tert-butyl N-(4-hydroxy-2-methylphenyl)carbamate

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

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

Procedure: To a 200 mL round bottomed flask with a stirring bar, and an argon inlet was added 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenol (5.00 g, 22.39 mmol), Cs2CO3 (14.59 g, 44.78 mmol), DMF (50 mL), and ethyl bromoacetate (2.61 mL, 23.51 mmol). This mixture was stirred vigorously at ambient temperature for 24 h. The mixture was filtered through a frit and the DMF was removed under high vacuum. The residue was dissolved in EtOAc (300 mL) and washed with H2O (2×) and brine (1×). Drying (MgSO4), filtration, and removal of the solvent in vacuo gave a solid. This material was triturated with 5% Et2O-hexane, the solid was collected by filtration and dried in vacuo to give 5.40 g (78%) of ethyl 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetate as a white, crystalline solid. The mixture was filtered through a frit the DMF was removed under high vacuum The residue was dissolved in EtOAc (300 mL) washed with H2O (2×) and brine (1×) Drying (MgSO4), filtration, and removal of the solvent in vacuo gave a solid This material was triturated with 5% Et2O-hexane the solid was collected by filtration dried in vacuo

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

Procedure: To a 200 mL round bottomed flask with a stirring bar, and an argon inlet was added 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenol (5.00 g, 22.39 mmol), Cs2CO3 (14.59 g, 44.78 mmol), DMF (50 mL), and ethyl bromoacetate (2.61 mL, 23.51 mmol). This mixture was stirred vigorously at ambient temperature for 24 h. The mixture was filtered through a frit and the DMF was removed under high vacuum. The residue was dissolved in EtOAc (300 mL) and washed with H2O (2×) and brine (1×). Drying (MgSO4), filtration, and removal of the solvent in vacuo gave a solid. This material was triturated with 5% Et2O-hexane, the solid was collected by filtration and dried in vacuo to give 5.40 g (78%) of ethyl 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetate as a white, crystalline solid. The mixture was filtered through a frit the DMF was removed under high vacuum The residue was dissolved in EtOAc (300 mL) washed with H2O (2×) and brine (1×) Drying (MgSO4), filtration, and removal of the solvent in vacuo gave a solid This material was triturated with 5% Et2O-hexane the solid was collected by filtration dried in vacuo

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

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

Procedure: Tri-n-butylphosphine (1.9 mL, 7.5 mmol) and azodicarboxylic acid dipiperidine (1.90 g, 7.54 mmol) are added to a mixture of [4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol (1.50 g, 5.03 mmol), (4-hydroxy-2-methyl-phenyl)-carbamic acid tert-butyl ester (1.35 g, 6.03 mmol) and toluene at room temperature. After 1 h, additional tri-n-butylphosphine (0.6 mL) is added and the mixture is stirred for 2 h. The mixture is concentrated and the residue is purified by flash chromatography (20 to 50% EtOAc/heptane) to give the title compound (1.92 g, 76%). LC-ES/MS m/e 504.2 (M+1). The mixture is concentrated the residue is purified by flash chromatography (20 to 50% EtOAc/heptane)

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

Procedure: Tri-n-butylphosphine (1.9 mL, 7.5 mmol) and azodicarboxylic acid dipiperidine (1.90 g, 7.54 mmol) are added to a mixture of [4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol (1.50 g, 5.03 mmol), (4-hydroxy-2-methyl-phenyl)-carbamic acid tert-butyl ester (1.35 g, 6.03 mmol) and toluene at room temperature. After 1 h, additional tri-n-butylphosphine (0.6 mL) is added and the mixture is stirred for 2 h. The mixture is concentrated and the residue is purified by flash chromatography (20 to 50% EtOAc/heptane) to give the title compound (1.92 g, 76%). LC-ES/MS m/e 504.2 (M+1). The mixture is concentrated the residue is purified by flash chromatography (20 to 50% EtOAc/heptane)

