ETHYL 3-AMINO-4-HYDROXYBENZOATE

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

実験手順: A mixture of 10.4 grams (0.05 mole) of ethyl 3-nitro-4-hydroxybenzoate, 0.3 gram of platinum oxide (catalyst) in 200 mL of ethyl acetate was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. The mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, yielding 9.6 grams of ethyl 3-amino-4-hydroxybenzoate as a solid. The NMR spectrum was consistent with the proposed structure. This 3-amino derivative, 9.0 grams (0.05 mole), was dissolved in 150 mL of ethanol and 9.7 grams (0.06 mole) of triethyl orthopropionate was added. The reaction mixture was heated at reflux for three hours, then cooled to ambient temperature and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, with 1:4 ethyl acetate: heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of ethyl (2-ethylbenzoxazol-5-yl)carboxylate, mp 35-37° C. The NMR spectrum was consistent with the proposed structure. The mixture was filtered to remove the catalyst the filtrate was concentrated under reduced pressure

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

実験手順: A mixture of 10.4 grams (0.05 mole) of ethyl 3-nitro-4-hydroxybenzoate, 0.3 gram of platinum oxide (catalyst) in 200 mL of ethyl acetate was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. The mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, yielding 9.6 grams of ethyl 3-amino-4-hydroxybenzoate as a solid. The NMR spectrum was consistent with the proposed structure. This 3-amino derivative, 9.0 grams (0.05 mole), was dissolved in 150 mL of ethanol and 9.7 grams (0.06 mole) of triethyl orthopropionate was added. The reaction mixture was heated at reflux for three hours, then cooled to ambient temperature and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of ethyl (2-ethylbenzoxazol-5-yl)carboxylate, mp 35-37° C. The NMR spectrum was consistent with the proposed structure. The mixture was filtered to remove the catalyst the filtrate was concentrated under reduced pressure

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

実験手順: A mixture of 10.4 grams (0.05 mole) of ethyl 3-nitro-4-hydroxybenzoate, 0.3 gram of platinum oxide (catalyst) in 200 mL of ethyl acetate was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. The mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, yielding 9.6 grams of ethyl 3-amino-4-hydroxybenzoate as a solid. The NMR spectrum was consistent with the proposed structure. This 3-amino derivative, 9.0 grams (0.05 mole), was dissolved in 150 mL of ethanol and 9.7 grams (0.06 mole) of triethyl orthopropionate was added. The reaction mixture was heated at reflux for three hours, then cooled to ambient temperature and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of ethyl(2-ethylbenzoxazol-5-yl)carboxylate, mp 35°-37° C. The NMR spectrum was consistent with the proposed structure. The mixture was filtered to remove the catalyst the filtrate was concentrated under reduced pressure

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

実験手順: A mixture of 10.4 grams (0.05 mole) of ethyl 3-nitro-4-hydroxybenzoate, 0.3 gram of platinum oxide (catalyst) in 200 mL of ethyl acetate was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. The mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, yielding 9.6 grams of ethyl 3-amino-4-hydroxybenzoate as a solid. The NMR spectrum was consistent with the proposed structure. This 3-amino derivative, 9.0 grams (0.05 mole), was dissolved in 150 mL of ethanol and 9.7 grams (0.06 mole) of triethyl orthopropionate was added. The reaction mixture was heated at reflux for three hours, then cooled to ambient temperature and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of ethyl (2-ethylbenzoxazol-5-yl)carboxylate, mp 35-37° C. The NMR spectrum was consistent with the proposed structure. The mixture was filtered to remove the catalyst the filtrate was concentrated under reduced pressure

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

実験手順: A mixture of 10.4 grams (0.05 mole) of ethyl 3-nitro-4-hydroxybenzoate, 0.3 gram of platinum oxide (catalyst) in 200 mL of ethyl acetate was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. The mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, yielding 9.6 grams of ethyl 3-amino-4-hydroxybenzoate as a solid. The NMR spectrum was consistent with the proposed structure. This 3-amino derivative, 9.0 grams (0.05 mole), was dissolved in 150 mL of ethanol and 9.7 grams (0.06 mole) of triethyl orthopropionate was added. The reaction mixture was heated at reflux for three hours, then cooled to ambient temperature and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, with 1:4 ethyl acetate: heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of ethyl (2-ethylbenzoxazol-5-yl)carboxylate, mp 35-37° C. The NMR spectrum was consistent with the proposed structure. The mixture was filtered to remove the catalyst the filtrate was concentrated under reduced pressure

