ethyl 3-bromo-4-oxobutanoate

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

実験手順: To a 0-5° C. mechanically-stirred solution in diethyl ether (100 mL) of succinaldehydic acid ethyl ester (10.0 g, 77 mmol) was added bromine (3.9 g, 151 mmol) over 2.5 hours. The reaction mixture was stirred for an additional 1.25 hours and the ether was distilled at atmospheric pressure. The remaining yellow oil was distilled (6.0-6.5 mm Hg, bp 95-101° C.) to give 3-bromosuccinaldehydic acid ethyl ester (10.7 g, 66%). the ether was distilled at atmospheric pressure The remaining yellow oil was distilled (6.0-6.5 mm Hg, bp 95-101° C.)

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

実験手順: A mixture of 28.7 g of ethyl 3-bromo-4-oxo-butyrate, 300 ml of dichloroethane and 11.2 g of thioacetamide was refluxed for 10 hours with stirring while replacing the dichloroethane that distilled to keep the volume constant and then the mixture was cooled to room temperature. The mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. The solution was extracted with 2N hydrochloric acid and the pH of the aqueous extracts was made alkaline by addition of ammonium hydroxide. The mixture was extracted with ethyl acetate and the organic extract was washed with water, dried and evaporated to dryness to obtain 8.3 g of ethyl 2-methyl-5-thiazole acetate. The IR spectrum in CHCl3 showed ester C=O at 1737cm-1 and C=C and C=N at 1535cm-1. was refluxed for 10 hours that distilled The mixture was evaporated to dryness the residue was dissolved in ethyl acetate The solution was extracted with 2N hydrochloric acid by addition of ammonium hydroxide The mixture was extracted with ethyl acetate the organic extract was washed with water dried evaporated to dryness

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

実験手順: Pyridine-4-thioamide (1.38 g, 0.01 mole) and 3-bromo-4-oxobutyric acid ethyl ester (3.1 g., 0.015 mole) in ethanol (50 ml) are heated at reflux for six hours. After cooling the solvent is evaporated and the residue is neutralized with sodium bicarbonate solution and then extracted with chloroform (300 ml.). The chloroform solution is washed with water, dried with (MgSO4) and evaporated to yield crude 2-(4-pyridyl)-thiazole-5-acetic acid ethyl ester. Purification is carried out by dissolving in acetone and adding petroleum ether to induce crystallization. When this ester intermediate is treated with methanol solution saturated with ammonia gas (25 ml./g. of ester) for 3 days at room temperature 2-(4-pyridyl)thiazol-5-ylacetamide is obtained after partial evaporation of the methanol. Purification is carried out by recrystallization from ethanol. When the amide is treated according to the procedure in Example 1, there is obtained 3-hydroxy-4-[2-(4-pyridyl)thiazol-5-yl]-3-pyrroline-2,5-dione. at reflux for six hours After cooling the solvent is evaporated extracted with chloroform (300 ml.) The chloroform solution is washed with water dried with (MgSO4) evaporated

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-mercaptoethanol (38.2 g.) in anhydrous ethanol (146 cc.) is added, at about 10° C. and over the course of one hour, to a solution of sodium ethoxide in ethanol [prepared by reacting sodium (11.2 g.) with anhydrous ethanol (350 cc.)]. After heating the reaction mixture to a temperature of 45°-f 50° C., ethyl 3-bromo-3-formylpropionate (102.8 g.) is added over the course of 20 minutes. The reaction mixture is stirred for 15 hours at a temperature of about 25° C. After filtration, the solvent is evaporated at about 50° C. under reduced pressure (20 mm.Hg). The residue is dissolved in anhydrous toluene (500 cc.); the solution is filtered and toluene-p-sulphonic acid monohydrate (1.5 g.) is then added. The reaction mixture is heated under reflux until complete dehydration has taken place (the water formed being removed in a Dean-Stark apparatus) and then the solvent is evaporated at about 50° C. under reduced pressure (20 mm.Hg). The residue is taken up in diethyl ether (700 cc.); some insoluble matter appears and is removed by filtration through "Supercel". The ether solution is washed three times with water (total 600 cc.), then dried over sodium sulphate, treated with decolourizing charcoal and filtered. The solution is concentrated to dryness under reduced pressure (20 mm.Hg); a residue (65 g.) is obtained and is chromatographed on alumina (600 g.). Elution is effected using a mixture (2.6 liters) of ethyl acetate and cyclohexane (1-19 by volume). After concentration to dryness under reduced pressure (20 mm.Hg), ethyl (5,6-dihydro-1,4-oxathiin-3-yl )acetate (16.8 g.) is obtained in the form of an oil. is added over the course of 20 minutes After filtration the solvent is evaporated at about 50° C. under reduced pressure (20 mm.Hg) The residue is dissolved in anhydrous toluene (500 cc.) the solution is filtered toluene-p-sulphonic acid monohydrate (1.5 g.) is then added The reaction mixture is heated under reflux until complete dehydration formed being removed in a Dean-Stark apparatus) and then the solvent is evaporated at about 50° C. under reduced pressure (20 mm.Hg) is removed by filtration through "Supercel" The ether solution is washed three times with water (total 600 cc.) dried over sodium sulphate treated with decolourizing charcoal filtered The solution is concentrated to dryness under reduced pressure (20 mm.Hg) a residue (65 g.) is obtained is chromatographed on alumina (600 g.) Elution After concentration to dryness under reduced pressure (20 mm.Hg)

