5-tert-butyl-2-hydroxybenzaldehyde

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

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At −30° C. 4.84 g nitroniumtetrafluoroborate are added to a solution of 5.00 g 5-tert-butyl-2-hydroxy-benzaldehyde in 200 ml acetonitrile. The solution is heated to −15° C. within 1 h and then combined with ethyl acetate and saturated aqueous NaHCO3 solution. The resulting mixture is extracted with ethyl acetate, and the combined extracts are washed with saturated aqueous saline solution, dried (MgSO4) and evaporated down. The residue is taken up in 2 ml of water and 40 ml concentrated acetic acid, and the resulting mixture is refluxed for 2 h. The cooled solution is poured into ice-cold water, and the precipitate formed is filtered off and dissolved in ethyl acetate. The organic solution is dried (MgSO4) and evaporated down. The oil remaining rapidly solidifies. At −30° C The resulting mixture is extracted with ethyl acetate the combined extracts are washed with saturated aqueous saline solution dried (MgSO4) evaporated down 40 ml concentrated acetic acid, and the resulting mixture is refluxed for 2 h The cooled solution is poured into ice-cold water the precipitate formed is filtered off dissolved in ethyl acetate The organic solution is dried (MgSO4) evaporated down

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

Procedure: Sulfamic acid (1.76 g, 18.1 mmol) and sodium dihydrogenphosphate (7.33 g, 47 mmol) were added to a solution of 5-[(1,1-dimethyl)ethyl]-2-hydroxybenzaldehyde (2.15 g, 12.1 mmol) in 1,4-dioxane (100 mL) and water (40 mL). A solution of sodium chlorite (1.76 g, 15.5 mmol) in water (10 mL) was added to the mixture under ice cooling, and it was stirred for 1 hour. Then, sodium sulfite (1.80 g, 14.3 mmol) was added to the mixture, and it was stirred for 30 minutes. Concentrated hydrochloric acid was added to the reaction mixture, and pH was adjusted to 1. The residue obtained by evaporation of 1,4-dioxane under reduced pressure was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with n-hexane under suspension to give the title compound (1.81 g, 77.4%) as a white powder. was stirred for 30 minutes was extracted with ethyl acetate The organic layer was washed with water and brine dried over anhydrous magnesium sulfate The residue obtained by evaporation of the solvent under reduced pressure was washed with n-hexane under suspension

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of compound 2 (614.5 g, 3.33 mol) in DMF (3.5 L) was added K2CO3 (953 g, 6.90 mol) and benzyl chloride (480 g, 3.80 mol). The mixture was heated to 90° C. and left stirring for 3 hours. The suspension was cooled to room temperature, then MTBE (2 L) was added, followed by water (12 L). The mixture was then stirred for 10 minutes and the aqueous layer was separated and extracted with MTBE (2 L×3). The organic layers were combined and washed with water (2 L×2) and brine (1.5 L×1) and concentrated to give compound 3 as a light-yellow solid. 1H NMR (DMSO-d6; 400 MHz) δ 10.42 (s), δ 7.71 (m), δ 7.51 (m), δ 7.43 (m), δ 7.35 (m), δ 7.24 (m), δ 5.27 (s), δ 1.26 (s). left The suspension was cooled to room temperature The mixture was then stirred for 10 minutes the aqueous layer was separated extracted with MTBE (2 L×3) washed with water (2 L×2) and brine (1.5 L×1) concentrated

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of compound 2 (614.5 g, 3.33 mol) in DMF (3.5 L) was added K2CO3 (953 g, 6.90 mol) and benzyl chloride (480 g, 3.80 mol). The mixture was heated to 90° C. and left stirring for 3 hours. The suspension was cooled to room temperature, then MTBE (2 L) was added, followed by water (12 L). The mixture was then stirred for 10 minutes and the aqueous layer was separated and extracted with MTBE (2 L×3). The organic layers were combined and washed with water (2 L×2) and brine (1.5 L×1) and concentrated to give compound 3 as a light-yellow solid. 1H NMR (DMSO-d6; 400 MHz) δ 10.42 (s), δ 7.71 (m), δ 7.51 (m), δ 7.43 (m), δ 7.35 (m), δ 7.24 (m), δ 5.27 (s), δ 1.26 (s). left The suspension was cooled to room temperature The mixture was then stirred for 10 minutes the aqueous layer was separated extracted with MTBE (2 L×3) washed with water (2 L×2) and brine (1.5 L×1) concentrated