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

実験手順: A mixture of 10.4 grams (0.05 mole) of ethyl 3-nitro-4-hydroxybenzoate, 0.3 gram of platinum oxide (catalyst) in 200 mL of ethyl acetate was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. The mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, yielding 9.6 grams of ethyl 3-amino-4-hydroxybenzoate as a solid. The NMR spectrum was consistent with the proposed structure. This 3-amino derivative, 9.0 grams (0.05 mole), was dissolved in 150 mL of ethanol and 9.7 grams (0.06 mole) of triethyl orthopropionate was added. The reaction mixture was heated at reflux for three hours, then cooled to ambient temperature and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of ethyl (2-ethylbenzoxazol-5-yl)carboxylate, mp 35-37° C. The NMR spectrum was consistent with the proposed structure. The mixture was filtered to remove the catalyst the filtrate was concentrated under reduced pressure

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

実験手順: A mixture of 10.4 grams (0.05 mole) of ethyl 3-nitro-4-hydroxybenzoate, 0.3 gram of platinum oxide (catalyst) in 200 mL of ethyl acetate was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. The mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, yielding 9.6 grams of ethyl 3-amino-4-hydroxybenzoate as a solid. The NMR spectrum was consistent with the proposed structure. This 3-amino derivative, 9.0 grams (0.05 mole), was dissolved in 150 mL of ethanol and 9.7 grams (0.06 mole) of triethyl orthopropionate was added. The reaction mixture was heated at reflux for three hours, then cooled to ambient temperature and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of ethyl (2-ethylbenzoxazol-5-yl)carboxylate, mp 35-37° C. The NMR spectrum was consistent with the proposed structure. The mixture was filtered to remove the catalyst the filtrate was concentrated under reduced pressure

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

実験手順: In a 100 mL round bottom flask ethyl 3-amino-4-hydroxybezoate (1.10 g, 6.07 mmol) and 4a (1.00 g, 2.98 mmol) were refluxed in ethanol (50 mL). After 2 h, the condenser was rearranged for distillation and ethanol (25 mL) was distilled off. The resulting solution was slowly poured into a vigorously stirred solution of ice cold water (200 mL) and citric acid (50 mg) giving a pink solid precipitate. The mixture was stirred for 10 min and then the solid was collected by filtration and rinsed with cold water to give 5h (1.23 g, 98.5%) after drying. The product was recrystallized from ethanol to give pale pink needles; m.p. 129.2-130° C. 1H NMR (600 MHz, CD2Cl2) δ 8.58 (s, 1H), 7.89 (dd, J=2.1, 8.7, 1H), 7.67 (d, J=2.1, 1H), 7.36-7.29 (m, 2H), 7.28-7.18 (m, 3H), 6.97 (d, J=8.7, 1H), 4.25 (q, J=7.1, 2H), 3.27 (s, 3H), 3.17 (s, 3H), 1.30 (t, J=7.1, 3H). 13C NMR (151 MHz, CD2Cl2) δ 165.40, 159.72, 156.82, 151.91, 136.06, 132.09, 130.86, 130.65, 129.49, 128.99, 128.83, 127.84, 125.70, 122.92, 117.65, 104.70, 103.11, 61.23, 32.02, 28.08, 14.24. MS (ES+) (m/z): [M+1]+ calculated for C23H22N3O5, 420.16. found 420.13. the condenser was rearranged for distillation and ethanol (25 mL) was distilled off The resulting solution was slowly poured into a vigorously stirred solution of ice cold water (200 mL) and citric acid (50 mg) giving a pink solid precipitate the solid was collected by filtration rinsed with cold water

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

実験手順: In a 300 mL round bottom flask was placed, 3-amino-4-hydroxybezoic acid (5.50 g, 35.9 mmol), ethanol (200 mL), and a magnetic stir bar. The mixture was cooled in an ice bath to 10° C. and anhydrous HCl gas was bubbled through the stirred mixture until homogenous. The round bottom flask was then equipped with a condenser and the solution refluxed. After 1 hour the condensor was rearranged for distillation and 125 mL of ethanol was distilled off. The resulting solution was then dried in vacuo to give crude ethyl 3-amino-4-hydroxybezoate hydrochloride (7.73 g 35.5 mmol). Water (125 mL) containing NaHCO3 (3.0 g 35.7 mmol) was slowly added to the crude HCl salt and the resulting mixture was extracted 3×100 mL EtOAc. The EtOAc extracts were pooled, washed with brine, and then dried over NaSO4. The EtOAc was removed in vacuo to give ethyl 3-amino-4-hydroxybezoate (5.08 g, 78.0%) as a viscous oil which crystallized on standing. 1H NMR (600 MHz, CD2Cl2) δ 7.42 (d, J=2.0, 1H), 7.37 (dd, J=2.0, 8.2, 1H), 6.76 (d, J=8.2, 1H), 5.56-5.37 (s, 1H), 4.28 (q, J=7.1, 2H), 3.76 (s, 2H), 1.34 (t, J=7.1, 3H). 13C NMR (151 MHz, CD2Cl2) δ 167.79, 149.37, 134.83, 123.28, 122.37, 117.91, 114.98, 61.48, 14.63. MS (ES+) (m/z): [M+1]+ calculated for C9H12NO3, 182.08. found 182.09. the resulting mixture was extracted 3×100 mL EtOAc washed with brine dried over NaSO4 The EtOAc was removed in vacuo

