Hydrochloric Acid → HCID 58778970, compound

Temperature

0 °C

1-Methyl-1H-indole-3-carboxylic acid (700 mg, 4.0 mmol) was dissolved in methylene chloride (8 ml). Oxalyl chloride (0.53 ml, 6.1 mmol) was added dropwise to the solution under stirring at 0° C. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour and distilled under reduced pressure to remove the solvent. The residue was dissolved in methylene chloride (6 ml). The resulting solution was added to a solution of triethylamine (0.84 ml, 6.0 mmol) and ethyl 4-amino-2-fluoro-5-methoxyphenylacetate (909 mg, 4.0 mmol) in methylene chloride (3 ml) under stirring at 0° C. The reaction mixture was heated at reflux for 18 hours. After cooling to room temperature, the reaction mixture was poured into ice water, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (middle pressure Yamazen, linear gradient of n-hexane/ethyl acetate form 9:1 to 7:3, 12 ml/min, φ 50 mm×300 mm, charged by dry silica gel method). The purified ester was added with THF (45 ml) and 0.25M NaOH (18 ml, 4.5 mmol), followed by stirring at room temperature for 4 hours. The reaction mixture was poured into water and 1M HCl was added to the resulting mixture to make it acidic. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give 2-fluoro-5-methoxy-4-((1-methyl-1H-3-indolylcarbonyl)amino)phenylacetic acid (1.01 g, 71%) as a colorless solid.

1. additionAfter completion of the dropwise addition
2. stirringthe reaction mixture was stirred at room temperature for 1 hour
3. distillationdistilled under reduced pressure
4. customto remove the solvent
5. dissolutionThe residue was dissolved in methylene chloride (6 ml)
6. stirringunder stirring at 0° C
7. temperatureThe reaction mixture was heated
8. temperatureat reflux for 18 hours
9. temperatureAfter cooling to room temperature
10. extractionfollowed by extraction with chloroform
11. washThe extract was washed with saturated brine
12. dry with materialdried over anhydrous magnesium sulfate
13. distillationdistilled under reduced pressure
14. customto remove the solvent
15. customThe residue was purified by silica gel column chromatography (middle pressure Yamazen, linear gradient of n-hexane/ethyl acetate form 9:1 to 7:3, 12 ml/min, φ 50 mm×300 mm, charged by dry silica gel method)
16. stirringby stirring at room temperature for 4 hours
17. additionwas added to the resulting mixture
18. customThe crystals thus precipitated
19. filtrationwere collected by filtration under reduced pressure
20. washwashed with water
21. customdried under reduced pressure

ORD record

ord-ec829fd900f74d9e99405aa978c07066

Source dataset

uspto-grants-2007_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07157487B2