2-amino-4-tert-butylphenol

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

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

Procedure: In a 100 ml round bottom flask was placed 7.25 g (0.044 mol) of 2-Amino-4-tert-butylphenol, (Aldrich Cat #193282) with 6.0 g (0.055 mol) of Methyl acetimidate hydrochloride (Aldrich Cat #254940) with 50 ml of MeOH. This was refluxed for 4 hours. Then the MeOH was removed under vacuum. This was separated between 50 ml of ether and 50 ml of water. The ether was separated, dried, and removed under vacuum. Then 50 ml of hexanes was added to the resulting solid. Remaining 2-Amino-4-tert-butylphenol was insoluble in hexanes and was removed by filtration. The remaining oil was chromatographed using 2% MeOH/CH2Cl2 to provide 5-tert-butyl-2-methylbenzoxazole (Yield=2 g, 24%). In a 100 ml round bottom flask was placed This was refluxed for 4 hours Then the MeOH was removed under vacuum This was separated between 50 ml of ether and 50 ml of water The ether was separated dried removed under vacuum Then 50 ml of hexanes was added to the resulting solid was removed by filtration The remaining oil was chromatographed

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

Procedure: A mixture of 0.66 g of 2-chloro-5-trifluoromethyl isonicotinic acid and 4 ml of thionyl chloride was heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to give 2-chloro-5-trifluoromethyl isonicotinic acid chloride. A mixture of the resultant 2-chloro-5-trifluoromethyl isonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 0.48 g of 2-amino-4-tert-butylphenol, 0.59 g of triethylamine and 4 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour, and stirred while heating at 50° C. for one hour. The mixture was cooled to room temperature, and water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.75 g of N-(5-tert-butyl-2-hydroxyphenyl)-2-chloro-5-trifluoromethylisonicotinamide. cooling stirred while heating at 50° C. for one hour The mixture was cooled to room temperature followed by extraction with ethyl acetate twice The combined organic layers were washed with water a saturated sodium chloride solution, dried over anhydrous magnesium sulfate concentrated under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.5 g of 3-fluoroisonicotinic acid, 5 ml of thionyl chloride and 50 mg of DMF was heated to reflux for two hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure to give 3-fluoroisonicotinic acid chloride. A mixture of the resultant 3-fluoroisonicotinic acid chloride and 5 ml of DMF was added dropwise to a mixture of 1.76 g of 2-amino-4-tert-butylphenol, 2.18 g of triethylamine and 10 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hours and at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then water was added. Precipitated crystals were collected by filtration. The resultant crystals were dissolved in ethyl acetate, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give 2.41 g of N-(5-tert-butyl-2-hydroxyphenyl)-3-fluoroisonicotinamide. cooling The reaction mixture was cooled to room temperature Precipitated crystals were collected by filtration The resultant crystals were dissolved in ethyl acetate washed with water a saturated sodium chloride solution, dried over anhydrous magnesium sulfate concentrated under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.5 g of 3-fluoroisonicotinic acid, 5 ml of thionyl chloride and 50 mg of DMF was heated to reflux for two hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure to give 3-fluoroisonicotinic acid chloride. A mixture of the resultant 3-fluoroisonicotinic acid chloride and 5 ml of DMF was added dropwise to a mixture of 1.76 g of 2-amino-4-tert-butylphenol, 2.18 g of triethylamine and 10 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hours and at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then water was added. Precipitated crystals were collected by filtration. The resultant crystals were dissolved in ethyl acetate, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give 2.41 g of N-(5-tert-butyl-2-hydroxyphenyl)-3-fluoroisonicotinamide. cooling The reaction mixture was cooled to room temperature Precipitated crystals were collected by filtration The resultant crystals were dissolved in ethyl acetate washed with water a saturated sodium chloride solution, dried over anhydrous magnesium sulfate concentrated under reduced pressure

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

Procedure: Commercially available 4-t-butyl phenol (30 g, 0.2 mole) was dissolved in 200 mL ethyl acetate in a 600-mL round-bottomed flask fitted with a mechanical stirrer, and cooled to 0° C. The mixture was treated with nitric acid (13 mL, in 13 mL water) dropwise over 10 min and then a catalytic amount of NaNO2. After 45 min the reaction was washed with excess 1N HCl and the organic layer was dried over MgSO4 and stripped to yield 37 g of 2-nitro-4-t-butyl phenol. This nitrophenol (37 g, 0.19 mole) was dissolved in 100 mL ethyl acetate and placed into a Parr bottle with a teaspoon of 10% Pd/C. The mixture was placed on a hydrogenator under 50 psi hydrogen with agitation for 1 hr. The catalyst was filtered off through celite, and the ethyl acetate was stripped off under vacuum. The material crystallized with the addition of about 200 mL heptane to give 25.6 g of the corresponding amine (2-amino-4-t-butyl phenol). The catalyst was filtered off through celite The material crystallized with the addition of about 200 mL heptane

