反应详情

温度

150 °C

(3R,4R)-1-Benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)-4-methylpyrrolidine (793 mg, 2.12 mmol) was dissolved in ethanol (50 ml), and the solution was mixed with 5% palladium-carbon (790 mg) to carry out hydrogenation under a pressure of 5 atmospheres. After completing the reaction, the 5% palladium carbon was removed by filtration and ethanol was evaporated. The thus obtained residue was dissolved in dimethyl sulfoxide (8 ml), and the solution was mixed with triethylamine (2 ml) and 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl)-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (330 mg, 1.06 mmol) and stirred at 150° C. for 18 hours. After completing the reaction, dimethyl sulfoxide was evaporated, and the thus obtained residue was mixed with chloroform (100 ml) and washed with 10% citric acid (100 ml) and saturated brine (100 ml) in that order. The organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (10 ml), followed by 1 hour of stirring at room temperature. After completing the reaction, the reaction solution was washed with dichloromethane (20 ml). The aqueous layer was adjusted to pH 12 with a sodium hydroxide aqueous solution and then to pH 7.4 with hydrochloric acid, subsequently carrying out extraction with chloroform (100 ml×4). The organic layers were combined and dried over anhydrous sodium sulfate and then the solvent was evaporated. The thus obtained residue was subjected to silica gel thin layer chromatography and developed with the bottom layer of a mixture solvent of chloroform:methanol=3:1, and then the resulting silica gel was scratched off and extracted with the same solvent system. The solvent was evaporated and the thus obtained residue was dissolved in a 1 N hydrochloric acid aqueous solution (6 ml) and stirred at room temperature for 10 minutes. After evaporating the solvent, the resulting crude product was recrystallized from isopropyl alcohol to obtain 20.1 mg (4%) of the title compound.

1. customthe reaction
2. customthe 5% palladium carbon was removed by filtration and ethanol
3. customwas evaporated
4. dissolutionThe thus obtained residue was dissolved in dimethyl sulfoxide (8 ml)
5. customwas evaporated
6. additionthe thus obtained residue was mixed with chloroform (100 ml)
7. washwashed with 10% citric acid (100 ml) and saturated brine (100 ml) in that order
8. dry with materialThe organic layer was dried over anhydrous sodium sulfate
9. customthe solvent was evaporated
10. temperatureTo the thus obtained residue, which was cooled in an ice bath
11. additionwas added dropwise concentrated hydrochloric acid (10 ml)
12. waitfollowed by 1 hour
13. stirringof stirring at room temperature
14. customthe reaction
15. washthe reaction solution was washed with dichloromethane (20 ml)
16. extractionextraction with chloroform (100 ml×4)
17. dry with materialdried over anhydrous sodium sulfate
18. customthe solvent was evaporated
19. extractionextracted with the same solvent system
20. customThe solvent was evaporated
21. dissolutionthe thus obtained residue was dissolved in a 1 N hydrochloric acid aqueous solution (6 ml)
22. stirringstirred at room temperature for 10 minutes
23. customAfter evaporating the solvent
24. customthe resulting crude product was recrystallized from isopropyl alcohol