methyl 5-chloro-4-fluoro-1H-indole-2-carboxylate

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethanol (100 ml) was added to sodium hydride (content: 60%, 4.7 g) at 0° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. After 2-nitropropane (11 ml) was added to the reaction mixture to stir the mixture for 10 minutes, 1-(bromomethyl)-3-chloro-2-fluorobenzene (10 g) was added to stir the resultant mixture at room temperature for 3.5 hours. Precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was partitioned in diethyl ether and water, and an organic layer was successively washed with a 1N aqueous solution of sodium hydroxide, water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=3:7) to obtain crude 3-chloro-2-fluorobenzaldehyde (5.5 g) as a pale yellow oil. Methanol (20 ml) was added to sodium hydride (content: 60%, 1.6 g) at 0° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. The reaction mixture was cooled to −20° C., and the crude 3-chloro-2-fluorobenzaldehyde (5.5 g) and a solution of methyl 2-azidoacetate (5.0 g) in methanol (10 ml) were added within 20 minutes. The temperature of the reaction mixture was raised to 0° C., and after the mixture was stirred for 2.5 hours, water (40 ml) was added thereto. The reaction mixture was concentrated under reduced pressure, the residue was extracted with a mixed solvent of methylene chloride and ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography on silica gel (toluene:hexane=3:17) to obtain crude methyl 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylate (2.6 g). This product was dissolved in xylene (50 ml), and the solution was stirred at 130° C. to 140° C. for 3 hours. The reaction mixture was concentrated, and the resultant residue was purified by column chromatagraphy on silica gel (methylene chloride) and then crystallized from diethyl ether-hexane to obtain the title compound (440 mg). The temperature of the reaction mixture was raised to 0° C. after the mixture was stirred for 2.5 hours The reaction mixture was concentrated under reduced pressure the residue was extracted with a mixed solvent of methylene chloride and ethyl acetate The extract was washed with saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate The solvent was distilled off the residue was purified by column chromatography on silica gel (toluene:hexane=3:17) to obtain crude methyl 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylate (2.6 g) the solution was stirred at 130° C. to 140° C. for 3 hours The reaction mixture was concentrated the resultant residue was purified by column chromatagraphy on silica gel (methylene chloride) crystallized from diethyl ether-hexane

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethanol (100 mL) was added to sodium hydride (60% sodium hydride content, 4.7 g) at 0° C. under argon atmosphere, and the mixture was stirred for 10 minutes. 2-Nitropropane (11 mL) was added to the reaction mixture, and after the thus-obtained mixture was stirred for 10 minutes, 1-(bromomethyl)-3-chloro-2-fluorobenzene (10 g) was added thereto, followed by stirring at room temperature for 3.5 hours. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was partitioned between diethyl ether and water. The organic layer was sequentially washed with 1N aqueous sodium hydroxide, water, and saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7), to thereby give crude 3-chloro-2-fluorobenzaldehyde (5.5 g) as a pale-yellow oily compound. Methanol (20 mL) was added to sodium hydride (60% sodium hydride content, 1.6 g) under argon atmosphere at 0° C., and the thus-obtained mixture was stirred for 10 minutes. After the reaction mixture was cooled to −20° C., a solution of the crude 3-chloro-2-fluorobenzaldehyde (5.5 g) and methyl 2-azidoacetate (5.0 g) in methanol (10 mL) was added thereto within 20 minutes. After the reaction mixture was heated to 0° C., the mixture was stirred for 2.5 hours, and water (40 mL) was added thereto. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with a mixture of methylene chloride and ethyl acetate. The extract was washed with saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (toluene:hexane=3:17), to thereby give crude 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylic acid methyl ester (2.6 g). This compound was dissolved in xylene (50 mL), and the solution was stirred at 130-140° C. for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride). The thus-obtained compound was crystallized from diethyl ether-hexane, to thereby give the title compound (440 mg). within 20 minutes After the reaction mixture was heated to 0° C. the mixture was stirred for 2.5 hours The reaction mixture was concentrated under reduced pressure the residue was extracted with a mixture of methylene chloride and ethyl acetate The extract was washed with saturated brine was dried over sodium sulfate anhydrate The solvent was distilled away the residue was purified by silica gel column chromatography (toluene:hexane=3:17) to thereby give crude 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylic acid methyl ester (2.6 g) the solution was stirred at 130-140° C. for 3 hours The reaction mixture was concentrated the residue was purified by silica gel column chromatography (methylene chloride) The thus-obtained compound was crystallized from diethyl ether-hexane

