Ethyl Acetate → 2-Chloro-5-methoxyquinoline

Temperature

0 °C

After 5-methoxyquinoline (104.3 mg, 0.655 mmol) was dissolved in dichloromethane (3 mL), meta-chloroperbenzoic acid (mCPBA; 195 mg, 1.13 mmol) was added thereto at 0° C., and the resulting mixture was stirred for 30 min. After the stirring for 30 min, the reaction temperature was increased from 0° C. to room temperature, followed by further stirring for 3 hr. The completion of the reaction was confirmed by TLC (EtOAc/MC/Hexane=1:2:4). When the reaction was completed, the reaction mixture was extracted with an aqueous solution of 4 N NaOH and dichloromethane, to thereby separate an organic layer. The organic layer was dried over anhydrous MgSO4 and filtered. The resulting filtrate was concentrated under reduced pressure, to thereby generate a white solid. The thus generated solid was dissolved in dichloromethane (2.5 mL) and added with phosphorous oxychloride (POCl3; 0.09 mL, 0.992 mmol). The resulting mixture was subjected to distillation under reflux at 60° C. for 3 hr. The completion of the reaction was confirmed by TLC (EtOAc/CHCl3/Hexane=1:2:10). When the reaction was completed, the reactant was cooled down to room temperature, followed by further cooling down with the gentle addition of ice. The pH of the resulting mixture was then adjusted to 10 by dropwise addition of an aqueous solution of 4 N NaOH. When the pH was adjusted to 10, the reaction mixture was extracted with distilled water and dichloromethane, to thereby separate an organic layer. The organic layer was dried over anhydrous MgSO4 and filtered. The resulting filtrate was concentrated under reduced pressure and purified by column chromatography (EtOAc/CHCl3/Hexane=1:2:10, R.f: 0.6), to thereby obtain 2-chloro-5-methoxyquinoline (40.1 mg, 32%) as a white solid.

1. waitAfter the stirring for 30 min
2. temperaturethe reaction temperature was increased from 0° C. to room temperature
3. stirringby further stirring for 3 hr
4. extractionthe reaction mixture was extracted with an aqueous solution of 4 N NaOH and dichloromethane
5. customto thereby separate an organic layer
6. dry with materialThe organic layer was dried over anhydrous MgSO4
7. filtrationfiltered
8. concentrationThe resulting filtrate was concentrated under reduced pressure
9. dissolutionThe thus generated solid was dissolved in dichloromethane (2.5 mL)
10. distillationThe resulting mixture was subjected to distillation
11. temperatureunder reflux at 60° C. for 3 hr
12. temperaturethe reactant was cooled down to room temperature
13. temperatureby further cooling down with the gentle addition of ice
14. additionThe pH of the resulting mixture was then adjusted to 10 by dropwise addition of an aqueous solution of 4 N NaOH
15. extractionthe reaction mixture was extracted with distilled water and dichloromethane
16. customto thereby separate an organic layer
17. dry with materialThe organic layer was dried over anhydrous MgSO4
18. filtrationfiltered
19. concentrationThe resulting filtrate was concentrated under reduced pressure
20. custompurified by column chromatography (EtOAc/CHCl3/Hexane=1:2:10, R.f: 0.6)

ORD record

ord-69c56ac4738d4ce68c2949ef1cfa2731

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08946431B2