Water → Methyl 5-chloro-4-fluoro-1H-indole-2-carboxylate

Temperature

-20 °C

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).

1. temperatureThe temperature of the reaction mixture was raised to 0° C.
2. stirringafter the mixture was stirred for 2.5 hours
3. concentrationThe reaction mixture was concentrated under reduced pressure
4. extractionthe residue was extracted with a mixed solvent of methylene chloride and ethyl acetate
5. washThe extract was washed with saturated aqueous solution of sodium chloride
6. dry with materialdried over anhydrous sodium sulfate
7. distillationThe solvent was distilled off
8. customthe residue was purified by column chromatography on silica gel (toluene:hexane=3:17)
9. customto obtain crude methyl 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylate (2.6 g)
10. stirringthe solution was stirred at 130° C. to 140° C. for 3 hours
11. concentrationThe reaction mixture was concentrated
12. customthe resultant residue was purified by column chromatagraphy on silica gel (methylene chloride)
13. customcrystallized from diethyl ether-hexane

ORD record

ord-8c91241f5ed1474883aeed1ebdcf22e9

Source dataset

uspto-grants-2008_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07365205B2