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethanol (100 ml) was added to sodium hydride (content: 60%, 4.7 g) at 0° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. After 2-nitropropane (11 ml) was added to the reaction mixture to stir the mixture for 10 minutes, 1-(bromomethyl)-3-chloro-2-fluorobenzene (10 g) was added to stir the resultant mixture at room temperature for 3.5 hours. Precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was partitioned in diethyl ether and water, and an organic layer was successively washed with a 1N aqueous solution of sodium hydroxide, water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatagraphy on silica gel (ethyl acetate:hexane=3:7) to obtain crude 3-chloro-2-fluorobenzaldehyde (5.5 g) as a pale yellow oil. Methanol (20 ml) was added to sodium hydride (content: 60%, 1.6 g) at 0° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. The reaction mixture was cooled to −20° C., and the crude 3-chloro-2-fluorobenzaldehyde (5.5 g) and a solution of methyl 2-azidoacetate (5.0 g) in methanol (10 ml) were added within 20 minutes. The temperature of the reaction mixture was raised to 0° C., and after the mixture was stirred for 2.5 hours, water (40 ml) was added thereto. The reaction mixture was concentrated under reduced pressure, the residue was extracted with a mixed solvent of methylene chloride and ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatagraphy on silica gel (toluene:hexane=3:17) to obtain crude methyl 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylate (2.6 g). This product was dissolved in xylene (50 ml), and the solution was stirred at 130° C. to 140° C. for 3 hours. The reaction mixture was concentrated, and the resultant residue was purified by column chromatography on silica gel (methylene chloride) and then crystallized from diethyl ether-hexane to obtain the title compound (440 mg). The temperature of the reaction mixture was raised to 0° C. after the mixture was stirred for 2.5 hours The reaction mixture was concentrated under reduced pressure the residue was extracted with a mixed solvent of methylene chloride and ethyl acetate The extract was washed with saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate The solvent was distilled off the residue was purified by column chromatagraphy on silica gel (toluene:hexane=3:17) to obtain crude methyl 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylate (2.6 g) the solution was stirred at 130° C. to 140° C. for 3 hours The reaction mixture was concentrated the resultant residue was purified by column chromatography on silica gel (methylene chloride) crystallized from diethyl ether-hexane

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethanol (100 ml) was added to sodium hydride (content: 60%, 4.7 g) at 0° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. After 2-nitropropane (11 ml) was added to the reaction mixture to stir the mixture for 10 minutes, 1-(bromomethyl)-3-chloro-2-fluorobenzene (10 g) was added to stir the resultant mixture at room temperature for 3.5 hours. Precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was partitioned in diethyl ether and water, and an organic layer was successively washed with a 1N aqueous solution of sodium hydroxide, water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=3:7) to obtain crude 3-chloro-2-fluorobenzaldehyde (5.5 g) as a pale yellow oil. Methanol (20 ml) was added to sodium hydride (content: 60%, 1.6 g) at 0° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. The reaction mixture was cooled to −20° C., and the crude 3-chloro-2-fluorobenzaldehyde (5.5 g) and a solution of methyl 2-azidoacetate (5.0 g) in methanol (10 ml) were added within 20 minutes. The temperature of the reaction mixture was raised to 0° C., and after the mixture was stirred for 2.5 hours, water (40 ml) was added thereto. The reaction mixture was concentrated under reduced pressure, the residue was extracted with a mixed solvent of methylene chloride and ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography on silica gel (toluene:hexane=3:17) to obtain crude methyl 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylate (2.6 g). This product was dissolved in xylene (50 ml), and the solution was stirred at 130° C. to 140° C. for 3 hours. The reaction mixture was concentrated, and the resultant residue was purified by column chromatagraphy on silica gel (methylene chloride) and then crystallized from diethyl ether-hexane to obtain the title compound (440 mg). The temperature of the reaction mixture was raised to 0° C. after the mixture was stirred for 2.5 hours The reaction mixture was concentrated under reduced pressure the residue was extracted with a mixed solvent of methylene chloride and ethyl acetate The extract was washed with saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate The solvent was distilled off the residue was purified by column chromatography on silica gel (toluene:hexane=3:17) to obtain crude methyl 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylate (2.6 g) the solution was stirred at 130° C. to 140° C. for 3 hours The reaction mixture was concentrated the resultant residue was purified by column chromatagraphy on silica gel (methylene chloride) crystallized from diethyl ether-hexane