ethyl 4-amino-2-chlorobenzoate

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

実験手順: An iodine solution in ethanol was admixed with silver(I) sulphate and ethyl 4-amino-2-chlorobenzoate and then stirred at room temperature for 45 min. The reaction mixture was filtered through a frit and the filtrate was concentrated under reduced pressure. The residue was slurried in EtOAc and admixed with dilute sodium hydrogencarbonate solution. Once everything had gone into solution, the aqueous phase was removed and sodium thiosulphate was dissolved therein. The organic phase was washed again with the aqueous phase, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 33% ethyl acetate). The reaction mixture was filtered through a frit the filtrate was concentrated under reduced pressure the aqueous phase was removed sodium thiosulphate was dissolved The organic phase was washed again with the aqueous phase the aqueous phase was extracted with ethyl acetate The combined organic phases were dried over sodium sulphate filtered concentrated under reduced pressure Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 33% ethyl acetate)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylic acid (1.00 g, 2.70 mmol), ethyl 4-amino-2-chlorobenzoate (1.08 g, 5.41 mmol), 4-methylmorpholine (1.37 g, 13.5 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluoro-phosphate (1.54 g, 4.06 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 min, then 4-(dimethylamino)pyridine (337 mg, 2.70 mmol) were added, and the solution was stirred at 60° C. for 18 h. After cooling, the reaction mixture was partitioned between water, heptane, and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 2-chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester (849 mg, 57%). Off-white solid, MS (ISP)=551.2 (M+H)+. After cooling the reaction mixture was partitioned between water, heptane, and ethyl acetate The organic layer was washed with brine dried (MgSO4) evaporated

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of ethyl 4-amino-2-chlorobenzoate (20 g), glycerol (32.17 g) and sodium 3-nitrobenzenesulfonate (46.73 g) in sulfuric acid (75%) (160 ml) was stirred for 3 hours at 100° C. and for 1 hour at 140° C. After the mixture was cooled to 60° C. and ethanol (200 ml) was added, the mixture was stirred for 16 hours at 60° C. Ethanol was evaporated and the residue was poured into ice water, neutralized with NH4OH and extracted with ethylacetate. The separated organic layer was dried over MgSO4, filtered and the filtrate evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /ethylacetate 97.5/2.5). The desired pure fractions were collected and evaporated, yielding 7.56 g (28%) ethyl 5-chloro-6-quinolinecarboxylate (intermediate 1). After the mixture was cooled to 60° C. the mixture was stirred for 16 hours at 60° C Ethanol was evaporated the residue was poured into ice water extracted with ethylacetate The separated organic layer was dried over MgSO4 filtered the filtrate evaporated The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /ethylacetate 97.5/2.5) The desired pure fractions were collected evaporated

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

実験手順: An iodine solution in ethanol was admixed with silver(I) sulphate and ethyl 4-amino-2-chlorobenzoate and then stirred at room temperature for 45 min. The reaction mixture was filtered through a frit and the filtrate was concentrated under reduced pressure. The residue was slurried in EtOAc, and dilute sodium hydrogencarbonate solution was added. Once everything had gone into solution, the aqueous phase was removed and sodium thiosulphate was dissolved therein. The organic phase was washed again with the aqueous phase and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 33% ethyl acetate) gave 1.85 g (74% of theory) of ethyl 4-amino-2-chloro-5-iodobenzoate. The reaction mixture was filtered through a frit the filtrate was concentrated under reduced pressure dilute sodium hydrogencarbonate solution was added the aqueous phase was removed sodium thiosulphate was dissolved The organic phase was washed again with the aqueous phase the aqueous phase was extracted with ethyl acetate The combined organic phases were dried over sodium sulphate filtered concentrated under reduced pressure Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 33% ethyl acetate)

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

実験手順: An iodine solution in ethanol was admixed with silver(I) sulphate and ethyl 4-amino-2-chlorobenzoate and then stirred at room temperature for 45 min. The reaction mixture was filtered through a frit and the filtrate was concentrated under reduced pressure. The residue was slurried in EtOAc and admixed with dilute sodium hydrogencarbonate solution. Once everything had gone into solution, the aqueous phase was removed and sodium thiosulphate was dissolved therein. The organic phase was washed again with the aqueous phase, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 33% ethyl acetate). The reaction mixture was filtered through a frit the filtrate was concentrated under reduced pressure the aqueous phase was removed sodium thiosulphate was dissolved The organic phase was washed again with the aqueous phase the aqueous phase was extracted with ethyl acetate The combined organic phases were dried over sodium sulphate filtered concentrated under reduced pressure Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 33% ethyl acetate)

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

実験手順: An iodine solution in ethanol was admixed with silver(I) sulphate and ethyl 4-amino-2-chlorobenzoate and then stirred at room temperature for 45 min. The reaction mixture was filtered through a frit and the filtrate was concentrated under reduced pressure. The residue was slurried in EtOAc and admixed with dilute sodium hydrogencarbonate solution. Once everything had gone into solution, the aqueous phase was removed and sodium thiosulphate was dissolved therein. The organic phase was washed again with the aqueous phase, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 33% ethyl acetate). The reaction mixture was filtered through a frit the filtrate was concentrated under reduced pressure the aqueous phase was removed sodium thiosulphate was dissolved The organic phase was washed again with the aqueous phase the aqueous phase was extracted with ethyl acetate The combined organic phases were dried over sodium sulphate filtered concentrated under reduced pressure Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 33% ethyl acetate)