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

Procedure: Commercially available 4-t-butyl phenol (30 g, 0.2 mole) was dissolved in 200 mL ethyl acetate in a 600-mL round-bottomed flask fitted with a mechanical stirrer, and cooled to 0° C. The mixture was treated with nitric acid (13 mL, in 13 mL water) dropwise over 10 min and then a catalytic amount of NaNO2. After 45 min the reaction was washed with excess 1N HCl and the organic layer was dried over MgSO4 and stripped to yield 37 g of 2-nitro-4-t-butyl phenol. This nitrophenol (37 g, 0.19 mole) was dissolved in 100 mL ethyl acetate and placed into a Parr bottle with a teaspoon of 10% Pd/C. The mixture was placed on a hydrogenator under 50 psi hydrogen with agitation for 1 hr. The catalyst was filtered off through celite, and the ethyl acetate was stripped off under vacuum. The material crystallized with the addition of about 200 mL heptane to give 25.6 g of the corresponding amine (2-amino-4-t-butyl phenol). The catalyst was filtered off through celite The material crystallized with the addition of about 200 mL heptane

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

Procedure: In a 100 ml round bottom flask was placed 7.25 g (0.044 mol) of 2-Amino-4-tert-butylphenol, (Aldrich Cat #193282) with 6.0 g (0.055 mol) of Methyl acetimidate hydrochloride (Aldrich Cat #254940) with 50 ml of MeOH. This was refluxed for 4 hours. Then the MeOH was removed under vacuum. This was separated between 50 ml of ether and 50 ml of water. The ether was separated, dried, and removed under vacuum. Then 50 ml of hexanes was added to the resulting solid. Remaining 2-Amino-4-tert-butylphenol was insoluble in hexanes and was removed by filtration. The remaining oil was chromatographed using 2% MeOH/CH2Cl2 to provide 5-tert-butyl-2-methylbenzoxazole (Yield=2 g, 24%). In a 100 ml round bottom flask was placed This was refluxed for 4 hours Then the MeOH was removed under vacuum This was separated between 50 ml of ether and 50 ml of water The ether was separated dried removed under vacuum Then 50 ml of hexanes was added to the resulting solid was removed by filtration The remaining oil was chromatographed

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

Procedure: In a 100 ml round bottom flask was placed 7.25 g (0.044 mol) of 2-Amino-4-tert-butylphenol, (Aldrich Cat #193282) with 6.0 g (0.055 mol) of Methyl acetimidate hydrochloride (Aldrich Cat #254940) with 50 ml of MeOH. This was refluxed for 4 hours. Then the MeOH was removed under vacuum. This was separated between 50 ml of ether and 50 ml of water. The ether was separated, dried, and removed under vacuum. Then 50 ml of hexanes was added to the resulting solid. Remaining 2-Amino-4-tert-butylphenol was insoluble in hexanes and was removed by filtration. The remaining oil was chromatographed using 2% MeOH/CH2Cl2 to provide 5-tert-butyl-2-methylbenzoxazole (Yield=2 g, 24%). In a 100 ml round bottom flask was placed This was refluxed for 4 hours Then the MeOH was removed under vacuum This was separated between 50 ml of ether and 50 ml of water The ether was separated dried removed under vacuum Then 50 ml of hexanes was added to the resulting solid was removed by filtration The remaining oil was chromatographed

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

Procedure: Commercially available 4-t-butyl phenol (30 g, 0.2 mole) is dissolved in 200 ml ethyl acetate in a 500 ml round bottom flask fitted with a mechanical stirrer, and cooled to 0° C. The mixture is treated with nitric acid (13 ml, in 13 ml water) dropwise over 10 minutes and then a catalytic amount of NaNO2. After 45 minutes the reaction is washed with excess 1N HCl and the organic layer is dried over MgSO4 and stripped to yield 37 g of 2-nitro-4-t-butyl phenol. This nitrophenol (37 g, 0.19 mole) is dissolved in 100 ml ethyl acetate and placed into a parr bottle with a teaspoon of 10% Pd/C. The mixture is placed on a hydrogenator under 50 psi hydrogen with agitation for one hour. The catalyst is filtered off through celite, and the ethyl acetate is stripped off under vacuum. The material crystallizes with the addition of about 200 ml heptane to give 25.6 g of the corresponding amine (2-amino-4-t-butyl phenol). The catalyst is filtered off through celite The material crystallizes with the addition of about 200 ml heptane

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

Procedure: 2-Amino-4-(1,1dimethylethyl)phenol (90.0 g, 546 mol, described in Example 1) was dissolved in acetone (900 ml) and heated at reflux for 2 days in the presence of anhydrous potassium carbonate (81.0 g, 534 mmol) and chloroacetonitrile (40.5 g, 535 mmol). The mixture was allowed to stand for an additional day at 20°-24° C. The mixture then was treated with more potassium carbonate (15.0 g) and chloroacetonitrile (10 g) under the same conditions. The mixture was mixed with charcoal and filtered through diatomaceous earth. The filtrate was evaporated to afford a residue which, when dissolved in hexane containing a small amount of ethyl acetate, afforded tan crystals of the title compound; Anal. Calc'd for C12H16N2O: C, 70.56%; H, 7.90%; N, 13.72%; Found: C, 70.60% H, 8.00%; N, 13.85%; IR(CHCl3) 3460, 3380, 2240, 1620, 1515, 1166, cm-1 ; NMR(CDCl3) δ 1.3 (s, 9H), 3.7 (s,2H), 4.7 (s,2H), 6.75 (s, 3H). heated to stand for an additional day at 20°-24° C filtered through diatomaceous earth The filtrate was evaporated to afford a residue which, when

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