Indoline-2-carboxylic Acid Ethyl Ester

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of 5.12 g of ethyl indoline-2-carboxylate (prepared as described in Preparation 1) in 20 ml of anhydrous tetrahydrofuran was added dropwise, whilst ice-cooling, to a mixture of 1.20 g of lithium aluminum hydride and 80 ml of anhydrous tetrahydrcfuran, and the resulting mixture was stirred at room temperature for 2 hours. After this, an excess of sodium sulfate decahydrate was added to the mixture, which was then stirred for 20 minutes. At the end of this time, insoluble materials were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.81 g of the title compound having Rf=0.16 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent). was then stirred for 20 minutes At the end of this time, insoluble materials were filtered off the filtrate was concentrated by evaporation under reduced pressure The concentrate was purified by column chromatography through silica gel by volume mixture of hexane and ethyl acetate as the eluent

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

Procedure: A mixture of 25.2 g of indoline-2-carboxylic acid, 50 ml of ethanol and 200 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 3 days. At the end of this time, the reaction mixture was poured into an aqueous solution of potassium carbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 28.1 g of the title compound having Rf=0.81 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent). after which it was extracted with ethyl acetate The extract was washed with an aqueous solution of sodium chloride dried over anhydrous sodium sulfate The solvent was removed by distillation under reduced pressure the residue thus obtained was purified by column chromatography through silica gel by volume mixture of hexane and ethyl acetate as the eluent

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-carboxy-2,3-dihydro-7-hydroxy-9-methoxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (1.5 g), 2-ethoxycarbonylindoline (2.3 g) and 1,3-dicyclohexylcarbodiimide (3 g) in toluene (20 ml) was stirred at 90° C. for 3 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (30:1) to give 2,3-dihydro-6-(2-ethoxycarbonyl-1-indolinylcarbonyl)-7-hydroxy-9-methoxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (2.8 g). The mixture was filtered the filtrate was concentrated in vacuo The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (30:1)

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

Procedure: To a chilled and stirred mixture of 2,3-dihydroindole-2-carboxylic acid ethyl ester (14.34 g.), triethylamine (7.65 g.) and anhydrous ether (600 ml.) was added dropwise acryloyl chloride (7.1 g.) dissolved in a small amount of ether. The ice bath was removed, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was chilled in ice, then a precipitate was removed by filtration. The filter residue was washed with ether. The combined filtrate and washing were washed with water, then with saline, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure on a rotary evaporator gave the titled compound (14.4 g.) as an oil. To a chilled The ice bath was removed the reaction mixture was stirred at room temperature for 4 hours The reaction mixture was chilled in ice a precipitate was removed by filtration The filter residue was washed with ether The combined filtrate and washing were washed with water with saline, and dried over anhydrous magnesium sulfate Evaporation of the solvent under reduced pressure on a rotary evaporator

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

Procedure: To a chilled and stirred mixture of 2,3-dihydroindole-2-carboxylic acid ethyl ester (14.34 g.), triethylamine (7.65 g.) and anhydrous ether (600 ml.) was added dropwise acryloyl chloride (7.1 g.) dissolved in a small amount of ether. The ice bath was removed, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was chilled in ice, then a precipitate was removed by filtration. The filter residue was washed with ether. The combined filtrate and washing were washed with water, then with saline, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure on a rotary evaporator gave the titled compound (14.4 g.) as an oil. To a chilled The ice bath was removed the reaction mixture was stirred at room temperature for 4 hours The reaction mixture was chilled in ice a precipitate was removed by filtration The filter residue was washed with ether The combined filtrate and washing were washed with water with saline, and dried over anhydrous magnesium sulfate Evaporation of the solvent under reduced pressure on a rotary evaporator

