAc/ pentane (1:9→1:4)]

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The benzylether from stage (iii) (9.27 g, 39.5 mmol) was dissolved in DCM (5 mL), ethanethiol (5 mL) and BF3.OEt2 (5 mL, 39.5 mol) were then added at room temperature under a nitrogen atmosphere. The mixture was stirred overnight before the reaction was quenched with 2M HCl and stirred for a further 30 min. The mixture was then basified by the addition of 2M NaOH until pH 10 was attained. The mixture was then washed with EtOAc (3×50 mL). The aqueous layer was re-acidified by the addition of 2M HCl to pH 1 and extracted with EtOAc (4×50 mL). The extracts were combined, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography [SiO2; EtOAc/pentane (1:9→1:4)] afforded the desired phenol compound as a colourless solid (1.73 g, 28%); δH (CDCl3, 400 MHz) 2.21 (3H, s), 3.70 (3H, s), 6.30 (1H, d), 6.35 (1H, s), 6.96 (1H, d), 9.39 (1H, brs). was quenched with 2M HCl stirred for a further 30 min The mixture was then basified by the addition of 2M NaOH until pH 10 The mixture was then washed with EtOAc (3×50 mL) The aqueous layer was re-acidified by the addition of 2M HCl to pH 1 extracted with EtOAc (4×50 mL) dried (MgSO4) evaporated to an oil Purification by flash chromatography [SiO2; EtOAc/pentane (1:9→1:4)]

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Chloro-5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-nicotinamide (150 mg, 0.55 mmol), 4-methylsulfanyl-3-methoxy-phenol (94 mg, 0.55 mmol) and caesium carbonate (358 mg, 1.10 mmol) were suspended in DMF (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 (1.5 ml) and water (1.5 ml) and the organic phase was collected by passing the mixture through a Chemelute™ cartridge, washing with ethyl acetate. The solvent was removed on a Genevac™ and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 96:4, by volume) to give 5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-2-(4-methylsulfanyl-3-methoxy-phenoxy)-nicotinamide (99 mg) as an off-white foam. The reaction was quenched with sat. ammonium chloride solution (1.5 ml) and water (1.5 ml) the organic phase was collected washing with ethyl acetate The solvent was removed on a Genevac™ the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 96:4, by volume)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium borohydride (18.92 g, 0.5 mol) was added portionwise to a solution of 4-(allyloxy)-2-methoxy-1-(methylsulfanyl)benzene (26.0 g, 0.124 mol), and tetrakis(triphenylphosphine)palladium (0) (7.14 g, 6.18 mol) in THF (600 ml) at 5° C. The resultant solution was allowed to warm to RT and then heated to 45° C. for 14 h whilst protected under an atmosphere of nitrogen. After cooling in an ice-bath, the reaction mixture was acidified to pH5 with HCl (2M, 200 ml). Water (200 ml) and EtOAc (300 ml) were added, and the aqueous phase separated and extracted with EtOAc (2×200 ml). The combined organics were dried over MgSO4 and concentrated to a black solid (40 g) which was purified by flash column chromatography on silica gel eluting with EtOAc:pentane (1:9 to 3:7) to afford the title compound as a white solid (11.85 g, 0.07 mol). heated to 45° C. for 14 h After cooling in an ice-bath the aqueous phase separated extracted with EtOAc (2×200 ml) The combined organics were dried over MgSO4 concentrated to a black solid (40 g) which was purified by flash column chromatography on silica gel eluting with EtOAc:pentane (1:9 to 3:7)