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

実験手順: To a 0-5° C. mechanically-stirred solution in diethyl ether (100 mL) of succinaldehydic acid ethyl ester (10.0 g, 77 mmol) was added bromine (3.9 g, 151 mmol) over 2.5 hours. The reaction mixture was stirred for an additional 1.25 hours and the ether was distilled at atmospheric pressure. The remaining yellow oil was distilled (6.0-6.5 mm Hg, bp 95-101° C.) to give 3-bromosuccinaldehydic acid ethyl ester (10.7 g, 66%). the ether was distilled at atmospheric pressure The remaining yellow oil was distilled (6.0-6.5 mm Hg, bp 95-101° C.)

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

実験手順: 4-Methoxythiobenzamide (1.62 g, 9.7 mmol) and ethyl 3-bromo-4-oxobutanoate (2.02 g, 9.7 mmol) were suspended in 1,2-dichloroethane (25 ml), and the mixture was heated under reflux for 3 hours. The reaction mixture was diluted with ethyl acetate, successively washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=2/1) to give ethyl [2-(4-methoxyphenyl)-1,3-thiazol-5-yl]acetate (1.79 g, yield: 67%). the mixture was heated under reflux for 3 hours successively washed with a saturated aqueous sodium hydrogencarbonate solution a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=2/1)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.40 g), ethyl 3-bromo-4-oxobutyrate (0.48 g) and N,N-dimethylacetamide (25 mL) was stirred at 90° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.28 g, yield 55%) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 126-127° C. the mixture was extracted with ethyl acetate The ethyl acetate layer was washed with saturated brine dried (MgSO4) concentrated

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

実験手順: A mixture of 4-bromothiobenzamide (2.16 g., 0.01 mole) and ethyl 3-bromo-4-oxobutyrate (3.2 g., 0.015 mole) in ethanol (50 ml.) is heated at reflux for 6 hours. On cooling and partial evaporation there is obtained 2-(4-bromophenyl)thiazol-5-ylacetic acid ethyl ester. Reaction of this product with ammonia according to the procedure of Example 3 gives 2-(4-bromophenyl)thiazol-5-ylacetamide, which on reaction with diethyl oxalate and base in dimethylformamide, according to the general procedure of Example 6, affords the title compound. is heated at reflux for 6 hours On cooling partial evaporation there

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

実験手順: A mixture of 4-bromothiobenzamide (2.16 g., 0.01 mole) and ethyl 3-bromo-4-oxobutyrate (3.2 g., 0.015 mole) in ethanol (50 ml.) is heated at reflux for 6 hours. On cooling and partial evaporation there is obtained 2-(4-bromophenyl)thiazol-5-ylacetic acid ethyl ester. Reaction of this product with ammonia according to the procedure of Example 3 gives 2-(4-bromophenyl)thiazol-5-ylacetamide, which on reaction with diethyl oxalate and base in dimethylformamide, according to the general procedure of Example 6, affords the title compound. is heated at reflux for 6 hours On cooling partial evaporation there

