ethyl 4-(3-ethoxy-3-oxopropyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of 10 g (38.9 mmol) ethyl 2,4-dimethyl-5-(ethoxycarbonyl)-3-pyrrolepropionate (commercially available) in a mixture of water (250 mL) and methanol (MeOH) (50 mL) was added 3.0 g of KOH in 50 mL of water. The mixture was stirred at 70° C. for 4 hr. The reaction mixture was cooled and the methanol was stripped from the mixture under vacuum. The remaining solution was filtered and the filtrate was then acidified with 6N hydrochloric acid to pH 3. The precipitate which formed was collected by filtration, washed with a 2:1 mixture of water and ethanol and dried under vacuum to give 7.5 g of 4-(2-carboxy-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid. The reaction mixture was cooled The remaining solution was filtered The precipitate which formed was collected by filtration washed with a 2:1 mixture of water and ethanol dried under vacuum

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of 10 g (38.9 mmol) ethyl 2,4-dimethyl-5-(ethoxycarbonyl)-3-pyrrolepropionate (commercially available) in a mixture of water (250 mL) and methanol (MeOH) (50 mL) was added 3.0 g of KOH in 50 mL of water. The mixture was stirred at 70° C. for 4 hr. The reaction mixture was cooled and the methanol was stripped from the mixture under vacuum. The remaining solution was filtered and the filtrate was then acidified with 6N hydrochloric acid to pH 3. The precipitate which formed was collected by filtration, washed with a 2:1 mixture of water and ethanol and dried under vacuum to give 7.5 g of 4-(2-carboxy-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid. The reaction mixture was cooled The remaining solution was filtered The precipitate which formed was collected by filtration washed with a 2:1 mixture of water and ethanol dried under vacuum

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,4-Dimethyl-5-ethoxycarbonyl-3-(2-ethoxycarbonylethyl)pyrrole (1.07 kg) and 3.2 L 5 N sodium hydroxide were mechanically stirred in a 12 L three-neck round bottom flask equipped with a reflux condenser and an addition funnel and heated in an oil bath. The mixture was refluxed for 3 hours after which time the internal temperature was 96° C., all solids were dissolved and thin layer chromatography showed hydrolysis to be complete. The heating bath was removed and the mixture cooled to 50° C. in a water bath. 12 N Hydrochloric acid (˜1.3 L) was slowly added. After about 50% of the acid was added gas evolution began and the temperature reached 60° C. As more acid was added, gas evolution increased and a yellow precipitate formed. The final pH was adjusted to 3.5 with hydrochloric acid. The mixture was cooled in an ice bath to 8° C. The solids were collected by vacuum filtration, washed twice with 0.5 L of distilled water and dried for 48 hours in a vacuum oven at 55-60° C. to give 677 g (101% yield) of 3-(2-carboxyethyl)-2,4-dimethylpyrrole. equipped with a reflux condenser and an addition funnel heated in an oil bath The mixture was refluxed for 3 hours after which time the internal temperature was 96° C. all solids were dissolved hydrolysis The heating bath was removed 12 N Hydrochloric acid (˜1.3 L) was slowly added After about 50% of the acid was added gas evolution reached 60° C As more acid was added gas evolution increased a yellow precipitate formed The mixture was cooled in an ice bath to 8° C The solids were collected by vacuum filtration washed twice with 0.5 L of distilled water dried for 48 hours in a vacuum oven at 55-60° C.

