反应详情

温度

0 °C

In methylene chloride (8 ml) was dissolved 1,2-dimethyl-1H-indole-3-carboxylic acid (270 mg, 1.43 mmol) was dissolved. Oxalyl chloride (0.19 ml, 2.1 mmol) was added to the solution under stirring at 0° C. 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) and the resulting solution was added to a solution of triethylamine (0.56 ml, 4.3 mmol) and ethyl (4-amino-3-chloro-6-fluorophenyl)acetate (331 mg, 1.4 mmol) in methylene chloride (3 ml) under stirring at 0° C. The reaction mixture was heated at reflux for 18 hours. HOBt (catalytic amount) was added to the reaction mixture and the mixture was heated under reflux for 48 hours. After cooling, the reaction mixture was added with chloroform and a saturated aqueous solution of citric acid. The mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium 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, 20 ml/min, φ 50 mm×150 mm, dry silica gel adsorption method). The purified product was dissolved in THF (15 ml) and to the resulting solution was added 0.25M NaOH (8.6 ml, 2.2 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into 1M HCl to acidify therewith. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (5-chloro-2-fluoro-4-((1,2-dimethyl-1H-3-indolylcarbonyl)amino)phenyl)acetic acid (264 mg, 49%) as a colorless solid.

1. dissolutionwas dissolved
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. temperaturethe mixture was heated
10. temperatureunder reflux for 48 hours
11. temperatureAfter cooling
12. extractionThe mixture was extracted with chloroform
13. washThe extract was washed with saturated brine
14. dry with materialdried over anhydrous sodium sulfate
15. distillationdistilled under reduced pressure
16. customto remove the solvent
17. 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, 20 ml/min, φ 50 mm×150 mm, dry silica gel adsorption method)
18. dissolutionThe purified product was dissolved in THF (15 ml) and to the resulting solution
19. stirringThe mixture was stirred at room temperature for 18 hours
20. customThe crystals thus precipitated
21. filtrationwere collected by filtration under reduced pressure
22. washwashed with water
23. customdried under reduced pressure