ethyl 5-chloro-2-hydroxybenzoate

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 5-chlorosalicylate (147 mg), 4-chloro-6,7-dimethoxyquinoline (165 mg), and 4-dimethylaminopyridine (270 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (41 mg, yield 15%). The reaction solution was cooled to room temperature the solvent was removed by distillation under the reduced pressure Water was then added to the residue the mixture was extracted with chloroform The chloroform layer was washed with water was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure the residue was purified by column chromatography

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

Procedure: 5-Chlorosalicylic acid (344 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-chlorosalicylate (147 mg, yield 37%). to prepare a solution which the mixture was extracted with ethyl acetate The ethyl acetate layer was then washed with water was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure the residue was purified by column chromatography

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 5-chlorosalicylate (147 mg), 4-chloro-6,7-dimethoxyquinoline (165 mg), and 4-dimethylaminopyridine (270 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (41 mg, yield 15%). The reaction solution was cooled to room temperature the solvent was removed by distillation under the reduced pressure Water was then added to the residue the mixture was extracted with chloroform The chloroform layer was washed with water was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure the residue was purified by column chromatography

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

Procedure: 5-Chlorosalicylic acid (344 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-chlorosalicylate (147 mg, yield 37%). to prepare a solution which the mixture was extracted with ethyl acetate The ethyl acetate layer was then washed with water was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure the residue was purified by column chromatography

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

Procedure: To a suspension of 5-chlorosalicylic acid (500 g) in ethanol (2 L) was added concentrated sulphuric acid (40 ml) with stirring at room temperature. After the reaction mixture was refluxed for 12 hours, the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% NaCl solution and 4% sodium hydrogen carbonate solution, and then evaporated under reduced pressure, dried over anhydrous magnesium sulphate. After filtration, the solvent was evaporated under reduced pressure to give the title compound (514 g, 88%) as a pale-yellow oil. After the reaction mixture was refluxed for 12 hours the solvent was evaporated under reduced pressure the residue was dissolved in ethyl acetate The organic layer was washed with 10% NaCl solution and 4% sodium hydrogen carbonate solution evaporated under reduced pressure dried over anhydrous magnesium sulphate After filtration the solvent was evaporated under reduced pressure

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

Procedure: A solution of 5-chlorosalicylic acid (5.0 g) in ethanol (50 mL) was added with concentrated sulfuric acid (2.0 mL), and heated under reflux for 24 hours. After the ethanol was evaporated under reduced pressure, the resultant oil was dissolved in ethyl acetate, and the solution was washed with saturated aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to obtain roughly purified 5-chlorosalicylic acid ethyl ester (5.3 g). This product was treated with 70% nitric acid (7.2 mL, d=1.42) in acetic anhydride (40 mL) under ice cooling. The reaction mixture was stirred at the same temperature for 6 hours, and poured into iced water, and the deposited crystals were collected by filtration. The crystals were washed with water, and dried under reduced pressure to obtain the title compound (1.48 g). heated under reflux for 24 hours After the ethanol was evaporated under reduced pressure the resultant oil was dissolved in ethyl acetate the solution was washed with saturated aqueous solution of sodium hydrogencarbonate The ethyl acetate layer was washed successively with water and saturated brine dried over anhydrous magnesium sulfate Then, the solvent was evaporated under reduced pressure

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

Procedure: A solution of 124.8 g of ethyl iodide in 200 ml of anhydrous ether was added dropwise to a stirred dispersion of 19.5 g of magnesium turnings in 100 ml of anhydrous ether and the mixture was refluxed for 45 minutes and cooled in a ice water bath. A solution of 37.2 g of ethyl 5-chloro-salicylate in 120 ml of anhydrous ether was added thereto dropwise and the ether was distilled off while being replaced with 350 ml of anhydrous benzene. The solution was refluxed for 6 hours and was then cooled to room temperature and poured into an ice solution of 2 N hydrochloric acid. The decanted aqueous phase was washed 3 times with 75 ml of ether and the ether phase was washed twice with 100 ml of water until the wash water was neutral. The organic phase was dried over magnesium sulfate, was treated with activated carbon and was filtered. The filtrate was evaporated to dryness to obtain 38.3 g of raw product which was crystallized from 100 ml of cyclohexane and dried to obtain 27.5 g of 5-chloro-α,α-diethyl-2-hydroxy-benzene-methanol melting at 76° C. the mixture was refluxed for 45 minutes cooled in a ice water bath dropwise and the ether was distilled off The solution was refluxed for 6 hours poured into an ice solution of 2 N hydrochloric acid The decanted aqueous phase was washed 3 times with 75 ml of ether the ether phase was washed twice with 100 ml of water until the wash water The organic phase was dried over magnesium sulfate was treated with activated carbon was filtered The filtrate was evaporated to dryness to obtain 38.3 g of raw product which was crystallized from 100 ml of cyclohexane dried

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 5-chlorosalicylate (147 mg), 4-chloro-6,7-dimethoxyquinoline (165 mg), and 4-dimethylaminopyridine (270 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (41 mg, yield 15%). The reaction solution was cooled to room temperature the solvent was removed by distillation under the reduced pressure Water was then added to the residue the mixture was extracted with chloroform The chloroform layer was washed with water was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure the residue was purified by column chromatography

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

Procedure: 5-Chlorosalicylic acid (344 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-chlorosalicylate (147 mg, yield 37%). to prepare a solution which the mixture was extracted with ethyl acetate The ethyl acetate layer was then washed with water was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure the residue was purified by column chromatography