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

Procedure: To a chilled and stirred mixture of 2,3-dihydroindole-2-carboxylic acid ethyl ester (4.78 g., 25.0 mmole), triethylamine (2.7 g., 26.7 mmole), and anhydrous ether (500 ml) was added dropwise methacryloyl chloride (2.9 g., 27.7 mmole) dissolved in a small amount of ether. After the completion of the addition, the ice bath was removed, and the reaction mixture was stirred for 4 hours. The precipitate which separated was removed by filtration, and the filter residue was washed with ether. The combined filtrate and washing were washed with water (two 700-ml portions), then with saline, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure on a rotary evaporator gave the product as an oil. The product was purified by preparative HPLC (Prep LC/System 500, Waters Associates), using a micro porasil column eluted with a mixture of hexane (95%) and ethyl acetate (5%). The crude oil may be used directly in the following reaction. To a chilled After the completion of the addition the ice bath was removed the reaction mixture was stirred for 4 hours The precipitate which separated was removed by filtration the filter residue was washed with ether The combined filtrate and washing were washed with water (two 700-ml portions) with saline, and dried over anhydrous magnesium sulfate Evaporation of the solvent under reduced pressure on a rotary evaporator

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

Procedure: To a chilled and stirred mixture of 2,3-dihydroindole-2-carboxylic acid ethyl ester (4.78 g., 25.0 mmole), triethylamine (2.7 g., 26.7 mmole), and anhydrous ether (500 ml) was added dropwise methacryloyl chloride (2.9 g., 27.7 mmole) dissolved in a small amount of ether. After the completion of the addition, the ice bath was removed, and the reaction mixture was stirred for 4 hours. The precipitate which separated was removed by filtration, and the filter residue was washed with ether. The combined filtrate and washing were washed with water (two 700-ml portions), then with saline, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure on a rotary evaporator gave the product as an oil. The product was purified by preparative HPLC (Prep LC/System 500, Waters Associates), using a micro porasil column eluted with a mixture of hexane (95%) and ethyl acetate (5%). The crude oil may be used directly in the following reaction. To a chilled After the completion of the addition the ice bath was removed the reaction mixture was stirred for 4 hours The precipitate which separated was removed by filtration the filter residue was washed with ether The combined filtrate and washing were washed with water (two 700-ml portions) with saline, and dried over anhydrous magnesium sulfate Evaporation of the solvent under reduced pressure on a rotary evaporator

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

Procedure: The starting material is prepared as follows: To the mixture of 3.0 g of indoline-2-carboxylic acid ethyl ester, 4.3 g of powdered potassium carbonate and 30 ml of methylene chloride is added 1.64 g of methacryloyl chloride in 5 ml of methylene chloride during 1 minute. After stirring at room temperature for 3 hours the mixture is partitioned between 50 ml of water and 100 ml of diethyl ether. The organic layer is washed with 30 ml of 1N hydrochloric acid and 25 ml of saturated sodium chloride, dried and evaporated, to yield the 1-methacryloylindoline-2-carboxylic acid ethyl ester as an oil. The starting material is prepared is partitioned between 50 ml of water and 100 ml of diethyl ether The organic layer is washed with 30 ml of 1N hydrochloric acid and 25 ml of saturated sodium chloride dried evaporated

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

Procedure: The starting material is prepared as follows: To 2.7 g of indoline-2-carboxylic acid ethyl ester and 3.4 g of powdered potassium carbonate in 30 ml of methylene chloride, 2.42 g of 2-bromopropanoyl chloride in 10 ml of methylene chloride are added during 2 minutes. The mixture is stirred at room temperature for 2 hours and then partitioned between 50 ml of water and 100 ml of diethyl ether. The organic layer is washed twice with 30 ml of 1N hydrochloric acid and 25 ml of saturated aqueous sodium chloride, dried and evaporated, to yield the 1-(2-bromopropanoyl)-indoline-2-carboxylic acid ethyl ester melting at 101°-103°. The starting material is prepared partitioned between 50 ml of water and 100 ml of diethyl ether The organic layer is washed twice with 30 ml of 1N hydrochloric acid and 25 ml of saturated aqueous sodium chloride dried evaporated