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

実験手順: An iodine solution in ethanol was admixed with silver(I) sulphate and ethyl 4-amino-2-chlorobenzoate and then stirred at room temperature for 45 min. The reaction mixture was filtered through a frit and the filtrate was concentrated under reduced pressure. The residue was slurried in EtOAc and admixed with dilute sodium hydrogencarbonate solution. Once everything had gone into solution, the aqueous phase was removed and sodium thiosulphate was dissolved therein. The organic phase was washed again with the aqueous phase, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, littered and concentrated under reduced pressure. Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 33% ethyl acetate). The reaction mixture was filtered through a frit the filtrate was concentrated under reduced pressure the aqueous phase was removed sodium thiosulphate was dissolved The organic phase was washed again with the aqueous phase the aqueous phase was extracted with ethyl acetate The combined organic phases were dried over sodium sulphate concentrated under reduced pressure Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 33% ethyl acetate)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylic acid (1.00 g, 2.70 mmol), ethyl 4-amino-2-chlorobenzoate (1.08 g, 5.41 mmol), 4-methylmorpholine (1.37 g, 13.5 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (1.54 g, 4.06 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 min, then 4-(dimethylamino)pyridine (337 mg, 2.70 mmol) were added, and the solution was stirred at 60° C. for 18 h. After cooling, the reaction mixture was partitioned between water, heptane, and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 2-chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester (849 mg, 57%). Off-white solid, MS (ISP)=551.2 (M+H)+. After cooling the reaction mixture was partitioned between water, heptane, and ethyl acetate The organic layer was washed with brine dried (MgSO4) evaporated

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylic acid (1.00 g, 2.70 mmol), ethyl 4-amino-2-chlorobenzoate (1.08 g, 5.41 mmol), 4-methylmorpholine (1.37 g, 13.5 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluoro-phosphate (1.54 g, 4.06 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 min, then 4-(dimethylamino)pyridine (337 mg, 2.70 mmol) were added, and the solution was stirred at 60° C. for 18 h. After cooling, the reaction mixture was partitioned between water, heptane, and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 2-chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester (849 mg, 57%). Off-white solid, MS (ISP)=551.2 (M+H)+. After cooling the reaction mixture was partitioned between water, heptane, and ethyl acetate The organic layer was washed with brine dried (MgSO4) evaporated

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylic acid (1.00 g, 2.70 mmol), ethyl 4-amino-2-chlorobenzoate (1.08 g, 5.41 mmol), 4-methylmorpholine (1.37 g, 13.5 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluoro-phosphate (1.54 g, 4.06 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 min, then 4-(dimethylamino)pyridine (337 mg, 2.70 mmol) were added, and the solution was stirred at 60° C. for 18 h. After cooling, the reaction mixture was partitioned between water, heptane, and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 2-chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester (849 mg, 57%). Off-white solid, MS (ISP)=551.2 (M+H)+. After cooling the reaction mixture was partitioned between water, heptane, and ethyl acetate The organic layer was washed with brine dried (MgSO4) evaporated

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of ethyl 4-amino-2-chlorobenzoate (20 g), glycerol (32.17 g) and sodium 3-nitrobenzenesulfonate (46.73 g) in sulfuric acid (75%) (160 ml) was stirred for 3 hours at 100° C. and for 1 hour at 140° C. After the mixture was cooled to 60° C. and ethanol (200 ml) was added, the mixture was stirred for 16 hours at 60° C. Ethanol was evaporated and the residue was poured into ice water, neutralized with NH4OH and extracted with ethylacetate. The separated organic layer was dried over MgSO4, filtered and the filtrate evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /ethylacetate 97.5/2.5). The desired pure fractions were collected and evaporated, yielding 7.56 g (28%) ethyl 5-chloro-6-quinolinecarboxylate (intermediate 1). After the mixture was cooled to 60° C. the mixture was stirred for 16 hours at 60° C Ethanol was evaporated the residue was poured into ice water extracted with ethylacetate The separated organic layer was dried over MgSO4 filtered the filtrate evaporated The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /ethylacetate 97.5/2.5) The desired pure fractions were collected evaporated

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

実験手順: An iodine solution in ethanol was admixed with silver(I) sulphate and ethyl 4-amino-2-chlorobenzoate and then stirred at room temperature for 45 min. The reaction mixture was filtered through a frit and the filtrate was concentrated under reduced pressure. The residue was slurried in EtOAc, and dilute sodium hydrogencarbonate solution was added. Once everything had gone into solution, the aqueous phase was removed and sodium thiosulphate was dissolved therein. The organic phase was washed again with the aqueous phase and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 33% ethyl acetate) gave 1.85 g (74% of theory) of ethyl 4-amino-2-chloro-5-iodobenzoate. The reaction mixture was filtered through a frit the filtrate was concentrated under reduced pressure dilute sodium hydrogencarbonate solution was added the aqueous phase was removed sodium thiosulphate was dissolved The organic phase was washed again with the aqueous phase the aqueous phase was extracted with ethyl acetate The combined organic phases were dried over sodium sulphate filtered concentrated under reduced pressure Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 33% ethyl acetate)