反応条件: temp:99.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 5 L three-neck flask equipped with a thermometer and a mechanical stirrer and heated on a steam bath was added 350 g ethyl 5-acetyl-4-oxohexanoate, 329 g ethyl aminomalonate hydrochloride, 133 g sodium acetate and 1.2 L acetic acid. The mixture was heated to 99° C. over 37 minutes. By 62° C., carbon dioxide evolution was already rapid. After a total of 35 minutes at 99° C. gas, CO2 evolution had greatly slowed. After another hour, the mixture was cooled, sodium chloride removed by vacuum filtration, and the solvent evaporated. The residue was mixed with 1 L of cold water. The precipitate was collected by vacuum filtration, washed with 400 mL water, and dissolved in 1 L of hot 95% ethanol. The solution was treated with 20 g of Darco G-60, hot-filtered, and cooled to room temperature. The crystalline solid was collected by vacuum filtration, washed twice on the filter with 200 mL of 50% ethanol and dried under vacuum at 70° C. to give 285 g (64% yield) of 2-ethoxycarbonyl-4-(2-ethoxycarbonylethyl)-3,5-dimethylpyrrole. The filtrate was refrigerated overnight to give another 53.1 g (11.9% yield) of product for a total yield of 75.9%). To a 5 L three-neck flask equipped with a thermometer and a mechanical stirrer heated on a steam bath By 62° C. After a total of 35 minutes at 99° C. After another hour the mixture was cooled sodium chloride removed by vacuum filtration the solvent evaporated The residue was mixed with 1 L of cold water The precipitate was collected by vacuum filtration washed with 400 mL water dissolved in 1 L of hot 95% ethanol The solution was treated with 20 g of Darco G-60 hot-filtered cooled to room temperature The crystalline solid was collected by vacuum filtration washed twice on the filter with 200 mL of 50% ethanol dried under vacuum at 70° C.

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of 10 g (38.9 mmol) ethyl 2,4-dimethyl-5-(ethoxycarbonyl)-3-pyrrolepropionate (commercially available) in a mixture of water (250 mL) and methanol (MeOH) (50 mL) was added 3.0 g of KOH in 50 mL of water. The mixture was stirred at 70° C. for 4 hr. The reaction mixture was cooled and the methanol was stripped from the mixture under vacuum. The remaining solution was filtered and the filtrate was then acidified with 6N hydrochloric acid to pH 3. The precipitate which formed was collected by filtration, washed with a 2:1 mixture of water and ethanol and dried under vacuum to give 7.5 g of 4-(2-carboxy-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid. The reaction mixture was cooled The remaining solution was filtered The precipitate which formed was collected by filtration washed with a 2:1 mixture of water and ethanol dried under vacuum

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

実験手順: 2,4-Dimethyl-3-carbethoxy ethyl-5-carbethoxy-pyrrole was reductively alkylated with paraformaldehyde to yield 2,4,5-trimethyl-3-carboxyethyl-pyrrole. ##STR110##

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,4-dimethyl-5-ethoxycarbonyl-3-(2-ethoxycarbonylethyl)-pyrrole (1.07 kg) and 3.2 L 5 N sodium hydroxide were mechanically stirred in a 12 L three-neck round bottom flask equipped with a reflux condenser and an addition funnel and heated in an oil bath. The mixture was refluxed for 3 hours after which time the internal temperature was 96° C., all solids were dissolved and thin layer chromatography showed hydrolysis to be complete. The heating bath was removed and the mixture cooled to 50° C. in a water bath. 12N Hydrochloric acid (˜1.3 L) was slowly added. After about 50% of the acid was added gas evolution began and the temperature reached 60° C. As more acid was added, gas evolution increased and a yellow precipitate formed. The final pH was adjusted to 3.5 with hydrochloric acid. The mixture was cooled in an ice bath to 8° C. The solids were collected by vacuum filtration, washed twice with 0.5 L of distilled water and dried for 48 hours in a vacuum oven at 55-60° C. to give 677 g (101% yield) of 3-(2-carboxyethyl)-2,4-dimethylpyrrole. equipped with a reflux condenser and an addition funnel heated in an oil bath The mixture was refluxed for 3 hours after which time the internal temperature was 96° C. all solids were dissolved hydrolysis The heating bath was removed 12N Hydrochloric acid (˜1.3 L) was slowly added After about 50% of the acid was added gas evolution reached 60° C As more acid was added gas evolution increased a yellow precipitate formed The mixture was cooled in an ice bath to 8° C The solids were collected by vacuum filtration washed twice with 0.5 L of distilled water dried for 48 hours in a vacuum oven at 55-60° C.

