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

Temperatur

-20 °C

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).

1. waitwithin 20 minutes
2. temperatureAfter the reaction mixture was heated to 0° C.
3. stirringthe mixture was stirred for 2.5 hours
4. concentrationThe reaction mixture was concentrated under reduced pressure
5. extractionthe residue was extracted with a mixture of methylene chloride and ethyl acetate
6. washThe extract was washed with saturated brine
7. dry with materialwas dried over sodium sulfate anhydrate
8. distillationThe solvent was distilled away
9. customthe residue was purified by silica gel column chromatography (toluene:hexane=3:17)
10. customto thereby give crude 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylic acid methyl ester (2.6 g)
11. stirringthe solution was stirred at 130-140° C. for 3 hours
12. concentrationThe reaction mixture was concentrated
13. customthe residue was purified by silica gel column chromatography (methylene chloride)
14. customThe thus-obtained compound was crystallized from diethyl ether-hexane

ORD-Eintrag

ord-fc332e694f6e4d86b1105e8140a68a5b

Quelldatensatz

uspto-grants-2009_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07576135B2