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

実験手順: To a suspension of 4-hexyloxybenzoic acid in oxalyl chloride (10 ml) and dichloromethane (10 ml) was added N,N-dimethylformamide (0.1 ml). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give crude 4-hexyloxybenzoyl chloride. To a suspension of Ethyl 3-amino-4-hydroxybenzoate (733 mg) and triethylamine (1.38 ml) and 4-dimethylaminopyridine (DMAP, 10 mg) in methylene chloride (10 ml) was added the solution of 4-hexyloxybenzoyl chloride obtained above in dichloromethane (5 ml) dropwise at 10° C. The reaction mixture was stirred at 10° C. for 1.5 hours and diluted with dichloromethane (20 ml). The solution was washed with H2O (20 ml), 1 N HCl aq. (20 ml×2), H2O (20 ml) and brine (20 ml) successively. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. To the residue was added toluene (15 ml) and p-toluenesulfonic acid (10 mg). The mixture was refluxed for 6 hours and the solvent was removed under reduced pressure. The residue was triturated with acetonitrile, and precipitate was collected with filtration and dried over PO5 to give 2-(4-Hexyloxyphenyl)-5-ethoxycarbonylbenzoxazole (0.60 g). The solvent was removed under reduced pressure to give crude 4-hexyloxybenzoyl chloride The reaction mixture was stirred at 10° C. for 1.5 hours The solution was washed with H2O (20 ml), 1 N HCl aq. (20 ml×2), H2O (20 ml) and brine (20 ml) successively The organic layer was dried over MgSO4 the solvent was removed under reduced pressure To the residue was added toluene (15 ml) and p-toluenesulfonic acid (10 mg) The mixture was refluxed for 6 hours the solvent was removed under reduced pressure The residue was triturated with acetonitrile, and precipitate was collected with filtration dried over PO5

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

実験手順: A mixture of 10.4 grams (0.05 mole) of ethyl 3-nitro-4-hydroxybenzoate, 0.3 gram of platinum oxide (catalyst) in 200 mL of ethyl acetate was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. The mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, yielding 9.6 grams of ethyl 3-amino-4-hydroxybenzoate as a solid. The NMR spectrum was consistent with the proposed structure. This 3-amino derivative, 9.0 grams (0.05 mole), was dissolved in 150 mL of ethanol and 9.7 grams (0.06 mole) of triethyl orthopropionate was added. The reaction mixture was heated at reflux for three hours, then cooled to ambient temperature and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of ethyl (2-ethylbenzoxazol-5-yl)carboxylate, mp 35°-37° C. The NMR spectrum was consistent with the proposed structure. The mixture was filtered to remove the catalyst the filtrate was concentrated under reduced pressure

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

実験手順: To a suspension of 4-hexyloxybenzoic acid in oxalyl chloride (10 ml) and dichloromethane (10 ml) was added N,N-dimethylformamide (0.1 ml). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give crude 4-hexyloxybenzoate chloride. To a suspension of Ethyl 3-amino-4-hydroxybenzoate (733 mg) and triethylamine (1.38 ml) and 4-dimethylaminopyridine (DMAP, 10 mg) in methylene chloride (10 ml) was added the solution of 4-hexyloxybenzoyl chloride obtained above in dichloromethane (5 ml) dropwise at 10° C. The reaction mixture was stirred at 10° C. for 1.5 hours and diluted with dichloromethane (20 ml). the solution was washed with H2O (20 ml), 1N HCl aq. (20 ml×2), H2O (20 ml) and brine (20 ml) successively. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. To the residue was added toluene (15 ml) and p-toluenesulfonic acid (10 mg). The mixture was refluxed for 6 hours and the solvent was removed under reduced pressure. The residue was triturated with acetonitrile, and precipitate was collected with filtration and dried over PO5 to give 2-(4-Hexyloxyphenyl)-5-ethoxycarbonylbenzoxazole (0.60 g). The solvent was removed under reduced pressure to give crude 4-hexyloxybenzoate chloride The reaction mixture was stirred at 10° C. for 1.5 hours the solution was washed with H2O (20 ml), 1N HCl aq. (20 ml×2), H2O (20 ml) and brine (20 ml) successively The organic layer was dried over MgSO4 the solvent was removed under reduced pressure To the residue was added toluene (15 ml) and p-toluenesulfonic acid (10 mg) The mixture was refluxed for 6 hours the solvent was removed under reduced pressure The residue was triturated with acetonitrile, and precipitate was collected with filtration dried over PO5