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

実験手順: A mixture of 28.7 g of ethyl 3-bromo-4-oxo-butyrate, 300 ml of dichloroethane and 11.2 g of thioacetamide was refluxed for 10 hours with stirring while replacing the dichloroethane that distilled to keep the volume constant and then the mixture was cooled to room temperature. The mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. The solution was extracted with 2N hydrochloric acid and the pH of the aqueous extracts was made alkaline by addition of ammonium hydroxide. The mixture was extracted with ethyl acetate and the organic extract was washed with water, dried and evaporated to dryness to obtain 8.3 g of ethyl 2-methyl-5-thiazole acetate. The IR spectrum in CHCl3 showed ester C=O at 1737cm-1 and C=C and C=N at 1535cm-1. was refluxed for 10 hours that distilled The mixture was evaporated to dryness the residue was dissolved in ethyl acetate The solution was extracted with 2N hydrochloric acid by addition of ammonium hydroxide The mixture was extracted with ethyl acetate the organic extract was washed with water dried evaporated to dryness

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

実験手順: Pyridine-4-thioamide (1.38 g, 0.01 mole) and 3-bromo-4-oxobutyric acid ethyl ester (3.1 g., 0.015 mole) in ethanol (50 ml) are heated at reflux for six hours. After cooling the solvent is evaporated and the residue is neutralized with sodium bicarbonate solution and then extracted with chloroform (300 ml.). The chloroform solution is washed with water, dried with (MgSO4) and evaporated to yield crude 2-(4-pyridyl)-thiazole-5-acetic acid ethyl ester. Purification is carried out by dissolving in acetone and adding petroleum ether to induce crystallization. When this ester intermediate is treated with methanol solution saturated with ammonia gas (25 ml./g. of ester) for 3 days at room temperature 2-(4-pyridyl)thiazol-5-ylacetamide is obtained after partial evaporation of the methanol. Purification is carried out by recrystallization from ethanol. When the amide is treated according to the procedure in Example 1, there is obtained 3-hydroxy-4-[2-(4-pyridyl)thiazol-5-yl]-3-pyrroline-2,5-dione. at reflux for six hours After cooling the solvent is evaporated extracted with chloroform (300 ml.) The chloroform solution is washed with water dried with (MgSO4) evaporated

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-mercaptoethanol (38.2 g.) in anhydrous ethanol (146 cc.) is added, at about 10° C. and over the course of one hour, to a solution of sodium ethoxide in ethanol [prepared by reacting sodium (11.2 g.) with anhydrous ethanol (350 cc.)]. After heating the reaction mixture to a temperature of 45°-f 50° C., ethyl 3-bromo-3-formylpropionate (102.8 g.) is added over the course of 20 minutes. The reaction mixture is stirred for 15 hours at a temperature of about 25° C. After filtration, the solvent is evaporated at about 50° C. under reduced pressure (20 mm.Hg). The residue is dissolved in anhydrous toluene (500 cc.); the solution is filtered and toluene-p-sulphonic acid monohydrate (1.5 g.) is then added. The reaction mixture is heated under reflux until complete dehydration has taken place (the water formed being removed in a Dean-Stark apparatus) and then the solvent is evaporated at about 50° C. under reduced pressure (20 mm.Hg). The residue is taken up in diethyl ether (700 cc.); some insoluble matter appears and is removed by filtration through "Supercel". The ether solution is washed three times with water (total 600 cc.), then dried over sodium sulphate, treated with decolourizing charcoal and filtered. The solution is concentrated to dryness under reduced pressure (20 mm.Hg); a residue (65 g.) is obtained and is chromatographed on alumina (600 g.). Elution is effected using a mixture (2.6 liters) of ethyl acetate and cyclohexane (1-19 by volume). After concentration to dryness under reduced pressure (20 mm.Hg), ethyl (5,6-dihydro-1,4-oxathiin-3-yl )acetate (16.8 g.) is obtained in the form of an oil. is added over the course of 20 minutes After filtration the solvent is evaporated at about 50° C. under reduced pressure (20 mm.Hg) The residue is dissolved in anhydrous toluene (500 cc.) the solution is filtered toluene-p-sulphonic acid monohydrate (1.5 g.) is then added The reaction mixture is heated under reflux until complete dehydration formed being removed in a Dean-Stark apparatus) and then the solvent is evaporated at about 50° C. under reduced pressure (20 mm.Hg) is removed by filtration through "Supercel" The ether solution is washed three times with water (total 600 cc.) dried over sodium sulphate treated with decolourizing charcoal filtered The solution is concentrated to dryness under reduced pressure (20 mm.Hg) a residue (65 g.) is obtained is chromatographed on alumina (600 g.) Elution After concentration to dryness under reduced pressure (20 mm.Hg)