反応条件: temp:99.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 5 L three-neck flask equipped with a thermometer and a mechanical stirrer and heated on a steam bath was added 350 g ethyl 5-acetyl-4-oxohexanoate, 329 g ethyl aminomalonate hydrochloride, 133 g sodium acetate and 1.2 L acetic acid. The mixture was heated to 99° C. over 37 minutes. By 62° C., carbon dioxide evolution was already rapid. After a total of 35 minutes at 99° C. gas, CO2 evolution had greatly slowed. After another hour, the mixture was cooled, sodium chloride removed by vacuum filtration, and the solvent evaporated. The residue was mixed with 1 L of cold water. The precipitate was collected by vacuum filtration, washed with 400 mL water, and dissolved in 1 L of hot 95% ethanol. The solution was treated with 20 g of Darco G-60, hot-filtered, and cooled to room temperature. The crystalline solid was collected by vacuum filtration, washed twice on the filter with 200 mL of 50% ethanol and dried under vacuum at 70° C. to give 285 g (64% yield) of 2-ethoxycarbonyl-4-(2-ethoxycarbonylethyl)-3,5-dimethylpyrrole. The filtrate was refrigerated overnight to give another 53.1 g (11.9% yield) of product for a total yield of 75.9%). To a 5 L three-neck flask equipped with a thermometer and a mechanical stirrer heated on a steam bath By 62° C. After a total of 35 minutes at 99° C. After another hour the mixture was cooled sodium chloride removed by vacuum filtration the solvent evaporated The residue was mixed with 1 L of cold water The precipitate was collected by vacuum filtration washed with 400 mL water dissolved in 1 L of hot 95% ethanol The solution was treated with 20 g of Darco G-60 hot-filtered cooled to room temperature The crystalline solid was collected by vacuum filtration washed twice on the filter with 200 mL of 50% ethanol dried under vacuum at 70° C.

反応条件: temp:99.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 5 L three-neck flask, equipped with a thermometer and a mechanical stirrer and heated on a steam bath, was added 350 g of ethyl 5-acetyl-4-oxohexanoate, 329 g of diethyl aminomalonate hydrochloride, 133 g of sodium acetate, and 1.2 L of acetic acid. The mixture was heated to 99° C. over 37 minutes. By 62° C., carbon dioxide evolution was already rapid. After a total of 35 minutes at 99° C., gas evolution had greatly slowed. After another hour, the mixture was cooled, the sodium chloride removed by vacuum filtration, and the solvent evaporated. The residue was mixed with 1 L of cold water. The precipitate was collected by vacuum filtration, washed with 400 mL of water, and dissolved in 1 L of hot 95% ethanol. The solution was treated with 20 g of Darco G-60, hot-filtered, and cooled to room temperature. The crystalline solid was collected by vacuum filtration, washed twice on the filter with 200 mL of 50% ethanol each time, and dried under vacuum at 70° C. to give 285 g (64% yield) of 2-ethoxycarbonyl-4-(2-ethoxycarbonylethyl)-3,5-dimethylpyrrole. The filtrate was refrigerated overnight to give another 53.1 g (11.9% yield) of product, for a total yield of 75.9%. To a 5 L three-neck flask, equipped with a thermometer and a mechanical stirrer heated on a steam bath By 62° C. After a total of 35 minutes at 99° C. After another hour the mixture was cooled the sodium chloride removed by vacuum filtration the solvent evaporated The residue was mixed with 1 L of cold water The precipitate was collected by vacuum filtration washed with 400 mL of water dissolved in 1 L of hot 95% ethanol The solution was treated with 20 g of Darco G-60 hot-filtered cooled to room temperature The crystalline solid was collected by vacuum filtration washed twice on the filter with 200 mL of 50% ethanol each time dried under vacuum at 70° C.