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-6,7-dimethoxyquinoline (111 mg), 5-tert-butyl-2-hydroxybenzaldehyde (356 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 5-(tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde. The reaction solution was cooled to room temperature the mixture was extracted with ethyl acetate The ethyl acetate layer was then washed with water and saturated brine was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure the residue was purified by chromatography on silica gel

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-6,7-dimethoxyquinoline (111 mg), 5-tert-butyl-2-hydroxybenzaldehyde (356 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 5-(tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde. The reaction solution was cooled to room temperature the mixture was extracted with ethyl acetate The ethyl acetate layer was then washed with water and saturated brine was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure the residue was purified by chromatography on silica gel

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

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

Procedure: 5-tert-Butyl-2-hydroxy-benzaldehyde (1.4 g, 6.0 mmol, prepared according to Smith W. E. J. Org. Chem. 1972, 37, 3972-3973) was taken up in 30 mL of a 2M solution of 2-methyl-2-butene in tetrahydrofuran. t-Butanol (30 mL) was added. Sodium dihydrogenphosphate (2.6 g, 18.8 mmol) and sodium chlorite (1.4 g, 12.3 mmol) were then added as a solution in 12 mL of water. The reaction mixture was stirred at room temperature for 2 h. It was diluted with ethyl acetate and washed with 1N hydrochloric acid. The aqueous layers were extracted three times with ethyl acetate. The combined organic layers were washed with a saturated solution of Na2S2O3, brine, and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated to give 5-tert-butyl-2-hydroxy-benzoic acid (1.5 g, quant.), which was used in the next step without further purification. washed with 1N hydrochloric acid The aqueous layers were extracted three times with ethyl acetate The combined organic layers were washed with a saturated solution of Na2S2O3, brine dried over anhydrous magnesium sulfate The solids were filtered off the filtrate was concentrated

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

Procedure: 5-tert-Butyl-2-hydroxy-benzaldehyde (1.4 g, 6.0 mmol, prepared according to Smith W. E. J. Org. Chem. 1972, 37, 3972-3973) was taken up in 30 mL of a 2M solution of 2-methyl-2-butene in tetrahydrofuran. t-Butanol (30 mL) was added. Sodium dihydrogenphosphate (2.6 g, 18.8 mmol) and sodium chlorite (1.4 g, 12.3 mmol) were then added as a solution in 12 mL of water. The reaction mixture was stirred at room temperature for 2 h. It was diluted with ethyl acetate and washed with 1N hydrochloric acid. The aqueous layers were extracted three times with ethyl acetate. The combined organic layers were washed with a saturated solution of Na2S2O3, brine, and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated to give 5-tert-butyl-2-hydroxy-benzoic acid (1.5 g, quant.), which was used in the next step without further purification. washed with 1N hydrochloric acid The aqueous layers were extracted three times with ethyl acetate The combined organic layers were washed with a saturated solution of Na2S2O3, brine dried over anhydrous magnesium sulfate The solids were filtered off the filtrate was concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 0.50 g of 5-tert-butyl-2-hydroxybenzaldehyde, 0.48 g of 4-(chloromethyl)pyridine hydrochloride, 0.78 g of potassium carbonate, 0.49 g of potassium iodide and 10 ml of DMF was stirred at 80° C. for 2 hours. Subsequently, 0.78 g of potassium carbonate was added to the reaction mixture, and the mixture was stirred at 150° C. for 8 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. This solid was dissolved in ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.48 g of 4-(5-tert-butylbenzofuran-2-yl)pyridine (hereinafter, referred to as “Present Active Compound 1”). the mixture was stirred at 150° C. for 8 hours The reaction mixture was cooled to room temperature the precipitated solid was collected by filtration This solid was dissolved in ethyl acetate The organic layer was washed with water and saturated brine dried over sodium sulfate concentrated under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 0.50 g of 5-tert-butyl-2-hydroxybenzaldehyde, 0.48 g of 4-(chloromethyl)pyridine hydrochloride, 0.78 g of potassium carbonate, 0.49 g of potassium iodide and 10 ml of DMF was stirred at 80° C. for 2 hours. Subsequently, 0.78 g of potassium carbonate was added to the reaction mixture, and the mixture was stirred at 150° C. for 8 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. This solid was dissolved in ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.48 g of 4-(5-tert-butylbenzofuran-2-yl)pyridine (hereinafter, referred to as “Present Active Compound 1”). the mixture was stirred at 150° C. for 8 hours The reaction mixture was cooled to room temperature the precipitated solid was collected by filtration This solid was dissolved in ethyl acetate The organic layer was washed with water and saturated brine dried over sodium sulfate concentrated under reduced pressure