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

Procedure: A solution of tert-butyl 4-hydroxy-2-methylphenylcarbamate (3.0 g, 13.4 mmol), triphenylphosphine (3.53 g, 13.4 mmol), and [3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methanol (3.85 g, 13.4 mmol) in dichloromethane (40 mL) at 0° C. was treated with a solution of diisopropylazidodicarboxylate (2.65 mL, 13.4 mmol) in dichloromethane (10 mL) dropwise. The reaction was allowed to stir at 0° C. for 30 minutes, then warmed to ambient temperature for 1 h after which time the solvent was removed in vacuo. The resulting oil was chromatographed on silica gel eluting with 20% ethyl acetate/hexanes. Yield=4.34 g (66%) of tert-butyl 4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenylcarbamate. warmed to ambient temperature for 1 h after which time the solvent was removed in vacuo The resulting oil was chromatographed on silica gel eluting with 20% ethyl acetate/hexanes

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

Procedure: A solution of tert-butyl 4-hydroxy-2-methylphenylcarbamate (3.0 g, 13.4 mmol), triphenylphosphine (3.53 g, 13.4 mmol), and [3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methanol (3.85 g, 13.4 mmol) in dichloromethane (40 mL) at 0° C. was treated with a solution of diisopropylazidodicarboxylate (2.65 mL, 13.4 mmol) in dichloromethane (10 mL) dropwise. The reaction was allowed to stir at 0° C. for 30 minutes, then warmed to ambient temperature for 1 h after which time the solvent was removed in vacuo. The resulting oil was chromatographed on silica gel eluting with 20% ethyl acetate/hexanes. Yield=4.34 g (66%) of tert-butyl 4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenylcarbamate. warmed to ambient temperature for 1 h after which time the solvent was removed in vacuo The resulting oil was chromatographed on silica gel eluting with 20% ethyl acetate/hexanes

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

Procedure: To a 200 mL round bottomed flask with a stirring bar, and an argon inlet was added 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenol (5.00 g, 22.39 mmot), Cs2CO3 (14.59 g, 44.78 mmol), DMF (50 mL), and bromoacetamide (3.24 g, 23.51 mmol). This mixture was stirred vigorously at ambient temperature for 24 h. The mixture was filtered through a frit and the DMF was removed under high vacuum. The residue was dissolved in EtOAc (300 mL) and washed wit H2O (2×) and brine (1×). Drying (MgSO4), filtration, and removal of the solvent in vacuo gave a solid. This material was triturated with EtOAc, the solid was collected by filtration and dried in vacuo to give 4.91 g (78%) of 4-(1,1-dimethyl-ethoxycarbonyl)amino-3-methylphenoxyacetamide as a white, crystalline solid. The mixture was filtered through a frit the DMF was removed under high vacuum The residue was dissolved in EtOAc (300 mL) washed wit H2O (2×) and brine (1×) Drying (MgSO4), filtration, and removal of the solvent in vacuo gave a solid This material was triturated with EtOAc the solid was collected by filtration dried in vacuo

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

Procedure: To a 200 mL round bottomed flask with a stirring bar, and an argon inlet was added 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenol (5.00 g, 22.39 mmol), Cs2CO3 (14.59 g, 44.78 mmol), DMF (50 mL), and ethyl bromoacetate (2.61 mL, 23.51 mmol). This mixture was stirred vigorously at ambient temperature for 24 h. The mixture was filtered through a frit and the DMF was removed under high vacuum. The residue was dissolved in EtOAc (300 mL) and washed with H2O (2×) and brine (1×). Drying (MgSO4), filtration, and removal of the solvent in vacuo gave a solid. This material was triturated with 5% Et2 O-hexane, the solid was collected by filtration and dried in vacuo to give 5.40 g (78%) of ethyl 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetate as a white, crystalline solid. The mixture was filtered through a frit the DMF was removed under high vacuum The residue was dissolved in EtOAc (300 mL) washed with H2O (2×) and brine (1×) Drying (MgSO4), filtration, and removal of the solvent in vacuo gave a solid This material was triturated with 5% Et2 O-hexane the solid was collected by filtration dried in vacuo