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,4-Dimethyl-5-ethoxycarbonyl-3-(2-ethoxycarbonylethyl)-pyrrole (1.07 kg) and 3.2 L 5 N sodium hydroxide were mechanically stirred in a 12 L three-neck round bottom flask equipped with a reflux condenser and an addition funnel and heated in an oil bath. The mixture was refluxed for 3 hours after which time the internal temperature was 96° C., all solids were dissolved and thin layer chromatography showed hydrolysis to be complete. The heating bath was removed and the mixture cooled to 50° C. in a water bath. 12N Hydrochloric acid (˜1.3 L) was slowly added. After about 50% of the acid was added gas evolution began and the temperature reached 60° C. As more acid was added, gas evolution increased and a yellow precipitate formed. The final pH was adjusted to 3.5 with hydrochloric acid. The mixture was cooled in an ice bath to 8° C. The solids were collected by vacuum filtration, washed twice with 0.5 L of distilled water and dried for 48 hours in a vacuum oven at 55-60° C. to give 677 g (101% yield) of 3-(2-carboxyethyl)-2,4-dimethylpyrrole. equipped with a reflux condenser and an addition funnel heated in an oil bath The mixture was refluxed for 3 hours after which time the internal temperature was 96° C. all solids were dissolved hydrolysis The heating bath was removed 12N Hydrochloric acid (˜1.3 L) was slowly added After about 50% of the acid was added gas evolution reached 60° C As more acid was added gas evolution increased a yellow precipitate formed The mixture was cooled in an ice bath to 8° C The solids were collected by vacuum filtration washed twice with 0.5 L of distilled water dried for 48 hours in a vacuum oven at 55-60° C.

反応条件: temp:99.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 5 L three-neck flask equipped with a thermometer and a mechanical stirrer and heated on a steam bath was added 350 g ethyl 5-acetyl-4-oxohexanoate, 329 g ethyl aminomalonate hydrochloride, 133 g sodium acetate and 1.2 L acetic acid. The mixture was heated to 99° C. over 37 minutes. By 62° C., carbon dioxide evolution was already rapid. After a total of 35 minutes at 99° C. gas, CO2 evolution had greatly slowed. After another hour, the mixture was cooled, sodium chloride removed by vacuum filtration, and the solvent evaporated. The residue was mixed with 1 L of cold water. The precipitate was collected by vacuum filtration, washed with 400 mL water, and dissolved in 1 L of hot 95% ethanol. The solution was treated with 20 g of Darco G-60, hot-filtered, and cooled to room temperature. The crystalline solid was collected by vacuum filtration, washed twice on the filter with 200 mL of 50% ethanol and dried under vacuum at 70° C. to give 285 g (64% yield) of 2-ethoxycarbonyl-4-(2-ethoxycarbonylethyl)-3,5-dimethylpyrrole. The filtrate was refrigerated overnight to give another 53.1 g (11.9% yield) of product for a total yield of 75.9%). To a 5 L three-neck flask equipped with a thermometer and a mechanical stirrer heated on a steam bath By 62° C. After a total of 35 minutes at 99° C. After another hour the mixture was cooled sodium chloride removed by vacuum filtration the solvent evaporated The residue was mixed with 1 L of cold water The precipitate was collected by vacuum filtration washed with 400 mL water dissolved in 1 L of hot 95% ethanol The solution was treated with 20 g of Darco G-60 hot-filtered cooled to room temperature The crystalline solid was collected by vacuum filtration washed twice on the filter with 200 mL of 50% ethanol dried under vacuum at 70° C.

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of 10 g (38.9 mmol) ethyl 2,4-dimethyl-5-(ethoxycarbonyl)-3-pyrrolepropionate (commercially available) in a mixture of water (250 mL) and methanol (MeOH) (50 mL) was added 3.0 g of KOH in 50 mL of water. The mixture was stirred at 70° C. for 4 hr. The reaction mixture was cooled and the methanol was stripped from the mixture under vacuum. The remaining solution was filtered and the filtrate was then acidified with 6N hydrochloric acid to pH 3. The precipitate which formed was collected by filtration, washed with a 2:1 mixture of water and ethanol and dried under vacuum to give 7.5 g of 4-(2-carboxy-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid. The reaction mixture was cooled The remaining solution was filtered The precipitate which formed was collected by filtration washed with a 2:1 mixture of water and ethanol dried under vacuum